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Cancro Gastrico

Università degli Studi di Napoli “Federico II” Corso di Laurea di Medicina e Chirurgia Corso Integrato Malattie del sistema Endocrino-Metabolico, Apparato Digerente, Nutrizione. Cancro Gastrico. Gerardo Nardone nardone@unina.it. Hippocrates 400 BC . Karkinos or Karkinoma.

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Cancro Gastrico

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  1. Università degli Studi di Napoli “Federico II” Corso di Laurea di Medicina e Chirurgia Corso Integrato Malattie del sistema Endocrino-Metabolico, Apparato Digerente, Nutrizione Cancro Gastrico Gerardo Nardone nardone@unina.it

  2. Hippocrates 400 BC Karkinos or Karkinoma Patients with black vomiting or melania

  3. NEOPLASIE GASTRICHE GIST

  4. GASTRIC CARCINOMA CLASSIFICATION Lauren 1965 Diffuse type Intestinal type • Common in elderly men • Preneoplastic lesions • Occurs earlier (<50 yrs) • No histological precursor

  5. 50 40 Stomach 30 Breast Colon 20 Prostate 10 Lung 0 1930 1940 1950 1960 1970 1980 Andamento temporale neoplasie in USA

  6. GASTRIC CANCER Incidence 1930: 50/100.000 1995: 8/100.000 In spite of a progressive decline it continues to be one of the most frequent neoplasia

  7. GASTRIC CANCER • 1.000.000 new cases worldwide per year • 800.000 subjects die worldwide per year • The 5-years survival rate is less than 20% Rappresenta una delle maggiori sfide della comunità scientifica

  8. Host factors ILI- HLA-DQ1 Cancer Diet Alcohol Smoking H. pylori Gastric Cancer Ethiologies Environment Genetic CG è l’esito finale di un processo multifattoriale in cui Ambiente e Genetica svolgono un ruolo determinante

  9. Gastric Cancer Epidemiology +++ Frequente in Europa est, Cina, Giappone, Sud America - - - Africa, India, Sud-est Asiatico

  10. Bonaparte Family Bonaparte family CANCRO GASTRICO EREDO-FAMILIARE < 1% di tutti i tumori gastrici • Mutazione Germinale E.Caderine

  11. Cancer Diet Alcohol Smoking H. pylori Gastric Cancer Ethiologies Environment

  12. Virchow 1821-1902 Inflammation is the origin of cancer Cancer must be viewed as an “adaptative response to an adverse environment” Acute Inflammation self limited proliferation Chronic Inflammation: sustained proliferation that predisposes to neoplastic transformation

  13. Environmental Risk factors Cancer Preneoplastic lesions INFLAMMATION 20-30 y 10-15 y High-risk lesions 40-50 y 60-70 y Age Gastric Cancer Etiology Normal GENETIC 5-10 y

  14. Environmental Factors Migration studies have shown that early life environmental exposures are important in the development of cancer First generation:cancer risk similar to those in their country origin Second generation:cancer risk similar to those in their adopted country

  15. refined carbohydrates, salted, pickled or smoked foods, dried fish, and cooking oil DNA mutations during cellular turnover High risk Fresh fruit and vegetables  DNA alterations during cell replication Low risk Diet and Gastric Cancer

  16. Bioactive Food Components and Gene Expression Salted, pickled or smoked food, dried fish and meat Cooking and Curing Heterocyclic Amines Polycyclic Amines Hydrocarbons N-Nitroso Compounds Binding to Histones DNA Genetic make-up Epigenetic Changes DNA Methylation Gene Expression Cell Replication Cell Growth Cell Differentiation

  17. 3 Food Components that Intercept DNA Reactive Species Green Tea Garlic Cruciferous Phytochemicals Polyphenolic Antioxidant Scavenging effects Other polyphenolic compounds inhibiting cancer are Curcumin, ellagic acid

