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Colorectal Cancer (CRC)

Colorectal Cancer (CRC). Epidemiology, Risk Factors Symptoms, Stages, Therapy 3) Molecular Biology & Pathology Screening. EPIDEMIOLOGY. one of the most common cancers in the world US: 4 th most common cancer (after lung, prostate, and breast cancers)

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Colorectal Cancer (CRC)

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  1. Colorectal Cancer (CRC) Epidemiology, Risk Factors Symptoms, Stages, Therapy 3) Molecular Biology & Pathology Screening

  2. EPIDEMIOLOGY one of the most common cancers in the world US: 4th most common cancer (after lung, prostate, and breast cancers) 2nd most common cause of cancer death (after lung cancer) 2001: 130,000 new cases of CRC 56,500 deaths caused by CRC

  3. Typical sites of incidence and sympoms of colon cancer

  4. Risk factors for CRC Age Adenomas, Polyps Sedentary lifestyle, Diet, Obesity Family History of CRC Inflammatory Bowel Disease (IBD) Hereditary Syndromes (familial adenomatous polyposis (FAP))

  5. Development of CRC result of interplay between environmental and genetic factors Central environmental factors: diet and lifestyle 35% of all cancers are attributable to diet 50%-75% of CRC in the US may be preventable through dietary modifications

  6. Dietary factors implicated in colorectal carcinogenesis consumption of red meat animal and saturated fat refined carbohydrates alcohol increased risk

  7. Dietary factors implicated in colorectal carcinogenesis dietary fiber vegetables fruits antioxidant vitamins calcium folate (B Vitamin) decreased risk

  8. Symptoms associated with CRC rectal bleeding change in bowel habits obstruction abdominal pain & mass iron-deficiency anemia weight loss loss of appetite night sweats fever

  9. Staging of CRC TNM system Primary tumor (T) Regional lymph nodes (N) Distant metastasis (M)

  10. Staging of CRC Dukes staging system A Mucosa 80% B Into or through M. propria 50% C1 Into M. propria, + LN ! 40% C2 Through M. propria, + LN! 12% D distant metastatic spread <5%

  11. Sites of metastasis Via blood Via lymphatics Per continuitatem Liver Lung Brain Bones Lymph nodes Abdominal wall Nerves Vessels

  12. Therapy Surgical resection the only curative treatment Likelihood of cure is greater when disease is detected at early stage Early detection and screening is of pivotal importance

  13. Screening What is screening? a public health service in which members of a defined population are examined to identify those individuals who would benefit from treatment to benefit: to reduce the risk of a disease or its complications

  14. Types of Screening fecal occult blood test (FOBT) chemical test for blood in a stool sample. annual screening by FOBT reduces colorectal cancer deaths by 33% Flexible sigmoidoscopy can detect about 65%–75% of polyps and 40%–65% of colorectal cancers. rectum and sigmoid colon are visually inspected

  15. Current Screening Guidelines regular screening for all adults aged 50 years or older is recommended FOBT every year flexible sigmoidoscopy every 5 years total colon examination by colonoscopy every 10 years or by barium enema every 5–10 years

  16. Changes resulting in colon cancer

  17. Molecular Biology & Pathology CRCs arise from a series of histopathological and molecular changes that transform normal epithelial cells Intermediate step is the adenomatous polyp Adenoma-Carcinoma-Sequence (Vogelstein & Kinzler) Polyps occur universally in FAP, but FAP accounts for only 1% of CRCs Adenomatous Polyps in general population: 33% at age 50 70% at age 70

  18. Mutations in the APC pathway cause increased proliferation

  19. MMR defects give rise to TGF-beta RII mutations, which prevent cell cycle inhibitor (p15) and protease inhibitor (PAI-1) expression

  20. -1 COX -2 Cyclooxygenase (COX) cell membrane lipids Phospholipase A2 arachidonic acid (aa) aspirin ibuprofen indomethacin prostaglandins

  21. COX and CRC COX-2 not detectable in normal colon but in 90% of CRCs and 40% of adenomas Animal models: COX-inhibition results in 50% reduction of carcinomas and >90% reduction of adenomas Epidemiological studies: patients regularly taking aspirin showed 40-50% reduced risk of CRC But: minimal effective dose and duration of treatment have not yet been determined

  22. Microenvironment Control mechanisms of mitosis & apotosis lost High metabolic rates, glycolysis (Warburg), high lactic acid output Result: hostile microenvironmental conditions (Hypoxia, low pH, low glucose, free oxygen radicals)

  23. Hypoxia Central factor for tumor growth and spread Correlated to tumor hypoxia: Therapy outcome & probablility of metastasis Hypoxia exerts selective pressure genetic instability results in survival of cells better adapted to lack of oxygen Evolution of highly aggressive tumor cells

  24. CRC and the Internet “Sign up to receive an e-mail message reminding you to have your colon screened at www.wewantthebestforyou.com”

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