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Purpose: Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), ∼30% of patients in advanced stages may eventually die as result of the disease, and current methods to predict prognosis are rather unreliable. Thus, the application of robust techniques for the identification of biomarkers associated with treatment response is essential if new predictive tools are to be developed.Experimental Design: We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functional pathways associated with unfavorable outcome that were significantly enriched in either the Hodgkin's and Reed-Sternberg cells (regulation of the G2-M checkpoint, chaperones, histone modification, and signaling pathways) or the reactive cell microenvironment (mainly represented by specific T-cell populations and macrophage activation markers).Results: To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach.Conclusions: The results of this assay can be combined in a single risk score integrating these biological pathways associated with treatment response and eventually used in a larger series to develop a new molecular outcome predictor for advanced cHL.

Supplementary Data from A TaqMan Low-Density Array to Predict Outcome in Advanced Hodgkin's Lymphoma Using Paraffin-Embedded Samples

This paper presents a new approach to the project of steel buildings, mainly focused on the architectural, structural, and seismic design of stairs. The objective is to design a structural stair system capable of controlling seismic damage and contributing to the bracing system of the building. The article begins with a review of the seismic standard (ATC, FEMA, and EC8) on which the current design criteria for new buildings with stairs are based. The research is based on two spatial building models (A–B) with the same bracing elements but placed differently. Reference Model A follows classical design approaches. It means, stairs are considered nonstructural elements that do not influence the seismic behavior of the building. This structure corresponds to typical braced frames (IV-CBF and EBF) according to EC8. Model B includes a stair system designed to help control the effects of inter-story drifts and inertia forces. In this case, the same bracing elements of Model A were integrated into the stair structure of Model B. A comparative seismic behavior analysis of typically braced frames (A) versus specially braced stairs (B) is presented. The research was based on the static nonlinear (pushover) analysis and the capacity spectrum method (ATC-40) according to the seismic performance levels (FEMA) and damage limitation (EC8). Finally, the braced stairs was verified via nonlinear time-history analysis in order to better capture the structural safety of the evacuation routes and their influence on the behavior of the building. This deterministic analysis of the braced stairs verified satisfactory results compared to reference bracing systems.

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to 90Y-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m2 every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving 90Y-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.

The classic Hodgkin lymphoma (cHL) tumor microenvironment (TME) is by far the most abundant component of tumors and is responsible for most of their biological and clinical characteristics. Recent advances in our knowledge of these networks in cellular interactions allow us to understand that the neoplastic Hodgkin and Reed Sternberg (HRS) cells, although they are in the minority, are the main architects of this dysregulated immune milieu. Here, we review the major changes that have happened in recent years: from TME as a helpless bystander, reflecting an ineffective immune response, to a dynamic tumor-promoting and immunosuppressive element. The HRS cells promote survival through interconnected intrinsic and extrinsic alterations, boosting pro-tumoral signaling pathways through genetic aberrations and autocrine growth signals, in parallel with abnormal cytokine secretion for the recruitment and selection of the best cell partners for this immunosuppressive TME. In turn, cHL is already proving to be the perfect model with which to address an immune checkpoint blockade. Preliminary data demonstrate the utility of druggable key signaling pathways in this ensemble, such as JAK-STAT, NF-κB, and others. In addition, myriad biomarkers predicting a response await validation by new in situ multiplex analytical methods, single-cell gene expression, and other techniques. Together, these components will define the functional phenotypes with which we will elucidate the molecular pathogenesis of the disease and improve the survival of patients who are refractory to conventional therapies.