  18. TOTAL RADICAL-TRAPPING ANTIOXIDANTPOTENTIAL (TRAP) OF FRUIT AND VEGETABLE Spinach Garlic Kale M/100 g Broccoli Oranges Potatoes Cabbage Apple/pear Tomatoes Carrots Onion TRAP is inversely related with the risk of gastric cancer OR 0.65; CI 95%; 0.48-0.89 Serafini, 2003

  19. Relative risk for gastric cancer in a large population-based prospective study 54.498 subjects followed per 10-years 95% C.I. O.R. Fruit 0.70 0.49-1.00 Yellow vegetable 0.64 0.45-0.92 White vegetable 0.48 0.25-0.89 1 or more d/w compared with less than 1/w Kobayashi M. 2002

  20. The most important environmental factors is the H. pylori infection 1983 Discovery 1983 Cause of gastritis and peptic ulcer 1994 Class I Carcinogen

  21. Risk Duodenal ulcer Gastritis Atrophy Months Days Years 15% Gastric ulcer Weeks Neoplasia Decades 1% Natural history of H. pylori infection Modified by Sipponen et al.1993

  22. H. pylori and gastric cancer relationship Epidemiological analyses In vivo studies “animal model” Interventional human studies

  23. A combined analysis of 12 case control studies nested within prospective cohorts 6 from Europe 4 from Asia 2 from USA 1228 cancer 3406 controls H. pylori and Cancer Collaborative Group, 2001

  24. Association between H. pylori and gastric cancer histotype H. pylori and Cancer Collaborative Group, 2001

  25. Animal Models The animal model best reproducing H. pylori-related human disease is the Mongolian Gerbil • At 62 week after infection 37 % develop gastric cancer Watanabe 1998, Honda 1998 • Eradication was effective in reducing gastric cancer incidence Shimizu, 2000

  26. Non randomized trial of 132 patients with endoscopic resection of early gastric cancer 132 H. pylori-positive 65 Eradicated 67 Not eradicated 0 GC recurrence 6 (9%) GC recurrence 3 anni Uemura N, 1997

  27. KAPLAN-MEIER ANALYSIS OF THE PROPORTION OF 1246 H. PYLORI-POSITIVE AND 280 H. PYLORI-NEGATIVE PATIENTS WHO REMAINED FREE OF GASTRIC CANCER 1 H. pylori-negative 0.98 0.96 1246 H. pylori positive Proportion free of gastric cancer 280 H. pylori negative 0.94 H. pylori-positive Gastric Cancer 36 0.92 0.9 0 2 4 6 8 10 12 Years of follow-up Uemura N, 2001

  28. Kaplan-Meier analysis of gastric cancer development with respect to treatment in participants with no atrophy, intestinal metaplasia, or dysplasia Wong, 2004

  29. Inflammatory process H. Pylori H. Pylori Gastrite Gastrite Atrofia Metaplasia Dysplasia Diffuse Adenocarcinoma Intestinal Adenocarcinoma

  30. DNA p53 -catenin MIN E-caderin H. pylori- related carcinogenesis process Gastrite Gastrite ROS NO Cytokines Atrofia Metaplasia Apoptosis Proliferation Dysplasia Diffuse Adenocarcinoma Intestinal Adenocarcinoma DNA-mutation

  31. From a molecular view point There is growing understanding that gastric carcinogenesis must be viewed as an accumulation of molecular alterations in the genome of gastric epithelial cells C-erb B-2 APC Dcc c-met bcl-2 p53 K-ras trp-met DNA repair Intestinal metaplasia Normal mucosa Non atrophic gastritis Atrophic gastritis Dysplasia Dysplasia Cancer Cancer Modified from AR Goldstone 1996

  32. 1863 Waldeyer Cancer arising from “resident epithelial cells “Epithelial theory of cancer “ 2007: Is yet this theory valid?

