Direttore Dipartimento di Gastroenterologia Olio d'oliva e salute Prof. Attilio Giacosa Direttore Dipartimento di Gastroenterologia Policlinico di Monza attilio.giacosa@policlinicodimonza.it

COLTIVAZIONE DELL’OLIVO Origini: 5000 a.C. (Medio Oriente) 4500 a.c. Codice di Hammurabi In Italia: 500 a.c. 800 milioni di piante nel mondo 700 milioni di piante nel Mediterraneo

Mediterranean Diet Dietary patterns found in olive growing regions of the Mediterranean Countries

Ancel Keys

Mediterranean Diet

Basso rischio cardiovascolare Basso rischio di cancro “Vantaggio” Mediterraneo RUOLO DELL’OLIO D’OLIVA

IMPORTANZA BIOLOGICA DELL’OLIO D’OLIVA MUFA - Fluidità di membrana cellulare ANTIOSSIDANTI - Anti radicali liberi - Anti perossidazione MALATTIE CARDIOSVACOLARI -  LDL - colesterolo -  Ipertrigliceridemia

IMPORTANZA BIOLOGICA DELL’OLIO D’OLIVA APPARATO DIGERENTE -  attività della colecisti -  secrezione pancreatica CANCRO - > apoptosi -  oncogene ras, - < addotti al DNA

WITH MEDITERRANEAN DIET: < 10% PROSTATE, PANCREAS, ENDOMETRIUM < 25% COLON < 15% BREAST (Trichopoulou et al., 2000)

CANCER RISK FACTORS GENETICS DIET SMOKING PHYSICAL ACTIVITY

FATS The issue of fats, and of specific types of fats, on the risk of colorectal and breast cancers, as well as of several other neoplasms, remains a major open question.

RRs and 95% CI of selected cancers according to RED MEAT consumption RRs and 95% CI of selected cancers according to RED MEAT consumption. Italy, 1983-1997

CARNE & CANCRO DEL COLON Meta-analisi, IARC, Lione 2002 Carni lavorate 1.8 Carni rosse 1.6 Carni bianche Tutte le carni 1.4       1.2  Pesce   1      0.8  0.6   Cohort studies Case-control studies  All studies

GENETICA E DIETA Nei Giapponesi emigrati negli Stati Uniti: Marcato aumento del cancro del colon in soggetti con genotipo rapid NAT2: Ma solo in chi consumava carni rosse molto cotte J Natl Cancer Inst Monogr 1999;(26):101-5 COMBINED INFLUENCE OF GENETIC AND DIETARY FACTORS ON COLORECTAL CANCER INCIDENCE IN JAPANESE AMERICANS. Marchand LL. (Honolulu, USA)

P53: tumor suppressor gene Cancer Epidemiol Biomarkers Prev 2002 Jun;11(6):541-8 DIET ACTIVITY, AND LIFESTYLE ASSOCIATIONS WITH P53 MUTATIONS IN COLON TUMORS. Slattery ML, Curtin K et al. (Salt Lake City, USA) P53: tumor suppressor gene Casi con mutazione del gene P53 più frequentemente: consumano una dieta “occidentale” presentano indice glicemico alto seguono una dieta ricca in carni rosse e fast food

Il Pesce

GRASSI N-6 E N-3 IN RAPPORTO TRA ACIDI VARIE POPOLAZIONI n-6:n-3 Periodo paleolitico 0,79 Grecia prima del 1960 1,00 / 2,00 Stati Uniti 2000 16,74 Regno Unito e Nord Europa 15 Giappone 4 Italia 13

RRs and 95% CI of selected cancers according to FISH consumption RRs and 95% CI of selected cancers according to FISH consumption. Italy, 1983-1997.

N-3 Polyunsaturated fatty acids QUINTILE OF INTAKE CANCER SITE CASES/CONTROLS (N) 3RD 5TH (HIGHEST) Oral cavity/pharynx 736/1772 0.7 (0.5-0.9) 0.5 (0.3-0.7) Oesophagus 395/1066 0.7 (0.5-1.1) Large bowel 2280/4765 1.0 (0.9-1.2) 0.7 (0.6-0.9) Colon 1394/4765 0.9 (0.8-1.1) 0.7 (0.5-0.8) Rectum 886/4765 1.1 (0.9-1.4) 0.8 (0.6-1.0) Breast 2900/3122 1.0 (0.8-1.1) 0.8 (0.7-1.0) Ovary 1031/2411 0.6 (0.4-0.7)

