1. |
- Van Deerlin, Vivian M, et al.
(author)
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
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Journal article (peer-reviewed)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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2. |
- Wang, Li-San, et al.
(author)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Journal article (peer-reviewed)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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3. |
- Ferrari, Raffaele, et al.
(author)
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Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
-
In: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
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Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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4. |
- Engert, Andreas, et al.
(author)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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In: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Journal article (peer-reviewed)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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5. |
- Kun-Rodrigues, Celia, et al.
(author)
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A comprehensive screening of copy number variability in dementia with Lewy bodies.
- 2019
-
In: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 75
-
Journal article (peer-reviewed)abstract
- The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
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6. |
- Manzoni, Claudia, et al.
(author)
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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
- 2024
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In: American Journal of Human Genetics. - 0002-9297. ; 111:7, s. 1316-1329
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Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
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7. |
- Cleynen, Isabelle, et al.
(author)
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Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : a genetic association study
- 2016
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In: The Lancet. - New York, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 387:10014, s. 156-167
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Journal article (peer-reviewed)abstract
- Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.Findings: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)).Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
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8. |
- Franke, Andre, et al.
(author)
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Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
- 2010
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1118-1125
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Journal article (peer-reviewed)abstract
- We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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9. |
- Guerreiro, Rita, et al.
(author)
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Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases.
- 2016
-
In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 38, s. 7-214
-
Journal article (peer-reviewed)abstract
- The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.
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10. |
- Kun-Rodrigues, Celia, et al.
(author)
-
Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies
- 2017
-
In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 49
-
Journal article (peer-reviewed)abstract
- . C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of . C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of . C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that . C9orf72 repeat expansions are not causally associated with DLB.
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11. |
- Armand, Philippe, et al.
(author)
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Five-year follow-up of KEYNOTE-087 : pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma
- 2023
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:10, s. 878-886
-
Journal article (peer-reviewed)abstract
- Previous analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received pembrolizumab for <= 2 years. Patients in CR who discontinued treatment and subsequently experienced PD were eligible for second-course pembrolizumab. Primary end points were the objective response rate (ORR) using blinded central review and safety. The median follow-up was 63.7 months. ORR was 71.4% (95% confidence interval [CI], 64.8-77.4; CR, 27.6%; partial response, 43.8%). Median duration of response (DOR) was 16.6 months; median progression-free survival was 13.7 months. A quarter of responders, including half of complete responders, maintained a response for >= 4 years. Median overall survival was not achieved. Among 20 patients receiving second-course pembrolizumab, ORR for 19 evaluable patients was 73.7% (95% CI, 48.8-90.8); median DOR was 15.2 months. Any-grade treatment-related adverse events occurred in 72.9% of patients and grade 3 or 4 adverse events occurred in 12.9% of patients; no treatment-related deaths occurred. Single-agent pembrolizumab can induce durable responses, particularly in patients achieving CR. Second-course pembrolizumab frequently reinduced sustained responses after relapse from initial CR.
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12. |
- Barrington, Sally F., et al.
(author)
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Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma
- 2010
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 37:10, s. 1824-1833
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Journal article (peer-reviewed)abstract
- To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between 'core' laboratories operating in different countries. Four centres reported scans from 50 patients with stage II-IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using 'normal' mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading). There was agreement that the response scan was 'positive' or 'negative' for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74-0.96) for conservative reading and 0.79 (95% CI 0.67-0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively. The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting.
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13. |
- Barrington, Sally F, et al.
(author)
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PET-CT for staging and early response : results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study.
- 2016
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 127:12, s. 1531-1538
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Journal article (peer-reviewed)abstract
- International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a κ (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice.
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14. |
- Bosly, Andre, et al.
