Browsing by Subject "MULTIPLE-MYELOMA"

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  • Turunen, A; Silvennoinen, R; Partanen, A; Valtola, J; Siitonen, T; Putkonen, M; Sankelo, M; Pyorala, M; Kuittinen, T; Penttila, K; Sikio, A; Savolainen, ER; Mantymaa, P; Pelkonen, J; Varmavuo, V; Jantunen, E (2021)
    Background Autologous stem cell transplantation (auto-SCT) is a widely used treatment option in multiple myeloma (MM) patients. The optimal graft cellular composition is not known. Study design and methods Autograft cellular composition was analyzed after freezing by flow cytometry in 127 MM patients participating in a prospective multicenter study. The impact of graft cellular composition on hematologic recovery and outcome after auto-SCT was evaluated. Results A higher graft CD34(+) cell content predicted faster platelet recovery after auto-SCT in both the short and long term. In patients with standard-risk cytogenetics, a higher graft CD34(+) count (>2.5 x 10/kg) was linked with shorter progression-free survival (PFS; 28 vs. 46 months, p = 0.04), but there was no difference in overall survival (OS) (p = 0.53). In a multivariate model, a higher graft CD34(+)CD133(+)CD38(-) (>0.065 x 10/kg, p = 0.009) and NK cell count (>2.5 x 10/kg, p = 0.026), lenalidomide maintenance and standard-risk cytogenetics predicted better PFS. In contrast, a higher CD34(+) count (>2.5 x 10/kg, p = 0.015) predicted worse PFS. A very low CD3(+) cell count ( Conclusions Autograft cellular composition may impact outcome in MM patients after auto-SCT. More studies are needed to define optimal graft composition.
  • Dufva, Olli; Pölönen, Petri; Brück, Oscar; Keränen, Mikko A. I.; Klievink, Jay; Mehtonen, Juha; Huuhtanen, Jani; Kumar, Ashwini; Malani, Disha; Siitonen, Sanna; Kankainen, Matti; Ghimire, Bishwa; Lahtela, Jenni; Mattila, Pirkko; Vähä-Koskela, Markus; Wennerberg, Krister; Granberg, Kirsi; Leivonen, Suvi-Katri; Meriranta, Leo; Heckman, Caroline; Leppä, Sirpa; Nykter, Matti; Lohi, Olli; Heinäniemi, Merja; Mustjoki, Satu (2020)
    Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.
  • Bolomsky, Arnold; Vogler, Meike; Kose, Murat Cem; Heckman, Caroline A.; Ehx, Gregory; Ludwig, Heinz; Caers, Jo (2020)
    Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
  • Kolstad, Arne; Pedersen, Lone Bredo; Eskelund, Christian W.; Husby, Simon; Gronbaek, Kirsten; Jerkeman, Mats; Laurell, Anna; Räty, Riikka; Elonen, Erkki; Andersen, Niels Smedegaard; Brown, Peter deNully; Kimby, Eva; Bentzen, Hans; Sundstrom, Christer; Ehinger, Mats; Karjalainen-Lindsberg, Marja-Liisa; Delabie, Jan; Ralfkiaer, Elisabeth; Fagerli, Unn-Merete; Nilsson-Ehle, Herman; Lauritzsen, Grete Fossum; Kuittinen, Outi; Niemann, Carsten; Geisler, Christian Hartman; Nordic Lymphoma Grp (2017)
    The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rear-rangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P
  • Korvala, Johanna; Jueppner, Harald; Mäkitie, Outi; Sochett, Etienne; Schnabel, Dirk; Mora, Stefano; Bartels, Cynthia F.; Warman, Matthew L.; Deraska, Donald; Cole, William G.; Hartikka, Heini; Ala-Kokko, Leena; Mannikko, Minna (2012)
  • Arpalahti, Leena; Saukkonen, Kapo; Hagström, Jaana; Mustonen, Harri; Seppänen, Hanna; Haglund, Caj; Holmberg, Carina I. (2017)
