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Key Points The development of multiple myeloma is preceded by pre-malignant stages, and therefore constitutes a well-defined model of disease progression that is appropriate for studies of clonal evolution and heterogeneity Whole-exome sequencing studies have enabled the characterization of the genomic alterations underlying the pathogenesis of multiple myeloma The primary genomic events involved in multiple myeloma are the acquisition of hyperdiploidy or translocations affecting the IGH genes; these events are mutually exclusive Secondary genomic events include chromosomal translocations, copy-number variations and single-nucleotide variants Genomic events underlying multiple myeloma affect multiple signalling pathways including the MYC, NF-κB, and MAPK pathways, plasma-cell differentiation, cell-cycle regulation or DNA-damage repair In the past 5 years, results from large-scale whole-exome sequencing studies have brought new insight into the clonal heterogeneity and evolution of multiple myeloma, a genetically complex disease. Herein, the authors describe the driver gene alterations and sequential acquisition of the main genomic aberrations involved in this disease, with a focus on the clonal heterogeneity of multiple myeloma and its clinical implications. Multiple myeloma (MM) is a genetically complex disease that evolves from pre-malignant stages, such as monoclonal gammaopathy of undetermined significance and smouldering multiple myeloma, and progresses to symptomatic MM; this continuum provides a unique framework to study the sequential genomic evolution of MM. In the past 5 years, results from large-scale whole-exome sequencing studies have provided new insights into the clonal heterogeneity and evolution of the disease. Moreover, the recurrent co-occurrence of genomic events helps to dissect the genomic complexity underlying tumour progression. According to the primary genetic events involved in tumorigenesis, MM tumours are hierarchically subdivided into hyperdiploid and non-hyperdiploid subtypes; subsequently, secondary genetic events lead to tumour progression. In this Review, we describe the 'driver' gene alterations involved in the development and progression of MM, with a focus on the sequential acquisition of the main genomic aberrations. We also provide valuable insight into the clonal heterogeneity and clonal evolution of the disease, as well as into the therapeutic implications of a comprehensive understanding of the genomic complexity of MM.

Myeloma bone disease is a devastating complication of multiple myeloma (MM) and is caused by dysregulation of bone remodeling processes in the bone marrow microenvironment. Previous studies showed that microRNA-138 (miR-138) is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and that inhibiting its function enhances bone formation in vitro. In this study, we explored the role of miR-138 in myeloma bone disease and evaluated the potential of systemically delivered locked nucleic acid (LNA)-modified anti-miR-138 oligonucleotides in suppressing myeloma bone disease. We showed that expression of miR-138 was significantly increased in MSCs from MM patients (MM-MSCs) and myeloma cells compared to those from healthy subjects. Furthermore, inhibition of miR-138 resulted in enhanced osteogenic differentiation of MM-MSCs in vitro and increased the number of endosteal osteoblastic lineage cells (OBCs) and bone formation rate in mouse models of myeloma bone disease. RNA sequencing of the OBCs identified TRPS1 and SULF2 as potential miR-138 targets that were de-repressed in anti-miR-138-treated mice. In summary, these data indicate that inhibition of miR-138 enhances bone formation in MM and that pharmacological inhibition of miR-138 could represent a new therapeutic strategy for treatment of myeloma bone disease.

Rosai‐Dorfman disease (RDD) is a proliferative disorder of histiocytes typically found in nodal sites and commonly observed in females. Patients often present with systemic symptoms such as fever, lymphadenopathy, and weight loss. However, extra‐nodal disease has been identified in locations including the skin and subcutaneous tissue. We present a case of a 59‐year‐old female presenting with abnormal bilateral findings on screening mammography, who was found to have a rare presentation of Rosai‐Dorfman disease. Rosai‐Dorfman disease (RDD) is a rare proliferative disorder of histiocytes typically found in nodal sites, however, it can also present initially as an asymptomatic mass in the breast. Presenting symptoms may include fever, lymphadenopathy, and weight loss. Tissue sampling is definitive for diagnosis and close surveillance is recommended.

