Suppression of Mesenchymal Stromal Cell (MSC) Differentiation in Multiple Myeloma (MM) Is Restricted to the Osteoblast Lineage

Abstract Lytic bone lesions in patients with MM rarely heal even when patients are in complete remission for long periods of time. The mechanism behind this prolonged suppression of osteoblast activity is yet to be elucidated, and when or whether the osteoblast suppression can be reversed is unknown. Several possibilities could explain osteoblast suppression in MM: quantitative MSCs depletion induced by MM cells; a permanent block in MSC differentiation to the osteoblast lineage; and/or an inability of MSCs to differentiate in a hostile microenvironment. To distinguish among these possibilities, we developed a murine model of MM bone disease that permits us to assess the time course for development of osteoblast inhibition of MSC differentiation of osteoblasts, if this inhibition is reversible anytime during the process, and if the differentiation is restricted to permanent blockade of osteoblast differentiation. We generated a murine MM cell line genetically modified to contain the TK gene, which allows ablation of the cells by ganciclovir while sparing hematopoietic and stromal cell progenitors. MM cells also contained GFP for tumor estimation and a blasticidin resistance cassette for selection of transfected cells. Hematopoietic precursors and MSCs were cocultured with the MM cells in media containing ganciclovir to assess for toxic effects of this drug on cell differentiation (bystander effect). Murine MM cells or saline was also injected into the right tibia of SCID mice on day 0 and tumor lesions were documented by weekly imaging of right tibias by micro-QCT and by measurement of IgG2b in serum. Mice were treated with intraperitoneal ganciclovir or saline for 14 days starting at different time points (group 1 = 1d; group 2 = 8d; or group 3 = 14d) after tumor injection, and were sacrificed at week 5. MSCs were recovered from right tibias, cultured in osteogenic media, and alkaline phosphatase levels determined after 10 days of culture to assess osteoblast activity. MSCs were also cultured in adipogenic media, and the presence of mature adipocytes was visualized by Oil Red O staining. There was no toxic effect of ganciclovir on hematopoietic colony formation or osteoblast differentiation. Lytic bone lesions were documented in mice injected with MM cells by micro-QCT at 4 weeks in groups 2 and 3 and progressed thereafter, but not in group 1 after intratibial injection of MM cells. MSCs from group 1 mice showed greater osteoblast activity when sacrificed at 5 weeks compared to other groups. Mice in group 1 surviving 5 weeks eventually developed MM bone disease and succumbed to it at a much later time than the other groups (p<.01). Significant elevations of serum IgG2b levels were detectable at week 4 in mice from groups 2 and 3 and correlated with the development of bone lytic lesions. Harvesting cells from tumor bearing tibias yielded similar numbers of MSCs in all groups. Comparable levels of adipocytic differentiation by Oil Red O staining were observed among MSC from all groups of mice. These results demonstrate that MSC depletion cannot explain the absent osteoblast activity in this model of MM. MSC differentiation appears to be selectively blocked from the osteoblast lineage. Suppression of osteoblast activity required >24hr exposure to MM cells in vivo and correlated with relative tumor burden. Studies are underway to determine if osteoblast suppression is permanent or can be reversed in this model. This model of MM bone disease should permit the further elucidation of the mechanisms responsible for osteoblast suppression in MM, and testing of anabolic agents in a model that does not require treatment of mice with agents to eradicate MM cells and that are toxic to the marrow microenvironment.

