With the advent of immunotherapy the topic of biomarkers of immune response is of high interest. Along with the expression of programmed death ligand 1 (PD-L1) or tumor infiltrating lymphocytes (TIL), biomarkers of macrophage activation could be of interest. Neopterin is a biomarker of immune activation increased in different disorders associated with immune activation, including cancer. Neopterin synthesis is induced by interferon-γ that also induces indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing catabolism of tryptophan to kynurenine. Increased urinary or serum concentrations of neopterin have been associated with poor prognosis across a spectrum of malignant disorders of different primary location. Neopterin concentration in peripheral blood as well as in the tumor microenvironment correlates with phenotypic and functional changes of lymphocytes, indicating immune dysfunction. Increased neopterin concentrations are also accompanied by increased rate of conversion of tryptophan to kynurenine. Increasing neopterin concentrations also accompany side effects of anticancer treatment and could predict subsequent complications. Although almost four decades have elapsed since the discovery of increased neopterin concentrations in cancer patients, the full potential of neopterin as a biomarker in this setting has not been so far realized.

3rd Department of Medicine Charles University Medical School and Teaching Hospital Hradec Králové Czech Republic

4th Department of Medicine Charles University Medical School and Teaching Hospital Hradec Králové Czech Republic

Department of Analytical Chemistry Faculty of Pharmacy Charles University Hradec Králové Czech Republic

Department of Oncology and Radiotherapy Charles University Medical School and Teaching Hospital Hradec Králové Czech Republic

Department of Oncology Palacký University Medical School and Teaching Hospital Olomouc Czech Republic

Zobrazit více v PubMed

Melichar B. Laboratory medicine and medical oncology: the tale of two Cinderellas. Clin Chem Lab Med 2013;51:99-112. 10.1515/cclm-2012-0496 PubMed DOI

Melichar B, Plebani M. Targeted therapy for HER-2: personalized medicine for her, too. Clin Chem Lab Med 2012;50:1-4. 10.1515/cclm.2011.724 PubMed DOI

Buchler T, Klapka R, Melichar B, et al. Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma-data from the Czech registry. Ann Oncol 2012;23:395-401. 10.1093/annonc/mdr065 PubMed DOI

Kirkwood JM, Butterfield LH, Tarhnini AA, et al. Immunotherapy of cancer in 2012. CA Cancer J Clin 2012;62:309-35. 10.3322/caac.20132 PubMed DOI PMC

Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006-17. 10.1056/NEJMoa1414428 PubMed DOI PMC

Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320-30. 10.1056/NEJMoa1412082 PubMed DOI

Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372:2018-28. 10.1056/NEJMoa1501824 PubMed DOI

Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521-32. 10.1056/NEJMoa1503093 PubMed DOI

Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. 10.1056/NEJMoa1507643 PubMed DOI PMC

Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:123-35. 10.1056/NEJMoa1504627 PubMed DOI PMC

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373:1803-13. 10.1056/NEJMoa1510665 PubMed DOI PMC

Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol 2015;33:1430-7. 10.1200/JCO.2014.59.0703 PubMed DOI PMC

Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015;16:257-65. 10.1016/S1470-2045(15)70054-9 PubMed DOI PMC

Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. 10.1056/NEJMoa1606774 PubMed DOI

Čermáková P, Melichar B, Tomšová M, et al. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in patients with endometrial carcinoma. Anticancer Res 2014;34:5555-61. PubMed

Tomsová M, Melichar B, Sedláková I, et al. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol 2008;108:415-20. 10.1016/j.ygyno.2007.10.016 PubMed DOI

Melichar B, Studentová H, Kalabova H, et al. Predictive and prognostic significance of tumor-infitrating lymphocytes in patients with breast cancer treated with neodjuvant systemic therapy. Anticancer Res 2014;34:1115-25. PubMed

Hornychova H, Melichar B, Tomsova M, et al. Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest 2008;26:1024-31. 10.1080/07357900802098165 PubMed DOI

Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an indepedent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 2010;28:105-13. 10.1200/JCO.2009.23.7370 PubMed DOI