(author)
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A Randomized Study of Interferon alpha-2b Versus No Treatment as Consolidation After High Dose Therapy and Autologous Stem Cell Transplantation for Patients With Relapsed Lymphoma
- 2013
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In: The Oncologist. - : Oxford University Press (OUP). - 1083-7159 .- 1549-490X. ; 18:11, s. 1189-1189
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Journal article (other academic/artistic)abstract
- Background. Patients with lymphoma who have experienced a first relapse or progression and have disease deemed sensitive to salvage chemotherapy nevertheless have a high likelihood of having a second relapse. To decrease the likelihood of a second relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), interferon (IFN) alpha-2b was given in a prospective randomized international trial. Methods. In this trial, 221 patients with varying histologic diagnoses (8 small lymphocytic, 37 follicular, 9 mantle, 90 diffuse large B-cell, 20 peripheral T-cell, 3 high-grade B-cell non-Hodgkin lymphoma, and 54 Hodgkin lymphoma) were randomly assigned to receive no further treatment (armA: 117 patients) or IFN alpha-2b, 3 MU three times weekly, for 18 months (arm B: 104 patients). Results. In arm B, 21 patients (20%) did not receive IFN alpha-2b because of early progression or absence of hematologic recovery, 29 patients (28%) completed the 18 months of treatment, and 54 patients (52%) interrupted treatment because of progression (23%) or toxicity (29%). Event-free survival and overall survival were not different between the two arms on an intent-to-treat analysis and also if analysis was restricted to patients who were a live and had not experienced disease progression three months after transplantation. The study was not sufficiently powered to evaluate effects in histologic subtypes. Conclusion. In this trial, post-autograft IFN alpha-2b did not improve outcomes in a heterogeneous group of patients with lymphoma.
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15. |
- Bras, Jose, et al.
(author)
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Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.
- 2014
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 23:23, s. 6139-6146
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Journal article (peer-reviewed)abstract
- Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
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16. |
- Chen, Robert, et al.
(author)
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Pembrolizumab in relapsed or refractory Hodgkin lymphoma : 2-year follow-up of KEYNOTE-087
- 2019
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 134:14, s. 1144-1153
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Journal article (peer-reviewed)abstract
- Programmed death-1 inhibitors are approved for patients with relapsed or refractory classic Hodgkin lymphoma (RRcHL). We present the 2-year follow-up of the phase 2 KEYNOTE-087 study of pembrolizumab in 210 patients, based on HL progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV; cohort 1); salvage chemotherapy and BV, with ineligibility for SCT owing to chemorefractory disease (cohort 2); and progression after SCT without BV (cohort 3). With a median follow-up of 27.6 months, the objective response rate (ORR) by blinded independent central review was 71.9% (95% CI, 65.3-77.9), the complete response rate (CRR) was 27.6%, and the partial response (PR) rate was 44.3%. Median duration of response was 16.5months (range, 0.0+ to 27.0+ [+, no progressive disease at last assessment]) in all patients, 22.1months in cohort 1, 11.1 months in cohort 2, and 24.4 months in cohort 3. Median progression-free survival was not reached in all patients with CR: 13.8 months (95% CI, 12.0-22.1) for patients with PR and 10.9 months (95% CI, 5.6-11.1) for patients with stable disease. Median overall survival was not reached in all patients or in any cohort. Treatment-related adverse events (TRAEs) of any grade occurred in 153 (72.9%) patients; grades 3 and 4 occurred in 25 (12.0%) patients; none resulted in death. Results confirmed effective antitumor activity, durability of response, and manageable safety of pembrolizumab monotherapy in RRcHL, regardless of prior treatment and including chemoresistant cHL.
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17. |
- Chen, Robert, et al.