  33. PROGENITOR STEM CELL STEM CELL THEORY OF CANCER ORIGIN

  34. The New Model for Epithelial Cancer Houghton, 2005

  35. The New Theory of Gastric Cancer Houghton J Science 2004 The target cells for malignant transformation are the Tissue-Specific Stem Cells • Self-renewal growth programs constitutively active • Susceptible to acquire genetic defect • Long-lived cells • Inherently mutagenic

  36. SEDE 40 % corpo 35 % antro 20 % cardias 5 % diffuso Aspetto macroscopico (Borrman 1920) Tipo I simil polipoide , vegetante corpo Tipo II ulcerata a margini netti Tipo III infiltrante/ulcerante cardiale Tipo IV piatto, diffusa ed infiltrante

  37. SEGNI & SINTOMI Anoressia dimagramento 95% Anemia: (ematemesi o melena 2-3%) Vomito: tipo alimentare, 2-3 ore dopo il pasto Disfagia: sede cardiale, ingravescente, solidi/liquidi Dolore: infiltrazione fibre nervose, segno tardivo, non risponde alla terapia PPI Masse addominali: segno tardivo Epatomegalia: metastasi Segno di Troisseau: linfonodo sopraclaveare Sx Ascite: metastasi peritoneali  ovaio Krukenberg

  38. DIAGNOSI LABORATORIO Markers Tumorali (CEA, Ca19.9) Bassa accuratezza diagnostica RADIOLOGIASufficiente per formulare un’ipotesi diagnostica specie nelle forme avanzate ma non dirimente Difetti di riempimento (vegetanti, occupazione lume) Nicchie irregolari, con pliche corte e tozze Rigidità del viscere (sovrapposizione dei profili) Stenosi corpo-antro irregolari

  39. DIAGNOSI ENDOSCOPIA + BIOPSIE (GOLD STANDARD) 3 biopsie accuratezza diagnostica 60% 6 biopsie accuratezza diagnostica 80% 8-10 biopsie accuratezza diagnostica 90-100% TAC (Stadiazione) Rapporti con gli organi viciniori e con i vasi Interessamento linfonodale/metastasi

  40. TERAPIA CHIRURGICA:gastrectomia totale Potenzialmente curativa di fatto palliativa nei 2/3 dei casi MEDICA:chemioterapia (5FU; Mitomicina C; Doxorubicina) Pazienti inoperabili; Post terapia chirurgica Limite: intrinsecamente resistente RADIOTERAPIA: ?? Limite: intrinsecamente resistente T. ENDOSCOPICA:mucosectomia Indicazione (early gastric cancer)

  41. Primary prevention • Increase fresh vegetables and fruit intake • No sigarette smoking • Low amount of alcohol • Search and treat H. pylori in offspring of GC patients • Search and treat H. pylori in high-risk area of GC • Testing for E- cadherin mutation in relatives of FGC

  42. RELATIVE RISK OF DEVELOPING GASTRIC CANCER: GENETIC AND MICROBIOLOGICAL ASPECT Ebert, 2003

  43. Secondary Prevention Identification of high-risk patients

  44. Intestinal type Carcinogenesis “ Correa’s model” 1993 Normal Superficial gastritis Atrophic gastritis Small intestine metaplasia Colonic metaplasia Dysplasia Cancer decades

  45. Relative cancer-risk in patients with gastritis Corpus mucosa Antral mucosa N =Normal; S = Superficial gastritis; A= Atrophy A1 = Mild A2 = Moderate; A3 = Severe Sipponen; 1985

  46. pH pH Nitrite Scavenger Food Nitrates Bacterial Reductase pH Nitrites Nitroso amine Nitroso amide Amine Cellular DNA Damage

  47. Diet H. pylori Integrated model of H. pylori gastritis and diet Gastritis Nitrate Atrophy  HCl  pH Nitriti Normal HCl < 10 mmol/l Achloridria 150 mmol/l Amine Amides Nitrosamine Nitrosamides DNA damage Lancet 2004

  48. West East Over-nutrition H. pylori +/- Under-Nutrition H. pylori ++ Gastric Cancer Incidence

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