Treatment of patients with early stage gastric mucosa-associated lymphoid tissue (MALT) remains undefined. We began a controlled clinical trial to evaluate efficacy and toxicity of the most common therapies. Two hundred and forty-one patients with gastric low-grade MALT lymphoma in early stage (IE and IIE) were randomized to surgery (80 cases), radiotherapy (78 cases), and chemotherapy (83 cases). With a median follow-up of 7.5 yr, actuarial curves at 10 yr showed that event-free survival was 52% in patients treated with surgery, 52% in radiotherapy arm, and 87% in the chemotherapy group (p < 0.01). However, overall survival did not showed any statistical differences: 80%, 75% and 87%, respectively (p = 0.4). Acute and late toxicities were mild. No death-related treatments were observed. No clear differences were observed between the most common therapies in patients with primary gastric MALT lymphoma in early stages, probably because this type of lymphoma has an high response rate to salvage treatment after failure to local treatment (surgery and radiotherapy). Thus considered, chemotherapy alone is an effective and safe therapeutic approach in this setting of patients. Surgery or radiotherapy will be reserved to patients that are not candidates for chemotherapy.

Krüppel-Like Factor 4 (KLF4) is a member of the KLF transcription factor family, and evidence suggests that KLF4 is either an oncogene or a tumor suppressor. The regulatory mechanism underlying KLF4 expression in cancer, and specifically in lymphoma, is still not understood. Bioinformatics analysis revealed two YY1 putative binding sites in the KLF4 promoter region (-950 bp and -105 bp). Here, the potential regulation of KLF4 by YY1 in NHL was analyzed. Mutation of the putative YY1 binding sites in a previously reported system containing the KLF4 promoter region and CHIP analysis confirmed that these binding sites are important for KLF4 regulation. B-NHL cell lines showed that both KLF4 and YY1 are co-expressed, and transfection with siRNA-YY1 resulted in significant inhibition of KLF4. The clinical implications of YY1 in the transcriptional regulation of KLF4 were investigated by IHC in a TMA with 43 samples of subtypes DLBCL and FL, and all tumor tissues expressing YY1 demonstrated a correlation with KLF4 expression, which was consistent with bioinformatics analyses in several databases. Our findings demonstrated that KLF4 can be transcriptionally regulated by YY1 in B-NHL, and a correlation between YY1 expression and KLF4 was found in clinical samples. Hence, both YY1 and KLF4 may be possible therapeutic biomarkers of NHL.

Objectives: We conducted a randomized clinical trial to evaluate the role of interferon alfa 2b (IFN) as maintenance therapy in patients with diffuse large B‐cell lymphoma with high or high–intermediate clinical risk on complete remission (CR) after CHOP–BLEO regimens. Methods: Patients were initially treated with CHOP–BLEO regimens (which include increased doses of cyclophosphamide and epirubicine, instead of doxorubicin). If the patients achieved CR they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU, three times at week by 1 yr, or no treatment (control group). Results: Two hundred and twenty‐three patients were considered as candidates for the study. They were of high (80%) or high–intermediate (20%) clinical risk; additionaly most patients had poor prognostic factors such as high levels of beta 2 microglobulin, lactic dehydrogenase levels, bulky disease (defined as a tumor mass >10 cm) or multiple extranodal involvement. In an intent‐to‐treat analysis all patients were evaluable to efficacy and toxicity. Median follow‐up was 45 months, the estimated 5‐yr overall survival and event‐free survival (EFS) for patients who received IFN were 71% (95% confidence interval (CI): 61–83%) and 57% (95% CI: 39–69%), respectively, values which were not statistically different from the control group: 69% (95% CI: 63–79%) and 54% (95% CI: 37–63%), respectively (p=0.2). Toxicity was mild. Conclusions: These results suggest that IFN used as maintenance therapy at these doses and schedules is not useful in aggressive malignant lymphoma when more intensive chemotherapy has been employed during induction treatment. Nevertheless, follow‐up is too short, and long‐term follow‐up would be necessary in order to draw definitive conclusions. Probably, an multicenter study is necessary to define the role of IFN as maintenance therapy in this patient setting.