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Targeting the BMP Pathway in Prostate Cancer Induced Bone Disease

Frontiers in Endocrinology ◽

10.3389/fendo.2021.769316 ◽

2021 ◽

Vol 12 ◽

Author(s):

Desiree M. Straign ◽

Claire L. Ihle ◽

Meredith D. Provera ◽

Philip Owens

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Bone Metastases ◽

Bone Disease ◽

Bone Health ◽

Metastatic Prostate Cancer ◽

Bone Lesions ◽

Prostate Cell ◽

Prostate Cell Line ◽

Lytic Bone Lesions

From the 33,000 men in the U.S. who die from prostate cancer each year, the majority of these patients exhibit metastatic disease with bone being the most common site of metastasis. Prostate cancer bone metastases are commonly blastic, exhibiting new growth of unhealthy sclerotic bone, which can cause painful skeletal related events. Patient’s current care entails androgen deprivation therapy, anti-resorptive agents, radiation, and chemotherapy to help control the spread of the cancer but little intervention is available to treat blastic bone disease. The transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) pathways are known to regulate bone growth and resorption of destructive lytic bone lesions, yet the role of TGFβ/BMP signaling in prostate cancer blastic vs lytic bone lesions are not fully understood. We hypothesized that to target the BMP/TGFβ pathway, a useful biomarker of bone lytic or blastic pathology would have superior response. We show distinct BMP vs. TGFβ signaling in clinical samples of human prostate cancer bone metastases with either lytic or blastic pathologies. BMPs exhibit distinct effects on bone homeostasis, so to examine the effect of BMP inhibition on healthy bone, we treated mice with the BMP receptor small molecule antagonist DMH1 and saw a modest temporary improvement in bone health, with increased trabecular bone. We next sought to use the BMP inhibitor DMH1 to treat bone metastasis engraftment seeded by a caudal artery injection of the lytic human prostate cell line PC3 in immunodeficient mice. The colonization by PC3 cells to the bone were restricted with DMH1 treatment and bone health was importantly preserved. We next proceeded to test BMP inhibition in an injury model of established bone metastasis via intratibial injection of the MYC-CaP mouse prostate cell line into FVBN syngeneic mice. DMH1 treated mice had a modest decrease in trabecular bone and reduced lymphocytes in circulation without affecting tumor growth. Taken together we show unique responses to BMP inhibition in metastatic prostate cancer in the bone. These studies suggest that profiling bone lesions in metastatic prostate cancer can help identify therapeutic targets that not only treat the metastatic tumor but also address the need to better treat the distinct tumor induced bone disease.

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The Src Inhibitor AZD0530 Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.3018.3018 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3018-3018

Author(s):

Roy Heusschen ◽

Joséphine Muller ◽

Marilène Binsfeld ◽

Erwan Plougonven ◽

Nadia Mahli ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Osteoblast Differentiation ◽

