Cell-of-origin classification using the Hans and Lymph2Cx algorithms in primary cutaneous large B-cell lymphomas

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma with a diffuse population of large cells (PCFCL-LC) are both primary cutaneous B-cell lymphomas with large-cell morphology (CLBCL) but with different clinical characteristics and behavior. In systemic diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), gene-expression profiling (GEP) revealed two molecular subgroups based on their cell-of-origin (COO) with prognostic significance: the germinal center B-cell-like (GCB) subtype and the activated B-cell-like (ABC) subtype. This study investigated whether COO classification is a useful tool for classification of CLBCL. For this retrospective study, 51 patients with PCDLBCL-LT and 15 patients with PCFCL-LC were analyzed for their COO according to the immunohistochemistry-based Hans algorithm and the NanoString GEP-based Lymph2Cx algorithm. In PCFCL-LC, all cases (100%) classified as GCB by both Hans and Lymph2Cx. In contrast, COO classification in PCDLBCL-LT was heterogeneous. Using Hans, 75% of the PCDLBCL-LT patients classified as non-GCB and 25% as GCB, while Lymph2Cx classified only 18% as ABC, 43% as unclassified/intermediate, and 39% as GCB. These COO subgroups did not differ in the expression of BCL2 and IgM, mutations in MYD88 and/or CD79B, loss of CDKN2A, or survival. In conclusion, PCFCL-LC uniformly classified as GCB, while PCDLBCL-LT classified along the COO spectrum of DLBCL-NOS using the Hans and Lymph2Cx algorithms. In contrast to DLBCL-NOS, the clinical relevance of COO classification in CLBCL using these algorithms has limitations and cannot be used as an alternative for the current multiparameter approach in differentiation of PCDLBCL-LT and PCFCL-LC

Moving Beyond the 2018 Minimum International Care Considerations for Osteoporosis Management in Duchenne Muscular Dystrophy (DMD)

Individuals living with Duchenne muscular dystrophy (DMD) are at significant risk of bone fragility due to osteoporosis, with the most potent drivers of fragility fractures in this context stemming from the aggressive myopathy and long term oral glucocorticoid therapy. Young people with DMD have a high fracture burden, with reported total and vertebral fracture rates that are four [1, 2] and 535 times [1] higher than those of healthy growing boys, respectively. Vertebral fractures can occur as early as six months following daily glucocorticoid initiation [3]. Up to 75% of young people with DMD sustain at least one fracture after eight years of glucocorticoid therapy [4]. Fractures in DMD can lead to devastating outcomes, including steeper rates of functional decline, premature and permanent loss of ambulation, chronic pain, and even death from fat embolism syndrome or adrenal crisis following long bone fractures [2, 5–8]. The potential for serious consequences and medical complications linked to fractures has driven efforts to develop effective guidelines for timely bone health surveillance and treatment with more recent efforts to develop fracture prevention strategies.To guide clinicians in the management of DMD and its related co-morbidities (including skeletal health), the first internationally-endorsed, minimum standards of care were published in 2010 under the moniker “Clinical Care Considerations” [9, 10]. This document recommends that osteoporosis monitoring include spine x-rays if back pain or kyphosis is present, followed by initiation of intravenous bisphosphonate therapy if vertebral fractures are identified [10]. In the years following the inaugural 2010 Clinical Care Considerations, studies were published showing that vertebral fractures, a key manifestation of bone fragility among children and adults living with glucorticoid-treated chronic conditions, were frequently asymptomatic, necessitating routine surveillance for early detection [3, 11]. It was also better appreciated that even a single long bone fracture can signal osteoporosis in a persistently high-risk setting such as DMD, and prompt initiation of bone protection therapy is important.With this new knowledge, the latest international, minimum standards of clinical care for DMD published in 2018, known as Care Considerations [12–14], recommended routine, standardized spine imaging for early detection of vertebral fractures, combined with more timely bone-targeted (bisphosphonate) intervention in the presence of vertebral or low trauma long bone fractures [12]. At the same time, the ever-changing therapeutic landscape for the treatment of the underlying condition calls for ongoing examination of the intimate relationship between muscle and bone development in DMD, including the effect of different DMD treatment approaches on the skeletal and endocrine systems. The overall goal of such focus is to harvest discussions about optimal management that will foster bone strength and prevent fractures in this high-risk setting across all underlying disease-targeted treatment paradigms for people with DMD

Moving beyond the 2018 minimum international care considerations for osteoporosis management in duchenne muscular dystrophy (DMD): Meeting report from the 3rd International Muscle-Bone Interactions Meeting 7th and 14th November 2022

This current manuscript summarizes the proceedings of the “Third Muscle-bone interactions in Duchenne Muscular Dystrophy Symposium: Moving Beyond the 2018 Minimum International Standards of Care for Osteoporosis Management”, an event co-organized by the World Duchenne Organization (www.worldduchenne.org) and the International Conference on Children’s Bone Health (www.theiscbh.org). This virtual symposium, held on November 7th and 14th 2022, brought together a total of 385 delegates representing 55 countries registered for the symposium, which included 239 clinicians, 70 researchers, 40 patient representatives and others from pharmaceutical companies and regulators. This symposium aimed to review the evidence base that informed the 2018 international minimum Care Considerations, best practices for implementation of these Care Considerations, and emerging knowledge that has arisen from research since the 2018 Care Considerations that shines light on the path forward. The online symposium and this report cover the following areas: 1. Current understanding of the bone morbidity in DMD, especially in relation to conventional glucocorticoid therapy. 2. The published, 2018 minimum international Care Considerations for osteoporosis monitoring and management in DMD. 3. Real world initiatives and challenges in the implementation of the 2018 minimum international Care Considerations for osteoporosis monitoring and management in DMD. 4. The need to consider strategies to move beyond the 2018 minimum international Care Considerations to prevent first fractures in DMD. 5. New therapies in DMD with potential impact on skeletal outcomes

MYD88 mutations identify a molecular subgroup of diffuse large B-cell lymphoma with an unfavorable prognosis

The 2016 World Health Organization classification defines diffuse large B-cell lymphoma (DLBCL) subtypes based on Epstein-Barr virus (EBV) infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis. A subset of DLBCL, however, is characterized by activating mutations in MYD88/CD79B. We investigated whether MYD88/CD79B mutations could improve the classification and prognostication of DLBCL. In 250 primary DLBCL, MYD88/CD79B mutations were identified by allele-specific polymerase chain reaction or next-generationsequencing, MYC/BCL2/BCL6 rearrangements were analyzed by fluorescence in situ hybridization, and EBV was studied by EBV-encoded RNA in situ hybridization. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to the International Prognostic Index (IPI) were investigated. MYD88 and CD79B mutations were identified in 29.6% and 12.3%, MYC, BCL2, and BCL6 rearrangements in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, and MYD88/CD79B mutations established the value of molecular markers for the recognition of biologically distinct DLBCL subtypes. MYD88-mutated DLBCL had a significantly inferior 5-year overall survival than wild-type MYD88 DLBCL (log-rank; P=0.019). DLBCL without any of the studied aberrations had superior overall survival compared to cases carrying .1 aberrancy (log-rank; P=0.010). MYD88 mutations retained their adverse prognostic impact upon adjustment for other genetic and clinical variables by multivariable analysis and improved the prognostic performance of the IPI. This study demonstrates the clinical utility of defining MYD88-mutated DLBCL as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of MYD88 in routine diagnostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies

The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data

The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.Peer reviewe