Cancer cachexia - Pathophysiology and management

Journal of Gastroenterology

Volumn 48, Issue 5, 2013, Pages 574-594

  Suzuki, Hajime ^a   Asakawa, Akihiro ^a   Amitani, Haruka ^a   Nakamura, Norifumi ^a   Inui, Akio ^a  

^a KAGOSHIMA UNIVERSITY   (Japan)

Author keywords

Anorexia; Cachexia; Cytokine; Palliative care; Skeletal muscle

Indexed keywords

ANABOLIC AGENT; BRANCHED CHAIN AMINO ACID; C REACTIVE PROTEIN; CANNABINOID DERIVATIVE; CARNITINE; CISPLATIN; CYPROHEPTADINE; CYTOKINE INHIBITOR; GAMMA INTERFERON ANTIBODY; GHRELIN; ICOSAPENTAENOIC ACID; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1; INTERLEUKIN 1 ANTIBODY; INTERLEUKIN 6 ANTIBODY; LEPTIN; MYOSTATIN; NEUROPEPTIDE Y; NITROGEN; NONSTEROID ANTIINFLAMMATORY AGENT; PROTEASOME; PROTEIN INHIBITOR; SEROTONIN ANTAGONIST; SOMATOMEDIN C; STEROID; THALIDOMIDE; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; UBIQUITIN; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ADIPOSE TISSUE; ANOREXIA; BIOMEDICINE; CACHEXIA; CANCER CHEMOTHERAPY; CANCER SURVIVAL; CHEMOTHERAPY INDUCED EMESIS; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MUSCLE ATROPHY; MUSCLE MASS; NAUSEA; NITROGEN BALANCE; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN SYNTHESIS INHIBITION; QUALITY OF LIFE; REVIEW; SIDE EFFECT; SKELETAL MUSCLE; SOCIAL PSYCHOLOGY;

APPETITE STIMULANTS; C-REACTIVE PROTEIN; CACHEXIA; CYTOKINES; HUMANS; NEOPLASMS; PROGESTINS;

EID: 84878110577     PISSN: 09441174     EISSN: 14355922     Source Type: Journal    
DOI: 10.1007/s00535-013-0787-0     Document Type: Review

References (212)

1. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395(6704):763-70.
2. Flier JS, Maratos-Flier E. Obesity and the hypothalamus: novel peptides for new pathways. Cell. 1998;92(4):437-40.
3. Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte D. Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev. 1992;13(3):387-414.
4. Inui A. Feeding and body-weight regulation by hypothalamic neuropeptides - mediation of the actions of leptin. Trends Neurosci. 1999;22(2):62-7.
5. Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res. 1999;59(18):4493-501.
6. Yakabi K, Sadakane C, Noguchi M, Ohno S, Ro S, Chinen K, et al. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia. Endocrinology [Internet]. 2010;151(8):3773-82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20534732.
7. Liu Y, Hamaue N, Endo T, Hirafuji M, Minami M. 5-hydroxytryptamine (5-HT) concentrations in the hippocampus, the hypothalamus and the medulla oblongata related to cisplatin-induced pica of rats. Res Commun Mol Pathol Pharmacol. 2003;113-114:97-113.
8. De Vry J, Schreiber R. Effects of selected serotonin 5-HT1 and 5-HT2 receptor agonists on feeding behavior: possible mechanisms of action. Neuroscience & Biobehavioral Reviews [Internet]. 2000;24(3):341-53. Available from: http://www.sciencedirect.com/science/article/pii/ S0149763499000834.
9. Schreiber R, Selbach K, Asmussen M, Hesse D, De Vry J. Effects of serotonin(1/2) receptor agonists on dark-phase food and water intake in rats. Pharmacol Biochem Behav. 2000;67(2):291-305.
10. Fujitsuka N, Asakawa A, Uezono Y, Minami K, Yamaguchi T, Niijima A, et al. Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival. Transl Psychiatry. 2011;1(7):e23.
11. Takeda H, Sadakane C, Hattori T, Katsurada T, Ohkawara T, Nagai K, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology. 2008;134(7):2004-13.
12. Haslett PA. Anticytokine approaches to the treatment of anorexia and cachexia. Semin Oncol. 1998;25(2 Suppl 6):53-7.
13. Mantovani G, Maccio A, Lai P, Massa E. Cytokine activity in cancer-related anorexia/cachexia: role of megestrol acetate and medroxyprogesterone acetate. Semin Oncol. 1998;25:45-52.
14. Sternberg EM. Neural-immune interactions in health and disease. J Clin Invest. 1997;100(11):2641-7.
15. Licinio J, Wong ML. Pathways and mechanisms for cytokine signaling of the central nervous system. J Clin Invest. 1997;100(12):2941-7.
