Mads Hansen

Early Interim 2-[18F]Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography Is Prognostically Superior to International Prognostic Score in Advanced-Stage Hodgkin's Lymphoma: A Report From a Joint Italian-Danish Study

PURPOSE Starting from November 2001, 260 newly diagnosed patients with Hodgkins lymphoma (HL) were consecutively enrolled in parallel Italian and Danish prospective trials to evaluate the prognostic role of an early interim 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and the International Prognostic Score (IPS) in advanced HL, treated with conventional ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy. PATIENTS AND METHODS Most patients (n = 190) presented with advanced disease (stages IIB through IVB), whereas 70 presented in stage IIA with adverse prognostic factors. All but 11 patients were treated with standard ABVD therapy followed by consolidation radiotherapy in case of bulky presentation or residual tumor mass. Conventional radiologic staging was performed at baseline. FDG-PET scan was performed at baseline and after two courses of ABVD (PET-2). No treatment change was allowed on the basis of the PET-2 results. RESULTS After a median follow-up of 2.19 years (range, 0.32 to 5.18 years), 205 patients were in continued complete remission and two patients were in partial remission. Forty-three patients progressed during therapy or immediately after, whereas 10 patients relapsed. The 2-year progression-free survival for patients with positive PET-2 results was 12.8% and for patients with negative PET-2 results was 95.0% (P < .0001). In univariate analysis, the treatment outcome was significantly associated with PET-2 (P < .0001), stage IV (P < .0001), WBC more than 15,000 (P < .0001), lymphopenia (P < .001), IPS as a continuous variable (P < .0001), extranodal involvement (P < .0001), and bulky disease (P = .012). In multivariate analyses, only PET-2 turned out to be significant (P < .0001). CONCLUSION PET-2 overshadows the prognostic value of IPS and emerges as the single most important tool for planning of risk-adapted treatment in advanced HL.

Hepatitis C infection and risk of malignant lymphoma

The association between hepatitis C virus (HCV) infection and risk of malignant lymphoma remains controversial, perhaps due to small‐sized studies and low prevalence of HCV in the general population. On the basis of a large Danish‐Swedish population‐based case‐control study, 2,819 lymphoma patients and 1,856 controls of second‐generation Danish‐Swedish origin were screened for HCV infection using an enzyme‐linked immunosorbent assay and a confirming recombinant immunoblot assay (RIBA) test. Positive samples were tested with real‐time PCR for the presence of HCV RNA. The association between HCV infection and risk of malignant lymphoma was assessed by logistic regression. When intermediate RIBA test results were interpreted as positive, anti‐HCV antibody positivity was associated with a nonsignificant increased risk of non‐Hodgkin lymphoma (NHL) overall (odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.9–5.3; n = 20 cases), of B‐cell lymphomas combined (OR = 2.4 [1.0–5.8]; n = 20) and of lymphoplasmacytic lymphoma (OR = 5.2 [1.0–26.4]; n = 2). No patients with T‐cell or Hodgkin lymphoma were HCV‐positive. A more conservative definition of HCV positivity (disregarding intermediate RIBA results) resulted in an OR = 1.6 (0.3–8.5; n = 5) for NHL overall. When the definition was further restricted to require HCV RNA positivity, OR was 1.7 (0.2–16.2; n = 3) for NHL overall. Our findings from a population with a low prevalence of HCV suggest a positive association between HCV and risk of NHL, in particular of B‐cell origin.

