The bone marrow (BM) microenvironment of multiple myeloma (MM) is reported to play a role in the biology of disease. In this study, we found that the extracellular BM microenvironment in MM contains a unique miRNA signature detectable by miRNA microarray and quantitative real-time PCR, which is partially represented in the peripheral blood. Eleven miRNAs were significantly decreased in both BM and serum of MM patients in comparison with controls. Evaluation of these miRNAs in plasma of a separate cohort of MM patients and controls confirmed significantly aberrant levels of let-7a, let-7b, let-7i, miR15b, miR-16, and miR-20a in both serum and plasma. We then studied the myeloma precursor diseases and found that a subset of the MM miRNAs exhibited aberrant expression in monoclonal gammopathy of undetermined significance and smoldering myeloma. miRNA analysis of enriched CD138 þ plasma cells from MM and monoclonal gammopathy of undetermined significance found that most of the validated MM BM signature miRNAs were significantly decreased in MM plasma cells. Gene expression profiling indicated that multiple targets of the decreased miRNAs found increased expression in MM plasma cells, including ATF2, HRAS, HDAC4, TGFB1, TGFBR1, and mitogen-activated protein kinases. The findings suggest that these miRNAs are detectable in aberrant levels in the peripheral blood of patients with plasma cell proliferation and may play a role in aberrant plasma cell proliferation and disease progression. Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm that evolves from an underlying asymptomatic precursor clonal PC proliferation designated monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in >3% of the population aged >50 years and progresses to myeloma at a rate of nearly 1% per year. 1Smoldering myeloma (SMM) represents an intermediate entity with increased bone marrow (BM) clonal PCs without symptomatic disease and carries an increased rate of progression to myeloma of nearly 10% per year.2 Currently, no single factor can predict patients with MGUS that are likely to progress to MM. A biomarker of disease progression in the peripheral blood (PB) could assist in the early identification of patients evolving to MM. Recent data suggest that serum miRNAs are altered in MM and MGUS and may serve as diagnostic and prognostic biomarkers. 3,4 miRNAs use a post-transcriptional gene regulation mechanism that was shown to play a role in development, differentiation, and tumorigenesis. 5e7 miRNAs are evolutionarily conserved small non-coding RNAs, which regulate gene

The lymph node (LN) is the site of chronic lymphocytic leukemia (CLL) cell activation and proliferation. Aberrant microRNA (miRNA) expression has been shown to have a role in CLL pathogenesis; however, a comparison of miRNA expression between CLL cells in the LN and the peripheral blood (PB) has previously not been reported. On the basis of the analysis of 17 paired LN and PB samples from CLL patients, we identify a panel of miRNAs that are increased in LN CLL cells correlating with an activation phenotype. When evaluated in CLL cells from 38 patients pre and post treatment with ibrutinib, a subset of these miRNAs (miR-22, miR-34a, miR-146b and miR-181b) was significantly decreased in response to ibrutinib. A concomitant increase in putative miRNA target transcripts (ARID1B, ARID2, ATM, CYLD, FOXP1, HDAC1, IBTK, PTEN and SMAD4) was also observed. Functional studies confirmed targets of ibrutinib-responsive miRNAs to include messenger RNA transcripts of multiple tumor suppressors. Knockdown of endogenous miR-34a and miR146b resulted in increased transcription of tumor suppressors and inhibition of cell proliferation. These findings demonstrate that ibrutinib downregulates the expression of a subset of miRNAs related to B-cell activation leading to increased expression of miRNA targets including tumor suppressors and a reduction in cell proliferation.

Benign metastasizing leiomyomas (BML) represent a rare phenomenon consisting of the extra-uterine spread of smooth muscle cells with similar histological, immunological, and molecular patterns to those of benign uterine leiomyomas. They are considered benign based off their low mitotic activity, lack of anaplasia or necrosis, and limited vascularization. This condition represents an interesting diagnostic and treatment challenge based on their rarity and indolent nature. Our case represents a unique finding of BML in the thoracic spine in a postmenopausal woman many years after hysterectomy and partial oophorectomy. There are currently no standard guidelines for treatment of BML, given the rare nature of this condition, with most patients treated with a combination of surgical resection and radiotherapy, followed by hormonal treatment and radiological surveillance serving as the primary backbone of current management plans. Given that these patients present a unique clinical challenge in terms of diagnosis and management, it is important to delineate and further examine these rare entities.