16. Hopkins SJ, Rothwell NJ. Cytokines and the nervous system. I: expression and recognition. Trends Neurosci. 1995;18(2):83-8.
17. Rothwell NJ, Hopkins SJ. Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci. 1995;18(3):130-6.
18. Tisdale M. Biology of cachexia. J Natl Cancer Inst. 1997;89:1763-73.
19. Plata-Salamán CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev. 1991;15(2):185-215.
20. Plata-Salamán CR. Anorexia during acute and chronic disease. Nutrition. 1996;12(2):69-78.
21. Moldawer LL, Copeland EM. Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options. Cancer. 1997;79(9):1828-39.
22. Donohoe CL, Ryan AM, Reynolds JV. Cancer cachexia: mechanisms and clinical implications. Gastroenterol Res Pract. 2011;2011:601434.
23. Moldawer LL, Rogy MA, Lowry SF. The role of cytokines in cancer cachexia. J Parenter Enteral Nutr. 1992;16(6 Suppl):43S-9S.
24. Noguchi Y, Yoshikawa T, Matsumoto A, Svaninger GS, Gelin J. Are cytokines possible mediators of cancer cachexia? Surg Today. 1996;26(7):467-75.
25. Matthys P, Billiau A. Cytokines and cachexia. Nutrition. 1997;13(9):763-70.
26. Gelin J, Moldawer L, Lönnroth C, Sherry B. Role of endogenous tumor necrosis factor α and interleukin 1 for experimental tumor growth and the development of cancer cachexia. Cancer Res. 1991;51:415-21.
27. Torelli G, Meguid M. Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats. Am J Physiol Regul Integr Comp Physiol. 1999;277:R850-5.
28. McCarthy HD, Crowder RE, Dryden S, Williams G. Megestrol acetate stimulates food and water intake in the rat: effects on regional hypothalamic neuropeptide Y concentrations. Eur J Pharmacol. 1994;265(1-2):99-102.
29. Scarlett JM, Jobst EE, Enriori PJ, Bowe DD, Batra AK, Grant WF, et al. Regulation of Central Melanocortin Signaling by Interleukin-1β. Endocrinology. 2007;148(9):4217-25.
30. Lenk K, Schuler G, Adams V. Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. J Cachex Sarcopenia Muscle. 2010;1(1):9-21.
31. Williams A, Sun X, Fischer J. The expression of genes in the ubiquitin-proteasome proteolytic pathway is increased in skeletal muscle from patients with cancer. Surgery. 1999;1999(126):744-9.
32. Llovera M, García-Martínez C, López-Soriano J, Carbó N, Agell N, López-Soriano FJ, et al. Role of TNF receptor 1 in protein turnover during cancer cachexia using gene knockout mice. Mol Cell Endocrinol. 1998;142(1-2):183-9.
33. Ungureanu-Longrois D, Balligand J. Myocardial contractile dysfunction in the systematic inflammatory response syndrome: role of a cytokine-inducible nitric oxide synthase in cardiac myocytes. J Mol Cell Cardiol. 1995;1995(27):155-67.
34. Sherry B, Gelin J, Fong Y, Marano M, Wei H. Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of cachexia in tumor models. FASEB J. 1989;3:1956-62.
35. Trikha M, Corringham R, Klein B. Targeted anti-interleukin-6 monoclonal antibody therapy for cancer. Clin Cancer Res. 2003;9:4653-65.
36. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340(6):448-54.
37. Falconer JS, Fearon KC, Ross JA, Elton R, Wigmore SJ, Garden OJ, et al. Acute-phase protein response and survival duration of patients with pancreatic cancer. Cancer. 1995;75(8):2077-82.
38. Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg. 1994;219(4):325-31.
39. O'Gorman P, McMillan DC, McArdle CS. Prognostic factors in advanced gastrointestinal cancer patients with weight loss. Nutr Cancer. 1999;37(1):36-40.
40. McMillan DC. An inflammation-based prognostic score and its role in the nutrition-based management of patients with cancer. Proc Nutr Soc. 2008;67(03):257-62.
41. McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care. 2009;12(3):223-6.
42. Marsik C, Kazemi-Shirazi L, Schickbauer T, Winkler S, Joukhadar C, Wagner OF, et al. C-reactive protein and all-cause mortality in a large hospital-based cohort. Clin Chem. 2008;54(2):343-9.
43. Scott HR, McMillan DC, Brown DJF, Forrest LM, McArdle CS, Milroy R. A prospective study of the impact of weight loss and the systemic inflammatory response on quality of life in patients with inoperable non-small cell lung cancer. Lung Cancer. 2003;40(3):295-9.
