Biology And Pathophysiology Of Cancer

Biology of Cancer Pathophysiology of Cancer Raul H. Morales-Borges, M.D., FICPS, FIACATH Ashford Institute of Hematology & Oncology

Introduction Cancer is a leading cause of death and source of morbidity of adults in the Western world. There are many causes including environment, heredity, and behavior interactions.

Introduction All malignant cells arise from a transformation of a normal cell into an immortal cell which growth uncontrolled. Such transformation occurs when the genetic blueprint - the cell’s DNA - is damaged or altered. Every cell contain a series of genetic markers known as protooncogenes.

Introduction Tumor development is a multistep process. Molecular research is providing interesting new modalities of treatments. Management is multidisciplinary. Our goals should be prevention, early detection, and provide good quality of life.

Cancer Cancer = Karkinoma, Crab (Cangrejo) Neoplasm = New Growth (Crecimiento Nuevo) Oncos = Tumor

Definition from 1922 It is a tissue overgrowth independently from the governing laws of the body.

Caracteristicas de Tumor Benigno Crecimiento lento Son bien diferenciados Tienen una capsula bien definida No invasion a otros tejidos No metastasis

Ejemplos de tumores benignos Papiloma Adenoma Cystadenoma Nevus Neurofibroma Lipoma Hemangioma Linfangioma Fibromatosis (desmoide) Osteoma Condroma Leiomioma Rhabdomioma Meningioma

Caracteristicas de Tumor Maligno Proliferacion de celulas neoplasticas No encapsulados Pierden la diferenciacion Estroma de soporte Neovascularizacion (vasos sanguineo nuevos) Invasion y Metastasis

Ejemplos de tumores malignos Carcinoma Adenocarcinoma Melanoma Seminoma Mieloma Linfoma Leucemias Condrosarcoma Neuroblastoma Retinoblastoma Tumor de Wilm Tumor de Ewing Mesotelioma Sarcoma Fibrosarcoma Angiosarcoma

Estadios de Tumores malignos Depende del tamano del tumor, nodulos linfaticos y metastasis Estadio I – pequeno Estadio II – algo mas grande, algunos nodulos Estadio III – invasion de estructuras vecinas, mas nodulos Estadio IV - metastasis

Carcinoma in situ (CIS) Pre-invasive epithelial malignant tumors of glandular or squamous cell origin. Localized to the epithelium. No broken local basement membrane. No invasion of surrounded tissues. Seen in the cervix, beast, skin, oral cavity, esophagus, stomach, bronchus.

Cancer Cells: Transformation Transformation means the process by which a cell becomes cancerous. Autonomy is when the cancer cell is independently from normal cellular controls. Cancerous cells show uninhibited growth. They are often anchorage-independent (they divide even in a soft agar gel). They are usually immortal.

Cancer Cells: Differentiation Differentiation refers to the process of acquiring a specialized function and organization. Anaplasia is the absence of differentiation. It is recognized by a loss of organization and a marked increase in nuclear size, with evidence of ongoing proliferation. The cells are of variable size and shape ( pleomorphism ).

Cancer Stem Cells Two characteristics: Self-renew & Multipotent. When a stem cell divides, each daughter cell has a choice: It can either continue as a stem cell or go on to become terminally differentiated, that is, completely matured (e.g., neuron, myocyte, erythrocyte).

Grado de Tumores Grado I – Bien diferenciados Grado II – Moderadamente diferenciados Grado III – Pobremente diferenciados Grado IV - Anaplasticos

The Genetic Basis of Cancer Clonal selection : Cancer is a disease of aging because the cells acquires a number of genetic mutations over time and the cells then may have a selective advantage over its mutant neighbors ( Clonal proliferation or clonal expansion ).