Denkert C, von Minckwitz G, Brase JC, et al. Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2-Positive and Triple-Negative Primary Breast Cancers. J Clin Oncol 2015;33:983-91. 10.1200/JCO.2014.58.1967 PubMed DOI

Ying HQ, Deng QW, He BS, et al. The prognostic value of preoperative NLR, d-NLR, PLR and LMR for predicting clinical outcome in surgical colorectal cancer patients. Med Oncol 2014;31:305. 10.1007/s12032-014-0305-0 PubMed DOI

Absenger G, Szandera J, Pichler M, et al. A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. Br J Cancer 2013;109:395-400. 10.1038/bjc.2013.346 PubMed DOI PMC

Cho H, Hur HW, Kim SW, et al. Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother 2009;58:15-23. 10.1007/s00262-008-0516-3 PubMed DOI PMC

Eryilmaz MK, Mutlu H, Salim DK, et al. The neutrophil to lymphocyte ratio has a high negative predictive value for pathologic complete response in locally advanced breast cancer patients receiving neoadjuvant chemotherapy. Asian Pac J Cancer Prev 2014;15:7737-40. 10.7314/APJCP.2014.15.18.7737 PubMed DOI

Guthrie GJ, Charles KA, Roxburgh CS, et al. The systemic inflammation-based neutrophil-lymphocyte ratio: Experience in patients with cancer. Crit Rev Oncol Hematol 2013;88:218-30. 10.1016/j.critrevonc.2013.03.010 PubMed DOI

Li MX, Liu XM, Zhang JF, et al. Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis. Int J Cancer 2014;134:2403-13. 10.1002/ijc.28536 PubMed DOI

Melichar B, Študentová H, Vitásková D, et al. Association of urinary neopterin, neutrophil-to-lymphocyte ratios with long-term survival in patients with breast cancer. Pteridines 2016;27:59-65. 10.1515/pterid-2016-0001 DOI

Benites-Zapata VA, Hernandez AV, Nagarajan V, et al. Usefulness of neutrophil-to-lymphocyte ratio in risk stratification of patients with advanced heart failure. Am J Cardiol 2015;115:57-61. 10.1016/j.amjcard.2014.10.008 PubMed DOI PMC

Wang X, Zhang G, Jiang X, et al. Neutrophil to lymphocyte ratio in relation to risk of all-cause mortality and cardiovascular events among patients undergoing angiography or cardiac revascularization: A meta-analysis of observational studies. Atherosclerosis 2014;234:206-13. 10.1016/j.atherosclerosis.2014.03.003 PubMed DOI

Fidler IJ. Therapy of cancer metastasis by systemic activation of macrophages. Adv Pharmacol 1994;30:271-326. 10.1016/S1054-3589(08)60177-5 PubMed DOI

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74. 10.1016/j.cell.2011.02.013 PubMed DOI

Melichar B, Savary CA, Patenia R, et al. Phenotype and antitumor activity of ascitic fluid monocytes in patients with ovarian carcinoma. Int J Gynecol Cancer 2003;13:435-43. 10.1046/j.1525-1438.2003.13331.x PubMed DOI

Hibbs JB, Taintor RR, Vavrin Z, et al. Nitric oxide: A cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 1988;157:87-94. 10.1016/S0006-291X(88)80015-9 PubMed DOI

Klostergaard J, Leroux ME, Hung MC. Cellular models of macrophage tumoricidal effector mechanisms in vitro. Characterization of cytolytic responses to tumor necrosis factor and nitric oxide pathways in vitro. J Immunol 1991;147:2802-8. PubMed

Tayeh MA, Marletta MA. Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. J Biol Chem 1989;264:19654-8. PubMed

Huber C, Batchelor JR, Fuchs D, et al. Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. J Exp Med 1984;160:310-6. 10.1084/jem.160.1.310 PubMed DOI PMC

Leitner KL, Meyer M, Leimbacher W, et al. Low tetrahydrobiopterin biosynthetic capacity of human monocytes is caused by exon skipping in 6-pyruvoyl tetrahydropterin synthase. Biochem J 2003;373:681-8. 10.1042/bj20030269 PubMed DOI PMC