Osteoclast Differentiation ◽

Disease Stage ◽

Bone Lesions ◽

Mrna Levels ◽

Osteoblast Function ◽

Src Inhibitor ◽

Osteolytic Bone Disease

Abstract Destructive bone lesions due to osteolytic bone disease are a major cause of morbidity and mortality in multiple myeloma patients, occurring in more than 80% of cases. Underlying osteolytic bone disease is an uncoupling of the bone remodeling process, with an increased activity of osteoclasts and a decreased activity of osteoblasts. Current strategies to treat osteolytic bone disease focus on anti-resorptive agents, which do not rebuild bone loss. Src kinase has been implicated in both osteoclast and osteoblast function. In this study, we assessed the effect of Src inhibition with AZD0530 (saracatinib, Astra Zeneca) on the development of multiple myeloma and its associated osteolytic bone disease. We first determined Src family kinase expression in the multiple myeloma microenvironment and found that patient-derived myeloma cells express Src at low levels but disease stage does not correlate with Src expression levels. In accordance with the literature, Src mRNA expression was found to increase during osteoclast differentiation and decrease during osteoblast differentiation in publicly available microarray datasets. Next, we validated an inhibitory role of AZD0530 on osteoclast differentiation and function. At a pharmacological relevant concentration of 1 micromolar, AZD0530 inhibited the differentiation of RAW264.7 osteoclasts (Oc.N/FOV: 15.5+-1.6 treated vs. 53+-1.5 non-treated). AZD0530 treatment appeared to hamper efficient progenitor cell fusion and osteoclast polarization, reflected by a decrease of CTSK and DC-STAMP mRNA levels and a defective actin ring formation in treated cultures, which culminated in a complete inhibition of bone resorption. When assessing the effect of AZD0530 on osteoblast function we found that AZD0530 inhibits osteoblast differentiation, with a decreased expression of OSX and OCN, and alters osteoblast morphology. In vivo, AZD0530 did not alter myeloma cell bone marrow infiltration in both the 5TGM.1 (37+-6.3% AZD0530 treated vs. 25.2+-6.7% non-treated) and 5T2MM (26.1+-7.7% vs. 29.1+-6.4%) murine multiple myeloma models. However, bone health was significantly improved in both models following treatment with AZD0530. In the 5TGM.1 model multiple trabecular bone parameters were restored to levels observed in healthy control mice following AZD0530 treatment, including BV/TV (11.7+-0.3% treated vs. 6.4+-0.3% non-treated), Tb.N. (2.5+-6x10^-2/mm vs. 1.7+-9x10^-2/mm) and Tb.Th (46.2+-1micron vs. 37+-0.8micron). These results were confirmed in the 5T2MM model, which displays a more severe osteolytic bone disease. In addition, AZD0530 treatment resulted in an increase in cortical thickness (157.8+-0.8micron treated vs. 151.4+-0.7micron non-treated) and a decrease in the number and size of cortical lesions in 5TGM.1 mice. Finally, our findings were corroborated by histomorphometric analyses. In conclusion, we report a potent inhibitory effect of the Src inhibitor AZD0530 on the development of osteolytic bone disease in multiple myeloma. Our results indicate that AZD0530 exerts this effect via the modulation of both osteoclast and osteoblast function. These findings warrant further study of the feasibility and efficacy of AZD0530 to treat osteolytic bone disease in multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

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Electrochemotherapy and Simultaneous Photodynamic Bone Stabilization of Upper Limbs in Metastatic Renal Cancer Disease: Case Report and Literature Review

Case Reports in Medicine ◽

10.1155/2020/8408943 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Ugo Albertini ◽

Andrea Conti ◽

Nicola Ratto ◽

Pietro Pellegrino ◽

Michele Boffano ◽

...

Keyword(s):

Quality Of Life ◽

Minimally Invasive ◽

Bone Disease ◽

Metastatic Bone Disease ◽

Invasive Technique ◽

Bone Lesions ◽

Disease Case ◽

Lytic Bone Lesions

Introduction. Metastatic bone disease represents a systemic pathology that heavily affects the quality of life of oncologic patients causing pain and functional disability. Methodology. We present the case of a patient with a history of renal cell cancer presenting pathologic fractures of both humeri and proximal right radius. Results. After a careful multidisciplinary approach, an adjuvant anticancer therapy and a photodynamic bone stabilization procedure were performed with a minimally invasive technique aiming to minimize pain and local disease progression, while restoring functional autonomy and improving the patient’s quality of life. Electrochemotherapy was delivered on the lytic bone lesions with extraskeletal involvement of the proximal left humerus and the proximal right radius, and then polymeric bone stabilization was performed on both humeri. At two months of follow-up, the patient presented satisfactory functional scores (MSTS score: 12/30 bilaterally; DASH scores: 46.7/100 for the right side and 48.3/100 for the left one), and pain was well controlled with opioid analgesics. Radiographs showed good results in terms of ossification of lytic bone lesions and durability of polymeric stabilization. At four months of follow-up, the patient reported a stable clinical scenario. Six months after surgery, due to extremely poor prognosis after the progression of primary disease, the patient was referred to palliative care and died shortly thereafter. Conclusion. Over the last decade, the management of metastatic bone disease has changed. Low-toxicity and minimally invasive procedures such as electrochemotherapy and polymeric bone stabilization might be performed concomitantly in selected patients, as an alternative to radiation therapy and to more demanding surgical procedures such as plating and adjuvant cementing.

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Surface Chemistry Proteomics and Biomarker Discovery in Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.2493.2493 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2493-2493

Author(s):

Bangzheng J. Chen ◽

Huixiao Hong ◽

Weigong Ge ◽

Weida Tong ◽

Ronald Walker ◽

...

