Purpose: Peripheral T-cell non–Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs. Experimental Design: Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay. Results: Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99–3.14 with P = 0.056]. A protective role of IL-10–1087A, −824T, and −597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92–4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22–5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different. Conclusions: Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs. Clin Cancer Res; 18(13); 3637–47. ©2012 AACR.

<div>Abstract<p><b>Purpose:</b> Peripheral T-cell non–Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs.</p><p><b>Experimental Design:</b> Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay.</p><p><b>Results:</b> Patients characterized by <i>TNFRI-609GG</i> (rs4149570) showed a trend toward better event free survival [EFS; univariate: <i>P</i> = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99–3.14 with <i>P</i> = 0.056]. A protective role of <i>IL-10–1087A</i>, −<i>824T</i>, and −<i>597A</i> reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: <i>P</i> = 0.0034; multivariate: HR, 2.07; CI, 0.92–4.70 with <i>P</i> = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: <i>P</i> = 0.00068; multivariate: HR, 2.49; CI, 1.22–5.08 with <i>P</i> = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different.</p><p><b>Conclusions:</b> Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs. <i>Clin Cancer Res; 18(13); 3637–47. ©2012 AACR</i>.</p></div>

<div>Abstract<p><b>Purpose:</b> Peripheral T-cell non–Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs.</p><p><b>Experimental Design:</b> Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay.</p><p><b>Results:</b> Patients characterized by <i>TNFRI-609GG</i> (rs4149570) showed a trend toward better event free survival [EFS; univariate: <i>P</i> = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99–3.14 with <i>P</i> = 0.056]. A protective role of <i>IL-10–1087A</i>, −<i>824T</i>, and −<i>597A</i> reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: <i>P</i> = 0.0034; multivariate: HR, 2.07; CI, 0.92–4.70 with <i>P</i> = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: <i>P</i> = 0.00068; multivariate: HR, 2.49; CI, 1.22–5.08 with <i>P</i> = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different.</p><p><b>Conclusions:</b> Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs. <i>Clin Cancer Res; 18(13); 3637–47. ©2012 AACR</i>.</p></div>

So ist das adulte T-Zell-Lymphom (ATLL) mit dem humanen T-Zell-Leukämie-Virus Typ 1 (HTLV1) assoziiert und kommt besonders häug im südlichen Japan und in den karibischen Ländern vor, wo das HTLV1 endemisch ist. Das intestinale T-Zell-Lymphom kommt in erster Linie bei Patienten mit unbehandelter glutensensitiver Enteropathie vor. Daher beobachtet man in Gebieten wie Groÿbritannien, wo die Zöliakie vermehrt auftritt, eine erhöhte Inzidenz dieser sonst seltenen Subgruppe. Ein weiterer Faktor, der die Inzidenz von T-Zell-Lymphomen und NK-Zell-Lymphomen beeinusst, ist die Herkunft der Patienten. Nasale NK-und T-Zell-Lymphome kommen bei Asiaten sehr viel häuger als bei Menschen anderer genetischer Herkunft vor. Weitere Populationen mit einem erhöhten Risiko für diese EBV-assoziierten Krankheiten (EBV, Epstein-Barr-Virus) sind indianische Völker in Nord-und Südamerika. Es wird postuliert, dass eine genetische Prädisposition, die mit einem Immundefekt gegenüber dem EBV verbunden ist, für diese Verteilung der EBV-assoziierten Lymphome verantwortlich ist (Jaffe 2006; Isaacson und Wright 1978). Die in Mitteleuropa häugsten Subtypen sind das unspezische periphere T-Zell-Lymphom (PTCL), das angioimmunoblastische T-Zell-Lymphom (AILT) und das anaplastische groÿzellige T-Zell-Lymphom (ALCL) mit und ohne ALK-Expression (Rüdiger et al. 2002). 1.1.3 Klassikation Hinter dem Begri Lymphom verbirgt sich eine Vielzahl an unterschiedlichen und eigenständigen Krankheitsentitäten. Die Klassikation deniert diese spezischen lymphatischen Neoplasien und bildet damit die Grundlage für die reproduzierbare Diagnose und eine optimal angepasste Therapie. Die aktuell gültige WHO-Klassikation basiert auf der REAL-Klassikation (Revised European American Lymphoma Classikation, Harris et al. 1994). Die WHO-Klassikation deniert die Non-Hodgkin-Lymphome nach zytomorphologischen, immunologischen und genetischen Kriterien. Grundsätzlich erfolgt eine Unterscheidung in B-und T-/NK-Zell-Lymphome sowie unreife (lymphoblastische) und reife (periphere) Lymphome. Die reifen Lymphome können weiter in primär leukämische, primär nodale und primär extranodale Lymphome unterteilt werden (siehe Tabelle 1.1). Die WHO-Klassikation stellt das erste weltweit akzeptierte Einteilungssystem der malignen Lymphome dar und ermöglicht damit den Vergleich klinischer und wissenschaftlicher Studien auf internationaler Ebene. Die WHO-Klassikation ist keine endgültige Klassikation. Vielmehr muss jede klinische Klassizierung als permanenter Prozess angesehen werden. So wird in der WHO-Klassikation die Möglichkeit erwähnt, mittels Genexpressionsanalyse in naher Zukunft Untereinheiten diuser B-Zell-Lymphome mit prognostischer Relevanz zu denieren (Canellos et al. 2006; Hiddemann et al. 2004). ALK-positive und ALK-negative Lymphome Zu den häugeren T-Zell-Lymphomen gehören in Europa das periphere unklassizierte T-Zell-Lymphom, das angioimmunoblastische T-Zell-Lymphom und das groÿzellige anaplastische Lymphom (ALCL). Nach molekularen und

<p>PDF file, 109KB, S1: Genotype and allele frequency of the analyzed IL-10, IL-4R, TNFRI and II gene variations in patients with T-NHL (n = 117); S2: 2. 3-year survival rates for OS and EFS of patients suffering from T-NHL in relation to analyzed gene variation; S3: Real time PCR Taqman� assays used to analyze IL-10, IL-4R, TNFRI and TNFRII gene variations; S4: Primer for SNaPshot Assay used to analyze IL-10 gene variations.</p>