Our goal is to assess the ability of physicians to detect coronary calcifications in dual energy chest X-rays processed by a previously developed advanced algorithm. Because the chest X-ray is the most common imaging procedure, because the presence of coronary calcium provides proof of coronary artery disease, and because adherence to therapy can improve health, successful detection could positively impact healthcare for a large number of patients. Both dual energy chest and corroborative CT calcium score images were acquired. Dual energy images were processed with the advanced techniques, including sliding organ registration, so as to enhance coronary calcifications in two-shot dual energy acquisitions. We performed ROC to determine physicians’ ability to detect coronary calcifications. Since detection might be easier with heavier calcifications, we used various Agatston score cut-points for determining cases actually positive with calcification in the ROC analysis. In many cases, coronary calcifications were made more visible with the advanced processing as compared to conventional processing. At an Agatston cut-point of 300, coronary calcifications were detected with AUC = 0.85. There were marginal effects on detection performance found with increased X-ray exposure, nearby Agatston cut-point values, and coronary artery territory. Coronary calcifications can be detected in dual energy chest X-rays. The ability to detect disease compares very favorably to other accepted screening methods (e.g., X-ray mammography). As the chest X-ray is an already ordered procedure, there is an opportunity to detect a very large number of persons with coronary artery disease at zero or low cost.

MYC is a major oncogenic driver of multiple myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC , itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28 / let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo , demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC -dependent cancers as well.

The role of confessionalism in the Lebanese healthcare sector, especially since the resolution of the Lebanese civil war (1975-1990), has yet to discussed at length in reproductive health research. Using biopolitical and structural violence models to describe how community leaders in two low-income neighbourhoods in Beirut describe reproductive healthcare - specifically through judgments of perceived sect size vis-à-vis perceived use of birth control measures - this paper attempts to provide critical analysis of the state of reproductive health in this setting. By using a theoretical model of analysis, which we refer to as the political anatomy of reproduction, we hope to unmask how confessionalism is perpetuated through discussions of reproductive health and how public health and medical communities can challenge this technique of power.

High‐dose therapy followed by autologous hematopoietic cell transplantation (HCT) represents the standard therapy for patients with chemosensitive relapsed diffuse large B‐cell lymphoma and Hodgkin lymphoma. While no randomized controlled trial exists comparing total body irradiation with chemotherapy‐based regimens, the latter appears to be used more commonly. Rituximab has been incorporated for in vivo purging or as part of conditioning regimens for autografting, but no randomized data exist to support a survival benefit with this approach. Adding radioimmunoconjugates to preparative regimens, namely 131 I‐tositumomab, failed to improve the outcomes when compared with adding rituximab. With further refinement and incorporation of novel targeted agents, future preparative regimens in autologous HCT for lymphoid malignancies may evolve to a personalized conditioning. Additionally, future research should explore augmentation of antitumor responses coupled with immunotherapy utilizing tumor vaccines and immune checkpoint targeting.

BackgroundDrug–drug interaction (DDI) alerts target the co-prescription of two potentially interacting medications and are a frequent feature of electronic medical records (EMRs). There have been few controlled studies evaluating the effectiveness of DDI alerts. This study aimed to determine the impact of DDI alerts on rates of DDIs and on associated patient harms.MethodsQuasi-experimental controlled pre–post study in five Australian hospitals. Three hospitals acted as control hospitals (EMR with no DDI alerts) and two as intervention (EMR with DDI alerts). Only DDI alerts at the highest severity level (defined as ‘major contraindicated’) were switched on at intervention hospitals. These alerts were not tailored to clinical context (ie, patient, drug). A total of 2078 patients were randomly selected from all patients (adult and paediatric) admitted to hospitals 6 months before and 6 months after EMR implementation. A retrospective chart review was performed by study pharmacists. The primary outcome was the proportion of admissions with a clinically relevant DDI. Secondary outcomes included the proportions of admissions with a potential DDI and with DDI-related harm.ResultsPotential DDIs were identified in the majority of admissions (n=1574, 74.7%) and clinically relevant DDIs identified in half (n=1026, 48.7%). DDI alerts were associated with a reduction in the proportion of admissions with potential DDIs (adjusted OR (AOR)=0.38 (0.19, 0.78)) but no change in clinically relevant DDIs (AOR=1.12 (0.68, 1.84)) or in DDI-related harm (AOR=2.42 (0.47,12.31)). 199 DDIs (76 at control and 123 at intervention hospitals) for 35 patient admissions were associated with patient harm, and 2 patients experienced severe DDI-related harm pre-EMR implementation.DiscussionImplementation of DDI alerts, without tailoring alerts to clinical context, is unlikely to reduce patient harms from DDIs. Organisations should reconsider implementation of DDI alerts in EMRs where significant tailoring of alerts is not possible. Future research should focus on identifying safe, efficient and cost-effective ways of refining DDI alerts, so expected clinical benefits are achieved, and negative consequences of excessive alerting are minimised.