Gastrointest Tumors 2015;2:188–194 DOI: 10.1159/000441822 Published online: November 18, 2015

© 2015 S. Karger AG, Basel 2296–3774/15/0024–0188$39.50/0 www.karger.com/gat

Mini-Review

Nutrition and Hepatocellular Cancer Kerstin Schütte

Christian Schulz

Peter Malfertheiner

Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany 

Key Words Diet · Hepatocellular carcinoma · Malnutrition · Nutrition · Prognosis · Risk Abstract Background: Hepatocellular carcinoma (HCC) significantly contributes to the global burden of cancer. Liver cancer is the third most frequent cause of cancer-related death with HCC representing more than 90% of primary liver cancers. The majority of patients are not only affected by the malignant disease but do also suffer from chronic liver disease. Therefore, several factors impact on the prognosis of patients with HCC, including tumor-related factors, liver function and patient-related factors such as performance status and other comorbidities. The nutritional status is of high significance for the patients’ performance status, the tolerance of tumor-targeting therapy and the prognosis of cancer of any type and is specially referenced in HCC. This overview is on current concepts on the role of nutritional factors in hepatocarcinogenesis and the role of nutrition in patients affected by HCC. Summary: Nutritional status and composition of diet are relevant factors related to the risk of HCC. They also have an important role concerning the prognosis of patients with HCC. Besides risk factors, several macro- and micronutrient components have been found to be inversely correlated with the risk of HCC. To prevent disease progression to liver cirrhosis or HCC in patients with nonalcoholic steatohepatitis, it is crucial to optimize the metabolic state. Key Message and Practical Implication: Evidence from well-designed prospective interventional trials with the aim to reduce the HCC incidence or to prolong survival in patients with HCC based on nutritional © 2015 S. Karger AG, Basel modification is still to be generated.

Introduction

  ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒȋȌ•‹‰‹ˆ‹…ƒ–Ž›ƒ††•–‘–Š‡‰Ž‘„ƒŽ„—”†‡‘ˆ…ƒ…‡”ǤŠ‡ ‘•–•‹‰‹ˆ‹…ƒ–”‹•ˆƒ…–‘”ˆ‘”‹•Ž‹˜‡”…‹””Š‘•‹•ǡ™Š‹…Š‹•’”‡•‡–‹͹ͲȂͻͲΨ‘ˆ’ƒ–‹‡–• ȏͳȐǤ‘™‡˜‡”ǡƒŽŽ”‹•ˆƒ…–‘”•–Šƒ–…ƒŽ‡ƒ†–‘‹–Š‡’”‡•‡…‡‘ˆŽ‹˜‡”…‹””Š‘•‹•ƒ”‡ƒŽ•‘ Peter Malfertheiner Department of Gastroenterology, Hepatology and Infectious Diseases Otto-von-Guericke University Leipziger Strasse 44, DE–39120 Magdeburg (Germany) E-Mail peter.malfertheiner @ med.ovgu.de

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Gastrointest Tumors 2015;2:188–194 DOI: 10.1159/000441822

© 2015 S. Karger AG, Basel www.karger.com/gat

Schütte et al.: Nutrition and Hepatocellular Cancer

”‹•ˆƒ…–‘”•ˆ‘”–Š‡†‡˜‡Ž‘’‡–‘ˆ‹–Š‡ƒ„•‡…‡‘ˆ…‹””Š‘•‹•ȏʹȐǤ‘”Ž†™‹†‡ǡ…Š”‘‹… ˜‹”ƒŽŠ‡’ƒ–‹–‹•ȋȌƒ†ȋȌƒ”‡–Š‡‘•–”‡Ž‡˜ƒ–ˆƒ…–‘”•ƒ••‘…‹ƒ–‡†™‹–ŠŠ‡’ƒ–‘…ƒ”Ǧ …‹‘‰‡‡•‹•Ǥ ‹†—•–”‹ƒŽ‹œ‡†…‘—–”‹‡•ǡˆƒ––›Ž‹˜‡”†‹•‡ƒ•‡ǡƒ’ƒ”–ˆ”‘˜‹”ƒŽŠ‡’ƒ–‹–‹•ǡ‹•…Ž‘•‡Ž› ”‡Žƒ–‡† –‘ —–”‹–‹‘ƒŽ ˆƒ…–‘”•ǡ ƒ† –Š‡ ’”‡˜ƒŽ‡…‡ ‘ˆ ˆƒ––› Ž‹˜‡” †‹•‡ƒ•‡ ‹• ‘ –Š‡ ”‹•‡Ǥ ‹‰Š …‘•—’–‹‘‘ˆƒŽ…‘Š‘Ž‹•‘‡‘ˆ–Š‡‘•–•‹‰‹ˆ‹…ƒ–”‹•ˆƒ…–‘”•ˆ‘”†‡˜‡Ž‘’‡–‘ˆŽ‹˜‡” …‹””Š‘•‹•ƒ†Ǥ‘™‡˜‡”ǡ‹”‡…‡–›‡ƒ”•ǡ‘ƒŽ…‘Š‘Ž‹…ˆƒ––›Ž‹˜‡”†‹•‡ƒ•‡ȋ ȌŠƒ• „‡…‘‡‘”‡ƒ†‘”‡’”‡˜ƒŽ‡–ƒ†‘™ƒ†ƒ›•Šƒ•„‡…‘‡–Š‡Ž‡ƒ†‹‰…ƒ—•‡‘ˆ‹ •‘‡”‡‰‹‘•‘ˆ—”‘’‡ȏ͵ȐǤ ’ƒ–‹‡–•™‹–Š –Š‡’”‘‰”‡••‹‘–‘‹•ˆ”‡“—‡–‹–Š‡ ƒ„•‡…‡‘ˆ…‹””Š‘•‹•Ǥ‡–ƒ„‘Ž‹…”‹•ˆƒ…–‘”••—…Šƒ•‘„‡•‹–›ƒ††‹ƒ„‡–‡•‡ŽŽ‹–—•Šƒ˜‡„‡‡ ‹†‡–‹ˆ‹‡†ƒ•‹†‡’‡†‡–”‹•ˆƒ…–‘”•ˆ‘”†‡˜‡Ž‘’‡–ȏͶȂ͹ȐǤ   Š‡‘™Ž‡†‰‡‘–Š‡”‘Ž‡‘ˆ†‹‡–ƒ”›Šƒ„‹–•™Š‹…Šƒ”‡’”‘–‡…–‹˜‡‘”…‘–”‹„—–‡–‘Š‡’ƒǦ –‘…ƒ”…‹‘‰‡‡•‹•ǡ ‡‹–Š‡” ƒ••‘…‹ƒ–‡† ™‹–Š ‡–ƒ„‘Ž‹… ”‹• ˆƒ…–‘”• ‘” ‹†‡’‡†‡– ‘ˆ –Š‡•‡ǡ ‹• Ž‹‹–‡†Ǥ  ’ƒ–‹‡–•†‹ƒ‰‘•‡†™‹–Šǡ–Š‡—–”‹–‹‘ƒŽ•–ƒ–—•‹•‘ˆ…”‹–‹…ƒŽ‹’‘”–ƒ…‡…‘…‡”‹‰ –Š‡–‘Ž‡”ƒ„‹Ž‹–›‘ˆ–—‘”Ǧ†‹”‡…–‡†–Š‡”ƒ’›ƒ†•—”˜‹˜ƒŽǤ Nutritional Factors in Hepatocarcinogenesis

Alcohol   Ž…‘Š‘Ž ‹• ƒ ™‡ŽŽǦ‡•–ƒ„Ž‹•Š‡† …ƒ”†‹ƒŽ ”‹• ˆƒ…–‘” ˆ‘”  †‡˜‡Ž‘’‡–Ǥ Š‡”‡ ‹• Ž‹––Ž‡ ‡˜‹†‡…‡‘ˆƒ†‹”‡…–…ƒ”…‹‘‰‡‹…‡ˆˆ‡…–‘ˆƒŽ…‘Š‘ŽǤŠ‡‡ˆˆ‡…–‘ˆƒŽ…‘Š‘Ž‘†‡˜‡Ž‘’‡– ‹•†”‹˜‡„›–Š‡ƒŽ…‘Š‘ŽǦ‹†—…‡†Š‡’ƒ–‹…‹ˆŽƒƒ–‹‘™‹–Š’”‘‰”‡••‹‘–‘Ž‹˜‡”ˆ‹„”‘•‹•‘” …‹””Š‘•‹•Ǥ ‘™‡˜‡”ǡ ƒŽ…‘Š‘Ž ‹• ‡–ƒ„‘Ž‹œ‡† –‘ ƒ…‡–ƒŽ†‡Š›†‡ǡ ™Š‹…Š ‹• …ƒ’ƒ„Ž‡ ‘ˆ †ƒƒ‰‹‰ Ǥ†‘•‡Ǧ‡ˆˆ‡…–”‡Žƒ–‹‘•Š‹’Šƒ•„‡‡†‡‘•–”ƒ–‡†ˆ‘”ƒŽ…‘Š‘ŽǦ”‡Žƒ–‡†ȏͺȐǤŽ…‘Š‘Ž Šƒ•ƒ•›‡”‰‹•–‹…‡ˆˆ‡…–™‹–Š‘–Š‡””‹•ˆƒ…–‘”•ˆ‘”ǡ‹…‘Œ—…–‹‘™‹–Šƒ†‹ˆ‡…Ǧ –‹‘•ƒ†ǡ–‘ƒŽ‡••‡”‡š–‡–ǡ™‹–Š†‹ƒ„‡–‡•ȏͻȐǤ Aflatoxin B1   ˆŽƒ–‘š‹ͳǡƒ’”‘†—…–‘ˆˆ—‰‹‘ˆ–Š‡Aspergillus •’‡…‹‡•ǡ‹•ƒ…‘‘…‘–ƒ‹ƒ–‘ˆ ‰”ƒ‹•ǡ—–•ƒ†˜‡‰‡–ƒ„Ž‡•‹”‡‰‹‘•‹™Š‹…Š…Ž‹ƒ–‡ƒ†•–‘”ƒ‰‡ˆƒ˜‘”‹–•†‡˜‡Ž‘’‡– •—…Šƒ••‹ƒƒ†ˆ”‹…ƒǡƒ†‹•ƒ†‹”‡…–…ƒ”…‹‘‰‡‹†—…‹‰•’‡…‹ˆ‹…’‘‹–—–ƒ–‹‘•‹ͷ͵ ȏ ͳͲȐǤ•‹—Ž–ƒ‡‘—•‹ˆ‡…–‹‘™‹–Š–Š‡’‘–‡–‹ƒ–‡•–Š‡…ƒ”…‹‘‰‡‹…‡ˆˆ‡…–‘ˆƒˆŽƒ–‘š‹ ͳ•‹‰‹ˆ‹…ƒ–Ž›ȏͳͳȐǤ –Šƒ•„‡‡‡•–‹ƒ–‡†–Šƒ–„›”‡†—…‹‰ƒˆŽƒ–‘š‹‡š’‘•—”‡‹Š‹‰ŠǦ”‹• ”‡‰‹‘•–Š‡—„‡”‘ˆ…ƒ•‡•…ƒ„‡”‡†—…‡†„›‘”‡–ŠƒʹͲΨȏͳʹȐǤ Iron  ”‘‘˜‡”Ž‘ƒ†‘ˆ–Š‡Ž‹˜‡”‹•ƒˆƒ…–‘”…‘–”‹„—–‹‰–‘…ƒ”…‹‘‰‡‡•‹•Ǥ –…ƒ‘……—”‹Š‡”‡†Ǧ ‹–ƒ”›Š‡‘…Š”‘ƒ–‘•‹•‘”ƒ••‡…‘†ƒ”›‹”‘‘˜‡”Ž‘ƒ†„‡…ƒ—•‡‘ˆ…Š”‘‹…‹ˆŽƒƒ–‹‘ǡ‡•’‡Ǧ …‹ƒŽŽ› ‹ ’ƒ–‹‡–• ™‹–Š ƒŽ…‘Š‘Ž ƒ„—•‡Ǥ ”‡ƒ–‡– ™‹–Š …Š‡Žƒ–‹‰ ƒ‰‡–• ƒ† ”‡’‡ƒ–‡† ’ŠŽ‡Ǧ „‘–‘›‹’ƒ–‹‡–•™‹–ŠŠ‡‘…Š”‘ƒ–‘•‹•”‡†—…‡•–Š‡”‹•ȏͳ͵ȐǤ •‘‡”‡‰‹‘•‘ˆ–Š‡ ™‘”Ž†ǡ‡Ǥ‰Ǥ—„ǦƒŠƒ”ƒˆ”‹…ƒǡŠ‹‰ŠŽ‡˜‡Ž•‘ˆ‹‰‡•–‡†‹”‘Ž‡ƒ†–‘Š‡’ƒ–‹…‹”‘‘˜‡”Ž‘ƒ†ȏͳͶȐ ™‹–ŠŽ‡˜‡Ž•…‘’ƒ”ƒ„Ž‡–‘–Š‘•‡‹Š‡”‡†‹–ƒ”›Š‡‘…Š”‘ƒ–‘•‹•ǤŠ‡Š‹‰Šƒ‘—–‘ˆ‹‰‡•–‡† ‹”‘”‡•—Ž–•ˆ”‘Žƒ”‰‡˜‘Ž—‡•‘ˆ„‡‡”…‘•—‡†™Š‹…Š‹•Š‘‡Ǧ„”‡™‡†‹…ƒ•–‹”‘†”—• ‘”’‘–•Ǥ –‹•‡•–‹ƒ–‡†–Šƒ––Š‹•†‹‡–ƒ”›‹”‘‘˜‡”Ž‘ƒ†ǡˆ‘”‡”Ž›”‡ˆ‡””‡†–‘ƒ•ƒ–—•‹†‡”‘•‹•ǡ ƒˆˆ‡…–•ƒ„‘—–ͳͷΨ‘ˆ„Žƒ…”—”ƒŽˆ”‹…ƒ•ȏͳͷǡͳ͸ȐǤ Obesity and the Metabolic Syndrome   „‡•‹–›‹•‘‡‘ˆ–Š‡†”‹˜‹‰ˆƒ…–‘”•‘ˆ Ǥ††‹–‹‘ƒŽŽ›ǡ•‡˜‡”ƒŽ•–—†‹‡•Šƒ˜‡‹†‡Ǧ –‹ˆ‹‡† ‘„‡•‹–› ƒ• ‹†‡’‡†‡– ”‹• ˆƒ…–‘” ˆ‘”  ™‹–Š ƒ ”‡’‘”–‡†  ‘ˆ ͳǤ͵ͻȂͶǤͷʹ ȏ ͶȂ͸ȐǤ