Weinberg JB, Misukonis MA, Shami PJ, et al. Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): Analysis of iNOS MRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages. Blood 1995;86:1184-95. PubMed

Koide Y, Yoshida A. The signal transduction mechanism responsible for gamma interferon-induced indoleamine 2,3-dioxygenase gene expression. Infect Immun 1994;62:948-55. PubMed PMC

Burke F, Knowles RG, East N, et al. The role of indoleamine 2,3-dioxygenase in the anti-tumour activity of human interferon-gama in vivo. Int J Cancer 1995;60:115-22. 10.1002/ijc.2910600117 PubMed DOI

Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998;281:1191-3. 10.1126/science.281.5380.1191 PubMed DOI

Friberg M, Jennings R, Alsarraj M, et al. Indoleamin 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int J Cancer 2002;101:151-5. 10.1002/ijc.10645 PubMed DOI

Soliman H, Rawal B, Fulp J, et al. Analysis of indoleamine 2-3 dioxygenase (IDO1) expression in breast cancer tissues by immunohistochemistry. Cancer Immunol Immunother 2013;62:829-37. 10.1007/s00262-013-1393-y PubMed DOI PMC

Wachter H, Hausen A, Grassmayr K. Erhohte Ausscheidung von Neopterin im Harn von Patienten mit malignen Tumoren und mit Viruserkrankungen. Hoppe Seylers Z Physiol Chem 1979;360:1957-60. PubMed

Wachter H, Fuchs D, Hausen A, et al. Neopterin as marker for activation of cellular immunity: immunologic basis and clinical application. Adv Clin Chem 1989;27:81-141. 10.1016/S0065-2423(08)60182-1 PubMed DOI

Fuchs D, Jager H, Popescu M, et al. Immune activation markers to predict AIDS and survival in HIV-1 seropositives. Immunology Letters 1990;26:75-9. 10.1016/0165-2478(90)90178-S PubMed DOI

Fuchs D, Banekovich M, Hausen A, et al. Neopterin estimation compared with the ratio of T-cell subpopulations in persons infected with human immunodeficiency virus-1. Clin Chem 1988;34:2415-7. PubMed

Fuchs D, Chiodi F, Albert J, et al. Neopterin concentrations in cerebrospinal fluid and serum of individuals infected with HIV-1. AIDS 1989;3:285-8. 10.1097/00002030-198905000-00006 PubMed DOI

Pálóczi K, Ujhelyi E, Fuchs D, et al. Correlation of the percentage of activated, CD3 + DR + lymphocytes to serum neopterin level in HIV- seropositive haemophiliacs. Klin Wochenschr 1991;69:143-5. 10.1007/BF01665853 PubMed DOI

Nübling CM, Chudy M, Volkers P, et al. Neopterin levels during the early phase of human immunodeficiency virus, hepatitis C virus, or hepatitis B virus infection. Transfusion 2006;46:1886-91. 10.1111/j.1537-2995.2006.00994.x PubMed DOI

Daito K, Suou T, Kawasaki H. Clinical significance of serum and urinary neopterin levels in patients with various liver diseases. Am J Gastroenterol 1992;87:471-6. PubMed

Hönlinger M, Fuchs D, Hausen A, et al. Serum neopterin determination for the additional safeguarding of blood transfusions. Our experiences with 76,587 blood donors. Dtsch Med Wochenschr 1989;114:172-6. PubMed

Tatzber F, Rabl H, Koriska K, et al. Elevated serum neopterin levels in atherosclerosis. Atherosclerosis 1991;89:203-8. 10.1016/0021-9150(91)90061-7 PubMed DOI

Weiss G, Willeit J, Kiechl S, et al. Increased concentrations of neopterin in carotid atherosclerosis. Atherosclerosis 1994;106:263-71. 10.1016/0021-9150(94)90131-7 PubMed DOI

Melichar B, Gregor J, Solichova D, et al. Increased urinary neopterin in acute myocardial infarction. Clin Chem 1994;40:338-9. PubMed

