Challenging the Concept of Functional High-Risk Myeloma through Transcriptional and Genetic Profiling.

Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, but also on what treatment patients received. To establish the true incidence of FHR, we analysed uniformly treated, transplant-eligible (TE) patients from the UK NCRI Myeloma-XI trial that had been profiled for IMS/IMWG defined high-risk cytogenetic aberrations (HRCA) and the SKY92 gene expression HR signature (GEP-HR). 135 TE MyXI patients meeting these criteria were studied, with a median follow-up of 88 months.

Hormone-active ovarian steroid cell tumor in a 2-year-old girl.

Objectives: Steroid cell tumors are very rare in children. During the past 25 years, only 3 cases have been reported in Germany. Symptoms may vary from virilization to signs of precocious puberty and increased growth velocity, making it diagnostically challenging.

Whole body MRI by MY-RADS for imaging response assessment in multiple myeloma.

Minimal residual disease (MRD) testing has underpinned the evaluation and expansion of therapeutic options for patients with multiple myeloma (MM). Imaging is essential for evaluating residual disease status, overcoming sampling errors inherent with other MRD modalities. The accuracy of whole-body MRI (WB-MRI) has led to its incorporation into MM diagnostic imaging guidelines.

EHA-EMN Evidence-Based Guidelines for diagnosis, treatment and follow-up of patients with multiple myeloma.

Since the publication in 2021 of the European Hematology Association (EHA) Clinical Practice Guidelines for the treatment of patients with smouldering multiple myeloma (SMM) and multiple myeloma (MM), developed in collaboration with the European Society for Medical Oncology, a novel international staging system (R2-ISS) has been developed, several prognostic factors are entering clinical practice (such as minimal residual disease, circulating plasma cells and monoclonal protein assessed by mass spectrometry) and, at the time of writing, 14 novel regimens have been approved by the EMA and/or the FDA for the treatment of patients with MM. A multidisciplinary group of experts from the EHA and European Myeloma Network, based in various institutions mostly located in Europe, have updated the previous guidelines and produced algorithms for everyday clinical practice that incorporate levels of evidence and grades of recommendation based on the aforementioned new data. In these Evidence-Based Guidelines, we provide key treatment recommendations for both patients with newly diagnosed MM and those with relapsed and/or refractory MM, including guidance for the use of established drugs as well as contemporary immunotherapies.

Optimising T-cell immunotherapy in patients with multiple myeloma: practical considerations from the European Myeloma Network.

Novel T-cell immunotherapies (chimeric antigen receptor [CAR] T cells and T-cell redirecting bispecific antibodies) are changing the treatment landscape of relapsed or refractory multiple myeloma. In this Review, the European Myeloma Network provides recommendations to optimise both safety and efficacy of T-cell immunotherapy. In patients who are eligible for both CAR T-cell therapy and bispecific antibodies, we recommend using CAR T-cell therapy first due to the high response rate and durable progression-free survival, accompanied by improved quality of life.

Risk adapted therapy for newly diagnosed multiple myeloma delivered through local cytogenetic laboratories in a National Clinical Trial: UKMRA RADAR study.

The UKMRA RADAR study is a phase II/III clinical trial for newly diagnosed multiple myeloma patients eligible for autologous stem cell transplant. It offers a risk-adapted approach with the addition of isatuximab for genetically high-risk patients, evaluated using local cytogenetics laboratories rather than centralised testing. We have observed excellent overall success rates, with > 90% patients assigned to a risk-adapted pathway following cytogenetic testing in 25 local laboratories nationwide, with clinically-relevant turnaround times allowing > 70% patients to commence isatuximab at the earliest opportunity if indicated.

An open-source repository-based tool for quality control of imaging protocol compliance: demonstration in a multicentre MRI study.

Objectives: Clinical translation of advanced MRI techniques can be hindered by the challenges of performing standardized multicentre imaging trials. This work aims to develop and demonstrate an automated tool for monitoring imaging protocol deviations, enabling corrective action to be taken.

Methods: A Python-based tool, integrated into the imaging repository XNAT, was developed to compare DICOM series with an agreed imaging protocol, highlighting missing series and parameter deviations.

Traumatic hip dislocations in children and adolescents: diagnostic challenges and the significance of MRI imaging-a multi-center study.

Background: Traumatic hip dislocations in children and adolescents are rare but can lead to severe outcomes like avascular necrosis. Delayed reductions, often due to overlooked dislocations in initial imaging, pose a major risk. The variability in symptoms and emergency care challenges early diagnosis.

Mendelian randomization of immune cell phenotypes to discover potential drug targets for B-cell malignancy.

Although treatment options for B-cell malignancies have expanded, many patients continue to face limited response rates, highlighting an urgent need for new therapeutic targets. To prioritize candidate drug targets for B-cell malignancies, we employed Mendelian Randomization to estimate potentially causal relationships between 445 immune cell traits and six B-cell cancers: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), totaling 22,922 cases and 394,204 controls. 163 traits showed a suggestive association with at least one B-cell malignancy (P < 0.

