Zusammenfassung
Zur Evaluierung von serologischen Verlaufsparametern der fernmetastasierten Melanom-Erkrankung wurden drei prospektive Studien durchgeführt. Die Ergebnisse der Staging-Untersuchungen wurden als unabhängiger Referenz-Standard zur Diagnose einer Erkrankungs-Progredienz verwandt, und Interleukin-6 (Il-6), sein Surrogat C-reaktives Protein (CRP) und der konventionelle Parameter Laktatdehydrogenase (LDH) wurden zum Zeitpunkt der Staging-Untersuchungen im Serum bestimmt. Zum Vergleich wurden die Melanom-Marker S100β und „melanoma inhibitory activity” (MIA) in den Seren gemessen. Die Patienten mit Progredienz der Metastasierung wiesen statistisch signifikant höhere Konzentrationen der Serumparameter als die Patienten mit Therapieansprechen auf, wenn beide Gruppen durch Medianwerte verglichen wurden. Mit der Fläche unter den „Receiver Operating Characteristic” (ROC)-Kurven zeigten sich sowohl Il-6, sein Surrogat CRP und die LDH als auch S100β und MIA geeignet, eine Progression der Metastasierung tendenziell zu erkennen. In der multiplen logistischen Regressions-Analyse resultierte die LDH als relevanter Faktor. Aufgrund ihrer hohen Korrelationen mit der LDH konnten S100β und MIA die Information der LDH nur geringfügig verbessern. Unter Anwendung von „classification and regression trees” (CART) erwies sich das CRP mit einem Grenzwert von 0,5 mg/dl als der am meisten relevante Parameter.
Abstract
Monitoring melanoma patients suffering from distant metastases (American Joint Committee on Cancer stage IV), we evaluated serum markers for the ability to discriminate progressive from non-progressive disease. In three prospective studies, results of staging examinations were used as independent reference standard for diagnosing progressive disease, and interleukin-6 (Il-6), its surrogate C-reactive protein (CRP) and the conventional parameter lactate dehydrogenase (LDH) were determined in serum just before. For comparison, the melanoma markers S100β and melanoma inhibitory activity (MIA) were measured in the sera. We found all tested serum parameters to be significantly elevated in progressive disease by median values. Calculating the areas under the Receiver Operating Characteristic (ROC) curves, Il-6, its surrogate CRP and LDH as well as S100β and MIA were useful in diagnosing progressive disease. By multiple logistic regression analysis, LDH resulted as relevant factor. S100β and MIA did not provide additional significant information as they highly correlated with LDH with respect to clinical outcome. Applying classification and regression trees (CART), we found CRP with a cut off value of 0.5 mg/dl to be the most relevant serum marker.
Literatur
-
1
Mouawad R, Benhammouda A, Rixe O, Antoine E C, Borel C, Weil M, Khayat D, Soubrane C.
Endogenous interleukin 6 levels in patients with metastatic malignant melanoma, correlation with tumor burden.
Clin Cancer Res.
1996;
2
1405-1409
-
2
Tartour E, Dorval T, Mosseri V, Deneux L, Mathiot C, Brailly H, Montero F, Joyeux I, Pouillart P, Fridman W H.
Serum interleukin 6 and C-reactive protein levels correlate with resistance to Il-2 therapy and poor survival in melanoma patients.
Br J Cancer.
1994;
69
911-913
-
3
Tartour E, Blay J Y, Dorval T, Escudier B, Mosseri V, Douillard J Y, Deneux L, Gorin I, Negrier S, Mathiot C, Pouillart P, Fridman W H.
Predictors of clinical response to interleukin-2-based immunotherapy in melanoma patients, a French multiinstitutional study.
J Clin Oncol.
1996;
14
1697-1703
-
4
Candi E, Knight R A, Spinedi A, Guerrieri P, Melino G.
A possible growth factor role of Il-6 in neuroectodermal tumors.
J Neurooncol.
1997;
31
115-122
-
5
Kishimoto T, Akira S.
Interleukin-6 and its receptor, a paradigm for cytokines.
Science.
1992;
258
593-597
-
6
Lee J D, Sievers T M, Skotzko M, Chandler C F, Morton D L, McBride W H, Economou J S.
Interleukin-6 production by human melanoma cell lines.
Lymphokine Cytokine Res.
1992;
11
161-166
-
7
Francis G M, Krohn E G, Woods K V, Buzaid A C, Grimm E A.
Interleukin-6 production and secretion in human melanoma cell lines, regulation by interleukin-1.
Melanoma Res.
1996;
6
191-201
-
8
Lu C, Kerbel R S.
Interleukin-6 undergoes transition from paracrine growth inhibitor to autocrine stimulator during human melanoma progression.
J Cell Biol.
1993;
120
1281-1288
-
9
Mattei S, Colombo M P, Melani C, Silvani A, Parmiani G, Herlyn M.
Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes.
Int J Cancer.
1994;
56
853-857
-
10
Colombo M P, Maccalli C, Mattei S, Melani C, Radrizzani M, Parmiani G.
Expression of cytokine genes, including Il-6, in human malignant melanoma cell lines.
Melanoma Res.
1992;
2
181-189
-
11
Castell J V, Gomez-Lechon M J, David M, Andus T, Geiger T, Trullenque R, Fabra R, Heinrich P C.
Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes.
FEBS Lett.
1989;
242
237-239
-
12
Moshage H J, Roelofs H MJ, van Pelt J F, Hazenberg B PC, van Leeuwen M A, Limburg P C, Aarden L A, Yap S H.
The effect of interleukin-1, interleukin-6 and its interrelationship on the synthesis of serum amyloid A and C-reactive protein in primary cultures of adult human hepatocytes.
Biochem Biophys Res Commun.
1988;
155
112-117
-
13
Heimdal K, Hannisdal E, Gunderson S.
Metastatic malignant melanoma.
Eur J Cancer.
1989;
25
1219-1223
-
14
Keilholz U, Scheibenbogen C, Sommer M, Pritsch M, Geuke A M.
Prognostic factors for response and survival in patients with metastatic melanoma receiving immunotherapy.
Melanoma Res.
1996;
6
173-178
-
15
Sirott M N, Bajorin D F, Wong G YN, Tao Y, Chapman P B.
Prognostic factors in patients with metastatic malignant melanoma.
Cancer.
1993;
72
3091-3098
-
16
Balch C M, Buzaid A C, Atkins M B, Cascinelli N, Coit D G, Fleming I D, Houghton A, Kirkwood J M, Mihm M F, Morton D L, Reintgen D, Ross M I, Sober A, Soong S J, Thompson J A, Thompson J F, Gerhenwald J E, McMasters K M.
A new American joint committee on cancer staging system for cutaneous melanoma.
Cancer.
2000;
88
1484-1491
-
17
Miller R, Siegmund D.
Maximally selected chi square statistics.
Biometrics.
1982;
38
1011-1016
-
18 Efron B, Tibshirani R J. An Introduction to the Bootstrap. New York; Chapman & Hall 1993
-
19
DeLong E R, DeLong D M, Clarke-Pearson D L.
Comparing the areas under two or more correlated receiver operating characteristic curves, a nonparametric approach.
Biometrics.
1988;
44
837-845
-
20 Hellmich M. Receiver Operating Characteristic (ROC) Kurven und Flächen darunter. Anwendungen in der Psychiatrie. Dissertationsschrift. Med. Fakultät, Universität Münster 1996
-
21
Coughlin S S, Trock B, Criqui M H, Pickle L, Browner D, Tefft M C.
The logistic modelling of sensitivity, specificity and predictive value of a diagnostic test.
J Clin Epidemiol.
1992;
45
1-7
-
22
Smith P J, Thompson T J, Engelgau M, Herman W H.
A generalized linear model for analysing receiver operating characteristic curves.
Statistics in Medicine.
1996;
15
323-333
-
23 Harrell F E. Predicting outcomes, applied survival analysis and logistic regression. University of Virginia 2001
-
24 Breiman L, Friedman J H, Olshen R A, Stone C J. Classification and Regression Trees. Belmont, CA; Wadsworth Inc 1984
-
25 Lausen B, Sauerbrei W, Schumacher M. Classification and regression trees (CART) used for the exploration of prognostic factors measured on different scales. In: Dirschedl P, Ostermann R (Eds) Computational Statistics. Heidelberg; Physica Verlag 1994: 483-496
-
26 Harman A J. Wilks' tolerance limit sample size. In: Sachs L (Ed) Angewandte Statistik. Heidelberg; Springer Verlag 1997: 215-218
-
27
Deichmann M, Benner A, Jäckel A, Bock M, Waldmann V, Näher H.
Elevated interleukin-6 serum levels indicate progressive disease in metastasized malignant melanoma.
J Exp Clin Cancer Res.
2000;
19
301-307
-
28
Deichmann M, Benner A, Bock M, Jäckel A, Waldmann V, Uhl K, Näher H.
S100-beta, melanoma-inhibiting activity, and lactate dehydrogenase discriminate progressive from nonprogressive American Joint Committee on Cancer stage IV melanoma.
J Clin Oncol.
1999;
17
1891-1896
-
29
Deichmann M, Benner A, Kuner N, Wacker J, Waldmann V, Näher H.
Are responses to therapy of metastasized malignant melanoma reflected by decreasing serum values of S100β or melanoma inhibitory activity (MIA)?.
Melanoma Res.
2001;
11
291-296
-
30
Paglia D, Oran A, Lu C, Kerbel R S, Sauder D N, McKenzie R C.