Molecular abnormalities in lung cancer Commonly observed genetic changes Tobacco carcinogen Inappropriate response to external signals Loss of cell cycle control Loss of apoptosis pathway Loss of contact inhibition Ability to metastasise Angiogenesis Immortality Autocrine growth loops Atypical alveolar hyperplasia Premalignant adenomas Lung cancer Carcinoma in situ Dysplasia Bronchial metaplasia Normal epithelium

Sequential changes during lung cancer pathogenesis Early Intermediate Late Normal epithelium Hyperplasia Dysplasia CIS Invasive carcinoma ~80% 3p LOH/small telomeric deletions 3p LOH/contiguous deletions ~50% Microsatellite alterations ~70% 9p21 LOH ~80% Telomerase dysregulation Telomerase upregulation ~60% myc overexpression ~80% 8p21-23 LOH ~40% Neoangiogenesis ~40% Loss of Fhit immunostaining ~70% p53 LOH p53 mutations ~80% Aneuploidy ~100% Methylation ~30% 5q21 APC-MCC LOH ~20% K-ras mutation Hirsch et al 2001 LOH, loss of heterozygosity

Oncogenes and Tumor-suppressor genes Oncogenes are mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate proliferation. Tumor-suppressor genes encode proteins that in their normal state negatively regulate proliferation.

It’s an oncogene in a normal, nonmutant state. The protooncogenes serve to many basic functions to the normal cell such as: growth, maturation and proliferation However, such protooncogenes can be altered and become Oncogenes Such Oncogenes confers certain characteristic to the cell : uncontrolled growth, invasiveness and immortality PROTOONCOGENES

How does the change from protooncogenes to Oncogenes occur? There are several steps toward the malignant transformation of a cell Non-lethal genetic damage lies at the heart of carcinogenesis A genetic damage ( mutation ) may be acquired by the action of environmental agents such as chemicals, radiation or viruses, or it may be inherited

Two classes of normal regulatory genes - the growth promoting protooncogenes and the growth inhibiting genes ( antioncogenes ) - are the principal targets of genetic damage Carcinogenesis is a multistep process at both the phenotypic and genetic level Every human cancer that has been analyzed reveals multiple genetic alterations involving activation of several Oncogenes and inactivation of two or more antioncogenes

The genetic damage that activates Oncogenes may be subtle or large enough to be detected in a gross chromosomal analysis: a karyotype analysis. In some cancers such alterations are nonrandom and common Specific alterations have been identified for most leukemia's and lymphomas

The most common types of such alterations are: translocations deletions gene amplification point mutations

Point Mutations They are the most common events in small scale changes in DNA. It’s an alteration of one or a few nucleotide base pairs. e.g., ras gene is associated with pancreatic and colorectal cancer.

Chromosome Translocation It can cause excess and inappropriate production of a proliferation factor (e.g., t(8;14) in Burkitt lymphomas) such as MYC protein. It can also lead to production of novel proteins with growth promoting properties (e.g., t(9;22) in CML) such as BCR-ABL protein.

Gene Amplification Result of duplication of a small piece of a chromosome over and over again, so that instead of normal two copies of a gene, tens or even hundreds of copies are present. Results in increased expression of an oncogene, or in some cases, drug resistance genes. E.g.: N-myc in Neuroblastoma & erb2 in Breast cancer.

Tumor-Suppressor genes They are genes whose major function is to negatively regulate cell growth and prevent mutations. Needs two (2) mutational events to contribute to the cancer. Loss of function, acts in recessive fashion. Inherited form is common and has a tissue preference. Examples: p53 (GBM, SCLC, BCA, CRC), Rb (retinoblastoma), APC & MCC (CRC).

Loss of heterozygosity Loss of a chromosome region in a tumor. Unmasks inactivating mutations in recessive tumor suppression genes. Also named as allelic loss. Examples: LOH for 5q for sporadic adenomas to carcinomas, Loss of the 13q14 chromosome region on one chromosome for Rb.

Gene Silencing The epigenetic silencing is associated with methylation of both the DNA and associated chromatin. So, no functional protein will be produced.

Holistic scheme of multistage carcinogenesis with 3 types of control systems Agonist induced signal transduction Cell cycle control Fidelity of DNA and Chromosome replication

In the near past, our understanding of cellular function was rudimentary Now, our knowledge of cells has progressed to an understanding of many complex interactions and networks: extracellular intracellular intranuclear

The genome project has amplified this capacity through numerous techniques, including the cluster array analysis Breast cancer cells are now classified in five groups basal like - null cell erb2+ A & B normal

Alterations in progrowth and antigrowth Cancer cells have mutations that enable them to proliferate in the absence of external growth signals. To achieve this, some caner cells acquire the ability to secrete growth factors that stimulate their own growth ( Autocrine stimulation). Other have an increase in growth factor receptors (EGFR), an activating mutation in an intracellular signaling protein called ras, an antigrowth signaling such as Rb, and a self-destruction mechanism such as apoptosis (p53).

