Browsing by Subject "Multiple Myeloma"

Now showing 1 - 7 of 7
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    Cognitive and Situational Precipitants of Loneliness Among Patients With Cancer: A Qualitative Analysis
    (Oncology Nursing Society, 2016-03) Adams, Rebecca N.; Mosher, Catherine E.; Abonour, Rafat; Robertson, Michael J.; Champion, Victoria L.; Kroenke, Kurt; Department of Psychology, School of Science
    PURPOSE/OBJECTIVES: To identify situations and thoughts that may precipitate or protect against loneliness experienced by patients with cancer. RESEARCH APPROACH: Qualitative. SETTING: The hematology/oncology clinic at the Indiana University Melvin and Bren Simon Cancer Center, an outpatient oncology center in Indianapolis. PARTICIPANTS: Purposive sample of 15 patients undergoing treatment for multiple myeloma or non-Hodgkin lymphoma. METHODOLOGIC APPROACH: Individual, semistructured qualitative interviews were conducted. Theoretical thematic analysis was used to analyze interview data. FINDINGS: Factors that appeared to precipitate loneliness included several situations (e.g., physical isolation, social constraints such as criticism) and thoughts (e.g., unmet expectations for visits or questions about health, belief that others do not understand their cancer experience). Several situations (e.g., social support, normal routine) and thoughts (e.g., beliefs that time alone is desirable and that others' discomfort with cancer-related discussions is normative) appeared to protect against loneliness. Certain social situations were loneliness-inducing for some patients and not for others, suggesting that patients' thoughts about their situations, rather than the situations themselves, have the greatest impact on their loneliness. CONCLUSIONS: The current study fills gaps in loneliness theory by identifying cancer-related situations and thoughts that patients associate with their loneliness. Consistent with theory, patients reported feeling lonely when they had negative thoughts about their social situations. INTERPRETATION: Findings inform nursing assessment and intervention strategies to incorporate into care plans. For instance, when conducting assessments, nurses should be more attentive to patients' satisfaction with their social environment than actual characteristics of the environment. Normalizing patients' experiences and encouraging positive thoughts about others' behavior may reduce patients' loneliness.
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    Excess TGF-β mediates muscle weakness associated with bone metastases in mice
    (SpringerNature, 2015-11) Waning, David L.; Mohammad, Khalid S.; Reiken, Steven; Xie, Wenjun; Andersson, Daniel C.; John, Sutha; Chiechi, Antonella; Wright, Laura E.; Umanskaya, Alisa; Niewolna, Maria; Trivedi, Trupti; Charkhzarrin, Sahba; Khatiwada, Pooja; Wronska, Anetta; Haynes, Ashley; Benassi, Maria Serena; Witzmann, Frank A.; Zhen, Gehua; Wang, Xiao; Cao, Xu; Roodman, G. David; Marks, Andrew R.; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.
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    FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells
    (Oncotarget, 2015-08-14) Suvannasankha, Attaya; Tompkins, Douglas R.; Edwards, Daniel F.; Petyaykina, Katarina V.; Crean, Colin D.; Fournier, Pierrick G.; Parker, Jamie M.; Sandusky, George E.; Ichikawa, Shoji; Imel, Erik A.; Chirgwin, John M.; Department of Medicine, IU School of Medicine
    Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone.
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    Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer
    (Springer Nature, 2021-12-02) Ghamlouch, Hussein; Boyle, Eileen M.; Blaney, Patrick; Wang, Yubao; Choi, Jinyoung; Williams, Louis; Bauer, Michael; Auclair, Daniel; Bruno, Benedetto; Walker, Brian A.; Davies, Faith E.; Morgan, Gareth J.; Medicine, School of Medicine
    Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.
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    International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease
    (American Society of Clinical Oncology, 2013-06-20) Terpos, Evangelos; Morgan, Gareth; Dimopoulos, Meletios A.; Drake, Matthew T.; Lentzsch, Suzanne; Raje, Noopur; Sezer, Orhan; Garcıa-Sanz, Ramon; Shimizu, Kazuyuki; Turesson, Ingemar; Reiman, Tony; Jurczyszyn, Artur; Merlini, Giampaolo; Spencer, Andrew; Leleu, Xavier; Cavo, Michele; Munshi, Nikhil; Rajkumar, S. Vincent; Durie, Brian G.M.; Roodman, G. David; Department of Medicine, IU School of Medicine
    PURPOSE: The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease. METHODOLOGY: An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. RECOMMENDATIONS: Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.
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    Multiple Myeloma and Bone: The Fatal Interaction
    (Cold Spring Harbor Laboratory Press, 2018-08-08) Marino, Silvia; Roodman, G. David; Medicine, School of Medicine
    Multiple myeloma (MM) is the second-most-common hematologic malignancy and the most frequent cancer to involve bone. MM bone disease (MMBD) has devastating consequences for patients, including dramatic bone loss, severe bone pain, and pathological fractures that markedly decrease the quality of life and impact survival of MM patients. MMBD results from excessive osteoclastic bone resorption and persistent suppressed osteoblastic bone formation, causing lytic lesions that do not heal, even when patients are in complete and prolonged remission. This review discusses the cellular and molecular mechanisms that regulate the uncoupling of bone remodeling in MM, the effects of MMBD on tumor growth, and potential therapeutic approaches that may prevent severe bone loss and repair damaged bone in MM patients.
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    Role of osteocytes in multiple myeloma bone disease
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-12) Delgado-Calle, Jesus; Bellido, Teresita; Roodman, G. David; Department of Medicine, IU School of Medicine
    PURPOSE OF REVIEW: Despite the increased knowledge of osteocyte biology, the contribution of this most abundant bone cell to the development and progression of multiple myeloma in bone is practically unexplored. RECENT FINDINGS: Multiple myeloma bone disease is characterized by exacerbated bone resorption and the presence of osteolytic lesions that do not heal because of a concomitant reduction in bone formation. Osteocytes produce molecules that regulate both bone formation and resorption. Recent findings suggest that the life span of osteocytes is compromised in multiple myeloma patients with bone lesions. In addition, multiple myeloma cells affect the transcriptional profile of osteocytes by upregulating the production of pro-osteoclastogenic cytokines, stimulating osteoclast formation and activity. Further, patients with active multiple myeloma have elevated circulating levels of sclerostin, a potent inhibitor of bone formation which is specifically expressed by osteocytes in bone. SUMMARY: Understanding the contribution of osteocytes to the mechanisms underlying the skeletal consequences of multiple myeloma bone disease has the potential to provide important new therapeutic strategies that specifically target multiple myeloma-osteocyte interactions.