25 research outputs found
FinnGen provides genetic insights from a well-phenotyped isolated population
Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% †minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 Ă 10â11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.publishedVersionPeer reviewe
Deep Immune Profiling of Multiple Myeloma at Diagnosis and under Lenalidomide Maintenance Therapy
The bone marrow microenvironment interacts with malignant cells and regulates cancer survival and immune evasion in multiple myeloma (MM). We investigated the immune profiles of longitudinal bone marrow samples from patients with newly diagnosed MM (n = 18) using cytometry by time-of-flight. The results before and during treatment were compared between patients with good (GR, n = 11) and bad (BR, n = 7) responses to lenalidomide/bortezomib/dexamethasone-based treatment. Before treatment, the GR group had a lower tumor cell burden and a higher number of T cells with a phenotype shifted toward CD8+ T cells expressing markers attributed to cytotoxicity (CD45RA and CD57), a higher abundance of CD8+ terminal effector cells, and a lower abundance of CD8+ naĂŻve T cells. On natural killer (NK) cells, increased expression of CD56 (NCAM), CD57, and CD16 was seen at baseline in the GR group, indicating their maturation and cytotoxic potential. During lenalidomide-based treatment, the GR patients showed an increase in effector memory CD4+ and CD8+ T-cell subsets. These findings support distinct immune patterns in different clinical contexts, suggesting that deep immune profiling could be used for treatment guidance and warrants further exploration
Deep Immune Profiling of Multiple Myeloma at Diagnosis and under Lenalidomide Maintenance Therapy
The bone marrow microenvironment interacts with malignant cells and regulates cancer survival and immune evasion in multiple myeloma (MM). We investigated the immune profiles of longitudinal bone marrow samples from patients with newly diagnosed MM (n = 18) using cytometry by time-of-flight. The results before and during treatment were compared between patients with good (GR, n = 11) and bad (BR, n = 7) responses to lenalidomide/bortezomib/dexamethasone-based treatment. Before treatment, the GR group had a lower tumor cell burden and a higher number of T cells with a phenotype shifted toward CD8+ T cells expressing markers attributed to cytotoxicity (CD45RA and CD57), a higher abundance of CD8+ terminal effector cells, and a lower abundance of CD8+ naĂŻve T cells. On natural killer (NK) cells, increased expression of CD56 (NCAM), CD57, and CD16 was seen at baseline in the GR group, indicating their maturation and cytotoxic potential. During lenalidomide-based treatment, the GR patients showed an increase in effector memory CD4+ and CD8+ T-cell subsets. These findings support distinct immune patterns in different clinical contexts, suggesting that deep immune profiling could be used for treatment guidance and warrants further exploration
A Phase 2 Study of Carfilzomib Plus Elotuzumab Plus Dexamethasone for Myeloma Patients Relapsed after 1-3 Prior Treatment Lines
Blood graft and outcome after autologous stem cell transplantation in patients with primary central nervous system lymphoma
Abstract
Background: Autologous stem cell transplantation (auto-SCT) is a treatment option for patients with primary central nervous system lymphoma (PCNSL).
Methods: In this prospective multicenter study, the effects of blood graft cellular content on hematologic recovery and outcome were analyzed in 17 PCNSL patients receiving auto-SCT upfront.
Results: The infused viable CD34âș cell count > 1.7 Ă 10â¶/kg correlated with more rapid platelet engraftment (10 vs. 31 days, P = 0.027) and with early neutrophil recovery (day + 15) (5.4 vs. 1.6 Ă 10âč/L, P = 0.047). A higher number of total collected CD34âș cells > 3.3 Ă 106/kg infused predicted worse 5-year progression-free survival (PFS) (33% vs. 100%, P = 0.028). In addition, CD3âșCD8âș T cells > 78 Ă 10â¶/kg in the infused graft impacted negatively on the 5-year PFS (0% vs. 88%, P = 0.016).
Conclusions: The cellular composition of infused graft seems to impact on the hematologic recovery and PFS post-transplant. Further studies are needed to verify the optimal autograft cellular content in PCNSL
A prospective comparison of pegfilgrastim and lipegfilgrastim combined with chemotherapy in the mobilization of CD34
Comparison of filgrastim, pegfilgrastim, and lipegfilgrastim added to chemotherapy for mobilization of CD34+ cells in non-Hodgkin lymphoma patients
RVD induction and autologous stem cell transplantation followed by lenalidomide maintenance in newly diagnosed multiple myeloma:a phase 2 study of the Finnish Myeloma Group
Abstract
Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity. The primary endpoint was the proportion of flow-negative patients. Molecular response was assessed if patients were flow-negative or in stringent complete response (sCR). By intention to treat, the overall response rate was 89%. Neither median progression-free survival nor overall survival (OS) has been reached. The OS at 3 years was 83%. Flow-negativity was reached in 53% and PCR-negativity in 28% of the patients. With a median follow-up of 27 months, 29 (36%) patients are still on lenalidomide and 66% of them have sustained flow-negativity. Lenalidomide maintenance phase was reached in 8/16 high-risk patients but seven of them have progressed after a median of only 6 months. In low- or standard-risk patients, the outcome was promising, but high-risk patients need more effective treatment approach. Flow-negativity with the conventional flow was an independent predictor for longer PFS
BloodâBrain Barrier Disruption (BBBD)-Based Immunochemotherapy for Primary Central Nervous System Lymphoma (PCNSL), Early Results of a Phase II Study
Primary central nervous system lymphoma is a rare but aggressive brain malignancy. It is associated with poor prognosis even with the current standard of care. The aim of this study was to evaluate the effect and tolerability of bloodâbrain barrier disruption treatment combined with high-dose treatment with autologous stem cell transplantation as consolidation on primary central nervous system lymphoma patients. We performed a prospective phase II study for 25 patients with previously untreated primary central nervous system lymphoma. The bloodâbrain barrier disruption treatment was initiated 3â4 weeks after the MATRix regimen using the previously optimized therapy protocol. Briefly, each chemotherapy cycle included two subsequent intra-arterial bloodâbrain barrier disruption treatments on days 1 and 2 via either one of the internal carotid arteries or vertebral arteries. Patients received the therapy in 3-week intervals. The treatment was continued for two more courses after achieving a maximal radiological response to the maximum of six courses. The complete treatment response was observed in 88.0% of the patients. At the median follow-up time of 30 months, median progression-free and overall survivals were not reached. The 2-year overall and progression-free survival rates were 67.1% and 70.3%, respectively. Bloodâbrain barrier disruption treatment is a promising option for primary central nervous system lymphoma with an acceptable toxicity profile
Ex vivo venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia
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