OMEGA-3 & CANCRO (olio di pesce) DHA Riduce l’espressione di COX-2 Induce apoptosi (Da Caterina,01)

Olive oil & Colorectal cancer Tertile of intake 2 3 (high) Colorectal 0.78 (0.62-0.99) 0.77 (0.59-0.99) Colon 0.79 (0.59-1.04) 0.82 (0.60-1.12) Rectum 0.79 (0.57-1.11) 0.69 (0.46-1.02)

FATS In a large study from Italy, isocaloric substitution of 5% of total calories as saturated fats by unsaturated ones was associated with reductions in breast (OR= 0.67) and colorectal (OR= 0.78) cancer risk

FATS DIETARY CHANGE BREAST (OR 95% CI) COLON RECTUM Replacement of saturated fat by complex carbohydrate (10% of cal.) 0.95 (0.73-1.25) 0.96 (0.74-1.24) Replacement of saturated fat by polyunsaturated fat (5% of cal.) 0.67 (0.54-0.83) 0.78 (0.65-0.95) Replacement of complex carbohydrate by polyunsaturated fat 0.69 (0.58-0.81) 0.80 (0.69-0.93)

FATS DIETARY CHANGE BREAST (OR 95% CI) COLON RECTUM Replacement of saturated fat by monounsaturated fat (5% of cal.) 0.91 (0.73-1.12) 0.89 (0.73-1.09) Replacement of complex carbohydrate by monounsaturated fat 0.93 (0.83-1.04) (0.82-1.00)

Olive oil Oral and pharyngeal cancer UPPER LIMIT - (g per day) INTAKE QUINTILE 1 3 5 Olive oil 3.2 29.5 - OR (95% CI) 0.7 (0.5-1.1) 0.4 (0.3-0.7) Vegetable-adjusted OR (95% CI) 0.8 (0.5-1.2) 0.6 (0.4-0.9) Mixed seed oils 0.3 2.3 1.0 (0.7-1.4) 1.1 (0.7-1.7) 0.9 (0.6-1.4) Butter 0.4 1.9 1.3 (0.8-1.9) 2.3 (1.6-3.5) 1.3 (0.9-2.0) 2.4 (1.6-3.5)

FATS Substituting olive oil for other seasoning fats has favourable effects on the risk of oral, laringeal and pharyngeal (OR= 0.7), and oesophageal (OR= 0.4) cancers

Mediterranean diet score and cancers of the upper digestive tract An a priori defined score, summarising eight of the major characteristics of the Mediterranean diet, was applied to data of case-control studies of oral (n=599), oesophageal (n=304) and laryngeal (n=460) cancers

Diet and cancers of the upper digestive tract CANCER, OR (95% CI) ORAL/PHARYNGEAL OESOPHAGEAL LARYNGEAL Monounsaturated/ saturated fat ratio 0.72 (0.56-0.93) 0.73 (0.51-1.01) 0.97 (0.73-1.28) Alcohol 4.26 (3.11-5.83) 6.04 (3.79-9.62) 2.77 (2.01-3.83) Legumes 1.09 (0.87-1.38) 1.03 (0.74-1.42) 0.75 (0.58-0.98) Cereals 0.77 (0.59-1.00) 0.96 (0.67-1.38) 0.92 (0.68-1.24) Fruit 1.06 (0.83-1.35) 0.95 (0.68-1.31) 0.82 (0.62-1.07) Vegetables 0.79 (0.62-1.01) 0.72 (0.51-1.01) 0.51 (0.39-0.67) Meat and meat products 1.42 (1.11-1.81) 1.50 (1.06-2.13) 1.53 (1.15-2.04) Milk and dairy products 1.09 (0.86-1.40) 1.24 (0.87-1.75) 1.07 (0.81-1.42)

Mediterranean diet score Mediterranean diet score and cancers of the upper digestive tract (Bosetti, ‘03) Cancer Mediterranean diet score <3 4 6 Oral/pharyngeal Cases/controls 214/241 120/376 41/201 OR (95% CI) 1 0.41 (0.30-0.57) 0.40 (0.26-0.62) Oesophageal 102/147 66/174 14/83 0.63 (0.41-0.95) 0.26 (0.13-0.51) Laryngeal 183/225 98/279 19/124 0.47 (0.33-0.66) 0.23 (0.13-0.40)

Pizza and cancer risk Pizza is one of the best known and most widespread Italian foods, and it is the most common generic commercial sign worldwide. Investigating the role of pizza on cancer risk may have interesting implications in respect to dietary advice not only in Italy