(author)
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Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma
- 2017
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In: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 35:19, s. 2125-2132
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Journal article (peer-reviewed)abstract
- Purpose Hodgkin Reed-Sternberg cells harbor alterations in chromosome 9p24.1, leading to overexpression of programmed death-ligand 1 (PD-L1) and PD-L2. Pembrolizumab, a programmed death 1-blocking antibody, demonstrated a high overall response rate (ORR) in patients with relapsed or refractory classic Hodgkin lymphoma (rrHL) in phase I testing. Methods KEYNOTE-087 (ClinicalTrials.gov identifier, NCT02453594) was a single-arm phase II study of pembrolizumab in three cohorts of patients with rrHL, defined on the basis of lymphoma progression after (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus, ineligible for ASCT because of chemoresistant disease; and (3) ASCT, but without BV after transplantation. Patients received pembrolizumab 200 mg once every 3 weeks. Response was assessed every 12 weeks. The primary end points were ORR by central review and safety. Results A total of 210 patients were enrolled and treated (69 in cohort 1, 81 in cohort 2, and 60 in cohort 3). At the time of analysis, patients received a median of 13 treatment cycles. Per central review, the ORR was 69.0% (95% CI, 62.3% to 75.2%), and the complete response rate was 22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs were 73.9% for cohort 1, 64.2% for cohort 2, and 70.0% for cohort 3. Thirty-one patients had a response >= 6 months. The safety profile was largely consistent with previous pembrolizumab studies. Conclusion Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease.
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18. |
- Couthouis, Julien, et al.
(author)
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A yeast functional screen predicts new candidate ALS disease genes
- 2011
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:52, s. 20881-20890
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Journal article (peer-reviewed)abstract
- Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of the segenes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having amore severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.
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19. |
- Cove-Smith, Laura, et al.
(author)
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An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity
- 2014
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In: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-0929 .- 1096-6080. ; 140:1, s. 3-15
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Journal article (peer-reviewed)abstract
- Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to
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20. |
- d'Amore, Francesco, et al.
(author)
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Phase II trial of zanolimumab (HuMax-CD4) in relapsed or refractory non-cutaneous peripheral T cell lymphoma
- 2010
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 150:5, s. 565-573
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Journal article (peer-reviewed)abstract
- The efficacy and safety of zanolimumab (HuMax-CD4) in patients with relapsed or refractory peripheral T Cell lymphoma (PTCL) was evaluated. Twenty-one adult patients with relapsed or refractory CD4+ PTCL of non-cutaneous type (angioimmunoblastic T cell lymphoma (AITL) n = 9, PTCL-not otherwise specified (NOS) n = 7, anaplastic large cell lymphoma (ALCL) n = 4 and enteropathy type T cell lymphoma n = 1) were treated in a single-arm multi-centre study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. Median age was 69 years (range 26-85). Seventeen of the patients had advanced stage disease (Ann Arbor stages III-IV). Objective tumour responses were obtained in 24% of the patients with two complete responses unconfirmed (CRu) and three partial responses (PR). One of the CRus lasted more than 252 d. Responses were obtained in different PTCL entities: AITL (n = 3), ALCL (n = 1) and PTCL-NOS (n = 1). In general, the trial drug was well tolerated with no major toxicity. Zanolimumab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor-prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.
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21. |
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22. |
- Elsawy, Mahmoud, et al.
(author)
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Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma
- 2022
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 140:21, s. 2248-2260
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Journal article (peer-reviewed)abstract
- Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and >= 1 follow-up PRO completion. Pre-specified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/ R LBCL.
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23. |
- Fomalont, E. B., et al.
(author)
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THE 2014 ALMA LONG BASELINE CAMPAIGN: AN OVERVIEW
- 2015
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 808:1
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Journal article (peer-reviewed)abstract
- A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to similar to 15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from 2014 September to late November, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C 138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at similar to 350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy.
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24. |
- Gisselbrecht, Christian, et al.
(author)
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Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20(+) Diffuse Large B-Cell Lymphoma : Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma
- 2012
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In: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:36, s. 4462-4469
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Journal article (peer-reviewed)abstract
- Purpose The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods In total, 477 patients with CD20(+) DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P=.7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P<.05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P<.001), as was male sex (P=.01). Conclusion In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.
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25. |
- Heap, Graham A., et al.