44. Deans D, Tan B, Wigmore S, Ross J, de Beaux A, Paterson-Brown S, et al. The influence of systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastro-oesophageal cancer. Br J Cancer. 2009;100(1):63-9.
45. Tisdale MJ. Mechanisms of Cancer Cachexia. Physiol Rev. 2009;89(2):381-410.
46. Guttridge DC. The biology of cancer cachexia and the role of TNF-α. In: Caligiuri MA, Lotze MT, editors. Cytokines in the genesis and treatment of cancer. Totowa, NJ: Humana Press; 2007. p. 285-303.
47. Lum JJ, DeBerardinis RJ, Thompson CB. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol. 2005;6(6):439-48.
48. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004;117(3):399-412.
49. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6(6):458-71.
50. Dodd SL, Gagnon BJ, Senf SM, Hain BA, Judge AR. Ros-mediated activation of NF-kappaB and Foxo during muscle disuse. Muscle Nerve. 2010;41(1):110-3.
51. Lorite MJ, Smith HJ, Arnold JA, Morris A, Thompson MG, Tisdale MJ. Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro by a proteolysis-inducing factor (PIF). Br J Cancer. 2001;85(2):297-302.
52. Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA. 2006;103(44):16260-5.
53. Glass DJ. Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol. 2003;5(2):87-90.
54. Guttridge DC. Signaling pathways weigh in on decisions to make or break skeletal muscle. Curr Opin Clin Nutr Metab Care. 2004;7(4):443-50.
55. Eley HL, Russell ST, Tisdale MJ. Effect of branched-chain amino acids on muscle atrophy in cancer cachexia. Biochem J. 2007;407(1):113-20.
56. Elkina Y, Haehling S, Anker SD, Springer J. The role of myostatin in muscle wasting: an overview. J Cachex Sarcopenia Muscle. 2011;2(3):143-51.
57. Benny Klimek ME, Aydogdu T, Link MJ, Pons M, Koniaris LG, Zimmers TA. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochem Biophys Res Commun. 2010;391(3):1548-54.
58. Bonetto A, Penna F, Minero VG, Reffo P, Bonelli G, Baccino FM, et al. Deacetylase inhibitors modulate the myostatin/follistatin axis without improving cachexia in tumor-bearing mice. Curr Cancer Drug Targets. 2009;9(5):608-16.
59. van Royen M, Carbó N, Busquets S, Alvarez B, Quinn LS, López-Soriano FJ, et al. DNA fragmentation occurs in skeletal muscle during tumor growth: a link with cancer cachexia? Biochem Biophys Res Commun. 2000;270(2):533-7.
60. Belizário JE, Lorite MJ, Tisdale MJ. Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia. Br J Cancer. 2001;84(8):1135-40.
61. Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol. 2009;296(6):C1258-70.
62. Amirouche A, Durieux A-C, Banzet S, Koulmann N, Bonnefoy R, Mouret C, et al. Down-regulation of Akt/mammalian target of rapamycin signaling pathway in response to myostatin overexpression in skeletal muscle. Endocrinology. 2009;150(1):286-94.
63. Morissette MR, Cook SA, Buranasombati C, Rosenberg MA, Rosenzweig A. Myostatin inhibits IGF-I-induced myotube hypertrophy through Akt. Am J Physiol Cell Physiol. 2009;297(5):C1124-32.
64. Chen RH, Su YH, Chuang RL, Chang TY. Suppression of transforming growth factor-beta-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway. Oncogene. 1998;17(15):1959-68.
65. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol. 2001;3(11):1014-9.
66. Zdychová J, Komers R. Emerging role of Akt kinase/protein kinase B signaling in pathophysiology of diabetes and its complications. Physiol Res. 2005;54(1):1-16.
67. Brink M, Wellen J, Delafontaine P. Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. J Clin Invest. 1996;97(11):2509-16.
68. Musarò A, Giacinti C, Borsellino G, Dobrowolny G, Pelosi L, Cairns L, et al. Stem cell-mediated muscle regeneration is enhanced by local isoform of insulin-like growth factor 1. Proc Natl Acad Sci USA. 2004;101(5):1206-10.
69. Costelli P, Muscaritoli M, Bossola M, Penna F, Reffo P, Bonetto A, et al. IGF-1 is downregulated in experimental cancer cachexia. Am J Physiol Regul Integr Comp Physiol. 2006;291(3):R674-83.
70. Buck M, Chojkier M. Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants. EMBO J. 1996;15(8):1753-65.
71. Laviano A, Meguid MM, Preziosa I, Fanelli FR. Oxidative stress and wasting in cancer. Curr Opin Clin Nutr Metab Care. 2007;10(4):449-56.