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Gastrointest Tumors 2015;2:188–194 DOI: 10.1159/000441822

© 2015 S. Karger AG, Basel www.karger.com/gat

Schütte et al.: Nutrition and Hepatocellular Cancer

‡‹‰Š–Ž‘••‹•–Š‡…‘”‡”•–‘‡‹–Š‡–”‡ƒ–‡–‘ˆ ǤŠƒ‰‡•‹Ž‹ˆ‡•–›Ž‡ǡ’Šƒ”ƒ…‘Ǧ Ž‘‰‹…ƒŽ ‹–‡”˜‡–‹‘• ƒ†Ȁ‘” „ƒ”‹ƒ–”‹… •—”‰‡”› …ƒ …‘–”‹„—–‡ –‘ ™‡‹‰Š– ‘”ƒŽ‹œƒ–‹‘Ǥ Š‡–Š‡”’‡”•‹•–‡–™‡‹‰Š–Ž‘••‹‘„‡•‡’ƒ–‹‡–•ƒŽ•‘Šƒ•–Š‡’‘–‡–‹ƒŽ–‘’‘•‹–‹˜‡Ž›‹ˆŽ—‡…‡ –Š‡”‹•ˆ‘”Šƒ•‘–„‡‡ƒ†‡“—ƒ–‡Ž›ƒ††”‡••‡†‹’”‘•’‡…–‹˜‡…Ž‹‹…ƒŽ•–—†‹‡•Ǥ   Š‡‘’–‹‘•–‘’‘•‹–‹˜‡Ž›‹ˆŽ—‡…‡ „›’Šƒ”ƒ…‘–Š‡”ƒ’›ƒ”‡Ž‹‹–‡†Ǥ •—Ž‹”‡•‹•Ǧ –ƒ…‡‹•ƒ‹’‘”–ƒ–ˆƒ…–‘”‹’”‘‘–‹‰ ƒ†ƒ›ƒŽ•‘„‡ƒ…ƒ—•ƒ–‹˜‡ˆƒ…–‘”‹Š‡’ƒǦ –‘…ƒ”…‹‘‰‡‡•‹•Ǥ ”—‰• †‡…”‡ƒ•‹‰ ‹•—Ž‹ ”‡•‹•–ƒ…‡ ƒ† Ž‘™‡”‹‰ ‹•—Ž‹ Ž‡˜‡Ž•ǡ Ž‹‡ –Š‡ ‹•—Ž‹•‡•‹–‹œ‡”‡–ˆ‘”‹ǡ‰Ž‹–ƒœ‘‡•‘” ͳƒƒŽ‘‰—‡•Ž‹‡Ž‹”ƒ‰Ž—–‹†‡ǡ’‘–‡–‹ƒŽŽ›Šƒ˜‡ƒ ’‘•‹–‹˜‡‹’ƒ…–‘–Š‡”‹•ˆ‘”‹’ƒ–‹‡–•™‹–Š ȏͳͶǡͳ͹ȐǤŠ‡•ƒ‡Š‘Ž†•–”—‡ˆ‘” ‘–Š‡”‹–‡”˜‡–‹‘•…‘””‡…–‹‰ƒ•’‡…–•‘ˆ–Š‡‡–ƒ„‘Ž‹…•›†”‘‡•—…Šƒ••–ƒ–‹•ȏͳͺǡͳͻȐǤ „‡–‹…Š‘Ž‹…ƒ…‹†‹‰Š–‡š’ƒ†–Š‡–Š‡”ƒ’‡—–‹…‘’–‹‘•‹‘ƒŽ…‘Š‘Ž‹…•–‡ƒ–‘Š‡’ƒ–‹–‹•ǡ„—–‹–• Ž‘‰Ǧ–‡”„‡‡ˆ‹…‹ƒŽ‡ˆˆ‡…–•‹–Š‡’”‡˜‡–‹‘‘ˆƒ”‡‘–…Ž‡ƒ”›‡–ȏʹͲȐǤ Composition of the Diet