Keyword(s):

Bone Disease ◽

Response To Therapy ◽

Bone Lesions ◽

Protein Patterns ◽

Serum Samples ◽

Lytic Lesions ◽

Protein Chips ◽

Lytic Bone Lesions ◽

Surface Chemistries ◽

Tof Ms

Abstract Introduction: To further evaluate the utility of surface-enhanced laser desorption and ionization-time of flight mass spectroscopy (SELDI-TOF MS) proteomics in the diagnosis, prognosis, monitoring response to therapy, and follow up of patient with myeloma, we examined the ability of protein chips with 4 different surface chemistries to detect biomarkers of lytic bone disease. Method: Sera from 47 untreated myeloma patients were collected and stored at −80°C for future analysis. 22 serum samples were from patients with 1–26 lytic bone lesions as identified on X-ray skeletal surveys and 25 serum samples were from patients without lytic lesions. The sera were analyzed by SELDI-TOF MS using Ciphergen’s ProteinChip Biology System II (PBS II), to identify protein patterns associated with lytic bone disease. Each sample was applied in 2 replicates to randomly assigned spots on protein chips with different surface chemistries: immobilized metal affinity capture (IMAC30) activated with Cu++, weak cathion exchange (CM10), reverse phase (H50), and strong anaion exchange (Q10), all under conditions of low stringency, using a Biomek2000 robot. The mass spectra of proteins, generated using an average of 66 laser shots, were calibrated using peptide standards and normalized to total ion current using CiphergenExpress 3.0 software. We randomly selected 80% of patients for developing classification models that separate patients with lytic bone lesions from those without lesions, using a stepwise logistic regression method; 76 calibrated and normalized spectra from randomly selected patients, 18 with lytic bone lesions and 20 without lytic lesions were used for model development. The other 18 spectra from 4 patients with lytic lesions and 5 without lesions were used as a test dataset. The same datasets were used for all 4 chip types. Protein peaks that were significantly different between the two groups were used for modeling. Results: All 4 chip types yielded models with fit accuracies of 71%–92%. The spectra produced by each chip were different, reflecting the differences in surface chemistries, and each model used different protein peaks from each of the chip types; the IMAC30-based model used 11 protein peaks ranging in size from 2903 to 8226 kilodaltons (KDa); H50 model used 7 peaks, 2802–18837 KDa in size; CM10 model used 5 peaks, 2805–23307 KDa; and Q10 used 3 peaks, 6975–37210 KDa. Prediction accuracy was 89% for CM10, 78% for IMAC30, 76% for Q10 and only 33% for H50. CM10 and IMAC30 based models correctly assigned all patients with no lytic bone lesions. Wrongly assigned patients were different for the two chip types. Conclusions: Since each model wrongly assigned different patients and used different protein peaks, it is likely that a model that combines information from several surface types (consensus approach) will prove to provide the most accurate predictions, as needed for making clinical decision.

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Syndecan-1 Facilitates the Human Mesenchymal Stem Cell Osteo-Adipogenic Balance

International Journal of Molecular Sciences ◽

10.3390/ijms21113884 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3884

Author(s):

Chieh Yu ◽

Ian W. Peall ◽

Son H. Pham ◽

Rachel K. Okolicsanyi ◽

Lyn R. Griffiths ◽

...

Keyword(s):