72. Barreiro E, la Puente de B, Busquets S. Both oxidative and nitrosative stress are associated with muscle wasting in tumour-bearing rats. FEBS Lett. 2005;579:1646-52.
73. Mantovani G, Macciò A, Madeddu C, Mura L, Gramignano G, Lusso MR, et al. Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J Mol Med. 2003;81(10):664-73.
74. Chlebowski RT, Heber D. Hypogonadism in male patients with metastatic cancer prior to chemotherapy. Cancer Res. 1982;42(6):2495-8.
75. Zitzmann M. Hormone substitution in male hypogonadism. Mol Cell Endocrinol. 2000;2000(161):73-88.
76. Lobo RA. Androgens in postmenopausal women: production, possible role, and replacement options. Obstet Gynecol Surv. 2001;56(6):361-76.
77. Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr. 2008;27(6):793-9.
78. Hein L, Barsh G, Pratt R, Dzau V. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor gene in mice. Nature. 1995;1995(377):744-7.
79. Garcia J, Li H, Mann D, Epner D, Hayes T. Hypogonadism in male patients with cancer. Cancer. 2006;2006(106):2583-91.
80. Fearon K, Dahele M, Skipworth R. Citation information. In: Nicholson J, Hofbauer K, Anker S, Inui A, editors. Pharmacotherapy of Cachexia. Boca Raton: CRC Press; 2009. p. 117-42.
81. Bozzetti F. Basics in clinical nutrition: nutritional support in cancer. Eur J Clin Nutr Metab (e-SPEN). 5(3):e148-52.
82. Tohgo A, Kumazawa E, Akahane K, Asakawa A, Inui A. Anticancer drugs that induce cancer-associated cachectic syndromes. Expert Rev Anticancer Ther. 2002;2(1):121-9.
83. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489-95.
84. Mahmoud FA, Rivera NI. The role of C-reactive protein as a prognostic indicator in advanced cancer. Curr Oncol Rep. 2002;4(3):250-5.
85. Deans CC, Wigmore SJS. Systemic inflammation, cachexia and prognosis in patients with cancer. Curr Opin Clin Nutr Metab Care. 2005;8(3):265-9.
86. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102(18):2165-8.
87. Pasceri V, Cheng JS, Chang J. 5. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001;103(21):2531-4.
88. Mantovani G. The Current Management of Cancer Cachexia. Mantovani G, Anker SD, Inui A, Morley JE, Fanelli FR, Scevola D, et al., editors. Cachexia and wasting: a modern approach. link.springer.com. Milan: Springer; 2006. p. 563-79.
89. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, et al. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci USA. 2000;97(9):4844-9.
90. Schwartz SA, Hernandez A, Mark Evers B. The role of NF-kappaB/IkappaB proteins in cancer: implications for novel treatment strategies. Surg Oncol. 1999;8(3):143-53.
91. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225-60.
92. Lawrence T, Gilroy DW, Colville-Nash PR, Willoughby DA. Possible new role for NF-kappaB in the resolution of inflammation. Nat Med. 2001;7(12):1291-7.
93. Loewe R, Holnthoner W, Gröger M, Pillinger M, Gruber F, Mechtcheriakova D, et al. Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells. J Immunol. 2002;168(9):4781-7.
94. Langen RCR, Schols AMA, Janssen-Heininger YMY. 5. Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor-kappaB. FASEB J. 2001;15(7):1169-80.
95. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989;170(6):2081-95.
96. Groesdonk HV, Senftleben U. Modulation of inhibitor kappaB kinase/nuclear factor kappaB signaling during critical illness: a double-edged sword. Crit Care Med. 2004;32(5):1239-40.
97. Radbruch L, Elsner F, Trottenberg P, Strasser F, Fearon K. Clinical practice guidelines on cancer cachexia in advanced cancer patients. Aachen, Department of Palliative Medicinen/European Palliative Care Research Collaborative. 2010.
98. Barber MD, Ross JA, Fearon KC. Cancer cachexia. Surg Oncol. 1999;8(3):133-41.
99. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin. 2002;52(2):72-91.
100. Del Fabbro E, Dalal S, Bruera E. Symptom control in palliative care - Part II: cachexia/anorexia and fatigue. J Palliat Med. 2006;9(2):409-21.
101. Topkan E, Yavuz AA, Ozyilkan O. Cancer cachexia: pathophysiologic aspects and treatment options. Asian Pac J Cancer Prev. 2007;8(3):445-51.