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Background Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of HIV-associated lymphoma. Since the introduction of combined antiretroviral therapy (cART), the prognosis of HIV-related DLBCL has substantially improved, resembling that of the general population. However, non-Hodgkin lymphoma still remains the first cause of AIDS-related deaths. The International Prognostic Index (IPI) is the most widely used score for DLBCL and it has been validated in the rituximab era (R-IPI). However, it has limited accuracy to identify a very high-risk prognostic subset. Although IPI has been demonstrated to be useful for predicting prognosis in HIV-related DLBCL, new scores subsequently developed, such as National Cancer Comprehensive Network IPI (NCCN-IPI), GELTAMO-IPI and a new score, which includes data from peripheral blood count, have not been applied in the HIV setting. The aim of this study was to assess the prognostic significance of the new variables -beta2-microglobulin (β2M), lymphocyte/monocyte (L/M) ratio and red blood cell width (RDW)- and to validate the new scores in a series of homogeneously treated HIV-related DLBCL patients. Methods Retrospective multicentric study of patients with HIV infection diagnosed with DLBCL in 16 hospitals from GELTAMO group in Spain, from 1998 to 2020. All patients were treated with R-CHOP and cART +/- radiotherapy. The main clinical and biological variables were collected. Peripheral absolute neutrophil, lymphocyte and monocyte counts were studied, including L/M ratio and CD4 + lymphocyte count. Moreover, HIV load, serum lactate dehydrogenase (LDH), β2M and RDW were evaluated. Univariable and multivariable analysis were performed using the binary logistic regression model for complete response (CR) rate and Cox proportional-hazards regression model for overall survival (OS) and progression-free survival (PFS). Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. The discrimination power of IPI, aaIPI (age-adjusted IPI), R-IPI, NCCN-IPI, GELTAMO-IPI and the new score including L/M ratio (L Bento et al., Br J Haematol. 2020) was assessed by the C-index. Results One hundred and five patients were retrospectively analysed with a median follow up of 7.08 (0.36-25.21) years. The characteristics of the patients are summarized in Table 1. In the univariable analysis, performance status ≥2, extranodal sites ≥2, lymphocytopenia and low L/M ratio were associated with shorter OS and shorter PFS probabilities. Neutropenia was also associated with lower OS and advanced Ann Arbor stage was associated with lower PFS. On the other hand, monocytosis, low CD4 + lymphocyte count, positive HIV load and high values of serum LDH, RDW and β2M had no prognostic impact. By multivariable analysis, only L/M ratio With the aim of validating the prognostic power of each score system, the patients were divided in two groups: patients corresponding with low or intermediate-low risk versus those with intermediate-high or high risk. R-IPI, NCCN-IPI and the new score including L/M ratio showed significant differences in two groups for CR rate, OS and PFS. IPI also significantly discriminated the groups for PFS. NCCN-IPI was the strongest score to discriminate OS with a C-index of 0.638, and the new score including L/M ratio was the best one for CR rate and PFS discrimination, with a C-index of 0.669 and 0.666 respectively. Conclusions Lymphocyte/monocyte ratio is a strong prognostic factor, which can be used in patients with DLBCL and HIV infection. NCCN-IPI and the new score including L/M ratio provided the best discriminative capacity to predict prognosis in patients with HIV-related DLBCL treated with R-CHOP and cART. Supported in part by Gilead Sciences S.L., Spain (GLD19/00121); 2017 SGR288 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds from Josep Carreras International Foundation and "la Caixa" Foundation. Figure 1 Figure 1. Disclosures Lopez-Guillermo: Roche, Gilead/Kite, Celgene, Novartis, Janssen, AbbVie, Spectrum: Consultancy, Honoraria, Research Funding. Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gilead: Research Funding. de la Cruz Vicente: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ferrer Lores: Janssen: Membership on an entity's Board of Directors or advisory committees. Abrisqueta: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. Ribera: SHIRE: Consultancy, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Navarro: NOVARTIS, Roche: Honoraria; EUSA Pharma: Consultancy; GILEAD, EUSA Pharma: Research Funding.

Extranodal mucosa associated lymphoid tissue (ENMALT) marginal zone lymphomas may arise at any site of the body. The most frequent localizations other than gastrointestinal and eye are salivary gland, skin, lung and thyroid. These lymphomas usually arise in a setting of inflammation due to a persistent infection or autoimmune diseases such as Sjogren syndrome in salivary MALT lymphomas and Hashimoto's thryroiditis in thyroid lymphomas. They affect middle-aged patients with a female predominance when lymphoma arises in certain locations. Patients often present with localised stage I or II although disseminated disease may be present at diagnosis or relapse in a third of the cases. Biopsy of the affected site is mandatory to establish the diagnosis and a full work-up staging is recommended. The clinical course is indolent and prognosis is good despite that recurrences following response to therapy are frequent. Surgery, radiotherapy and/or Rituximab based regimens are effective in these lymphomas.

Objectives Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. Methods From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). Results Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. Conclusions (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets.

To the editor: Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) present in most cases as localized disease and can be successfully treated with local therapies or antibiotics.[1][1][⇓][2][⇓][3]-[4][4] Moreover, patients with multicentric or extensive disease

The international prognostic score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on E2496. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis 2 factors (age, stage) remained significant for FFP and 3 factors (age, stage, hemoglobin) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage, and hemoglobin, which provided 4 distinct risk groups [FFP (p=0.0001) and OS (p

The Grupo Espanol de Linfomas y Trasplantes de Medula Osea International Prognostic Index (GELTAMO-IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low-intermediate (LIR), high-intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO-IPI in the DLBCL subtypes defined by the immunohistochaemistry-based Hans algorithm, Germinal Centre B (GCB) and non-GCB. A multivariate Cox regression model including GELTAMO-IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non-GCB) and both the GELTAMO-IPI and the COO subtype in 780 (353 GCB; 427 non-GCB). There were no differences in 5-year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO-IPI risk groups and the COO subtypes (P = 0·005), indicating that GELTAMO-IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5-year OS of 100%, 75% and 52%, respectively. In the non-GCB subtype, LR, the combined LIR+HIR and HR had a 5-year OS of, 97%, 82% and 35% respectively. GELTAMO-IPI identifies a genuine poor outcome group of patients in the DLBCL non-GCB subtype.

