Search

Abstract Background Adult patients with T‐cell lymphoblastic lymphoma (T‐LBL) are treated with high‐intensity chemotherapy regimens, but the response rate is still unsatisfactory because of frequent drug resistance. We aimed to investigate the potential mechanisms of drug resistance in adults with T‐LBL. Methods Gene expression microarray was used to identify differential mRNA expression profiles between chemotherapy‐resistant and chemotherapy‐sensitive adult T‐LBL tissues. Real‐time PCR and immunohistochemistry were performed to detect the expression of bromodomain‐containing protein 2 (BRD2) and c‐Myc in fresh‐frozen T‐LBL tissues from 85 adult patients. The Ras pull‐down assay was performed to monitor Ras activation. Chromatin immunoprecipitation assays were used to analyze the binding of E2F transcription factor 1 (E2F1)/BRD2 to the RAS guanyl releasing protein 1 (RasGRP1) promoter region. The drug resistance effect and mechanism of BRD2 were determined by both in vivo and in vitro studies. Results A total of 86 chemotherapy resistance‐related genes in adult T‐LBL were identified by gene expression microarray. Among them, BRD2 was upregulated in chemotherapy‐resistant adult T‐LBL tissues and associated with worse progression‐free survival and overall survival of 85 adult T‐LBL patients. Furthermore, BRD2 suppressed doxorubicin (Dox)‐induced cell apoptosis both in vitro and in vivo. The activation of RasGRP1/Ras/ERK signaling might contribute to the Dox resistance effect of BRD2. Besides, OTX015, a bromodomain and extra‐terminal (BET) inhibitor, reversed the Dox resistance effect of BRD2. Patient‐derived tumor xenograft demonstrated that the sequential use of OTX015 after Dox showed superior therapeutic effects. Conclusions Our data showed that BRD2 promotes drug resistance in adult T‐LBL through the RasGRP1/Ras/ERK signaling pathway. Targeting BRD2 may be a novel strategy to improve the therapeutic efficacy and prolong survival of adults with T‐LBL.

Abstract Background The 8th American Joint Committee on Cancer tumor–node–metastasis (AJCC-TNM) staging system is based on a few retrospective single-center studies. We aimed to test the prognostic validity of the staging system and to determine whether a modified clinicopathological tumor staging system that includes lymphovascular embolization could increase the accuracy of prognostic prediction for patients with stage T2–3 penile cancer. Methods A training cohort of 411 patients who were treated at 2 centers in China and Brazil between 2000 and 2015 were staged according to the 8th AJCC-TNM staging system. The internal validation was analyzed by bootstrap-corrected C-indexes (resampled 1000 times). Data from 436 patients who were treated at 15 centers over four continents were used for external validation. Results A survivorship overlap was observed between T2 and T3 patients (P = 0.587) classified according to the 8th AJCC-TNM staging system. Lymphovascular embolization was a significant prognostic factor for metastasis and survival (all P