102. Mantovani G, Macciò A, Madeddu C, Serpe R, Massa E, Dessì M, et al. Randomized Phase III Clinical Trial of Five Different Arms of Treatment in 332 Patients with Cancer Cachexia. Oncologist. 2010;15(2):200-11.
103. Tazi E, Errihani H. Treatment of cachexia in oncology. Indian J Palliat Care. 2010;16(3):129-37.
104. Nelson KA. The cancer anorexia-cachexia syndrome. Semin Oncol. 2000;27(1):64-8.
105. Gagnon B, Bruera E. A review of the drug treatment of cachexia associated with cancer. Drugs. 1998;55(5):675-88.
106. Argiles JM, Meijsing SH, Pallarés-Trujillo J, Guirao X, López-Soriano FJ. Cancer cachexia: a therapeutic approach. Med Res Rev. 2000;21(1):83-101.
107. Nelson K, Walsh D, Deeter P, Sheehan F. A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. J Palliat Care. 1993;10(1):14-8.
108. Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG. Recent clinical experience with dronabinol. Pharmacol Biochem Behav. 1991;40(3):695-700.
109. Mantovani G, Maccio A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs. 2001;61(4):499-514.
110. Kardinal CG, Loprinzi CL, Schaid DJ, Hass AC, Dose AM, Athmann LM, et al. A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer. 1990;65(12):2657-62.
111. Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, et al. Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition. 2000;16(10):843-57.
112. Laviano A, Meguid MM, Yang ZJ, Gleason JR, Cangiano C, Fanelli FR. Cracking the riddle of cancer anorexia. Nutrition. 1996;12(10):706-10.
113. Moertel CG, Kvols LK, Rubin J. A study of cyproheptadine in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer. 1990;67(1):33-6.
114. Daviss WB, Scott J. A chart review of cyproheptadine for stimulant-induced weight loss. J Child Adolesc Psychopharmacol. 2004;14(1):65-73.
115. Genazzani AD, Strucchi C, Malavasi B, Tortolani F, Vecchi F, Luisi S, et al. Effects of cyproheptadine clorhydrate, a serotonin receptor antagonist, on endocrine parameters in weight-loss related amenorrhea. Gynecol Endocrinol. 2001;15(4):279-85.
116. Feliui J, Gontález-Barón M, Berrocal A, Ordónez A, Barón-Saura JM. Treatment of cancer anorexia with megestrol acetate: which is the optimal dose? J Natl Cancer Inst. 1991;83(6):449-50.
117. Loprinzi CL, Ellison NM, Schaid DJ, Krook JE, Athmann LM, Dose AM, et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst. 1990;82(13):1127-32.
118. Loprinzi CL, Michalak JC, Schaid DJ, Mailliard JA, Athmann LM, Goldberg RM, et al. Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J Clin Oncol. 1993;11(4):762-7.
119. Bruera E, Macmillan K, Kuehn N, Hanson J, MacDonald RN. A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advanced cancer. Cancer. 1990;66(6):1279-82.
120. Tchekmedyian NSN, Hickman MM, Siau JJ, Greco FAF, Keller JJ, Browder HH, et al. Megestrol acetate in cancer anorexia and weight loss. Cancer. 1992;69(5):1268-74.
121. Loprinzi CL, Schaid DJ, Dose AM, Burnham NL, Jensen MD. Body-composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol. 1993;11(1):152-4.
122. Rowland KM, Loprinzi CL, Shaw EG, Maksymiuk AW, Kuross SA, Jung SH, et al. Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer Treatment Group study. J Clin Oncol. 1995;14(1):135-41.
123. Maltoni M, Nanni O, Scarpi E, Rossi D, Serra P, Amadori D. High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: a systematic review of randomised clinical trials. Ann Oncol. 2001;12(3):289-300.
124. Bruera EE. Pharmacological treatment of cachexia: any progress? Support Care Cancer. 1998;6(2):109-13.
125. Schwartz M, Dallman M. Hypothalamic response to starvation: implications for the study of wasting disorders. Am J Physiol. 1995;269:R949-57.
126. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS. Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci. 1998;1(6):445-50.
127. Woods SC, Seeley RJ, Porte D, Schwartz MW. Signals that regulate food intake and energy homeostasis. Science. 1998;280(5368):1378-83.
128. Bray G, York D. The MONA LISA hypothesis in the time of leptin. Recent Prog Horm Res. 1998;53:95-117.
129. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev. 1999;20(1):68-100.
130. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661-71.
131. Inui A. Transgenic approach to the study of body weight regulation. Pharmacol Rev. 2000;52(1):35-61.
132. Inui A. Transgenic study of energy homeostasis equation: implications and confounding influences. FASEB J. 2000;14(14):2158-70.
