scholarly journals Biomarkers that Discriminate Multiple Myeloma Patients with or without Skeletal Involvement Detected Using SELDI-TOF Mass Spectrometry and Statistical and Machine Learning Tools

2006 ◽  
Vol 22 (4) ◽  
pp. 245-255 ◽  
Author(s):  
Sudeepa Bhattacharyya ◽  
Joshua Epstein ◽  
Larry J. Suva
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Univariate Analysis ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Neoplastic Disease ◽  
Serum Samples ◽  
Skeletal Involvement ◽  
Specificity And Sensitivity ◽  
Potential Biomarkers

Multiple Myeloma (MM) is a severely debilitating neoplastic disease of B cell origin, with the primary source of morbidity and mortality associated with unrestrained bone destruction. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to screen for potential biomarkers indicative of skeletal involvement in patients with MM. Serum samples from 48 MM patients, 24 with more than three bone lesions and 24 with no evidence of bone lesions were fractionated and analyzed in duplicate using copper ion loaded immobilized metal affinity SELDI chip arrays. The spectra obtained were compiled, normalized, and mass peaks with mass-to-charge ratios (m/z) between 2000 and 20,000 Da identified. Peak information from all fractions was combined together and analyzed using univariate statistics, as well as a linear, partial least squares discriminant analysis (PLS-DA), and a non-linear, random forest (RF), classification algorithm. The PLS-DA model resulted in prediction accuracy between 96–100%, while the RF model was able to achieve a specificity and sensitivity of 87.5% each. Both models as well as multiple comparison adjusted univariate analysis identified a set of four peaks that were the most discriminating between the two groups of patients and hold promise as potential biomarkers for future diagnostic and/or therapeutic purposes.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

scholarly journals Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Downstream Target ◽  
Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

1989 ◽  
Vol 7 (12) ◽  
pp. 1909-1914 ◽  
Author(s):  
R Bataille ◽  
D Chappard ◽  
C Marcelli ◽  
P Dessauw ◽  
J Sany ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Cell Mass ◽  
Bone Destruction ◽  
Myeloma Cell ◽  
Bone Lesions ◽  
Mass Reduction

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

scholarly journals MULTIPLE MYELOMA AS A FORM OF LEUKEMIA

Blood ◽  
1949 ◽  
Vol 4 (9) ◽  
pp. 1049-1067 ◽  
Author(s):  
MICHAEL A. RUBINSTEIN
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Bone Destruction ◽  
Tumor Formation ◽  
Diffuse Infiltration ◽  
Skeletal Involvement ◽  
The Difference ◽  
Distinguishing Features ◽  
Osseous System

Abstract The conventional points in the differential diagnosis between myeloma and leukemia have been discussed. Evidence has been brought to show that these points of distinction cannot be regarded as being of fundamental nature. Instances are abstracted where cases of multiple myeloma show the various characteristics of leukemia and vice versa. 1. Leukemic features in myeloma have been shown in: a. diffuse infiltration in multiple myeloma without circumscribed tumor formation and without any gross bone destruction; b. extraskeletal visceral myelomatous spread involving the kidney, spleen, lymph nodes, etc.; c. invasion of peripheral blood in myeloma—occasional myeloma cells (corresponding to the aleukemic forms of leukemia) may frequently be found in concentrated smears, even though they may be missed on routine examination; however, massive invasion of peripheral blood is rare; d. increased uric acid content of the blood and elevated basal metabolism, characteristic of leukemia, frequently seen also in myeloma; e. occurrence of myeloma in youth; f. symptomatology of multiple myeloma at times not referable to the osseous system. 2. Myeloma features in leukemia have been shown in: a. skeletal involvement in leukemia; b. very rare medullary forms of leukemia (without visceral involvement); c. occurrence of Bence-Jones proteinuria or d. hyperproteinemia with hyperglobulinemia in rare cases of leukemia; e. instances when the symptomatology of leukemia was referable to the osseous system. 3. Coexistence of multiple myeloma and leukemia is reviewed from the literature, and a case is reported of extensive mixed lymphocytic and plasma cell infiltration. In conclusion, the difference between myeloma and leukemia, as far as the listed conventional distinguishing features are concerned, is merely one of incidence: what is rare in one disease, is common in the other, and vice versa. Multiple myeloma is in all probability a leukemia of plasma cells.