Vengen IT, Dale AC, Wiseth R, et al. Neopterin predicts the risk for fatal ischemic heart disease in type 2 diabetes mellitus. Long-term follow-up og the HUNT 1 study. Atherosclerosis 2009;207:239-44. 10.1016/j.atherosclerosis.2009.04.003 PubMed DOI

Grammer TB, Fuchs D, Boehm BO, et al. Neopterin as a predictor of total and cardiovascular mortality in individuals undergoing angiography in the Ludwigshafen Risk and Cardiovascular Health Study. Clin Chem 2009;55:1135-46. 10.1373/clinchem.2008.118844 PubMed DOI

Reibnegger G, Egg D, Fuchs D, et al. Urinary neopterin reflects clinical activity in patients with rheumatoid arthritis. Arthritis Rheum 1986;29:1063-70. 10.1002/art.1780290902 PubMed DOI

Reibnegger G, Bollbach R, Fuchs D, et al. A simple index relating clinical activity of Crohn's disease with T cell activation: Hematocrit, frequency of liquid stools and urinary neopterin as parameters. Immunobiology 1986;173:1-11. 10.1016/S0171-2985(86)80084-5 PubMed DOI

Wirleitner B, Obermoser G, Bock G, et al. Induction of apoptosis in human blood T cells by 7, 8-dihydroneopterin: the difference between healthy controls and patients with systemic lupus erythematosus. Clin Immunol 2003;107:152-9. 10.1016/S1521-6616(03)00040-8 PubMed DOI

Niederwieser D, Fuchs D, Hausen A, et al. Neopterin as a new biochemical marker in the clinical assessment of ulcerative colitis. Immunobiology 1985;170:320-6. 10.1016/S0171-2985(85)80080-2 PubMed DOI

Melichar B, Solichová D, Melicharová K, et al. Urinary neopterin in patients with advanced colorectal carcinoma. Int J Biol Markers 2006;21:190-8. 10.5301/JBM.2008.782 PubMed DOI

Fyfe A, Daly P, Galligan L, et al. Coronary sinus sampling of cytokines after heart transplantation: Evidence for macrophage activation and interleukin-4 production within the graft. J Am Coll Cardiol 1993;21:171-6. 10.1016/0735-1097(93)90733-H PubMed DOI

Humbert M, Delattre RM, Cerrina J, et al. Serum neopterin after lung transplantation. Chest 1993;103:449-54. 10.1378/chest.103.2.449 PubMed DOI

Margreiter R, Fuchs D, Hausen A, et al. Neopterin as a new biochemical marker for diagnosis of allograft rejection. Transplantation 1983;36:650-3. 10.1097/00007890-198336060-00013 PubMed DOI

Reibnegger G, Aichberger C, Fuchs D, et al. Posttransplant neopterin excretion in renal allograft recipients-a reliable diagnostic aid for acute rejection and a predictive marker of long-term graft survival. Transplantation 1991;52:58-63. 10.1097/00007890-199107000-00012 PubMed DOI

Tilg H, Vogel W, Aulitzky WE, et al. Neopterin excretion after liver transplantation and its value in differential diagnosis of complications. Transplantation 1989;48:594-9. PubMed

Fuith LC, Fuchs D, Hausen A, et al. Neopterin, a marker of cell-mediated immune activation in human pregnancy. Int J Fertil 1991;36:372-5. PubMed

Solichova D, Melichar B, Blaha V, et al. Biochemical profile and survival in nonagenarians. Clin Biochem 2001;34:563-9. 10.1016/S0009-9120(01)00261-2 PubMed DOI

Melichar B, Solichová D, Freedman RS. Neopterin as an indicator of immune activation and prognosis in patients with gynecological malignancies. Int J Gynecol Cancer 2006;16:240-52. 10.1111/j.1525-1438.2006.00294.x PubMed DOI

Reibnegger GJ, Bichler AH, Dapunt O, et al. Neopterin as a prognostic indicator in patients with carcinoma of the uterine cervix. Cancer Res 1986;46:950-5. PubMed

Reibnegger G, Hetzel H, Fuchs D, et al. Clinical significance of neopterin for prognosis and follow-up in ovarian cancer. Cancer Res 1987;47:4977-81. PubMed