Mata et al., Defining the mutational landscape of classic Hodgkin lymphoma is still a major research goal. New targeted next-generation sequencing (NGS) techniques may identify pathogenic mechanisms and new therapeutic opportunities related to this disease. We describe the mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg (HRS) cells. Overall, the results confirm the presence of strong genomic heterogeneity. However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others. This unexpectedly high prevalence of mutations affecting the BCR pathway suggests some requirement for active BCR signaling for cHL cell viability. Additionally, incubation of a panel of cHL cellular models with selective BTK inhibitors in vitro constrains cell proliferation and causes cell death. Our results indicate new pathogenic mechanisms and therapeutic opportunities in this disease., This work was supported by grants from the Plan Nacional de I+D+I co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), PI12/1832, RTICC RD06/0020/0107, PI14/00221, CIBER de Cancer, PIE15/0081 and PI16/01294, the Spanish Association for Cancer Research (AECC), and by funds of the U.T M.D. Anderson Cancer Center. MSB currently holds a Miguel Servet contract (CP11/00018 and CPII16/00024) from the ISCIII- MINECO-AES-FEDER (P.N.I+D+I 2008-2011), Spain.

Summary Background No standard first-line systemic treatment for mucosa-associated lymphoid tissue (MALT) lymphoma is available. In a phase 2 study we aimed to assess the safety and activity of a response-adapted combination of bendamustine plus rituximab as upfront treatment for this type of lymphoma. Methods In a multicentre, single-arm, non-randomised, phase 2 trial, we enrolled patients with MALT lymphoma at any site and stage and treated them with bendamustine (90 mg/m 2 on days 1 and 2) plus rituximab (375 mg/m 2 on day 1), every 4 weeks. Inclusion criteria were measurable or evaluable disease, age 18–85 years, and unequivocal active lymphoma; we also enrolled patients with MALT lymphoma arising in the stomach after failure of Helicobacter pylori eradication and primary cutaneous cases after failure of local therapies. Exclusion criteria included evidence of histological transformation, CNS involvement, and active hepatitis B or C virus or HIV infection. After three cycles, patients achieving complete response received one additional cycle (total four cycles) and those achieving partial response received three additional cycles (total six cycles). The primary endpoint was 2-year event-free survival. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01015248. Findings 60 patients from 19 centres in Spain were enrolled between May 27, 2009, and May 23, 2011, and received treatment; 57 patients were evaluable for the primary endpoint. Only 14 (25%) patients needed more than four cycles of treatment. After a median follow-up of 43 months (IQR 37–51), median event-free survival was not reached. Event-free survival at 2 years was 93% (95% CI 84–97) and at 4 years was 88% (95% CI 74–95). The most frequently observed grade 3–4 adverse events were haematological: lymphopenia in 20 (33%) patients, neutropenia in 12 (20%) patients, and leucopenia in three (5%) patients. Grade 3–4 febrile neutropenia or infections were reported in three (5%) and four (7%) patients, respectively. Interpretation This response-adapted schedule of bendamustine plus rituximab appears to be an active and well tolerated first-line treatment for patients with MALT lymphoma. Funding Grupo Espanol de Linfomas/Trasplante de Medula Osea (GELTAMO), Mundipharma Spain, and Roche Pharma Spain.

The study included 1848 diffuse large B-cell lymphoma (DLBCL)patients treated with chemotherapy/rituximab. The aims were to validate the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and explore the effect of adding high Beta-2 microglobulin (β2M), primary extranodal presentation and intense treatment to the NCCN-IPI variables in order to develop an improved index. Comparing survival curves, NCCN-IPI discriminated better than IPI, separating four risk groups with 5-year overall survival rates of 93%, 83%, 67% and 49%, but failing to identify a true high-risk population. For the second aim the series was split into training and validation cohorts: in the former the multivariate model identified age, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, Stage III-IV, and β2M as independently significant, whereas the NCCN-IPI-selected extranodal sites, primary extranodal presentation and intense treatments were not. These results were confirmed in the validation cohort. The Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)-IPI developed here, with 7 points, significantly separated four risk groups (0, 1-3, 4 or ≥5 points) with 11%, 58%, 17% and 14% of patients, and 5-year overall survival rates of 93%, 79%, 66% and 39%, respectively. In the comparison GELTAMO IPI discriminated better than the NCCN-IPI. In conclusion, GELTAMO-IPI is more accurate than the NCCN-IPI and has statistical and practical advantages in that the better discrimination identifies an authentic high-risk group and is not influenced by primary extranodal presentation or treatments of different intensity.

