The ETS transcription factor ESE3/EHF as a regulator of prostate epithelial cell differentiation and stem cell properties

This is a collaborative international clinical study on the management of primary mediastinal B-cell lymphoma (PMLBCL), a distinct subtype of large B-cell lymphoma (DLBCL), which mainly affects young adults with a female predominance. Here, we ask for funding for the study coordination, data management and processing, which will be performed entirely in Switzerland and for central histology and positron emission tomography (PET) scans reviews that will also be performed in Switzerland, at least in part.Initial therapy is critical in PMLBCL. Salvage therapy for recurrence or progressive disease is often of limited efficacy; thus, the imperative is to cure at the first attempt. There is, however, a tension between delivery of the highest possible cure fraction and minimizing long-term morbidity. Hence, the optimal management remains a matter of debate. In particular, there is uncertainty as to whether consolidation radiotherapy to the mediastinum is always required and whether PET scanning can be used to discriminate patients who require radiation therapy from those who do not.Until very recently it was generally accepted that very intensive front line chemotherapy (with third-generation regimens such as MACOP-B or VACOP-B) was more active than the standard CHOP regimen. However, the introduction of chemoimmunotherapy with rituximab combined to the standard CHOP regimen has resulted in improved outcomes, similar to those previously achieved with third generation regimens. Retrospective studies (mainly performed before the introduction of rituximab) suggest that the best outcomes are obtained when consolidation radiotherapy is given. A residual mediastinal mass is indeed most often present at the end of chemotherapy, but does not necessarily contain active tumour. Lesions that have become PET-negative at the end of chemoimmunotherapy are nowadays considered as complete response and whether mediastinal irradiation is needed in patients with a PET-negative residual disease is unclear. Moreover, there are concerns about late effects of mediastinal radiotherapy, particularly the risks of second malignancies and cardiac disorders, that justify studies to investigate scenarios where radiotherapy may not be required.This phase III randomized trial is designed to assess the role of involved-field radiotherapy in PMLBCL patients with a PET-negative mediastinal residual lesion after immunochemotherapy. The trial should be able to demonstrate a non-inferior outcome in patients not receiving radiotherapy after immunochemotherapy. Albeit modern radiotherapy techniques may minimize the morbidity to other tissues and reduce the long-term toxicity, they may not completely control the risks of late side-effects, therefore safety remains an important issue. Such a study may eventually allow to individualize treatment for each patient by adapting it to the PET response, limiting the indication for additional radiotherapy only to the patients who show an inadequate response to immunochemotherapy.In this trial, patients who have received one of the standard anthracycline-based chemotherapy regimens and at least 6 doses of rituximab, and who have a post-chemotherapy FDG-PET/CT scan -which is confirmed as negative after central review- will be randomized to either no further treatment or mediastinal radiotherapy (30Gy). The primary endpoint is progression-free survival and the study is powered to exclude a difference of 10% or more. This will require around 375 patients to be randomized in 36-48 months. According to the preliminary data of our previous study, a CT-PET remains positive in approximately half of the patients at the end of chemoimmunotherapy, indicating that approximately 750 patients will have to be registered. Because of the large required sample size we secured international collaboration and obtained from several institutions and cooperative groups a confirmation of their intent to participate.