| 2. |
- Carraro, Marco, et al.
(författare)
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Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI
- 2017
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:9, s. 1042-1050
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Tidskriftsartikel (refereegranskat)abstract
- Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype-phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of 10 variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene. Twenty-two pathogenicity predictors were assessed with a variety of accuracy measures for reliability in a medical context. Different assessment measures were combined in an overall ranking to provide more robust results. The R scripts used for assessment are publicly available from a GitHub repository for future use in similar assessment exercises. Despite a limited test-set size, our findings show a variety of results, with some methods performing significantly better. Methods combining different strategies frequently outperform simpler approaches. The best predictor, Yang&Zhou lab, uses a machine learning method combining an empirical energy function measuring protein stability with an evolutionary conservation term. The p16INK4a challenge highlights how subtle structural effects can neutralize otherwise deleterious variants.
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| 3. |
- Felberg, Anna, et al.
(författare)
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Monitoring of the Complement System Status in Patients With B-Cell Malignancies Treated With Rituximab
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Rituximab is a pioneering anti-CD20 monoclonal antibody that became the first-line drug used in immunotherapy of B-cell malignancies over the last twenty years. Rituximab activates the complement system in vitro, but there is an ongoing debate on the exact role of this effector mechanism in therapeutic effect. Results of both in vitro and in vivo studies are model-dependent and preclude clear clinical conclusions. Additional confounding factors like complement inhibition by tumor cells, loss of target antigen and complement depletion due to excessively applied immunotherapeutics, intrapersonal variability in the concentration of main complement components and differences in tumor burden all suggest that a personalized approach is the best strategy for optimization of rituximab dosage and therapeutic schedule. Herein we critically review the existing knowledge in support of such concept and present original data on markers of complement activation, complement consumption, and rituximab accumulation in plasma of patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphomas (NHL). The increase of markers such as C4d and terminal complement complex (TCC) suggest the strongest complement activation after the first administration of rituximab, but not indicative of clinical outcome in patients receiving rituximab in combination with chemotherapy. Both ELISA and complement-dependent cytotoxicity (CDC) functional assay showed that a substantial number of patients accumulate rituximab to the extent that consecutive infusions do not improve the cytotoxic capacity of their sera. Our data suggest that individual assessment of CDC activity and rituximab concentration in plasma may support clinicians’ decisions on further drug infusions, or instead prescribing a therapy with anti-CD20 antibodies like obinutuzumab that more efficiently activate effector mechanisms other than complement.
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| 4. |
- Munshi, Pashna N., et al.
(författare)
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Age no bar : A CIBMTR analysis of elderly patients undergoing autologous hematopoietic cell transplantation for multiple myeloma
- 2020
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Ingår i: Cancer. - : WILEY. - 0008-543X .- 1097-0142. ; 126:23, s. 5077-5087
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Tidskriftsartikel (refereegranskat)abstract
- Background Upfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults. Methods The authors investigated the outcomes of AHCT in patients with MM who were aged >= 70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged >= 70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, aPvalue <.01 was considered to be statistically significant a priori. Results An increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged >= 70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m(2)overall, 58% of the patients aged >= 70 years received Mel at a dose of 140 mg/m(2). On multivariate analysis, patients aged >= 70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1-1.7 [P = .06]), REL (HR, 1.03; 99% CI, 0.9-1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1-1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1-1.4 [P = .02]) compared with the reference group (those aged 60-69 years). In patients aged >= 70 years, Mel administered at a dose of 140 mg/m(2)was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m(2), including day 100 NRM (1% [95% CI, 1%-2%] vs 0% [95% CI, 0%-1%];P = .003]), 2-year PFS (64% [95% CI, 60%-67%] vs 69% [95% CI, 66%-73%];P = .003), and 2-year OS (85% [95% CI, 82%-87%] vs 89% [95% CI, 86%-91%];P = .01]), likely representing frailty. Conclusions The results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups.
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