(author)
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HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
- 2014
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:10, s. 1131-1134
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Journal article (peer-reviewed)abstract
- Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
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26. |
- Johnson, Peter, et al.
(author)
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Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma
- 2016
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:25, s. 2419-2429
-
Journal article (peer-reviewed)abstract
- BACKGROUND We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin's lymphoma. METHODS Patients with newly diagnosed advanced classic Hodgkin's lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points. RESULTS A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin's lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%. CONCLUSIONS Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy.
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27. |
- Li, Dalin, et al.
(author)
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A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition
- 2016
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In: Gastroenterology. - : Saunders Elsevier. - 0016-5085 .- 1528-0012. ; 151:4, s. 724-732
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Journal article (peer-reviewed)abstract
- Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.Results: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).Conclusions: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.
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28. |
- Luminari, Stefano, et al.
(author)
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Long-Term Follow-Up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma Trial
- 2024
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In: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 42:1, s. 13-18
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Journal article (peer-reviewed)abstract
- Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We analyzed long-term results of the response-adapted trial for adult patients with advanced-stage Hodgkin lymphoma. The aim was to confirm noninferiority of treatment de-escalation by omission of bleomycin from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for interim fluorodeoxyglucose positron emission tomography (iPET)–negative patients and assess efficacy and long-term safety for iPET-positive patients who underwent treatment intensification with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP/BEACOPP14). The median follow-up is 7.3 years. For all patients, the 7-year progression-free survival (PFS) and overall survival (OS) are 78.2% (95% CI, 75.6 to 80.5) and 91.6% (95% CI, 89.7 to 93.2), respectively. The 1.3% difference in 3-year PFS (95% CI, –3.0 to 4.7) between ABVD and doxorubicin, vinblastine, and dacarbazine (AVD) now falls within the predefined noninferiority margin. Among 172 patients with positive iPET, the 7-year PFS was 65.9% (95% CI, 58.1 to 72.6) and the 7-year OS was 83.2% (95% CI, 76.2 to 88.3). The cumulative incidence of second malignancies at 7 years was 5.5% (95% CI, 4.0 to 7.5) for those receiving ABVD/AVD and 2.5% (95% CI, 0.8 to 7.7) for those escalated to BEACOPP. With extended follow-up, these results confirm noninferiority of treatment de-escalation after a negative iPET. Escalation with BEACOPP for iPET-positive patients is effective and safe, with no increase in second malignancies.
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29. |
- O'Bryant, Sid E, et al.
(author)
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Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research.
- 2015
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 11:5, s. 549-560
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Journal article (peer-reviewed)abstract
- The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross-validation across cohorts and laboratories.
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30. |
- Smith, Peter B., et al.
(author)
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Demographic Effects on the Use of Vertical Sources of Guidance by Managers in Widely Differing Cultural Contexts
- 2005
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In: International Journal of Cross Cultural Management. - : Sage Publications. - 1470-5958 .- 1741-2838. ; 5:1, s. 5-26
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Journal article (peer-reviewed)abstract
- Data provided by 7380 middle managers from 60 nations are used to determine whether demographic variables are correlated with managers’ reliance on vertical sources of guidance in different nations and whether these correlations differ depending on national culture characteristics. Significant effects of Hofstede’s national culture scores, age, gender, organization ownership and department function are found. After these main effects have been discounted, significant although weak interactions are found, indicating that demographic effects are stronger in individualist, low power distance nations than elsewhere. Significant non-predicted interaction effects of uncertainty avoidance and masculinity-femininity are also obtained. The implications for theory and practice of the use of demographic attributes in understanding effective management procedures in various parts of the world are discussed.
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31. |
- Swift, Imogen J, et al.
(author)
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A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
- 2024
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In: Alzheimer's Research & Therapy. - 1758-9193. ; 16:1
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Journal article (peer-reviewed)abstract
- Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p=0.007) with a trend in non-carriers (p=0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
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32. |
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33. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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