Advanced Bone Disease Research Articles

Efficacy of Calcium Sulfate Antibiotic Carriers in the Treatment of Severe Infections of the Temporal Bone

Objective: To study the additional use of topical antibiotic-loaded calcium sulfate pellets in difficult-to-treat cases of temporal bone infections. Patients: Four patients with advanced and pretreated temporal bone disease. Intervention: Application of topical antibiotic-loaded calcium sulfate pellets following surgical debridement in infections of the temporal bone. Main Outcome Measures: Reinfection- and revision-free follow-up analysis and assessment of audiometric data. Results: A total of 4 patients were included (3 females and 1 male, mean age of 29.5 years [SD 19.8]). All patients (4/4) had a revision-free follow-up during a mean of 24.5 (SD, 6.19) months. Reinfections (n = 3) were observed in 2 patients (2/4) occurring 1 and 15, as well as 8 months after surgery. Reinfections could be successfully treated using topically and/or orally applied antibiotic therapy. No change in air-conducted pure-tone average was observed after treatment (mean change 1.3 dB; P = 0.99). Conclusion: Local application of antibiotic-loaded calcium sulfate pellets in combination with surgical debridement represents an effective treatment for local infection control in difficult-to-treat cases of temporal bone infections.

Randomised open-label phase II study of induction standard of care fulvestrant and CDK4/6 inhibition with addition of ipatasertib in metastatic ER+/HER2- breast cancer patients without circulating tumour (ct) DNA suppression (FAIM).

TPS1111 Background: The combination of fulvestrant and one of the three approved CDK4/6 inhibitors (i) is the standard of care for patients with ER+/HER2 metastatic breast cancer progressing on first-line endocrine therapy, or relapsing on or within a year of completing adjuvant endocrine therapy. AKT inhibition combined with fulvestrant has recently demonstrated clinically important activity in patients with advanced ER+/HER2- breast cancer progressing on first-line CDK4/6i plus an AI. Monitoring ctDNA dynamics has potential utility as an early response evaluation tool: Lack of suppression of ctDNA at day 15 in patients treated with palbociclib and fulvestrant in the PALOMA-3 trial was predictive for shorter PFS. We designed FAIM to establish whether the addition of the AKT inhibitor, ipatasertib, improves PFS in patients with poor ctDNA suppression during cycle 1 of fulvestrant and CDK4/6i. Methods: FAIM is a phase 2 multi-centre, randomised, open-label superiority trial in patients with ER+/HER2- advanced breast cancer, recruiting at centres in the UK. Patients will undergo ctDNA testing at days 1 and 15 of cycle 1 fulvestrant and CDK4/6 inhibitor. Eligible patients must be aged ≥18, have ER+ (≥1% or Allred score 3/8 or greater) and HER2- advanced breast cancer, measurable disease or assessable bone disease (RECIST 1.1), adequate organ function, fasting glucose ≤150mg/dL and HbA1c ≤7.5% and be eligible for NHS treatment with fulvestrant and CDK4/6i. Patients with diabetes requiring insulin, significant cardiac disease, a history of pneumonitis, or prior exposure to CDK4/6i are excluded. The FoundationOne Liquid CDx assay will be used for ctDNA analysis, a pan-cancer, tumour-agnostic liquid biopsy test that uses error-corrected next-generation sequencing. Patients with poor ctDNA suppression at day 15 will be eligible for the randomised (minimisation) study. Up to 483 patients starting fulvestrant andCDK4/6i will enroll for ctDNA screening to allow 174 patients to enter the randomised study. The primary endpoint of the study is to compare PFS in patients randomised to palbociclib/fulvestrant +/- ipatasertib. Secondary endpoints include safety, overall survival and overall response rate in all randomised patients and PFS in the sub-group of patients with alterations in the PIK3CA/AKT1/PTEN pathway. One hundred patients with ctDNA suppression at day 15, and up to 50 patients with no detectable ctDNA at day 1, will form additional control groups for exploratory outcome comparison to patients with poor ctDNA suppression. Enrolment began in December 2022 and is anticipated to continue for 2 years (NCT04920708). Clinical trial information: NCT04920708 .

The outcome of autologous hematopoietic stem cell transplantation in patients with multiple myeloma. The experience of King Fahad Specialist Hospital in Dammam, Saudi Arabia

Background: Aautologous hematopoietic stem cell transplants (HSCT) is the standard of care for newly diagnosed patients with multiple myeloma (MM) who are eligible for autologous transplantation. Although cryopreservation is routinely employed, autologous HSCT can be performed using non-cryopreserved stem cells. Methods and materials: A retrospective study of patients with MM who received autologous HSCT between the 10th of October 2010 and the 31st of January 2022 at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia was performed. Results: Over 11 years and 113 days, a total of 135 autologous HSCTs were performed for 119 patients with MM at our institution. Single autologous HSCTs were performed for 119 patients, while 16 of these patients received either planned tandem autologous transplants or second autografts due to either progression or relapse of their myeloma. The median age of patients with MM at autologous HSCT was 51.5 years. At presentation of their MM, the following high-risk (HR) features were encountered: stage III disease according to the revised international scoring system (RISS) in 12.3%; adverse cytogenetics in 31.93% of patients; advanced bone disease in 60.50%; and renal dysfunction or failure in 11.76% of patients. A total of 104 autologous HSCTs (77.04%) were performed without cryopreservation while 31 autografts (22.96%) were performed using cryopreserved apheresis stem cell products. Additionally, 54 autologous HSCTs (40.00%) were done at outpatient while 81 autografts (60.00%) were performed in an inpatient setting. Survival for 100 days post-HSCT for all patients with MM who received autologous transplants including those done at outpatient was 100%. The 4 years overall survival (OS) an progression-free survival (PFS) for patients with MM who received non- cryopreserved or fresh autologous HSCTs were 82% and 68% respectively. Conclusion: Autologous HSCT without cryopreservation is safe, and feasible and can lead to short-term as well as long-term outcomes that are comparable to autologous transplantation with cryopreservation. Non- cryopreserved autologous grafts allow the performance of autologous transplants in an outpatient setting to save beds and reduce costs.

