Turkiye Klinikleri Journal of Internal Medicine

.: REVIEW
Kanser Kaşeksisi: Etiyopatogenez ve Klinikte Az Bilinen Komplikasyonlar: Sistematik Derleme
Cancer Cachexia: Etiopathogenesis & Clinically Ignored Complications: Systematic Review
Onur Yazdan BALÇIKa, Sabri BARUTCAa
aAydın Adnan Menderes Üniversitesi Tıp Fakültesi, Tıbbi Onkoloji BD, Aydın, TÜRKİYE
Turkiye Klinikleri J Intern Med. 2021;6(3):117-23
doi: 10.5336/intermed.2021-83221
Article Language: TR
Full Text
ÖZET
Kaşeksi, kanser hastalarında yüksek oranda morbidite ve mortaliteye sebep olan karmaşık bir metabolik sendromdur. Kaşeksi, çok sayıda fonksiyonel, metabolik ve immünolojik bozukluklarla seyretmekle kalmayıp tedavi toleransı ve toksisitesini de olumsuz etkilemektedir. Kanser kaşeksisinin oluşumunda interlökin-1 (IL-1), IL-6, tümör nekrozis faktörü-alfa (TNF-α) gibi proinflamatuar sitokinler ve TNF ile ilişkili zayıf apoptoz indükleyicisi reseptörü Fn14 rol oynamaktadır. Tümör hücrelerince üretilen lipid mobilize edici faktör, yağ dokusunu azaltırken, kas kaybından ise ubikuitin ve Januskinaz-sinyal translasyon ve transkripsiyon yolağı ve kemik metastazlarında salgılanan transforme edici büyüme faktörü betanın katkısının olduğu düşünülmektedir. Bağırsak mikrobiyotasının da kaşeksi gelişiminde rol oynayabileceği düşünülmektedir. Kaşekside serotonin, dopamin, histamin ve kalsitonin gen-ilişkili peptid gibi nörotransmitterlerin ve ghrelin, leptin, kortikotropin salıcı faktör, nöropeptid Y, alfa-melanosit uyarıcı hormon gibi hormonların artışı sonucunda anoreksiye yatkınlık oluşmaktadır. Kanser kaşeksisinde kas kaybının yanında göz ardı edilen birçok klinik etki vardır. Kalp yetersizliği, trombositoz ve endotel geçirgenliğinde artış sonucunda oluşan koagülasyona yatkınlık mortaliteye sebep olabilmektedir. Kanser hastalarında artan glukoneogenez, artmış ghrelin üretimi, testosteron eksikliği ve düşük D vitamini seviyeleri glukoz metabolizmasının değişmesine katkıda bulunabilir. Kaşekside nöropati ve otonomik disfonksiyon da oluşabilir. Kaşekside hepatosteatoz ve psikososyal problemler de ortaya çıkabilmektedir. Kanser kaşeksisi patogenezi konusunda daha fazla araştırmaya ihtiyaç duyulmaktadır. Özellikle kanser hastalarını takip eden klinisyen hekimler bu süreci daha doğru yönetebilmek için kaşeksi etiyopatogenezi ve göz ardı edilen klinik bulgular konusunda bilgi sahibi olmalıdır.