Human Mesenchymal Stem Cell ◽

Protein Marker ◽

Lineage Differentiation ◽

Stems Cells ◽

Membrane Bound ◽

Adipogenic Gene ◽

Lineage Markers ◽

Oil Red O Staining ◽

Osteoblast Lineage ◽

Oil Red O

Bone marrow-derived human mesenchymal stems cells (hMSCs) are precursors to adipocyte and osteoblast lineage cells. Dysregulation of the osteo-adipogenic balance has been implicated in pathological conditions involving bone loss. Heparan sulfate proteoglycans (HSPGs) such as cell membrane-bound syndecans (SDCs) and glypicans (GPCs) mediate hMSC lineage differentiation and with syndecan-1 (SDC-1) reported in both adipogenesis and osteogenesis, these macromolecules are potential regulators of the osteo-adipogenic balance. Here, we disrupted the HSPG profile in primary hMSC cultures via temporal knockdown (KD) of SDC-1 using RNA interference (RNAi) in undifferentiated, osteogenic and adipogenic differentiated hMSCs. SDC-1 KD cultures were examined for osteogenic and adipogenic lineage markers along with changes in HSPG profile and common signalling pathways implicated in hMSC lineage fate. Undifferentiated hMSC SDC-1 KD cultures exhibited a pro-adipogenic phenotype with subsequent osteogenic differentiation demonstrating enhanced maturation of osteoblasts. In cultures where SDC-1 KD was performed following initiation of differentiation, increased adipogenic gene and protein marker expression along with increased Oil Red O staining identified enhanced adipogenesis, with impaired osteogenesis also observed in these cultures. These findings implicate SDC-1 as a facilitator of the hMSC osteo-adipogenic balance during early induction of lineage differentiation.

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Role of 18f-FDG PET/CT in the Management of Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.3492.3492 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3492-3492

Author(s):

Elena Zamagni ◽

Cristina Nanni ◽

Patrizia Tosi ◽

Stefano Fanti ◽

Delia Cangini ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Fdg Pet ◽

Bone Lesions ◽

Pet Ct ◽

Lytic Bone Lesions ◽

18F Fdg ◽

Fdg Pet Ct ◽

Ct And Mri

Abstract Multiple myeloma (MM) is a malignant plasma cell disorder which involves the skeleton in more than 80% of patients at diagnosis. For almost four decades bone lesions have traditionally been detected by Whole Body X-Ray (WBXR) survey. Over the last years, newer methods of evaluation have been increasingly used for the detection of MM bone disease, including magnetic resonance imaging (MRI) of the spine. In comparison with WBXR, MRI has proven to be more sensitive, although its partial field of view (FOV) is a main limitation in clinical practice. 18F-FDG PET/CT is a non invasive and total body imaging method that may be usefully employed to explore bones and soft tissues in MM, to assess the degree and extent of active MM bone disease, as well as to evaluate response to therapy by distinguishing between active and inactive bone lesions. Aim of the present study was to compare WBXR survey, MRI and 18F-FDG PET/CT scanning in a series of 28 consecutive patients with newly diagnosed MM. Moreover, we compared post-treatment evaluation with MRI and 18F-FDG PET/CT with clinical response in 14/28 patients who received double autologous transplantation as up-front therapy for MM. All patients underwent WBXR, MRI and 18F-FDG PET/CT at baseline and 3 months after the second transplantation. Findings of 18 F-FDG PET/CT were compared to those of WBXR and MRI with respect to number and site of detected bone lesions. Results of comparison of 18 F-FDG PET/CT with WBXR at diagnosis were as follows: in 16/28 pts (57%) 18 F-FDG PET/CT detected more lesions, all of whom were located in the skeleton; notably, 9 of these 16 patients had a completely negative WBXR survey. In 12/28 pts (43%) both methods were superimposable. Results of comparison of 18 F-FDG PET/CT with MRI at diagnosis were as follows: in 7/28 pts (25%), 18 F-FDG PET/CT detected more lytic bone lesions which were all located out of the FOV of MRI (6 bone lesions, 1 soft tissue lesion); in 13/28 pts (46%) 18 F-FDG PET/CT and MRI detected the same number of lesions in the spine and pelvis; in 8/28 pts (29%) MRI detected an infiltrative pattern of the spine, without evidence of lytic lesions, whereas 18 F-FDG PET/CT was negative. Results of comparison of post-transplantation 18 F-FDG PET/CT and MRI with clinical response were as follows: 5 out of 12 patients with negative 18 F-FDG PET/CT were in clinical CR and the remaining 7 patients were in 3 PR. Only 7 out of 12 patients with negative 18 F-FDG PET/CT had normal MRI. In summary, in 57% of patients at diagnosis 18 F-FDG PET/CT was more sensitive than WBXR for the detection of lytic bone lesions. MRI of the spine was superior over 18 F-FDG PET/CT in 29% of patients, particularly with a diffuse bone marrow replacement. Based on these data, it can be concluded that careful evaluation of MM bone disease at diagnosis should include both MRI of the spine and 18 F- FDG PET/CT. More data are needed to understand the role of 18 F-FDG PET/CT in assessing response to treatment.

