Epidemiology and Pathogenesis of Myelodysplastic Syndrome.

ABSTRACT: Myelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hematopoiesis and variable cytopenias with a considerable risk of progression to acute myeloid leukemia. Epidemiological assessment of MDS remains challenging because of evolving classification systems, but the overall incidence in the United States is estimated to be approximately 4 per 100,000 and increases with age. The sequential accumulation of mutations drives disease evolution from asymptomatic clonal hematopoiesis (CH) to CH of indeterminate potential, clonal cytopenia of unknown significance, to frank MDS. The molecular heterogeneity seen in MDS is highly complex and includes mutations of genes involved in splicing machinery, epigenetic regulation, differentiation, and cell signaling. Recent advances in the understanding of the molecular landscape of MDS have led to the development of improved risk assessment tools and novel therapies. Therapies targeting the underlying pathophysiology will hopefully further expand the armamentarium of MDS therapeutics, bringing us closer to a more individualized therapeutic approach based on the unique molecular profile of each patient and eventually improving the outcomes of patients with MDS. We review the epidemiology of MDS and the newly described MDS precursor conditions CH, CH of indeterminate potential, and CCUS. We then discuss central aspects of MDS pathophysiology and outline specific strategies targeting hallmarks of MDS pathophysiology, including ongoing clinical trials examining the efficacy of these therapeutic modalities.

Visualizing surface marker expression and intratumoral heterogeneity with SERRS-NPs imaging.

Cell surface marker expression in tumors dictates the selection of therapeutics, therapy response, and survival. However, biopsies are invasive, sample only a small area of the tumor landscape and may miss significant areas of heterogeneous expression. Here, we investigated the potential of antibody-conjugated surface-enhanced resonance Raman scattering nanoparticles (SERRS-NPs) to depict and quantify high and low tumoral surface marker expression, focusing on the surface markers epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in an intracerebral and peripheral setting with an inter- and intratumoral comparison of Raman signal intensities. Methods: ICR-Prkdc mice were injected with glioblastoma, epidermoid carcinoma, or breast tumor cell lines intracerebrally and peripherally. SERRS-NPs were functionalized with cetuximab or trastuzumab and administered via tail vein injection. Raman imaging was performed 18 hours post-injection in excised tumors and in vivo through the skull. Tumors were then fixed and processed for immunohistochemical evaluation. Results: Confirmed by MRI and immunohistochemistry for EGFR and HER2, our results demonstrate that antibody-conjugated SERRS-NPs go beyond the delineation of a tumor and offer clear and distinct Raman spectra that reflect the distribution of the targeted surface marker. The intensity of the SERRS-NP signal accurately discriminated high- versus low-expressing surface markers between tumors, and between different areas within tumors. Conclusion: Biopsies can be highly invasive procedures and provide a limited sample of molecular expression within a tumor. Our nanoparticle-based Raman imaging approach offers the potential to provide non-invasive and more comprehensive molecular imaging and an alternative to the current clinical gold standard of immunohistochemistry.