WorldWideScience

Sample records for attenuates bone cancer

  1. Bone Cancer

    Science.gov (United States)

    Cancer that starts in a bone is uncommon. Cancer that has spread to the bone from another ... more common. There are three types of bone cancer: Osteosarcoma - occurs most often between ages 10 and ...

  2. Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-α expression in a mouse model

    Science.gov (United States)

    2010-01-01

    Background Tumor necrosis factor α (TNF-α) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-α production. Previous studies have suggested that thalidomide exerts anti-nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up-regulated expression of spinal TNF-α in a mouse model. Results Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-α in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-α in the spinal cord. Conclusions These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-α in the development of bone cancer pain. PMID:20923560

  3. Down-regulation of Toll-like receptor 4 gene expression by short interfering RNA attenuates bone cancer pain in a rat model

    Directory of Open Access Journals (Sweden)

    Fang Li

    2010-01-01

    Full Text Available Abstract Background This study demonstrates a critical role in CNS innate immunity of the microglial Toll-like receptor 4 (TLR4 in the induction and maintenance of behavioral hypersensitivity in a rat model of bone cancer pain with the technique of RNA interference (RNAi. We hypothesized that after intramedullary injection of Walker 256 cells (a breast cancer cell line into the tibia, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. Results We assessed tactile allodynia and spontaneous pain in female Sprague-Dawley (SD rats after intramedullary injection of Walker 256 cells into the tibia. In a complementary study, TLR4 small interfering RNA(siRNA was administered intrathecally to bone cancer pain rats to reduce the expression of spinal TLR4. The bone cancer pain rats treated with TLR4 siRNA displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines compared with controls. Only intrathecal injection of TRL4 siRNA at post-inoculation day 4 could prevent initial development of bone cancer pain; intrathecal injection of TRL4 siRNA at post-inoculation day 9 could attenuate, but not completely block, well-established bone cancer pain. Conclusions TLR4 might be the main mediator in the induction of bone cancer pain. Further study of this early, specific, and innate CNS/microglial response, and how it leads to sustained glial/neuronal hypersensitivity, might lead to new therapies for the prevention and treatment of bone cancer pain syndromes.

  4. Mas-Related Gene (Mrg C Activation Attenuates Bone Cancer Pain via Modulating Gi and NR2B.

    Directory of Open Access Journals (Sweden)

    Yu'e Sun

    Full Text Available This study is to investigate the role of Mas-related gene (Mrg C in the pathogenesis and treatment of bone cancer pain (BCP.BCP mouse model was established by osteosarcoma cell inoculation. Pain-related behaviors were assessed with the spontaneous lifting behavior test and mechanical allodynia test. Expression levels of MrgC, Gi, and NR2B in the spinal cord were detected with Western blot analysis and immunohistochemistry.Pain-related behavior tests showed significantly increased spontaneous flinches (NSF and decreased paw withdrawal mechanical threshold (PWMT in mouse models of BCP. Western blot analysis showed that, compared with the control group and before modeling, all the expression levels of MrgC, Gi, and NR2B in the spinal cord of BCP mice were dramatically elevated, which were especially increased at day 7 after operation and thereafter, in a time-dependent manner. Moreover, the treatment of MrgC agonist BAM8-22 significantly up-regulated Gi and down-regulated NR2B expression levels, in the spinal cord of BCP mice, in a time-dependent manner. On the other hand, anti-MrgC significantly down-regulated Gi expression, while dramatically up-regulated NR2B expression, in the BCP mice. Similar results were obtained from the immunohistochemical detection. Importantly, BAM8-22 significantly attenuated the nociceptive behaviors in the BCP mice.Our results indicated the MrgC-mediated Gi and NR2B expression alterations in the BCP mice, which might contribute to the pain hypersensitivity. These findings may provide a novel strategy for the treatment of BCP in clinic.