Anahtar Kelimeler: Kanser; kaşeksi; etiyopatogenez; komplikasyonlar
ABSTRACT
Cachexia is a complicated metabolic syndrome, characterized by increased morbidity and mortality in cancer patients. Many functional, metabolic and immunological disorders accompany, and also the tolerance and toxicities of treatments are negatively affected in cancer cachexia. Proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α) and TNF-related weak apoptosis inducer receptor Fn14 play a role in the formation of cancer cachexia. While lipid mobilizing factor produced by tumor cells reduces adipose tissue, it is thought that ubiquitin and Janus kinase-signal translation and transcription pathway and transforming growth factor beta secreted in bone metastases contribute to muscle loss. Intestinal microbiata mat also have a role in the etiopathogenesis of cachexia. In cachexia, a predisposition to anorexia occurs as a result of the increase in neurotransmitters such as serotonin, dopamine, histamine and calcitonin gene-related peptide, and hormones such as ghrelin, leptin, corticotropin-releasing factor, neuropeptide Y, alpha-melanocyte stimulating hormone. Among many ignored clinical effects of cancer cachexia, cardiac insufficiency, hypercoagulation secondary to thrombocytosis and increased endothelial permeability can be mentioned. Increased gluconeogenesis, increased ghrelin production, testosterone deficiency, and low vitamin D levels in cancer patients may contribute to altered glucose metabolism. In cachexia, neuropathy and autonomic dysfunction can emerge hepatosteatosis as psychosocial problems can be seen in cachectic patients. Especially the clinicians who treat and follow the cancer patients should be more acknowledged on the etiopathogenesis and clinically ignored complications of cachexia for better management of this process.

Keywords: Cancer; cachexia; ethiopathogenesis; clinical complications
REFERENCES:
  1. Kotler DP. Cachexia. Ann Intern Med. 2000; 133(8):622-34. [Crossref]  [PubMed] 
  2. Davis MP, Dickerson D. Cachexia and anorexia: cancer's covert killer. Support Care Cancer. 2000;8(3):180-7. [Crossref]  [PubMed] 
  3. 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. [Crossref]  [PubMed] 
  4. Blum D, Strasser F. Cachexia assessment tools. Curr Opin Support Palliat Care. 2011;5(4):350-5. [Crossref]  [PubMed] 
  5. 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. [Crossref]  [PubMed] 
  6. Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH. Cancer-associated cachexia. Nat Rev Dis Primers. 2018;4:17105. [Crossref]  [PubMed] 
  7. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002;2(11):862-71. [Crossref]  [PubMed] 
  8. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med. 1995;332(10): 621-8. Erratum in: N Engl J Med 1995;333(6): 399. [Crossref]  [PubMed] 
  9. Fredrix EW, Wouters EF, Soeters PB, van der Aalst AC, Kester AD, von Meyenfeldt MF, et al. Resting energy expenditure in patients with non-small cell lung cancer. Cancer. 1991; 68(7):1616-21. [Crossref]  [PubMed] 
  10. Staal-van den Brekel AJ, Schols AM, ten Velde GP, Buurman WA, Wouters EF. Analysis of the energy balance in lung cancer patients. Cancer Res. 1994;54(24):6430-3. Erratum in: Cancer Res 1995;55(8):1809. [PubMed] 
  11. Tocco-Bradley R, Georgieff M, Jones CT, Moldawer LL, Dinarello CA, Blackburn GL, et al. Changes in energy expenditure and fat metabolism in rats infused with interleukin-1. Eur J Clin Invest. 1987;17(6):504-10. [Crossref]  [PubMed] 