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Serum High Expression of Micorna-214 Is a Novel Predictor for Myeloma Bone Disease and Poor Prognosis

Blood ◽

10.1182/blood.v126.23.4186.4186 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4186-4186

Author(s):

Mu Hao ◽

Meirong Zang ◽

Yan Xu ◽

Yu Qin ◽

Lei Zhao ◽

...

Keyword(s):

Bone Disease ◽

Operating Characteristic ◽

Area Under The Curve ◽

Serum Levels ◽

Bone Lesions ◽

Myeloma Bone Disease ◽

Serum Mirna ◽

Normal Bone ◽

Healthy Donors ◽

Lytic Bone Lesions

Abstract Background: Multiple myeloma (MM) originates from clonal expansion of malignant plasma cells in bone marrow, leading to multiple destructive lytic bone lesions that occur in more than 80% of MM patients. MicroRNAs (miRNAs), such as miR-214, miR-34a and Mir-135 are reported to be involved in maintaining normal bone formation and development of metastatic bone lesions in cancers. Recent studies have demonstrated that miRNAs are stably expressed in human plasma and serum samples. And serum miRNAs have been used as biomarkers in diagnosis and prognosis of multiple cancers, including MM. However, the functional roles of miRNA in myeloma bone disease have not been elucidated yet. Materials and methods: In the present study, the serum miRNA expression was assessed from 152 samples including 108 MM samples and 44 healthy donors (HD) of serum. Microarray-based assay and real-time PCR was used to determine differentially expressed miRNAs. The correlation of miRNA expression and bone disease detected by whole body X-ray scanning was evaluated by the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Survival analysis was performed using the Kaplan-Meier method with a log-rank test and the generalized Wilcoxon procedure. Results: We performed serum miRNA profiles from 7 newly diagnosed MMs and 5 normal donors using a microarray-based assay. Our results identified that twenty-seven miRNAs which were reported to be involved in maintaining normal bone formation and development of bone lesions were significantly dysregulated, 4 miRNAs were significantly up-regulated and 23 miRNAs were significantly down-regulated in patient serum. We further performed real-time PCR to verify the expression of miR-214, miR-135, miR-132 and miR-92a in a large cohort of 108 MM patients and 44 healthy donors. We found that miR-214 (0.43±0.17 vs. 2.3±0.14, p<0.0001) and miR-135 (-0.13±0.08 vs. 1.84±0.13, p=0.0022) levels were significantly increased, while serum levels of miR-92a (-0.19±0.20 vs. -1.03±0.11, p=0.0023) were significantly decreased in MM patients. However, we did not found that miR-132 was obviously altered between normal and patient serum. Furthermore, serum levels of miR-214 and miR-135 were notably increased in the patients with lytic bone lesions compared to those without bone disease (both p<0.0001), and a positive correlation was observed between the expression levels of miR-214 (r=0.455, p<0.0001) and miR-135 (r=0.404, p<0.001) with grades of lytic bone lesions. Receiver operating characteristic (ROC) analysis revealed that serum levels of miR-214 and miR-135 can be used to distinguish bone disease in myeloma patients with area under the curve (AUC) > 0.7. Moreover, patients had a significantly shortened OS with high levels of circulating miR-214 (50.0 months vs. NR (not reached); p=0.039) or miR-135 (34.0 months vs.NR; p=0.041) versus those patients with down-regulated levels of miR-214 and miR-135. Patients with higher serum levels of miR-214 were responsible to bisphosphonates with extended OS (NR comparing to 26.0 months, p=0.029), suggesting that bisphosphonates is suitable to treat patients with high expression of circulating miR-214. Conclusion: Our findings reveal that the circulating miR-214 level is a biomarker for prediction of bone disease and prognosis in multiple myeloma. The detail mechanism how miR-214 involves in disease progression will be further explored. The result of this study also set the foundation for searching more circulating miRNA as biomarkers for metastatic bone lesions. Disclosures No relevant conflicts of interest to declare.