Narrative review of the epidemiology, economic burden, and societal impact of metastatic bone disease.

As the prevalence of cancer continues to rise in the United States due to a combination of both early detection and increased life expectancy, the number of clinically symptomatic skeletal metastases will continue to grow. Healthcare expenditures on cancer treatment have steadily increased each decade to our estimated level of approximately $200 billion in 2020. Metastatic bone disease is a significant driver of this cost, accounting for nearly one-fifth of the total cost of oncologic treatment. Understanding the impact of metastatic bone disease can help to identify the gaps between diagnosis and initiation of treatment in an effort to decrease the socioeconomic and psychosocial implications of the disease. In this paper, we review the epidemiology and economic burden of metastatic bone disease in addition to other sequelae that affect patients, including financial hardship, caregiver burden, diminished quality of life and psychological impact. Upon literature review of multiple studies investigating these factors, we found that advanced metastatic bone disease had overall poor outcomes with regards to the socioeconomic and psychosocial effects on not only patients and their families, but also society at large. These consequences may be improved by early referral to orthopedic specialists and establishment of a multi-disciplinary team.

Megaprosthesis for Metastatic Bone Disease-A Comparative Analysis.

Background: Megaprosthetic reconstruction is sometimes indicated in advanced metastatic bone disease (MBD) of the appendicular skeleton with large degrees of bone loss or need for oncological segmental resection. Outcome after megaprosthetic reconstruction was studied in the setting of primary bone sarcoma with high levels of complications, but it is not known if this applies to MBD. Method: We performed a comparative analysis of complications and revision surgery for MBD and bone sarcoma surgery in an institutional cohort from 2005–2019. Presented are the descriptive data of the cohort, with Kaplan–Meier (K–M) rates of revision at 1, 2 and 5 years together with a competing risk analysis by indication type. Results: Rates of revision surgery are significantly lower for MBD (8% at 1 year, 12% at 2 years), in the intermediate term, compared to that of sarcoma (18% at 1 year, 24% at 2 years) (p = 0.04). At 5 years this is not significant by K–M analysis (25% for MBD, and 33% for sarcoma), but remains significant in a competing risk model (8% for MBD, and 20% for sarcoma) (p = 0.03), accounting for death as a competing event. Conclusion: Rates of revision surgery after megaprosthetic reconstruction of MBD are significantly lower than that for primary bone sarcoma in this cohort.

A humanised rat model of osteosarcoma reveals ultrastructural differences between bone and mineralised tumour tissue.

Current xenograft animal models fail to accurately replicate the complexity of human bone disease. To gain translatable and clinically valuable data from animal models, new in vivo models need to be developed that mimic pivotal aspects of human bone physiology as well as its diseased state. Above all, an advanced bone disease model should promote the development of new treatment strategies and facilitate the conduction of common clinical interventional procedures. Here we describe the development and characterisation of an orthotopic humanised tissue-engineered osteosarcoma (OS) model in a recently genetically engineered x-linked severe combined immunodeficient (X-SCID) rat. For the first time in a genetically modified rat, our results show the successful implementation of an orthotopic humanised tissue-engineered bone niche supporting the growth of a human OS cell line including its metastatic spread to the lung. Moreover, we studied the inter- and intraspecies differences in ultrastructural composition of bone and calcified tissue produced by the tumour, pointing to the crucial role of humanised animal models.

