Diffuse Bone Disease Research Articles

Diffuse Bone Disease as Primary Clinical Manifestation in Patients With Adult T-Cell Leukemia/Lymphoma

Diffuse Bone Disease as Primary Clinical Manifestation in Patients With Adult T-Cell Leukemia/Lymphoma

TCL-759 Diffuse Bone Disease as Primary Clinical Manifestation in Patients With Adult T-cell Leukemia/Lymphoma

TCL-759 Diffuse Bone Disease as Primary Clinical Manifestation in Patients With Adult T-cell Leukemia/Lymphoma

Diffuse Bone Disease as Primary Clinical Manifestation in Hispanic Patients with Adult T-cell Leukemia/Lymphoma

Diffuse Bone Disease as Primary Clinical Manifestation in Hispanic Patients with Adult T-cell Leukemia/Lymphoma

Relative fat fraction of malignant bone lesions from breast cancer, prostate cancer and myeloma are significantly lower than normal bone marrow and shows excellent interobserver agreement.

To compare relative fat fraction (rFF) of active bone lesions from breast, prostate and myeloma malignancies and normal bone marrow; to assess its inter-reader agreement. Patients with breast (n = 26), myeloma (n = 32) and prostate cancer (n = 52) were retrospectively evaluated. 110 baseline rFF maps from whole-body MRI were reviewed by two radiologists. Regions of interest for up to four focal active lesions in each patient were drawn on rFF maps, one each at the cervicothoracic spine, lumbosacral spine, pelvis and extremity. The mean and standard deviation of rFF were recorded. The rFF of normal marrow was measured in the pelvis for patients without diffuse bone disease (n = 88). We compared the rFF of malignant bone lesions and normal marrow using Mann-Whitney test. Interobserver agreement was assessed by interclass correlation coefficient. Malignant bone lesions showed significantly lower median rFF (13.87%) compared with normal marrow (89.76%) with little overlap (p < 0.0001). There was no significant difference in the median rFF of malignant lesions from breast (14.46%), myeloma (13.12%) and prostate cancer (13.67%) (p > 0.017, Bonferroni correction) and in the median rFF of bone disease according to their anatomical locations (p > 0.008, Bonferroni correction). There was excellent interobserver agreement (0.95). The low rFF of active bone lesions in breast, prostate and myeloma malignancies provides high image contrast relative to normal marrow that may be used to detect bone metastases. This study shows the importance of rFF towards detecting bone metastases.

Management of Frail Older Adults with Newly Diagnosed Multiple Myeloma — Moving Toward a Personalized Approach

Case vignetteA 75-year-old male undergoes an evaluation for progressively worsening fatigue with associated shortness of breath. He also reports back pain worse at night, which does not resolve with acetaminophen. He is retired, but over the past 2 months he is unable to garden or perform household chores. Due to his pain and fatigue, he has limited his activity. He currently takes 9 prescription medications for chronic medical conditions, which include diabetes mellitus with neuropathy, hypertension, hyperlipidemia, and COPD. Initial evaluation reveals anemia (Hgb 9.0 g/dl last known normal was 2 years ago, Hgb 13.5 g/dl), renal impairment (serum creatinine 2.5 mg/dL), hypercalcemia (11.5 g/dl). Plain X-rays reveal compression fractures involving T3 and T4. Multiple myeloma is suspected, further labs confirm the diagnosis of IgG kappa multiple myeloma. LDH is elevated, beta-2-microglobulin is elevated at 6.1 mg/L and albumin < 3.5 mg/dl. Bone marrow aspiration and biopsy reveal plasmacytosis of 55% and on fluorescence in situ hybridization testing, del 17p/TP53 mutation in 85% of cells is detected. PET/CT confirms diffuse bone disease involving the axial and appendicular skeleton. His Karnofsky performance status (KPS) is 70%. He is widowed and lives alone but has 2 adult children who currently live out of state.This abstract will discuss how assessments of fitness/frailty may be used to develop personalized care tailored to the unique needs of older frail adults with multiple myeloma.

Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease

Management of osteonecrosis of the jaw associated with antiresorptive agents is challenging, and outcomes are unpredictable. The severity of disease is the main guide to management, and can help to predict prognosis. Most available staging systems for osteonecrosis, including the widely-used American Association of Oral and Maxillofacial Surgeons (AAOMS) system, classify severity on the basis of clinical and radiographic findings. However, clinical inspection and radiography are limited in their ability to identify the extent of necrotic bone disease compared with computed tomography (CT). We have organised a large multicentre retrospective study (known as MISSION) to investigate the agreement between the AAOMS staging system and the extent of osteonecrosis of the jaw (focal compared with diffuse involvement of bone) as detected on CT. We studied 799 patients with detailed clinical phenotyping who had CT images taken. Features of diffuse bone disease were identified on CT within all AAOMS stages (20%, 8%, 48%, and 24% of patients in stages 0, 1, 2, and 3, respectively). Of the patients classified as stage 0, 110/192 (57%) had diffuse disease on CT, and about 1 in 3 with CT evidence of diffuse bone disease was misclassified by the AAOMS system as having stages 0 and 1 osteonecrosis. In addition, more than a third of patients with AAOMS stage 2 (142/405, 35%) had focal bone disease on CT. We conclude that the AAOMS staging system does not correctly identify the extent of bony disease in patients with osteonecrosis of the jaw.

The Murine Vk*MYC Myeloma Shares Defining Genetic Lesions with Human Multiple Myeloma.

Abstract 1808Poster Board I-834We have developed the first mouse model of multiple myeloma (MM), Vk*MYC, in an immune competent mouse, with indolent plasma cell (PC) growth confined to the bone marrow, and in which the major biological and clinical features of the human disease are recapitulated, including the post germinal center origin of the tumor cells, the presence of a M-spike in the serum, anemia, diffuse bone disease and drug sensitivity.To further characterize karyotypically and phenotypically the Vk*MYC tumors, we performed gene expression profile (GEP) and aCGH analysis on CD138+ purified MM cells from Vk*MYC mice. For GEP, we analyzed 33 individual tumors on the Affymetrix 430_2 array for which publicly available datasets can be used to compare levels of gene expression. For aCGH, we used the Agilent 244K array to analyze 19 individual tumors.By GEP we first confirmed the PC origin of the Vk*MYC tumors, that clearly express the typical PC markers, including CD138, IRF4, BLIMP, XBP1, IgG or IgA, but not B cell markers like IgM, IgD, PAX5, or BCL6. Next, we analyzed the expression of the three cyclin D, that are almost universally dysregulated in human myeloma patients and cell lines, but are not expressed in normal human or murine PCs. We found that the Vk*MYC tumors express high levels of cyclin D2, and occasionally cyclin D1, but never cyclin D3 that, instead, is commonly expressed in B cells. Interestingly, in one sample lacking any D type cyclin expression we detected loss of Rb expression (and homozygous deletion of the gene, see below), as in the “TC none” group of human MM patients, highlighting once again the importance of this pathway in both human and mouse myeloma.aGCH analysis indicated that the genomic complexity of Vk*MYC tumors is low, and complex rearrangements were rarely observed. In contrast with the recurrent trisomy of odd number chromosomes present in approximately 50% of human MM patients, we found no evidences of hyperdiploidy in Vk*MYC mice, except perhaps in one tumor with trisomy 15 and 17. Instead, we detected monosomy 5 in 10/19, monosomy 14 in 4/19 and trisomy 16 in 4/19 tumors. Interestingly a large portion of the murine chr.14 is syntenic to the human chr.13, frequently lost in MM patients. After monosomy 13, the most frequent chromosomal change in human MM is loss of a sex chromosome. In the mouse, the most common numerical abnormality identified was loss of a sex chromosome: 10/11 male had loss of Y and 5/8 female had loss of X.From the analysis of aCGH data publicly available on the MMRC portal, we have generated a list of the most common bi-allelic deletions present in human myeloma patients and cell lines. Interestingly, several of these lesions are also present in Vk*MYC tumors. The Rb1 gene, frequently affected by monosomy 13 in human MM, is bi-allelically lost in 3/19 Vk*MYC tumors. In one case, we also detected a focal monoallelic deletion encompassing Rb1, in addition to the four tumors with monosomy 14. Other focal bi-allelic deletion identified are: Cdkn2a (p16 and p19ARF), FHIT and PTEN. The latter was found in a Vk*MYC tumor selected in-vivo to be bortezomib resistant. On chr.X we identified recurrent (5/19 tumors) bi-allelic deletions of UTX, the histone demethylase gene recently reported to be deleted in various cancers, including MM tumors and human myeloma cell lines. While we are in the process of performing functional studies in human cell lines to identify a role for UTX in myeloma pathogenesis, we took advantage of the relative genetic uniformity of the Vk*MYC mice to identify by GEP a signature associated with UTX lost. We separated our cohort of Vk*MYC tumors for which GEP data are available in two groups based on expression of UTX and generated by volcano plot a list of genes that distinguished the two groups. Strikingly, loss of UTX was associated with loss of expression of a subset of lymphoid genes and acquisition of a “macrophage signature”, suggesting a role for UTX in lineage commitment. These data provide a genetic basis for tumor plasticity similar to epithelial mesenchymal transition observed in some solid tumors, in which the tumor gradually acquires supporting characteristics of its microenvironment.We conclude that the Vk*MYC provide a remarkably faithful model of MM not only phenotypically but also genetically, that provides an excellent framework for functional characterization of the molecular pathogenesis of MM DisclosuresBergsagel:Genentech: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding.