Pizza and cancer risk CANCER OR (95% CI) OCCASIONAL REGULAR ALL EATERS Oral cavity and pharynx 0.76 (0.60-0.95) 0.66 (0.47-0.93) 0.73 (0.59-0.91) Oesophagus 0.57 (0.42-0.78) 0.41 (0.25-0.69) 0.53 (0.39-0.72) Larynx 0.86 (0.66-1.11) 0.82 (0.56-1.19) 0.85 (0.66-1.08) Colon 0.84 (0.72-0.97) 0.74 (0.61-0.89) 0.81 (0.70-0.93) Rectum 0.85 (0.71-1.02) 0.93 (0.75-1.17) 0.88 (0.74-1.04)

Pizza

Cancer Causes Control 2000 Aug;11(7):609-15 Cancer Causes Control 2000 Aug;11(7):609-15 MEN WHO CONSUME VEGETABLE OILS RICH IN MONOUNSATURATED FAT: THEIR DIETARY PATTERNS AND RISK OF PROSTATE CANCER (NEW ZEALAND). Norrish AE, Jackson RT et al. (Auckland, New Zealand) 317 prostate cancer cases vs 480 controls. Increasing levels of MUFA-rich vegetable oil intake were associated with a progressive reduction in prostate cancer risk - multivariate relative risk = 0.5 (> 5.5 ml per day vs. nonconsumption - P trend = 0.005) Prostate cancer risk was not associated with intake of total MUFA or the major animal food sources of MUFA CONCLUSION: 1) protective effect of an associated dietary pattern high in antioxidants and fish oils. 2) Independent protective effect of MUFA-rich vegetable oils unrelated to the MUFA component

PHENOLIC AND LIPID COMPONENTS OF OLIVE OILS-2: THE CONCENTRATION AND ANTIOXIDANT ACTIVITY OF TOTAL PHENOLS, SIMPLE PHENOLS, SECOIRIDOIDS, LIGNANS AND SQUALENE.   Robert W. Owen,1 Attilio Giacosa,2 Walter Mier, Bertold Spiegelhalder1 and Helmut Bartsch1 1German Cancer Research Center, Heidelberg, Germany  2National Institute of Cancer Research, Genoa, Italy

TOTAL AND INDIVIDUAL PHENOLIC COMPOUNDS IN OLIVE OIL PHENOLIC COMPOUND mg/kg OLIVE OIL ALL VOQ RVO P value Total 196  19 232  15 62  12 < 0.00001 Hydroxytyrosol 11.66  2.60 14.42  3.01 1.74  0.84 < 0.05 Tyrosol 22.13  3.82 27.45  4.05 2.98  1.33 < 0.01 Total simple phenols (TSP) 33.79  4.48 41.87  6.17 4.72  2.15 SID-1 7.97  2.57 9.62  3.18 2.00  0.87 ns SID-2 15.75  3.54 18.09  4.31 7.30  3.01 Total secoiridoids (SID) 23.71  5.61 27.72  6.84 9.30  3.81 Lignans 34.09  4.42 41.53  3.93 7.29  2.56 < 0.001 TSP + SID + LIGNANS 91.59  10.57 111.12  9.99 21.31  8.03

POLYPHENOLS

LIGNANS

Eur J Cancer Prev 2002 Aug;11(4):351-8 Eur J Cancer Prev 2002 Aug;11(4):351-8 Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis. Fabiani R, De Bartolomeo A, Rosignoli P, Servili M, Montedoro GF, Morozzi G. (Perugia, Italy) Hydroxytyrosol inhibited proliferation of both human promyelocytic leukaemia cells HL60 and colon adenocarcinoma cells HT29 At concentrations ranging from 50 to 100 micromol/l, hydroxytyrosol induced an appreciable apoptosis Hydroxytyrosol (50-100 micromol/l) arrested the cells in the G0/G1 phase with a concomitant decrease in the cell percentage in the S and G2/M phases.