Š‡”‡‹••—ˆˆ‹…‹‡–‡˜‹†‡…‡–Šƒ– ‹•ƒ••‘…‹ƒ–‡†™‹–Š…‡”–ƒ‹†‹‡–ƒ”›’ƒ––‡”•ȏʹͳȂ ʹ͵ȐǤ‡˜‡”ƒŽŽƒ”‰‡…‘Š‘”–•–—†‹‡•ƒ†ˆ‡™’”‘•’‡…–‹˜‡”ƒ†‘‹œ‡†…‘–”‘ŽŽ‡†–”‹ƒŽ•Šƒ˜‡„‡‡ …‘†—…–‡†–‘ƒƒŽ›œ‡–Š‡”‘Ž‡‘ˆ†‹‡–ƒ†—–”‹–‹‘‹Ž‹˜‡”…ƒ…‡”’”‡˜‡–‹‘ǡ„—––Š‡‡˜‹†‡…‡ ˆ‘”’‘–‡–‹ƒŽƒ••‘…‹ƒ–‹‘•„‡–™‡‡—–”‹–‹‘ƒ†‹•—…Š™‡ƒ‡”ǤŠ‹Ž‡•‘‡‘ˆ–Š‡•‡ •–—†‹‡•‡˜ƒŽ—ƒ–‡–Š‡”‘Ž‡‘ˆ†‹‡–ƒ”›’ƒ––‡”•ǡ‘–Š‡”•ˆ‘…—•‘†‹•–‹…–—–”‹‡–•Ǥ   ’”‘•’‡…–‹˜‡•–—†›ˆ”‘Š‹ƒƒƒŽ›œ‡†ˆ‘‘†’ƒ––‡”•‹–™‘Žƒ”‰‡ƒ†’”‘•’‡…–‹˜‡Ž› ˆ‘ŽŽ‘™‡†…‘Š‘”–•Ǥ•‹‰ˆ‘‘†ˆ”‡“—‡…›“—‡•–‹‘ƒ‹”‡•ƒ–„ƒ•‡Ž‹‡ǡ‹–™ƒ••Š‘™–Šƒ–ƒ˜‡‰‡Ǧ –ƒ„Ž‡Ǧ„ƒ•‡††‹‡–ƒ”›’ƒ––‡”‹•ƒ••‘…‹ƒ–‡†™‹–Š”‡†—…‡†Ž‹˜‡”…ƒ…‡””‹•ǡ™Š‹Ž‡ˆ”—‹–Ǧƒ†‡ƒ–Ǧ „ƒ•‡††‹‡–•†‹†‘–•Š‘™ƒ›ƒ••‘…‹ƒ–‹‘ȏʹͶȐǤŠ‹•‘„•‡”˜ƒ–‹‘™ƒ•…‘ˆ‹”‡†„›ƒ‡–ƒǦ ƒƒŽ›•‹•‘’—„Ž‹•Š‡†•–—†‹‡•‘–Š‡ƒ••‘…‹ƒ–‹‘„‡–™‡‡˜‡‰‡–ƒ„Ž‡ƒ†ˆ”—‹–…‘•—’–‹‘ ƒ†–Š‡”‹•‘ˆǣ–Š‡”‹•‘ˆ†‡…”‡ƒ•‡•„›ͺΨˆ‘”‡˜‡”›ͳͲͲ‰Ȁ†ƒ›‹…”‡ƒ•‡‹˜‡‰‡–ƒ„Ž‡ ‹–ƒ‡ȏʹͷȐǤ ƒŽƒ”‰‡’”‘•’‡…–‹˜‡‡˜ƒŽ—ƒ–‹‘‹ƒŽƒ”‰‡…‘Š‘”–ƒ††”‡••‹‰–Š‡ƒ••‘…‹ƒ–‹‘ ‘ˆ–™‘†‹‡–ƒ”›‹†‹…‡•ǡ–Š‡‡ƒŽ–Š›ƒ–‹‰ †‡šǦʹͲͳͲȋ ǦʹͲͳͲȌƒ†–Š‡ƒŽ–‡”ƒ–‡‡†‹–‡”Ǧ ”ƒ‡ƒ ‹‡– …‘”‡ ȋƒȌǡ ™‹–Š  ‹…‹†‡…‡ ƒ† …Š”‘‹… Ž‹˜‡” †‹•‡ƒ•‡ ‘”–ƒŽ‹–›ǡ ‹– ™ƒ• •Š‘™–Šƒ–ƒ†Š‡”‡…‡–‘†‹‡–ƒ”›”‡…‘‡†ƒ–‹‘•Šƒ•–Š‡’‘–‡–‹ƒŽ–‘”‡†—…‡–Š‡”‹•‘ˆ „‘–Š†‹•‡ƒ•‡•Ǥ‹‰Š‡” ǦʹͲͳͲ•…‘”‡•™‡”‡•‹‰‹ˆ‹…ƒ–Ž›ƒ••‘…‹ƒ–‡†™‹–ŠƒŽ‘™‡””‹•‘ˆ ȋͲǤ͹ʹǢͻͷΨ ͲǤͷ͵ȂͲǤͻ͹Ȍǡƒ†–Š‡•ƒ‡Š‘Ž†•–”—‡ˆ‘”Š‹‰Šƒ•…‘”‡•ȋͲǤ͸ʹǢͻͷΨ  ͲǤͶ͹ȂͲǤͺͶȌȏʹ͸ȐǤ ƒ—”‘’‡ƒ•–—†›‘–™‘…‘Š‘”–•ˆ”‘ ”‡‡…‡ƒ† –ƒŽ›ǡ‹–™ƒ•ƒŽ•‘ †‡‘•–”ƒ–‡†–Šƒ––Š‡ƒ†Š‡”‡…‡–‘ƒ‡†‹–‡””ƒ‡ƒ†‹‡–’ƒ––‡”‹•ƒ••‘…‹ƒ–‡†™‹–ŠƒŽ‘™‡” ”‹•ˆ‘”ȏʹ͹ȐǤ „‘–Š…‘Š‘”–•ǡƒŠ‹‰Š‰Ž›…‡‹…Ž‘ƒ†‘ˆ†‹‡–Šƒ†ƒ‡‰ƒ–‹˜‡‹’ƒ…–‘–Š‡ ”‹•ȏʹͺǡʹͻȐǤ    ‹•ƒ‘‰‘‹‰—Ž–‹…‡–‡”’”‘•’‡…–‹˜‡…‘Š‘”–•–—†›‘–Š‡”‘Ž‡‘ˆ†‹‡–ǡŽ‹ˆ‡•–›Ž‡ƒ† ‡˜‹”‘‡–ƒŽˆƒ…–‘”•‹–Š‡‡–‹‘Ž‘‰›‘ˆ…ƒ…‡”ƒ†‘–Š‡”†‹•‡ƒ•‡•ƒ†Šƒ•”‡…”—‹–‡†‘”‡ –ŠƒͷͲͲǡͲͲͲ’ƒ”–‹…‹’ƒ–•ˆ”‘ƒŽŽ‘˜‡”—”‘’‡Ǥ ”‘–Š‡•‡•–—†‹‡••‡˜‡”ƒŽ‹’‘”–ƒ–†ƒ–ƒ Šƒ˜‡„‡‡…‘ŽŽ‡…–‡†Ǥ‹˜‡”•‡ƒ••‘…‹ƒ–‹‘„‡–™‡‡–‘–ƒŽˆƒ–‹–ƒ‡ƒ†”‹•‘ˆȋ’‡”ͳͲ ‰Ȁ†ƒ›ͲǤͺͲǢͻͷΨ ͲǤ͸ͷȂͲǤͻͻȌŠƒ•„‡‡‘„•‡”˜‡†ƒ†ƒ’’‡ƒ”•–‘„‡ƒ‹Ž›†”‹˜‡„› ‘‘—•ƒ–—”ƒ–‡†ˆƒ–•ȏ͵ͲȐǤ‘–ƒŽˆ‹•Š‹–ƒ‡™ƒ•ƒŽ•‘‹˜‡”•‡Ž›ƒ••‘…‹ƒ–‡†™‹–Š”‹•ȋ’‡” ʹͲ‰Ȁ†ƒ›ͲǤͺ͵ǢͻͷΨ ͲǤ͹ͶȂͲǤͻͷȌ™Š‹Ž‡–Š‡”‡™ƒ•‘ƒ••‘…‹ƒ–‹‘™‹–Š‡ƒ–…‘•—’–‹‘ ȏ͵ͳȐǤ‹‰Š‡”…‘•—’–‹‘‘ˆ†‹‡–ƒ”›ˆ‹„‡”ȋ’‡”ͳͲ‰Ȁ†ƒ›ͲǤ͹ͲǢͻͷΨ ͲǤͷʹȂͲǤͻ͵Ȍǡ„—–‘– –Š‡‹–ƒ‡‘ˆ–‘–ƒŽ…ƒ”„‘Š›†”ƒ–‡ǡ‘”–Š‡‰Ž›…‡‹…Ž‘ƒ†‘”–Š‡‰Ž›…‡‹…‹†‡š‘ˆ†‹‡–ǡ‹ˆŽ—‡…‡† –Š‡”‹•ˆ‘”•‹‰‹ˆ‹…ƒ–Ž›ȏ͵ʹȐǤ’”‘–‡…–‹˜‡’‘–‡–‹ƒŽ‘ˆˆ”—‹–•ƒ†˜‡‰‡–ƒ„Ž‡•Š‹‰Š‹ˆŽƒ˜‘Ǧ ‘‹†•ƒ†ƒ–‹‘š‹†ƒ–•†‹†‘–”‡ƒ…Š•–ƒ–‹•–‹…ƒŽ•‹‰‹ˆ‹…ƒ…‡ȏ͵͵ȐǤŠ‡•‡†ƒ–ƒ‘„–ƒ‹‡†ˆ”‘ ’‘’—Žƒ–‹‘•ˆ”‘–Š‡—”‘’‡ƒ •–—†›ƒ”‡†‹ˆˆ‡”‡–ˆ”‘–Š‡”‡•—Ž–•‘„–ƒ‹‡†ˆ”‘ …‘Š‘”–•ǤŠ‡ Ǧ•–—†›–Šƒ–Šƒ•’”‘•’‡…–‹˜‡Ž›‡”‘ŽŽ‡†ƒŽ‘•–ͷͲͲǡͲͲͲ‡ƒ†™‘‡

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Gastrointest Tumors 2015;2:188–194 DOI: 10.1159/000441822

© 2015 S. Karger AG, Basel www.karger.com/gat

Schütte et al.: Nutrition and Hepatocellular Cancer

”‡’‘”–•ƒ‹…”‡ƒ•‡†”‹•ˆ‘”ƒ••‘…‹ƒ–‡†™‹–Š–Š‡‹–ƒ‡‘ˆ”‡†‡ƒ–ƒ†•ƒ–—”ƒ–‡†ˆƒ–ǡ ƒ†ƒ•–”‘‰‡”‡ˆˆ‡…–™‹–Š–Š‡‹–ƒ‡‘ˆ•ƒ–—”ƒ–‡†ˆƒ–ƒ•…‘’ƒ”‡†–‘‘‘—•ƒ–—”ƒ–‡†ˆƒ–Ǥ   ”‡…‡–‡–ƒǦƒƒŽ›•‹•‘–Š‡”‹•‘ˆƒ†‡ƒ–…‘•—’–‹‘‹†‡–‹ˆ‹‡†•‡˜‡…‘Š‘”– •–—†‹‡•ƒ†–‡…ƒ•‡Ǧ…‘–”‘Ž•–—†‹‡•Ǥ –†‹†‘–•Š‘™ƒƒ••‘…‹ƒ–‹‘‘ˆ–Š‡‹–ƒ‡‘ˆ”‡†‡ƒ–ǡ ’”‘…‡••‡†‡ƒ–‘”–‘–ƒŽ‡ƒ–™‹–Š”‹•Ǥ‹‰ŠŽ‡˜‡Ž•‘ˆ™Š‹–‡‡ƒ–‘”ˆ‹•Š…‘•—’–‹‘‘ –Š‡‘–Š‡”Šƒ†…ƒ”‡†—…‡–Š‡”‹•‘ˆ•‹‰‹ˆ‹…ƒ–Ž›ȏ͵ͶȐǤ   ƒ–ƒˆ”‘”ƒ†‘‹œ‡†…‘–”‘ŽŽ‡†–”‹ƒŽ•‘—–”‹–‹‘ƒ†…ƒ…‡”’”‡˜‡–‹‘ƒ”‡•…ƒ”…‡Ǥ ’”‘•’‡…–‹˜‡”ƒ†‘‹œ‡†…‘–”‘ŽŽ‡†–”‹ƒŽ‹’‘•–‡‘’ƒ—•ƒŽ™‘‡…‘—Ž†‘–•Š‘™ƒ„‡‡Ǧ ˆ‹…‹ƒŽ‡ˆˆ‡…–‘ˆƒŽ‘™Ǧˆƒ–†‹‡–‘–Š‡‹…‹†‡…‡‘ˆŽ‹˜‡”…ƒ…‡”ȏ͵ͷȐǤ   Š‡—–”‹–‹‘ƒŽ•–ƒ–—•‹•ƒ•‹‰‹ˆ‹…ƒ–’”‘‰‘•–‹…ˆƒ…–‘”‹ ’ƒ–‹‡–•™‹–ŠŽ‹˜‡”…‹””Š‘•‹• ȏ ͵͸ȐǤ –‡”ƒ–‹‘ƒŽ‰—‹†‡Ž‹‡•”‡…‘‡†—–”‹–‹‘ƒŽ–Š‡”ƒ’›ˆ‘”–Š‡•‡’ƒ–‹‡–•™Š‡‡˜‡” ‡…‡••ƒ”›Ǥ ’–‹ƒŽ —–”‹–‹‘ƒŽ •—’’‘”– ’”‘Ž‘‰• •—”˜‹˜ƒŽǡ ‹’”‘˜‡• Ž‹˜‡” ˆ—…–‹‘ ƒ† –Š‡ —–”‹–‹‘ƒŽ•–ƒ–—•‹’ƒ–‹‡–•™‹–ŠŽ‹˜‡”…‹””Š‘•‹•ȏ͵͹ǡ͵ͺȐǤ‘™‡˜‡”ǡ™Š‡ˆ‘…—•‹‰‘–Š‡ ’”‡˜‡–‹‘‘ˆǡ‡˜‹†‡…‡Ǧ†”‹˜‡”‡…‘‡†ƒ–‹‘•ƒ”‡Žƒ…‹‰Ǥ Coffee   —‡”‘—••–—†‹‡•Šƒ˜‡‰‹˜‡‡˜‹†‡…‡ˆ‘”ƒ‹˜‡”•‡ƒ••‘…‹ƒ–‹‘‘ˆ…‘ˆˆ‡‡…‘•—’–‹‘ ƒ†–Š‡”‹•ˆ‘”ȏ͵ͻȂͶ͵ȐǤ—’†ƒ–‡†‡–ƒǦƒƒŽ›•‹•”‡•—Ž–‡†‹ƒ”‹•”‡†—…–‹‘‘ˆͶͲΨ ˆ‘”ƒ›…‘ˆˆ‡‡…‘•—’–‹‘ǤŠ‡•—ƒ”›™ƒ•ͲǤͺͲȋͻͷΨ ͲǤ͹͹ȂͲǤͺͶȌˆ‘”ƒ‹…”‡‡– ‘ˆͳ…—’‘ˆ…‘ˆˆ‡‡’‡”†ƒ›ȏͶͶȐǤ Branched-Chain Amino Acids   ”ƒŽ„”ƒ…Š‡†Ǧ…Šƒ‹ƒ‹‘ƒ…‹†•—’’Ž‡‡–ƒ–‹‘‹’ƒ–‹‡–•™‹–Š†‡…‘’‡•ƒ–‡†Ž‹˜‡” …‹””Š‘•‹• ‹’”‘˜‡• –Š‡ —–”‹–‹‘ƒŽ •–ƒ–—• ƒ† ’”‡˜‡–• Ž‹˜‡”Ǧ”‡Žƒ–‡† …‘’Ž‹…ƒ–‹‘•Ǥ  ’”‘•’‡…–‹˜‡…Ž‹‹…ƒŽ–”‹ƒŽ•ǡ–Š‹•–Š‡”ƒ’›™ƒ•ƒŽ•‘•Š‘™–‘•‹‰‹ˆ‹…ƒ–Ž›Ž‘™‡”‘……—””‡…‡ ”ƒ–‡•‹’ƒ–‹‡–•™‹–ŠŽ‹˜‡”…‹””Š‘•‹•ȏͶͷǡͶ͸ȐǤ Vitamin D   ’‹†‡‹‘Ž‘‰‹…ƒŽ•–—†‹‡••Š‘™–Š‡‹˜‡”•‡ƒ••‘…‹ƒ–‹‘„‡–™‡‡˜‹–ƒ‹•–ƒ–—•ƒ†–Š‡ ‹…‹†‡…‡‘ˆ…ƒ…‡”ǡƒ†„‹‘…Š‡‹…ƒŽ•–—†‹‡••—‰‰‡•––Šƒ–˜‹–ƒ‹†‡ˆ‹…‹‡…›ƒ›’Žƒ›ƒ”‘Ž‡ ‹–Š‡…ƒ—•‡ƒ†’”‘‰”‡••‹‘‘ˆ…ƒ…‡”ȏͶ͹ȐǤ‡•—Ž–•‘ˆ–Š‡ –”‹ƒŽ”‡˜‡ƒŽ‡†–Šƒ–Š‹‰Š‡” „ƒ•‡Ž‹‡Ž‡˜‡Ž•‘ˆʹͷȋȌƒ”‡ƒ••‘…‹ƒ–‡†™‹–ŠƒŽ‘™‡””‹•‘ˆȋ’‡”ͳͲ‘ŽȀŽ‹…”‡ƒ•‡ ͲǤͺͲǢͻͷΨ ͲǤ͸ͺȂͲǤͻͶȌȏͶͺȐǤ …‘–”ƒ•–ǡ†‹‡–ƒ”›…ƒŽ…‹—ǡ˜‹–ƒ‹ǡˆƒ–ƒ†’”‘–‡‹ˆ”‘ †ƒ‹”›•‘—”…‡•ƒ”‡ƒ••‘…‹ƒ–‡†™‹–Š‹…”‡ƒ•‡†”‹•™Š‹Ž‡–Š‡•ƒ‡—–”‹‡–•ˆ”‘‘†ƒ‹”› •‘—”…‡••Š‘™‹˜‡”•‡‘”—ŽŽƒ••‘…‹ƒ–‹‘•ȏͶͻȐǤ Nutrition and Prognosis of HCC

