Cancer questions L10 DF neoplasm What is important about neoplastic growth Two properties of malignant growth Classification of tumours

(BHHF) Difference between benign and malignant DF cancer DF staging and outline TNM why important Outline histogenic Importance of differentiation Outline grading Why important DF anaplastic Classification of common neoplasms Naming cancers Epithelium Squamous Transitional Glandular Mesenchymal Fat Fibrous tissue SM Sk M Cartilage Bone benign malignant

What is uterine leiomyoma C. histological DF Histological subtype Papillary Follicular Anaplastic fq route of spread prognosis

D. functional DF Examples of hormone secreting

Other tumour like conditions DF teratoma and where usually found Difference btw ovary and testes version What is an embryonic tumour When does it resent and give 2 examples What is a hamartoma When does it present and stop growing Give examples Comparison btw benign and malignant tumours Essential differences Invasion Mets Gross appearance Encapsulation Size benign malignant

Haemorrhage Ulceration Necrosis Histological features Nuclear size Nucleoli Pleomorhism Mitoses Differentiation Effects on the host Mechanical pressure Invasion Metastases Death Paraneoplastic syndrome Growth characteristic Speed Spontaneous arrest

Lecture 11 Diagnosis and management of neoplastic disease Where do pathologists get specimens from BRCA What is fibroadeoma Who gets it Mobile? What is breast carcinoma

Who gets it? Prognosis Mobile?

CRC Layers of bowel Why bowel gets lots of CA How common is CA of the Caecum and how would it present Where is the most common place How would it present?

Types of specimen received (3) How are needle biopsies performed? Invasive? Purpose (3)? Limitations (3)

FNAC Outline Effect on morbidity? Other specimen examples?

Surgical resection specimens Aim? Purpose (4)?

Histological grading Difference btw differentiated and non diff?

What is staging? Is this the most important factor Outline TNM? Outline DUKEs classification and prognosis What do resection specimens show (5)

What does macroscopic assessment show What does microscopic assessment show

HCC What is the progression HCC What are the stages associated with? CIN DF How is it cured Cure rate? How detected

Imunohistochemistry Df? Purpose HPMT Where do insuloma begin How do they present

What % malignant Where do glucagonoma begin How do they present What % malignant Where do gastrinoma begin How present % malignant? What is an example of a prognostic marker What can this determine How would you treat HER2 +ve and TKR +ve

Molecular techniques What is in situ hybridisation Examples What is the role of the MDT and who males up it?

Lecture 12 Renal cell carcinoma How common Where does it arise and of what structures Which structure is it most common in? What % arise from the kidney parenchyma What are the three types of renal clear cell carcinoma Clinical features? (3) and triad is seen in what % Red flag (3) What investigations would be done?

What is the familial form of clear cell carcinoma What type of inheritance is VHL? Where do haemangioblastomas occur What chromosome is the mutation What model is there? Outline normal VHL gene function and how affected in mutation What three products are promoted What three processes increase (aga)

What is sporadic clear cell carcinoma What is the problem of VEGF What is an example of VEGF inh. What is the outcome of surgery> What is the management Stage 1 < 4cm and > 4cm / multiple Stage 2 normal contralateral kdney? And solitary kidney Stage 4 ? Prognosis Mortality? w/ mets? Average survival time with mets? What tx is given for met but what is the down side?

What is the role of the pathologist? (4)

L13 Colon cancer What does colonoscopic examination show What does biopsy show What does CT show? What is the Tx

TNM staging T1 2 3 4a and b

N1 2 3 M0 M1? Dukes classification A B C D

Histology Different types of CA Molecular prognosis factors What is microsatellite instability?

What % is sporadic? And what is the effect

What inheritance is HNPCC? Where is the mutation? Where is the cancer found What is the differentiation What is the histology like? How is the mutation detected and what is the effect on the family What is cetuximab? What does this target Which mutations show a resistance to cetuximab? What is the effect of mutation on prognosis

Where is UC found? Where is crohns found?

What is the sequence ?

Lecture 14 cancer causes to cure DF benign tumour Characterise malignant Features of benign (4) Features of malignant (4)

Lymphatic system

Sequence caps venous system DF lymphatic caps Diameter What are they lined by? Valves? Drainage Superficial system with? What is the superficial system Deep system with? And to? Where do they all drain to? What does the thoracic duct ? What is the cysterna chyli Where does it receive lymph from? What joins it? Where does it drain into What does not drain into the thoracic duct (3) Where do these drain into? How do you image the lymphatic system

Cancer mechanisms of spread (4)

What is direct spread? Is lymphatic spread predictable Is venous spread predictable

Primary / direct.