Developing In Vivo Model for Studying Mechanisms of Osteoblast Suppression in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4731-4731
Author(s):  
Chang-Sook Hong ◽  
Alisa Huston ◽  
Flavia Esteve ◽  
Judy Anderson ◽  
Ken Patrene ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Osteoblast Differentiation ◽  
Treated Group ◽  
Bone Lesions ◽  
Neoplastic Disease ◽  
In Vivo Models ◽  
Myeloma Cells ◽  
Ganciclovir Treatment

Abstract Multiple myeloma (MM) is an incurable neoplastic disease characterized by an accumulation of plasma cells in bone marrow. Osteolytic bone lesions are the major source of morbidity in MM patients and are associated with bone pain and fractures and hypercalcemia. The bone lesions result from increased osteoclastic bone destruction in areas adjacent to the myeloma cells. New bone formation that normally happens at sites of previous bone resorption still occurs in early stages of the disease but is absent in advanced MM. Although the molecular basis for the increased osteoclastic activity has been intensely investigated, the basis for the decreased osteoblast activity is just beginning to be understood. Recently, inhibitors of WNT signaling pathway, Dickkorpf1 (DKK1) and secreted Frizzle-Related Protein-2 (sFRP2) have been identified as factors involved in osteoblast suppression in MM. In addition, IL-3 and IL-7 are increased in plasma of MM patients and suppress osteoblastogenesis in cell culture models. However, the role of those factors in the osteoblastic activity in MM patients is unclear. Studies in patients are confounded by cytotoxic therapy as well as bisphosphonates, which are standard therapy for MM patients. Therefore, preclinical in vivo models are required to delineate the mechanisms responsible for the profound osteoblast suppression in MM. We have developed a mouse model of myeloma bone disease in which genetically modified myeloma cells can be selectively ablated without the confounding effects of cytotoxic therapies and allows us to tract the growth of MM cells. The 5TGM1 cell line which is the most common version of murine MM, was stably transfected with the thymidine kinase (TK) gene from herpes simplex virus, which permits eradication of myeloma cells with ganciclovir, as well as GFP and luciferase genes to detect the presence of MM cells. One ug/ml ganciclovir treatment in culture results in 100% death of the transfected 5TGM1 cells in 4 days. Importantly, ganciclovir treatment of primary marrow cell cultures had no effect on growth and differentiation of osteoblast and hematopoietic progentitors. Co-culturing of primary marrow cells with 5TGM1 expressing TK has no bystander effect on osteoblast differentiation with ganciclovir treatment. Subcutaneously implanted 5TGM1 cells into SCID mice were eradicated by intraperitoneal injection of 20mg/kg ganciclovir/d for 2 weeks. The dose of ganciclovir did not affect osteoblast differentiation of primary marrow culture from the mice treated with ganciclovir. Then we injected the 5TGM1 cells into tibia of SCID nude mice (n=4 per group). After measuring the increase of serum IgG2b level, half of the mice were treated with ganciclovir for 2 weeks and the other with saline. Our preliminary data show that osteogenic cultures of bone marrow from the ganciclovir treated mice had significantly higher alkaline phosphatase activity than cultures derived from the saline treated group (p=0.03). In addition, the ganciclovir treated mice had tendency of higher trabecular bone volume than the saline-treated group (p=0.08). These results demonstrate that this model should be useful for studying mechanisms of osteoblast suppression in MM.