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Skeletal Imaging and Management of Bone Disease

Hematology ◽

10.1182/asheducation-2008.1.313 ◽

2008 ◽

Vol 2008 (1) ◽

pp. 313-319 ◽

Cited By ~ 46

Author(s):

G. David Roodman

Keyword(s):

Bone Disease ◽

Ct Scanning ◽

Osteonecrosis Of The Jaw ◽

Bisphosphonate Therapy ◽

Bone Lesions ◽

Plain Radiographs ◽

Myeloma Bone Disease ◽

Osteoblast Activity ◽

Mri Scans ◽

Pet Scans

Abstract Up to 90% of patients with multiple myeloma develop bone lesions. The lesions are purely osteolytic because of increased osteoclast activity and markedly suppressed or absent osteoblast activity. The “gold standard” for imaging myeloma bone lesions is the metastatic bone survey. However, plain radiographs are relatively insensitive and can only demonstrate lytic disease when 30% of trabecular bone loss has occurred. Technicium-99m bone scanning is not appropriate for evaluating myeloma patients since bone scans underestimate the extent of bone involvement in patients with myeloma. The limited reproducibility of bone surveys have led to the use of computerized tomography (CT) scanning, magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to evaluate the extent of bone disease. CT scans are more sensitive than plain radiographs for detecting small lytic lesions, and MRI scans detect marrow involvement by the tumor. PET scans have been used to detect bone lesions in patients with myeloma, are more sensitive than plain radiographs, and have the same sensitivity as MRIs for detecting bone disease in the spine and pelvis. Treatment of myeloma bone disease involves treatment of the underlying malignancy and its manifestations. Current treatments that will be discussed include bisphosphonate therapy, kyphoplasty, vertebroplasty, radiation therapy, and novel agents to suppress osteoclastic bone resorption. In addition, complications with bisphosphonate therapy will be reviewed, in particular, osteonecrosis of the jaw associated with bisphosphonate therapy. As survival of myeloma patients increases, therapies to prevent the complications of aggressive myeloma bone disease become more important.

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Quantitative Imaging and Radiomics in Multiple Myeloma: opportunity or hype?

10.20944/preprints202011.0569.v1 ◽

2020 ◽

Author(s):

Alberto Stefano Tagliafico ◽

Alida Dominietto ◽

Liliana Belgioia ◽

Cristina Campi ◽

Daniela Schenone ◽

...

Keyword(s):

Multiple Myeloma ◽

Medical Imaging ◽

Bone Disease ◽

Quantitative Methods ◽

Quantitative Imaging ◽

High Variability ◽

Bone Lesions ◽

Imaging Data ◽

Lytic Bone Lesions ◽

Ct And Mri

Multiple Myeloma (MM) is the second most common type of hematological disease and, although it is rare among patients under 40 years of age, its incidence rises in elderly subject. MM manifestations are usually known with the abbreviation CRAB (hyperCalcemia, Renal failure, Anaemia, and lytic Bone lesions). In particular, the extent of the bone disease is negatively related to a decreased patients’ quality of life and, in general, bone disease in MM increases both morbidity and mortality. The detection of lytic bone lesions on imaging, especially CT and MRI, is becoming crucial from the clinical viewpoint to separate asymptomatic from symptomatic MM patients and the detection of focal lytic lesion in these imaging data is becoming relevant even when no clinical symptoms are present. Therefore, radiology is pivotal in the staging and accurate management of patients with MM even in early phases of the disease. In this review we describe the opportunities offered by quantitative imaging and radiomics in multiple myeloma. At present time there is still high variability in the choice between various imaging methods to study MM patients and high variability in image interpretation with suboptimal agreement among readers even in tertiary centres. Therefore, the potential of medical imaging for patients affected by MM is still to be completely unveiled. In the next years, new insights to study MM with medical imaging will derive from artificial intelligence (AI) and radiomics usage in different bone lesions and from the wide implementations of quantitative methods to report CT and MRI. Eventually, medical imaging data can be integrated with the patient's outcomes with the purpose to find radiological biomarkers for predicting the disease prognostic flow and its therapeutic response.

