CPAT3201 Notes - Cancer lectures 1-4 PDF

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Cancer lectures 1-4...

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CPAT3201 Pathogenesis of Human Disease: Course Notes

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CPAT3201: Lecture 1 Neoplasm: Tumour: -

An abnormal mass of tissue (Takes up space in the body and can fatally interfere with normal function of organs)

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The growth of the abnormal tissue exceeds and is uncoordinated with that of the adjacent normal tissue (mutation in the tumour DRIVE growth & PREVENT normal cell-cell contact inhibition)

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Growth persists in the same excessive manner, even after cessation of the stimuli which evoked the change (mutations incorporated into genome of tumour cells & passed onto daughter cells)

Etymology of “Cancer” -

Galen- 2nd century Greek ‘Karakinos’ for CRAB --> Became ‘cancer’ in Latin

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Cancer adheres to any part they seize in an obstinate manner, have legs like crabs

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Cancer= malignant tumour= a tumour capable of metastasis (spread)

E1: Is this cancer? -

NO--> Benign neoplasm of the breast --> A fibroadenoma that has grown to form a large mass

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It has characteristic morphology of a fibroadenoma -

Differentiated epithelial cells arranged in distinctive glandular patterns

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Embedded in a dense fibrous connective tissue stroma

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It is demarcated from the surrounding tissues

E2: Is this cancer? -

NO--> Colonic Polyps

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Histologically, these are benign adenomatous papilloma’s--> However they have a potential to progress to malignancy and are considered to be pre-malignant

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Classification of Tumours

E3: Lipoma – Benign tumour of mesenchymal origin -

Common benign tumour of fat cells (adipocytes)

E4: Common malignant tumour of epithelial origin: Adenocarcinoma of the colon

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E5: Common malignant tumour of epithelial origin: Squamous cell carcinoma of the skin -

Basal epithelium like cells, very atypical in appearance

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Often exhibit keratin “pearls” (attempts to differentiate into squamous epithelium)

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Carcinoma in situ prior to invasion through basemen membrane

E6: Hodgkin’s Lymphoma -

Solid malignant tumour of white cells

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Grows initially within lymph nodes

NB: -

“Rubbery” lymph nodes containing tumour

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Abdominal aorta

E7: Benign Teratoma of the Ovary -

Multiple cell types derived from pluripotent stem cell in gonad

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General Features of Benign vs Malignant Neoplasms

E1: Benign vs Malignant Neoplasms: Leiomyoma Leiomyoma -

Nuclei evenly sized and shaped

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Ordered, streaming arrangement

Leiomyosarcoma -

Pleomorphic, irregular, enlarged nuclei

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E2: Anaplastic Carcinoma Anaplasia: The condition of cells with poor cellular differentiation, losing their morphological characteristics -

NB: Lack of tissue-specific differentiation and poor cellular differentiation

E3: Anaplastic Sarcoma -

NB: Nuclear pleomorphism, mitotic figures (including abnormal), lack of cell and tissue differentiation

E4: Example of necrosis and haemorrhage: Cervical squamous cell carcinoma

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Macroscopic Differences between Benign and Malignant Tumours 1. Local Invasion Benign tumours grow by expansion, while Malignant tumours both expand and INVADE surrounding tissue Benign Tumours: -

Well circumscribed and round (cohesive expansile well demarcated masses

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Often have a capsule (due to adjacent atrophy & fibrosis; facilitates enucleation)

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Their size varies greatly

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Colour and texture: grey or white and uniform

Malignant Tumours: -

Finger like projections

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Irregular margins

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Are not usually circumscribed

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Fail to recognise normal anatomic boundaries (penetrate through organs e.g. wall of colon)

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Have variable texture and colour, often due to haemorrhage & necrosis

2. Ulceration Benign Ulcers: Rarely occur, tend to have very sharp edges, are shallow and the floor is not usually indurated Malignant Ulcers: Tend to have rolled edges and tend to feel hard, irregular in shape and may be irregularly indurated