Denosumab Induced Severe Prolonged Hypocalcemia in Metastatic Prostate Cancer

Background: Denosumab is a RANK-l inhibitor that, in addition to the treatment of osteoporosis, is used in patients with advanced cancer and metastatic bone disease to prevent skeletal-related events. Although denosumab is generally safe and effective, it can cause hypocalcemia which in some patients can be severe and life threatening. We present a case of severe prolonged hypocalcemia after a single dose of denosumab in a patient with metastatic prostate cancer. Case: A 78-year-old male with a past medical history of stage 4 prostate cancer on antiandrogen treatment with GnRH antagonist presented with severe hypocalcemia. Physical exam revealed a blood pressure 125/80 mm Hg, pulse 115 per min and weight 135 lb with negative Chvostek’s and Trousseau’s signs. The electrocardiogram showed supraventricular tachycardia with prolonged QTc interval of 503 ms (<430 ms). Labs showed serum calcium 4.9mg/dL (8.5–10.5), albumin 2.5g/dL (3.6–5.1), corrected calcium 5.7 mg/dL, ionized serum calcium 0.64mmol/L (1.05–1.3), creatinine 1.10mg/dL (0.7–1.2), eGFR >60, phosphorus 2.0mg/dL (2.5–4.5), magnesium 1.9 mg/dL (1.6–2.6), 25-OH vitamin D 29.7 ng/mL (30–100), 1,25 dihydroxy vitamin D 174 pg/mL (18–64), iPTH 244.0 pg/mL (11–68) and PSA 1860 ng/mL. Three weeks prior to presentation, the patient received 120 mg of subcutaneous denosumab. Pre-treatment serum calcium was 9.2 mg/dL (8.5–10.5), and Tc-99m bone scan showed multiple osteoblastic osseous metastatic lesions involving both axial and appendicular skeleton. The patient was diagnosed with denosumab-induced severe hypocalcemia and started on intravenous (IV) calcium gluconate infusion, oral phosphate 250 mg twice daily, and ergocalciferol 50,000 IU twice weekly. He required IV calcium gluconate up to 10 g per day in addition to oral calcium carbonate 2 g t.i.d. for 2 weeks to resolve hypocalcemia and normalize QTc interval. Patient was discharged to nursing home on calcium carbonate 2 g q.i.d. with IV calcium gluconate as needed to keep corrected calcium >8.0 mg/dL. After discharge he required up to 4 g of IV calcium and 8 g of oral calcium per day. Unfortunately, he presented again with severe hypocalcemia 5 weeks after discharge. In addition to current regimen of oral and IV calcium boluses, low dose calcitriol was started. We were only able to maintain his serum calcium>8.0 mg/dL by administering high daily dose of oral calcium carbonate 8 g /day and calcitriol 2 mcg daily. Due to poor prognosis, he was transitioned to hospice care and died 2 weeks later. Discussion: There are not many case reports on severe prolonged hypocalcemia secondary to denosumab in cancer patients but normal kidney function. Our patient remained on high dose of calcium even 101 days after denosumab administration. Reference: 1. Milat F et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013 Aug 1;55(2):305–8.

A modified Harrington technique for periacetabular reconstruction in advanced metastatic bone disease and a discussion of alternative treatment options.

Management of periacetabular lesions involves complex clinical decision making. The modified Harrington procedure with total hip arthroplasty can recreate pelvic stability with a cement rebar construct as well as a functional hip. This study analyzes the modified Harrington procedure to assess construct longevity and patient outcomes. We queried a prospectively maintained database to identify all patients at a large academic medical center from 2017 to 2019 with periacetabular metastatic disease treated with a modified Harrington. Medical records were reviewed and complications, patient outcomes, Musculoskeletal Society Tumor (MSTS) scores, and implant survival were recorded. A total of nine patients were treated with the modified Harrington between 2017 and 2019. At maximum follow- up there were zero revisions or longterm complications. The mean preoperative MSTS score was 2.2 (range, 0-18), compared to the mean postoperative MSTS score of 17.7 (range, 9-25) recorded at a mean 4 (range, 1-30) months following surgery (p<0.001). The modified Harrington technique total hip technique for reconstruction in periacetabular metastatic bone disease is a safe procedure with effective symptom relief, improvement in function, and excellent implant survivorship.

Individualized Bone-Protective Management in Long-Term Cancer Survivors With Bone Metastases.

Antiresorptive therapy is an important component of a multimodal approach to treating patients with advanced malignancies and metastatic bone disease. Over the past decade, overall survival of affected patients has improved in most cancer entities, and long-term disease control is a realistic goal in many cases. There are emerging clinical studies showing the benefits of an initial antiresorptive therapy using bisphosphonates or denosumab. However, some adverse events of these therapies, such as osteonecrosis of the jaw, correlate with the cumulative doses given, and there is an increasing clinical need for new antiresorptive concepts to treat long-term survivors. This review summarizes the clinical evidence of antiresorptive therapies across different cancers with bone involvement and presents concepts of dose-reduction protocols for long-term survivors with established metastatic bone disease. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Identification of risk features for complication in Gaucher\u2019s disease patients: a machine learning analysis of the Spanish registry of Gaucher disease

BackgroundSince enzyme replacement therapy for Gaucher disease (MIM#230800) has become available, both awareness of and the natural history of the disease have changed. However, there remain unmet needs such as the identification of patients at risk of developing bone crisis during therapy and late complications such as cancer or parkinsonism. The Spanish Gaucher Disease Registry has worked since 1993 to compile demographic, clinical, genetic, analytical, imaging and follow-up data from more than 400 patients. The aims of this study were to discover correlations between patients’ characteristics at diagnosis and to identify risk features for the development of late complications; for this a machine learning approach involving correlation networks and decision trees analyses was applied.ResultsA total of 358 patients, 340 type 1 Gaucher disease and 18 type 3 cases were selected. 18% were splenectomyzed and 39% had advanced bone disease. 81% of cases carried heterozygous genotype. 47% of them were diagnosed before the year 2000. Mean age at diagnosis and therapy were 28 and 31.5 years old (y.o.) respectively. 4% developed monoclonal gammopathy undetermined significance or Parkinson Disease, 6% cancer, and 10% died before this study. Previous splenectomy correlates with the development of skeletal complications and severe bone disease (p = 0.005); serum levels of IgA, delayed age at start therapy (> 9.5 y.o. since diagnosis) also correlates with severe bone disease at diagnosis and with the incidence of bone crisis during therapy. High IgG (> 1750 mg/dL) levels and age over 60 y.o. at diagnosis were found to be related with the development of cancer. When modelling the decision tree, patients with a delayed diagnosis and therapy were the most severe and with higher risk of complications.ConclusionsOur work confirms previous observations, highlights the importance of early diagnosis and therapy and identifies new risk features such as high IgA and IgG levels for long-term complications.