  5. Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice

    DEFF Research Database (Denmark)

    Hansen, Rikke Rie; Nasser, Arafat; Falk, Sarah

    2012-01-01

    The purinergic P2X3 and P2X2/3 receptors are in the peripheral nervous system almost exclusively confined to afferent sensory neurons, where they are found both at peripheral and central synapses. The P2X3 receptor is implicated in both neuropathic and inflammatory pain. However, the role of the P2......X3 receptor in chronic cancer-induced bone pain is less known. Here we investigated the effect of systemic acute and chronic administration of the selective P2X3, P2X2/3 receptor antagonist (5-[[[(3-Phenoxyphenyl)methyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl]-1......,2,4-benzenetricarboxylic acid sodium salt hydrate) (A-317491) in a murine model of cancer-induced bone pain. Chronic administration of A-317491 (30µmol/kgs.c., b.i.d.) resulted in a transient attenuation of pain related behaviours in the early stage of the bone cancer model, but had no effect in the late and more...

  6. Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice

    Science.gov (United States)

    Govey, Peter M.; Zhang, Yue; Donahue, Henry J.

    2016-01-01

    Exposure of bone to ionizing radiation, as occurs during radiotherapy for some localized malignancies and blood or bone marrow cancers, as well as during space travel, incites dose-dependent bone morbidity and increased fracture risk. Rapid trabecular and endosteal bone loss reflects acutely increased osteoclastic resorption as well as decreased bone formation due to depletion of osteoprogenitors. Because of this dysregulation of bone turnover, bone’s capacity to respond to a mechanical loading stimulus in the aftermath of irradiation is unknown. We employed a mouse model of total body irradiation and bone marrow transplantation simulating treatment of hematologic cancers, hypothesizing that compression loading would attenuate bone loss. Furthermore, we hypothesized that loading would upregulate donor cell presence in loaded tibias due to increased engraftment and proliferation. We lethally irradiated 16 female C57Bl/6J mice at age 16 wks with 10.75 Gy, then IV-injected 20 million GFP(+) total bone marrow cells. That same day, we initiated 3 wks compression loading (1200 cycles 5x/wk, 10 N) in the right tibia of 10 of these mice while 6 mice were irradiated, non-mechanically-loaded controls. As anticipated, before-and-after microCT scans demonstrated loss of trabecular bone (-48.2% Tb.BV/TV) and cortical thickness (-8.3%) at 3 wks following irradiation. However, loaded bones lost 31% less Tb.BV/TV and 8% less cortical thickness (both pbones also had significant increases in trabecular thickness and tissue mineral densities from baseline. Mechanical loading did not affect donor cell engraftment. Importantly, these results demonstrate that both cortical and trabecular bone exposed to high-dose therapeutic radiation remain capable of an anabolic response to mechanical loading. These findings inform our management of bone health in cases of radiation exposure. PMID:27936104

  7. Bone Cancer - Multiple Languages

    Science.gov (United States)

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Bone Cancer URL of this page: https://medlineplus.gov/languages/bonecancer.html Other topics A-Z Expand Section ...

  8. Breast Cancer and Bone Loss

    Science.gov (United States)

    ... Menopause Map Featured Resource Find an Endocrinologist Search Breast Cancer and Bone Loss July 2010 Download PDFs English ... G. Komen Foundation What is the link between breast cancer and bone loss? Certain treatments for breast cancer ...

  9. Drugs Approved for Bone Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for bone cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  10. Bone health in cancer patients

    DEFF Research Database (Denmark)

    Coleman, R; Body, J J; Aapro, M

    2014-01-01

    There are three distinct areas of cancer management that make bone health in cancer patients of increasing clinical importance. First, bone metastases are common in many solid tumours, notably those arising from the breast, prostate and lung, as well as multiple myeloma, and may cause major...... cancer for many patients resulting in a major reduction in skeletal complications, reduced bone pain and improved quality of life. Secondly, many of the treatments we use to treat cancer patients have effects on reproductive hormones, which are critical for the maintenance of normal bone remodelling....... This endocrine disturbance results in accelerated bone loss and an increased risk of osteoporosis and fractures that can have a significant negative impact on the lives of the rapidly expanding number of long-term cancer survivors. Finally, the bone marrow micro-environment is also intimately involved...

  11. Whole-body PET/MRI: The effect of bone attenuation during MR-based attenuation correction in oncology imaging

    DEFF Research Database (Denmark)

    Aznar, M.C.; Sersar, Rachida; Saabye, J.