Scavenging of ROS generated in the faecal matrix by tyrosol isolated from olive oil. Dihydroxy benzoic acids (%) 100 Tyrosol (µ M) 20 0.01 0.1 1 10 100 1000 10000

J Agric Food Chem 2002 Oct 9;50(21):5962-7 J Agric Food Chem 2002 Oct 9;50(21):5962-7 Influence of thermal treatments simulating cooking processes on the polyphenol content in virgin olive oil. Brenes M, Garcia A, Dobarganes MC et al. (Sevilla, Spain) Thermal oxidation: rapid degradation of alpha-tochopherol 180°: < tyrosol and tydroxytyrosol for 25 h.: lignans unchanged Microwave: for 10 min.: minor losses Pressure cooker: for 30 min: losses of polyphenols at ph <6 alpha-tocopherol: not modified Lignans: the least affected polyphenols

SQUALENE SQUALENE MG/100G

Squalene: potential chemopreventive agent. Smith TJ Squalene: potential chemopreventive agent. Smith TJ. (University of South Carolina, USA), 2000 The average intake: 30 mg/day in the United States 200-400 mg/day in Mediterranean countries (olive oil). Experimental studies have shown that squalene can effectively inhibit chemically-induced colon, lung and skin tumourigenesis in rodents. The mechanisms involved: inhibition of Ras farnesylation, modulation of carcinogen activation anti-oxidative activities.

Int J Cancer 2000 Aug 1;87(3):444-51 Diet, metabolic polymorphisms and dna adducts: the EPIC-Italy cross-sectional study. Palli D, Vineis P, Russo A, et al. (Florence, Italy) DNA adducts in peripheral leukocytes: reliable indicator of internal dose exposure to genotoxic agents and cancer risk. EPIC-Italy (section of European prospective study): 47,749 men and women, aged 35-64 years, in 5 centres. Among 309 volunteers, 72.8% had detectable levels of DNA adducts. Strong negative associations emerged with the reported frequency of consumption of fresh fruit and vegetables, olive oil, and the intake of antioxidants. DNA adducts were higher in subjects with GSTT1 null genotype (p = 0.05).

Cancer Preventive role of olive oil Study project CASES CONTROLS Italy 12000 10000 Greece 1500 1500 Spain ? ? Global analysis of a wide collection of dietary data in Mediterranean Countries

Dieta Mediterranea e prevenzione dei tumori e delle malattie cardiovascolari

Frutta e verdura

MICRONUTRIENTI & SOSTANZE BIOATTIVE VIT. C, E, ACIDO FOLICO, SE FRUTTA & VERDURA LUTEINA VEGETALI GIALLI E VERDI LICOPENE POMODORO FLAVONOIDI FRUTTA & VERDURA, THE, VINO CUMARINE AGRUMI DITIOLTIONI CRUCIFERE ISOTIOCIANATI INDOLO-3- CARBINOLO DIALLIL SOLFIDE AGLIO ALLIL METIL TRISOLFIDE

* Responsabili dei colori di molti vegetali FLAVONOIDI * Responsabili dei colori di molti vegetali * Presenti in semi, agrumi, the, vino rosso * Azione antiossidante e antiproliferativa

(arance, carote, pomodori) Spinaci, broccoli, sedano CAROTENOIDI E CANCRO Luteina < incidenza Ca mammella (premenopausa) > apoptosi Zeaxantina < Ca mammella (in storia familiare positiva!) Vegetali gialli (arance, carote, pomodori) Spinaci, broccoli, sedano

ANTIOSSIDANTI E FRUTTA (Unità ORAC) Arancia 1 983 unità Succo di arancia 1 bicchiere 1142 unità Fragole una tazza 1170 unità Prugne nere 3 1454 unità Mirtilli 1 tazza 3480 unità Melone 3 fette 197 unità Pesca 1 222 unità Mela 1 301 unità Spinaci cotti 1 tazza 2042 unità Succo di uva nera un bicchiere 5216 unità More 1 tazza 1466 unità

ANTIOSSIDANTI E FRUTTA (Unità ORAC) Arancia 1 983 unità Succo di arancia 1 bicchiere 1142 unità Fragole una tazza 1170 unità Prugne nere 3 1454 unità Mirtilli 1 tazza 3480 unità Melone 3 fette 197 unità Pesca 1 222 unità Mela 1 301 unità Spinaci cotti 1 tazza 2042 unità Succo di uva nera un bicchiere 5216 unità More 1 tazza 1466 unità

IL TUMORE DELLO STOMACO

QUANTA FRUTTA E VERDURA ? 500 – 600 g al giorno Almeno 5 porzioni al giorno Ogni porzione in più: < 10% rischio di CRC La più ampia varietà possibile Stagionalità, locoregionalità

CALORIE ,PESO e SALUTE (?!?)