133. Plata-Salamán C. Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition. 2000;16:1009-12.
134. 2+ channel current modulation by megestrol acetate via a G-protein alpha s-subunit in rat hypothalamic neurones. J Physiol (Lond.). 1995;487 (Pt 2):291-303.
135. John M. Appetite stimulants. In: Nicholson JR, Hofbauer KG, Anker SD, Inui A, editors. Pharmacotherapy of cachexia. Boca Raton: CRC Press; 2005. p. 291-302. http://www.crcnetbase.com/doi/abs/10.1201/9781420048957.ch16.
136. Kaegi E. Unconventional therapies for cancer: 4. Hydrazine sulfate. Task force on alternative therapies of the Canadian breast cancer research initiative. CMAJ. 1998;158(10):1327-30.
137. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-60.
138. Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci. 2001;2(8):551-60.
139. Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab. 2000;85(12):4908-11.
140. Arvat E, Maccario M, Di Vito L, Broglio F, Benso A, Gottero C, et al. Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab. 2001;86(3):1169-74.
141. Hataya Y, Akamizu T, Takaya K, Kanamoto N, Ariyasu H, Saijo M, et al. A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab. 2001;86(9):4552.
142. Akamizu T, Takaya K, Irako T, Hosoda H, Teramukai S, Matsuyama A, et al. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur J Endocrinol. 2004;150(4):447-55.
143. Akamizu T, Kangawa K. Ghrelin for cachexia. J Cachex Sarcopenia Muscle. 2010;1(2):169-76.
144. Gibney J, Healy ML, Sonksen PH. The growth hormone/insulin-like growth factor-I Axis in exercise and sport. Endocr Rev. 2007;28(6):603-24.
145. Velloso CP. Regulation of muscle mass by growth hormone and IGF-I. Br J Pharmacol. 2008;154(3):557-68.
146. Gonzalez-Rey E, Chorny A, Delgado M. Therapeutic action of ghrelin in a mouse model of colitis. Gastroenterology. 2006;130(6):1707-20.
147. Waseem T, Duxbury M, Ito H, Ashley SW, Robinson MK. Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery. 2008;143(3):334-42.
148. Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest. 2004;114(1):57-66.
149. Li WG, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll LL, et al. Ghrelin inhibits proinflammatory responses and nuclear factor-κB activation in human endothelial cells. Circulation. 2004;109:2221-6.
150. Wu R, Dong W, Zhou M, Zhang F, Marini CP, Ravikumar TS, et al. Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats. Am J Respir Crit Care Med. 2007;176(8):805-13.
151. Theil M-M, Miyake S, Mizuno M, Tomi C, Croxford JL, Hosoda H, et al. Suppression of experimental autoimmune encephalomyelitis by ghrelin. J Immunol. 2009;183(4):2859-66.
152. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117(2):289-96.
153. Balasubramaniam A, Joshi R, Su C, Friend LA, Sheriff S, Kagan RJ, et al. Ghrelin inhibits skeletal muscle protein breakdown in rats with thermal injury through normalizing elevated expression of E3 ubiquitin ligases MuRF1 and MAFbx. Am J Physiol Regul Integr Comp Physiol. 2009;296(4):R893-901.
154. Sheriff S, Joshi R, Friend LA, James JH, Balasubramaniam A. Ghrelin receptor agonist, GHRP-2, attenuates burn injury-induced MuRF-1 and MAFbx expression and muscle proteolysis in rats. Peptides. 2009;30(10):1909-13.
155. Yamamoto D, Ikeshita N, Matsubara T, Tasaki H, Herningtyas EH, Toda K, et al. GHRP-2, a GHS-R agonist, directly acts on myocytes to attenuate the dexamethasone-induced expressions of muscle-specific ubiquitin ligases, Atrogin-1 and MuRF1. Life Sci. 2008;82(9-10):460-6.
156. Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors 10.1016/S1097- 2765(04), 00211-4: molecular Cell | ScienceDirect.com. Mol Cell. 2004;14:395-403.
157. Nagaya N, Kojima M, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia. Intern Med. 2005;45(3):127-34.
158. Garcia J, Boccia R, Graham C. A phase II randomized, placebo-controlled, double-blind study of the efficacy and safety of RC-1291 (RC) for the treatment of cancer cachexia. J Clin Oncol. 2007;25:9133.
159. Olaku O, White JD. Herbal therapy use by cancer patients: a literature review on case reports. Eur J Cancer. 2011;47(4):508-14.
160. Kusunoki H, Haruma K, Hata J, Ishii M, Kamada T, Yamashita N, et al. Efficacy of Rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. Intern Med. 2010;49(20):2195-202.
