Bilateral breast Rosai-Dorfman disease screen detected by mammography.

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.

Detection of coronary calcifications with dual energy chest X-rays: clinical evaluation.

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.

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression.

PURPOSE: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

Utility of Iodine Density Perfusion Maps From Dual-Energy Spectral Detector CT in Evaluating Cardiothoracic Conditions: A Primer for the Radiologist.

OBJECTIVE. The purpose of this article is to outline the utility of iodine density maps for evaluating cardiothoracic disease and abnormalities. Multiple studies have shown that the variety of images generated from dual-energy spectral detector CT (SDCT) improve identification of cardiothoracic conditions. CONCLUSION. Understanding the technique of SDCT and being familiar with the features of different cardiothoracic conditions on iodine density map images help the radiologist make a better diagnosis.

Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche.

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.

Platelets Enhance Multiple Myeloma Progression via IL-1ß Upregulation.

Purpose: Tumor cell-platelet interactions contribute to tumor progression and metastasis in solid tumors. However, the role of platelets in hematological malignancies is not clear. We investigated the association of platelet activation status with clinical stages in multiple myeloma (MM) patients and explored the role of platelets in MM progression.Experimental Design: Platelets were obtained from healthy donors and MM patients. We examined platelet activation status in MM patients by flow cytometry and transmission electron microscopy. We also observed the enriched pathways that are involved with platelet activation in RNA sequencing of platelets. MM cell lines were used to assess the effect of platelets on MM cell proliferation in vitro and their engraftment in vivo RNA sequencing of MM cell lines was performed to explore molecular mechanisms underlying MM cell-platelet interaction and a CRISPR/Cas9 knockout approach was used for validation.Results: Platelets from MM patients were highly activated with disease progression. RNA sequencing of platelets revealed that genes involved in platelets were enriched in patients with smoldering MM (SMM) or MM. Platelets promoted MM cell proliferation in vitro and contributed to tumor engraftment in bone marrow in vivo RNA sequencing revealed that IL-1ß was upregulated in MM cell lines co-cultured with platelets, whereas IL-1ß knockout in MM cell lines abrogated the effects of platelets on MM cell proliferation and engraftment in vivoConclusions: Platelets from MM patients were highly activated with disease progression. IL-1ß is critical to platelet-mediated MM progression and might be a potential target for MM treatment. Clin Cancer Res; 24(10); 2430-9. ©2018 AACR.

TP53 and IDH2 Somatic Mutations Are Associated With Inferior Overall Survival After Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome.

BACKGROUND: Next-generation sequencing has identified somatic mutations that are prognostic of cancer. PATIENTS AND METHODS: We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen. RESULTS: The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P = .03) and IDH2 mutations (HR, 4.74; 95% CI, 1.33-16.91; P = .02) as predictors of inferior 3-year overall survival. CONCLUSION: This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy.

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma.

Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.

Prognostic role of circulating exosomal miRNAs in multiple myeloma.

Exosomes, secreted by several cell types, including cancer cells, can be isolated from the peripheral blood and have been shown to be powerful markers of disease progression in cancer. In this study, we examined the prognostic significance of circulating exosomal microRNAs (miRNAs) in multiple myeloma (MM). A cohort of 156 patients with newly diagnosed MM, uniformly treated and followed, was studied. Circulating exosomal miRNAs were isolated and used to perform a small RNA sequencing analysis on 10 samples and a quantitative reverse transcription polymerase chain reaction (qRT-PCR) array on 156 samples. We studied the relationship between miRNA levels and patient outcomes, including progression-free survival (PFS) and overall survival (OS). We identified miRNAs as the most predominant small RNAs present in exosomes isolated from the serum of patients with MM and healthy controls by small RNA sequencing of circulating exosomes. We then analyzed exosomes isolated from serum samples of 156 patients using a qRT-PCR array for 22 miRNAs. Two of these miRNAs, let-7b and miR-18a, were significantly associated with both PFS and OS in the univariate analysis and were still statistically significant after adjusting for the International Staging System and adverse cytogenetics in the multivariate analysis. Our findings support the use of circulating exosomal miRNAs to improve the identification of patients with newly diagnosed MM with poor outcomes. The results require further validation in other independent prospective MM cohorts.

Genomic complexity 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.

Exosomes in Tumor Angiogenesis.

Exosomes are small vesicles ranging in size between 30 and 150 nm, derived from the luminal membranes of the endosome and are constitutively released by fusion with the cell membrane. Several studies have revealed that exosomes play crucial roles in mediating local and systemic cell communication through the horizontal transfer of information in the form of nucleic material and proteins. This is particularly relevant in the context of the tumor-microenvironment cross talk. Here we describe the method of isolating exosomes and their role in modifying the tumor environment and more specifically in enabling metastasis and promoting angiogenesis.

Epigenetics in Multiple Myeloma.

Multiple myeloma is characterized by clonal proliferation of plasma cells within the bone marrow resulting in anemia, lytic bone lesions, hypercalcemia, and renal impairment. Despite advanced in our understanding of this complex disease in recent years, it is still considered an incurable malignancy. This is, in part, due to the highly heterogenous genomic and phenotypic nature of the disease, which is to date incompletely understood. It is clear that a deeper level of knowledge of the biological events underlying the development of these diseases is needed to identify new targets and generate effective novel therapies. MicroRNAs (miRNAs), which are single strand, 20-nucleotide, noncoding RNA's, are key regulators of gene expression and have been reported to exert transcriptional control in multiple myeloma. miRNAs are now recognized to play a role in many key areas such as cellular proliferation, differentiation, apoptosis and stress response. Substantial advances have been made in recent years in terms of our understanding of the biological role of miRNAs in a diverse range of hematological and solid malignancues, In multiple myeloma these advances have yielded new information of prognostic and diagnostic relevance which have helped to shed light on epigenetic regulation in this disease.

Genomic Aberrations in Multiple Myeloma.

Multiple myeloma (MM) is a genetically complex disease. The past few years have seen an evolution in cancer research with the emergence of next-generation sequencing (NGS), enabling high throughput sequencing of tumors-including whole exome, whole genome, RNA, and single-cell sequencing as well as genome-wide association study (GWAS). A few inherited variants have been described, counting for some cases of familial disease. Hierarchically, primary events in MM can be divided into hyperdiploid (HDR) and nonhyperdiploid subtypes. HRD tumors are characterized by trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and/or 21. Non-HRD tumors harbor IGH translocations, mainly t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20). Secondary events participate to the tumor progression and consist in secondary translocation involving MYC, copy number variations (CNV) and somatic mutations (such as mutations in KRAS, NRAS, BRAF, P53). Moreover, the dissection of clonal heterogeneity helps to understand the evolution of the disease. The following review provides a comprehensive review of the genomic landscape in MM.

Future Directions in the Evaluation and Treatment of Precursor Plasma Cell Disorders.

Multiple myeloma (MM) is an incurable disease that progresses from a premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS) and an intermediate stage of smoldering multiple myeloma (SMM). Recent major advances in therapy with more effective and less toxic treatments have brought reconsideration of early therapeutic intervention in management of SMM, with the goal of reducing progression of the disease before the occurrence of end-organ damage to MM and improving survival. Key to this effort is accurate identification of patients at high risk of progression who would truly benefit from early intervention. In this review, we discuss the current definitions, risk factors, risk stratification, prognosis, and management of MGUS and SMM, as well as new emerging therapeutic options under active investigation.

Primary plasmacytoma involving mediastinal lymph nodes: A diagnostic mimicry of primary mediastinal lymphoma.

Plasmacytomas could involve any organ, and at times might pose a diagnostic challenge when the site of involvement is unusual, or if the presentation is similar to other diseases. We describe a 48-year-old man presenting with worsening shortness of breath and chest discomfort with radiologic evidence of mediastinal enlargement, mimicking a lymphoma with mediastinal involvement. An excisional biopsy of a mediastinal lymph node showed a plasma-cell infiltrate strongly positive for CD138, with a flow-cytometry analysis showing a population of lambda-restricted neoplastic plasma cells. He failed to respond to 50Gy involved-field radiotherapy, but achieved a partial response to combination chemotherapy. He underwent high-dose chemotherapy with melphalan (200mg/m(2)) followed by lenalidomide maintenance, and is in complete remission 18months postautografting. This case illustrates a unique and rare presentation of primary lymph-node plasmacytomas involving the mediastinum potentially mistaken as lymphoid malignancy. Clinicians should be aware of the plasma-cell origin of the mediastinal neoplastic process.

The road to cure in multiple myeloma starts with smoldering disease.

INTRODUCTION: Smoldering multiple myeloma (SMM) is a heterogeneous clinical entity that defines patients in the spectrum of disease progression from monoclonal gammopathy of undetermined significance to multiple myeloma (MM). Current standard of care is observation until end organ damage occurs. In spite of this, the scientific community has begun to question whether the strategy of watchful waiting should be replaced with earlier therapeutic intervention with the ultimate goal of preventing clonal heterogeneity and end organ damage. AREAS COVERED: In this review, we challenge the concept of observation as the best option of therapy in SMM. We present current data on diagnosis, prognostic factors of disease progression and studies that have been conducted to date to determine whether earlier therapeutic interventions will lead to an improvement in overall survival of patients with MM. EXPERT OPINION: If the recommendations of treatment of SMM were to change, the scientific body of evidence would have to overcome four major hurdles: to demonstrate that early intervention leads to prolonged survival and delay in development of end organ damage, that it does not have long-term toxicities, that it is implemented in patients with a high-likelihood of developing myeloma and that it does not lead to the outgrowth of more resistant clones. Only well-designed clinical trials will determine whether cure can be achieved with earlier interventions.

Sectarianism and the problem of overpopulation: political representations of reproduction in two low-income neighbourhoods of Beirut, Lebanon.

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.