CALORIE & CANCRO DEL COLON Studio Italiano COLON-RETTO Quintili di Calorie ORs (95% CI) 1 1 2 1.10 (0.92-1.31) 3 1.18 (0.99-1.42) 4 1.16 (0.97-1.39) 5 1.50 (1.25-1.80) Continuous (100 kcal/day) 1.02 (1.01-1.03) (Franceschi ,Giacosa et al, 97)

ATTIVITA’ FISICA E CANCRO DEL COLON 2 1  Rischio relativo    0.6 0 1 2 3 4 5 Livello di attività fisica Slattery et al, 97

CARBOIDRATI & CANCRO DEL COLON Studio Italiano COLON-RETTO Alimenti ORs in highest (95% CI) vs lowest quintile Pane e farinacei 1.69 (1.36-2.10) Dolci 1.13 (0.93-1.37) Zucchero 1.43 (1.19-1.73) Patate 1.20 (0.96-1.51) (Franceschi ,Giacosa et al, 97)

CHO & CANCRO DELLA MAMMELLA Quintile di consumo 1 (basso) 2 3 4 5 (alto) Carboidrati disponibili OR 1 1.05 1.13 1.16 1.29 Amidi OR 1 1.05 1.28 1.24 1.39 Lancet, 96

IPOTESI INSULINICA Le farine raffinate e gli zuccheri possono indurre: - sovraccarico glicemico - resistenza insulinica Ciò può indurre promozione della crescita cellulare Attraverso ormoni specifici e fattori di crescita

E RISCHIO DI MORTALITA’ RELAZIONE TRA BMI E RISCHIO DI MORTALITA’ RISCHIO DI MORTALITA’ 2.5 2 1.5 1 ------------------------------------------------------------------------- 20 25 30 35 40 BODY MASS INDEX (kg/m2)

ARTROSI ERNIA IATALE COMPLICANZE DELL’OBESITA’ METABOLICHE CARDIOVASCOLARI DIABETE DISLIPIDEMIA GOTTA IPERTENSIONE EVENTI CEREBROVASC. CORONOPATIA SCOMPENSO CARDIACO INSUFFICIENZA VENOSA COMPLICANZE DELL’OBESITA’ ALTRE COLELITIASI • CALCOLOSI RENALE • APNEE NOTTURNE ARTROSI ERNIA IATALE

L’ERNIA IATALE IL REFLUSSO IL DOLORE IL BRUCIORE MAL DI CUORE ? ASMA? TOSSE?

Ernia iatale Esofagite Esofago di Barrett

L’ERNIA IATALE la cura

Calcolosi della colecisti

Calcolosi della colecisti

La dieta preventiva

DIETA E PREVENZIONE DEI TUMORI Mantieni attivo il fisico durante tutta la vita, effettuando almeno mezz’ora al giorno di attività fisica intensa, ma adeguando il tipo di esercizio al variare dell’età. Evita il soprappeso e l’obesità e tieni costantemente sott’occhio il peso corporeo, stando attento a ciò che mangi ed evitando la sedentarietà.

Assumi spesso alimenti ricchi in fibre e prodotti integrali. Cerca di limitare il consumo di zucchero, dolci e prodotti con farina bianca. Cerca di assumere almeno cinque porzioni al giorno tra frutta e verdura.

il pesce e i legumi sono splendide alternative alla carne. Modera l’apporto di grassi di origine animale (ad esempio latticini e carni grasse) scegliendo spesso latte e formaggi magri e togliendo il grasso visibile dalla carne e la pelle dal pollo. Per la cottura e per i condimenti, scegli preferibilmente olio extra-vergine d’oliva. Ricordati che il pesce e i legumi sono splendide alternative alla carne. Inoltre, l’olio presente nel pesce è utile per prevenire vari tumori (soprattutto il tumore della mammella) e le malattie cardiovascolari.

Bevi acqua in abbondanza e, se assumi alcolici, bevi al massimo due bicchieri al giorno di vino o birra se sei di sesso maschile, uno se sei di sesso femminile. La scelta e lo stoccaggio degli alimenti sono molto importanti. Controlla sempre l’etichetta e, per i vegetali, cerca di preferire prodotti locali, stagionali e freschi o surgelati.

IN OGNI CASO, NON FUMARE E GUSTA IL CIBO!! Per cucinare in modo salutare, fai uso di piccole quantità di grasso e olio, utilizza basse temperature e riduci il più possibile i tempi di cottura. IN OGNI CASO, NON FUMARE E GUSTA IL CIBO!!

Grazie a tutti per l'attenzione! attilio.giacosa@policlinicodimonza.it

Mediterranean diet score and cancers of the upper digestive tract This study provides evidence that an a priori defined nutritional pattern, which includes several aspects of the Mediterranean diet, favourably affects the risk of cancers of the upper aerodigestive tract