Xavier Sagaert

FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations

The transcription factor Forkhead box protein P1 (FOXP1) is highly expressed in a proportion of diffuse large B-cell lymphoma (DLBCL). In this report, we provide cytogenetic and fluorescence in situ hybridization (FISH) data showing that FOXP1 (3p13) is recurrently targeted by chromosome translocations. The genomic rearrangement of FOXP1 was identified by FISH in three cases with a t(3;14)(p13;q32) involving the immunoglobulin heavy chain (IGH) locus, and in one case with a variant t(2;3) affecting sequences at 2q36. These aberrations were associated with strong expression of FOXP1 protein in tumor cells, as demonstrated by immunohistochemistry (IHC). The cases with t(3p13) were diagnosed as DLBCL ( × 1), gastric MALT lymphoma ( × 1) and B-cell non-Hodgkins lymphoma, not otherwise specified ( × 2). Further IHC and FISH studies performed on 98 cases of DLBCL and 93 cases of extranodal marginal zone lymphoma showed a high expression of FOXP1 in approximately 13 and 12% of cases, respectively. None of these cases showed, however, FOXP1 rearrangements by FISH. However, over-representation of the FOXP1 locus found in one additional case of DLBCL may represent another potential mechanism underlying an increased expression of this gene.

Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma

PURPOSE Gene expression profiling studies have reported upregulated mRNA expression of forkhead box protein P1 (FOXP1) in response to normal B-cell activation and high expression in a poor prognosis subtype of diffuse large B-cell lymphoma (DLBCL). Recently, it was also found that FOXP1 rearrangements and expression of its protein occur in mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we investigated FOXP1 expression in its relationship to morphology, genetic features, and prognosis in a series of 70 MALT lymphomas. PATIENTS AND METHODS All samples were morphologically reviewed and stained for FOXP1. Presence of structural and/or numeric aberrations of the FOXP1, BCL10, and MALT1 genes was investigated. For all patients, a complete clinical data set was collected. RESULTS We detected nuclear expression of FOXP1 in 20 of the 70 MALT lymphomas (nine of them featuring structural or numeric aberrations of the FOXP1 locus). FOXP1 positivity was confined to MALT lymphomas with poor clinical outcome (with impact of FOXP1 expression on relapse rate and disease-free survival). It was also found that MALT lymphomas with strong FOXP1 expression are at risk of transforming into an aggressive DLBCL of nongerminal center phenotype if they feature, in addition, a polymorphic histology and the presence of trisomy 3 and 18. CONCLUSION The data presented show that FOXP1 expression is an independent prognostic factor in MALT lymphomas. The data also support the hypothesis that a subgroup of nongerminal center DLBCLs (those marked by FOXP1 expression and trisomy 3 and 18) might represent a large-cell variant of MALT lymphomas.

The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer

Abstract Purpose. To investigate the use of FDG-PET/CT before, during and after chemoradiotherapy (CRT) and diffusion-weighted magnetic resonance imaging (DW-MRI) before CRT for the prediction of pathological response (pCR) in rectal cancer patients. Material and methods. Twenty-two rectal cancer patients treated with long course CRT were included. An FDG-PET/CT was performed prior to the start of CRT, after 10 to 12 fractions of CRT and five weeks after the end of CRT. The tumor was delineated using a gradient based delineation method and the maximal standardized uptake values (SUVmax) were calculated. A DW-MRI was performed before start of CRT. Mean apparent diffusion coefficients (ADC) were determined. The ΔSUVmax during and after CRT and the initial ADC values were correlated to the histopathological findings after total mesorectal excision (TME). Results. ΔSUVmax during and after CRT significantly correlated with the pathological response to treatment (during CRT: ΔSUVmax = 59% ± 12% for pCR vs. 25% ± 27% if no pCR, p=0.0036; post-CRT: 90% ± 11 for pCR vs. 63% ± 22 if no pCR p=0.013). ROC curve analysis revealed an optimal threshold for ΔSUVmax of 40% during CRT and 76% after CRT. The initial ADC value was also significantly correlated with pCR (0.94 ± 0.12 × 10−3 mm2/s for pCR vs. 1.2 ± 0.24 × 10−3 mm2/s, p=0.002) and ROC curve analysis revealed an optimal threshold of 1.06 × 10−3 mm2/s. Combining the provided ΔSUVmax thresholds during and after CRT increased specificity of the prediction (sensitivity 100% and specificity 94%). The combination of the thresholds for the initial ADC value and the ΔSUVmax during CRT increased specificity of the prediction to a similar level (sensitivity of 100% and specificity of 94%). Conclusions. The combination of the different time points and the different imaging modalities increased the specificity of the response assessment both during and after CRT.