  ƒŽ—–”‹–‹‘‹•ƒˆ”‡“—‡–„—–—†‡”†‹ƒ‰‘•‡†’”‘„Ž‡‹…ƒ…‡”’ƒ–‹‡–•ƒ†‹•†‡ˆ‹‡† ƒ•Ǯ†‡…Ž‹‡‹Ž‡ƒ„‘†›ƒ••™‹–Š–Š‡’‘–‡–‹ƒŽˆ‘”ˆ—…–‹‘ƒŽ‹’ƒ‹”‡–ǯƒ–—Ž–‹’Ž‡Ž‡˜‡Ž• ȏͷͲȐǤ Š‡”‡ ‹• ‘ …‘‘Ž› ƒ……‡’–‡† ‰‘Ž† •–ƒ†ƒ”† ˆ‘” –Š‡ †‹ƒ‰‘•‹• ‘ˆ ƒŽ—–”‹–‹‘ǡ „—– ƒ„‘—–‘‡–Š‹”†‘ˆ…ƒ…‡”’ƒ–‹‡–•ƒ”‡ƒŽ‘—”‹•Š‡†ȏͷͳȐǤƒ–‹‡–•™‹–Šƒ”‡ƒ–ƒ•’‡…‹ƒŽ ‹…”‡ƒ•‡† ”‹• ˆ‘” ƒŽ—–”‹–‹‘Ǥ  ’ƒ–‹‡–• ™‹–Š Ž‹˜‡” …‹””Š‘•‹•ǡ ƒŽ—–”‹–‹‘ ‹• ƒ …‘‘ ˆ‹†‹‰ƒ†ƒ••‘…‹ƒ–‡†™‹–Š‘”–ƒŽ‹–›ƒ†”‡†—…‡†“—ƒŽ‹–›‘ˆŽ‹ˆ‡ȏͷʹǡͷ͵ȐǤ ǡ–Š‡ƒŒ‘”‹–› ‘ˆ …ƒ•‡• ƒ”‡ ƒ••‘…‹ƒ–‡† ™‹–Š Ž‹˜‡” ˆ—…–‹‘ ‹’ƒ‹”‡– „‡…ƒ—•‡ ‘ˆ Ž‹˜‡” …‹””Š‘•‹• ȏ ͳȐǡ ƒ† –—‘”’”‘‰”‡••‹‘ƒ†–—‘”Ǧ†‹”‡…–‡†–Š‡”ƒ’‹‡•ƒ›ˆ—”–Š‡”†‡–‡”‹‘”ƒ–‡Ž‹˜‡”ˆ—…–‹‘ȏͷͶȐǤ   ”‘•’‡…–‹˜‡ …Ž‹‹…ƒŽ •–—†‹‡• Šƒ˜‡ ‹†‡–‹ˆ‹‡† ƒŽ—–”‹–‹‘ ƒ• ƒ ‹†‡’‡†‡– ‡‰ƒ–‹˜‡ ’”‘‰‘•–‹… ˆƒ…–‘” ‹ ǡ „—– ‹–‡”˜‡–‹‘ƒŽ •–—†‹‡• ƒ††”‡••‹‰ –Š‡ ‡ˆˆ‡…– ‘ˆ —–”‹–‹‘ƒŽ –Š‡”ƒ’›‹’ƒ–‹‡–•ƒ”‡ˆ‡™ȏͷͷȐǤ

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DOI: 10.1159/000441822 Schütte et al.: Nutrition and Hepatocellular Cancer

  ’ƒ–‹‡–• —†‡”‰‘‹‰ ”‡•‡…–‹‘ ‘ˆ  ‹ …—”ƒ–‹˜‡ ‹–‡–ǡ ’‡”‹‘’‡”ƒ–‹˜‡ —–”‹–‹‘ƒŽ ƒƒ‰‡‡–Šƒ•„‡‡‹†‡–‹ˆ‹‡†ƒ•‡›†‡–‡”‹ƒ–‘ˆ–”‡ƒ–‡–•—……‡••ȏͷ͸ȐǤ‘†‹ˆ‹…ƒ–‹‘• ‘ˆ–Š‡ƒ…”‘—–”‹‡–ƒ†‹…”‘—–”‹‡–…‘’‘•‹–‹‘‘ˆ–Š‡†‹‡–ƒ•™‡ŽŽƒ•’Šƒ”ƒ…‘Ž‘‰‹…ƒŽ ‹–‡”˜‡–‹‘• –ƒ”‰‡–‹‰ —–”‹–‹‘ƒŽ ƒ† ‡–ƒ„‘Ž‹… ’ƒ–Š™ƒ›• ƒ”‡ •—‰‰‡•–‡† –‘ ’‘•‹–‹˜‡Ž› ‹ˆŽ—‡…‡–Š‡’ƒ–‹‡–•ǯ’”‘‰‘•‹•ȏͳͶȐǤ ’ƒ–‹‡–•‘–Š‡”ƒ’›ˆ‘”ǡ–Š‡•—’’Ž‡‡–ƒ–‹‘‘ˆ „”ƒ…Š‡†Ǧ…Šƒ‹ƒ‹‘ƒ…‹†‹’”‘˜‡•Ž‹˜‡”ˆ—…–‹‘ȏͷ͹ǡͷͺȐƒ†Šƒ•–Š‡’‘–‡–‹ƒŽ–‘’”‘Ž‘‰ ”‡…—””‡…‡Ǧˆ”‡‡•—”˜‹˜ƒŽƒ†‘˜‡”ƒŽŽ•—”˜‹˜ƒŽȏͷͻȐǤŠ‡•‡‘„•‡”˜ƒ–‹‘•ƒ†‡ˆ”‘‹†‹˜‹†—ƒŽ •–—†‹‡•™‡”‡‘Ž›’ƒ”–‹ƒŽŽ›…‘ˆ‹”‡†„›ƒ”‡…‡–‡–ƒǦƒƒŽ›•‹•ȏ͸ͲȐǤ   ’”‘•’‡…–‹˜‡•–—†›‘ˆʹͲͲ’ƒ–‹‡–•™‹–Š”‡˜‡ƒŽ‡†–Šƒ–ʹͷȋȌ͵†‡ˆ‹…‹‡…›‹•ƒ••‘Ǧ …‹ƒ–‡†™‹–Šƒ†˜ƒ…‡†•–ƒ‰‡•‘ˆƒ†‹•ƒˆ—”–Š‡”’”‘‰‘•–‹…‹†‹…ƒ–‘”ˆ‘”’‘‘”‘—–…‘‡ ȏ͸ͳȐǤ‘™‡˜‡”ǡŽƒ”‰‡’”‘•’‡…–‹˜‡”ƒ†‘‹œ‡†…‘–”‘ŽŽ‡†–”‹ƒŽ•ƒ”‡•–‹ŽŽ–‘„‡’‡”ˆ‘”‡†‘–Š‡ ‡ˆˆ‡…–‘ˆ—–”‹–‹‘ƒŽ‹–‡”˜‡–‹‘•‘’”‘‰‘•‹•‘ˆ’ƒ–‹‡–•™‹–ŠǤ Conclusion

  —–”‹–‹‘ƒŽ•–ƒ–—•ƒ†…‘’‘•‹–‹‘‘ˆ†‹‡–ƒ”‡”‡Ž‡˜ƒ–ˆƒ…–‘”•”‡Žƒ–‡†–‘–Š‡”‹•‘ˆǤ Š‡› ƒŽ•‘ Šƒ˜‡ ƒ ‹’‘”–ƒ– ”‘Ž‡ …‘…‡”‹‰ –Š‡ ’”‘‰‘•‹• ‘ˆ ’ƒ–‹‡–• ™‹–Š Ǥ ‡˜‡”ƒŽ ƒ…”‘Ǧƒ†‹…”‘—–”‹‡–…‘’‘‡–•Šƒ˜‡„‡‡ˆ‘—†–‘„‡‹˜‡”•‡Ž›…‘””‡Žƒ–‡†™‹–Š–Š‡ ”‹•ˆ‘”Ǥ‘’”‡˜‡–†‹•‡ƒ•‡’”‘‰”‡••‹‘–‘Ž‹˜‡”…‹””Š‘•‹•‘”‹’ƒ–‹‡–•™‹–Š‘ƒŽǦ …‘Š‘Ž‹…•–‡ƒ–‘Š‡’ƒ–‹–‹•ǡ‹–‹•…”—…‹ƒŽ–‘‘’–‹‹œ‡–Š‡‡–ƒ„‘Ž‹…•–ƒ–‡Ǥ‘™‡˜‡”ǡ‡˜‹†‡…‡ˆ”‘ ™‡ŽŽǦ†‡•‹‰‡†’”‘•’‡…–‹˜‡‹–‡”˜‡–‹‘ƒŽ–”‹ƒŽ•™‹–Š–Š‡ƒ‹–‘”‡†—…‡‹…‹†‡…‡‘”–‘ ’”‘Ž‘‰•—”˜‹˜ƒŽ‹’ƒ–‹‡–•™‹–Š„ƒ•‡†‘—–”‹–‹‘ƒŽ‘†‹ˆ‹…ƒ–‹‘‹••–‹ŽŽ–‘„‡‰‡‡”ƒ–‡†Ǥ Disclosure Statement   Š‡ƒ—–Š‘”•†‡…Žƒ”‡‘…‘ˆŽ‹…–•‘ˆ‹–‡”‡•–”‡Žƒ–‡†–‘–Š‹•’ƒ’‡”Ǥ 