    2014-01-01

    Purpose: In combined PET/MRI standard PET attenuation correction (AC) is based on tissue segmentation following dedicated MR sequencing and, typically, bone tissue is not represented. We evaluate PET quantification in whole-body (WB)-PET/MRI following MR-AC without considering bone attenuation...... and then investigate different strategies to account for bone tissue in clinical PET/MR imaging. To this purpose, bone tissue representation was extracted from separate CT images, and different bone representations were simulated from hypothetically derived MR-based bone classifications. Methods: Twenty oncology...

  12. MRI-guided attenuation correction in whole-body PET/MR: assessment of the effect of bone attenuation.

    Science.gov (United States)

    Akbarzadeh, A; Ay, M R; Ahmadian, A; Alam, N Riahi; Zaidi, H

    2013-02-01

    Hybrid PET/MRI presents many advantages in comparison with its counterpart PET/CT in terms of improved soft-tissue contrast, decrease in radiation exposure, and truly simultaneous and multi-parametric imaging capabilities. However, the lack of well-established methodology for MR-based attenuation correction is hampering further development and wider acceptance of this technology. We assess the impact of ignoring bone attenuation and using different tissue classes for generation of the attenuation map on the accuracy of attenuation correction of PET data. This work was performed using simulation studies based on the XCAT phantom and clinical input data. For the latter, PET and CT images of patients were used as input for the analytic simulation model using realistic activity distributions where CT-based attenuation correction was utilized as reference for comparison. For both phantom and clinical studies, the reference attenuation map was classified into various numbers of tissue classes to produce three (air, soft tissue and lung), four (air, lungs, soft tissue and cortical bones) and five (air, lungs, soft tissue, cortical bones and spongeous bones) class attenuation maps. The phantom studies demonstrated that ignoring bone increases the relative error by up to 6.8% in the body and up to 31.0% for bony regions. Likewise, the simulated clinical studies showed that the mean relative error reached 15% for lesions located in the body and 30.7% for lesions located in bones, when neglecting bones. These results demonstrate an underestimation of about 30% of tracer uptake when neglecting bone, which in turn imposes substantial loss of quantitative accuracy for PET images produced by hybrid PET/MRI systems. Considering bones in the attenuation map will considerably improve the accuracy of MR-guided attenuation correction in hybrid PET/MR to enable quantitative PET imaging on hybrid PET/MR technologies.

  13. BRMS1 Suppresses Breast Cancer Metastasis to Bone via its Regulation of microRNA-125b and Downstream Attenuation of TNF-alpha and HER2 Signaling Pathways

    Science.gov (United States)

    2012-10-01

    capabilities to metastasize to ovaries, liver, lungs, kidneys, and bones following intravenous injection. We also observed skull -restricted bioluminescent...MP, Shen J, Chang SS, Yu D, Steeg PS, and Hung MC. (2012) A novel model of breast cancer metastasis: killing two birds with one stone. AACR Annual...novel model of breast cancer metastasis: killing two birds with one stone Yekaterina B. Khotskaya1, Mariano Ponz Sarvice1, Jia Shen1,2, Shih-Shin

  14. Osthole inhibits bone metastasis of breast cancer

    OpenAIRE

    Wu, Chunyu; Sun, Zhenping; Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

    2017-01-01

    Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potent...

  15. Bone marrow macrophages support prostate cancer growth in bone.

    Science.gov (United States)

    Soki, Fabiana N; Cho, Sun Wook; Kim, Yeo Won; Jones, Jacqueline D; Park, Serk In; Koh, Amy J; Entezami, Payam; Daignault-Newton, Stephanie; Pienta, Kenneth J; Roca, Hernan; McCauley, Laurie K

    2015-11-03

    Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone.