Examples of cavities in which seeds ? What is the effect in enclosed space What are the consequences of lung cancer

Lymphatic 2o spread How common What does this lead to? Predictable? How can it be unpredictable? How can regional lymph nodes be an effective barrier What does an enlarged lymph node mean

What is the sentinel node What cancers are these important in? What is a lymphscintogram? Example Breast What is the breast Where does it lie What does it overlie? What ribs over? What does a mammogram preferentially show?

What is the blood supply to the breast? (3) What is the lymphatics? Where mets?

Haematogenous 2o spread Why veins? Example: CRC

Which veins do the ascending travel with Which veins do the transverse and descending travel with?

Metastatic disease Where do bone mets come from? (4) What is bone pain at nigh indiciative of? Prognosis?

Brain mets? MC than 1o brain tumour? Where are they usually located? Lung mets Problems of diagnosis how can they be visualised two different sorts?

Interventions (RCS) What is the aim of radiotherapy What are different froms of chemotherapy What are the benefits of surgery

L15 What are the three most important cancers for incidence and mortality How is incidence affected by age?

How do patients present (3) What are examples of symptoms which are specific to a single disease and those which are non specific DF screening DF incidental Major presenting symptoms LC (5) CRC (4)

How are cancers diagnosed (3 steps) LC What is relevant from the history? (2) What will be picked up on examination (4)

CRC Relevant Hx (3) Examination (3)

Imaging and staging What is staging important for? Outline the TNM Why is this not appropriate for all CA

Investigations

LC What does a chest ray detect What does a CT detect What is the F: broncoscopy What is the F: mediastinoscopy What is the f: lab analysis Lung cancer staging 0 1 2 3 4 Impact on treatment What occurs in early stages, mid stages and advanced

CRC Staging 1 2 3 4

Hodgkins 1 2 3 4

Tissue biopsy and histological assessment What do you need to know (2)

What are the two types of tissue biopsy and their differences

Treatment of Ca

Two types of tx that treat the 1o disease

Mets disease

What is the metastatic process (6)

Metastatic disease treatment What are the conventional cytotoxic agents (3) How do these function Problems but efficacy? What are targeted agents? How is the negative? Examples?

What is combined therapeutics What is the f: of neoadjuvant What is the F: of surgery and radiotherapy What is the F: of adjuvant

Example pancreatic carcinoma What is the function of whipples manoeuvre How are residual cells treated What did the ESPAC 1 show

Palliative care How is this an example of holistic care What does it include (4)

L16 maintence of genomic integrity What are the five types of DNA repair

How does DNA damage occur? (3)

What is ethyl methane sulphonate What does it do? what is the overall transition what is this described as?

What is 7 methyl guanine What does this cause? Structural or mutational? What is the problem with and what does this lead to?

UV damage and thiamine dimers What are the two forms of UV damage What is the effect of thymine dimers What sort of lesion is this? How many genes are involved in DNA repair What are the substrates (2)

Reversal Substrate UV induced dimers O6 alkyl guanine Strand breaks enzymatic repair

Base excision repair Three types of substrates What is the process What is the function of DNA glycosylase What is the function of apurinic endonuclease, DNA polymerase and DNA ligase

Nucleotide excision repair What does this operate on? What cannot this act on? Specific on non specific? What does this recognise Does it cause mtations?

What are the 4 prinicples

Daughter strand gap repair When is there a DNA gap left What then happens to the gap Are the dimers still present? What is this an example of#? What can then occur?

Xeroderma pigmentosum Inheritance What do patients show What is the mechanism What pathway is essential diagnosis how made?

What are the three genes that can cause XP What pathway do they all act in?

NER mechanism 5 steps 1 2 3 4

5 What is mutated in XP? What do XP cells show What are the mutations due to?

Xp variants (4)

Repair of double strand breaks 2 contollers? What does a mutation in either predispose to?

Are the two genes related? Where is the BRCA 1 C terminal found What is the F: BRCA 2 What is the consequence of mutations to BRCA gene What are brca genes esp. sensitive to?