Angiogenesis Neovascularization is a characteristic of cancer cells to provide their own new vessel supply. It’s secondary to purified angiogenic factors such as bFGF & VEGF. Vascular endothelial growth factor is angiogenic in vivo for endothelial cells. Basic fibroblast growth factor is mitogenic for vascular endothelial cells and is strongly angiogenic.

Model of role of angiogenesis in metastasis Angiogenesis Expansion of Tumor cells Microinvasion Enter & Exit Circulation Limited growth in Target Organ Angiogenesis Expansion into detectable metastasis

Telomeres They are protective ends, or caps, on each chromosome and are placed and maintained by a specialized enzyme called telomerase . Telomerase is usually active only in germ cells in ovaries and testes and in stem cells. When the telomeres become critically small, the chromosomes become unstable and fragment, then the cells die. Cancer cells at critical activate telomerase to restore and maintain their telomere to survive and divide.

Cyclin E* Cell cycle and therapeutic targets DNA damage or oxygen deprivation Cell suicide (apoptosis) p53* p21 Inactive pRB protein External signal that inhibits cell division TGF  Rb + E2F Early G 1 Late G 1 S G 2 M Phases of cell cycle p15* p16* p27 green Activity that promotes cell division pink Activity that discourages cell division * Mutation or deregulation of gene for this protein has been found in human tumours R External signal that promotes cell division Cyclin E- CDK2 complex Proteins involved in DNA synthesis CDK2 DNA synthesis Cell division Cyclin B- CDK1 complex Cyclin A CDK1 Cyclin B Cyclin A- CDK1 complex Liberated transcription factors Cyclin D- CDK4/6 complex CDK4/6 Cyclin D*

Prognostic and predictive factors p53 status Other cell cycle components including p27, p15, p16, pRb, cyclin and CDK K-ras mutations HER2/neu and epidermal growth factor receptor (EGFR) Beta tubulin Expression of matrix metalloproteinase and inhibitors DNA topoisomerase II  and II  Single nucleotide polymorphism in myeloperoxidase gene reduces risk of lung cancer Heparin-binding growth factor pleiotrophin

Strategies for signalling inhibition Tyrosine kinase inhibitors (TKIs) Immune effector cell Anti-ligand mAbs Bispecific Abs Anti-receptor mAbs Ligand/toxin conjugate scFv/toxin conjugates Ligand- genistein conjugates Intracellular scFvs Nucleus Antisense Inhibitors of other signalling molecules

DNA Mode of action of EGFR inhibitors Membrane Extracellular Intracellular R K R K EGFR-TKI EGFR-TKI   Signalling Proliferation Cell survival (anti-apoptosis) Growth factors Chemotherapy/ radiotherapy sensitivity Angiogenesis Metastasis  R, epidermal growth factor receptor EGF/TGF α Antibody

Human Cancer & Family Genetics Germline mutations. Inheritance of a mutated gene that can cause cancer. Examples: Neuroblastoma, Wilm’s tumor, Neurofibromatosis, Breast Cancer, Familial Polyposis coli or Adenomas of the colon.

Causas Hereditarias Neurofibromatosis (Enfermedad de von Reckinghausen) : Neurofibro-sarcomas Sindrome de Gardner : Fibro-sarcomas desmoides del mesenterio Retinoblastoma familiar : Osteo-sarcomas Sindrome Familiar de Li-Fraumeni Sindrome de Stewart-Treves -Angiosarcomas Hemocromatosis

Causas Geneticas de Sarcomas Translocaciones: t(11;22), t(12;14), t(2;13), t(X;18), t(12;16) Expesion de MDR 1 Mutaciones: genes p53, Rb Deleciones: 1p-, 3p-, 13q- Proto-oncogenes: c-myc, N-myc, c-myb, c-mil/raf-1, c-fes, c-sis Pathologe 17(3):195-201, 1996 Diagnostic Molecular Pathology 5(2):98-106, 1996 Monographs in Pathology 38:65-128, 1996 American J of Pathology 150(6):1997-2007, 1997 Seminars in Oncology 24(5):515-525, 1997 J Cancer Research & Clinical Oncology 123(4):211-8, 1997

Inflammatory Conditions & Cancer Reactive Oxygen Species Increased COX2 Proliferation Release of growth factors Release of cytokines Injury Cancer