  16. Cancer Cell Colonisation in the Bone Microenvironment

    Directory of Open Access Journals (Sweden)

    Casina Kan

    2016-10-01

    Full Text Available Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow epithelial-to-mesenchymal transition, extravasation and migration. Within the bone metastatic niche, disseminated tumour cells may enter a dormancy stage or proliferate to adapt and survive, interacting with bone cells such as hematopoietic stem cells, osteoblasts and osteoclasts. Cross-talk with the bone may alter tumour cell properties and, conversely, tumour cells may also acquire characteristics of the surrounding microenvironment, in a process known as osteomimicry. Alternatively, these cells may also express osteomimetic genes that allow cell survival or favour seeding to the bone marrow. The seeding of tumour cells in the bone disrupts bone-forming and bone-resorbing activities, which can lead to macrometastasis in bone. At present, bone macrometastases are incurable with only palliative treatment available. A better understanding of how these processes influence the early onset of bone metastasis may give insight into potential therapies. This review will focus on the early steps of bone colonisation, once disseminated tumour cells enter the bone marrow.

  17. Whole-body PET/MRI: The effect of bone attenuation during MR-based attenuation correction in oncology imaging

    Energy Technology Data Exchange (ETDEWEB)

    Aznar, M.C., E-mail: marianne.aznar@regionh.dk [Department of Oncology, Section of Radiotherapy 3994, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen (Denmark); Sersar, R., E-mail: rachidadk@hotmail.com [DTU Informatics, Technical University of Denmark, Kongens Lyngby (Denmark); Saabye, J., E-mail: julie_saa@hotmail.com [DTU Informatics, Technical University of Denmark, Kongens Lyngby (Denmark); Ladefoged, C.N., E-mail: claesnl@gmail.com [Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen (Denmark); Andersen, F.L., E-mail: Flemming.Andersen@regionh.dk [Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen (Denmark); Rasmussen, J.H., E-mail: jacobrasmu@gmail.com [Department of Oncology, Section of Radiotherapy 3994, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen (Denmark); Löfgren, J., E-mail: Johan.Loefgren@regionh.dk [Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen (Denmark); Beyer, T., E-mail: thomas.beyer@meduniwien.ac.at [Centre for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna (Austria)

    2014-07-15

    Purpose: In combined PET/MRI standard PET attenuation correction (AC) is based on tissue segmentation following dedicated MR sequencing and, typically, bone tissue is not represented. We evaluate PET quantification in whole-body (WB)-PET/MRI following MR-AC without considering bone attenuation and then investigate different strategies to account for bone tissue in clinical PET/MR imaging. To this purpose, bone tissue representation was extracted from separate CT images, and different bone representations were simulated from hypothetically derived MR-based bone classifications. Methods: Twenty oncology patients referred for a PET/CT were injected with either [18F]-FDG or [18F]-NaF and imaged on PET/CT (Biograph TruePoint/mCT, Siemens) and PET/MRI (mMR, Siemens) following a standard single-injection, dual-imaging clinical WB-protocol. Routine MR-AC was based on in-/opposed-phase MR imaging (orgMR-AC). PET(/MRI) images were reconstructed (AW-OSEM, 3 iterations, 21 subsets, 4 mm Gaussian) following routine MR-AC and MR-AC based on four modified attenuation maps. These modified attenuation maps were created for each patient by non-linear co-registration of the CT images to the orgMR-AC images, and adding CT bone mask values representing cortical bone: 1200 HU (cortCT), spongiosa bone: 350 HU (spongCT), average CT value (meanCT) and original CT values (orgCT). Relative difference images of the PET following AC using the modified attenuation maps were compared. SUVmean was calculated in anatomical reference regions and for PET-positive lesions. Results: The relative differences in SUVmean across patients following orgMR-AC and orgCT in soft tissue lesions and in bone lesions were similar (range: 0.0% to −22.5%), with an average underestimation of SUVmean of 7.2% and 10.0%, respectively when using orgMR-AC. In bone lesions, spongCT values were closest to orgCT (median bias of 1.3%, range: –9.0% to 13.5%) while the overestimation of SUVmean with respect to orgCT was

  18. Osthole inhibits bone metastasis of breast cancer.

    Science.gov (United States)

    Wu, Chunyu; Sun, Zhenping; Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

    2017-08-29

    Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-β/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases.