Real-world data on incidence, clinical characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) in the era of novel therapies: A study of the Greco-Israeli collaborative myeloma working group.

We investigated incidence, characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) treated mainly with novel therapies. Based on definition (BMPCs <20% and lytic lesions/plasmacytomas, without anemia, renal insufficiency or hypercalcemia) we identified 140 patients with MFMM, among 4650 myeloma patients (3%). Twice the number of patients with typical myeloma were used as controls; 60% were <65 years and 70% had advanced bone disease. Plasmacytomas were more frequent in MFMM compared with standard myeloma (68% vs 15%, P < .05). Adverse prognostic parameters (high lactate dehydrogenase, advanced stage, high risk cytogenetics, immunoparesis) were less common in patients with MFMM compared with controls (P < .05); 90% received novel agents and 47% underwent autologous transplantation upfront; 90% achieved an objective response; 70% had at least very good partial response which was significantly higher compared with controls (P < .05). After a median follow-up of 52 months, 33 patients have died. Early death (<12 months) was infrequent in MFMM. Median progression-free survival and overall survival (OS) were 46 and 129 months respectively, both significantly longer compared with controls (P < .001). Proteasome inhibitor (PI)-based therapy was the only independent predictor for OS in the multivariate analysis (HR: 3.9; P < .001). In conclusion, MFMM is a distinct entity presented in young and elderly subjects, characterized by limited bone marrow infiltration, advanced bone disease and frequent presence of plasmacytomas; MFMM patients have less often adverse prognostic features and achieve excellent responses and prolonged OS especially when treated with PI-based therapies. Novel imaging will help in a more accurate classification of this entity.

Computational Analysis Model Applied to Spanish Gaucher Registry Data

Introduction Type 1 Gaucher disease (GD)(OMIM # 230800), has a pan-ethnic distribution, in Spain its prevalence is about 1/100,000. Since more than twenty years the impact of therapies in the awareness of the disease is changing the characteristics and expectations of patients. The Spanish Gaucher disease Registry (SGDR) is working since 1993 and compiled demographic, clinical, genetic, analytical and imaging data about 360 type 1 GD Spanish patients. The application of new high computing capacity and powerful network analysis to analyze the registered data could provide a visualization tool and allows to extract knowledge from complex and very numerous relationships. The objective of this analysis is to discover useful ideas and new correlations to predict the risk of developing late complications and to extract knowledge of complex and very numerous relationships. Patients &amp; Methods From 416 patients included in the SGDR we have selected 358 with more than 70% of data and follow-up. GD type 2 patients have been excluded. The variables included in the database at diagnosis: demographic data and the clinical, analytical and imaging information at diagnostic and during the treatment follow-up as well as comorbidities. With Kampal Data Solutions, a spin-off company of the University of Zaragoza dedicated to the development of computer applications and advanced data analytics, this company has experience in the homogenization of information and in the elaboration of classic and advanced statistics projects, as well as in the visualization of said information complex network techniques and the relationship between variables and model designs.Variables:Birthdate, age at diagnosis, gender, death date, severity category of disease (mild, moderate, severe), concomitant diseases, Parkinson disease in relatives, liver volume, spleen volume, spleen removal, bone disease, S-MRI, DEXA, chitotriosidase, CCL18/PARC, lyso Gb1, B12 vitamin level, iron concentration, ferritin, cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, AST, ALT, GGT, acid phosphatase, bilirubin, hemoglobin concentration, Hsc, WBC count, platelets count, serum gammaglobulin fraction, IgG, IgA, IgM, GBA activity, GBAgenotype, CHIT1genotype, age to start therapy, type of therapy (ERT, SRT), new bone crisis or joint replacement, development of malignancies or Parkinson disease. Results: The 358 subjects were mostly GD1 (340 vs 18 GD3), 18% were splenectomized and 39% have advanced bone disease and bone complications. Most of the patients have a complex heterozygous genotype (81% vs 19% homozygous). 47% of patients were diagnosed before 2,000 and 10% die before this study. Most of them are receiving ERT (54%). About comorbidities, 4% of patients developed MGUS or Parkinson disease and 6% malignant neoplasias. The main results have founded a significant correlation between skeletal complications and impaired and spleen removal (p=0.0005); this fact confirm previous reports. In this study a low IgA serum level shows a significant correlation with severe bone disease(p=0.0000), and with the incidence of new bone crisis during long term ERT. A IgG increase was related to the development of neoplasia. There were two more important factors that we have found; the age at diagnosis and the age to start therapy. Comments: Registries are key resources to help increasing timely and accurate diagnosis, improving patient's management, tailoring treatments, facilitating clinical trials, supporting healthcare planning and speeding up research. This is the very first attempt to establish a correlation network among different biomarkers and clinical characteristics in a national base cohort. As has been hypothesized seems that the impairment of immune system has a strong impact in long term complications, in our study the humoral immunity dysfunction pops up as an important factor. Despite of our short cohort, the quality of data is accurate and can reflect the own Spanish Gaucher disease characteristics. Currently we are working in the design of algorithms to help to predict patient outcomes. Disclosures No relevant conflicts of interest to declare.