The discovery and description of the role of microRNAs has become very important, specifically due to their participation in the regulation of proteins and transcription factors involved in the development of cancer. microRNA-7 (miR-7) has been described as a negative regulator of several proteins involved in cancer, such as YY1 and KLF4. We have recently reported that YY1 and KLF4 play a role in non-Hodgkin lymphoma (NHL) and that the expression of KLF4 is regulated by YY1. Therefore, in this study we analyzed the role of miR-7 in NHL through the negative regulation of YY1 and KLF4. qRT-PCR showed that there is an inverse expression of miR-7 in relation to the expression of YY1 and KLF4 in B-NHL cell lines. The possible regulation of YY1 and KLF4 by miR-7 was analyzed using the constitutive expression or inhibition of miR-7, as well as using reporter plasmids containing the 3 'UTR region of YY1 or KLF4. The role of miR-7 in NHL, through the negative regulation of YY1 and KLF4 was determined by chemoresistance and migration assays. We corroborated our results in cell lines, in a TMA from NHL patients including DLBCL and follicular lymphoma subtypes, in where we analyzed miR-7 by ISH and YY1 and KLF4 using IHC. All tumors expressing miR-7 showed a negative correlation with YY1 and KLF4 expression. In addition, expression of miR-7 was analyzed using the GEO Database; miR-7 downregulated expression was associated with pour overall-survival. Our results show for the first time that miR-7 is implicate in the cell migration and chemoresistance in NHL, through the negative regulation of YY1 and KLF4. That also support the evidence that YY1 and KLF4 can be a potential therapeutic target in NHL.

Presence of second neoplasms and cardiac toxicity has been recognized as potential late lethal second events in patients treated for Hodgkin's disease. However, most reports analyze these association independently. We reviewed 2980 cases of patients treated during 1970-1995 with long-term follow-up (> 4 years) in an attempt to identify all late events in Hodgkin's disease secondary to the treatment or those which are unrelated. Three hundred and ten patients died, and of these 156 were secondary to relapse and tumor progression. Death associated second tumors and cardiac events were increased 37 fold and 29 fold respectively compared to the general population. The risk factors for this complications did not differ to previous reports and included alkylating agents and/or radiotherapy for second neoplasms and anthracycline therapy and radiotherapy for cardiac toxicity. Moreover, 61 patients died secondary to non-related events. Nevertheless, at 20-years overall survival was 90 % (95 % confidence interval (CI): 78 % to 97 %) and event free survival was 88 % (95 % CI: 76 % to 96 %) for these patients. Thus, second events, fatal in most cases, should be considered as an expected risk to the treatment in patients with Hodgkin's disease; the proposed modifications of therapy may indeed be useful to avoid or diminish these complications in the future.

The use of adjuvant RT in patients with DLBCL and nodal bulky disease improves the outcome with PFS and OS, with minimal toxicity; thus, we felt that adjuvant RT will be considered as a part of the initial treatment in this setting of patients, even in the rituximab era.

ObjectivePrimary mediastinal B‐cell lymphoma is a rare and unique type of non‐Hodgkin's lymphoma that develops more frequently in younger patients and women. The combination of immunochemotherapy and radiotherapy (RT) has been suggested as the primary treatment choice. However, no consensus has been reached. Thus, we carried out an open‐label clinical trial. Patients with complete response after six cycles of immunochemotherapy were randomized to receive or not receive RT (control group).MethodsFrom July 2004 to December 2012, 324 patients with primary mediastinal B‐cell lymphoma were enrolled and randomized at 1:1, with 164 and 160 patients in the RT and control groups, respectively.ResultsThe 5‐year progression‐free survival was 84% (95% confidence interval [CI] 77–89%) in the RT group and 67% (95% CI 60–76%) in the control group (P < 0.01). The 5‐year overall survival was 86% (95% CI 79–96%) in the RT group and 68% (95% CI 60%–74%) in the control group (P < 0.01). Toxicity was minimal and well controlled. No late toxicities were observed.ConclusionRT as adjuvant treatment in patients with complete response after six cycles of immunochemotherapy improved the progression‐free survival and overall survival with minimal toxicities.

Objective To assess if the use of a dose-dense regimen of chemotherapy can improve the prognosis in patients with primary gastric diffuse large B-cell lymphoma in early stages (I–II) but associated with worse prognostic factors. Methods One hundred and eight consecutive patients with primary gastric diffuse large B-cell lymphoma in early stages (I–II) with high serum levels of lactic dehydrogenase and beta 2 microglobulin (more than >2 of normal levels), which were associated with a worse prognostic outcome, were treated with a dose-dense chemotherapy: CHOP with increased doses of cyclophosphamide and doxorubicin, was administered every 14 days (instead of 21 days). The end points of this study were to improve outcome measured from progression-free survival and overall survival and to evaluate acute toxicities. Results Complete response was achieved in 85 patients (78%). Actuarial curves at five years show that progression-free survival was 82% and overall survival was 85%. Hematological toxicities were severe, but no death-related treatment was observed. Conclusions We considered that in this setting of patients, the use of a dose-dense regimen could be of benefit because it improves outcome and toxicities were well controlled.