Borrelia infection and risk of non-Hodgkin lymphoma

Reports of the presence of Borrelia burgdorferi DNA in malignant lymphomas have raised the hypothesis that infection with B. burgdorferi may be causally related to non-Hodgkin lymphoma (NHL) development. We conducted a Danish-Swedish case-control study including 3055 NHL patients and 3187 population controls. History of tick bite or Borrelia infection was ascertained through structured telephone interviews and through enzyme-linked immunosorbent assay serum analyses for antibodies against B. burgdorferi in a subset of 1579 patients and 1358 controls. Statistical associations with risk of NHL, including histologic subtypes, were assessed by logistic regression. Overall risk of NHL was not associated with self-reported history of tick bite (odds ratio [OR] = 1.0; 95% confidence interval: 0.9-1.1), Borrelia infection (OR = 1.3 [0.96-1.8]) or the presence of anti-Borrelia antibodies (OR = 1.3 [0.9-2.0]). However, in analyses of NHL subtypes, self-reported history of B. burgdorferi infection (OR = 2.5 [1.2-5.1]) and seropositivity for anti-Borrelia antibodies (OR = 3.6 [1.8-7.4]) were both associated with risk of mantle cell lymphoma. Notably, this specific association was also observed in persons who did not recall Borrelia infection yet tested positive for anti-Borrelia antibodies (OR = 4.2 [2.0-8.9]). Our observations suggest a previously unreported association between B. burgdorferi infection and risk of mantle cell lymphoma.

Microarray-based classification of diffuse large B-cell lymphoma

Abstract:  Objective: Hierarchical clusterings of diffuse large B‐cell lymphoma (DLBCL) based on gene expression signatures have previously been used to classify DLBCL into Germinal Center B‐cell (GCB) and Activated B‐cell (ABC) types. To examine if it was feasible to perform a cross‐platform validation on the Affymetrix HG‐U133A oligonucleotide arrays and improve the classification, we determined the expression profiles of pretreatment, diagnostic samples from 52 primary nodal DLBCL. Methods and results: First, three previously published gene lists were converted to the HG‐U133A probe sets and used for hierarchical clustering. In this way, three subtypes, including the GCB type (n = 20), the ABC type (n = 25) and an intermediate group, Type‐3 (n = 5), were distinguished. The CD10 and Bcl‐6 expression as well as t(14;18) translocation were prevalent, but not exclusive to the GCB type. By contrast, MUM1 was only expressed in the ABC and in Type‐3 samples. The 5‐year survival was similar between the groups, but GCB patients showed a better initial response to CHOP or CHOP‐like regimens than the remaining patients and tended to have less advanced disease and lower IPI scores. As a next step, an improved set of classifier genes was generated by analysis of 34 patients that were consistently classified as GCB or ABC in the above analyses. Seventy‐eight genes were selected and demonstrated on two previously published data sets (Shipp et al. Nat Med 2002;8:68–74 and Houldsworth et al. Blood 2004;103:1862–1868) to exhibit a higher specificity than the original gene lists. Conclusion: We conclude that gene expression profiling with Affymetrix Genechips is efficient to distinguish between GCB and ABC types of DLBCL and that these are likely to represent separate biological entities. The Genechip platform is highly standardised and therefore useful for future prospective investigations to establish the value of gene expression profiling in the clinical management of DLBCL.

Profiling of diffuse large B-cell lymphoma by immunohistochemistry: identification of prognostic subgroups.

Diffuse large B‐cell lymphoma (DLBCL) is a frequent lymphoma subtype with a heterogeneous behavior and a variable response to conventional chemotherapy. This clinical diversity is believed to reflect differences in the molecular pathways leading to lymphomagenesis. In this study, we have analyzed pretreatment, diagnostic samples from 108 DLBCL by immunohistology for expression of four markers linked to germinal center B‐cells (CD10, Bcl‐6), postgerminal center B‐cells (MUM1) and apoptosis (Bcl‐2). The results indicate that both CD10 and Bcl‐6 are favorable prognostic indicators, in contrast to Bcl‐2, which is an adverse parameter. Furthermore, using two algorithms for distinction between low‐ and high‐risk patients proposed by Hans et al. (Blood, 2004; 103:275) and Muris et al. (Journal of Pathology, 2006; 208:714), it is shown that both are useful for predicting outcome in DLBCL. However, in this report, the algorithm of Hans et al. was superior to that of Muris et al. These findings confirm and extend other studies and indicate that different prognostic subgroups of DLBCL can be distinguished by simple immunohistological investigations for a limited number of markers. Whether these groups are also relevant for individual treatment decisions will be important to investigate in prospective studies.