Chronic Inflammation & Cancer Chronic Ulcerative Colitis : Colon Cancer Chronic Hepatitis B or Hepatitis C : Liver Cancer COPD, Chronic asthma : Lung Cancer Chronic Cystitis : Bladder Cancer Sjogren syndrome : Lymphoma Chronic Thyroiditis : Lymphoma Fibrocystic Breast Disease : Breast Cancer Benign Prostate Hyperplasia : Prostate Cancer

Histopathological Appearance of Benign Breast Disease (Hematoxylin and Eosin) Hartmann, L. et al. N Engl J Med 2005;353:229-237 BENIGN BREAST DISEASES (FIBROCYSTIC BREAST DISEASE)

Benign Breast Disease may not be so benign From Mayo Clinic Cancer Center If developed before 40 y/o the risk of BCA can increase by 83% and if we add a strong family history the risk increases by 93%.

Viral Infections & Cancer Ellerman in Denmark in 1908 and Rous in 1911: Retrovirus and Avian leukemia & Avian sarcoma. Hepatitis B & C viruses – Hepatocellular carcinoma Herpes virus / Epstein-Barr – Burkitt lymphoma, nasopharyngeal carcinoma KSHV / HHV-8 – Kaposi sarcoma HPV – Cervical and anogenital carcinoma Retrovirus HTLV-1 – Adult-T-cell leukemia/lymphoma HTLV-2 – Hairy- cell leukemia HIV – Kaposi sarcoma

HEAD & NECK CANCER Nasopharyngeal cancer and Epstein-Barr virus Endemic in regions of Northern Africa and Asia Etiology distinct from other head and neck cancers Epstein-Barr viral proteins detectable in majority of nasopharyngeal tumors Associated with frequent consumption of salted fish or nitrosamines Stupp R, Vokes EE. Current Cancer Therapeutics. 3rd ed. 1998;165-166.

HPV >100 types identified 2 30–40 anogenital 2,3 15–20 oncogenic* ,2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 58 4 HPV 16 (54%) and HPV 18 (13%) account for the majority of worldwide cervical cancers. 5 N ononcogenic † types include: 6, 11, 40, 42, 43, 44, 54 4 HPV 6 and 11 are most often associated with external genital warts. 3 1. Howley PM . In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott - Raven; 1996:2045–2076. 2. Schiffman M, Castle PE. Arch Pathol Lab Med . 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis . 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med . 2003;348:518–527. 5. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer . 2003:89;101–105. Nonenveloped double - stranded DNA virus 1 *High risk; † Low risk

Discovery of the Link Between HPV and Cervical Cancer 1. Jansen KU, Shaw AR. Annu Rev Med . 2004;55:319–331. 2. Schiffman M, Castle PE. Arch Pathol Lab Med . 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis . 2002;35(suppl 2):S210–S224. Body of information developed slowly based on advances in cellular, molecular, and immunological diagnostic technologies over the past 20 years 1 Epidemiological case - control studies completed 1 HPV defined as large, closely related family 1 : >100 types 2 ; 30 –40 anogenital 2,3 HPV genomes found in cervical carcinomas 1 HPV viruses cloned 1 Mechanisms of transformation elucidated (true “tumor virus”) 1 15–20 HPV types classified as oncogenic 2,3

Link Between HPV and Cervical Cancer 99% of Cervical cancers and High-grade cervical cancer precursor lesions associated with HPV Risk for developing cervical cancer with HPV is 50-100x higher than without HPV infection Risk of High-grade precursor lesion with HPV is 300-fold

Bacterial – Parasitic Infection & Cancer Helicobacter pylori – Gastric cancer, MALT Opisthorchis viverrini – Cholangio-carcinoma Schistosoma haematobium – Bladder carcinoma

Environmental Factors & Cancer Carcinogens are agents that can cause cancer. Xenobiotics are toxic, mutagenic, and canrcinogenic chemicals Important factors to be considered are: time of exposure, racial & gender disparities, human contamination & public health advocacy Tobacco smoke has polycyclic aromatic hydrocarbons, nitroso compounds, arylamines, benzo(a) pyrene metabolites, and benzene which are potent carcinogens.