Expression of leukemia inhibitory factor and interleukin-11 by human melanoma cell lines, LIF, Il-6 and Il-11 are not coregulated.
J Interferon Cytokine Res.
1995;
15
455-460
-
31
Klein B, Zhang X G, Jourdan B, Content B, Content J, Houssiau F, Aarden L, Piechaczyk M, Bataille R.
Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6.
Blood.
1989;
73
517-526
-
32
Deichmann M, Thome M, Bock M, Jäckel A, Waldmann V, Näher H.
The human herpesvirus-type 8 DNA is not detected in primary malignant melanoma.
Br J Cancer.
1999;
80
67-69
-
33
Helmke B M, Deichmann M, Otto H F.
Anorectal melanomas do not harbour the Kaposi's sarcoma associated human herpesvirus type 8 DNA.
J Med Virol.
2001;
64
47-50
-
34
Motro B, Itin A, Sachs L, Keshet E.
Patterns of interleukin-6 gene expression in vivo suggests a role for this cytokine in angiogenesis.
Proc Natl Acad Sci USA.
1990;
87
3092-3096
-
35
Okuno Y, Takahashi T, Suzuki A, Fukumoto M, Nakamura K, Fukui H, Koishihira Y, Ohsugi Y, Imura H.
Acquisition of growth autonomy and tumorigenicity by an interleukin 6-dependent human myeloma cell line transfected with interleukin 6 cDNA.
Exp Hematol.
1992;
20
395-400
-
36
Noma T, Mizuta T, Rosen A, Hirano T, Kishimoto T, Honjo T.
Enhancement of the interleukin 2 receptor expression on T cells by multiple B-lymphotropic lymphokines.
Immunol Lett.
1987;
15
249-253
-
37
Aderka D, Le J, Velcek J.
Il-6 inhibits lipopolysaccharide-induced tumour necrosis factor production in cultured human monocytes, U937 cells, and in mice.
J Immunol.
1989;
143
3517-3524
-
38
Zhou D, Munster A, Winchurch R A.
Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-β.
FASEB J.
1991;
5
2582-2585
-
39 Pepys M B. The acute phase response and C-reactive protein. In: Weatherall DJ, Ledingham JGG, Warrell DA (Eds) Oxford textbook of medicine. Oxford; Oxford University Press 1995: 1527-1533
-
40
Bosserhoff A K, Kaufmann M, Kaluza B, Bartke I, Zirngibl H, Hein R, Stolz W, Buettner R.
Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma.
Cancer Res.
1997;
57
3149-3153
-
41
Guo H B, Stoffel-Wagner B, Bierwirth T, Mezger J, Klingmüller D.
Clinical significance of serum S100 in metastatic malignant melanoma.
Eur J Cancer.
1995;
31
924-928
-
42
Hein R, Bosserhof A K, Stolz W, Kaufmann M, Kaluza B, Buettner R.
MIA serum levels as a detection and monitoring system of malignant melanoma.
Arch Dermatol Res.
1997;
289
30
-
43
Henze G, Dummer R, Joller-Jemelka H I, Böni R, Burg G.
Serum S100, a marker for disease monitoring in metastatic melanoma.
Dermatology.
1997;
194
208-212
-
44
Hauschild A, Michaelsen J, Brenner W, Rudolph P, Glaser R, Henze E, Christophers E.
Prognostic significance of serum S100β detection compared with routine blood parameters in advanced metastatic melanoma patients.
Melanoma Res.
1999;
9
155-161
-
45
Hauschild A, Engel G, Brenner W, Glaser R, Monig H, Henze E, Christophers E.
S100β protein detection is a significant prognostic factor in metastatic melanoma.
Oncology.
1999;
56
338-344
-
46
Jäckel A, Deichmann M, Waldmann V, Bock M, Näher H.
S100β protein in serum, a tumor marker in malignant melanoma, current state of knowledge and clinical experience.
Hautarzt.
1998;
50
250-256
-
47
Dietz U, Sandell L J.
Cloning of a retinoid acid-sensitive mRNA expressed in cartilage and during chondrogenesis.
J Biol Chem.
1996;
271
3311-3316
-
48
Fagnart O C, Sindic C JM, Laterre C.
Particle counting immunoassay of S100 protein in serum, possible relevance in tumors and ischemic disorders of the central nervous system.
Clin Chem.
1988;
34
1387-1391
-
49
Müller-Ladner U, Bosserhoff A K, Dreher K, Hein R, Neidhart M, Gay S, Scholmerich J, Buettner R, Lang B.
MIA (melanoma inhibitory activity), a potential serum marker for rheumatoid arthritis.
Rheumatology.
1999;
38
148-154
Dr. med. habil. M. Deichmann
Universitäts-Hautklinik Heidelberg
Voßstraße 2 · 69115 Heidelberg ·
eMail: martin_deichmann@med.uni-heidelberg.de