Murr C, Bergant A, Widschwendter M, et al. Neopterin is an independent prognostic variable in females with breast cancer. Clin Chem 1999;45:1998-2004. PubMed

Kalábová H, Krcmová L, Kasparová M, et al. Prognostic significance of increased urinary neopterin concentrations in patients with breast carcinoma. Eur J Gynaecol Oncol 2011;32:525-9. PubMed

Bower JE, Ganz PA, Aziz N, et al. T-cell homeostasis in breast cancer survivors with persistent fatigue. J Natl Cancer Inst 2003;95:1165-8. 10.1093/jnci/djg0019 PubMed DOI

Weiss G, Kronberger P, Conrad F, et al. Neopterin and prognosis in patients with adenocarcinoma of the colon. Cancer Res 1993;53:260-5. PubMed

Manes G, Spada OA, Rabitti PG, et al. Neopterin serum levels in pancreatic adenocarcinoma. Int J Pancreatol 1999;25:31-7. 10.1385/IJGC:25:1:31 PubMed DOI

Kawasaki H, Watanabe H, Yamada S, et al. Prognostic significance of urinary neopterin levels in patients with hepatocellular carcinoma. Tohoku J Exp Med 1988;155:311-8. 10.1620/tjem.155.311 PubMed DOI

Aulitzky W, Frick J, Fuchs D, et al. Significance of urinary neopterin in patients with malignant tumors of the genitourinary tract. Cancer 1985;55:1052-5. 10.1002/1097-0142(19850301)55:5<1052::AID-CNCR2820550521>3.0.CO;2-9 PubMed DOI

Lewenhaupt A, Ekman P, Eneroth P, et al. Serum levels of neopterin as related to the prognosis of human prostatic carcinoma. Eur Urol 1986;12:422-5. PubMed

Yoshida N, Ikemoto S, Narita K, et al. Serum neopterin levels in renal cell carcinoma. Pteridines 2000;11:133-6. 10.1515/pteridines.2000.11.4.133 DOI

Hausen A, Fuchs D, Grunewald K, et al. Urinary neopterin as marker for haematological neoplasias. Clin Chim Acta 1981;117:297-305. 10.1016/0009-8981(81)90117-0 PubMed DOI

Caenazzo A, Pietrogrande F, Sgarabotto D, et al. Serum neopterin levels in haematological malignancies. Haematologica 1993;78:225-9. PubMed

Hausen A, Fuchs D, Grunewald K, et al. Urinary neopterin in the assessment of lymphoid and myeloid neoplasia, and neopterin levels in haemolytic anaemia and benign monoclonal gammopathy. Clin Biochem 1982;15:34-7. 10.1016/S0009-9120(82)90403-9 PubMed DOI

Piccinini L, Zironi S, Federico M, et al. Urinary neopterin in malignant lymphoma. Int J Biol Markers 1991;6:231-6. PubMed

Boccadoro M, Battaglio S, Omede P, et al. Increased serum neopterin concentration as indicator of disease severity and poor survival in multiple myeloma. Eur J Haematol 1991;47:305-9. 10.1111/j.1600-0609.1991.tb01576.x PubMed DOI

Reibnegger G, Krainer M, Herold M, et al. Predictive value of interleukin-6 in patients with multiple myeloma. Cancer Res 1991;51:6250-3. PubMed

Weinlich G, Murr C, Richardsen L, et al. Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients. Dermatology 2007;214:8-14. 10.1159/000096906 PubMed DOI

Gerding H, Cremer-Bartels G, Krause K, et al. Neopterin in patients with choroidal melanoma. Eur J Clin Chem Clin Biochem 1993;31:221-4. PubMed

Berchtold J, Murr C, Norer B, et al. Urinary neopterin excretion in patients with squamous carcinoma of the oral cavity. Cancer Lett 1995;95:227-32. 10.1016/0304-3835(95)03888-4 PubMed DOI