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Biomarkers of Myeloma-Associated Lytic Bone Disease Using SELDI-TOF MS.

Blood ◽

10.1182/blood.v104.11.2463.2463 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2463-2463

Author(s):

Bangzheng Chen ◽

Hong Huixiao ◽

Tong Weida ◽

Walker Ronald ◽

Barlogie Bart ◽

...

Keyword(s):

Bone Turnover ◽

Bone Disease ◽

Classification Model ◽

Bone Lesions ◽

Serum Samples ◽

Focal Lesions ◽

Lytic Lesions ◽

Lytic Bone Lesions ◽

Risk Of Progression ◽

Tof Ms

Abstract MGUS is a pre-malignant state, with a 1% annual risk of progression to overt myeloma (Kyle, NEJM346:564, 2004). Progression of MGUS to myeloma is preceded and can be predicted by increased rates of bone turnover (Betaille, JCI88:62, 1991). Progress to overt myeloma is associated with lytic bone disease in about 80% of patients. A simple, reliable test that identifies MGUS patients at risk of progression to symptomatic myeloma would elucidate biological mechanisms that govern the process and identify targets for early intervention. The intimate association of progression with changes in bone biology suggested that early recognition of changes in bone turnover would serve such a purpose. Therefore, we sought to identify protein biomarkers of bone disease in the sera of patients with myeloma that can be used as early predictors of progression. Given the limited reliability of individual markers of bone turnover to identify changes in bone metabolism, we elected to adopt a global proteomics approach. Sera from 62 untreated myeloma patients were collected and stored at −80°C for future analysis. 35 serum samples were from myeloma patients with 1–26 lytic bone lesions as identified on X-ray skeletal surveys and 27 serum samples were from patients without lytic lesions. The sera were analyzed by surface-enhanced laser desorption and ionization-time of flight mass spectroscopy (SELDI-TOF MS) using Ciphergen’s ProteinChip Biology System II (PBS II), to identify protein patterns associated with lytic bone disease. Each sample was applied in 4 replicates to randomly assigned spots on 12 IMAC30 ProteinChips placed in a bioprocessor and activated with Cu++ ions using a Biomek2000 robot. The chips were read on a PBS II reader. The mass spectra of proteins, generated using an average of 66 laser shots, were calibrated using peptide and protein standards and normalized to total ion current using CiphergenExpress 2.0 software. To develop a classification model that separates non-treated patients with focal lesions from those without focal lesions, we identified among the low molecular weight (1500–25000 kDa) proteins a set of 17 protein peaks that were differentially expressed between the two groups at a significance level of p<0.005. We then randomly selected 80% of patients for developing a model based on these peaks using a stepwise logistic regression method; 198 calibrated and normalized spectra from 50 randomly selected patients,28 with lytic bone lesions and 22 without lytic lesions (2 samples had only 3 replicates) were used for model development. The model used 10 protein peaks to classify the patients, with a receiver operating characteristic (ROC) area of 0.897. Finally the model was challenged by the set-aside test set of 50 spectra from 12 randomly selected patients (one patient had 6 replicates). The model exhibits high sensitivity and specificity, and its overall prediction accuracy is around 90%. Studies are underway to identify the biomarkers and to validate the utility of this model to predicting progression of MGUS to overt myeloma.

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