PB1975 CHRONIC FATIGUE, ANAEMIA AND MUSCULOSKELETAL AFFECTATION IN GAUCHER DISEASE

Background:Chronic fatigue is the most prevalent symptom in type 1 Gaucher disease(GD1) (79%) and persists in spite of prolonged therapy which usually achieves the general goals (24.5%). It is mainly attributed to hypermetabolism, myopathy or increase in plasma cytokine concentration. There are several factors such as anaemia, pain, depression, anxiety, sleep disturbances, emotional distress, activity level or medication side effects that could be involved. Bone abnormalities are present in over 70% of the patients and peripheral neuropathy in about 11% of them, which contributes to the disabling and debilitating complications. Our hypothesis is that other factors including muscle‐tendinous weakness could have influence in the development of fatigue.Aims:The aim of the study is to evaluate for first time the study the fiber structure in muscle‐tendinous unit and compromised elasticity usefulness of real‐time tissue Strain‐Elastography in the assessment of the Achilles tendon fibres in GD patients with or without bone marrow infiltration by MRI and their influence in the chronic fatigue.Methods:We have study the fibrillar structure (rigidity) of muscletendinous tissues in Achilles tendon applying a noninvasive technique based on Strain‐Elastography (Hitachi system EUB‐8500, L54 M transducer, frequency 6‐13 MHz) and combined this exam with bone marrow burden study using Spanish‐MRI score and calcaneus ultrasound densitometry for bone mineral density evaluation. We have selected 21 GD1 and 2 type 3 patients (mean age: 46.9 y, 18‐65, 12 females) with chronic fatigue, on enzymatic replacement therapy (mean time 12.0 years, 2‐25). Non history of diabetes, endocrine diseases or concomitant steroid therapy were present. Control group: 20 healthy subjects matched by gender and age. Correlation study with blood cell counts, plasma biomarkers, genotype, concomitant diseases and SF36 quality of life scale (QoL) were performed. A longitudinal and axial scans was performed in each Achilles tendon in proximal, middle and distal third.Results:Mean Hb (g/dL) in females: 13.3 (12.2‐14.1), in males: 14.8 (13.0‐17.3), advanced bone disease 10 patients (43.5%), S‐MRI (5.1 points; 0‐18), Osteopenia 8 patients (34.7%), T‐score (mean ‐0.76, ‐2.68‐1.51), Z‐score (mean ‐0.53, ‐2.43‐1.45), genotype N370S/L444P (47.8%), N370S/other (34.7%), L444P/other (17.4%), Ferritin: 310.7 (30‐2000), Chitotriosidase (1,813 nmol/mL/h 50‐6,575). CCL18/PARC (256.3 ng/mL 55‐553), Lyso‐Gb1 (32.9 ng/mL 0‐144). All patientes have a normal tendinous structure (mode B). Intratendinuous alteration in Strain‐elastography (S‐ELA) grade 2‐3 was found in 14 /23 (61%) patients and bilateral in 9/23 (21.7%). There are not correlation between S‐ELA grade to other variables. QoL evaluation showed a low score in physical and emotional roles and general health and high in pain. There are a significant correlation between the degree of tendon hardness and the low score on the QoL scales, (p = 0.0035).Summary/Conclusion:In Achilles tendon Strain‐elastography is a sensitive method to detect subclinical disfunction of muscle‐tendinous that could contribute to fatigue symptom in GD. Intratendinuous alteration is one independent variable in GD patients. The cause of this disfunction probably has a mechanical origen and can be a risk factor for the development of skeletal complications. A project based on physical activity has been developed to Increase the functional strength of the lower limbs achieve greater stability, power and improvement in physical activities, as well as the reduction of fatigue.

Prognosis after Upfront Radiation Therapy in Plasma Cell Myeloma: Analysis of the National Cancer Data Base

