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78 Cards in this Set

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Bony mets - lytic (7)

RCC


Melanoma


MM (unless POEMS - then sclerotic!!)


NSCLC


Thyroid


NHL


Langerhans Cell histiocytosis




Most likely to cause hypercalcaemia


Best seen on plain XR


overactive bone RESORPTION mechanisms

Bony mets - sclerotic/blastic (5)

Prostate


Carcinoid


SCLC


HL


Medulloblastoma




more prominent on bone scan


overactivity of bone FORMING mechanisms

Bony mets - mixed lytic/sclerotic (3)

Breast


GI


SCC (most sites)

PTH-rp production (3)

SCC: lung, head and neck, skin


Breast


GU


GIT

ADH production (4)

Lung: SCC, SCLC


GIT


GU


Ovary

ACTH secreting tumours (5)

Cushing Syndrome


Lung: SCLC, bronchial carcinoid, adenocarcinoma, SCC


thymus


pancreatic islet


Medullary thyroid carcinoma

IGF secreting tumours (7)

Symptomatic hypoglycaemia




Mesenchymal tumours


sarcomas


Adrenal


hepatic


GIT


kidney


prostate

Major genes involved in initiating cancer

Lead to unregulated cell division, or ability to avoid programmed cell death




Oncogenes


- only one mutation required for activation


- autosomal dominant




Tumour suppressor genes


- both copies need to be inactivated for loss of function





Caretaker genes - function?

Subset of tumour suppressor genes with no direct effect on cell growth. Help to protect integrity of genome by repairing DNA defects.

Tyrosine Kinase - functin

signal transduction pathway often activated in cancer cells


normally only active for short periods


malignancy - permanently activated through mutation, gene amplification, gene translocation




TKI - effects


- decreaesd proliferation


- decreased survival


- impaired angiogenenesis

Imatinib - target?


- Indications

Bcr-Abl


(also c-abl, c-Kit, PDGFR-alpha or beta)




CML and GIST

Sunitinib - target?


- Indications

c-KIT, VEGF, PDGFR-beta, Flt-3




GIST (cKIT, PDGFR-beta)


RCC: VEGF

Sorafenib - target?


- Indications

RAF, VEGFR, PDGFR-alpha/Beta, Flt-3, c-KIT




RCC, HCC

Chemo causing Peripheral neuropathy?

Vincristine


Cisplatin

Gefitinib


- target


- indications

EGFR




NSCLC

Bortezomib


- target


- indication

Proteasome




Mulitple myeloma

Cetuximib


- target


- indication

EGFR




colon cancer, head and neck SCC

Panitumumab


- target


- indication

EGFR




colon cancer


(very similar to cetuximab)

Rituximab

- target


- indications

CD20




B-cell lymphoma and leukaemia expressing CD20





Alemtuzumab


- target


- indication

CD52




CLL and CD52-expressing lymphoid tumours

Bevacizumab


- target


- indications

VEGF



Colon, lung, breast (maybe other!)

Breast cancer - poor prognostic signs (7)

Pathologic staging


ER/PR negative


HER2+


high growth rate --> early relapse


More than medium number of cells in S phase --> higher risk of relapse


Higher nuclear grade


p53 overexpression


early menarche, late menopause, late first pregnancy (higher overall oestrogen exposure)

Target of BRCA?

DNA repair gene






10% of ovarian cancer


BRCA1: 30-50% lifetime risk ovarian cancer, breast cancer more common


BRCA2: Ovarian cancer 20-40%, lower risk of breast cancer, later onset, slight increased risk pancreatic cancer

Cytokeratin - positive in what sort of tumours?

Carcinomas




Good initial test for tumour unknown primary to establish whether carcinoma/other

Paraneoplastic syndromes associated with thymoma?

Pure red cell aplasia ~5%


Myasthenia gravis ~30%


Hypogammaglobulinaemia ~5%




Asymptomatic ~60%




Rarely can be associated with a huge range of other things including polymyositis, SLE, thyroiditis, Sjogren's, UC, pernicious anaemia, Addison's, scleroderma, panhypopit

DDx anterior mediastinal mass? (4)

Thymoma 40%


lymphoma


germ cell tumour


substernal thyroid tumours



Side effects of checkpoint inhibitors?