    Pancreatic ductal adenocarcinoma is a lethal disease with an overall 5-year survival of less than 5%. Prognosis among surgically treated patients is difficult and identification of new biomarkers is essential for accurate prediction of patient outcome. As part of one of the major cellular protein degradation systems, the proteasome plays a fundamental role in both physiological and pathophysiological conditions including cancer. The proteasome-associated deubiquitinating enzyme ubiquitin C-terminal hydrolase L5 (UCHL5)/Uch37 is a modulator of proteasome activity with cancer prognostic marker potential. Cytoplasmic and nuclear immunoexpression of UCHL5 was evaluated in 154 surgical specimens from pancreatic ductal adenocarcinoma patients treated at Helsinki University Hospital, Finland, in 2000-2011. UCHL5 expression in relation to clinicopathological parameters and the association between UCHL5 In this study, positive expression and patient survival were assessed. Positive nuclear UCHL5 expression was associated with increased patient survival (p = 0.005). A survival benefit was also detectable in these subgroups of patients: over 65 years (p <0.001), at tumor stages IIB to III (p = 0.007), or with lymph-node positivity (p = 0.006). In stages IIB to III disease, patients with positive nuclear UCHL5 expression showed a twofold increase in 5-year cancer-specific survival compared to those with negative expression. Multivariate analysis identified positive nuclear UCHL5 expression as an independent prognostic factor (p = 0.012). In conclusion, UCHL5 expression could function as a prognostic marker in pancreatic ductal adenocarcinoma, particularly at disease stages IIB to III. As UCHL5 is one of the few markers predicting increased survival, our results may be of clinical relevance.
  • Arpalahti, Leena; Laitinen, Alli; Hagström, Jaana; Mustonen, Harri; Kokkola, Arto; Böckelman, Camilla; Haglund, Caj; Holmberg, Carina I. (2018)
    Gastric cancer is the second most common cause of cancer-related mortality worldwide. Accurate prediction of disease progression is difficult, and new biomarkers for clinical use are essential. Recently, we reported that the proteasome-associated deubiquitinating enzyme UCHL5/Uch37 is a new prognostic marker in both rectal cancer and pancreatic ductal adenocarcinoma. Here, we have assessed by immunohistochemistry UCHL5 tumor expression in gastric cancer. The study cohort comprised 650 patients, who underwent surgery in Helsinki University Hospital, Finland, between 1983 and 2009. We investigated the association of cytoplasmic UCHL5 tumor expression to assess clinicopathological parameters and patient survival. Positive cytoplasmic UCHL5 tumor immunoexpression is linked to increased survival of patients with small (
  • Hemminki, Kari; Foersti, Asta; Tuuminen, Raimo; Hemminki, Otto; Goldschmidt, Hartmut; Sundquist, Kristina; Sundquist, Jan; Li, Xinjun (2016)
    Plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenstrom macroglobulinemia (WM) and light chain AL amyloidosis, are characterized by clonal expansion of plasma cells which produce a vast amount of an immunoglobulin-derived M-protein. We noted that MGUS diagnosis often coincided with diagnoses of senile cataract and glaucoma and tested the associations of MGUS, MM, WM and AL amyloidosis with subsequent eye diseases identified from the Swedish patient registers between 1997 and 2012. Standardized incidence ratios (SIRs) for senile cataract was significantly increased to 1.80 after MGUS, 1.70 after MM, 1.85 after WM and 2.31 after AL amyloidosis. The SIR for glaucoma was 1.60 after MGUS, 1.76 after WM and 2.18 after AL amyloidosis. All SIRs decreased systematically from age below 60 years to over 79 years, but most risks were also significant in age group over 79 years. The M-protein and the related increase in blood viscosity could be a novel etiologic discovery for these common eye diseases. As MGUS prevalence is around 3% at 60 years and close to 10% at age over 80 years, its contribution to the eye disease burden is expected to be remarkably high.