Plasmablastic differentiation can be found in a variety of large B-cell lymphomas, including plasmablastic lymphoma, ALK-positive large B-cell lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in human herpesvirus-8 (HHV-8)-associated multicentric Castleman disease and diffuse large B-cell lymphoma (DLBCL) with partial plasmablastic phenotype. These tumors are characterized by acquisition of the transcriptional profile of plasma cells (with overexpression of PRDM1/Blimp1 and XBP1s, in concert with extinction of the B-cell differentiation program) by proliferating immunoblasts. This particular biological entity, i.e. large B-cell lymphoma with plasmablastic differentiation, is almost always associated with an aggressive clinical behavior. This review summarizes the current knowledge of the biological basis of plasmablastic differentiation in large B-cell lymphomas, the diagnostic borders with DLBCL and multiple myeloma, the associated adverse molecular events (with concomitant MYC, p53 and ALK alterations) and the potential therapeutic targets so far identified (including the unfolded protein response pathway). The highly aggressive nature of these lymphomas and the relative paucity of molecular data available highlight the need for deeper insights into the molecular pathogenesis of large B-cell lymphomas with plasmablastic differentiation in order to identify new and effective alternative treatments.

DCK catalyzes the intracellular phosphorylation of fludarabine. The promoter and coding region of the DCK gene were analyzed in 74 follicular lymphoma (FL) patients receiving a therapeutic regimen that included fludarabine. DCK mRNA expression was quantified in a cohort of healthy donors. Four previously described genotypic variants, −360C>G, −201C>T (rs2306744), C28624T (rs11544786) and c.91+37G>C (rs9997790), as well as the new variant, −12C>G, were identified. Variant C28624T showed a lower risk of lymphopenia (P = 0.04), but a higher risk of neutropenia (P = 0.04). Statistical significance was found in bivariate logistic regression between lymphopenia and infectious episodes in the induction period (odds ratio 3.85, P = 0.04).

Introduction. The majority of SMZLs display an indolent course, however the disease is still incurable and a significant proportion of patients (~25-30%) experience poor outcomes surviving 5 years, and for whom tumor material collected before initiation of medical therapy was available. Mutation analysis was performed by CAPP-seq targeted deep next generation sequencing of tumor genomic DNA. A stringent bioinformatic pipeline was applied to suppress the background noise allowing to call variants with a sensitivity of 5x10-2 in FFPE derived DNA. Copy number variations (CNVs) were identified by using the sequencing reads-based GATK4-CNV algorithm. IGHV rearrangements were obtained by using LymphoTrack® IGH FR1 Assay Panel kit. Molecular clusters were identified by an iterative algorithm that maximizes genetic distinctiveness of subgroups by reassigning patients between clusters that are created a priori based on the co-occurrence of genetic lesions. Relative survival, defined as the ratio between actuarial survival observed in the SMZL cohort and expected survival of the general population matched to patients by geographical origin, sex, age and calendar year of diagnosis, was calculated using the Ederer II method. Results. The analysis included 303 patients with a SMZL diagnosis confirmed on spleen histology. The sample size allowed to identify 30% differences in survival for molecular subgroups comprising at least 5% of cases with a statistical power between 80-100%. Median follow-up was 9.2 years. At 10 years, 85% of patients were alive, consistent with the known indolent behavior of this lymphoma. Genes recurrently affected by non-synonymous somatic mutations in >10% of SMZL included KLF2 (24%), NOTCH2 (19%), KMT2D (15%), TNFAIP3 (13%), EP300 and TP53 (10%). Deletion 7q was documented in 25% of cases and IGHV1-2*04 usage in 32%. By cluster analysis, three major molecular subgroups were identified, each of them characterized by a NOTCH pathway mutated gene (Fig. 1A). The first cluster was defined by NOTCH2 and/or KLF2 mutations and was enriched in TNFAIP3 mutations and IGHV1-2*04 gene usage (Fig. 1A). The second cluster was defined by SPEN mutations, and was enriched in KMT2D and other epigenetic gene mutations (Fig. 1A). The third cluster was enriched in NOTCH1 mutations (Fig. 1A). By relative survival analysis, the NOTCH2/KLF2 cluster showed a lower survival compared to the matched general population, indicating a significant impact of the disease on patients' expected survival (Fig. 1B). Conclusions. The large sample size and inclusion of SMZL confirmed by spleen histopathology review allowed for precise estimation of the prevalence of KLF2 and NOTCH2 mutations in this lymphoma. Three molecular clusters were identified in SMZL, each of them containing a NOTCH pathway gene, supporting the relevance of NOTCH signaling in the pathogenesis of SMZL. Patients belonging to the NOTCH2/KLF2 cluster had a lower relative survival compared to the matched general population. Disclosures Traverse-Glehen: Astra Zeneca: Other: Travel; Takeda: Research Funding. Gomes da Silva:Roche: Other: Institution's payment for consultancy, Travelling support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Celgene: Other: Travelling support; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Ladetto:Celgene: Honoraria; Jannsen: Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Sandoz: Honoraria; Roche: Honoraria. Rambaldi:Pfizer: Consultancy; Novartis: Consultancy; Omeros: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy; Roche: Consultancy; Celgene: Consultancy. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Zinzani:MSD: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau. Gaidano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Salles:Servier: Honoraria; Abbvie: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Pfizer: Honoraria; Morphosys: Honoraria; Gilead: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria. Zucca:Celltrion: Consultancy; AstraZeneca: Consultancy.