161. Takahashi T, Endo S, Nakajima K, Souma Y, Nishida T. Effect of rikkunshito, a chinese herbal medicine, on stasis in patients after pylorus-preserving gastrectomy. World J Surg. 2009;33(2):296-302.
162. Oyachi N, Takano K, Hasuda N, Arai H. Effects of Rikkunshi-to on infantile hypertrophic pyloric stenosis, refractory to atropine. Pediatr Int. 2008;2008(50):581-3.
163. Oka T, Tamagawa Y, Hayashida S, Kaneda Y, Kodama N, Tsuji S. Rikkunshi-to attenuates adverse gastrointestinal symptoms induced by fluvoxamine. Biopsychosoc Med. 2007;1:21.
164. Yagi M, Homma S, Kubota M, Iinuma Y. The herbal medicine Rikkunshi-to stimulates and coordinates the gastric myoelectric activity in post-operative dyspeptic children after gastrointestinal surgery. Pediatr Surg Int. 2004;2004(19):760-5.
165. Kawahara H, Okuyama H, Nose K, Nakai H, Yoneda A, Kubota A, et al. Physiological and clinical characteristics of gastroesophageal reflux after congenital diaphragmatic hernia repair. J Pediatr Surg. 2010;45(12):2346-50.
166. Sadakane C, Muto S, Nakagawa K, Ohnishi S, Saegusa Y, Nahata M, et al. 10-Gingerol, a component of rikkunshito, improves cisplatin-induced anorexia by inhibiting acylated ghrelin degradation. Biochem Biophys Res Commun. 2011;412(3):506-11.
167. Huang C, Lin S, Liao P, Young S. The immunopharmaceutical effects and mechanisms of herb medicine. Cell Mol Immunol. 2008;5:23-31.
168. Kumar NB, Kazi A, Smith T, Crocker T, Yu D, Reich RR, et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr Treat Options Oncol. 2010;11(3-4):107-17.
169. Couch M, Lai V, Cannon T, Guttridge D, Zanation A, George J, et al. Cancer cachexia syndrome in head and neck cancer patients: part I. Diagnosis, impact on quality of life and survival, and treatment. Head Neck. 2007;29(4):401-11.
170. Fearon KCH, Von Meyenfeldt MF, Moses AGW, Van Geenen R, Roy A, Gouma DJ, et al. Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut. 2003;52(10):1479-86.
171. Fearon KCH. Cancer cachexia: developing multimodal therapy for a multidimensional problem. Eur J Cancer. 2008;44(8):1124-32.
172. Palesty JA, Dudrick SJ. Cachexia, malnutrition, the refeeding syndrome, and lessons from Goldilocks. Surg Clin North Am. 2011;91(3):653-73.
173. Khan LUR, Ahmed J, Khan S, Macfie J. Refeeding syndrome: a literature review. Gastroenterol Res Pract. 2010;2011.
174. Solomon SM, Kirby DF. The refeeding syndrome: a review. J Parenter Enteral Nutr. 1990;14(1):90-7.
175. Sobotka L. Refeeding syndrome. Basics in clinical nutrition. 3rd ed. Prague: Galen; 2004. p. 288-91.
176. Ardies CM. Exercise, cachexia, and cancer therapy: a molecular rationale. Nutr Cancer. 2001;42(2):143-57.
177. al-Majid S, McCarthy DO. Cancer-induced fatigue and skeletal muscle wasting: the role of exercise. Biol Res Nurs. 2001;2(3):186-97.
178. Doyle CC, Kushi LHL, Byers TT, Courneya KSK, Demark-Wahnefried WW, Grant BB, et al. Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices. CA Cancer J Clin. 2005;56:323-53.
179. Strasser F. Eating-related disorders in patients with advanced cancer. Support Care Cancer. 2003;11(1):11-20.
180. Ravasco P, Monteiro Grillo I, Camilo M. Cancer wasting and quality of life react to early individualized nutritional counselling! Clin Nutr. 2007;26(1):7-15.
181. Whitman MM. The starving patient: supportive care for people with cancer. Clin J Oncol Nurs. 2000;4(3):121-5.
182. Samuels SE, Knowles AL, Tilignac T, Debiton E, Madelmont JC, Attaix D. Protein metabolism in the small intestine during cancer cachexia and chemotherapy in mice. Cancer Res. 2000;60(17):4968-74.
183. Nelson K, Walsh D, Sheehan F. Cancer and chemotherapy-related upper gastrointestinal symptoms: the role of abnormal gastric motor function and its evaluation in cancer patients. Support Care Cancer. 2002;10(6):455-61.