Murr C, Berchtold J, Norer B, et al. Neopterin as a prognostic parameter in patients with squamous-cell carcinomas of the oral cavity. Int J Cancer 1998;79:476-80. 10.1002/(SICI)1097-0215(19981023)79:5<476::AID-IJC5>3.0.CO;2-Y PubMed DOI

Kronberger P, Weiss G, Tschmelitsch J, et al. Predictive value of urinary neopterin in patients with lung cancer. Eur J Clin Chem Clin Biochem 1995;33:831-7. PubMed

Melichar B, Zeimet A, Artner-Dworzak E, et al. Association between increased urinary zinc and neopterin concentrations in women with gynaecological cancer. TumorDiagnostik Ther 1993;14:110-2.

Denz H, Fuchs D, Huber H, et al. Correlation between neopterin, interferon-gamma and haemoglobin in patients with haematological disorders. Eur J Haematol 1990;44:186-9. 10.1111/j.1600-0609.1990.tb00374.x PubMed DOI

Studentova H, Vitaskova D, Sramek V, et al. Correlations of neutrophil-to-lymphocyte, lymphocyte-to-monocyte and platelet-to-lymphocyte ratios with biomarkers of atherosclerosis risk and inflammatory response in patients with a history of breast cancer. Pteridines 2015;26:161-72. 10.1515/pterid-2015-0009 DOI

Melichar B, Touskova M, Solichova D, et al. CD4+ T-lymphocytopenia and systemic immune activation in patients with primary and secondary liver tumours. Scand J Clin Lab Invest 2001;61:363-70. 10.1080/003655101316911404 PubMed DOI

Melichar B, Jandik P, Krejsek J, et al. Mitogen-induced lymphocyte proliferation and systemic immune activation in cancer patients. Tumori 1996;82:218-20. PubMed

Rehak S, Malirova E, Cermanova M, et al. Cerebrospinal fluid neopterin in patients with tumors and other disorders. Pteridines 2008;19:86-91. 10.1515/pteridines.2008.19.1.86 DOI

Pink R, Melichar B, Tomandl J, et al. Salivary neopterin concentrations in patients with cancer of the oral cavity. Pteridines 2016;27:53-8. 10.1515/pterid-2015-0017 DOI

Stadtler P, Reibnegger G, Vrecko K, et al. Correlation between periodontitis and neopterin in saliva and urine. J Dent Res 1998;77:1224.

Vrecko K, Staedtler P, Mischak I, et al. Periodontitis and concentrations of the cellular immune activation marker neopterin in saliva and urine. Clin Chim Acta 1997;268:31-40. 10.1016/S0009-8981(97)00154-X PubMed DOI

Millot F, Dhondt JL, Mazingue F, et al. Cerebrospinal fluid neopterin levels in children with central nervous system leukemia. Leuk Lymphoma 1993;9:351-6. 10.3109/10428199309148533 PubMed DOI

Höbarth K, Szabo N, Hallas A, et al. Serum neopterin as a parameter for monitoring the course of renal cell carcinoma during interferon-gamma therapy. Clin Immunol Immunopathol 1994;70:241-4. 10.1006/clin.1994.1035 PubMed DOI

Van Gool AR, Ojik HH, Kruit WH, et al. Pegylated interferon alfa 2b treatment in melanoma patients: influence on amino acids, 5-hydroxyindolacetic acid and pteridine plasma concentrations. Anti-Cancer Drugs 2004;15:587-91. 10.1097/01.cad.0000132230.51759.8d PubMed DOI

Melichar B, Solichova D, Jebavy L. Elevation de la neopterine apres traitement par le facteur stimulant des colonies granulo-macrophagiques (GM-CSF). Presse Medicale 1994;23:581. PubMed

Motzer RJ, Rakhit A, Thompson JA, et al. Randomized multicenter phase II trial of subcutaneous recombinant human interleukin-12 versus interferon-a2a for patients with advanced renal cell carcinoma. J Interferon Cytokine Res 2001;21:257-63. 10.1089/107999001750169934 PubMed DOI

Fumagalli L, Lissoni P, Di Felice G, et al. Pretreatment serum markers and lymphocyte response to interleukin-2 therapy. Br J Cancer 1999;80:407-11. 10.1038/sj.bjc.6690371 PubMed DOI PMC