  12. Van der Poll T, Romijn JA, Endert E, Borm JJ, Büller HR, Sauerwein HP. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol. 1991;261(4 Pt 1):E457-65. [Crossref]  [PubMed] 
  13. Hellerstein MK, Meydani SN, Meydani M, Wu K, Dinarello CA. Interleukin-1-induced anorexia in the rat. Influence of prostaglandins. J Clin Invest. 1989;84(1):228-35. [Crossref]  [PubMed]  [PMC] 
  14. Sonti G, Ilyin SE, Plata-Salamán CR. Anorexia induced by cytokine interactions at pathophysiological concentrations. Am J Physiol. 1996;270(6 Pt 2):R1394-402. [Crossref]  [PubMed] 
  15. Davis MP, Dreicer R, Walsh D, Lagman R, LeGrand SB. Appetite and cancer-associated anorexia: a review. J Clin Oncol. 2004;22(8):1510-7. [Crossref]  [PubMed] 
  16. Walsh D, Mahmoud F, Barna B. Assessment of nutritional status and prognosis in advanced cancer: interleukin-6, C-reactive protein, and the prognostic and inflammatory nutritional index. Support Care Cancer. 2003;11(1):60-2. [Crossref]  [PubMed] 
  17. Zeisler H, Tempfer C, Joura EA, Sliutz G, Koelbl H, Wagner O, et al. Serum interleukin 1 in ovarian cancer patients. Eur J Cancer. 1998;34(6):931-3. [Crossref]  [PubMed] 
  18. Mantovani G, Macciò A, Mura L, Massa E, Mudu MC, Mulas C, et al. Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites. J Mol Med (Berl). 2000;78(10):554-61. [Crossref]  [PubMed] 
  19. Staal-van den Brekel AJ, Dentener MA, Schols AM, Buurman WA, Wouters EF. Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. J Clin Oncol. 1995; 13(10):2600-5. [Crossref]  [PubMed] 
  20. 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. [Crossref]  [PubMed]  [PMC] 
  21. Kuroda K, Nakashima J, Kanao K, Kikuchi E, Miyajima A, Horiguchi Y, et al. Interleukin 6 is associated with cachexia in patients with prostate cancer. Urology. 2007;69(1):113-7. [Crossref]  [PubMed] 
  22. Johnston AJ, Murphy KT, Jenkinson L, Laine D, Emmrich K, Faou P, et al. Targeting of Fn14 prevents cancer-induced cachexia and prolongs survival. Cell. 2015;162(6):1365-78. [Crossref]  [PubMed] 
  23. 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. [Crossref]  [PubMed] 
  24. Guttridge DC, Mayo MW, Madrid LV, Wang CY, Baldwin AS Jr. NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science. 2000;289(5488):2363-6. [Crossref]  [PubMed] 
  25. Khan S, Tisdale MJ. Catabolism of adipose tissue by a tumour-produced lipid-mobilising factor. Int J Cancer. 1999;80(3):444-7. [Crossref]  [PubMed] 
  26. Todorov PT, McDevitt TM, Meyer DJ, Ueyama H, Ohkubo I, Tisdale MJ. Purification and characterization of a tumor lipid-mobilizing factor. Cancer Res. 1998;58(11):2353-8. [PubMed] 
  27. Islam-Ali B, Khan S, Price SA, Tisdale MJ. Modulation of adipocyte G-protein expression in cancer cachexia by a lipid-mobilizing factor (LMF). Br J Cancer. 2001;85(5):758-63. [Crossref]  [PubMed]  [PMC] 
  28. Bing C, Russell S, Becket E, Pope M, Tisdale MJ, Trayhurn P, et al. Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice. Br J Cancer. 2006;95(8):1028-37. [Crossref]  [PubMed]  [PMC] 
  29. Rydén M, Agustsson T, Laurencikiene J, Britton T, Sjölin E, Isaksson B, et al. Lipolysis--not inflammation, cell death, or lipogenesis--is invol ved in adipose tissue loss in cancer cac hexia. Cancer. 2008;113(7):1695-704. [Crossref]  [PubMed] 
  30. Das SK, Eder S, Schauer S, Diwoky C, Temmel H, Guertl B, et al. Adipose triglyceride lipase contributes to cancer-associated cac hexia. Science. 2011;333(6039):233-8. Erratum in: Science. 2011;333(6049):1576. [Crossref]  [PubMed] 