Purpose: Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), ∼30% of patients in advanced stages may eventually die as result of the disease, and current methods to predict prognosis are rather unreliable. Thus, the application of robust techniques for the identification of biomarkers associated with treatment response is essential if new predictive tools are to be developed. Experimental Design: We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functional pathways associated with unfavorable outcome that were significantly enriched in either the Hodgkin's and Reed-Sternberg cells (regulation of the G2-M checkpoint, chaperones, histone modification, and signaling pathways) or the reactive cell microenvironment (mainly represented by specific T-cell populations and macrophage activation markers). Results: To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach. Conclusions: The results of this assay can be combined in a single risk score integrating these biological pathways associated with treatment response and eventually used in a larger series to develop a new molecular outcome predictor for advanced cHL.

The employment of current treatments based on chemotherapy and immunotherapy leads to inmunosuppression. The presence of mutations or polymorphisms in genes related to immune system might involve an additional disadvantage. The aim of the present study was to analyze mannose-binding lectin (MBL-2 gene) mutations and their association with severe infections and event-free survival in patients diagnosed with follicular lymphoma, treated uniformly, in the clinical trial LNHF-03. The results of this trial showed impressive clinical efficacy but was complicated with 80 documented infectious episodes. Patients were classified into two genotypic groups, AA and AO/OO, based on their haplotypic inheritance. Neither the number of infectious episodes nor differences in event-free survival was found as a function of MBL-2 groups. Other factors, including the lymphoma malignancy and the immune alterations associated with the disease, should be considered responsible for this observation.

Follicular lymphomas (FLs) usually carry BCL2 translocations although BCL6 translocations are also present. We explored relationships between translocations status and clinical or histological parameters at diagnosis in 182 patients stratified in four groups: BCL2-/BCL6-, BCL2+/BCL6-, BCL2-/BCL6+ and BCL2+/BCL6+. BCL2-/BCL6- and BCL2+/BCL6-. Double negative cases were ascribed to lower histological grades. In contrast, BCL2-/BCL6+ cases corresponded to higher grades. However, a majority of BCL2+/BCL6+ tumours were classified as lower grades. These results were reinforced by the finding that double positive patients had lower LDH levels and PS than those with solitary BCL6 rearrangements. Bone marrow involvement was more frequent in BCL2+/BCL6+ compared with BCL2-/BCL6+ tumours. Our data confirm the presence of a relationship between histological grade and translocation status, suggesting that FLs carrying BCL6 translocations probably constitute a special biological subtype. Clinical and histological differences between BCL2-/BCL6+ and BCL2+/BCL6+ tumours could reflect an interplay between both translocations.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas that can be classified into three molecular subtypes by gene expression profiling (GEP): GCB, ABC and unclassified. Immunohistochemistry-based cell of origin (COO) classification, as a surrogate for GEP, using three available immunohistochemical algorithms was evaluated in TMA-arranged tissue samples from 297 patients with de novo DLBCL treated by chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). Additionally, the prognostic impacts of MYC, BCL2, IRF4 and BCL6 abnormalities detected by FISH, the relationship between the immunohistochemical COO classification and the immunohistochemical expression of MYC, BCL2 and pSTAT3 proteins and clinical data were evaluated. In our series, non-GCB DLBCL patients had significantly worse progression-free survival (PFS) and overall survival (OS), as calculated using the Choi, Visco-Young and Hans algorithms, indicating that any of these algorithms would be appropriate for identifying patients who require alternative therapies to R-CHOP. Whilst MYC abnormalities had no impact on clinical outcome in the non-GCB subtype, those patients with isolated MYC rearrangements and a GCB-DLBCL phenotype had worse PFS and therefore might benefit from novel treatment approaches.

Since the initial description of splenic marginal zone lymphoma (SMZL) in 1992, an increasing number of publications have dealt with multiple aspects of SMZL diagnosis, molecular pathogenesis and treatment. This process has identified multiple inconsistencies in the diagnostic criteria and lack of clear guidelines for the staging and treatment. The authors of this review have held several meetings and exchanged series of cases with the objective of agreeing on the main diagnostic, staging and therapeutic guidelines for patients with this condition. Specific working groups were created for diagnostic criteria, immunophenotype, staging and treatment. As results of this work, guidelines are proposed for diagnosis, differential diagnosis, staging, prognostic factors, treatment and response criteria. The guidelines proposed here are intended to contribute to the standardization of the diagnosis and treatment of these patients, and should facilitate the future development of clinical trials that could define more precisely predictive markers for histological progression or lack of response, and evaluate new drugs or treatments.