B608 Syndecan-1 Mediates HGF/c-Met Endocytosis and Signaling in Myeloma Cells

We have generated the first immuno-competent transgenic mouse model of multiple myeloma (MM), Vk*MYC, in which sporadic MYC activation in the germinal center is mediated by the same physiological process involved in the generation of immunoglobulin chromosome translocations. All of Vk*MYC mice develop monoclonal plasma cell (PC) expansion by 50 weeks of age, manifested by major M-spikes by SPEP. The PCs in Vk*MYC mice are fully differentiated, somatically mutated, have a low proliferation index and are found exclusively in the BM. Associated with a long lifespan, Vk*MYC mice develop anemia and diffuse bone disease, with sporadic occurrence of lytic bone lesions and hind limb paralysis. Furthermore, Vk*MYC mice MM displays therapeutic fidelity, as they show response to known clinically active anti-myeloma drugs, but not to drugs with no clinical activity as single agents. We have performed aCGH (Agilent 244K), using DNA from eight Vk*MYC CD138 selected MM cells. We found that the genomic complexity of Vk*MYC tumors is low, with only few all chromosome gains or losses, the only recurrent one being loss of chromosome Y in 3 out of 4 males. The most common abnormalities found are focal monoallelic deletions or amplification, targeting genes previously identified in MM. Among those, we found mono and bi-allelic deletion of Rb, amplification of BAFF-R and biallelic deletion of FHIT. We also detected a small region of amplification of mouse chromosome 3, syntenic to the larger region on human chromosome 1 frequently amplified in human MM and containing the Mcl1 gene, previously shown to be a crucial survival factor for MM cells. A focal homozygous deletion of several exons of a gene was identified in two tumors samples. Remarkably, a comparative analysis of the syntenic chromosomal region in human MM identified similar recurrent homozygous deletions in this putative novel tumor suppressor gene. Overall, these data indicate that the genomic complexity in this inbred strain of transgenic mice is significantly less then in patients with MM, simplifying the search for critical loci involved in MM tumorigenesis and further validate the Vk*MYC mice as a particularly faithful model of human MM.”

A Comparative Oncogenomic Analysis Identifies Genetic Events Associated with Myeloma Progression and Drug Resistance

We have successfully generated the first immuno-competent transgenic mouse model of multiple myeloma (MM), Vk*MYC, in which sporadic MYC activation in the germinal center is AID dependent and mediated by the somatic hypermutation process. All of Vk*MYC mice develop monoclonal PC expansion by 50 weeks of age, that is manifested by high levels of serum IgGs and major M-spikes by SPEP. The PCs in Vk*MYC mice are fully differentiated, somatically mutated, have a very low proliferation index and are found exclusively in the BM. Associated with the long lifespan (medium survival = 661d), Vk*MYC mice develop anemia and diffuse bone disease (osteoporosis with low bone mineral density), with sporadic occurrence of lytic bone lesions and hind limb paralysis. The phenotypic fidelity of the Vk*MYC mice translates in a therapeutic fidelity, as Vk*MYC mice show response to known clinically active anti-myeloma drugs (bortezomib, melphalane, dexamethasone), but not to drugs that have shown no clinical activity as single agents (vincristine, hydroxyurea, fludarabine). Furthermore, acquired bortezomib resistance could efficiently be induced in Vk*MYC mice after only four cycles of suboptimal treatment, and studies are in progress to identify genetic events associated with bortezomib resistance. Preliminary aCGH experiments on a high resolution Agilent 244K array, using genomic DNA from six Vk*MYC CD138+ selected PCs, showed that the genomic complexity of Vk*MYC tumors is quite low, with only few unbalanced rearrangements, such as trisomy of chromosome 15 detected in two samples or trisomy 9 present in another tumor. The most common abnormalities found are small focal monoallelic deletions, six of which are present in more than one tumor. A focal homozygous deletion of several exons of a gene was identified in two tumors samples. Remarkably, a comparative analysis of the syntenic chromosomal region in human MM cell lines and primary patient samples identified similar recurrent homozygous deletion in this putative novel tumor suppressor gene. Overall, these data suggest that the genomic complexity in this inbred strain of transgenic mice is significantly less then in patients with MM, simplifying the search for critical loci involved in MM tumorigenesis and drug resistance and further validate the Vk*MYC mice as a particularly faithful model of human MM.