References Ԙ ͳ …Šò––‡ǡ‘”•…Š‡‹ ǡƒŽˆ‡”–Š‡‹‡”ǣ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒȂ‡’‹†‡‹‘Ž‘‰‹…ƒŽ–”‡†•ƒ†”‹•ˆƒ…–‘”•Ǥ  ͹ǣͺ  ͲȂͻʹǤ ‹‰‹•ʹͲͲͻǢʹ  ͻǣ Ԙ ʹ ˜‡”– ǡ ‘„”‘™•‹ ǣ ‡’ƒ–‘œ‡ŽŽ—Ž¡”‡ ƒ”œ‹‘‡ ‹ †‡” ‹…Š–œ‹””Š‘–‹•…Š‡ ‡„‡”Ǥ ƒ–Š‘Ž‘‰‡ ʹͲͲͺǢʹ Ͷ  ͹ȂͷʹǤ Ԙ ͵ ›•‘ ǡ ƒ“—‡• ǡ Šƒ––‘’ƒ†›Šƒ› ǡ ‘…Šƒ ǡ ”ƒŠƒ ǡ ƒ• ǡ •Žƒ ǡ ƒ–ƒ™ƒŽƒ ǡ ƒ‰‰ƒ” ǡ ‘Ž‡ ǡ —’–‡”ǡ–‡™ƒ”–ǡ‘•‡ ǡ—†•‘ǡƒƒ•ǡ‡‡˜‡•ǣ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ…‡”ǣ–Š‡‹’ƒ…–‘ˆ‘„‡•‹–›ǡ  Ͳǣͳ  ͳͲȂͳͳ͹Ǥ –›’‡ʹ†‹ƒ„‡–‡•ƒ†ƒ—Ž–‹†‹•…‹’Ž‹ƒ”›–‡ƒǤ ‡’ƒ–‘ŽʹͲͳͶǢ͸ Ԙ Ͷ ƒŽ†™‡ŽŽǡ”‡•’‘ǡƒ‰ǡŽǦ•ƒ‹‹ǣ„‡•‹–›ƒ†Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǤ ƒ•–”‘‡–‡”‘Ž‘‰›  ʹ͹ȋͷ•—’’ŽͳȌǣͻ͹ȂͳͲ͵Ǥ ʹͲͲͶǢͳ Ԙ ͷ ‘”‡ƒǡ–”‘Šƒ‹‡”ǡ—ƒ‘˜ƒǡŒÞ”‰‡ǡ‹†˜‹•–ǡƒŽŽƒ• ǡ†Ž‹‰‡”ǡ–‘…•ǡƒ‰‡Ž ǡƒŒ‡”

ǡ‰‡Žƒ†ǡ‡Ž‡”ǡ¡‰‰•–”ڏǡ”‡–Ž‹ǡ‘…‹ǡ ‘••‘ǡ–ƒ––‹ǡŽ‡”ǣ‡–ƒ„‘Ž‹…”‹•ˆƒ…–‘”•  ͵ͳǣͳ  ͻ͵ȂʹͲͲǤ ƒ†’”‹ƒ”›Ž‹˜‡”…ƒ…‡”‹ƒ’”‘•’‡…–‹˜‡•–—†›‘ˆͷ͹ͺǡ͹ͲͲƒ†—Ž–•Ǥ – ƒ…‡”ʹͲͳʹǢͳ Ԙ ͸ ƒŽŽ‡ǡ‘†”‹‰—‡œǡƒŽ‡”ǦŠ—”‘†ǡŠ— ǣ˜‡”™‡‹‰Š–ǡ‘„‡•‹–›ǡƒ†‘”–ƒŽ‹–›ˆ”‘…ƒ…‡”‹ƒ  Ͷͺǣͳ  ͸ʹͷȂͳ͸͵ͺǤ ’”‘•’‡…–‹˜‡Ž›•–—†‹‡†…‘Š‘”–‘ˆǤǤƒ†—Ž–•Ǥ‰Ž ‡†ʹͲͲ͵Ǣ͵ Ԙ ͹ ‡Žœ‡Žǡ ”ƒ—„ƒ”† ǡ‡—œ‡ǡŽǦ‡”ƒ‰ǡƒ˜‹Žƒ ǡ… Ž›ǣ‡–ƒ„‘Ž‹…•›†”‘‡‹…”‡ƒ•‡•–Š‡”‹•  Ͷǣ ‘ˆ’”‹ƒ”›Ž‹˜‡”…ƒ…‡”‹–Š‡‹–‡†–ƒ–‡•ǣƒ•–—†›‹–Š‡Ǧ‡†‹…ƒ”‡†ƒ–ƒ„ƒ•‡Ǥ‡’ƒ–‘Ž‘‰›ʹͲͳͳǢͷ Ͷ  ͸͵ȂͶ͹ͳǤ Ԙ ͺ ƒ‰ƒ”†‹ǡŽƒ‰‹ƒ”†‘ǡƒ‡……Š‹ƒǡ‘””ƒ‘ ǣ‡–ƒǦƒƒŽ›•‹•‘ˆƒŽ…‘Š‘Ž†”‹‹‰ƒ†…ƒ…‡””‹•Ǥ”   ͷǣͳ  ͹ͲͲȂͳ͹ͲͷǤ ƒ…‡”ʹͲͲͳǢͺ Ԙ ͻ ŽǦ‡”ƒ‰ǡƒ™ƒŽ ǣ’‹†‡‹‘Ž‘‰›‘ˆŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒ‹–Š‡‹–‡†–ƒ–‡•ǣ™Š‡”‡ƒ”‡™‡ǫŠ‡”‡  Ͳǣͳ  ͹͸͹Ȃͳ͹͹ͷǤ †‘™‡‰‘ǫ‡’ƒ–‘Ž‘‰›ʹͲͳͶǢ͸ ͳ  Ͳ ƒ—Ž– ǣƒ–Š‘‰‡‡•‹•‘ˆŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒƒ……‘”†‹‰–‘ƒ‡–‹‘Ž‘‰›Ǥ‡•–”ƒ…–‡•Ž‹ ƒ•–”‘‡–‡”‘Ž  ͺǣͻ  ͵͹ȂͻͶ͹Ǥ ʹͲͳͶǢʹ  Ͷʹǣͳ  ʹ͸ͶȂ ͳ  ͳ ŽǦ‡”ƒ‰ǣ’‹†‡‹‘Ž‘‰›‘ˆ˜‹”ƒŽŠ‡’ƒ–‹–‹•ƒ†Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǤ ƒ•–”‘‡–‡”‘Ž‘‰›ʹͲͳʹǢͳ ͳʹ͹͵Ǥ‡ͳǤ 









































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Gastrointest Tumors 2015;2:188–194 © 2015 S. Karger AG, Basel www.karger.com/gat

