Browsing by Subject "Diffuse large B-cell lymphoma"

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  • Vähämurto, Pauli; Silventoinen, Kaija; Vento, Seija; Karjalainen-Lindsberg, Marja-Liisa; Haapaniemi, Aaro; Back, Leif; Mannisto, Susanna; Leppa, Sirpa; Makitie, Antti A. (2016)
    Sinonasally located lymphoid malignancies are rare lesions with first symptoms similar to other obstructive conditions. Additionally, they often coexist with nasal inflammation and mucosal necrosis. Therefore, time from the first symptoms to diagnosis tends to be long. Awareness and early diagnosis of this disease entity could improve treatment outcome. Altogether, 142 patients with sinonasal or nasopharyngeal (i.e. sinonasal tract, SNT) lymphoid malignancies, diagnosed and treated at the Helsinki University Hospital, during a 39-year period from 1975 to 2013, were retrospectively reviewed. There were 90 males (63 %) and 52 females (37 %) with a median age of 64 years (range 26-92). Eighty-four percent of the patients had primary diseases and 16 % had relapses of lymphoid malignancies primarily diagnosed at other locations. The mean duration of symptoms prior to diagnosis was 4.8 months (range 0.5-24). The most common histological entity was diffuse large B-cell lymphoma (43 %), followed by plasmacytoma (18 %). The most common location was nasopharynx (58 %) followed by nasal cavity (44 %) and paranasal sinuses (35 %). Sixty-nine percent of the lesions were at a single anatomic location of the sinonasal tract. Fifty-two percent of the cases were of Ann Arbor Stage I. Lymphoid malignancies form an important and diverse group in the differential diagnosis of SNT tumours. They most often present with general obstructive nasal symptoms due to tumour location. Most of them are primary lesions, highlighting the importance of an accurate diagnosis as early as possible.
  • Facciotto, Chiara; Casado, Julia; Turunen, Laura; Leivonen, Suvi-Katri; Tumiati, Manuela; Rantanen, Ville; Kauppi, Liisa; Lehtonen, Rainer; Leppä, Sirpa; Wennerberg, Krister; Hautaniemi, Sampsa (2019)
    Background The epigenome plays a key role in cancer heterogeneity and drug resistance. Hence, a number of epigenetic inhibitors have been developed and tested in cancers. The major focus of most studies so far has been on the cytotoxic effect of these compounds, and only few have investigated the ability to revert the resistant phenotype in cancer cells. Hence, there is a need for a systematic methodology to unravel the mechanisms behind epigenetic sensitization. Results We have developed a high-throughput protocol to screen non-simultaneous drug combinations, and used it to investigate the reprogramming potential of epigenetic inhibitors. We demonstrated the effectiveness of our protocol by screening 60 epigenetic compounds on diffuse large B-cell lymphoma (DLBCL) cells. We identified several histone deacetylase (HDAC) and histone methyltransferase (HMT) inhibitors that acted synergistically with doxorubicin and rituximab. These two classes of epigenetic inhibitors achieved sensitization by disrupting DNA repair, cell cycle, and apoptotic signaling. The data used to perform these analyses are easily browsable through our Results Explorer. Additionally, we showed that these inhibitors achieve sensitization at lower doses than those required to induce cytotoxicity. Conclusions Our drug screening approach provides a systematic framework to test non-simultaneous drug combinations. This methodology identified HDAC and HMT inhibitors as successful sensitizing compounds in treatment-resistant DLBCL. Further investigation into the mechanisms behind successful epigenetic sensitization highlighted DNA repair, cell cycle, and apoptosis as the most dysregulated pathways. Altogether, our method adds supporting evidence in the use of epigenetic inhibitors as sensitizing agents in clinical settings.
  • Meriranta, Leo (Helsingin yliopisto, 2019)
    Concomitant deregulation of MYC and BCL2, whether at the genomic or protein level, comprises a clinically significant poorly characterized biological high-risk feature in diffuse large B-cell lymphoma (DLBCL). To interrogate these lymphomas, we comprehensively characterized genomic alterations and protein expression of BCL2, BCL6 and MYC in the context of comprehensive mutational, transcriptomic and clinical data in 181 patients with primary DLBCL. While the structural variations of BCL2 were subtype-specific and specifically increased BCL2 expression, molecular dissection of MYC deregulation revealed associations with other lymphoma drivers, of which we highlight concurrent TP53 alterations. Double protein expression (DPE) arose from heterogeneous molecular backgrounds in a subtype-dependent manner. In GCB DLBCL, concurrent alterations of MYC and BCL2 loci gave rise to the majority of DPE DLBCLs, whereas in the ABC DLBCLs, concurrent alterations were infrequent. Clinically, DPE DLBCL defined a prognostic entity, which was independent of International Prognostic Index (IPI) and cell-of-origin, and together with TP53 alterations had synergistic dismal impact on survival. Importantly, BCL6 translocations identified non-GCB lymphomas with favorable BN2/C1 -like outcomes independent of IPI and concurrent DPE status. Our findings elucidate the pathogenesis and biological determinants of high-risk DLBCL and reveal subtype-specific and clinically feasible predictors of subtype and outcome.