Circulating Mir-130a in Multiple Myeloma and Extramedullary Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2043-2043 ◽  
Author(s):  
Lenka Kubiczkova-Besse ◽  
Lenka Sedlarikova ◽  
Fedor Kryukov ◽  
Lenka Radova ◽  
Jana Nekvindova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Area Under The Curve ◽  
Newly Diagnosed ◽  
Circulating Mirnas ◽  
Serum Samples ◽  
Reactive Protein ◽  
Specificity And Sensitivity ◽  
Healthy Donors ◽  
Wide Range

Abstract Background MicroRNAs (miRNAs) are a class of short, non-coding, single stranded RNAs regulating a broad spectrum of processes. Circulating miRNAs are an important emerging biomarker in cancer as well as a possible non-invasive diagnostic solution for a wide range of clinical disorders due to their high stability and association with disease state, although their source still remains uncertain. In multiple myeloma (MM), a plasma cell malignancy, circulating miRNAs have been reported to have a diagnostic and prognostic potential. It is therefore plausible to assume that they are involved in pathogenesis of this disease and thus could be used as diagnostic tool not only for MM, its extramedullary (EM) form but also for monitoring the clinical course of the disease. Therefore, in this study, we aimed to identify such miRNAs. Methods Screening analysis of 667 miRNAs was performed on 5 EM serum samples, 5 newly diagnosed MM samples and 6 healthy donors (HD) serum samples using TaqMan Low Density Arrays (TLDA) from Life Technologies. QPCR was performed for miR-130a on 118 serum samples obtained in Brno from newly diagnosed MM patients (pts) (35 pts), primary and secondary EM (35 pts), relapsed MM (18 pts) and HD (30). Further, 45 serum samples (12 diagnostic and 33 follow-up) of pts reaching VGPR/better response, enrolled in Italian CRD/MEL-200 and EMN-02 studies were used for circulating miRNA estimation. Receiver Operating Characteristic (ROC) analysis was used to calculate specificity and sensitivity of the miRNA as a biomarker. Biochemical characteristics were also available for EM and MM pts from Brno. P values <0.05 were considered as significant. Results TLDA profiling revealed 14 deregulated miRNAs (all p<0.05, adjusted p<0.41) between MM pts and EM pts, and 20 miRNAs were on the top of the list of deregulated miRNAs between EM and HD serum samples (all p<0.05, adjusted p<0.40). MiR-130a was chosen for further verification by qPCR as it was on the top of the list of deregulated miRNAs between the groups. qPCR revealed that level of miR-130a was significantly decreased in MM and EM samples when compared with HD (all p<0.005); moreover, level of miR-130a was decreased also in EM when compared with MM sera (p<0.06). To discriminate EM pts from other groups, ROC curve was calculated. It revealed that miR-130a is potent to distinguish EM pts from HD with area under the curve (AUC) = 0.805, specificity of 86.7% and sensitivity of 65.7% using cut-off value = 3377 copies/1ng of miRNA/RNA. Most importantly, miR-130a was able to distinguish EM pts from newly diagnosed MM pts with AUC = 0.628, specificity of 94.3% and sensitivity of 28.6% using cut-off value = 1438 copies/1ng of miRNA/RNA, and EM pts from MM pts in relapse with AUC = 0.702, specificity of 94.4% and sensitivity of 28.6% using cut-off value = 1438 copies/1ng of miRNA/RNA. In the cohort of EM pts, miR-130a significantly correlated with most of clinically relevant parameters; there was a positive correlation with level of hemoglobin and thrombocytes count (rs=0.397 and 0.439, all p<0.05) and a negative correlation with levels of monoclonal immunoglobulin, β2-microglobulin and C-reactive protein (rs=-0.398, -0.427 and -0.488, all p<0.05) and it was also associated with higher ISS stage (p=0.017). Further, in the analysis of miR-130a dynamics in follow-up samples from Italy, we observed increase of miR-130a levels in 8/12 MM pts during the follow-up sampling (p<0.06) in comparison with diagnostic samples, whereas in remaining 4 MM pts it remained stable or decreased. Conclusions In this study, miR-130a was decreased in serum samples of pts developing EM disease and distinguished EM pts from newly diagnosed MM pts and relapsed/progressed MM pts with specificity over 90%. Further, we observed increased level of miR-130a in the follow-up samples of MM pts. It suggests that miR-130a could be associated with EM disease; however, underlying biology and origin of miR-130a still remains to be explored. Work was supported by grants IGA NT 12130, NT 14575 and NT 13190. Disclosures Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Array BioPharma: Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Sanofi Aventis: Honoraria.