Musculoskeletal Manifestations of Osteomalacia

Osteomalacia (OM) is a condition that usually is overlooked and neglected when compared with other metabolic bone disease such as osteoporosis. Presenting with a wide spectrum of nonspecific clinical, radiographic, and biochemical manifestations, OM is a treatable metabolic disease that is precisely diagnosed by anterior iliac crest bone biopsy. Clinical clues to lead one to suspect OM in the context of a diffuse bone disease include the presence of generalized bone pain affecting mainly shoulders, hips and rib cage, proximal muscle weakness, low serum calcium x phosphorus product, increased serum alkaline phosphatase, low calcium in the 24-h urine test, and low serum 25 hydroxyvitamin D. Radiographic examination may show a characteristic "erased" or "fuzzy" type of demineralization, pseudofractures, or bone deformities. OM is confined usually to elderly individuals or to those patients with intestinal malabsorption and hypophosphatemia.

Psoriatic osteoarthropathy and bone scintigraphy

Psoriasis is a generalized disease that affects bone as well as skin. Three patterns of bone involvement can be differentiated in psoriatic arthritis distal, central, and distal combined with central. Distal involvement is more specific for psoriatic arthritis, with radial and/or transverse involvement of the distal interphalangeal joints. The progression dynamic and the pattern of distribution are different from those pattern of rheumatoid arthritis: psoriatic arthritis originates in the periarticular bone and extends towards the synovia, whereas in rheumatoid arthritis it extends in the opposite direction. In psoriatic arthritis anterior chest wall syndrome, insertion tendinopathies, and localized or diffuse bone disease are often observed. Bone scintigraphy is more sensitive in the diagnosis of psoriatic bone involvement than clinical examination or conventional radiological imaging, allowing earlier diagnosis through the visualization and documentation of specific patterns and presence of disease in multiple sites. It also allows more discriminating selection of subsequent X-ray examinations to limit radiation exposure. Thus, bone scintigraphy is now the most important diagnostic tool in the assessment of psoriatic arthritis.

Case report primary bone oxalosis: The roles of oxalate deposits and renal osteodystrophy

Primary oxalosis is a rare congenital disorder. The excessive oxalate biosynthesis induces deposits in many organs, particularly in kidney and bone. The late onset of primary oxalosis is reported in a 50-year-old man. His chronic renal failure was treated by maintenance hemodialysis for 3 years. He then developed a diffuse bone disease with osteosclerosis and roentgenographic features of hyperparathyroidism. A parathyroidectomy was performed, with debatable improvement of bone lesions. Laboratory results and histologic and histomorphometric studies before and after parathyroidectomy suggest a double histopathogenetic mechanism for this bone disease: renal osteodystrophy and massive bone oxalate deposits. Such deposits may induce both a heterogeneous osteosclerosis with dense metaphyseal bands and histologic bone lesions similar to those of hyperparathyroidism. The crystalline deposits induce in the bone tissue a granulomatous macrophagic reaction. These macrophages are unable to phagocytize the crystals and may be involved in active bone resorption. Bone lesions of oxalosis occur in patients with chronic renal failure, and hyperparathyroidism has a worsening role.

Pathologic Flail Chest Complicating Multiple Myeloma

Pathologic flail chest complicated the initial presentation of multiple myeloma in two patients. Both had severe hypercalcemia and diffuse bone disease. Atelectasis and pulmonary edema preceded the appearance of flail chest in one patient; atelectasis complicated the flail chest in the second patient and increased the severity of the flail. Both were treated with radiotherapy and chemotherapy. However, delay in stabilizing the first patient's chest wall with positive airway pressure was followed by extension of the flail chest and irreversible respiratory failure. On the other hand, prolonged stabilization of the chest wall in the second patient until a chemotherapy-induced remission occurred was associated with resolution of the flail chest.