  31. Llovera M, Garcia-Martinez C, Agell N, Lopez-Soriano FJ, Argiles JM. Muscle wasting associated with cancer cachexia is linked to an important activation of the ATP-dependent ubiquitin-mediated proteolysis. Int J Cancer. 1995;61(1):138-41. [Crossref]  [PubMed] 
  32. Baracos VE, DeVivo C, Hoyle DH, Goldberg AL. Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma. Am J Physiol. 1995; 268(5 Pt 1):E996-1006. [Crossref]  [PubMed] 
  33. Llovera M, García-Martínez C, Agell N, López-Soriano FJ, Argilés JM. TNF can directly induce the expression of ubiquitin-dependent proteolytic system in rat soleus muscles. Biochem Biophys Res Commun. 1997;230(2): 238-41. [Crossref]  [PubMed] 
  34. Zhang L, Tang H, Kou Y, Li R, Zheng Y, Wang Q, et al. MG132-mediated inhibition of the ubiquitin-proteasome pathway ameliorates cancer cachexia. J Cancer Res Clin Oncol. 2013;139(7):1105-15. [Crossref]  [PubMed]  [PMC] 
  35. Quintás-Cardama A, Verstovsek S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res. 2013;19(8):1933-40. [Crossref]  [PubMed]  [PMC] 
  36. Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R, Puzis L, et al. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am J Physiol Endocrinol Metab. 2012;303(3): E410-21. [Crossref]  [PubMed]  [PMC] 
  37. Stephens NA, Gallagher IJ, Rooyackers O, Skipworth RJ, Tan BH, Marstrand T, et al. Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia. Genome Med. 2010;2(1):1. [Crossref]  [PubMed]  [PMC] 
  38. Murphy KT. The pathogenesis and treatment of cardiac atrophy in cancer cachexia. Am J Physiol Heart Circ Physiol. 2016;310(4):H466-77. [Crossref]  [PubMed] 
  39. Kazemi-Bajestani SM, Becher H, Fassbender K, Chu Q, Baracos VE. Concurrent evolution of cancer cachexia and heart failure: bilateral effects exist. J Cachexia Sarcopenia Muscle. 2014;5(2):95-104. [Crossref]  [PubMed]  [PMC] 
  40. Martignoni ME, Kunze P, Hildebrandt W, Künzli B, Berberat P, Giese T, et al. Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia. Clin Cancer Res. 2005;11(16):5802-8. [Crossref]  [PubMed] 
  41. Kalantar-Zadeh K, Rhee C, Sim JJ, Stenvinkel P, Anker SD, Kovesdy CP. Why cachexia kills: examining the causality of poor outcomes in wasting conditions. J Cachexia Sarcopenia Muscle. 2013;4(2):89-94. [Crossref]  [PubMed]  [PMC] 
  42. Reddel CJ, Allen JD, Ehteda A, Taylor R, Chen VM, Curnow JL, et al. Increased thrombin generation in a mouse model of cancer cachexia is partially interleukin-6 dependent. J Thromb Haemost. 2017;15(3):477-86. [Crossref]  [PubMed] 
  43. Gros A, Ollivier V, Ho-Tin-Noé B. Platelets in inflammation: regulation of leukocyte activities and vascular repair. Front Immunol. 2015;5:678. [Crossref]  [PubMed]  [PMC] 
  44. Kolka CM, Bergman RN. The barrier within: endothelial transport of hormones. Physiology (Bethesda). 2012;27(4):237-47. [Crossref]  [PubMed]  [PMC] 
  45. Friesen DE, Baracos VE, Tuszynski JA. Modeling the energetic cost of cancer as a result of altered energy metabolism: implications for cachexia. Theor Biol Med Model. 2015; 12:17. [Crossref]  [PubMed]  [PMC] 
  46. Goncalves MD, Hwang SK, Pauli C, Murphy CJ, Cheng Z, Hopkins BD, et al. Fenofibrate prevents skeletal muscle loss in mice with lung cancer. Proc Natl Acad Sci U S A. 2018; 115(4):E743-E752. Erratum in: Proc Natl Acad Sci U S A. 2018;: [Crossref]  [PubMed]  [PMC] 
  47. Burfeind KG, Michaelis KA, Marks DL. The central role of hypothalamic inflammation in the acute illness response and cachexia. Semin Cell Dev Biol. 2016;54:42-52. [Crossref]  [PubMed]  [PMC] 