Lissoni P, Barni S, Ardizzoia A, et al. Correlation between pretreatment serum levels of neopterin and response to interleukin-2 immunotherapy in cancer patients. J Biol Regul Homeost Agents 1995;9:21-3. PubMed

Melichar B, Lenzi R, Rosenblum M, et al. Intraperitoneal fluid neopterin, nitrate, and tryptophan after regional administration of interleukin-12. J Immunother 2003;26:270-6. 10.1097/00002371-200305000-00010 PubMed DOI

Holečková P, Krčmová L, Létal J, et al. Urinary neopterin concentration and toxicity of radiotherapy in patients with head and neck carcinoma during external beam radiation. Anticancer Res 2013;33:4097-101. PubMed

Melichar B, Urbanek L, Krcmova L, et al. Urinary neopterin, hemoglobin and peripheral blood cell counts in breast carcinoma patients treated with dose-dense chemotherapy. Anticancer Res 2008;28:2389-96. PubMed

Melichar B, Nemcová I. Eye complications of cetuximab therapy. Eur J Cancer Care (Engl) 2007;16:439-43. 10.1111/j.1365-2354.2006.00763.x PubMed DOI

Poprach A, Pavlik T, Melichar B, et al. Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study. Ann Oncol 2012;23:3137-43. 10.1093/annonc/mds145 PubMed DOI

Melichar B, Dvorak J, Hyspler R, et al. Intestinal permeability in the assessment of intestinal toxicity of cytotoxic agents. Chemotherapy 2005;51:336-8. 10.1159/000088957 PubMed DOI

Melichar B, Hyspler R, Ticha A, et al. Intestinal permeability in patients with metastatic colon cancer treated with patupilone. Clin Chem Lab Med 2014;52:1649-55. PubMed

Melichar B, Kohout P, Bratova M, et al. Intestinal permeability in patients with chemotherapy-induced stomatitis. J Cancer Res Clin Oncol 2001;127:314-8. 10.1007/s004320000209 PubMed DOI

Zezulová M, Bartoušková M, Hlídková E, et al. Citrulline as a biomarker of gastrointestinal toxicity in patients with rectal carcinoma treated with chemoradiation. Clin Chem Lab Med 2016;54:305-14. 10.1515/cclm-2015-0326 PubMed DOI

Melichar B, Kalabova H, Urbanek L, et al. Serial urinary neopterin measurements reflect the disease course in patients with epithelial ovarian carcinoma treated with paclitaxel/platinum. Pteridines 2007;18:1-7. 10.1515/pteridines.2007.18.1.1 DOI

Melichar B, Ferrandina G, Verschraegen CF, et al. Growth inhibitory effects of aromatic fatty acids on ovarian tumor cell lines. Clin Cancer Res 1998;4:3069-76. PubMed

Mezrich JD, Fechner JH, Zhang XJ, et al. An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells. J Immunol 2010;185:3190-8. 10.4049/jimmunol.0903670 PubMed DOI PMC

Suzuki Y, Suda T, Furuhashi K, et al. Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer 2010;67:361-5. 10.1016/j.lungcan.2009.05.001 PubMed DOI

Huang A, Fuchs D, Widner B, et al. Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer. Br J Cancer 2002;86:1691-6. 10.1038/sj.bjc.6600336 PubMed DOI PMC

Engin A, Gonul I, Engin AB, et al. Relationship between indoleamine 2,3-dioxygenase activity and lymphatic invasion propensity of colorectal carcinoma. World J Gastroenterol 2016;22:3592-601. 10.3748/wjg.v22.i13.3592 PubMed DOI PMC

Pilka R, Marek R, Adam T, et al. Systemic Inflammatory Response After Open, Laparoscopic and Robotic Surgery in Endometrial Cancer Patients. Anticancer Res 2016;36:2909-22. PubMed

Neopterin, the Cell-Mediated Immune Response Biomarker, in Inflammatory Periodontal Diseases: A Narrative Review of a More than Fifty Years Old Biomarker