Hepatitis


Colitis




Mx of toxicity


- well-established role for steroids


- Mild = oral, severe = methylPNL


- Infliximab in steroid-refractory disease


- ??other immunosuppressives – CNI,MMF, ATG in hepatitis




Relative contraindication to further treatment or rechallenge


- higher risk of development with CTLA4 than with PD1 inhibitors


- Depends on response, other options for malignancy, availability of a test dose

Chemo causing Peripheral neuropathy?

Vincristine


Cisplatin

CTx causing leukaemia?

Etoposide

CTx causing HUS?

Mitomycin C

CTx causing Raynaud's

Bleomycin (also long-term IPF)


- raynaud's usually short term

Viruses associated with haematological malignancy?

HTLV1: often asx/acquired in infancy, associated with adult T-cell lymphoma/leukaemia


HIV: Burkitt's, DLBCL


EBV: HL, Burkitt's


HCV: lymphoblastic lymphoma


H. Pylori: MALT


HHV8: Castleman's disease

CTx contraindicated with AIHA?

Fludarabine - can worsen AIHA

risk factors for pancreatic cancer

long standing DM


obesity


smoking - 2-3x increased risk




(note ETOH abuse and HTN are not RF)

APC gene?

tumour suppressor gene




FAP - mutated APC - autosomal dominant germline mutation (plus second hit mutation in KRAS, p53 etc)




Sporadic CRC - can have mutations in APC, p53, KRAS

p53

tumour suppressor gene




many malignancies


- found in most tumour types




Li Fraumeni Syndrome - congenital p53 deficiency

HNPCC - mutations?

Variable germline mutations in MLH1, MSH2, MSH6 or PMS2 - loss of function mutations




cf. sporadic mismatch repair deficient CRC


- MLH1 promoter hypermethylation - epigenetic silencing of MLH1


- BRAF V600E 60%


- High MSI


- no response to 5FU but good response to pembro

RET

Ret = proto-oncogene




MEN2

MEN1 gene

MEN 1 (3Ps - parathyroid, pituitary, pancreas)

VHL

tumour suppressor gene




esp. clear cell RCC, CNS haemangioblastoma, phaeochromocytoma




Congenital mutation --> VHL syndrome (autosomal dominant)

Chemo with cardiovascular SEs

Anthracyclines - cardiomyopathy


HER2: reversible, non-dose dependent LV dysfunction (increased risk when combined with anthracyclines)


Bevacizumab: HTN, sometimes also CCF


5-FU: coronary artery spasm


Cisplatin: premature CAD

Key SEs of Aromatase inhibitors? (5)

Arthralgia, bone pain - can be severe!!


Sexual dysfunction, dryness


OP and fracture risk


CV risk


Hyperlipidaemia




BUT lower risk VTE and endometrial Ca



SEs of Tamoxifen? (3)

VTE risk


endometrial cancer


Hot flushes, low libido




BUT no osteoporosis

Worse prognostic hormone marker profile in breast cancer?

Triple negative




(although HER2 worse prognosis than oestrogen receptor +)

Early stage breast cancer - management

Surgery


Breast conservation therapy if possible: WLE


- if WLE done, need adjuvant RTx (increased survival, decreased recurrence) - WLE + RTx is equivalent to mastectomy


Mastectomy +/- reconstruction


- >4cm tumour


- multifocal


- previous chest RTx


- central tumour


Axillary clearance


- Sentinel node biopsy - if positive then axillary clearance indicated


- Note if nodes involved clinically (bulky, palpable) then should do AC anyway


- don't need SNB for DCIS




Chemotherapy


- Anthracyclines (doxorubicin/epirubicin) and/or Taxanes (paclitaxel, docetaxel)


Key toxicities:


- bone marrow suppression (both)


- Anthracyclines: dose-dependent cardiomyopathy, infertility


- Taxanes: peripheral neuropathy


Indications for chemo:


- node + cancer


- high risk featues: Grade 3, extensive PVI, size >4cm, weak ER/PR expression

Key anthracycline side effects

Infertility


cardiomyopathy


bone marrow suppression

Key taxane side effects

Bone marrow suppression


Peripheral neuropathy

Risk factors for chemotherapy-induced ovarian failure

Temporary or permanent




Age strongest risk factor (esp. >40y)


