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INTRODUCTION Multiple Myeloma is characterized by the neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin which can be detected by analysis of the protein electrophoresis of serum (SPEP) and/or urine(UPEP) and/or serum free light chain analysis. Here ,we present a rare case of non-secretory multiple myeloma in which no measurable monoclonal heavy or light chains can be identified. CASE 68 year-old female presented to the hospital with symptoms of intractable back pain and rib pain along with 20 lb weight loss over the past 2 months. Labs were significant for mild anemia with a hemoglobin of 11mg/dl, WBC count 5.6 K/ul , platelet 199 K/ul, Chemistry panel showed mild hypernatremia with serum sodium 149, serum K 4.1, BUN 23mg/dl, serum creatinine 1.20 mg/dl, serum calcium levels elevated to 13.7 mg/dl and normal liver function tests. Imaging with Computed Tomography of chest, abdomen, pelvis showed extensive lytic lesions in axial and appendicular skeleton, with pathologic fractures involving T3 and T9 vertebrae. Skeletal bone survey showed innumerable lytic lesions involving the calvarium, C- spine, humerus, scapula, pelvis and bilateral femurs. A core needle biopsy of the right sacral iliac crest bone lesion was performed with pathology showing evidence of plasma cell neoplasm. SPEP showed hypogammaglobulinemia, normal serum kappa and lambda light chains and normal free light chain ratio. Serum immunofixation, UPEP and urine IFE did not show any evidence of monoclonal protein. Serum beta-2 microglobulin was elevated to 13.8 mg/L. Subsequent bone marrow biopsy revealed hyper cellular marrow with 95% cellularity, with 80% involvement by plasma cells, congo red stain negative, findings consistent with plasma cell myeloma. Cytogenetics were normal with FISH showing duplication of 1q, but negative for 17p deletion, t(4,14) and t(14,16). Hypercalcemia was managed with pamidronate. She was diagnosed with Revised International Staging System(R-ISS) Stage II non secretory multiple myeloma. Patient received palliative radiation therapy for lytic lesions. Treatment was initiated with standard of care regimen Velcade, Revlimid and Dexamethasone along with bisphosphonates. DISCUSSION Non secretory myeloma(NSMM) constitutes about 1-2% of all MM cases. It is classically defined as clonal bone marrow plasma cells ≥10% or biopsy proven plasmacytoma, evidence of end-organ damage with anemia, renal insufficiency likely secondary to hypercalcemia, bone lesions and lack of serum and urinary monoclonal protein on electrophoresis and immunofixation. Majority of these patients have M protein detectable in the cytoplasm of plasma cells by Immunohistochemistry, but have impaired secretion of the protein, or they can be non-producer MM. The overall survival (OS) and progression free survival( PFS) of NSMM is similar or superior to patients with secretory myeloma phenotype. Monitoring of the these patients for treatment response is challenging and is mainly on the basis of imaging studies like PET-CT or MRI and bone marrow evaluation.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18896号 / 医博第4007号 / 新制||医||1009(附属図書館) / 31847 / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂井 義治, 教授 伊達 洋至, 教授 前川 平 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19269号 / 医博第4033号 / 新制||医||1011(附属図書館) / 32271 / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩井 一宏, 教授 髙折 晃史, 教授 山田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Final publication is available at http://www.sciencedirect.com/science/article/pii/S0006291X15310664 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19598号 / 医博第4105号 / 新制||医||1014(附属図書館) / 32634 / 京都大学大学院医学研究科医学専攻 / (主査)教授 三森 経世, 教授 開 祐司, 教授 妻木 範行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21009号 / 医博第4355号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 前川 平, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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The human bone marrow (BM) is one of the most complex and critical tissues in the adult, functioning as the site for blood and immune cell production in homeostasis, injury, and disease. The marrow acts as an incredibly diverse stem cell niche, containing stromal and blood cells that help support the maintenance and differentiation capacity of hematopoietic stem and progenitor cells (HSPCs). The cell-cell and cell-matrix interactions within the niche help alter the marrow to trigger blood cell production in response to injury, as well as harbor downstream changes that may persist in the hematopoietic system during disease, such as in cancer metastasis or leukemias of the BM. As the development of engineered human tissue models including organs-on-a-chip (OoC) have emerged over the past decade, there has been an increased relevance of using human BM models to study human- and patient-specific immune interactions in vitro. In this dissertation, we have developed patient-specific bioengineering technologies to model the BM, as well as those to study multi-organ interactions, for a host of translational applications of injury and disease. In Chapters 1 and 2, we introduce a number of concepts in bioengineering and stem cell biology for studying human organ functions outside of the body. In Chapter 3, we describe the tools that are critical for modeling individual organ functions (healthy human BM) and immune cells, as well as when combining multiple OoC systems together. In Chapter 4, we apply these tools for disease modeling, in studying the complex interactions in either acute leukemia development or metastatic colonization of the BM. In Chapter 5, we use our human-specific engineered models for studies of acute and systemic injury, including the effects of cosmic radiation on human tissue function. To tie together the tissue engineered tools developed in this thesis, we described in Chapter 6 the utility of scientific outreach and social media in the widespread dissemination of tissue engineering and stem cell principles to the broader scientific community and general public. Collectively, this dissertation provides a unique look at the use of engineered human tissue systems to model human blood and immune interactions using bioengineering tools, with applications in disease modeling of primary and metastatic cancers, as well as in acute and systemic injuries.

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