184. SMITH GF, TOONEN TR. Primary care of the patient with cancer. [Internet]. Am Fam Physician. 2007 [cited 2012 Mar 9]. pages 1207-14. Available from: http://www.aafp.org/afp/2007/0415/p1207.html.
185. Jenns K. Importance of nausea. Cancer Nurs. 1994;17:488-93.
186. Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD, Harker G, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15(1):103-9.
187. Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of antiemetic agents. J Natl Cancer Inst. 1991;83(9):613-20.
188. Koeller J, Aapro M, Gralla R, Grunberg S, Hesketh P, Kris M, et al. Antiemetic guidelines: creating a more practical treatment approach. Support Care Cancer. 2002;10(7):519-22.
189. Grunberg SM, Koeller JM. Palonosetron: a unique 5-HT3-receptor antagonist for the prevention of chemotherapy-induced emesis. Expert Opin Pharmacother. 2012;4(12):2297-303.
190. McNulty R. Are all 5-HT3 receptor antagonists the same? J Natl Compr Canc Netw. 2007;5(1):35-43.
191. Eisenberg PP, Figueroa-Vadillo JJ, Zamora RR, Charu VV, Hajdenberg JJ, Cartmell AA, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98(11):2473-82.
192. Roila F, Tonato M, Cognetti F, Cortesi E, Favalli G, Marangolo M, et al. Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol. 1991;9(4):675-8.
193. Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin-the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21(22):4112-9.
194. de Wit R, Herrstedt J, Rapoport B, Carides AD, Guoguang-Ma J, Elmer M, et al. The oral NK(1) antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebo-controlled phase III clinical trials. Eur J Cancer. 2004;40(3):403-10.
195. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;2002:730-51.
196. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966;64(2):328-40.
197. Balducci L, Hardy CL, Lyman GH. Hematopoietic growth factors in the older cancer patient. Curr Opin Hematol. 2001;8(3):170-87.
198. Sullivan DH, Walls RC. Impact of nutritional status on morbidity in a population of geriatric rehabilitation patients. J Am Geriatr Soc. 1994;42(5):471-7.
199. Sullivan DH. Impact of nutritional status on health outcomes of nursing home residents. J Am Geriatr Soc. 1995;43(2):195-6.
200. Sullivan DH, Walls RC, Bopp MM. Protein-energy undernutrition and the risk of mortality within one year of hospital discharge: a follow-up study. J Am Geriatr Soc. 1995;43(5):507-12.
201. Sullivan DH. The role of nutrition in increased morbidity and mortality. Clin Geriatr Med. 1995;11(4):661-74.
202. Omran ML, Morley JE. Assessment of protein energy malnutrition in older persons, part I: history, examination, body composition, and screening tools. Nutrition. 2000;16(1):50-63.
203. Thomas DR, Ashmen W, Morley JE, Evans WJ. Nutritional management in long-term care: development of a clinical guideline. Council for Nutritional Strategies in Long-Term Care. J Gerontol A Biol Sci Med Sci. 2000;55:M725-34.
204. Bastow M, Rawlings J, Allison S. Benefits of supplementary tube feeding after fractured neck of femur: a randomised controlled trial. Br Med J. 1983;287:1589-92.
205. Woo J, Ho SC, Mak YT, Law LK, Cheung A. Nutritional status of elderly patients during recovery from chest infection and the role of nutritional supplementation assessed by a prospective randomized single-blind trial. Age Ageing. 1994;23(1):40-8.
206. McMurtry CT, Rosenthal A. Predictors of 2-year mortality among older male veterans on a geriatric rehabilitation unit. J Am Geriatr Soc. 1995;43(10):1123-6.
207. Yeh S-S, Schuster MW. Treatment of cachexia in the elderly. In: Mantovani G, Anker SD, Inui A, Morley JE, Fanelli FR, Scevola D, et al., editors. Cachexia and wasting: a modern approach. link.springer.com. Milan: Springer; 2006. p. 701-17.
208. Brinksma A, Huizinga G, Sulkers E, Kamps W, Roodbol P, Tissing W. Malnutrition in childhood cancer patients: a review on its prevalence and possible causes. Crit Rev Oncol Hematol. 2012;83:249-75.
209. Cole TJ. Assessment of growth. Best Pract Res Clin Endocrinol Metab. 2002;16(3):383-98.
210. Wilcox WD, Nieburg P, Miller DS. Failure to thrive. A continuing problem of definition. Clin Pediatr (Phila). 1989;28(9):391-4.
211. Jolley CD. Failure to thrive. Curr Probl Pediatr Adolesc Health Care. 2003;33(6):183-206.
212. Lai J-S, Cella D, Goldman S. 5. Anorexia/cachexia-related quality of life for children with cancer. Cancer. 2005;104(7):1531-9.