IntroductionSystemic therapy with corticosteroids, immunomodulatory agents and/or proteasome inhibitors is the principal treatment modality for plasma cell myeloma. However, some patients with advanced bone disease may start treatment with radiation therapy (RT) to control pain from lytic lesions, fractures, or spinal cord compression. The degree of bone involvement may correlate with cytogenetic lesions, gene expression profile, and prognosis in myeloma (Zhan et al., Blood 2006; Kumar and Rajkumar, Nat Rev Clin Oncol 2018), yet the prognostic relevance of upfront RT use has not been previously studied. We hypothesized that the need for upfront RT may be associated with worse long-term outcomes, as an indicator of late-stage diagnosis or a biologically aggressive disease with bone destruction. Our objective was to examine patterns of use, factors associated with upfront RT, and survival outcomes among myeloma patients treated with upfront RT.MethodsFrom the National Cancer Data Base (NCDB), a nationwide registry containing records of >70% of incident cancers in the United States, we selected adult patients with histologically confirmed myeloma diagnosed between 2004 and 2015, who received chemotherapy within 12 months of diagnosis. We excluded patients with solitary plasmacytoma, those treated outside of the reporting facility, or those receiving palliative RT as the only therapy. We defined upfront RT as RT delivered before or within 14 days of the start of chemotherapy. We examined factors associated with upfront RT in a multivariable logistic model. We then examined the association between upfront RT and overall survival (OS) in a proportional hazard model adjusting for age, sex, race, income, insurance status, comorbidity index, year of diagnosis, type of treating hospital, and time from diagnosis to start of therapy.ResultsOf the 88,995 patients with myeloma, 15,223 (18%) received upfront RT, at median 15 days from diagnosis. Median radiation dose was 3000 cGy delivered over median 10 fractions, with the most common targets being spine/skull (59%), hips/pelvis (12%), and other bones (11%). Among patients receiving upfront RT, 73% started it before chemotherapy, while 27% started RT within 14 days of chemotherapy initiation.Use of upfront RT was significantly less common in academic than community hospitals (16% versus 20%, P<.0001). In the multivariable model, patients receiving upfront RT were significantly younger (odds ratio [OR] for a 10-year age increment: 0.92, 95% CI: 0.91-0.94), more likely to be male (OR: 1.11, 95% CI: 1.07-1.15), white non-Hispanic than black (OR: 1.13, 95% CI: 1.08-1.19), uninsured than privately insured (OR: 1.17, 95% CI: 1.06-1.29), and treated at a community rather than an academic hospital (OR: 1.28, 95% CI: 1.24-1.33). Receipt of upfront RT was also inversely associated with median income in the area of residence, distance to the hospital, and number of comorbidities (P<.0001).Median OS for the entire cohort was 4.2 years (95% CI, 4.1-4.2), longer for those treated with upfront systemic therapy (4.3 years, 95% CI, 4.2-4.3) than those receiving upfront RT (3.7 years, 95% CI, 3.6-3.8; Fig. A). After adjusting for baseline patient characteristics, treatment with upfront RT was associated with significantly worse OS (hazard ratio [HR]: 1.09, 95% CI: 1.07-1.12). This association was consistent in sensitivity analyses limited to patients who survived >1 year from diagnosis (HR: 1.15, 95% CI: 1.11-1.19), those who underwent autologous stem cell transplantation (HR: 1.11, 95% CI, 1.02-1.22; Fig. B), or accounting for baseline mortality rate using the endpoint of relative survival rather than OS (HR: 1.10, 95% CI: 1.07-1.14).ConclusionsIn this large nationwide cohort, nearly 1 in 5 of newly diagnosed myeloma patients received upfront RT. The association between socio-economic variables like income or insurance status and the use of upfront RT suggests that a delay in diagnosis may lead to severe skeletal complications of myeloma requiring RT. Worse survival with upfront RT may similarly correspond to more advanced disease, but persistent association in sensitivity analyses supports the hypothesis that a presentation with skeletal complications reflects a more aggressive myeloma biology. Further research should aim at disentangling the socio-economic, clinical, and molecular reasons underpinning this association. [Display omitted] DisclosuresOlszewski:Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding.

Real-World Data on Incidence, Clinical Characteristics and Outcome of Patients with Macrofocal Multiple Myeloma (MFMM) in the Era of Novel Therapies: A Study of the Greco-Israeli Collaborative Myeloma Working Group

Real-World Data on Incidence, Clinical Characteristics and Outcome of Patients with Macrofocal Multiple Myeloma (MFMM) in the Era of Novel Therapies: A Study of the Greco-Israeli Collaborative Myeloma Working Group

Exercise medicine across the cancer trajectory

Physical exercise is essential to maintaining human health and is now recognised by the American College of Sports Medicine and the American Heart Association as an essential component for both the prevention and management of chronic disease, injury and other illnesses. Previously, the recommendation for cancer treatment-related adverse effects had been rest; however, research on exercise has challenged this recommendation. It has become increasingly clear that exercise plays an important role in the management of many cancer patients and survivors across the disease trajectory (e.g. pre-, during and post-treatment). We have demonstrated clinical benefits of resistance training for improving physical and muscle function in prostate cancer survivors undergoing androgen deprivation therapy with significant improvements in muscle strength, physical function, balance, and cardiorespiratory fitness. We have also reported the rapid loss of bone and lean mass and increased total body fat due to androgen deprivation for prostate cancer and established the efficacy of exercise as medicine to reverse muscle loss, improve physical function and quality of life including general health, and reduce fatigue and low-grade systemic inflammation. This work has been further expanded in older cancer survivors who had completed primary therapy and in those with advanced bone disease. In addition, preliminary work indicates improved physical function post-surgery in patients with lung, colorectal and prostate cancer involved in prehabilitation programs. Exercise has also been shown to have numerous positive effects in breast cancer survivors during and following treatment including potential increase in chemotherapy completion. Evidence from large observational studies also suggests that regular exercise post-diagnosis is associated with increased survival in patients with breast, colorectal and prostate cancer. This presentation will cover clinical studies in exercise oncology across the cancer continuum from prehabilitation to long-term survivorship.

Multiple Myeloma with Advanced Bone Disease and Low Tumor Burden - Different Clinical Presentation but Similar Outcome after Bortezomib-Based Therapy and Radiotherapy.

