Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: final results of the multinational trial GPOH-HD95

UNLABELLED: PURPOSE To minimize the risk of late effects in pediatric Hodgkin lymphoma (HL) by omitting radiotherapy (RT) in patients in complete remission (CR) after chemotherapy and reducing the standard radiation dose to 20 Gy in patients in incomplete remission. PATIENTS AND METHODS: Between 1995 and 2001, 925 patients with classical HL (cHL) were registered from seven European countries in German Society of Pediatric Oncology and Hematology Hodgkin Lymphoma Trial 95. Patients in treatment group 1 (TG1; early stages) received two cycles of vincristine, prednisone, procarbazine, and doxorubicin or vincristine, prednisone, etoposide, and doxorubicin chemotherapy; additional two or four cycles of cyclophosphamide, vincristine, prednisone, and procarbazine were added in TG2 (intermediate stages) or TG3 (advanced stages), respectively. Patients in CR (assessed by computed tomography or magnetic resonance imaging) did not undergo RT. Those with tumor volume reduction more than 75% received reduced involved-field RT with 20 Gy and an additional 10- or 15-Gy boost only for larger residuals. RESULTS: Rates of overall survival, progression-free survival (PFS), and event-free survival at 10 years were (± SE) 96.3% ± 0.6%, 88.2% ± 1.1%, and 85.4% ± 1.3%, respectively. PFS for TG1 patients without or with RT was 97.0% ± 2.1% versus 92.2% ± 1.7% (P = .214) but was unsatisfactory for nonirradiated patients in TG2 (68.5% ± 7.4% v 91.4% ± 1.9%; P < .0001), with similar but not significant results in TG3 (82.6% ± 5.4% v 88.7% ± 2.0%, P = .259). Reduction of the standard radiation dose from 25 to 20 Gy did not increase failure rate. CONCLUSION: RT can be omitted in early stage HL in so defined CR following this chemotherapy. RT with 20(-35) Gy proved to be sufficient in patients with incomplete remission following chemotherapy

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations

Acknowledgements: We extend our thanks to all the former and current staff at the Lundbeck Foundation GeoGenetics Centre and the GeoGenetics Sequencing Core and to colleagues across the many institutions detailed below. We are particularly grateful to M. Madrona, L. Hansen and J. Bitz-Thorsen for laboratory assistance; to J. Hansen, S. Mularczyk, K. Thorø Michler and E. Neerup Nielsen for their help with sampling; and to L. Olsen as project manager for the Lundbeck Foundation GeoGenetics Centre project. The Lundbeck Foundation GeoGenetics Centre is supported by grants from the Lundbeck Foundation (R302-2018-2155, R155-2013-16338), the Novo Nordisk Foundation (NNF18SA0035006), the Wellcome Trust (214300), Carlsberg Foundation (CF18-0024), the Danish National Research Foundation (DNRF94, DNRF174), the University of Copenhagen (KU2016 programme), the Rise II project ‘Towards a New European Prehistory’ (M16-0455) and Ferring Pharmaceuticals A/S (to E.W.). We thank UK Biobank for access to the UK Biobank genomic resource. We also thank and acknowledge the participants and investigators of the FinnGen study. We are thankful to Illumina for collaboration. E.W. thanks St John’s College, Cambridge, for providing a stimulating environment of discussion and learning and the Lundbeck Foundation, the Novo Nordisk Foundation, the Wellcome Trust, the Carlsberg Foundation and the Danish National Research Foundation for financial support. R.N. acknowledges US National Institutes of Health grant R01GM138634. K.E.A., A.P.A., A.K.N.I. and L.F. thank the OAK Foundation.Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations

Acknowledgements: We extend our thanks to all the former and current staff at the Lundbeck Foundation GeoGenetics Centre and the GeoGenetics Sequencing Core and to colleagues across the many institutions detailed below. We are particularly grateful to M. Madrona, L. Hansen and J. Bitz-Thorsen for laboratory assistance; to J. Hansen, S. Mularczyk, K. Thorø Michler and E. Neerup Nielsen for their help with sampling; and to L. Olsen as project manager for the Lundbeck Foundation GeoGenetics Centre project. The Lundbeck Foundation GeoGenetics Centre is supported by grants from the Lundbeck Foundation (R302-2018-2155, R155-2013-16338), the Novo Nordisk Foundation (NNF18SA0035006), the Wellcome Trust (214300), Carlsberg Foundation (CF18-0024), the Danish National Research Foundation (DNRF94, DNRF174), the University of Copenhagen (KU2016 programme), the Rise II project ‘Towards a New European Prehistory’ (M16-0455) and Ferring Pharmaceuticals A/S (to E.W.). We thank UK Biobank for access to the UK Biobank genomic resource. We also thank and acknowledge the participants and investigators of the FinnGen study. We are thankful to Illumina for collaboration. E.W. thanks St John’s College, Cambridge, for providing a stimulating environment of discussion and learning and the Lundbeck Foundation, the Novo Nordisk Foundation, the Wellcome Trust, the Carlsberg Foundation and the Danish National Research Foundation for financial support. R.N. acknowledges US National Institutes of Health grant R01GM138634. K.E.A., A.P.A., A.K.N.I. and L.F. thank the OAK Foundation.Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations

Acknowledgements: We extend our thanks to all the former and current staff at the Lundbeck Foundation GeoGenetics Centre and the GeoGenetics Sequencing Core and to colleagues across the many institutions detailed below. We are particularly grateful to M. Madrona, L. Hansen and J. Bitz-Thorsen for laboratory assistance; to J. Hansen, S. Mularczyk, K. Thorø Michler and E. Neerup Nielsen for their help with sampling; and to L. Olsen as project manager for the Lundbeck Foundation GeoGenetics Centre project. The Lundbeck Foundation GeoGenetics Centre is supported by grants from the Lundbeck Foundation (R302-2018-2155, R155-2013-16338), the Novo Nordisk Foundation (NNF18SA0035006), the Wellcome Trust (214300), Carlsberg Foundation (CF18-0024), the Danish National Research Foundation (DNRF94, DNRF174), the University of Copenhagen (KU2016 programme), the Rise II project ‘Towards a New European Prehistory’ (M16-0455) and Ferring Pharmaceuticals A/S (to E.W.). We thank UK Biobank for access to the UK Biobank genomic resource. We also thank and acknowledge the participants and investigators of the FinnGen study. We are thankful to Illumina for collaboration. E.W. thanks St John’s College, Cambridge, for providing a stimulating environment of discussion and learning and the Lundbeck Foundation, the Novo Nordisk Foundation, the Wellcome Trust, the Carlsberg Foundation and the Danish National Research Foundation for financial support. R.N. acknowledges US National Institutes of Health grant R01GM138634. K.E.A., A.P.A., A.K.N.I. and L.F. thank the OAK Foundation.AbstractMultiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.</jats:p

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic&nbsp;period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in&nbsp;diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period&nbsp;and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated 1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age 2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment. </p

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations

Acknowledgements: We extend our thanks to all the former and current staff at the Lundbeck Foundation GeoGenetics Centre and the GeoGenetics Sequencing Core and to colleagues across the many institutions detailed below. We are particularly grateful to M. Madrona, L. Hansen and J. Bitz-Thorsen for laboratory assistance; to J. Hansen, S. Mularczyk, K. Thorø Michler and E. Neerup Nielsen for their help with sampling; and to L. Olsen as project manager for the Lundbeck Foundation GeoGenetics Centre project. The Lundbeck Foundation GeoGenetics Centre is supported by grants from the Lundbeck Foundation (R302-2018-2155, R155-2013-16338), the Novo Nordisk Foundation (NNF18SA0035006), the Wellcome Trust (214300), Carlsberg Foundation (CF18-0024), the Danish National Research Foundation (DNRF94, DNRF174), the University of Copenhagen (KU2016 programme), the Rise II project ‘Towards a New European Prehistory’ (M16-0455) and Ferring Pharmaceuticals A/S (to E.W.). We thank UK Biobank for access to the UK Biobank genomic resource. We also thank and acknowledge the participants and investigators of the FinnGen study. We are thankful to Illumina for collaboration. E.W. thanks St John’s College, Cambridge, for providing a stimulating environment of discussion and learning and the Lundbeck Foundation, the Novo Nordisk Foundation, the Wellcome Trust, the Carlsberg Foundation and the Danish National Research Foundation for financial support. R.N. acknowledges US National Institutes of Health grant R01GM138634. K.E.A., A.P.A., A.K.N.I. and L.F. thank the OAK Foundation.Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment