Bone Lesions In Patients Research Articles

Показники еритрограми та їх констеляції у хворих на цироз печінки різної етіології з остеопенією й остеопорозом: їх зміни і діагностична цінність

Introduction. There is a need to search for new publicly available methods for screening and diagnosing bone lesions in patients with liver cirrhosis (LC), one of which the detection of changes in individual parameters of the erythrogram and their combination in a routine general blood test could be. The aim of the study. To characterize the parameters of erythrogram and their constellation in patients with liver cirrhosis of various etiologies with osteopenia and osteoporosis, to find out their diagnostic value. Materials and methods. The study involved 79 patients with LC (women - 22; men - 57 aged 18 to 66 years) with bone mineral density (BMD) disorders (experimental group) (62 (78.48 %) , which is divided into 2 subgroups: patients with LC with osteopenia (38 (48.10 %) and osteoporosis (24 (30.38%)) and without it (comparison group (17 (21.52 %)). The control group consisted of 25 healthy individuals of the same gender and age. We studied the characteristics of changes in individual erythrogram parameters and their constellations: sensitivity (Se), specificity (Sp), accuracy (Ac), positive and negative predicted values (PPV and NPV), the likelihood ratios of positive and negative result (LR + and LR-), post-test probability of bone damage, the difference between the frequency of cases. The relationship between individual erythrogram parameter or constellation and bone damage was considered statistically confirmed at the modulus of G. U. Yule's coefficient of association (YCA) more than 0.5 or contingency coefficient (CC) more than 0.3. Results. We found the confirmed inverse stochastic relationship between the constellation «normal hemoglobin (HGB) + normal mean cell hemoglobin (MCH) + increase in red cell distribution width in percent (RDWC)», which may be combined with normal red blood cells (RBC) and/or normal mean corpuscular hemoglobin concentration (MCHC), and each of the bone lesions (with osteopenia: YCA = -0.69; CC = -0.33, with osteoporosis: YCA = -1.00, CC = -0.39), which most likely indicates BMD within normal limits. The individual erythrogram parameters and their constellations diagnostically valuable for osteopenia were not identified. We found such changes of the individual erythrogram parameters: revealed highly sensitive decrease in RBC, as the the most valuable (Se = 95.83 %; NPV = 83.33 %; LR- = 0.14; post-test probability of osteoporosis in its absence - 5.82%), decrease in HGB, decrease in hematocrit (HCT), moderately sensitive increase in red cell distribution width standard deviation in femtoliters (RDWS) (Se = 87.50-95.83%; NPV = 66.67-80.00 %; LR- = 0.17-0.35) and highly specific decrease in MCH (Sp = 94.12 %; PPV = 80.00 %; LR + = 2.83), between which and osteoporosis the direct stochastic relationship was confirmed (YCA = 0.52-0.81), being characteristic for the diagnosis of osteoporosis. Among the constellations, «normal RBC + normal mean corpuscular volume (MCV) + normal MCHC» and «normal RBC + normal MCH + normal MCHC + normal RDWS» were found indicating the absence of osteoporosis, as evidenced by the presence of an inverse stochastic relationship between constellations and osteoporosis (YCA = -1.00; CC = -0.33). Also the moderately sensitive constellation «decrease in RBC + increase in RDWS» (Se = 83.33 %; LR- = 0.35) and constellations - highly specific «decrease in MCV + increase in RDWS» and the most specific (most valuable) «decrease in RBC + decrease in MCV + increase in RDWS» were found which can be combined with a decrease in HGB, and/or a decrease in HCT, and/or an increase in RDWC, and/or normal MCHC (Sp = 94.12-100.00 %; PPV = 88.89-100,00 %; LR + = 5.67 - tends to infinity), between which there and osteoporosis there is a confirmed direct stochastic relationship (YCA = 0.63-1.00; SS = 0.33-0.38). Conclusions. The presence of the constellation «normal HGB + normal MCH + increase in RDWC», which may be combined with normal RBC and/or normal MCHC, indicates the absence of bone damage in a patient with liver cirrhosis. The individual erythrogram parameters or their constellations diagnostically valuable for osteopenia were not identified. The absence of such highly sensitive changes of erythrogram parameters as decrease in RBC being of the greatest diagnostic value, or decrease in HGB content, HCT, or moderately sensitive increase in RDWS, or constellation «decrease in RBC + increase in RDWS», or presence of constellations «normal RBC + normal MCV + normal MCHC» or «normal RBC + normal MCH + normal MCHC + normal RDWS» most likely indicates the absence of osteoporosis in patients with liver cirrhosis. The presence of highly specific decrease in MCH and/or constellations - highly specific «decrease in MCV + increase in RDWS», or the most specific and most valuable «decrease in RBC + decrease in MCV + increase in RDWS» which can be combined with decrease in HGB and/or decrease in HCT, and/or increase in RDWC, and/or normal MCHC, indicates that patients with liver cirrhosis have osteoporosis.

To study the effectiveness of core needle biopsy in diagnosing bone lesions in patients attending tertiary care centre, Telangana State, South India

To study the effectiveness of core needle biopsy in diagnosing bone lesions in patients attending tertiary care centre, Telangana State, South India

Percutaneous CT-guided biopsy of lytic bone lesions in patients clinically suspected of lung cancer: Diagnostic performances for pathological diagnosis and molecular testing

ObjectivesBone is a common location for lung cancer metastasis. Clinicians are often reluctant to biopsy bone metastases, as they are known to require a decalcification process that damages nucleic acids, which makes it incompatible with molecular testing. We performed this study to assess the diagnostic performance of histopathology and molecular testing of computed tomography (CT)-guided percutaneous bone biopsies of lytic bone lesions during the initial assessment or during the progression of lung cancer. Materials and methodsThis retrospective study included all patients suspected of having or known to have primary lung cancer and CT-guided percutaneous bone biopsies of lytic bone from January 2010 to June 2017. The main judgment criterion was the diagnostic performance of the pathological analysis. Secondary endpoints were the diagnostic performance of molecular testing and incidence of complications. ResultsFifty patients were included. The yield of CT-guided percutaneous bone biopsies for pathological analysis was 100 %, allowing for a diagnosis of certainty in all cases. The percentage of tumor cells in samples was higher than the 20 % threshold in 83.9 % of cases. The yield of molecular analysis was 94.6 %. A mutation was found in 60 % of cases; most frequently in KRAS (Kirsten rat sarcoma viral oncogene homolog) (28.6 %) and EGFR (epidermal growth factor receptor) (14.3 %). The complication rate was 2 %, i.e. a minor undrained pneumothorax. ConclusionCT-guided percutaneous biopsies of lytic bone is associated with a very low complication rate and high diagnostic performance for histopathology and mutation testing.

Progression-Free Survival Analysis of Denosumab Vs Zoledronic Acid in Intent to Transplant Multiple Myeloma Patients Based on Treatment Regimen and Baseline Characteristics

Introduction: Denosumab is a monoclonal antibody targeting Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) that has been shown to reduce skeletal related events associated with bone lesions in patients with multiple myeloma and solid tumors. Results from the full primary analysis of 1718 patients with newly diagnosed multiple myeloma in an international double blind, randomized, controlled phase 3 (20090482) study that assessed the efficacy of denosumab (Dmab) vs zoledronic acid (ZA) for preventing SREs met its primary end point of non-inferiority regarding time to first SRE. The analysis of the PFS exploratory endpoint showed a clinically meaningful 10.7 months median PFS benefit (HR, 0.82; 95% CI, 0.68-0.99; descriptive P= 0.036) of Dmab vs ZA. This benefit was most pronounced in patients who were stratified into the "intent to undergo Autologous Stem Cell Transplant (ASCT)" group at randomization. Thus, we present an in-depth analysis of relevant baseline characteristics, treatment regimens and PFS outcome in patients with intent to undergo transplant receiving Dmab and ZA. Methods: Adult patients with newly diagnosed multiple myeloma (NDMM) and stratified as "intent to undergo ASCT" at randomization were included in this analysis. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo in 4-week cycles. In this subgroup, the PFS outcome was examined. Baseline characteristics and treatment regimens were compared between treatment arms. Results: 54.1% of the 1718 enrolled patients were stratified into "intent to undergo ASCT" as part of their front-line therapy, and 61.8% of "intent to undergo ASCT" did receive an ASCT. In the "intent to undergo ASCT" group, 19.6% patients had disease progression in the Dmab arm compared to 28.0% in the ZA arm (HR 0.65 (0.49-0.85)) (Figure 1). No imbalance in terms of triplet therapy use between the two study arms (TABLE 1). 55.1% in Dmab vs 52.6% in ZA arm received Triplet Therapies which included Bortezomib, Cyclophosphamide, Dexamethasone (VCD), Bortezomib, Thalidomide, Dexamethasone (VTD), Cyclophosphamide, Thalidomide, Dexamethasone (CTD), or Bortezomib, Lenalidomide, Dexamethasone (VRD). The percentage of triplet therapies used in the "intent to undergo ASCT"patients was higher than in patients with no intent to undergo ASCT. Percentage of patients with ECOG performance status 2 was 19.4% in the Dmab group vs 18.6% in the ZA group. 26.2% of patients in the Dmab arm and 25% in the ZA arm had Multiple Myeloma ISS stage III upon diagnosis. Among intent to transplant patients there was no imbalance in terms of age, performance status, ISS stage, risk status, weight, bone marrow plasma cell % between the ZA and the Dmab arm Conclusion: Results from this post-hoc subgroup analysis suggest a more profound PFS benefit in the "intent to undergo ASCT" patient subgroup. Multiple myeloma treatment received in the intent to undergo transplant subjects was similar between the denosumab and zoledronic acid arms. No significant imbalance in demographics or baseline disease characteristics was observed between the two treatment arms. Disclosures Terpos: Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria. Shimizu:Medical Biological Laboratory: Consultancy; Takeda: Speakers Bureau; Daiichi: Consultancy; Amgen: Consultancy; Fujimoto: Consultancy. Willenbacher:Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; oncotyrol: Employment, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commission: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Fujimoto: Consultancy, Honoraria; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees. Glennane:amgen: Employment, Equity Ownership. Dai:Amgen: Employment, Equity Ownership. Pasteiner:Amgen: Employment, Equity Ownership. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

Targeting Adipocytes for Treatment of Bone Lesions in Patients with Myeloma

Targeting Adipocytes for Treatment of Bone Lesions in Patients with Myeloma

Prospective Comparison of PET Imaging with PSMA-Targeted 18F-DCFPyL Versus Na18F for Bone Lesion Detection in Patients with Metastatic Prostate Cancer