In the last couple of decades, breast conservation therapy, which utilizes a combination of surgery, radiotherapy, and endocrine or chemotherapy, has become the standard of care for treating early-stage breast cancer. This practice has been greatly beneficial in the improvement of the patient’s quality of life but has also led to the increased use of radiotherapy and associated soft-tissue sarcomas, with angiosarcoma being the most common malignancy. Radiation-associated angiosarcoma (RAS) of the breast is a rare phenomenon, which has been reported to occur in approximately 0.9 out of 1,000 cases, with a reported onset as late as 23 years following radiotherapy. Here we report 2 cases of RAS that occurred within 6 and 13 years following radiotherapy of their primary breast lesion. We discuss the diagnostic and therapeutic challenges regarding this disease and review the current literature. This case report serves as cautionary lessons on the importance of considering RAS of the breast in the differential diagnosis during evaluation for recurrent breast neoplasms. Ongoing clinical trials using combinations of vascular endothelial growth factor inhibitors and chemotherapy may provide future avenues of treatment for this difficult-to-treat disease.

Sinonasal undifferentiated carcinoma (SNUC) is a rare, poorly differentiated and aggressive malignancy of the nasal cavity and paranasal sinuses first reported by Frierson et al. in 1986 with less than 300 known cases reported since then. Due to the rarity and aggressive nature of the disease, there is a lack of consensus regarding optimal management in these patients. Treatment decisions have mostly been guided by a small number of cases series and can vary widely between institutions. In this unique case presentation, we review a case of sinonasal undifferentiated carcinoma in a young Hispanic male reviewing the literature on a rare disease, in order to elucidate effective treatment options for improved future outcomes. Based off of literature review and prior case series, the multiple modality approach should result in the best possible outcome for this rare and aggressive disease. In this specific case of a young Hispanic male with Stage IVB SNUC, we proceeded with Neo-adjuvant TPF (Docetaxel, cisplatin and fluorouracil) with effective results, followed by Cisplatin and concurrent radiation once the patient had interval progression, and was deemed unresectable. Given the rarity and complexity of this disease, a prospective randomized controlled study should eventually be pursued to properly determine the most effective mode and combination of therapies. At this time treatment can only be based on reported case series and a small number of retrospective studies, and therefore it is important to continue to evaluate different institutions’ methods of treatment.

GATA2 is a transcription factor critical for hematopoiesis. Germline mutations in GATA binding protein 2 (GATA2) led to haploinsufficiency, severe cytopenias of multiple cell lineages, susceptibility to infections and strong propensity to develop myelodysplastic syndrome, and acute myeloid leukemia. Mechanisms of progressive cytopenias remain unclear. MicroRNA (miRNA) represents a unique mechanism of post-transcriptional gene regulation. In this study, miRNA profiles were evaluated and eight miRNAs were found to be differentially expressed (≥2-fold, P ≤ 0.05) in patient-derived cell lines (N = 13) in comparison to controls (N = 10). miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582 showed increased expression, whereas miR-223 and miR-424-3p showed decreased expression. Cell death assays indicated that miR-181c potently induces cell death in lymphoid (Ly-8 and SP-53) and myeloid (HL-60) cell lines. miR-181c was predicted to target myeloid cell leukemia (MCL)1, which was confirmed by transfection assays, resulting in significantly reduced MCL1 mRNA and decreased live cell numbers. Bone marrow analysis of 34 GATA2 patients showed significantly decreased cellularity, CD34-positive cells, monocytes, dendritic cells, NK cells, B cells, and B cell precursors in comparison to healthy controls (N = 29; P < 0.001 for each), which was accompanied by decreased levels of MCL1 (P < 0.05). GATA2 expression led to significant repression of miR-181c expression in transfection experiments. Conversely, knockdown of GATA2 led to increased miR-181c expression. These findings indicate that miR-181c expression is increased and MCL1 levels decreased in GATA2 deficiency cells, and that GATA2 represses miR-181c transcription. Increased miR-181c may contribute to elevated cell death and cytopenia in GATA2 deficiency potentially through down-regulation of MCL1.

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