  19. Monocyte chemotactic protein-1 deficiency attenuates and high-fat diet exacerbates bone loss in mice with Lewis lung carcinoma.

    Science.gov (United States)

    Yan, Lin; Nielsen, Forrest H; Sundaram, Sneha; Cao, Jay

    2017-04-04

    Bone loss occurs in obesity and cancer-associated complications including wasting. This study determined whether a high-fat diet and a deficiency in monocyte chemotactic protein-1 (MCP-1) altered bone structural defects in male C57BL/6 mice with Lewis lung carcinoma (LLC) metastases in lungs. Compared to non-tumor-bearing mice, LLC reduced bone volume fraction, connectivity density, trabecular number, trabecular thickness and bone mineral density and increased trabecular separation in femurs. Similar changes occurred in vertebrae. The high-fat diet compared to the AIN93G diet exacerbated LLC-induced detrimental structural changes; the exacerbation was greater in femurs than in vertebrae. Mice deficient in MCP-1 compared to wild-type mice exhibited increases in bone volume fraction, connectivity density, trabecular number and decreases in trabecular separation in both femurs and vertebrae, and increases in trabecular thickness and bone mineral density and a decrease in structure model index in vertebrae. Lewis lung carcinoma significantly decreased osteocalcin but increased tartrate-resistant acid phosphatase 5b (TRAP 5b) in plasma. In LLC-bearing mice, the high-fat diet increased and MCP-1 deficiency decreased plasma TRAP 5b; neither the high-fat diet nor MCP-1 deficiency resulted in significant changes in plasma concentration of osteocalcin. In conclusion, pulmonary metastasis of LLC is accompanied by detrimental bone structural changes; MCP-1 deficiency attenuates and high-fat diet exacerbates the metastasis-associated bone wasting.

  20. Bone health in patients with prostate cancer.

    Science.gov (United States)

    Miñana, B; Cózar, J M; Alcaraz, A; Morote, J; Gómez-Veiga, F J; Solsona, E; Rodríguez-Antolín, A; Carballido, J

    2014-12-01

    In patients with prostate cancer, bone health is compromised by advanced age at diagnosis, androgen suppression treatments and the developmentofbone metastases. In this paper the medical literature is reviewed in order to update the state of the art on their incidence, prevention and management. A literature review about bone involvement in patients with prostate cancer in different clinical settings is performed. Decreased bone mineral density is higher in patients diagnosed of prostate cancer before starting treatment than in healthy men with the same age. During the first year of treatment, a severe loss bone density is reported due to androgen suppression therapy. From then on, loss bone density seems to slow down, persisting at long-term. It is important to know the starting point and the dynamics of loss bone in order to prevent its progression. The skeletal events have an important impact on quality of life in patients with prostate cancer. Both Denosumab and Zoledronic Acid have proven effective in reducing loss bone. The prevention and management of bone involvement in patients with prostate cancer is critical to quality of life in these patients and requires an individualized approach. Before starting a prolonged androgen deprivation, baseline risk of fracture should be evaluated in order to adopt the proper protective measures. In patients with metastases, early treatments reducing the risk of bone events should be taken into account. Copyright © 2014 AEU. Published by Elsevier Espana. All rights reserved.

  1. The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain

    DEFF Research Database (Denmark)

    Appel, Camilla Kristine; Gallego-Pedersen, Simone; Andersen, Line

    2017-01-01

    Pain is a severe and debilitating complication of metastatic bone cancer. Current analgesics do not provide sufficient pain relief for all patients, creating a great need for new treatment options. The Src kinase, a non-receptor protein tyrosine kinase, is implicated in processes involved in cancer......-induced bone pain, including cancer growth, osteoclastic bone degradation and nociceptive signalling. Here we investigate the role of dasatinib, an oral Src kinase family and Bcr-Abl tyrosine kinase inhibitor, in an animal model of cancer-induced bone pain. Daily administration of dasatinib (15 mg/kg, p.......o.) from day 7 after inoculation of MRMT-1 mammary carcinoma cells significantly attenuated movement-evoked and non-evoked pain behaviour in cancer-bearing rats. Radiographic - and microcomputed tomographic analyses showed significantly higher relative bone density and considerably preserved bone micro...