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3. Polyps Benign Polyps: Usually pedunculated (have a stalk) and have a uniform texture Malignant Polypus: Usually sessile (flat); may ulcerate & bleed; often have an indurated base

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4. Organisation of Tumour Cells -

Tumour cells may be organised into structures that resemble their tissue of origin -

e.g. glandular tumours often form glandular (acinar) tumour structures

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The more regular and ordered these structures, the less likely that they are malignant

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Glands that are haphazard in size and organisation suggest malignancy

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Malignant glands may become substantially more anaplastic in more malignant tumours and lose all glandular organisation

Examples of the arrangement of individual cells in a gland

Normal: Nuclei at base of cells (polarity), single layer of cells of uniform size arranged around lumen of regular size

Benign: Nuclei remain basal but usually enlarged, may be higher density of cells, but remain regularly related to each other, may be slight increase in mitotic rate with normal mitoses

Malignant: 1. Markedly enlarged central nuclei (loss of polarity and increase in nuclear cytoplasmic ratio to greater than 50%) 2. Cells variable in size and shape (pleomorphic), and haphazardly arranged “don’t dtant up straight´(loss of polarity) 3. Cells may become stratified into two or more layers 4. Noticeably increased mitotic rate with abnormal mitoses Cells may become multinucleate

E1: Junction between benign colonic polyp and normal mucosa

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E2: Adenocarcinoma of the colon

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5. Altered cell function and differentiation Benign and well differentiated malignant tumours often retain function; anaplastic malignant tumours are more likely to loose all function or express bizarre functions -

Synthesis of mucin: Occurs in well differentiated adenocarcinomas but not in anaplastic adenocarcinomas

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Synthesis of keratin: May occur in abnormal locations (keratin pearls) or not at all in anaplastic tumours)

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Synthesis of melanin: A primary melanoma usually is pigmented but occasionally a metastasis form a primary lesion may lose its pigmentation, suggesting more anaplastic change in that subclone of metastatic cells

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Synthesis of normal or abnormal hormones: The tumour may produce large amounts of normal or abnormal hormone e.g. -

Pheochromocytoma produces excess normal catecholamines (adrenalin & noradrenaline); many tumours produce abnormal ‘hormones’

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Tumour selection of abnormal parathyroid hormone resulting in hypercalcemia

NB: If the hormone is not normally produced by the tissue of origin of the tumour it is referred to as a paraneoplastic effect

E1: Squamous cell carcinoma of the skin

6. Rate of Growth Benign: Slow, low mitotic rate, well demarcated 9encapsulated) expansion Malignant: Rapid, high mitotic rate & abnormal mitoses; irregular border, not encapsulated 7. Secondary Changes

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Vascularity: Benign tumours not very vascular (except a haemangioma); malignant tumours are very vascular

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Necrosis/ulceration: Not common in benign tumours, common in malignant

8. Host Responses -

Inflammatory response: Common around a malignant tumour (tumour seen as “foreign” by immune system), May correlate with prognosis e.g. the greater the lymphocyte infiltration in a melanoma, the better the prognosis

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Malignant tumours may excite a strong fibrous (collagenous) response (referred to as desmoplasia)

Dysplasia: -

Literally “disordered growth”

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Phenomenon seen in epithelia

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Cells shown some of the abnormalities seen in malignant cells (see table)

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Non-invasive, hence benign by definition

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Related terms: intraepithelial neoplasia, carcinoma in Situ

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CPAT3201: Lecture 2 Metastases: The secondary implants of a tumour that are discontinuous with the primary tumour and located in the remote tissues Anaplasia: The condition of cells with poor cellular differentiation, losing their morphological characteristics Embolism: The lodging of an embolus, a blockage causing material in a blood vessel N.B. It is the property of metastasis that distinguishes a neoplasm from it benign counterparts to malignant tumour Factors that increase the likelihood of metastasis 1. The larger the tumour 2. The older the tumour 3. The less differentiated the tumour 4. Certain cell types are more likely to cause metastasis (e.g. 50% patients usually present with metastasised sarcomas) Mechanisms of metastasis Lymphatic Metastasis -