-epigenomic reprogramming and maintenance of plasma cell phenotype in t(4;14) myeloma.

Overexpression of the H3K36 histone methyltransferase NSD2 in t(4;14) multiple myeloma (MM) is an early, oncogenic event, and understanding its impact on genomic organisation and expression is relevant to understanding MM biology. We performed epigenetic, transcriptional and phenotypic profiling of the t(4;14) KMS11 myeloma cell line and its isogenic translocation knock out (TKO) to characterise the sequelae of NSD2 overexpression. We found a marked global impact of NSD2 on gene expression and DNA organisation implicating cell identity genes; notably the early lymphocyte regulator, LAIR1 and MM cell surface markers, including CD38, a classical marker of plasma cells which was reduced in TKO cells.

Distal Humeral Coronal Shear Fractures in Children and Adolescents: Need for Cross-Sectional Imaging and a Revised Classification.

The classification of fractures is necessary to ensure a reliable means of communication for clinical interaction, research, and education. Distal humeral coronal plane shear fractures (CSFs) are very rare in the growing-age population, despite that multiple classification schemes exist.The aim of this study was to assess the inter- and intrarater reliability of the four most commonly used CSF classifications and their role in guiding treatment decisions in everyday clinical practice.

An Attribution of Value Framework for Combination Treatments.

Objectives: The use of cost-effectiveness methods to support policy decisions has become well established, but difficulties can arise when evaluating a new treatment that is indicated to be used in combination with an established backbone treatment. If the latter has been priced close to the decision maker's willingness-to-pay threshold, this may mean that there is no headroom for the new treatment to demonstrate value, at any price, even if the combination is clinically effective. Without a mechanism for attributing value to component treatments within a combination therapy, the health system risks generating negative funding decisions for combinations of proven clinical benefit to patients.

Advanced imaging for earlier diagnosis and morbidity prevention in multiple myeloma: A British Society of Haematology and UK Myeloma Society Good Practice Paper.

This Good Practice Paper provides recommendations for the use of advanced imaging for earlier diagnosis and morbidity prevention in multiple myeloma. It describes how advanced imaging contributes to optimal healthcare resource utilisation by in newly diagnosed and relapsed myeloma, and provides a perspective on future directions of myeloma imaging, including machine learning assisted reporting.

Diagnosis and initial treatment of transplant-eligible high-risk myeloma patients: A British Society for Haematology/UK Myeloma Society Good Practice Paper.

This Good Practice Paper provides recommendations for the diagnosis and initial management of transplant-eligible high-risk myeloma patients. It describes recent updates to the genetic diagnostics of high-risk myeloma and provides recommendations for treatment on the basis of recent prospective clinical trial evidence.

Museomics help resolving the phylogeny of snowfinches (Aves, Passeridae, Montifringilla and allies).

Historical specimens from museum collections provide a valuable source of material also from remote areas or regions of conflict that are not easily accessible to scientists today. With this study, we are providing a taxon-complete phylogeny of snowfinches using historical DNA from whole skins of an endemic species from Afghanistan, the Afghan snowfinch, Pyrgilauda theresae. To resolve the strong conflict between previous phylogenetic hypotheses, we generated novel mitogenome sequences for selected taxa and genome-wide SNP data using ddRAD sequencing for all extant snowfinch species endemic to the Qinghai-Tibet Plateau (QTP) and for an extended intraspecific sampling of the sole Central and Western Palearctic snowfinch species (Montifringilla nivalis).

Still high risk? A review of translocation t(14;16) in multiple myeloma.

Multiple myeloma (MM) is a heterogeneous and complex disease, both in mutational biology as well as in the clinical presentation of patients. While tailored and biomarker-targeted therapy remains the direct goal for patient-centric management, existing therapies in MM remain largely uniform. Translocation t(14;16) is a rare primary genetic event found in less than 5% of patients with newly diagnosed MM.

Phenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers.

For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls.

Curation of myeloma observational study MALIMAR using XNAT: solving the challenges posed by real-world data.

Objectives: MAchine Learning In MyelomA Response (MALIMAR) is an observational clinical study combining "real-world" and clinical trial data, both retrospective and prospective. Images were acquired on three MRI scanners over a 10-year window at two institutions, leading to a need for extensive curation.

Methods: Curation involved image aggregation, pseudonymisation, allocation between project phases, data cleaning, upload to an XNAT repository visible from multiple sites, annotation, incorporation of machine learning research outputs and quality assurance using programmatic methods.

Coherent olfactory bulb gamma oscillations arise from coupling independent columnar oscillators.

Spike timing-based representations of sensory information depend on embedded dynamical frameworks within neuronal networks that establish the rules of local computation and interareal communication. Here, we investigated the dynamical properties of olfactory bulb circuitry in mice of both sexes using microelectrode array recordings from slice and in vivo preparations. Neurochemical activation or optogenetic stimulation of sensory afferents evoked persistent gamma oscillations in the local field potential.