The stomach is the extranodal site most commonly involved by non-Hodgkin lymphomas. Diffuse large B-cell lymphoma is the most common histotype category arising in this organ. This is an aggressive lymphoma usually presenting as limited disease, being associated or not to Helicobacter pylori infection and mucosa-associated lymphoid tissue-type areas. Histopathological characteristics are similar to those reported for other diffuse large B-cell lymphomas. It occurs more frequently in males with a median age ranging between 50 and 60 years. With an adequate therapeutic strategy, its prognosis is good, with a 5-year overall survival near to 90%. Conservative treatment with anthracycline-containing chemotherapy, followed or not by involved-field radiotherapy has replaced gastrectomy as standard approach against this malignancy. Several questions on the best treatment remain unanswered. Among others, the role of rituximab, consolidation radiotherapy as well as of more conservative approaches like H. pylori-eradicating antibiotic therapy should be better defined.

Around 20% to 30% of patients with Hodgkin lymphoma (HL) do not benefit from standard therapies and finally succumb to their disease. The factors that influence the outcome of HL have not been elucidated, underscoring the demand for the identification of biologic risk factors and new therapeutic targets. We analyzed the gene expression profiles of samples from 29 patients with advanced classic HL treated with standard therapy and compared the expression profiles of patients with favorable and unfavorable clinical outcome. Using supervised methods, we identified 145 genes associated with outcome, which were grouped into 4 signatures representing genes expressed by either the tumoral cells (genes involved in the regulation of mitosis and cell growth/apoptosis) or the tumor microenvironment. The relationship between the expression of 8 representative genes and survival was successfully validated in an independent series of 235 patients by quantification of protein expression levels on tissue microarrays. Analysis of centrosomes and mitotic checkpoint confirmed the existence of an abnormal transition through mitosis in HL cells. Therefore, genes related to tumor microenvironment, cell growth/apoptosis, and regulation of mitosis are associated with treatment response and outcome of patients with HL.

Background: Localized low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma can regress after Helicobacter pylori eradication, but IgVH gene monoclonality may persist. We studied the long-term histological and molecular follow-up of 24 patients and the possible association of t(11;18) with the persistent monoclonality. Patients and methods: From January 1994, 24 untreated patients with stage I low-grade gastric MALT lymphoma associated with H. pylori were prospectively studied. They all received eradication treatment and were sequentially followed-up with endoscopies for histological and molecular studies. Rearrangement of the IgVH gene was studied by PCR analysis. MALT1 locus alterations were studied by FISH. Results: Twenty-two of the 24 patients (91%) achieved disappearance of the lymphoma. Eighteen (82%) of the 22 histologically cured patients and 16 of the 19 (84%) with long follow-up had monoclonality. Three patterns of development of IgVH gene rearrangements were observed: four patients (21%) had polyclonal rearrangements; eight (58%) had maintained/intermittent monoclonality and four (21%) had occasional monoclonality, mostly after H. pylori reinfection. Only one patient (6%) with persistent monoclonality relapsed. The remaining 18 patients maintained the remission, despite the persistent monoclonality in 15, for a median of 66 months (range 20–113). t(11;18) was not found in any of the patients with persistent monoclonality. Time and the number of endoscopies performed were not related with the occurrence of monoclonality. Conclusions: In stage I low-grade gastric MALT lymphoma eradication of H. pylori achieves prolonged histological remission in 90% of patients, but molecular remission is not accomplished in most cases. Molecular disease persists for years, but is not associated with t(11;18).

p18INK4c is a cyclin-dependent kinase (CDK) inhibitor that interferes with the Rb-kinase activity of CDK6/CDK4. Disruption of p18INK4c in mice impairs B-cell terminal differentiation and confers increased susceptibility to tumor development; however, alterations of p18INK4c in human tumors have rarely been described. We used a tissue-microarray approach to analyze p18INK4c expression in 316 Hodgkin lymphomas (HLs). Nearly half of the HL cases showed absence of p18INK4c protein expression by Reed-Sternberg (RS) cells, in contrast with the regular expression of p18INK4c in normal germinal center cells. To investigate the cause of p18INK4c repression in RS cells, the methylation status of the p18INK4c promoter was analyzed by methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing. Hypermethylation of the p18INK4c promoter was detected in 2 of 4 HL-derived cell lines, but in none of 7 non-Hodgkin lymphoma (NHL)–derived cell lines. We also detected p18INK4c hypermethylation, associated with absence of protein expression, in 5 of 26 HL tumors. The correlation of p18INK4c immunostaining with the follow-up of the patients showed shorter overall survival in negative cases, independent of the International Prognostic Score. These findings suggest that p18INK4c may function as a tumor suppressor gene in HL, and its inactivation may contribute to the cell cycle deregulation and defective terminal differentiation characteristic of the RS cells.