Bone metastases in prostate cancer (PCa) have important prognostic significance, and imaging modalities used for PCa staging should have high sensitivity for detecting such lesions. Prostate-specific membrane antigen (PSMA)-targeted PET radiotracers are promising new agents for imaging PCa. We undertook a head-to-head comparison of PSMA-targeted 2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) PET to Na18F PET to determine which modality was more sensitive for the detection of lesions suggestive of bone metastases in a group of patients with metastatic PCa. Methods: Patients with progressive, metastatic PCa were prospectively imaged with both 18F-DCFPyL and Na18F PET/CT, with both scans occurring within 24 h of each other. A consensus 2-reader central review was performed to identify all bone lesions suggestive of sites of PCa involvement on both scans, and maximized SUVs corrected for body weight (SUVmax) and lean body mass (SULmax) were recorded. Soft-tissue lesions were also noted on both scans, and SUVmax, SULmax, and PSMA reporting and data system (RADS) version 1.0 scores were recorded. Data from the 2 scans were compared using a generalized estimating equation. Results: In total, 16 patients meeting all inclusion criteria were enrolled in this study, and 15 of the 16 (93.8%) were imaged with both PET radiotracers. In total, 405 bone lesions suggestive of sites of PCa were identified on at least 1 scan. On 18F-DCFPyL PET/CT, 391 (96.5%) were definitively positive, 4 (1.0%) were equivocally positive, and 10 (2.5%) were negative. On Na18F PET/CT, the corresponding values were 388 (95.8%), 4 (1.0%), and 13 (3.2%). Of the definitively negative lesions on 18F-DCFPyL PET, 8 of 10 (80.0%) were sclerotic and 2 of 10 (20.0%) were infiltrative or marrow-based. Additionally, 12 of 13 (92.3%) of the definitively negative lesions on Na18F PET were infiltrative or marrow-based and 1 of 13 (7.7%) was lytic. Also identified were 78 PSMA-RADS-4, 17 PSMA-RADS-5, and 1 PSMA-RADS-3C soft-tissue lesions. Conclusion: PET/CT imaging using 18F-DCFPyL and Na18F PET had nearly identical sensitivities for the detection of bone lesions in patients with metastatic PCa. As would be expected, PSMA-targeted PET provides more information on soft-tissue disease. There may be little additional value to imaging PCa patients with Na18F after a PSMA-targeted PET scan has already been performed.

Fully automated analysis for bone scintigraphy with artificial neural network: usefulness of bone scan index (BSI) in breast cancer.

Artificial neural network (ANN) technology has been developed for clinical use to analyze bone scintigraphy with metastatic bone tumors. It has been reported to improve diagnostic accuracy and reproducibility especially in cases of prostate cancer. The aim of this study was to evaluate the diagnostic usefulness of quantitative bone scintigraphy with ANN in patients having breast cancer. We retrospectively evaluated 88 patients having breast cancer who underwent both bone scintigraphy and 18F-fluorodeoxyglucose (FDG) positron-emission computed tomography/X-ray computed tomography (PET/CT) within an interval of 8weeks between both examinations for comparison. The whole-body bone images were analyzed with fully automated software that was customized according to a Japanese multicenter database. The region of interest for FDG-PET was set to bone lesions in patients with bone metastasis, while the bone marrow of the ilium and the vertebra was used in patients without bone metastasis. Thirty of 88 patients had bone metastasis. Extent of disease, bone scan index (BSI) which indicate severity of bone metastasis, the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and serum tumor markers in patients with bone metastasis were significantly higher than those in patients without metastasis. The Kaplan-Meier survival curve showed that the overall survival of the lower BSI group was longer than that with the higher BSI group in patients with visceral metastasis. In the multivariate Cox proportional hazard model, BSI (hazard ratio (HR): 19.15, p = 0.0077) and SUVmax (HR: 10.12, p = 0.0068) were prognostic factors in patients without visceral metastasis, while the BSI was only a prognostic factor in patients with visceral metastasis (HR: 7.88, p = 0.0084), when dividing the sample into two groups with each mean value in patients with bone metastasis. BSI, an easily and automatically calculated parameter, was a well prognostic factor in patients with visceral metastasis as well as without visceral metastasis from breast cancer.

Intravoxel incoherent motion diffusion MR and diffusion kurtosis imaging for discriminating atypical bone metastasis from benign bone lesion.

Objectives:To investigate the feasibility of intravoxel incoherent motion (IVIM) diffusion MR and diffusion kurtosis imaging (DKI) in discriminating atypical bone metastasis from benign bone lesion in patients with tumors.Methods:Patients with bone lesions in lower extremity suspected of metastases were enrolled in this prospective study. IVIM diffusion MR and DKI were performed before biopsy. Apparent diffusion coefficient (ADC), true diffusion (D), perfusion fraction (f) and perfusion-related pseudodiffusion (D*) were generated with IVIM, while mean kurtosis (MK) and mean diffusion (MD) generated with DKI. Two radiologists blinded to pathology results separately measured these parameters for each lesion through drawing region of interest. Intraclass correlation coefficient was used to determine the inter-reader viability in measurement. The patients with pathology-confirmed metastasis or benign lesion were analyzed. The Mann–Whitney test was used to compare IVIM and DKI parameters between metastasis group and benign lesion group. Receiver operating characteristic curves were constructed to evaluate the ability of discrimination.Results:Bone lesions from 28 patients (metastasis, n = 15; benign lesion, n = 13; mean age = 55 years; age range, 34~77) were analyzed with IVIM and DKI. Intraclass correlation coefficient was greater than 0.8 for all parameters. ADC, D and MD were significantly lower in metastases versus benign lesions (p<0.05). MK and f value were significantly higher in metastases versus benign lesions (p<0.05). D* was not significantly different between the two groups (p>0.05). Areas under curve for ADC, D, f, MK and MD were 0.935, 0.939, 0.891, 0.840 and 0.844 respectively.Conclusions:IVIM and DKI derived parameters distinguish between atypical bone metastasis and benign bone lesion in selected patients with tumors.Advances in knowledge:Bone metastasis and benign bone lesion differ in water molecular diffusion.Intravoxel incoherent motion derived true diffusion distinguishes between atypical bone metastasis and benign lesion.