Lymphatic spread is favoured by carcinoma

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The first mechanism of metastasis

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Neoplastic cells infiltrate into lymphatic ducts --> embolism to draining (regional) lymph nodes (which form tumour deposit)

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Spread further throughout the lymphatics

E1: Cancer cells have grown along the lymphatic channels in the parietal pleura, producing reticular pattern on the surface of the lung

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E2: Malignant melanoma metastasis to lymph nodes

E3: Lymph node cortex containing metastatic adenocarcinoma

Haematogenous Metastasis -

Tumour cells infiltrate into blood vessels and spread through the circulation- typical of sarcomas

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Tumour cells may form distant secondary deposits by passing through a) Systemic veins and/ or pulmonary arteries --> Capillaries of lung b) Portal veins from gut --> Sinusoids of liver c) Pulmonary veins and/or systemic arteries from lung --> anywhere in body

E1: Metastasis from bronchial carcinoma to brain & Lung metastases from osteogenic sarcoma

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E2: Haematogenous spread from adenocarcinoma of colon via portal vein to liver

E3: Renal cell carcinoma metastasis to vertebral column causing spinal compression -

Paravertebral veins anastomose with lumbar, portal and pelvic veins

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Allows for the passage of tumour cells into vertebral bodies and canal

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May cause collapse of vertebrae and press on spinal cord, causing paraplegia

E4: Renal cell carcinoma metastasis to renal vein causing kidney oedema -

Tumour cells may spread along veins, as a solid tumour mass, eventually blocking them

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E.g. renal cell carcinoma may spread along the renal vein

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Can obstruct the inferior vena cava, causing catastrophic oedema (blockage and characterised by swelling) of the lower trunk and legs

Transcoelomic seeding across body cavity The route of tumour metastasis across a body cavity, such as the pleural, pericardial, or peritoneal cavity Examples: -

Ovarian cancer may spread through the peritoneal cavity

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Lung cancer may spread though the pleural cavity

Seeding may also occur in -

Pericardial space

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Subarachnoid space 15

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Joint cavities

Peritoneal cavity filled with gelatinous ovarian tumour

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E1: Gastric Carcinoma -

Invades through stomach wall into peritoneal cavity

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Selectively seeds onto ovaries (Krukenberg tumour)

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Spread may also be via lymphatics

Intra-epithelial Pagetoid Spread -

Intra-epidermal spread of tumour cells (invasion)

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Paget’s disease of nipple (also rarely around vulva and anus)

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Carcinoma spreads along duct lumen, infiltrates epidermis of nipple

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Nipple and areola become fissured, ulcerated and inflammatory hyperaemia

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Initially carcinoma in-stu

E1: Paget’s disease of the nipple -

Invasion of carcinoma along ducts into adjacent epidermis, with radial spread from nipple within epidermis, causing epidermal destruction and ulceration

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Perineural Spread -

Tumour cells may spread along a nerve in perineural space

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May cause severe pain in nerve distribution, which may require surgical ablation of nerve

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e.g. prostrate cancer

Implantation Spread -

Largely theoretical

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Cells may be “transplanted” by medical implements to second site

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This concept in part underlies the argument that a cancer should be resected at the time of surgical biopsy if a frozen section of the tumour shows malignancy e.g. surgical biopsy of breast neoplasm

Metastatic Cascade in Haematogenous Spread -

For successful metastasis to occur the malignant cells must be able to complete a series of sequential steps --> The “Invasion-Metastasis cascade” -

Local Invasion Intravasation into blood and lymph vessels Transit through vasculature Extravasation from the vessels Formation of micrometastases  Growth of micrometastases into macroscopic tumours

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Nb: The sequence of steps may be interrupted at any stage by host-related or tumour related factors

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E1: MMP (Matrix metalloproteinases) inhibitors used in clinical trials to inhibit metastasisLimited success

1: Invasion of Extracellular Matrix (ECM)

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A tumour must interact with the ECM at several stages during the metastatic cascade

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A carcinoma must first breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular BM

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This cycle is repeated when the tumour cell emboli extravasate at a distant site

In short: To metastasise, the tumour cells must cross several different basement membranes, including negotiation of at least two interstitial matrices Nb: Invasion of ECM is an active process that involves four steps

1. Loosening of tumour cells

2.