  2. Study of radiation dose attenuation by skull bone in head during radiotherapy treatment using MCNP

    Energy Technology Data Exchange (ETDEWEB)

    Menezes, Artur F.; Boia, Leonardo S.; Trombetta, Debora M.; Martins, Maximiano C.; Reis Junior, Juraci P.; Silva, Ademir X., E-mail: ademir@con.ufrj.b [Coordenacao dos Programas de Pos-Graduacao de Engenharia (PEN/COPPE/UFRJ), RJ (Brazil). Programa de Engenharia Nuclear; Batista, Delano V.S., E-mail: delano@inca.gov.b [Instituto Nacional do Cancer (INCa), Rio de Janeiro, RJ (Brazil). Dept. de Fisica Medica

    2011-07-01

    In this study the MCNPX code was used to investigate possible influences of the attenuation beam by the surface bone during radiotherapy treatments of the skull. The computer simulation was performed on topographic image obtained from the National Cancer Institute, in Rio de Janeiro, database of patients treated with radiotherapy. The image segmentation process were performed using the SAPDI program developed to this purpose. The segmented image conversion for the input file recognized by MCNPX code was performed by SCAN2MCNP Software. The simulation was done using 10MeV Clinac 2300C spectrum considering two opposite parallel beams, with field size 2x2 and 4x4 cm{sup 2}, incident on a slice located above the eyes, containing two row of detectors positioned on the central region with a radius of 0.03 cm and arranged perpendicular to the radiation beams. After analyze the results, the relative error values in the range of 2 at 4% for the high dose region, and 26 at 37% for the low dose area were found, respectively. These differences were attributed to the radiation field attenuation on the bone surface at the entrance of the beam. It was observed that most situations on the high dose region the beam profile, from more realistic scenarios, became smaller than the one obtained when the tomography image was considered consisting of water. However for the low dose area the profile, obtained of the realistic situation, became higher than the one which was obtained when the tomography image was considered consisting of water. The results showed significant differences between both analyzed cases which show the need to use a correction factor by the treatment planning system used in radiotherapy services when the real chemical composition of patient head is unconsidered during the patient treatment planning. (author)

  3. The Extravehicular Suit Impact Load Attenuation Study for Use in Astronaut Bone Fracture Prediction

    Science.gov (United States)

    Lewandowski, Beth E.; Gilkey, Kelly M.; Sulkowski, Christina M.; Samorezov, Sergey; Myers, Jerry G.

    2011-01-01

    The NASA Integrated Medical Model (IMM) assesses the risk, including likelihood and impact of occurrence, of all credible in-flight medical conditions. Fracture of the proximal femur is a traumatic injury that would likely result in loss of mission if it were to happen during spaceflight. The low gravity exposure causes decreases in bone mineral density which heightens the concern. Researchers at the NASA Glenn Research Center have quantified bone fracture probability during spaceflight with a probabilistic model. It was assumed that a pressurized extravehicular activity (EVA) suit would attenuate load during a fall, but no supporting data was available. The suit impact load attenuation study was performed to collect analogous data. METHODS: A pressurized EVA suit analog test bed was used to study how the offset, defined as the gap between the suit and the astronaut s body, impact load magnitude and suit operating pressure affects the attenuation of impact load. The attenuation data was incorporated into the probabilistic model of bone fracture as a function of these factors, replacing a load attenuation value based on commercial hip protectors. RESULTS: Load attenuation was more dependent on offset than on pressurization or load magnitude, especially at small offsets. Load attenuation factors for offsets between 0.1 - 1.5 cm were 0.69 +/- 0.15, 0.49 +/- 0.22 and 0.35 +/- 0.18 for mean impact forces of 4827, 6400 and 8467 N, respectively. Load attenuation factors for offsets of 2.8 - 5.3 cm were 0.93 +/- 0.2, 0.94 +/- 0.1 and 0.84 +/- 0.5, for the same mean impact forces. Reductions were observed in the 95th percentile confidence interval of the bone fracture probability predictions. CONCLUSIONS: The reduction in uncertainty and improved confidence in bone fracture predictions increased the fidelity and credibility of the fracture risk model and its benefit to mission design and operational decisions.