Epigenetic-Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease.

ABSTRACTMultiple myeloma (MM) bone disease is characterized by the development of osteolytic lesions, which cause severe complications affecting the morbidity, mortality, and treatment of myeloma patients. Myeloma tumors seeded within the bone microenvironment promote hyperactivation of osteoclasts and suppression of osteoblast differentiation. Because of this prolonged suppression of bone marrow stromal cells’ (BMSCs) differentiation into functioning osteoblasts, bone lesions in patients persist even in the absence of active disease. Current antiresorptive therapy provides insufficient bone anabolic effects to reliably repair MM lesions. It has become widely accepted that myeloma‐exposed BMSCs have an altered phenotype with pro‐inflammatory, immune‐modulatory, anti‐osteogenic, and pro‐adipogenic properties. In this review, we focus on the role of epigenetic‐based modalities in the establishment and maintenance of myeloma‐induced suppression of osteogenic commitment of BMSCs. We will focus on recent studies demonstrating the involvement of chromatin‐modifying enzymes in transcriptional repression of osteogenic genes in MM‐BMSCs. We will further address the epigenetic plasticity in the differentiation commitment of osteoprogenitor cells and assess the involvement of chromatin modifiers in MSC‐lineage switching from osteogenic to adipogenic in the context of the inflammatory myeloma microenvironment. Lastly, we will discuss the potential of employing small molecule epigenetic inhibitors currently used in the MM research as therapeutics and bone anabolic agents in the prevention or repair of osteolytic lesions in MM. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Dose Selection for Multiple Myeloma in Modern Era

PurposeThe management of multiple myeloma (MM) has evolved over the past 20 years, secondary to novel biologic therapeutics. Radiation therapy remains an important intervention in the management of painful lytic bone lesions. However, the currently used radiation therapy regimens were developed in the pre-biologic therapy era. The goal of this study is to assess the effects of dose and fractionation in pain control for patients with MM in the modern era. Methods and materialsWe conducted a retrospective study based on data collected from patients who received radiation therapy at our institute between 2007 and 2017. A total of 130 patients (266 treatment sites) were included in this study. Univariate Cox proportional hazards models were used to analyze the association of risk of pain recurrence with treatment characteristics and compute the hazard ratios (HRs). ResultsThe median follow-up time was 14 months. Patients who received a total dose of 20 to <30 Gy (including 20 Gy) had a significantly lower probability of pain recurrence when compared with those who received <20 Gy (HR, 0.36; 95% confidence interval, 0.14-0.94; P = .0365). There was no statistically significant difference in treatment response or pain recurrence between the different fraction numbers and sizes. However, we noted a trend indicating lower pain recurrence in the group that received 6 to 10 fractions of radiation therapy (P = .06). Among the most commonly used regimens, 8 Gy in a single fraction resulted in a statistically significant increased chance of pain recurrence compared with 20 Gy in 10 fractions and a borderline statistically significant increased chance of pain recurrence when compared with 30 Gy in 10 fractions. ConclusionsRadiation therapy remains highly effective at managing lytic bone lesions in patients with MM, and 6- to 10-fraction treatment courses are equally as effective as longer courses at treating these lesions. Treatment with 20 Gy in 10 fractions resulted in a significantly lower probability of pain recurrence when compared with 8 Gy in 1 fraction.

The need for bone biopsies in the diagnosis of new bone lesions in patients with a known primary malignancy: A comparative review of 117 biopsy cases

ObjectiveThis study used a clinical dataset to investigate the proportion of the newly found bone lesions in malignant patients diagnosed by biopsy as being benign, malignant but unrelated to the primary malignancy, or bone metastases of the primary malignancy. The clinical factors that might affect the correlation between bone lesions and the primary malignancy were also analyzed. It is expected to obtain some information contributing to the clinical decision-making regarding the need for biopsy of these lesions from the research results. MethodsData from patients with a single known malignant tumor who had undergone biopsy of newly found bone lesions at our research institution between January 2012 and December 2017 were reviewed. Based on the pathology results, included cases were divided into a bone-metastasis-of-primary-tumor group (Group 1) and a non-bone-metastasis-of-primary-tumor group (Group 2). The sex, age, diagnostic interval time between the primary malignancy and bone lesions, clinical symptoms, number of involved bones, sites of bone biopsy, and 18F-FDG PET/CT results were compared between groups. ResultsA total of 117 patients (92 in Group 1 and 25 in Group 2) were included in the study. There was no significant difference in the sex, age or diagnostic interval time between patient groups. Of all the cases, 17.9% (21/117) were identified to be benign lesions such as fibrous dysplasia (n = 2), bone tuberculosis (n = 1), simple bone cyst (n = 1), aneurysmal bone cyst (n = 1), or solitary fibrous tumor (n = 1). Meanwhile, 3.4% (4/117) were new malignancies including chondrosarcoma (n = 1), plasmacytoma (n = 1) and bone metastases unrelated to the primary malignancy (n = 2). Bone metastases pertinent to the primary tumor accounted for 78.6% (92/117) of cases. Liver (n = 18), kidney (n = 14), breast (n = 13) and lung (n = 12) were the most common cancers among cases. Cases with clinical symptoms exhibited a higher likelihood of their bone lesions being diagnosed as bone metastases of their primary malignancy than those without clinical symptoms (81.3% (87/107) vs. 50.0% (5/10)) (P = 0.021). Neither the number of bone lesions nor the biopsy sites appeared to influence whether the bone lesions were metastases of the primary malignancy or not. In PET/CT examination, the mean maximum standardized uptake values of the two groups were similar. ConclusionsThis study indicated that more than 1/5 of newly identified bone lesions in patients with a single known malignancy were not clinically associated with their primary tumors. Furthermore, 3.4% of these were newly discovered malignant bone tumors. The presence of clinical symptoms may be a significant factor affecting whether a new bone lesion is clinically linked to a patient's primary malignancy. Based on the experience from these patients, as for the newly found bone lesions, it is worthy to perform an active biopsy on those asymptomatic ones to avoid misdiagnosis and less biopsy on symptomatic ones for the sake of less cost and risks.

Asian Subgroup Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study

Introduction: Denosumab is a monoclonal antibody targeting receptor activator of nuclear factor-kappa B ligand (RANKL) that has been shown to reduce skeletal-related events (SREs) associated with bone lesions in patients with multiple myeloma. Results from the full primary analysis of an international, double-blind, double-dummy, randomized controlled phase 3 (20090482) study that assessed the efficacy and safety of denosumab vs zoledronic acid for preventing SREs in patients with multiple myeloma (MM) indicated that denosumab was non-inferior to zoledronic acid for time to SREs. Here we present a sub-analysis to evaluate efficacy and safety outcomes in a subgroup of Asian patients enrolled in the 20090482 study.Methods: Adult patients from Asian countries with newly diagnosed MM and ≥1 documented lytic bone lesion were included in this analysis. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo in 4-week cycles. The primary endpoint was time to first on-study SRE; the incidence of adverse events (AEs) by preferred term was also examined.Results: Overall, 196 Asian patients (denosumab, n=103; zoledronic acid, n=93) were included in this analysis. Patient demographics were generally well balanced between groups. Median (interquartile range [IQR]) number of months on study was 17.5 (9.8-30.2) for the denosumab group and 20.2 (13.1-29.2) for the zoledronic acid group. Median (IQR) cumulative drug exposure was 15.9 (8.5-24.0) months for denosumab and 17.4 (9.1-26.7) months for zoledronic acid. Fewer patients in the denosumab group developed first on-study SRE compared with the zoledronic acid group; the crude incidence of SREs at the primary analysis cutoff was 38.8% in the denosumab group and 50.5% in the zoledronic acid group. Median (95% CI) time in months to first on-study SRE was not reached (11.2-not reached) for the denosumab group and 12.3 (3.1-not reached) for the zoledronic acid group (hazard ratio [HR], 0.77; 95% CI, 0.48-1.26; Figure 1). Overall, all patients (100%) experienced ≥1 treatment-emergent AE; the AEs reported in ≥20% of patients in either treatment arm are presented in Table 1. The most common AEs reported in either subgroup (denosumab, zoledronic acid) were diarrhea (51.0%, 51.1%), nausea (42.2%, 46.7%), pyrexia (38.2%, 41.3%), upper respiratory tract infection (37.3%, 40.2%), and constipation (33.3%, 31.5%). Renal toxicity (preferred terms of blood creatinine increased, renal failure, urine output decreased, acute kidney injury, renal impairment, and blood urea decreased) occurred in 9 of 102 (8.8%) patients in the denosumab group and 20 of 92 (21.7%) patients in the zoledronic acid group. Adjudicated osteonecrosis of the jaw was reported in 7 (6.9%) patients in the denosumab group and 5 (5.4%) patients in the zoledronic acid group. Hypocalcemia was reported in 19 (18.6%) patients in the denosumab group and 17 (18.5%) patients in the zoledronic acid group.Conclusion: Results from this Asian subgroup analysis were comparable to those of the full analysis set. In addition, in this analysis there were numerically fewer patients in the denosumab arm that developed a first on-study SRE compared with those in the zoledronic acid arm, and the time to first on-study SRE had a trend favoring the denosumab-treated patients. The AE profiles for denosumab and zoledronic acid in the Asian subgroup were comparable to those observed in the full primary analysis, with renal toxicity similarly reported to be higher in the zoledronic acid group. Overall, this analysis supports that denosumab may be an additional treatment option for the standard of care for Asian patients with newly diagnosed MM with bone disease. [Display omitted] DisclosuresChng:Merck: Research Funding; Aslan: Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses. Chang:BMS: Consultancy, Speakers Bureau; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Roche: Consultancy, Speakers Bureau; Novarits: Consultancy, Speakers Bureau. Wong:Amgen: Consultancy, Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Archigen: Research Funding; Baxalta: Research Funding; Pfizer: Research Funding; Apellis: Research Funding; Roche: Research Funding; Boehringer: Research Funding; Ingelheim: Research Funding; AbbVie: Research Funding; Alexion: Consultancy; Astellas: Speakers Bureau. Shimizu:Amgen Inc.: Other: Non-remunerative Position of Influence, Denosumab 20090482 Global Steering Committee Member; Fujimoto Pharmacuetical Corp: Consultancy; Daiichi-Sankyo, Co., Ltd: Consultancy. Gao:Amgen Asia Holding Limited: Employment, Equity Ownership. Glennane:Amgen: Employment, Equity Ownership. Guan:Amgen: Employment, Equity Ownership.

A Role for Syntenin-1 in Multiple Myeloma Cell Survival

Multiple myeloma is the second most common hematological malignancy in the U.S. with an estimated 30,700 new diagnoses in 2018. It is a clonal disease of plasma cells that, despite recent therapeutic advances, remains incurable. Myeloma cells retain numerous characteristics of normal plasma cells including reliance on survival signals in the bone marrow for long term viability. However, malignant transformation of plasma cells imparts the ability to proliferate, causing harmful bone lesions in patients, and in advanced stages independence of the bone-marrow microenvironment. Therefore, we are investigating the molecular mechanisms of myeloma cell survival that allow them to become extramedullary.We identified syntenin-1 (SDCBP) as a protein involved in myeloma cell survival and a potential therapeutic target. Syntenin-1 is an adapter protein that has been shown to regulate surface expression of several transmembrane proteins by binding with membrane phospholipids and mediating vesicular trafficking of proteins throughout the cell. Syntenin-1 regulates the surface expression of CD138, a plasma/myeloma cell marker. Syntenin-1 has been shown to regulate apoptosis in numerous cancer cell lines including breast cancer, glioma, and pancreatic cancer but its role in multiple myeloma survival has not been studied. To determine if syntenin-1 expression has an effect on myeloma cell survival, we utilized the CoMMpass dataset (IA12), a longitudinal study of myeloma patients that includes transcriptomic analysis throughout treatment. We found that patients with the highest expression of syntenin-1 mRNA (top quartile) had significantly worse overall survival, progression-free survival, and a shorter response duration than those in the bottom quartile of expression. To determine if syntenin-1 has a role in myeloma cell survival, we used short hairpin RNA to knock down syntenin-1 (shsyn) in RPMI 8226 and MM1.s myeloma cell lines. We then determined the amount of cell death using Annexin-V staining flow cytometry four days following lentiviral infection. We found increased cell death in syntenin-1-silenced cells compared to our empty vector control in both RPMI 8226 (control=42.17%, shsyn=71.53%, p=0.04) and MM1.s cell lines (control=8.57%, shsyn=29.9%, p=0.04) suggesting that syntenin-1 is important for myeloma cell survival.Syntenin-1 contains two PDZ domains that allow it to bind to receptor proteins via their corresponding PDZ-binding motifs. We therefore wanted to look at correlation of syntenin-1 expression with CD138 and CD86, two PDZ-binding domain containing proteins expressed on the surface of myeloma cells. Using the CoMMpass dataset, we found patients with high expression of syntenin-1 had a median expression of CD86 that was twice as high as the total population (P<0.0001) while syntenin-1-low patients expressed CD86 at levels that were half as much as the population (P<0.0001). In contrast, there was no clear relationship between syntenin-1 and CD138 mRNA expression. Indeed if one takes into account all patients, there is a positive correlation between CD86 and syntenin-1 expression (r=0.228, P<0.0001) while there is a negative correlation between CD138 and syntenin-1 (r=-0.1923, P<0.0001). The correlation with CD86 but not CD138 suggests a previously undescribed role for syntenin-1 in myeloma cells. Our lab has previously shown that expression of CD86 is necessary for myeloma cell survival, and signals via its cytoplasmic domain to confer drug resistance. Silencing syntenin-1 results in a decrease in CD86 surface expression. However, there is no change in CD86 transcript or total cellular CD86 protein levels in our shsyn treated cells. Moreover, knockdown of CD86 resulted in increased protein expression and transcript levels of syntenin-1. Taken together, these data suggest that syntenin-1 may regulate CD86 expression on the cell surface.Our data supports a novel role for syntenin-1 in myeloma cell viability and as a potential regulator of CD86 surface expression. The role of syntenin-1 has not previously been explored in multiple myeloma and determining its molecular function is warranted as it may be an attractive target for therapeutic treatment of the disease. DisclosuresLonial:Amgen: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy.

Abstract 3671: Phenotypic heterogeneity within prostate cancer bone metastases measured by 18F-DCFBC PET/CT and 18F-NaF PET/CT

Abstract Purpose: The purpose of this study was to compare the spatial colocalization of prostate-specific membrane antigen (PSMA) targeting agent 18F-DCFBC PET/CT, a marker which demonstrates correlation with tumor aggressiveness, and 18F-NaF PET/CT, a marker of osteoblastic activity, within bone lesions of patients with metastatic prostate cancer. Methods: Twenty-eight metastatic prostate cancer patients received 18F-DCFBC PET/CT and 18F-NaF PET/CT scans (median interval 7 days, range 1-57). Tracer-specific regions of interest (ROI) were derived from threshold containing 80% of maximum SUV (SUV80%). Lesion detection and uptake was compared across the two PET/CT agents using non-parametric testing (Spearman correlation, Wilcoxon rank sum) accounting for intra-patient correlation. Lesion-specific registration was completed by global alignment of skeletal segments followed by local neighborhood optimization of area surrounding lesion. Spatial concordance was evaluated using overlap volume (OV), calculated as the volume of ROI intersection (shared volume) relative to the minimum volume of NaF-ROI or PSMA-ROI to account for differences in ROI volumes. Differences in uptake and CT Hounsfield units (HU) were compared within concordant (overlapping) and discordant (NaF-only, PSMA-only) regions of the same lesion using Wilcoxon signed rank test accounting for intra-patient correlation. Results: Twenty-six patients had positive NaF or DCFBC PET/CT scans, with a total of 241 metastatic sites identified. Lesion-level NaF SUV80% and DCFBC-2hr SUV80% were not significantly correlated at baseline (ρ=0.41, p&amp;gt;0.1). Lesion-level NaF-SUV80% was lower in bone lesions detected only by NaF (N=96) compared to NaF-SUV80% in bone lesions detected by both tracers (N=82), nearing significance (p=0.065). This pattern was not observed in DCFBC-SUV80% (p=0.5). To avoid bias from motion artifacts, only lesions in pelvis and spine were considered for voxel-based analysis (N=42). NaF and PSMA ROIs showing varying levels of spatial concordance (OV mean=0.26, range=0-1), which was modestly associated with higher sclerosis (ρ=0.4, p=0.01) and weakly associated with lower PSMA activity (ρ=0.3, p=0.07). Intra-lesion PSMA-only regions were significantly less sclerotic compared to concordant (p=0.04) and NaF-only (p=0.03) regions, indicating regions of active tumor seeding extend beyond regions of active bone remodeling within the tumor. Conclusions: Metastatic seeding and growth of prostate cancer in bone is biologically complex and dependent on bone microenvironment. We find regions of aggressive cellular activity (PSMA-targeting PET/CT) show heterogeneous colocalization with regions of rapid bone remodeling (NaF PET/CT) within sites of metastatic bone disease. These preliminary findings are important for consideration of targeted radionuclide therapies in metastatic prostate cancer. Citation Format: Stephanie A. Harmon, Esther Mena, Joanna Shih, Ethan Bergvall, Stephen Adler, Sherif Mehralivand, Ravi A. Madan, James L. Gulley, William L. Dahut, Baris Turkbey, Peter L. Choyke, M Liza Lindenberg. Phenotypic heterogeneity within prostate cancer bone metastases measured by 18F-DCFBC PET/CT and 18F-NaF PET/CT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3671.

Abstract 319: Syntenin regulates multiple myeloma cell survival

Abstract Multiple myeloma is the second most common hematological malignancy with an estimated 30,000 new diagnoses in 2017. Myeloma cells retain numerous characteristics of normal plasma cells including reliance on survival signals in the bone marrow for long term viability. However, they have gained the capacity to proliferate, causing harmful bone lesions in patients, and in advanced stages become extramedullary. Therefore, we are investigating molecular mechanisms of myeloma cells that allow them to survive independently of the bone marrow microenvironment. We have identified syntenin as a protein involved in myeloma cell survival and a potential therapeutic target. Syntenin has been reported to bind to and regulate levels of the plasma cell marker, CD138. We used the CoMMpass dataset, a longitudinal study of myeloma patients following their transcriptomic expression throughout treatment, and discovered that patients expressing in the top quartile for syntenin trend toward lower overall survival, progression-free survival, and shorter response duration than those in the bottom quartile. To determine whether it is involved in myeloma cell survival, we used short hairpin RNA to knock down syntenin (shsyn) in RPMI 8226 and MM1.s myeloma cell lines and determined cell death using Annexin-V staining four days following lentiviral infection. We observed increased death in syntenin-silenced cells compared to our empty vector control in both RPMI 8226 (control=57.83% viable, shsyn=29.47% viable, p=0.04) and MM1.s cell lines (control=91.43% viable, shsyn=70.1% viable, p=0.04) suggesting that syntenin is important for myeloma cell survival. Syntenin is a PDZ-domain containing protein that has been shown to regulate expression of several transmembrane proteins. We, therefore, wanted to look at correlation of syntenin expression with CD138 and CD86, two PDZ-binding domain containing proteins expressed on the surface of myeloma cells. Using the CoMMpass dataset, we found patients with high expression of syntenin had increased expression of CD86 while syntenin-low patients had decreased CD86 expression. This correlation does not exist with CD138 as syntenin-low patients express higher levels of CD138. The correlation with CD86 but not CD138 suggests a previously undescribed role for syntenin in myeloma cells. Our lab has shown that expression of CD86 is necessary for myeloma cell survival, and signals to confer drug resistance. When we silenced syntenin, we observed decreased CD86 expression. Moreover, knockdown of CD86 showed increased expression of syntenin. Taken together, these data suggest that syntenin may regulate CD86 expression on the cell surface. We now show a novel role for syntenin in myeloma cell viability and as a potential regulator of CD86 expression. Syntenin has not previously been explored in multiple myeloma and determining its molecular function is warranted as it may be an effective target for therapeutic treatment of the disease. Citation Format: Tyler Moser-Katz, Catherine M. Gavile, Benjamin G. Barwick, Sagar Lonial, Lawrence H. Boise. Syntenin regulates multiple myeloma cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 319.

PATHOMORPHOLOGICAL FEATURES OF BONE LESIONS AND CORRELATION OF CLINICAL, LABORATORY AND MORPHOMETRIC CRITERIA IN PATIENTS WITH LATENT SCLEROSING HEMATOGENOUS OSTEOMYELITIS (GARRÉ)

Introduction. Sclerosing hematogenous osteomyelitis of Garré (SHO) holds a significant place among cases of latent hematogenous osteomyelitis. Pathomorphological studies of sclerosing hematogenous osteomyelitis are needed to improve differentiated diagnostics, to prognosticate morphology specifics of nidus and to choose the optimal treatment tactics.Purpose of the study — to identify statistical differences between manifestation patterns of various disease types and correlation between clinical, laboratorial and morphometric criteria of bone lesions in patients with sclerosing hematogenous osteomyelitis.Material and methods. The authors studied tissue fragments of affected bones of 25 patients with SHO which was diagnosed by clinical, laboratorial, visualizing and morphological methods. Gradation morphometric criteria were used to reflect condition of nidus tissues. The authors made the analysis of qualitative characters and correlation analysis of dependencies between clinical and laboratorial criteria on the one hand, and with morphometric criteria — on the other, and identified association factor. Results. Pathomorphological study of SHO nidus demonstrated variances of bone lesions in separate disease cases despite the overall similarity of morphological manifestation. About 2/3 of all cases correspond to fibrosing type whereby even small exudative inflammation sites are absent. In about 1/3 of all cases apart from fibrosis, osteosclerosis and remodeling, the osteomyelitis niduses contain microabscesses indicative of suppurative inflammation as well as the authors observed small sequestration. The maximum differences in patients with various types of SHO were identified in such parameters as share of stab microphages and erythrocyte sedimentation rate (ESR). In cases of long term morbidity the fibrosing disease type is prevailing, in cases of short term lesion (1–2 years) — a fibrosing type with microabscesses formation.A series of correlation dependencies was reported between clinical and laboratorial criteria on the one hand, and with morphometric criteria — on the other hand.Conclusion. Pathomorphological features of bone lesions in sclerosing hematogenous osteomyelitis are nonhomogeneous. Every case in the study demonstrated stereotype alterations such as substantial diffuse fibroses of marrow spaces in cancellous bone and bone regenerate, remodeling of bone tissues with gradual acceleration of osteosclerosis and persisting productive inflammation. Only in sone cases featured small sites of exudative inflammation — microabscesses with microsequestration.

Can 18F-FDG PET/MR Imaging Contribute to the Assessment of Bone Lesions in Patients with Plasma Cell Dyscrasias?

Objective: Two patient groups were studied for evaluation of detection efficacy of 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). The first group was dedicated to assess the possible early bone lesions of those patients who had been diagnosed with monoclonal gammopathy of undetermined significance/smouldering multiple myeloma (MGUS/SMM). In the second group, the detection sensitivity of the PET/CT and PET/MRI for bone lesions was compared to each other in patients with symptomatic plasmacytic myeloma (PCM). Methods: 14 patients with MGUS/SMM and 27 patients with PCM were enrolled in this study. Initially, all patients underwent an 18F-FDG PET/CT examination and it was followed by a PET/MRI imaging. Results: No bone lesion was detected with PET/CT and PET/MRI in patients either with MGUS and SMM. Bone marrow alteration was also not detected with PET/MRI in this group. Disease progression has not been revealed in the course of the 18 months follow-up period. In regard to lesion detection, there was no difference between the PET/CT and PET/MRI in the symptomatic PCM group. The metabolic tumor volume (MTV) was found to be strongly correlating with both the β2-microglobulin serum level and the ISS stage. Conclusion: PET/MRI is a reliable diagnostic tool for detection of bone lesions in plasma cell discrasias, and it is not inferior to the PET/CT imaging. The MTV measurement can provide a promising diagnostic tool for the direct assessment of myeloma tumor loading in the future.

Stability of Spinal Bone Lesions in Patients With Multiple Myeloma After Radiotherapy-A Retrospective Analysis of 130 Cases.

The objective of the present retrospective analysis was the response evaluation regarding bone density and stability of patients with osteolytic spinal bone lesions due to multiple myeloma after palliative radiotherapy (RT). Patients with multiple myeloma who had undergone spinal RT from March 2003 to May 2016 were analyzed before and 3 and 6 months after RT. Assessment of spinal stability and bone density was performed using the internationally recognized Taneichi scoring system and measurement of bone density using computed tomography imaging-based Hounsfield units. For statistical analysis, we used the Bowker test, McNemar test, and κ statistics to detect possible asymmetries in the distribution of the Taneichi score over time. We used the Student t test for comparison of the density values (Hounsfield units) before and after treatment. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Additionally, overall survival was calculated using the Kaplan-Meier method. We evaluated 130 patients (69% male; 31% female) with multiple myeloma and a median age of 58 years. The median follow-up period was 41 months. Before treatment, 51% of the lesions were classified as unstable. At 3 and 6 months after RT, this rate had decreased to 41% (P= .0047) and 24% (P= .2393), respectively. The computed tomography measurements showed a significant increase in bone density at 3 and 6 months after RT. Acute RT-related grade 1 and 2 complications were detected in 34% of patients. Late side effects (grade 1-2) were detected in 23% of the patients. No severe grade 3 or 4 acute or late toxicities were identified. The median overall survival was 19.7 months for all patients and 6.6 months for patients with a Karnofsky performance score of≤ 70%. To the best of our knowledge, ours is the first report to analyze the bone density and stability in patients with multiple myeloma after RT using a validated scoring system and computed tomography imaging. Palliative RT is an effective method resulting in a significant increase in bone density for local response and stability without severe RT-related toxicity. Furthermore, recalcification could already be detected at 3 months after treatment.

Improving Bisphosphonate Infusion Monitoring at Haematology Medical Day Unit

This project was started after an incident of bisphosphonate-induced hypocalcaemia in September 2015. As part of management of lytic bone lesions in patients with multiple myeloma were given either Zoledronic...

Osteoclasts Promote Immune Suppressive Microenvironment in Multiple Myeloma: Therapeutic Implication

Purpose: The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesion in patients with multiple myeloma (MM). Mechanisms remain elusive whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment.Methods: We examined if OCs could modulate T cell-mediated anti-MM immunity; Inhibitory immune molecules expression during osteoclastogenesis; The impact of APRIL on PDL1 expression in MM and the pathway; The impact of Anti-CD38 mAb on osteoclastogenesis and T cell response;Results: Here, we first show that OCs significantly protect MM cells against T cell-mediated cytotoxicity via direct inhibition of proliferating CD4+and CD8+ T cells. The immune checkpoint molecules PDL1, Galectin-9, HVEM, and CD200, as well as T cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO) and CD38 are significantly up-regulated during osteoclastogenesis. Importantly, levels of these molecules, except CD38, are higher in OCs than MM cells. Anti-PDL1 monoclonal antibody and IDO inhibitor partly overcome OC-inhibited T cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), mainly secreted by OCs, are significantly up-regulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PDL1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly up-regulated during osteoclastogenesis. When targeted by an anti-CD38 monoclonal antibody, suppressive T cell function by OCs is alleviated, associated with down-regulation of HVEM and IDO.Conclusion: Taken together, these results define expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support combination of targeting these molecules to improve anti-MM immunity. DisclosuresAnderson:Celgene: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.