scholarly journals Management of Myeloma Bone Lesions

2021 ◽  
Vol 22 (7) ◽  
pp. 3389
Author(s):  
Jeng-Shiun Du ◽  
Chia-Hung Yen ◽  
Chin-Mu Hsu ◽  
Hui-Hua Hsiao
Keyword(s):  
Bone Disease ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Bone Destruction ◽  
Cord Compression ◽  
Bone Diseases ◽  
Novel Agents ◽  
Bone Lesions ◽  
Skeletal Involvement ◽  
Skeletal Related Events

Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal plasma–cell proliferation. The survival and prognosis of this condition have been significantly improved by treatment with active anti-MM drugs such as bortezomib or lenalidomide. Further, the discovery of novel agents has recently paved the way for new areas of investigation. However, MM, including myeloma-related bone diseases, remains fatal. Bone disease or bone destruction in MM is a consequence of skeletal involvement with bone pain, spinal cord compression, and bone fracture resulting from osteolytic lesions. These consequences affect disease outcomes, including patients’ quality of life and survival. Several studies have sought to better understand MM bone disease (MBD) through the classification of its molecular mechanisms, including osteoclast activation and osteoblast inhibition. Bisphosphonates and the receptor activator of the nuclear factor-kappa B (NF-κB) ligand (RANKL) inhibitor, denosumab, prevent skeletal-related events in MM. In addition, several other bone-targeting agents, including bone-anabolic drugs, are currently used in preclinical and early clinical evaluations. This review summarizes the current knowledge of the pathogenesis of MBD and discusses novel agents that appear very promising and will soon enter clinical development.

The evaluation of the multiple myeloma pathological osseous tissue of Microarchitecture

2020 ◽  
Vol 16 ◽  
Author(s):  
Lianxiang Chen ◽  
Xing Wang ◽  
Shaojie Zhang ◽  
Yidan Wang ◽  
Baoke Su ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Structure ◽  
Imaging Finding ◽  
Structural Parameters ◽  
Bone Destruction ◽  
Micro Ct ◽  
Osteolytic Lesions ◽  
Microstructural Damage ◽  
Specificity And Sensitivity ◽  
Bone Damage

Background: The typical imaging finding of MM is bone destruction in the form of diffuse patchy osteolytic lesions or punctate destruction. However, it is difficult to accurately determine the fine structure of bone affected by MM with these techniques due to low specificity and sensitivity. Introduction: This study aimed to investigate the microscopic anatomical morphology and analyze the microstructure changes of trabeculae affected by multiple myeloma (MM) based on micro-CT. Methods: MM-affected and normal trabecular bone samples were imaged by micro-CT to obtain bone structure parameters to assess statistical differences between them and evaluate the degree of microstructural damage of MMaffected trabeculae. Results: Micro CT images clearly showed the microstructure of MM-affected trabeculae. The degree of trabecular osteoporosis varied with the severity of MM. There were significant differences in the structural parameters between MMaffected and normal trabeculae (P < 0.05). Conclusions: Micro-CT clearly reveals the microstructure of MM-affected trabeculae. The obtained bone structure data will help to determine the degree of bone damage caused by MM and assess the efficacy.