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E-Cadherins act as intercellular glue and their cytoplasmic portions bind to β-Cadherin

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Adjacent E-Cadherin molecules keep the cells together

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NB: E-Cadherin function is lost in almost all epithelial cancers, either by mutational inactivation of E-Cadherin genes or by activation of β-Cadherin genes

Local degradation of the basement membrane and interstitial connective tissue -

Tumour cells may secrete proteolytic enzymes (enzymes which break long chained AA to small peptides) or induce stromal cells to elaborate proteases

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MMPs regulate tumour invasion not only remodelling insoluble of the BM and interstitial matrix but also by releasing ECMsequestered grown factors

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NB: Benign tumours of the breast show little IV collagen activity, whereas their malignant counterparts overexpress the enzyme, contributing to the metastasis

3. Changes in attachment of tumour cells to ECM proteins -

Loss of adhesion in normal cells leads to induction of apoptosis, while tumour cells are resistant to this type of cell death

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The matrix is modified to promote invasion and metastasis -e.g. cleavage BM proteins, collagen IV and laminin, by MMP’s generates novel sites that bind to receptors on tumour cells and stimulate migration

4. Locomotion -

The propelling of tumour cells through the degraded BMs and zones of matrix proteolysis

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Movement is driven by tumour cell-derived cytokines, such as autocrine motility factors

2: Vascular dissemination and homing of tumour cells -

In circulation, tumour cells are vulnerable to destruction by hose immune cells, this is mitigated by the formation of emboli, through the aggregation and adherence to circulating leukocytes, especially circulating leukocytes (particularly platelets)

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Aggregated tumour cells are thus provided with a level of protection

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Many tumours metastasise to the organ that presents the first capillary bed they encounter after entering circulation

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NB: The natural pathways of drainage do not readily explain the distribution of metastases

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E1: >1% of neoplasms occur in skeletal muscle, despite high blood flow -

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The organ tropism may be due to: -

Expression of adhesion molecules by tumour cells whose ligands are expressed preferentially of the endothelium of target organs

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Expression of chemokines and their receptors

Tumour cells are inefficient in colonizing distant organs

Clonal Theory of Metastasis -

Over a period of time malignant tumours tend to become more aggressive and acquire greater malignant potential --> Tumour progression

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Individual subclones of a malignant tumour progressively evolve

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The phenotypic attributes of these subclones have a greater ability to metastasise successfully

SUMMARY: 

The ability to invade tissues, the hallmark of malignancy, occurs in four steps, 1. Loosening of tumour cells 2. Local degradation of basement membrane and interstitial CT (The ECM) 3. Changes in attachment of tumour cells to ECM proteins 4. Migration of tumour cells

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Cell-cell contacts are lost by the inactivation of E-Cadherin through a variety of pathways

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Basement membrane and interstitial matrix degradation is mediated by proteolytic enzymes secreted by tumour cell and stromal cells, such as MMPs and cathepsin

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Metastatic site of tumours can be predicted by the location of the primary tumour- Many embedding in the first capillary they encounter (lung and liver mostly)

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Some tumours show tropism, probably due to activation of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site

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CPAT3201: Lecture 3 – Epidemiology and Aetiology of Cancer Incidence and Demographic Distribution -

Australia 2014 -

123,920 new cases of cancer (incidence)

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45,780 deaths from cancer (37% mortality)

Females: -

New cases: Breast, colorectal, melanoma, lung

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Mortality: Lung, breast colorectal, unknown site

Males: -

New cases: Prostrate, colorectal, melanoma, lung

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