DOI: 10.1159/000441822 Schütte et al.: Nutrition and Hepatocellular Cancer

ͳ  ʹ ‹—ǡŠƒ‰ǡƒ”•Š ǡ— ǣ‘’—Žƒ–‹‘ƒ––”‹„—–ƒ„Ž‡”‹•‘ˆƒˆŽƒ–‘š‹Ǧ”‡Žƒ–‡†Ž‹˜‡”…ƒ…‡”ǣ•›•–‡ƒ–‹…  ͺǣʹ  ͳʹͷȂʹͳ͵͸Ǥ ”‡˜‹‡™ƒ†‡–ƒǦƒƒŽ›•‹•Ǥ—” ƒ…‡”ʹͲͳʹǢͶ ͳ  ͵ ‹‡†‡”ƒ—ǡ ‹•…Š‡”ǡò”•…Š‡Žǡ–”‡‡Žǡ¡—••‹‰‡”ǡ–”‘Š‡›‡” ǣ‘‰Ǧ–‡”•—”˜‹˜ƒŽ‹’ƒ–‹‡–•  ͳͲǣͳ  ͳͲ͹ȂͳͳͳͻǤ ™‹–ŠŠ‡”‡†‹–ƒ”›Š‡‘…Š”‘ƒ–‘•‹•Ǥ ƒ•–”‘‡–‡”‘Ž‘‰›ͳͻͻ͸Ǣͳ  ǣͺ  ͻȂͻ͸Ǥ ͳ  Ͷ ‹–Š ǣ—–”‹–‹‘ƒ†‡–ƒ„‘Ž‹•‹Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǤ‡’ƒ–‘„‹Ž‹ƒ”›—”‰—–”ʹͲͳ͵Ǣʹ  ǣ͵  ͳȂͶͲǤ ͳ  ͷ ‡™ǣ‡’ƒ–‹…‹”‘‘˜‡”Ž‘ƒ†ƒ†Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǤ‹˜‡”ƒ…‡”ʹͲͳͶǢ͵ ͳ  ͸ ‘”†‡— ǡ ‘›† ǡ ”‹––‡Šƒ ǣ ‹‡–ƒ”› ‹”‘ ‘˜‡”Ž‘ƒ† ’‡”•‹•–• ‹ ”—”ƒŽ •—„ǦƒŠƒ”ƒ ˆ”‹…ƒǤ ƒ…‡–  ȋͺͶͻ͵Ȍǣͳ͵ͳͲȂͳ͵ͳ͵Ǥ ͳͻͺ͸Ǣͳ ͳ  ͹ ƒ‹ ǡ Š‡ ǡ ‹ƒ‘ ǡ —‘ ǡ ‹ ǡ —‰ ǣ ‹• ‘ˆ Š‡’ƒ–‘…‡ŽŽ—Žƒ” …ƒ”…‹‘ƒ ‹ †‹ƒ„‡–‹… ’ƒ–‹‡–• ƒ† ”‹• ”‡†—…–‹‘ƒ••‘…‹ƒ–‡†™‹–Šƒ–‹Ǧ†‹ƒ„‡–‹…–Š‡”ƒ’›ǣƒ’‘’—Žƒ–‹‘Ǧ„ƒ•‡†…‘Š‘”–•–—†›Ǥ  ƒ•–”‘‡–‡”‘ŽʹͲͳʹǢ ͳ  Ͳ͹ǣͶ  ͸ȂͷʹǤ ͳ  ͺ ‘•…Š ǡ ‘”•ǣŠ‡”ƒ’›Ǥ–ƒ–‹•ƒ†Ž‹˜‡”†‹•‡ƒ•‡ǣˆ”‘…‘…‡”–‘Ǯ™‘†‡”ǯ†”—‰•ǫƒ–‡˜ ƒ•–”‘‡–‡”‘Ž  ʹǣ͵  ʹͲȂ͵ʹͳǤ ‡’ƒ–‘ŽʹͲͳͷǢͳ ͳ  ͻ … Ž›ǡ‹˜‹‡ ǡƒŠƒ•”ƒ„—††Š‡ǡ‰‡ŽǡƒŽ‘‘–‡ǡ‡ŽŽ•ǡ‘‘†ǡŽˆ‘”†ǣ–ƒ–‹—•‡  ͺǣͷ  ʹ͵Ȃͷʹ͹Ǥ ƒ†”‹•‘ˆŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒ‹ƒǤǤ’‘’—Žƒ–‹‘Ǥƒ…‡”’‹†‡‹‘ŽʹͲͳͶǢ͵ ʹ  Ͳ ‡—•…Š™ƒ†‡”Ǧ‡–”‹ǡ‘‘„ƒǡƒ›ƒŽ ǡƒ˜‹‡ ǡ˜ƒƒ––ƒǡ„†‡ŽƒŽ‡ ǡŠƒŽƒ•ƒ‹ǡƒ•ƒ”ƒ–Š› ǡ‹‡ŠŽǡƒ‡‡†ǡ‘™†Ž‡›ǡ…—ŽŽ‘—‰Šǡ‡””ƒ—Ž–ǡŽƒ” ǡ‘ƒ•…‹ƒ ǡ”—–ǡŽ‡‹‡”ǡ‘‘ ǣ ƒ”‡•‘‹†  —…Ž‡ƒ” ”‡…‡’–‘” Ž‹‰ƒ† ‘„‡–‹…Š‘Ž‹… ƒ…‹† ˆ‘” ‘Ǧ…‹””Š‘–‹…ǡ ‘ǦƒŽ…‘Š‘Ž‹… •–‡ƒ–‘Š‡’ƒ–‹–‹•  ͺͷǣͻ  ͷ͸Ȃͻ͸ͷǤ ȋ  Ȍǣƒ—Ž–‹…‡–”‡ǡ”ƒ†‘‹•‡†ǡ’Žƒ…‡„‘Ǧ…‘–”‘ŽŽ‡†–”‹ƒŽǤƒ…‡–ʹͲͳͷǢ͵ ʹ  ͳ ƒ‰ǡŠ—ǡƒ‰ǡƒ‰ ǡŠ‘—ǡ—ƒǡƒ‰ǣ‹‡–ƒ”›’ƒ––‡”•‘†—Žƒ–‡–Š‡”‹•‘ˆ‘ǦƒŽ…‘Š‘Ž‹…  ǣͶ  ͹͹ͺȂͶ͹ͻͳǤ ˆƒ––›Ž‹˜‡”†‹•‡ƒ•‡‹Š‹‡•‡ƒ†—Ž–•Ǥ—–”‹‡–•ʹͲͳͷǢ͹ ʹ  ʹ ††›ǡ‡”„‹•‘ǡ ƒ…‘„›ǡ„”‘•‹‹ ǡǯ—ŽŽ‹˜ƒǡ›‘”‹†‡ǡŽ›› ǡŽƒ… ǡ‡‹Ž‹ ǡ ‘”‹ǡƒ†•ǡ†ƒ•ǣŠ‡‡•–‡”†‹‡–ƒ”›’ƒ––‡”‹•’”‘•’‡…–‹˜‡Ž›ƒ••‘…‹ƒ–‡†™‹–Š‘ƒŽ…‘Š‘Ž‹…ˆƒ––›  Ͳͺǣ͹  ͹ͺȂ͹ͺͷǤ Ž‹˜‡”†‹•‡ƒ•‡‹ƒ†‘Ž‡•…‡…‡Ǥ  ƒ•–”‘‡–‡”‘ŽʹͲͳ͵Ǣͳ ʹ  ͵ ‹Ǧ ¡”˜‹‡ǣ‘ǦƒŽ…‘Š‘Ž‹…ˆƒ––›Ž‹˜‡”†‹•‡ƒ•‡ƒ•ƒ…ƒ—•‡ƒ†ƒ…‘•‡“—‡…‡‘ˆ‡–ƒ„‘Ž‹…•›†”‘‡Ǥƒ…‡–  ǣͻ  ͲͳȂͻͳͲǤ ‹ƒ„‡–‡•†‘…”‹‘ŽʹͲͳͶǢʹ ʹ  Ͷ Šƒ‰ǡ‹ƒ‰ǡ‹ǡƒ‰ ǡƒ‹ǡ ‹ǡ ƒ‘ǡŠ‡‰ǡŠ—ǣ‡‰‡–ƒ„Ž‡Ǧ„ƒ•‡††‹‡–ƒ”›’ƒ––‡”ƒ†Ž‹˜‡”  ͲͶǣͳ  ͵ͷ͵Ȃͳ͵͸ͳǤ …ƒ…‡””‹•ǣ”‡•—Ž–•ˆ”‘–Š‡Šƒ‰Šƒ‹™‘‡ǯ•ƒ†‡ǯ•Š‡ƒŽ–Š•–—†‹‡•Ǥƒ…‡”…‹ʹͲͳ͵Ǣͳ ʹ  ͷ ƒ‰ǡŠƒ‰ǡ ‡‰ǡŠ‡ ǡ‹— ǡŠ‡ ǡŠ—ǣ …”‡ƒ•‡†‹–ƒ‡‘ˆ˜‡‰‡–ƒ„Ž‡•ǡ„—–‘–ˆ”—‹–ǡ”‡†—…‡•”‹•  Ͷ͹ǣͳ  Ͳ͵ͳȂͳͲͶʹǤ ˆ‘”Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǣƒ‡–ƒǦƒƒŽ›•‹•Ǥ ƒ•–”‘‡–‡”‘Ž‘‰›ʹͲͳͶǢͳ ʹ  ͸ ‹ ǡ ƒ” ǡ … Ž› ǡ ‘ŽŽ‡„‡… ǡ ƒ›Ž‘” ǡ ‘Ž†•–‡‹ ǡ ”‡‡†ƒ ǣ †‡šǦ„ƒ•‡† †‹‡–ƒ”› ’ƒ––‡”•ƒ†”‹•‘ˆ‹…‹†‡–Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒƒ†‘”–ƒŽ‹–›ˆ”‘…Š”‘‹…Ž‹˜‡”†‹•‡ƒ•‡‹ƒ’”‘•’‡…–‹˜‡  Ͳǣͷ  ͺͺȂͷͻ͹Ǥ •–—†›Ǥ‡’ƒ–‘Ž‘‰›ʹͲͳͶǢ͸ ʹ  ͹ —”ƒ–‹ ǡ”‹…Š‘’‘—Ž‘•ǡ‘Ž‡•‡Ž ǡ”ƒ˜‹ ǡ‘••‹ǡƒŽƒ‹‹ǡ ”ƒ…‡•…Š‹ǡ‘–‡ŽŽƒǡ”‹…Š‘’‘—Ž‘—ǡƒ  Ͳǣ͸  Ͳ͸Ȃ͸ͳͳǤ ‡……Š‹ƒǡƒ‰‹‘—ǣ‡†‹–‡””ƒ‡ƒ†‹‡–ƒ†Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǤ ‡’ƒ–‘ŽʹͲͳͶǢ͸ ʹ  ͺ ‘••‹ǡ‹’™‘”–Šǡƒ•‘ǡƒŽƒ‹‹ǡ‘–‡ŽŽƒǡ‘Ž‡•‡Ž ǡ…ƒ—‰ŠŽ‹ ǡƒ”’‹‡Žǡ ”ƒ…‡•…Š‹ǡ ƒ‰‹‘—ǡƒ‡……Š‹ƒǣ‹‡–ƒ”›‰Ž›…‡‹…Ž‘ƒ†ƒ†Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒ™‹–Š‘”™‹–Š‘—–…Š”‘‹…Š‡’ƒ–‹–‹•  Ͳǣͳ  ͹͵͸Ȃͳ͹ͶͲǤ ‹ˆ‡…–‹‘Ǥ…‘ŽʹͲͲͻǢʹ ʹ  ͻ ƒ‰‹‘—ǡ‘••‹ǡœ‘‘—ǡ ‡‘”‰‹Žƒǡ”‹…Š‘’‘—Ž‘•ǡƒ‡……Š‹ƒǣ Ž›…‡‹…Ž‘ƒ†‹”‡Žƒ–‹‘–‘Š‡’ƒ–‘…‡ŽǦ  Ͳǣͳ  ͹ͶͳȂͳ͹ͶͷǤ Ž—Žƒ”…ƒ”…‹‘ƒƒ‘‰’ƒ–‹‡–•™‹–Š…Š”‘‹…Š‡’ƒ–‹–‹•‹ˆ‡…–‹‘Ǥ…‘ŽʹͲͲͻǢʹ ͵  Ͳ —ƒ”–‡ǦƒŽŽ‡•ǡ ‡†‹”‘ǡ–‡’‹‡ǡŽ‡•ƒ†”‘˜ƒǡƒ‹ƒǡƒ‰‹‘—ǡ‡–ƒŽǣ‹‡–ƒ”›ˆƒ–ǡˆƒ–•—„–›’‡•ƒ†  ͵͹ǣʹ  ͹ͳͷȂʹ͹ʹͺǤ Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒ‹ƒŽƒ”‰‡—”‘’‡ƒ…‘Š‘”–Ǥ – ƒ…‡”ʹͲͳͷǢͳ ͵  ͳ ‡†‹”‘ǡ”‹…Š‘’‘Ž‘—ǡƒ‹ƒǡ—ƒ”–‡ǦƒŽŽ‡•ǡ”‡’‘ǡŽ‡•ƒ†”‘˜ƒǡ‡–ƒŽǣ‘•—’–‹‘‘ˆˆ‹•Šƒ† ‡ƒ–•ƒ†”‹•‘ˆŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǣ–Š‡—”‘’‡ƒ”‘•’‡…–‹˜‡ ˜‡•–‹‰ƒ–‹‘‹–‘ƒ…‡”ƒ†—–”‹–‹‘  Ͷǣʹ  ͳ͸͸Ȃʹͳ͹͵Ǥ ȋ ȌǤ…‘ŽʹͲͳ͵Ǣʹ ͵  ʹ ‡†‹”‘ǡ—ƒ‘˜ƒǡƒ‹ƒǡ”‹…Š‘’‘Ž‘—ǡ”‡’‘ǡږŠŽ‹‰•ǡ‡–ƒŽǣ Ž›…‡‹…‹†‡šǡ‰Ž›…‡‹…Ž‘ƒ†ǡ †‹‡–ƒ”›…ƒ”„‘Š›†”ƒ–‡ǡƒ††‹‡–ƒ”›ˆ‹„‡”‹–ƒ‡ƒ†”‹•‘ˆŽ‹˜‡”ƒ†„‹Ž‹ƒ”›–”ƒ…–…ƒ…‡”•‹‡•–‡”—”‘’‡ƒ•Ǥ  Ͷǣͷ  Ͷ͵Ȃͷͷ͵Ǥ …‘ŽʹͲͳ͵Ǣʹ ͵  ͵ ƒ‘”ƒǦ‘•ǡ ‡†‹”‘ǡ”‹…Š‘’‘—Ž‘—ǡ ‘œžŽ‡œǡƒ‹ƒǡ”‡’‘ǡ‡–ƒŽǣ‹‡–ƒ”›ˆŽƒ˜‘‘‹†ǡŽ‹‰ƒƒ† ƒ–‹‘š‹†ƒ– …ƒ’ƒ…‹–› ƒ† ”‹• ‘ˆ Š‡’ƒ–‘…‡ŽŽ—Žƒ” …ƒ”…‹‘ƒ ‹ –Š‡ —”‘’‡ƒ ’”‘•’‡…–‹˜‡ ‹˜‡•–‹‰ƒ–‹‘ ‹–‘  ͵͵ǣʹ  ͶʹͻȂʹͶͶ͵Ǥ …ƒ…‡”ƒ†—–”‹–‹‘•–—†›Ǥ – ƒ…‡”ʹͲͳ͵Ǣͳ ͵  Ͷ —‘ ǡƒ‰ǡ‹— ǡ—ǡƒ‰ǡ‹—ǡ‹—ǡŠ—ǣ›•–‡ƒ–‹…”‡˜‹‡™™‹–Š‡–ƒǦƒƒŽ›•‹•ǣ‡ƒ–…‘•—’–‹‘  ͻǣͻ  ͳ͵ȂͻʹʹǤ ƒ†–Š‡”‹•‘ˆŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǤŽ‹‡–Šƒ”ƒ…‘ŽŠ‡”ʹͲͳͶǢ͵ ͵  ͷ ”‡–‹…‡ǡŠ‘•‘ǡƒƒǡ—„„‡ŽŽ ǡ†‡”•‘ ǡ‡”‡•ˆ‘”†ǡ‡––‹‰‡”ǡƒ‡ǡ‡••‹ǡ ƒ•‡‡ǡ‹‰ŠǡŠƒ†‡ƒ” ǡŠ‹ƒ› ǡƒ––‡”ˆ‹‡Ž†ǡŠŽ‡„‘™•‹ǣ‘™Ǧˆƒ–†‹‡–ƒ”›’ƒ––‡”ƒ†…ƒ…‡” ‹…‹†‡…‡‹–Š‡‘‡ǯ•‡ƒŽ–Š ‹–‹ƒ–‹˜‡‹‡–ƒ”›‘†‹ˆ‹…ƒ–‹‘ƒ†‘‹œ‡†‘–”‘ŽŽ‡†”‹ƒŽǤ ƒ–Žƒ…‡”  ͻǣͳ  ͷ͵ͶȂͳͷͶ͵Ǥ •–ʹͲͲ͹Ǣͻ  Ͳǣ ͵  ͸ ‘–ƒ‘Ǧ‘œƒ ǣŽ‹‹…ƒŽ”‡Ž‡˜ƒ…‡‘ˆ•ƒ”…‘’‡‹ƒ‹’ƒ–‹‡–•™‹–Š…‹””Š‘•‹•Ǥ‘”Ž†  ƒ•–”‘‡–‡”‘ŽʹͲͳͶǢʹ ͺ  Ͳ͸ͳȂͺͲ͹ͳǤ ͵  ͹ ‹”•…Šǡ—‘—–ǡƒƒœƒ†‡ǡ –—””‹ƒ‰ƒǡ‡–‡”ƒǡ …ƒœƒ” ǡ ƒ––ƒ•ǡ‰ƒ”–‡ ǣ‘–”‘ŽŽ‡†–”‹ƒŽ‘ —–”‹–‹‘•—’’Ž‡‡–ƒ–‹‘‹‘—–’ƒ–‹‡–•™‹–Š•›’–‘ƒ–‹…ƒŽ…‘Š‘Ž‹……‹””Š‘•‹•Ǥ  ƒ”‡–‡”–‡”ƒŽ—–”  ͹ǣͳ  ͳͻȂͳʹͶǤ ͳͻͻ͵Ǣͳ ͵  ͺ ‘†”—’ ǡòŽŽ‡” ǣ‡”‰›ƒ†’”‘–‡‹”‡“—‹”‡‡–•‘ˆ’ƒ–‹‡–•™‹–Š…Š”‘‹…Ž‹˜‡”†‹•‡ƒ•‡Ǥ ‡’ƒ–‘Žͳͻͻ͹Ǣ ʹ  ͹ǣʹ  ͵ͻȂʹͶ͹Ǥ 









































































