Causas de Sarcomas Exposicion a Radioterapia Pacientes inmunocomprometidos Exposicion a quimicos como hidro-carburos policiclicos, cloruro de polivinil, asbestos, dioxina de los herbicidas. Cicatrices de cirugias previas, quemaduras, dano e implantacion de cuerpo extrano Hespes virus 8, HIV, HTLV-III, Rous Sarcoma virus Tumores Benignos de huesos: condromas, displasia fibrosa, Enfermedad de Paget del hueso

Tobacco & Related Cancers Lung Oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, esophagus & stomach Pancreas & Liver Penis, kidney, bladder Cervix uteri Myeloid leukemia

Radiation & Cancer 20 to 250 cGy for linear energy transfer radiation, such as x-rays or gamma-rays is the human cancer risk dose. Radiation-induced gene mutations or chromosomal abnormalities that can be detected early (within 24 hours of radiation exposure) are not solely responsible for tumor development in normal human cells.

Genomic instability & Radiation Bystander effect & Gap Junction Intercellular Communication Mitotic failure Cell death Chromosome alteration Gene mutation DNA damage Ionizing radiation

Ultraviolet radiation & Skin Cancer It causes melanoma, basal cell carcinoma and squamous cell carcinoma of the skin. The degree of damage depends on the intensity and wavelength content and the depth of penetration. It induces release of tumor necrosis factor in the epidermis. Inflammation is a critical component through hydrogen peroxide. Activation of the mitogen-activated protein kinase (MAPK) (eg. Melanoma)

Multistep skin Carcinogenesis Protein oxidation Lipid peroxidation Xenobiotics Mutate protooncogenes Inflammation ROS Direct DNA Damage UVR Oxidative Stress

Alcohol Consumption Associated with cancer of the: oral cavity, pharynx, hypopharynx, esophagus, liver, breast, colorectum. Mechanisms: effect of acetaldehyde, induction of cytochrome P-4502 E1 leading to the generation of ROS, increased procarcinogen activation, modulation of cellular regeneration, nutritional deficiency, altered mucosal integrity, enzyme and metabolic dysfunction, structural abnormalities.

Physical Activity Related with breast and colon cancers. Mechanisms: increases insulin and insulin-like growth factors, obesity, decreasing free radical scavenger systems, inflammatory mediators, increasing estrogen and androgens, decreasing gut motility. Rx: for CRC we need 3.5 – 4 hours/week, for BCA we need 30 – 60 minutes /day.

Diet & Obesity Important risk factors: low fiber and high fat diet, obesity, alcohol consumption, contaminated corn, peanuts and rice with aflatoxin, Chinese-style salted fish, hot beverages, grilled meat, red or processed food. Overweight and obesity are linked with cancer of: breast, colorectal, esophagus, gastric, liver, gallbladder, pancreas, prostate, uterine, cervix, ovaries, non-Hodgkin’s lymphoma, multiple myeloma, leukemia.

Biologic mechanisms of obesity and cancer Free fatty acids, TNF, Resistin Increased bioavailability of Insulin-like growth factor-1 Increased WEIGHT ADIPOSITY Insulin resistant Decreased liver synthesis, blood, and tissue of insulin-like growth factor binding protein 1 & 2 Decreased apoptosis & Increased Cell proliferation Tumor development

Obesity, hormones, and cancer Aromatase & 17-B-Hydroxy Steroid Dehydrogenase Diffusion into target organs Decreased apoptosis Increased Proliferation Loss of differentiation Adipose tissue Increased bioavailability of Estradiol & testosterone Reduced levels of Sex Hormone Binding Globulin

Air Pollution Indoor pollution is worse than outdoor pollution. Indoor pollutants: Environmental Tobacco Smoke Radon gas (lung cancer) Inorganic Arsenic (bladder, skin, and lung cancers)

Electromagnetic fields It’s controversial, little evidence is available. Further research is needed. Some association: Leukemia in children & Brain Tumor in adults. EMR -> Thermal effect -> Protein phosphorylation (?)

Occupational Carcinogens Asbestos: mesothelioma, lung cancer Chromium, Nickel, Mustard gas: : lung cancer Heterocyclic Amines: Colon Cancer Dyes, Rubber, Paint, and Aromatic amines: Bladder cancer Aflatoxin B, Vinyl chloride: Liver cancer Cadmium: Prostate cancer Benzol inhalation & leukemia in shoemakers, rubber cement industry, explosives, and dyeing industry.