What are the two processes by which DS breaks are repaired 6 stages of homologous repair 1 2 3 4 5

6 What stages can homologous repair occur in? What is the function of Rad51 How does this initiate strand exchange

How does BRCA 2 show direct interaction with RAD 51 How is the release of Rad 51 controlled (2)

How is BRCA 1 also required? What does this interact with?

Non homologous end joining What does this not require When can this occur 7 stages 1 2 3 4 5 6 7 How is this involved in formation of Ab and T CR

How is this different in all other cells

Summary Non Homologous repair is independent of? And what is not involved? When is this normal ?

Summary BRCA1 and BRCA 2 F: BRCA 1 F: BRCA 2 Both act to? Novel treatmens of BRCA 1 or 2 tumour Treatment =? Normal function of PARP1? How does inhibition lead to cell death

DNA mismatch repair Function? What is HNPCC What is the main mutation What are the 2 functions? Most commonly mutated mismatch repair genes (3) What do they all have a role in?

What is the mutator phenotype hypothesis

Mismatch repair defects =? Example? Resul in tumour progression of initiation?

Summary DNA repair disorders HNPCC A result of? Nd which genes are mutated XP A result of? Mutated genes Fanconi anaemia A result of? And example

Ligase IV syndrome and ataxia telangiectasia Result due to?

Lecture 17 BRCA Caused by mutations in which 2 genes? Where does it commonly mets to? What % of breast tissue drains axilla

Incidence Uk women? Average age? Annual cases? Annual deaths Male cases annually 5 year survival % 10year survival %

Epidemiology Risk factors (9) 1 2 3 4 5 6 7 8 9

Which is the most important risk factor What % of 50 y/O have BRCA compared to 70 YO

How does BRCA present (4 ways)

What is the NHSBSP How often are women screened and what ages What is a mammogram not good for (age) Numbers of cases detected and deaths prevented What is the triple assessment that takes place at a one stop clinic

Histopathology What are the 3 types in situ and %

Which grades are likely to become malignant What are the (3) statuses

Spectrum of disease progression (5 steps)

Pagets disease What is the appearance on the nipple What percentage of all breast cancers? Where does it start and spread?

Molecular subtypes (4) Current treatment options Neoadjuvant = Surgery Adjuvant = What is compulsory

What is the MDT involved?

When is neo-adjuvant therapy used? What is important about inflammatory tumours and their characteristics

What is the function of aromatase inhibitor

Surgery 4 types What type of mastectomy is now performed What is the margin in BCS what must always take place afterwards What is SLNB which nodes are removed What is ALNC and what are the consequences

Mastectomy

What are the indications What is the risk reduction

Breast conserving surgery Indications What is mandatory after?>

SLNB How does it decrease morbidity

What is the ALNC Indications What can it cause damage to? Which nodes remain under the ribs and how are these treated

Breast reconstruction Why might some be delayed Where is the fat from in DIEP

Endocrine therapy (4) What is tamoxifen What % of BRCA involve the ER What Is the risk of tamoxifen Where do aromatase inhibitors block oestrogen production and where do they not work, who is this good for

Radiotherapy and chemotherapy How often and for how long does radio occur What does chemotherapy cause What is ZOLAdex- how long before fertility returns

Biological therapies (3) An example of extracellular mABS What is Herceptin the 1st line tx for What % of BRCA What is a negative Are HER 2 tumours more aggressive or less

Examples of intracellular TKIs (2) Where does gefitinib act Where does lapatinib act

Genetic subtyping What is the purpose of gene therapy What is the aim of tailored therapy What do gene signatories determine What are the hopes for the future

L18 Introduction to radiotherapy DF radiotherapy How are x rays produced What are the units of energy How much heat is produced What is the dose dependent upon

1. 2. 3.

What are the early effects of radiotherapy What is the aim of acute effects What are the late effects# What are the carcinogenic effects

What is the relative risk increase due to radiotherapy Why is this important Where are other secondary sites (8)

What is the role of radiotherapy (100 case) 30 30 40 Clinical delivery of radiotherapy Why given in fractions What is a radical regime What is a palliative regime example. What is the problem of delivering in fractions Radiobiology What is the desired outcome of radiotherapy

Why is reoxygenation important

Which cells does radiotherapy preferentially kill what is left

What are the three factors affecting tumour growth

What is the rate of growth proportional to? What is the Norton simon hypothesis growth rate

What is the skipper cell kill hypothesis Dose

Draw a graph of tumour responsiveness to radiotherapy

Clinical uses of radiotherapy What are the indications for RT (2)