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Gastrointest Tumors 2015;2:188–194 © 2015 S. Karger AG, Basel www.karger.com/gat

DOI: 10.1159/000441822 Schütte et al.: Nutrition and Hepatocellular Cancer

͵  ͻ ƒ‹ƒǡƒ‰‹‘—ǡ ‡ƒ„ǡ”‹…Š‘’‘—Ž‘—ǡ ‡†‹”‘ǡŽ‡•ƒ†”‘˜ƒǡ‡–ƒŽǣ‘ˆˆ‡‡ǡ–‡ƒƒ††‡…ƒˆˆ‡‹ƒ–‡† …‘ˆˆ‡‡ ‹ ”‡Žƒ–‹‘ –‘ Š‡’ƒ–‘…‡ŽŽ—Žƒ” …ƒ”…‹‘ƒ ‹ ƒ —”‘’‡ƒ ’‘’—Žƒ–‹‘ǣ —Ž–‹…‡–”‡ǡ ’”‘•’‡…–‹˜‡ …‘Š‘”– •–—†›Ǥ – ƒ…‡”ʹͲͳͷǢͳ  ͵͸ǣͳ  ͺͻͻȂͳͻͲͺǤ Ͷ  Ͳ ‡–‹ƒ™ƒǡ‹Ž‡•ǡ—ǡ‡”ƒ†‡œǡ‡ƒ”…Šƒ†ǡ‡†‡”•‘ǣ••‘…‹ƒ–‹‘‘ˆ…‘ˆˆ‡‡‹–ƒ‡ ™‹–Š ”‡†—…‡† ‹…‹†‡…‡ ‘ˆ Ž‹˜‡” …ƒ…‡” ƒ† †‡ƒ–Š ˆ”‘ …Š”‘‹… Ž‹˜‡” †‹•‡ƒ•‡ ‹ –Š‡  —Ž–‹‡–Š‹… …‘Š‘”–Ǥ  Ͷͺǣͳ  ͳͺȂͳʹͷǢ“—‹œ‡ͳͷǤ

ƒ•–”‘‡–‡”‘Ž‘‰›ʹͲͳͷǢͳ Ͷ  ͳ ƒ‹ ǡ‡‹•–‡‹ ǡŽ„ƒ‡•ǡƒ›Ž‘”ǡ… Ž›ǡ‹”–ƒ‘ ǡ‹Šƒǡ ”‡‡†ƒǣŠ‡ƒ••‘…‹ƒ–‹‘‘ˆ …‘ˆˆ‡‡‹–ƒ‡™‹–ŠŽ‹˜‡”…ƒ…‡”‹…‹†‡…‡ƒ†…Š”‘‹…Ž‹˜‡”†‹•‡ƒ•‡‘”–ƒŽ‹–›‹ƒŽ‡•‘‡”•Ǥ” ƒ…‡”  Ͳͻǣͳ  ͵ͶͶȂͳ͵ͷͳǤ ʹͲͳ͵Ǣͳ Ͷ  ʹ ‘—‡ ǡ ‘•Š‹‹ ǡ ‘„—‡ ǡ •—‰ƒ‡ ǣ ˆŽ—‡…‡ ‘ˆ …‘ˆˆ‡‡ †”‹‹‰ ‘ •—„•‡“—‡– ”‹• ‘ˆ Š‡’ƒ–‘…‡ŽŽ—Žƒ”  ͹ǣʹ  ͻ͵Ȃ͵ͲͲǤ …ƒ”…‹‘ƒǣƒ’”‘•’‡…–‹˜‡•–—†›‹ ƒ’ƒǤ ƒ–Žƒ…‡” •–ʹͲͲͷǢͻ Ͷ  ͵ ‡–”‹… ǡ ”‡‡†ƒǡ ”ƒ—„ƒ”† ǡƒŠƒ•”ƒ„—††Š‡ǡƒ‹ ǡŽƒ˜ƒŒƒǡ‡–ƒŽǣ‘ˆˆ‡‡…‘•—’–‹‘ƒ† ”‹• ‘ˆ Š‡’ƒ–‘…‡ŽŽ—Žƒ” …ƒ”…‹‘ƒ ƒ† ‹–”ƒŠ‡’ƒ–‹… …Š‘Žƒ‰‹‘…ƒ”…‹‘ƒ „› •‡šǣ –Š‡ ‹˜‡” ƒ…‡” ‘‘Ž‹‰  Ͷǣͳ  ͵ͻͺȂͳͶͲ͸Ǥ ”‘Œ‡…–Ǥƒ…‡”’‹†‡‹‘Ž‹‘ƒ”‡”•”‡˜ʹͲͳͷǢʹ Ͷ  Ͷ ”ƒ˜‹ ǡ‘•‡––‹ǡƒ˜ƒ‹ǡ ƒŽŽ—•ǡƒ‡……Š‹ƒǣ‘ˆˆ‡‡”‡†—…‡•”‹•ˆ‘”Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǣƒ—’†ƒ–‡†  ͳǣͳ  Ͷͳ͵ȂͳͶʹͳǤ‡ͳǤ ‡–ƒǦƒƒŽ›•‹•ǤŽ‹ ƒ•–”‘‡–‡”‘Ž‡’ƒ–‘ŽʹͲͳ͵Ǣͳ Ͷ  ͷ ƒ›ƒ‹•Š‹ǡŠ—‰ǡ—†‘ǡ •Š‹ƒ™ƒǡƒ‹–ƒǡ‡†ƒǡ‹–ƒ‹ǡ ‘—‡ǡƒ†ƒǡƒ‰‹™ƒ”ƒǡ‹ƒ‹ǡ ‡•Š‹ƒǣ”ƒŽ„”ƒ…Š‡†Ǧ…Šƒ‹ƒ‹‘ƒ…‹†‰”ƒ—Ž‡•”‡†—…‡–Š‡‹…‹†‡…‡‘ˆŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒƒ†  ͻǣ͵  ʹ͸Ȃ͵͵ʹǤ ‹’”‘˜‡‡˜‡–Ǧˆ”‡‡•—”˜‹˜ƒŽ‹’ƒ–‹‡–•™‹–ŠŽ‹˜‡”…‹””Š‘•‹•Ǥ‹‰‹•ʹͲͳͳǢʹ Ͷ  ͸ ƒ™ƒ‰—…Š‹ǡŠ‹”ƒ‹•Š‹ǡ –‘ǡ—œ—‹ǡ‘”‡‡†ƒǡŠ–ƒ‡ǡ‡–ƒŽǣ”ƒ…Š‡†Ǧ…Šƒ‹ƒ‹‘ƒ…‹†•’”‡˜‡–Š‡’ƒǦ  ʹǣͳ  ͲͳʹȂ –‘…ƒ”…‹‘‰‡‡•‹•ƒ†’”‘Ž‘‰•—”˜‹˜ƒŽ‘ˆ’ƒ–‹‡–•™‹–Š…‹””Š‘•‹•ǤŽ‹ ƒ•–”‘‡–‡”‘Ž‡’ƒ–‘ŽʹͲͳͶǢͳ ͳͲͳͺǤ‡ͳǤ Ͷ  ͹ Š‹ƒ‰ǡ‡ŠǡŠ‡ǡŠ‡ǣ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒƒ†˜‹–ƒ‹ǣƒ”‡˜‹‡™Ǥ  ƒ•–”‘‡–‡”‘Ž‡’ƒ–‘Ž  ͸ǣͳ  ͷͻ͹Ȃͳ͸Ͳ͵Ǥ ʹͲͳͳǢʹ Ͷ  ͺ ‡†‹”‘ǡ—ƒ”–‡ǦƒŽŽ‡•ǡƒ‹ƒǡ”‹…Š‘’‘—Ž‘—ǡŽ‡•ƒ†”‘˜ƒǡ”‹…Š‘’‘—Ž‘•ǡ‡–ƒŽǣ”‡†‹ƒ‰‘•–‹… …‹”…—Žƒ–‹‰ ˜‹–ƒ‹  Ž‡˜‡Ž• ƒ† ”‹• ‘ˆ Š‡’ƒ–‘…‡ŽŽ—Žƒ” …ƒ”…‹‘ƒ ‹ —”‘’‡ƒ ’‘’—Žƒ–‹‘•ǣ ƒ ‡•–‡† …ƒ•‡Ǧ  Ͳǣͳ  ʹʹʹȂͳʹ͵ͲǤ …‘–”‘Ž•–—†›Ǥ‡’ƒ–‘Ž‘‰›ʹͲͳͶǢ͸ Ͷ  ͻ —ƒ”–‡ǦƒŽŽ‡•ǡ ‡†‹”‘ǡ–‡’‹‡ǡ”‹…Š‘’‘—Ž‘—ǡƒ‹ƒǡƒ‰‹‘—ǡ‡–ƒŽǣƒ‹”›’”‘†—…–•ƒ†”‹•‘ˆ Š‡’ƒ–‘…‡ŽŽ—Žƒ” …ƒ”…‹‘ƒǣ –Š‡ —”‘’‡ƒ ”‘•’‡…–‹˜‡ ˜‡•–‹‰ƒ–‹‘ ‹–‘ ƒ…‡” ƒ† —–”‹–‹‘Ǥ –  ƒ…‡”  ͵ͷǣͳ  ͸͸ʹȂͳ͸͹ʹǤ ʹͲͳͶǢͳ ͷ  Ͳ ‡•‡ ǡ‹•–”‹ƒǡ‘—„‡‘ˆˆǡ‡‹„—”‰‡”ǣƒŽ—–”‹–‹‘•›†”‘‡•ǣƒ…‘—†”—˜•…‘–‹——Ǥ  ͵ǣ͹  ͳͲȂ͹ͳ͸Ǥ