Therapeutic drugs & Cancer Alkylating agents: melphalan, myleran – AML MOPP – AML Immunosuppressants: azathioprine and cyclosporin – Lymphoma Phenacetin – Renal & Bladder cancer Hormones (estrogen, OCP’s, tamoxifen) – Endometrial carcinoma

Tumor Spread, Invasion & Metastasis Direct Invasion (local) Cellular multiplication, mechanical pressure, release of lytic enzymes, decreased cell to cell adhesion, increased motility of cells, disruption of tumor-host microenvironment Metastases to distant organs through lymphatic and blood system Metastases by way of implantation (tissue spaces, body cavities, cerebrospinal spaces)

Tumor Invasion & Metastasis Anoikis: homelessness – cells detach from their matrix and undergo apoptosis. Lytic enzyems are: Matrix metallo-proteinases such as type IV collagenase, Cysteine proteinases such as cathepsin b and D, and Serine proteases such as urokinase-type plasminogen activator. Incresed expression of Twist expression causes a loss of E-cadherin-mediated cell to cell adhesion. Three step theory of invasion: attachment, degradation, and locomotion of the matrix.

Clinical Manifestations of Cancer (IL-1, TNF, IL-6, IFN) Pain is one of the main complaints. 25% of all cancer patients die with unrelieved pain. Fatigue is a second complaint. Cachexia is from IL-6, IL-8, TNF. Anemia is secondary to TNF, IL-1, decreased EPO, impaired iron utilization, and chemo/radio. Nausea & Vomiting is usually 2ry to chemo. Depression, anxiety, and delirium occurs in 50% of patients.

Paraneoplastic Syndromes Seen in 10% of cancer patients. Endocrine Manifestations: Ectopic ACTH (Cushing’s): SCLC, Bronchial carcinoid SIADH: Lung cancer Hypercalcemia: Lung (Sq.), Renal, Myeloma, ATCLL Hematologic Manifestations: Polycythemia: Renal, Liver DVT/PE: Pancreas, Lung Gastrointestinal Manifestations: Protein-losing enteropathy Anorexia, Cachexia Renal Manifestations: Membranous nephropathy: stomach, lung, colon Cutaneous: Acanthosis nigricans: GI cancer (Leser-Trelat) Dermatomyositis: Breast & Bronchogenic ca. Neurologic: Myasthenia: Bronchogenic ca. Rheumatologic: Hyperthtophic osteoarthropathy: Bronchogenic ca.

Tumor markers (Biologic markers) They are substances produced by cancer cells that are found on tumor plasma membranes or in the blood, spinal fluid, or urine. AFP : Liver, Germ cell tumors B-HCG: Germ cell tumors CEA: Colon, Pancreas, Lung, breast PSA: Prostate CA19-9: Pancreas, Billiary tree CA 125: Ovarian CA 15-3 or CA 27.29: Breast B-2-microglobulin: Myeloma, Lymphoma Catecholamines: Pheochromocytoma

FDG-PET Scanning FDG is a glucose analog that is taken up and trapped by tumor cells in most of patients with cancer. The positrons emitted by the F18 atom travel a short distance before they encounter an electron and undergo extinction with emission of a pair of photons in opposite directions.

Significance of FDG-PET scan Adds assessment to uncharacterized nodules and more accurately stages the tumor than CT. Intensity of uptake before tx is correlated with survival: high uptake = negative prognosis.

More about PET It is a complement to CT in instances where CT has failed to detect distant metastatic disease, and advising biopsies for LN’s > 1.0 cm on CT or positive on FDG-PET. Biopsy is still advised for radio-graphically enlarged LN’s even if FDG-PET scanning is negative.

Cancer treatment Surgery is the goal standard. Colorectal, Breast, Ovary, Lung, Thyroid, Skin, Uterus, Prostate Chemotherapy: Lymphoma, Leukemia, Testicular, Choriocarcinoma, Ovary, Breast Radiation therapy: Breast, Uterus, Cervix, Lymphoma, Lung Hormonal therapy: Breast, Prostate, Endometrial, Adrenal Immunotherapy: Melanoma, RCC, Leukemia Target therapy: Colon, Breast, Lung, RCC, Leukemia, Lymphomas

Progress in Oncology New diagnostic methods Preventive Medicine New Targeted and Personalized Therapy Palliative & Supportive Care

Biology And Pathophysiology Of Cancer

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