Where is radical therapy used? What is palliative therapy used for When is RT neoadjuvant When is RT adjuvant

Volume definitions (4 sizes) Which types of skin cancer require RT and what proportion of TR is for skin CA What is brachytherapy When is it used? What are new fractional regimes (3) What is hyperfractionation What is accelerated fractionation

What is CHART Outline the golgi coldman model What are the limitations of radiotherapy

L19 current issues in prostate cancer How common is prostate cancer When does it occur What proportion of post mortem show proscate cancer

What are the current controversies (4)

How does prostate cancer present (4) What are signs of local invasion What are signs of mets

How is a diagnosis made (5)

Why is the incidence rising? What does the prognosis depend on? (3) What is the aim of localised prostate cancer / metostatic

Treatment When is local treatment performed When is endocrine tx performed What is watchful waiting and when is it used?

What are the tx options

RT Criteria 3 What methods What are the SE

Active monitoring (am) vs watchful waiting Outline AM Outline WW

Surgery What is the aim of radical prostectomy What is palliative surgery for? What are the SE

Systemic therapy Example of a drug given for chemotherapy Example of a drug given for hormone refractory prostate cancer When is this used

How is palliation of bone mets achieved?

Conclusion What is the importance of PSA What is the effect of new treatments

L20 tumour immunology Why is this important History What was the tx in the 1890s What was proved in 1950s What was shown in the 20th cent

Sequence of immunogenic tumours What happens on challenge with live cells What is the evidence of tumour protective immunity in humans (3) What is the theory of cancer immunosurveillance What is the problem of cancer immunoediting

What are the three Es of cancer immunoediting How might T cells detect and destroy cancer cells How do T cells recognise antigens What are the two coreceptors What does their prescence increase the sensitivity to MHC binding by? What is signal 1 and signal 2 in T cell activation How are most T cells activated

What are the 5 types of tumour associated antigen How do mutated self proteins arise Examples Overexpressed self proteins Examples

Lineage specific differentiation antigen examples Examples of post translational modification of self proteins Examples of viral proteins

What makes a good target (4) Why tumour specific? Why shared amongst patients with same and difernt tumour types Why critical for tumour growth and survival? Why lack of immunological tolerance

What is central tolerance and peripheral tolerance Which is a hurdle in cancer Apply (5) tumour associated antigens below Examples of good target antigen 1. 2. 3. 4. Tumour specific Shared amongst tumours Critical to tumour growth and survival Lack of immunological tolerance good bad

Mechanisms by which tumours escape immune response Outline the MHC class I processing pathway What is the role of proteasome What does TAP do? What is the function of tapasin and calnectin What is presented on MHC I Mechanisms to escape immune response (7) 1. 2.

3. 4. 5. 6. 7. What is the function of TGF What is the function of IDO Examples of factors which inhibit differentiation, maturation and function of local dendritic cells How do dendritic cells function

T regs What is the F: How does it achive this What is FOXP3+ CD25+ and CD127 How to T reg mediate function What is this involved in What happens without T reg

Developing T cell based therapies 3 types

Non-specific T cell stimulation via (2) Vaccination 3 examples bbeing currently tested

Adoptive T cell therapy Problems and negatives of donor T cell Advantages of tumour specific infusion o Examples of success and draw diagrams

T cell therapy and conventional treatments for cancer

What does conditioning patients with chemotherapy before infusion ? (2) What is the effect of radiotherapy

Potential SE (2) What did TIL therapy result in?

What does chronic inflammation result in?

Monoclonal AB for cancer How do they work? Negatives?

Mechanism of action (2) What are the two immune mediated mechanisms What are the three direct effects

Lecture 21 new drug treatments for cancer Aim in primary disease How? Aim in mets disease how What is the aim of palliative

What are the drug treatments of advanced cancer (2)

Cytotoxic drugs How are they designed How were they discovered What are they renowned for? Advantages

Targeted drugs How designed How were they discovered Side effects? But?

Cytotoxic drugs What is the concept of serendipity How was cisplatin discovered? When is it given? What is the BEP combination Advantage and disadvantage

Mechanism of 5HT3 receptor blockers and CA associated nausea

What are the benefits of ondansetron? Examples of oter advances in drugs that are significant

What is translational research

Targeted therapy When is imatinib mesiliate given What is CML What are the effects of CML What are the phases of CML What is the translocation and the result What is the effect of BCR ABL signalling What is the MOA of imatinib

Tyrosine kinase inhibitors Suffix = 2 examples

Sorafenib What is its function How does it block tumour cell proliferation What is it used in? How does it target tumour vasculature What are the negatives SE Is it toxic?