Chemotherapy


- Alkylating agents e.g. cyclophosphamide


- MTx > anthracycline > everything else

what is TDM1 in breast cancer therapy?

antibody-drug conjugate of trastuzumab plus DM1 (cytotoxic)


Toxicity = thrombocytopenia

Poor prognostic markers in breast cancer

Positive axillary LN: strongest predictor of long-term prognosis


Negative hormone markers


- Triple negative: increased short term mortality


- ER/PR+: better prognosis, risk of late relapse


Increased size


Higher grade


Untreated HER2+ - however targeted therapies have changed this


Younger age: high grade and triple negative

BRCA - function

DNA repair genes - tumour suppressor genes


Several hundred mutations


Autosomal dominant with variable penetrance (50-80%)




Associated with


- breast


- Ovarian


- Prostate


- Pancreatic


- Male breast cancer

Risk reducing strategies with BRCA+?

Bilateral prophylactic mastectomy


- screening for those declining surgery froma ge 25




BSO


- Age ~40 or on completion of childbearing


- Improves survival


- Greatly reduces risk of ovarian/fallopian tube cancers

Staging - NSCLC?

PET/CT


- Gold standard


- Risk of false+ nodes




MRI Brain - better than CT, only if clinical suspicion

Management of Stage I/II NSCLC?



Surgical resection


- lobectomy preferred (higher risk of local recurrence with wedge resection)


- Pneumonectomy: unacceptable complication rates




Chemotherapy


- Imrpoves 5y survival by 11% in ressected stage II


- Cisplatin + Vinorelbine




RTx


- only if refusing surgery/not candidates

Mx Stage III NSCLC?

Concurrent RTx + chemotherapy


- Regimen: cisplatin/etoposide, carboplatin/paclitaxel




Surgical resection


- Neoadjuvant chemotherapy followed by surgery in N2 disease

Risk factors for EGFR mutation?

Female


Asian


Never smoker


Adenocarcinoma (can occur in squamous, but much more associated with smoking)

Side effects of EGFR inhibitors?

Erlotinib, gefitinib




Rash - acneiform, responds to doxycycline and steroid cream


Diarrhoea


Pneumonitis

ALK inhibitors - SEs (4)

4% adenocarcinomas


Crizotinib (oral TKI against intracellular domain of ALK)




SEs


- visual disturbance: flashing lights, floaters, shadows - 70%


- Diarrhoea, pneumonia


- Transaminitis


- Cardiac: bradycardia, QT prolongation

Staging SCLC?

Limited stage: confined to ipsilateral hemithorac


Extensive stage: metastatic disease outside ispilateral hemithorax




CT CAP


(PET not standard of care)


CTB routine: 10% asymptomatic brain mets

SCLC - treatment

Limited


- Chemo + RAdiotherapy




Extensive: chemo alone




Prophylactic cranial irradiation


- performed in limited and extensive stage in patients who respond to initial treatment (complete response or significant tumour regression)

Indications for adjuvant chemotherapy in colon cancer (6)

Stage III (definitely!!)


Stage II with high risk features (controversial)


- Inadequate LN sample (<12)


- T4 disease


- Lymophovascular disease


- Poorly differentiated


- Obstruction/perforation




Isolated liver/lung met: resect


Chemotherapy regimen: FOLFOX or FOLFIRI +/- targeted (EGFR or VEGF)

Toxicity: 5FU and oral prodrug (what is it called??!)

Coronary vasospasm


Diarrhoea


Mucositis


Plantar-Palmar erythema


(Increased toxicity in DPD deficiency)




Oral prodrug = capecitabine!!


- as above - but more palmar-plantar erythema





Toxicity: oxaliplatin?

NB: oxaliplatin-based regimens in colon cancer are superior to 5FU alone



Diarrhoea


myelosuppression


Peripheral neuropathy


Cold-induced laryngospasm

SEs of Bevacizumab?