There is a small but well recognized group of patients with multiple myeloma (MM), characterized by multiple bone lesions and low tumor burden, the so-called macrofocal form of MM (MF-MM). The aim of the study was to analyze the incidence, clinical manifestation, therapeutic outcome and prognosis of patients with MF-MM treated with bortezomib-based therapy and radiotherapy, in comparison to classic MM. There were 148 MM patients treated with bortezomibbased regimens, with 15 (10.1%) of them meeting the criteria for MF-MM. Comparative analysis involved disease- and therapy-related variables and markers of bone metabolism in MF-MM and classic MM groups. Event-free survival (EFS) and median survival (MS) were analyzed. Patients in MF-MM and classic MM groups had similar mean age and sex distribution. Patients with MF-MM had advanced myeloma bone disease (MBD), significantly lower clonal plasma cell infiltration in bone marrow, and lower paraprotein level. These patients were predominantly in an early International Staging System stage, showed non-secretory and light-chain variants, and significant association with extramedullary plasmacytomas. EFS was 20 months in MF-MM group versus 13 months in classic MM group (nonsignificant difference). MS was 42 months in both MF-MM and classic MM groups. MF-MM presents with imbalance of the minimal tumor burden and massive bone involvement. Along with advanced skeletal manifestations, these patients showed features of preserved bone marrow and no end-organ damages. Following bortezomib-based therapy and radiotherapy, the EFS and MS did not differ between MF-MM and classic MM groups.

Lack of hepcidin ameliorates anemia and improves growth in an adenine-induced mouse model of chronic kidney disease.

Growth delay is common in children with chronic kidney disease (CKD), often associated with poor quality of life. The role of anemia in uremic growth delay is poorly understood. Here we describe an induction of uremic growth retardation by a 0.2% adenine diet in wild-type (WT) and hepcidin gene (Hamp) knockout (KO) mice, compared with their respective littermates fed a regular diet. Experiments were started at weaning (3 wk). After 8 wk, blood was collected and mice were euthanized. Adenine-fed WT mice developed CKD (blood urea nitrogen 82.8 ± 11.6 mg/dl and creatinine 0.57 ± 0.07 mg/dl) and were 2.1 cm shorter compared with WT controls. WT adenine-fed mice were anemic and had low serum iron, elevated Hamp, and elevated IL6 and TNF-α. WT adenine-fed mice had advanced mineral bone disease (serum phosphorus 16.9 ± 3.1 mg/dl and FGF23 204.0 ± 115.0 ng/ml) with loss of cortical and trabecular bone volume seen on microcomputed tomography. Hamp disruption rescued the anemia phenotype resulting in improved growth rate in mice with CKD, thus providing direct experimental evidence of the relationship between Hamp pathway and growth impairment in CKD. Hamp disruption ameliorated CKD-induced growth hormone-insulin-like growth factor 1 axis derangements and growth plate alterations. Disruption of Hamp did not mitigate the development of uremia, inflammation, and mineral and bone disease in this model. Taken together, these results indicate that an adenine diet can be successfully used to study growth in mice with CKD. Hepcidin appears to be related to pathways of growth retardation in CKD suggesting that investigation of hepcidin-lowering therapies in juvenile CKD is warranted.

Abstract P3-07-45: Bone turnover marker levels and clinical outcomes in patients with breast cancer and bone metastases treated with bone antiresorptive therapies