  48. Campos CA, Bowen AJ, Han S, Wisse BE, Palmiter RD, Schwartz MW. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nat Neurosci. 2017;20(7):934-42. [Crossref]  [PubMed]  [PMC] 
  49. Cone RD. The central melanocortin system and energy homeostasis. Trends Endocrinol Metab. 1999;10(6):211-6. [Crossref]  [PubMed] 
  50. Elmquist JK. Anatomic basis of leptin action in the hypothalamus. Front Horm Res. 2000; 26:21-41. [Crossref]  [PubMed] 
  51. Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD, Wiegand SJ. The ciliary neurotrophic factor and its receptor, CNTFR alpha. Pharm Acta Helv. 2000;74(2-3):265-72. [Crossref]  [PubMed] 
  52. Williams G, Harrold JA, Cutler DJ. The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box. Proc Nutr Soc. 2000;59(3):385-96. [Crossref]  [PubMed] 
  53. Woods SC, Schwartz MW, Baskin DG, Seeley RJ. Food intake and the regulation of body weight. Annu Rev Psychol. 2000;51:255-77. [Crossref]  [PubMed] 
  54. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817):194-8. [Crossref]  [PubMed] 
  55. Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000; 407(6806):908-13. [Crossref]  [PubMed] 
  56. Ahima RS, Qi Y, Singhal NS, Jackson MB, Scherer PE. Brain adipocytokine action and metabolic regulation. Diabetes. 2006;55 Suppl 2:S145-54. [Crossref]  [PubMed] 
  57. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395(6704):763-70. [Crossref]  [PubMed] 
  58. Lau LHS, Wong SH. Microbiota, obesity and NAFLD. Adv Exp Med Biol. 2018;1061:111-25. [Crossref]  [PubMed] 
  59. Schieber AM, Lee YM, Chang MW, Leblanc M, Collins B, Downes M, et al. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science. 2015;350(6260):558-63. [Crossref]  [PubMed]  [PMC] 
  60. Choi E, Carruthers K, Zhang L, Thomas N, Battaglino RA, Morse LR, et al. Concurrent muscle and bone deterioration in a murine model of cancer cachexia. Physiol Rep. 2013;1(6):e00144. [Crossref]  [PubMed]  [PMC] 
  61. Waning DL, Mohammad KS, Reiken S, Xie W, Andersson DC, John S, et al. Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat Med. 2015; 21(11):1262-71. [Crossref]  [PubMed]  [PMC] 
  62. White JP, Puppa MJ, Narsale A, Carson JA. Characterization of the male ApcMin/+ mouse as a hypogonadism model related to cancer cachexia. Biol Open. 2013;2(12): 1346-53. [Crossref]  [PubMed]  [PMC] 
  63. Hetzler KL, Hardee JP, LaVoie HA, Murphy EA, Carson JA. Ovarian function's role during cancer cachexia progression in the female mouse. Am J Physiol Endocrinol Metab. 2017;312(5):E447-E459. [Crossref]  [PubMed]  [PMC] 
  64. Hundsberger T, Omlin A, Haegele-Link S, Vehoff J, Strasser F. Autonomic dysfunction in cancer cachexia coincides with large fiber polyneuropathy. J Pain Symptom Manage. 2014;48(4):611-8.e1. [Crossref]  [PubMed] 
  65. Dev R, Bruera E, Dalal S. Insulin resistance and body composition in cancer patients. Ann Oncol. 2018;29(suppl_2):ii18-ii26. [Crossref]  [PubMed] 
  66. Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, et al. Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation. 2001;104(17):2034-8. [Crossref]  [PubMed] 
  67. Oberholzer R, Hopkinson JB, Baumann K, Omlin A, Kaasa S, Fearon KC, et al. Psychosocial effects of cancer cachexia: a systematic literature search and qualitative analysis. J Pain Symptom Manage. 2013;46(1):77-95. [Crossref]  [PubMed] 

.: Up To Date

Login



Contact


Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com