Bone Spared Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-6-SCI-6
Author(s):  
Gregory R. Mundy
Keyword(s):  
Natural History ◽  
Conflicts Of Interest ◽  
Bone Destruction ◽  
Host Cells ◽  
Bone Lesions ◽  
Neoplastic Disease ◽  
Bone Microenvironment ◽  
Preclinical Models ◽  
Myeloma Cells ◽  
History Of

Abstract Abstract SCI-6 After many years, the precise role of the bone microenvironment in the initiation and progression of myeloma is still quite poorly understood. In part, this may be because it has such a complex but important role in the natural history of myeloma. Myeloma cells have dramatic effects on bone, which are well known. These effects are mediated by the effects of myeloma cells on the cells responsible for the normal bone remodeling cycle. What is less well appreciated is the effects of bone and its cellular constituents on the myeloma cells. It is apparent that myeloma cells interact closely with osteoclasts, osteoblasts and also marrow stromal cells in the bone microenvironment and these interactions probably lead to a change in the phenotype of the myeloma cells, and the subsequent production of factors that are associated with the bone destruction which is so common in myeloma. It is also becoming more appreciated that the actual quality of bone and its rigidity and integrity may have important effects on the myeloma cells. The bone loss associated with myeloma and the interaction of myeloma cells with host cells in the bone microenvironment seem to be local effects rather than generalized effects. The bone manifestations of myeloma, even at the clinical level, are still not well understood. For example, it is extremely likely that generalized osteoporosis is far more common in myeloma than is appreciated and occurs even in the presence of lytic bone lesions, and that bone mass may continue to decline in patients in remission. In experimental preclinical models of myeloma, it is quite apparent that modulation of the bone microenvironment has quite dramatic effects on the behavior of the myeloma cells and so the notion if the bone disease of myeloma could be abrogated or removed, the natural history of the neoplastic disease may be very different. Experiments are underway in the preclinical models to investigate this intriguing possibility. Disclosures No relevant conflicts of interest to declare.

[18F]NaF PET/CT imaging biomarkers of progression-free survival in metastatic prostate cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 277-277
Author(s):  
Stephanie Harmon ◽  
Tim Perk ◽  
Jens C. Eickhoff ◽  
Mary Jane Staab ◽  
Peter L. Choyke ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Imaging Biomarkers ◽  
Great Promise ◽  
Bone Lesions ◽  
Free Survival ◽  
Functional Changes ◽  
Skeletal Involvement ◽  
Pet Ct

277 Background: 18F-Sodium Fluoride (NaF) PET/CT has been shown to be superior to 99mTc-MDP SPECT in detection of bone metastases and shows great promise to reliably measure functional changes in bone. This study assesses the relationship of Progression Free Survival (PFS) with NaF PET/CT measures in patients with metastatic Castration-Resistant Prostate Cancer (CRPC). Methods: 55 CRPC patients had NaF PET/CT scans performed at baseline, which was repeated at week 9 if receiving taxane-based therapy (N = 16) or week 12 if receiving androgen-signaling pathway (AR) inhibitors (N = 39). Bone lesions were identified using a novel technique allowing for extraction and tracking of PET metrics from individual lesions at every timepoint. Cox proportional hazard regression analyses were conducted to evaluate associations between imaging metrics and PFS. Results: Median PFS was 8.3 months (range 1.0-30.3+). The strongest predictor of PFS in univariate analysis was total functional burden (SUVtotal) (P < 0.0001) during treatment for all patients. Predictors of PFS differed between both treatment cohorts of patients (Table 1), including number of lesions, fraction of skeletal involvement, and average lesion activity (SUVmean). Maximum PSA benefit (percent decrease) during the first 12 weeks of therapy was highly predictive of PFS in the AR-directed cohort of patients (HR = 1.012 , P = 0.0005), as was change in the number of lesions (HR = 1.01, P = 0.03). Conclusions: There is indication thattotal functional burden of disease during treatment with taxane or AR-directed therapy is a strong predictor of PFS. In addition, change in number of lesions was predictive of treatment efficacy. This supports ongoing development of NaF PET/CT based imaging biomarkers in mCRPC. Clinical trial information: NCT01516866. [Table: see text]

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