The pathogenesis of MALT lymphomas: where do we stand?

Mucosa-associated lymphoid tissue (MALT) lymphoma is a heterogeneous form of a B-cell non-Hodgkins lymphoma with extranodal location. The gastrointestinal tract is the most common site of disease, but involvement of multiple other organ systems has been documented. Four translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32), are specifically associated with MALT lymphoma. Remarkably, the genes targeted by at least three of these translocations are involved in one and the same pathway, leading to the activation of nuclear factor-κB (NF-κB). This review presents MALT lymphoma as a model of how sustained inflammation increases the risk of genotoxic insults and how these genetic events initiate oncogenesis.

Gastric MALT lymphoma: a model of chronic inflammation-induced tumor development

Mucosa-associated lymphoid tissue (MALT) lymphoma, or extranodal marginal zone lymphoma of MALT, is an indolent B-cell non-Hodgkin lymphoma arising in lymphoid infiltrates that are induced by chronic inflammation in extranodal sites. The stomach is the most commonly affected organ, in which MALT lymphoma pathogenesis is clearly associated with Helicobacter pylori gastroduodenitis. Gastric MALT lymphoma has attracted attention because of the involvement of genetic aberrations in the nuclear factor κB (NFκB) pathway, one of the most investigated pathways in the fields of immunology and oncology. This Review presents gastric MALT lymphoma as an outstanding example of the close pathogenetic link between chronic inflammation and tumor development, and describes how this information can be integrated into daily clinical practice. Gastric MALT lymphoma is considered one of the best models of how genetic events lead to oncogenesis, determine tumor biology, dictate clinical behavior and represent viable therapeutic targets. Moreover, in view of the association of gastric MALT lymphoma with dysregulation of the NFκB pathway, this signaling pathway will be discussed in depth in both normal and pathological conditions, highlighting strategies to identify new therapeutic targets in this lymphoma.

Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study

PURPOSE Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. PATIENTS AND METHODS After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). RESULTS The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors. CONCLUSION Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.

Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab.

Background: Immune therapies may act in inflammatory bowel diseases (IBD) by modulating regulatory T cells (Tregs). Therefore, we investigated the effect of infliximab (IFX) therapy on Forkhead box protein3 (Foxp3) T cells in blood and intestinal mucosa from Crohns disease (CD) and ulcerative colitis (UC). Methods: Forty patients with active IBD (23 CD / 17 UC) were treated with IFX 5 mg/kg intravenously at weeks 0, 2, 6, and each 8 weeks thereafter. Blood samples were obtained before every infusion and T‐lymphocyte subsets were characterized by flow cytometry. Foxp3 expression in intestinal biopsies from 43 patients with active IBD (19 CD / 24 UC) before and after IFX infusion and from 6 controls were assessed by quantitative reverse‐transcription polymerase chain reaction and immunohistochemistry. Plasma C‐reactive protein (CRP), clinical response, and endoscopic healing data were collected in parallel. Results: IFX therapy resulted in a significant and sustained relative increase of CD4+CD25+Foxp3+ Treg and of CD4+CD25−Foxp3+ Treg cells in peripheral blood (both P < 0.0001 compared to baseline), particularly in responders (both P < 0.05 compared to nonresponders). The change in CRP over time inversely correlated with the increase of CD25+Foxp3+ cells (P < 0.001, r = −0.39) and durable clinical response was associated with a sustained increase of circulating Foxp3+ cells. Surprisingly, IFX therapy downregulated mucosal mRNA and protein expression of Foxp3 in UC and CD responders (both P < 0.001) but not in nonresponders. Conclusions: IFX therapy has opposite effects in Foxp3+ Treg cells in blood and gut mucosa, which suggests a redistribution of this important T‐cell subset. Inflamm Bowel Dis 2010

Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: single-center series of 25 cases and meta-analysis of 277 reported cases.

Plasmablastic lymphoma (PBL) is a rare B-cell non-Hodgkin lymphoma often associated with Epstein-Barr virus (EBV) infection. To gain insight in this aggressive lymphoma subtype, the clinicopathologic characteristics of 25 unpublished single-center PBLs (2 in acquired immunodeficiency syndrome patients, 11 in immunocompetent individuals [IC-PBL], 12 in transplant recipients [PT-PBL]) and of 277 reported PBLs were summarized. In the reported series, PBL patients were predominantly male (77%) with a median age at diagnosis of 46 years (range, 1.2 to 87 y). The majority of the biopsies (66%) was EBV positive. Extranodal presentation was most frequent (88%, of which 35% were oral, 18% gastrointestinal, 12% cutaneous). PBL was diagnosed in acquired immunodeficiency syndrome patients (50%), immunocompetent individuals (35%), and transplant recipients (14%). These subgroups differed in age at diagnosis (median: 41, 64, 47 y, respectively), primary localization (oral, oral, cutaneous, respectively), EBV positivity (75%, 50%, 67%, respectively), CD45 expression (31%, 33%, 70%, respectively), and C-MYC aberrations (78%, 44%, 38%, respectively). Ann Arbor stage I, EBV positivity, CD45 expression, and lack of C-MYC aberrations were associated with better outcome (P<0.05). Our series of IC-PBL and PT-PBL cases revealed differential expression of CD10 (0% vs. 42%, respectively), CD56 (22% vs. 42%, respectively), TP53 (67% vs. 8%, respectively), and BCL2 (88% vs. 25%, respectively). Gene expression analysis of 5 of our PT-PBLs revealed upregulation of DNMT3B, PTP4A3, and CD320 in EBV-positive PT-PBL and suggested a role for cancer/testis antigens. The results of this retrospective study suggest different pathogenic mechanisms of PBL in different immunologic settings and a potentially important impact of EBV and CD45 on prognosis.

Selective expansion of marginal zone B cells in Emicro-API2-MALT1 mice is linked to enhanced IkappaB kinase gamma polyubiquitination

The translocation t(11;18)(q21;q21) that generates an API2-MALT1 fusion protein is the most common structural abnormality among the genetic defects reported in mucosa-associated lymphoid tissue (MALT)-type lymphomas, and its presence correlates with the apparent lack of further genetic instability or chromosomal imbalances. Hence, constitutive nuclear factor-κB (NF-κB) activation induced by the API2-MALT1 fusion protein is considered essential for B-cell transformation. To examine its role in B-cell development and lymphomagenesis, Eμ-API2-MALT1 transgenic mice were produced. Our data show that expression of the API2-MALT1 fusion protein alone is not sufficient for the development of lymphoma masses within 50 weeks. Nevertheless, API2-MALT1 expression affected B-cell maturation in the bone marrow and triggered the specific expansion of splenic marginal zone B cells. Polyubiquitination of IκB kinase γ (IKKγ), indicative for enhanced NF-κB activation, was increased in splenic lymphocytes and promoted the survival of B cells ex vivo . In addition, we show that the API2-MALT1 fusion resided in the cholesterol- and sphingolipid-enriched membrane microdomains, termed lipid rafts. We provide evidence that association of the MALT1 COOH terminal with the lipid rafts, which is mediated by the API2 portion, is sufficient to trigger NF-κB activation via enhanced polyubiquitination of IKKγ. Taken together, these data support the hypothesis that the API2-MALT1 fusion protein can contribute to MALT lymphoma formation via increased NF-κB activation. (Cancer Res 2006; 66(10): 5270-7)

Correlation between the endoscopic and histologic score in assessing the activity of ulcerative colitis

Background:In routine practice, scoring of activity and severity of ulcerative colitis is based on combined clinical and endoscopic assessment. Histology also allows sensitive scoring of ulcerative colitis activity. The correlation between endoscopy and histology has not been investigated thoroughly. It is still unknown how well they correlate and whether scoring both endoscopy and histology better reflects the true disease activity than each of the methods separately. Methods:Two hundred and sixty-three biopsy sets from 131 known patients with ulcerative colitis were reviewed by an experienced gastrointestinal pathologist and scored using the Geboes and Riley histologic scoring systems. Endoscopic scoring had been performed previously by inflammatory bowel disease specialists using the Mayo endoscopic subscore. Bidirectional comparison of the Mayo endoscopic subscore with the full and converted histologic scores was then performed. Results:We found a statistically significant overall correlation between the Mayo endoscopic subscore and the histologic scores (highest correlation: Kendalls &tgr; = 0.482, P < 0.0001). Although a very high concordance was found for inactive and severely active disease, a high diversity was detected between these extremes. For example, endoscopic mildly active disease (Mayo 1) was distributed over all different histologic grades (37%, grade 0; 21%, grade 1; 28%, grade 2; and 14%, grade 3). Conclusions:Both extremes of the histologic and endoscopic activity scores neatly correlate, but important misclassifications exist for mild disease. Microscopy may detect more severe disease than endoscopically suspected, possibly altering the clinical follow-up scheme. We also infer from our results that histologic scoring should be used in addition to endoscopy when scoring disease activity for clinical trials.