We have reviewed the clinical, morphologic, immunophenotypical, and molecular features of a series of 27 cases of nodal marginal zone lymphoma with the aim of defining this entity more precisely. The series was characterized by a relatively favorable clinical course, with a low clinical stage at diagnosis (59% patients with clinical stage I-II) and a 5-year overall survival probability of 79%. However, the disease persisted in a relatively large fraction of the patients, thus yielding a 5-year failure-free survival probability of 22%. Molecular and immunohistochemical analyses of the series revealed heterogeneity in the frequency of IgV(H) somatic mutation and in the expression of IgD, CD43, MUM1, and CD38. Apart from the absence of nuclear Bcl10, no clear distinction could be made from the expression profiling of other B-cell lymphomas claimed to be derived from marginal zone B cells. Additionally, the immunophenotype of the tumoral cells in all cases but one differed from that described in monocytoid B cells. It was characterized by a Bcl2-, p21+, cyclin E+ profile. The analysis of apoptosis-regulator proteins disclosed abnormalities in the expression of survivin and active caspase 3, which could partially explain the abnormal regulation of apoptosis observed in these tumors. Molecular and immunohistochemical data obtained in this study strongly imply that there is significant heterogeneity among the cases included in the category termed nodal marginal zone lymphoma.

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.

Introduction Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive B cell lymphomas, considering their biologic, pathological and clinical backgrounds. However, treatment of DLBCL is relatively homogeneous and standard, mainly based in the R-CHOP regimen. Several prognostic scores have been proposed for categorizing the risk and finding those with worse results with standard treatment, suitable to be treated with new schemes or drugs. The most important and widely used is the International Prognostic Index (IPI) proposed in 1993 and lately validated in the rituximab era (R-IPI). However, being a good prognostic score lacks the ability to identify a very high risk prognostic subset in the rituximab era. Trying to improve this situation several attempts have been made including NCCN-IPI or GELTAMO-IPI. In 1992, the MD Anderson Cancer Centre (MDACC) reported a prognostic score considering exclusively variables related to the tumor: the Tumor Score (TS). Two of them already present in IPI: high LDH and Ann Arbor stage III-IV but three different: high beta-2-microglobulin (B2M), bulky mass and presence of B symptoms. This index has not been studied in the rituximab era. Our aim is to validate the TS in the rituximab era and analyze its current potential role. METHODS From the nation-wide database of DLBCL of the Grupo Español de Linfoma y Trasplante de Médula Ósea (GELTAMO), we included for the validation those patients homogenously treated with R-CHOP and with all five TS variables available (n=1294). Patients had to be ≥ 18 years-old and a minimum of 1 year of follow-up; all histological subtypes of DLBCL and primary extranodal cases were acceptable, with the only exclusion of primary testicular or CNS sites. Failure-free survival (FFS) (including disease progression, no response to treatment or death events) and overall survival (OS) were analyzed with the Kaplan-Meier method and compared with the log-rank test. Cox Regression models were used for univariate and multivariate analysis. Comparisons between scores were performed with concordance probability estimates (CPEs). RESULTS Median follow-up was 60 months (12-176). 5y-FFS and OS of the series were 62% and 74%, respectively. All the variables of the original TS retained an independent prognostic role in our series. The TS in the rituximab era (R-TS) remains predictive and clearly identifies four different risk groups (Figure 1A), finding a particularly high risk subset with a worse outcome (5y-FFS of 29%). Comparison between TS and the other indexes (IPI, NCCN-IPI or GELTAMO-IPI) showed similar CPEs for FFS in our series: 0.64 vs 0.64, 0.64 and 0.65, respectively (Figure 1B). However, TS has a better discrimination of the higher risk subgroup than IPI (5y-FFS of 47%) and NCCN-IPI (5y-FFS of 39%), and the same that GELTAMO-IPI but with a better consistency between points of the score. As R-IPI and R-TS have complementary information, another option was combining R-IPI and R-TS: patients within high risk by R-IPI (5y-FFS of 47%) when tested with R-TS can be further subdivided in three risk categories (intermediate low, intermediate high and high with 5y-FFS of 75%, 61% and 37%, respectively). To further improve the ability of finding a very high risk subset with the variables included in TS, we tested categorizing B2M normalized (normal, >1 and >3), LDH normalized (normal, >1 and >3) and AA stage (I, II and III-IV). With these changes the new enhanced TS could identify a higher risk group with a 5y-FFS of 20% and a median FFS of 7 months (Figure 1C and 1D). CONCLUSIONS 1) All variables included in the original MD. Anderson TS retain an independent prognostic role in the rituximab era, including B symptoms, B2M and bulky mass; 2) TS remains predictive of FFS and OS in the rituximab era with a similar CPE in discrimination when compared to previously reported prognostic scores; 3) TS and GELTAMO-IPI showed a better identification of patients with high risk prognosis compared to IPI or NCCN-IPI; 4) R-IPI and R-TS may be combined in order to easily improve risk classification of DLBCL patients; 5) Further categorization of LDH, B2M and AA stage increased the ability of TS to identify high risk subsets of DLBCL; 6) TS could be a backbone for introducing other new molecular or biologic tumor related prognostic factors. Figure 1. FFS using R-TS (1A), R-IPI (1B) and enhanced TS (1C). OS using enhanced TS (1D). Figure 1 Figure 1. Disclosures Gutierrez: SERVIER: Speakers Bureau; GILEAD: Honoraria; TAKEDA: Speakers Bureau; PFIZER: Consultancy; JANSSEN: Consultancy, Research Funding, Speakers Bureau; ROCHE: Research Funding, Speakers Bureau. Diaz-Lopez: TFS: Employment. Lopez-Guillermo: Roche: Consultancy, Other: Research grant; Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Novartis: Consultancy. Martín: Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Consultancy. Salar: Roche: Speakers Bureau; Janssen: Speakers Bureau; Servier: Speakers Bureau.

BACKGROUND—Most low grade gastric lymphomas arising from the mucosa associated lymphoid tissue (MALT) are related to Helicobacter pylori colonisation. Cases with disease limited to the stomach can be cured after H pylori eradication and remain in remission for years. In contrast, high grade lymphomas of the stomach, although also related to H pylori, do not usually respond to eradication treatment. CASE REPORT—A 36 year old patient was referred from another hospital with a diagnosis of a low grade gastric MALT lymphoma associated with H pylori. The patient was in stage I and while waiting for the biopsies to be reviewed H pylori eradication therapy was given as the first step of treatment. Review of the biopsies showed a high grade immunoblastic lymphoma with areas of low grade gastric MALT lymphoma (high grade gastric MALT lymphoma or diffuse large B cell lymphoma with areas of MALT type lymphoma of the WHO classification). The patient received no further treatment but has been closely followed up for 32 months with sequential endoscopies to obtain biopsies for histological studies, H pylori cultures, and polymerase chain reaction analysis of the IgH gene. RESULTS—After H pylori eradication the patient had a complete histological response that has been maintained for 32 months. Monoclonal IgH gene rearrangement persisted for 32 months. CONCLUSION—The response of this patient indicates the possibility that some cases of high grade gastric MALT lymphoma (possibly patients in stage I with a superficial or limited disease) may still be responsive to H pylori antigenic drive and may be cured with eradication therapy. Prospective studies should be performed to identify patients with high grade gastric MALT lymphomas that may respond to eradication therapy and be spared of other more aggressive treatments. Keywords: mucosa associated lymphoid tissue; lymphoma; gastric lymphoma; immunoblastic lymphoma; Helicobacter pylori

Multiple lymphomatous polyposis is a rare type of non Hodgkin lymphoma that has aggressive biological behavior, early systemic dissemination and poor prognosis. In most cases it is considered to be a gastrointestinal manifestation of mantle cell nodal lymphoma. We describe a case of a 55 year old man, with favorable outcome after chemotherapy.

Summary Background: Peripheral T-cell lymphomas (PTCL) account for about 10% of all lymphomas in Western countries. The aim of the present study is to analyze the initial characteristics and prognostic factors in a large series of PTCL patients. Patients and methods: 174 patients (105 male/69 female; median age 61 years) were diagnosed with PTCL according to the R.E.A.L. Classification in nine Spanish institutions between 1985 and 1996. Cutaneous lymphomas and T-cell chronic lymphocytic/prolymphocytic leukemia were excluded from the study. Univariate and multivariate analyses were used to assess the prognostic value of the main initial variables. Results: The distribution according to histology subgroup was: PTCL unspecified, 95 cases (54.4%); anaplastic large-cell Ki-1-positive (ALCL), 30 cases (17%); angioimmunoblastic T cell, 22 cases (13%); angiocentric, 14 cases (8%); intestinal T cell, 12 cases (7%), and hepatosplenic y5 T cell, one case (0.6%). As compared to the other types, ALCL presented more frequently in ambulatory performance status, without extranodal involvement, in early stage, normal serum p"2-microglobulin (B2M) level and low-risk international prognostic index (IPI). Most patients were treated with adriamycin-containing regimens. The overall CR rate was 49% (69% for ALCL vs. 45% for other PTCL; P < 0.02). The risk of relapse was 48% at four years. Median survival of the series was 22 months (65 months for ALCL vs. 20 months for other PTCL; P = 0.03), with a four-year probability of survival of 38% (95% confidence intervals (95% CI): 28^t8). In the univariate analysis, in addition to the histology, older age, poor performance status, presence of B-symptoms, extranodal involvement, bone marrow infiltration, advanced Ann Arbor stage, high serum LDH, high serum B2M, and intermediate- or high-risk IPI were related to poor survival. In the multivariate analysis the histologic subgroup (ALCL vs. other PTCL) (P = 0.02; response rate (RR): 4.3), the presence of B-symptoms (P = 0.02, RR: 2.2), and the IPI (low vs. high) (P = 0.04, RR: 2) maintained independent predictive value. When the analysis was restricted to the unspecified subtype, only IPI had independent prognostic value (P - 0.003; RR: 3.5). Conclusions: PTCL have adverse prognostic features at diagnosis, respond poorly to therapy and have short survival, with no sustained remission. ALCL constitutes a subgroup which responds better to therapy and has a longer survival.

Splenic marginal zone lymphoma (SMZL) is a well- established type of indolent B-cell lymphoma [1] that usually involves the bone marrow, peripheral blood and spleen, and only rarely presents with n...