Abstract INTRODUCTION AND OBJECTIVES: Patients with advanced breast cancer (BC) and metastatic bone disease typically have elevated serum levels of bone turnover markers (BTMs). Potent antiresorptive agents, such as denosumab and zoledronic acid, can significantly reduce BTM levels (Stopeck et al. J Clin Oncol 2010). Prior studies have provided evidence that higher BTM baseline levels may be associated with worse clinical outcomes (Ali et al. Ann Oncol 2004). In this analysis, we assessed the association between BTM levels after treatment with antiresorptive agents and overall survival (OS), disease progression (DP) and disease progression in the bone (DPB) in patients with advanced BC and bone metastases. METHODS: This post-hoc analysis included data from patients with BC and bone metastases enrolled in an international, blinded phase 3 trial who were randomized to receive either denosumab (120 mg SC) or zoledronic acid (4 mg IV, adjusted for creatinine clearance). The BTMs urinary N-telopeptide (uNTx) and bone-specific alkaline phosphatase (BSAP) were measured at study entry and at study month 3. The clinical outcomes of OS, DP, and DPB were compared in patients with BTMs above or below median levels at month 3 of antiresorptive therapy. These covariate analyses were based on Cox models stratified by treatment, prior SRE before month 3, prior bisphosphonate use, chemotherapy at randomization, and region (Japan or other countries). RESULTS: A total of 1705 patients were measured for uNTx serum levels, with 895 patients ≥ and 810 &amp;lt; the median of 10.40 nmol/mmol at month 3. Similarly, BSAP levels were measured in a total of 1708 patients, with 855 patients ≥ and 853 &amp;lt; the median BSAP level of 10.89 ng/mL at month 3. Patients with uNTx levels ≥ the median at month 3 had a significantly reduced OS (by 54%) and a greater risk of both DP (by 21%) and DPB (by 23%) than patients with uNTx levels &amp;lt; median (see Table). Similarly, patients with BSAP levels ≥ the median level at month 3 had an increased risk for reduced OS (by 197%), DP (by 67%) and DPB (by 56%) compared with patients whose BSAP levels &amp;lt; median. After adjusting for risk factors suggestive of more advanced disease such as visceral metastases or &amp;gt; 2 bone metastases, the correlation between elevated BTMs and reduced OS and greater risk of DP and DPB was maintained. CONCLUSIONS: Patients with BTM levels ≥ median at month 3 of antiresorptive therapy had generally worse clinical outcomes than patients whose BTM levels were &amp;lt; median. Assessment of uNTx and BSAP serum levels after treatment with antiresorptive therapy can add to our understanding of which patients with breast cancer and bone metastases are most at risk for decreased OS, or increased DP or DPB. Month 3*Covariate Analysis Results: Risk of Decreased OS or Increased DP or DPBClinical OutcomeHazard Ratio (95% Confidence Interval)P-valueDecrease in OSuNTXa1.539 (1.270, 1.866)&amp;lt;0.0001BSAPb2.966 (2.422, 3.633)&amp;lt;0.0001Increase in DPuNTXa1.214 (1.071, 1.377)=0.0024BSAPb1.666 (1.470, 1.888)&amp;lt;0.0001Increase of DPBuNTXa1.231 (1.054, 1.437)=0.0087BSAPb1.563 (1.342, 1.821)&amp;lt;0.0001*Comparing ≥ median to &amp;lt; median. aMedian uNTx levels=10.40 nmol/mmol. bMedian BSAP level=10.89 ng/mL. Citation Format: Lipton A, Stopeck A, Body J-J, Von Moos R, De Boer R, Paiva Gadelha Guimaraes A, Tonkin K, Fujiwara Y, Zhu L, Warner D. Bone turnover marker levels and clinical outcomes in patients with breast cancer and bone metastases treated with bone antiresorptive therapies. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-45.

GDF15 Promotes Osteoclast Differentiation and High Serum GDF15 Levels are Associated with Multiple Myeloma Bone Disease

Introduction Growth differentiation factor 15 (GDF15) is a multifunctional growth factor of the transforming growth factor beta (TGFbeta) family that plays a complex role in several types of cancers. In multiple myeloma, GDF15 was recently shown to enhance the tumor-initiating and self-renewal potential of the cancer cells (Tanno et al, Blood 2014). Moreover, blood and bone marrow plasma levels of GDF15 are elevated in myeloma patients compared with healthy persons, and high serum levels are associated with a poor prognosis (Corre et al, Cancer Research 2012). GDF15 seems important for bone remodeling during hypoxia (Hino et al, JBMR 2012), and one study proposed GDF15 to increase osteoclast activation in prostate cancer metastasizing to bone (Wakchoure et al, Prostate 2009). Whether GDF15 plays a role in the bone disease of multiple myeloma is not well characterized. Aim Our aim was to investigate whether high GDF15 serum levels are associated with multiple myeloma bone disease and to characterize the effect of GDF15 on osteoclast differentiation in vitro. Methods GDF15 was measured in serum samples obtained at diagnosis from 138 myeloma patients and 58 age and sex-matched healthy controls. The patient serum samples were collected for the Nordic Myeloma Study Group during a randomized phase 3 clinical trial which compared the effect of two different doses of pamidronate on bone. The bone disease was therefore particularly well-characterized in this study (Gimsing et al, Lancet Oncol 2010). Peripheral blood mononuclear cells (PBMC) isolated from buffy coats were cultured in osteoclast medium (a-MEM with human serum (20%), M-CSF (30ng/ml) and RANKL (50ng/ml)) for up to 14 days with or without GDF15. Purchased pre-osteoclasts (Lonza Inc.) were cultured in purchased bullet kit (OC medium with M-CSF (33ng/ml) and RANKL (66ng/ml)) for 7 days with or without GDF15. Cells positive for tartrate resistant acidic phosphatase (TRAP) staining and with more than two nuclei were counted as osteoclasts. Results GDF15 was significantly higher in serum obtained from myeloma patients (median 1.08 ng/ml, range 27.91) compared with healthy controls (median 0.46 ng/ml, range 1.66, Independent samples Kruskal-Wallis test p In vitro, addition of GDF15 (0-100 ng/ml) to osteoclast precursors or PBMC increased numbers of multi-nucleated TRAP positive cells in a dose dependent manner (n=3, O ng/ml GDF15 mean 25.7, SEM 5.9, 2 ng/ml GDF15 mean 29.7, SEM 4.3, 20 ng/ml GDF15 mean 38.7, SEM 4.9, 50 ng/ml GDF15 mean 53.3, SEM 11.6, 100 ng/ml GDF15 mean 78.7 SEM 7.8). OPG inhibited the pro-osteoclastogenic activity of GDF15 inferring that the effect is mediated by RANKL. Hence, GDF15 increases osteoclast differentiation. Conclusion Serum GDF15 is elevated in myeloma patients with advanced osteolytic bone disease compared to patients with no lesions. GDF15 increases osteoclast differentiation in vitro. Hence, GDF15 could play a role in regulating bone remodeling in myeloma patients. Disclosures No relevant conflicts of interest to declare.