- MOA

anti-VEGF (circulating growth factor)


--> inhibits angiogenesis


Improves outcomes (increased by 3-4/12)


Approved in combination with oxaliplatin/irinotecan chemotherapy




SE


- HTN (actually a marker of response)


- GI perforation


- Impaired wound healing


- Bleeding/thrombosis

Cetuximab?

mAB to EGFR


Tumours MUST be KRAS WILDTYPE (non-mutant)


Alone or with chemotherapy


Improves outcomes: increased by 1.4-5/12

Lynch Syndrome

Autosomal dominant


Defect in DNA mismatch repair gene (identified on immunohistochemistry on tumour specimen)


Key MMR genes


- MLH1 + MSH2: 90%


- MSH6: 10%




Features


- early onset CRC


- typically R sided lesions


- Increased rates of synchronous (7-10%) and metachronous (20-40%) tumours


- however, better prognosis cf. sporadic




Extracolonic tumours


- Endometrial (early onset, strongest association)


- Ovarian


- Stomach


- small bowel


- hepatobiliary


- renal pelvis/ureter



Microsatellite instability - definition?

Microsatellites = short repetitive sequences of DNA




MSI: expansion or contraction of microsatellites due to dysfunction of DNA mismatch repair proteins




"Molecular signature" of HNPCC


- highly sensitive BUT not specific (15% sporadic CRC is MMR-high)

Prostate cancer - treatment

Castrate-Sensitive: Androgen Deprivation therapy

- Prolongs survival


- however, eventually most beocme castrate-resistant


GnRH Agonists (gosrelin, leuprolide)


- negative stimulation to hypothalamus --> switch off GnRH driver, decreased testosterone (initial"flare" response - need to cover with antiandrogens - esp. if mets in high risk locations)


GnRH antagonists (degarelix)


- block IMMEDIATELY, more rapid reduction


- Possible improvement in CV side effects




Castrate-Resistant


- Docetaxel, cabazitaxel


- New hormonal therapies: abiraterone, enzalutamide


Abiraterone: androgen synthesis inhibitor (inhibits 17a-hydroxylase, key enzyme in steroid synthesis)


- Toxicity: HTN, oedema, hypokalaemia, rare LFT deragnement


Enzalutamide: inhibits androgen receptor signalling

Key components of MAP kinase signalling pathway

Protein phosphorylation cascade in both normal and cancer cells - becomes dysregulated in cancers


- normally needs growth factor to activate - in cancer auto-activation




Dysregulation in upstream enzyme (NRAS, BRAF)


- Melanoma: BRAF mutation 40-60%, BRAF V600E 80-90% (BRAF inhibitors dabrafenib)




BRAF inhibition --> resistance develops via MEK pathway --> dual BRAF-MEK inhibition in the standard of care

BRAF inhibitors - toxicitiies (4)

Febrile reactions: esp. when combined with MEK inhibitors




SCCs and keratoacanthomas


- paradoxical activation of MAPK pathway, bypassing BRAF


- largely overcome by MEK inhitors




Rash, photosensitivity, hyperkeratosis


GI toxicity

SEs of immunotherapy? (7)

Rash - most common


Colitis


Thyroiditis


Hypophysitis


Hepatitis


Pneumonitis


Nephritis




Mx


- Steroids


- exclude other causes

Cancers where checkpoint inhibitors are indicated?

PBS listed:


- Melanoma


- Lung


- Renal




Other


- bladder


- Head and neck SCC


- MMR deficient solid tumours

Highest risk tumours for hypercalcaemia of malignancy?

Breast


SCC (head and neck)




IV hydration


IV bisphosphonate when vit D replete

Mx of spinal cord compression? (3)

Steroids (usually dexamethasone)


Neurosurgical review


Radiotherapy if not suitable for neurosurgery

SVC syndrome - Management (4)

Steroids (usually dex)


Anticoagulation if concurrent VTE


Stenting if possible


Radiotherapy if unable to stent

Testicular tumour with elevated AFP?

MUST have NON-seminomatous components




AFP: not produced by pure seminomas, 1 week half-life


B-hCG: both seminomas and non-seminomas


- half-life ~2 days





False positive CEA (1)

Smoking

Indications for prostate biopsy

Abnormal PSA + DRE in a patient >50y




PSA Velocity: if normal DRE, can use change in PSA over time to guide decision in biopsy


- if >0.75ng/ml/year - suggestive of cancer, biopsy indicated