Gefitinib What is it? What does it treat What is the mechanism of action What are the ligands What did trial say which population good and why?

Monoclonal AB Can be an example of?

Murine = composition Chimeric = Humanised = Suffix =

Cetuximab What is it? When Is it used When is it not used What is the pathway that it acts on? SE

Bevacizumab Also known as? What is the underlying concept When is it used MOA Actual effect

L22 Hormones and cancer What hormones does small cell lung cancer produce What hormones do pancreatic cancer produce What are the hormone responsive organs What is the difference btw oestrogen production pre and post menopause Breast cancer Draw synthesis of oestrogen diagram What are the risk factors for BRCA related to oestrogen

What did beatson do in 1896 that was the oldest form of molecular targeted therapy

How does oestrogen stimulate proliferation What % of BRCA expreses ER What is the risk of BRCA with contraceptive pill 6 months, 10 years, when is it back to normal Is pop SIMILAR HRT and BRCA What is the effect of HRT for 12 months When is the risk normalised Treatment of BRCA SERMs example o Can be used when in a treatment regime o SE Inhibition of GF pathways o What Is Iressa How does it work o What is thee trade name for trasuzumab What is it? o How do aromatase inhibitors function SE o What is Goserelin What is zoladex How does it work

Prostate cancer What is the effect of blocking testosterone Draw the sequence for testosterone release What % of testosterone = adrenal origin

Treatment Hormone treatment o PSA and local spread = trear with radio and hormone o But what will happen to cells eventually

What is androgen deprivation therapy What is gosrelin How does this reduce LH and FSH What is cypoterone SE

Endometrial cancer How stimulated and by what? Who usually gets it?

Clinical signs (7) Risk factors How does tamoxifen act on the uterus What difference is there in HRT

Treatment Successful? What do ER+ tumours reponsd well to?

L23 chemotherapy Cytotoxic chemotherapy What agents are selected What is dose intensity correlate to? What is efficacy marked by?

Cytotoxic agents What agents stop in G1 S S G2 G2 M M G1

Apoptosis decision How do cytotoxic drugs induce apoptosis In response to (3)

Antimetabolites Example Mechanism What is DHFR What is it required for

What is the end result

Anthracyclins What are they derived from Mechanism What does it inhibit What does it create Example Elimination? Toxicity?

Topoisomerase inhibitors Difference btw monomer and dimer Which phase of cell cycle do they both act in What is the normal function of topoisomerase

Microtubule inhibitors What are the essential functions (6) 2 examples of microtubule inhibitors How does vinca alkaloids work? o Toxicity How do taxanes work o Toxicity

Alkylating agents What do they attach and to where What is the effect Properties

Platinum analogues Example Mechanism End result

Cytotoxic chemotherapy What Is the therapeutic index What di normal cells vary in? Normal or cancer which cels recover faster

Reversible toxicities Effects? Examples of cells with rapid physiological turnover

What is the concept of reversibility?

Irreversible cumulative toxicities Examples of slow growing cells What does this dictate

Therapeutic index, high or low What are the toxicity grades (4)

What are the assumptions made (4) How does growth proceed relative to homeostasis What does each dose do Small or large more likely to contain non dividing cells

Gompertzian tumour growth kinetics DF How does growth fraction change with growth When is maximum growth

Clinical implications What kind of tumours have the highest growth fraction What is the problem with large tumours What is the disease free interval

Drug sensitivity and spontaneous mutation Tumour size = mean fraction of resistant cells dependent on?

Uses of chemotherapy

(6)

Combination chemotherapy What are the aims (3)

Principles (6) Dose intensity What is the effect of reducing dose What does dose delay do What is added to aid neutrophil recovery

Maximum dose intensity : (3)

Pharmacogenoimics Genetic variability

L24 the challenges we face What is the incidence of cancer Proportion of people who develop CA What % die

How many types of cancer are there What 4 Ca account for 50%

What are the hallmarks of CA What is the role of cancer stem cells in response to anti cancer treatment What are the stages in carcinoma development

Pancreatic cancer What is the 5 year survival rate What % eligible for whipples Post op survival 5 year How do they die

Examples of cell bases cancer vaccines Examples of antigen specific cancer vaccines

What is the future hope