 ƒ”‡–‡”–‡”ƒŽ—–”ʹͲͲͻǢ͵ ͷ  ͳ ‘œœ‡––‹ ǡƒ”‹ƒ‹ǡ‘—ŽŽ‘ǡ‡”‹‘ǡ‹ˆˆ‹ǡƒ……‹ƒŽƒœƒ ǡƒ’—ƒ‘ ǡƒ’—ƒ‘ ǡ‘””‡Œƒ ǡ‘œœƒ‰Ž‹‘ ǡ‹‡‘ǡ‹‘•‘ǡ ‹‘……Š‹ƒ”‘ǡ ƒ˜ƒœœ‹ǡ ‹ƒ‘‹ǡƒ‰ƒ‹‹ǡƒ–‘˜ƒ‹ ǡ‡ŽŽ‡‰”‹‹ǡ‘˜‡”ƒ ǡ ƒ†”‹ ǡ ‹‹˜‡ŽŽƒ ǡ ‹‰‡˜ƒ‹ ǣ Š‡ —–”‹–‹‘ƒŽ ”‹• ‹ ‘…‘Ž‘‰›ǣ ƒ •–—†› ‘ˆ ͳǡͶͷ͵ …ƒ…‡” ‘—–’ƒ–‹‡–•Ǥ  Ͳǣͳ  ͻͳͻȂͳͻʹͺǤ —’’‘”–ƒ”‡ƒ…‡”ʹͲͳʹǢʹ ͷ  ʹ ‘–ƒ‘Ǧ‘œƒ ǡ—ƒ”–‡Ǧ‘Œ‘ǡ‡œƒǦ —…‘ ǡƒ”ƒ…‘•ǡƒ™›‡”ǡƒ‰ ǡ‡ƒ—‘–ǡ•ˆƒ†‹ƒ”‹ǡ ›‡”•ǣ …Ž—•‹‘‘ˆƒ”…‘’‡‹ƒ™‹–Š‹ȋǦ•ƒ”…‘’‡‹ƒȌƒ†–Š‡’”‡†‹…–‹‘‘ˆ‘”–ƒŽ‹–›‹’ƒ–‹‡–•  ǣ‡ͳͲʹǤ ™‹–Š…‹””Š‘•‹•ǤŽ‹”ƒ•Ž ƒ•–”‘‡–‡”‘ŽʹͲͳͷǢ͸ ͷ  ͵ Ž„‡”‹‘ ǡ ƒ––ƒǡ‘†‹‘ǡ‡”‡Žǡ‹ƒ•…‘Ž‹ǡ‘ˆˆ‘ ǡƒ”‡‰ƒ”‘ǣ—–”‹–‹‘ƒ†•—”˜‹˜ƒŽ‹’ƒ–‹‡–•  ͹ǣͶ  ͶͷȂͶͷͲǤ ™‹–ŠŽ‹˜‡”…‹””Š‘•‹•Ǥ—–”‹–‹‘ʹͲͲͳǢͳ ͷ  Ͷ •—ǡ•ƒ‹ǡŠƒǡƒ‰ǡŠ—‰ǣ‹‹Ǧ—–”‹–‹‘ƒŽƒ••‡••‡–’”‡†‹…–•ˆ—…–‹‘ƒŽ•–ƒ–—•ƒ†“—ƒŽ‹–›  Ͷǣͷ  Ͷ͵ȂͷͶͻǤ ‘ˆŽ‹ˆ‡‘ˆ’ƒ–‹‡–•™‹–ŠŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒ‹ƒ‹™ƒǤ—–”ƒ…‡”ʹͲͳʹǢ͸ ͷ  ͷ …Šò––‡ǡ‹’’‡Ž–ǡ…Š—ŽœǡڊŽ ǡ ‡‡„‡”‰ǡ‡‹†‡•–‹…‡”ǡ”‡† ǡƒŽˆ‡”–Š‡‹‡”ǣƒŽ—–”‹–‹‘‹•ƒ ’”‘‰‘•–‹…ˆƒ…–‘”‹’ƒ–‹‡–•™‹–ŠŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒȋȌǤŽ‹—–”ʹͲͳͶǡ’—„ƒŠ‡ƒ†‘ˆ’”‹–Ǥ ͷ  ͸ ‹—‹ǡ‹‘†‹ǡ ”‘••‘ ǡ—ƒ”‹ ǡƒƒ•…‹ƒǡƒ†‹•‹ǡ‘Ž’‡•ǡ”…ƒ†‹’ƒ‡ǡƒ•‹Ž‡ ǡ ”‹†‡ŽŽ‹ǡ ”—–Ǧ  ͵ǣʹ  ͶͻȂʹͷʹǤ –ƒ†ƒ—”‹ƒǣ—–”‹–‹‘ƒŽƒ•’‡…–•‹’ƒ–‹‡–—†‡”‰‘‹‰Ž‹˜‡””‡•‡…–‹‘Ǥ’†ƒ–‡•—”‰ʹͲͳͳǢ͸ ͷ  ͹ ‘”‹Šƒ”ƒǡ ™ƒ–ƒǡƒƒ‘ǡ—‹‘–‘ǡ—‘ǡ ——ƒ‰ƒǡ‘–•—‘–‘ǡƒƒ–ƒǡƒƒƒǡƒ—”ƒ‹ ǡ ™ƒ•Š‹–ƒǡ‡†ƒǡ‹”ƒ‘ ǡ‘‘›ƒƒǡƒƒ‡ǡ‹•Š‹œƒ™ƒǡ‘•Š‹ƒ‡ǡƒǡƒ‡›ƒƒǡƒ—Ǧ ‹–•—ǡ‹–ƒ—”ƒǡƒƒ‘–‘ǡ ”‹‡ǡŠƒƒ†‘ǡ‘Š†ƒǡƒ–ƒƒ„‡ǡƒ‹•ƒƒǣƒ–‡Ǧ‡˜‡‹‰•ƒ…™‹–Š „”ƒ…Š‡†Ǧ…Šƒ‹ ƒ‹‘ ƒ…‹†• ‹’”‘˜‡• Ž‹˜‡” ˆ—…–‹‘ ƒˆ–‡” ”ƒ†‹‘ˆ”‡“—‡…› ƒ„Žƒ–‹‘ ˆ‘” Š‡’ƒ–‘…‡ŽŽ—Žƒ”  ʹǣ͸  ͷͺȂ͸͸͹Ǥ …ƒ”…‹‘ƒǤ‡’ƒ–‘Ž‡•ʹͲͳʹǢͶ ͷ  ͺ ‹•Š‹ƒ™ƒǡ•ƒ‹ǡ —œ—ƒǡƒ‡†ƒǡƒƒŒ‹ƒ ǡƒ–•—†ƒ ǡ‡‹ǡƒƒ‘–‘ǡ •Š‹ƒ™ƒǡƒ‹–‘ǡ ‹–ƒǡ‹—”ƒǣ”ƒ…Š‡†Ǧ…Šƒ‹ƒ‹‘ƒ…‹†–”‡ƒ–‡–„‡ˆ‘”‡–”ƒ•…ƒ–Š‡–‡”ƒ”–‡”‹ƒŽ…Š‡‘‡„‘Ž‹œƒ–‹‘ˆ‘”  ͺǣͳ  ͵͹ͻȂͳ͵ͺͶǤ Š‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǤ‘”Ž†  ƒ•–”‘‡–‡”‘ŽʹͲͳʹǢͳ ͷ  ͻ …Š‹ƒ™ƒǡƒ„ƒ›ƒ•Š‹ǡƒ‡†ƒǡƒ‹ƒ™ƒǡ ‹›ƒƒǡ—‰‹‘–‘ǡ‘„ƒ›ƒ•Š‹ǡ‹—”ƒǡƒƒœƒ‹ǣ ”ƒŽ •—’’Ž‡‡–ƒ–‹‘ ‘ˆ „”ƒ…Š‡†Ǧ…Šƒ‹ ƒ‹‘ ƒ…‹†• ”‡†—…‡• ‡ƒ”Ž› ”‡…—””‡…‡ ƒˆ–‡” Š‡’ƒ–‹… ”‡•‡…–‹‘ ‹  ͵ǣ͹  ʹͲȂ͹ʹ͸Ǥ ’ƒ–‹‡–•™‹–ŠŠ‡’ƒ–‘…‡ŽŽ—Žƒ”…ƒ”…‹‘ƒǣƒ’”‘•’‡…–‹˜‡•–—†›Ǥ—”‰‘†ƒ›ʹͲͳ͵ǢͶ ͸  Ͳ Š‡ǡŠ‡ǡƒ‰ǡ‹ǡŠƒ‰ǡ ‘‰ ǡŠ‡ǡ‹ǡ—ǣˆˆ‹…ƒ…›ƒ†•ƒˆ‡–›‘ˆ‘”ƒŽ„”ƒ…Š‡†Ǧ…Šƒ‹ ƒ‹‘ ƒ…‹† •—’’Ž‡‡–ƒ–‹‘ ‹ ’ƒ–‹‡–• —†‡”‰‘‹‰ ‹–‡”˜‡–‹‘• ˆ‘” Š‡’ƒ–‘…‡ŽŽ—Žƒ” …ƒ”…‹‘ƒǣ ƒ ‡–ƒǦ  Ͷǣ͸  ͹Ǥ ƒƒŽ›•‹•Ǥ—–” ʹͲͳͷǢͳ ͸  ͳ ‹‡Ž‡‹‡” ǡ ”‘‡„‡”‰‡” ǡ ڄ‡”Ž‡ ǡ ‘Œ—‰ƒ ǡ ‡—œ‡ ǡ ”‘Œƒ ǡ ‹‹’‡” ǡ ƒ‹†ƒ ǣ ‡˜‡”‡ ʹͷǦŠ›†”‘š›˜‹–ƒ‹  †‡ˆ‹…‹‡…› ‹†‡–‹ˆ‹‡• ƒ ’‘‘” ’”‘‰‘•‹• ‹ ’ƒ–‹‡–• ™‹–Š Š‡’ƒ–‘…‡ŽŽ—Žƒ” …ƒ”…‹‘ƒ Ȃ ƒ  ͻǣͳ  ʹͲͶȂͳʹͳʹǤ ’”‘•’‡…–‹˜‡…‘Š‘”–•–—†›ǤŽ‹‡–Šƒ”ƒ…‘ŽŠ‡”ʹͲͳͶǢ͵