  4. The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain

    DEFF Research Database (Denmark)

    Appel, Camilla Kristine; Gallego-Pedersen, Simone; Andersen, Line

    2017-01-01

    .o.) from day 7 after inoculation of MRMT-1 mammary carcinoma cells significantly attenuated movement-evoked and non-evoked pain behaviour in cancer-bearing rats. Radiographic - and microcomputed tomographic analyses showed significantly higher relative bone density and considerably preserved bone micro...... subunit 2B. These findings support a role of dasatinib as a disease modifying drug in pain pathologies characterized by increased osteoclast activity, such as bone metastases....

  5. Bone fracture in breast cancer patients with isolated bone metastasis.

    Science.gov (United States)

    Dibekoglu, C; Turanli, S; Karaman, N; Ozcelik, K Caglar; Erdogan, O

    2015-01-01

    To analyse the incidence of bone fracture of breast cancer patients with isolated bone metastasis and its effect on survival. We tried to find an answer to the question of "Can the development of bone fracture be predicted?" Between 1993-2006, 139 breast cancer patients with isolated bone metastasis were examined. Patients were divided into two groups depending on the development of pathologic bone fracture. Fractures were developed in 41 patients (29.5%)within 41 months of follow-up. The locations of pathologic bone fracture were vertebral fracture in 26 patients (63.4%),femur fracture in 11 patients (26.8%), and hip fracture in four patients (9.8%). Fracture rates in hormone sensitive and resistant patients were 31.2% and 14.3%, respectively. The fracture rates in 13 triple negative and non triple negative patients were 7.7% and 31.4%, respectively (p=0.07). High CA 15-3 levels at the time of metastasis in patients with and without fractures were 68.4% and 61.1%, respectively. The risk for fracture was also high in Her2-neu positive patients (38.7% vs. 26.5%). While the incidence of fracture with the presence of one factor mentioned above was 22.2%, it was increased to 36.1% in the presence of two or three factors(p=0.13). Median survivals of the patients with and without fractures were 48 and 39 months, respectively (p= 0.65). Hormone sensitivity, high CA 15-3 levels and positive Her2-neu status are slight risk factors for bone fractures. Survival was not different in patients with or without bone fractures. Celsius.

  6. Bone attenuation on routine chest CT correlates with bone mineral density on DXA in patients with COPD.

    Science.gov (United States)

    Romme, Elisabeth A P M; Murchison, John T; Phang, Kee F; Jansen, Frits H; Rutten, Erica P A; Wouters, Emiel F M; Smeenk, Frank W J M; Van Beek, Edwin J R; Macnee, William

    2012-11-01

    Chronic obstructive pulmonary disease (COPD), although primarily a disease of the lungs, is associated with extrapulmonary effects such as muscle weakness and osteoporosis. Fractures owing to osteoporosis cause significant morbidity and mortality, particularly in patients with COPD. To prevent osteoporotic fractures, it is important to diagnose osteoporosis in an early stage and to start anti-osteoporotic therapy in at-risk patients. Because routine chest computed tomography (CT) is increasingly used to assess the extent of emphysema and airways disease in patients with COPD, we investigated whether simple attenuation measurement of the thoracic spine on routine chest CT may provide useful information on bone health in patients with COPD. Fifty-eight patients with moderate to very severe COPD were included in our study. The average attenuation of thoracic vertebrae 4, 7, and 10 on chest CT was correlated with the lowest bone mineral density (BMD) of the hip and lumbar spine (L(1) to L(4)) on dual-energy X-ray absorptiometry (DXA) in patients with COPD. The inter- and intra-observer variabilities of the attenuation measurements were low as shown by Bland-Altman plots. Pearson's correlation coefficient between the average attenuation of the three thoracic vertebrae and the lowest BMD of the hip and lumbar spine was high (r = 0.827, p bone attenuation measured on routine chest CT correlated strongly with BMD assessed on DXA in patients with COPD. Routine chest CT may provide useful information on bone health in patients with COPD. Copyright © 2012 American Society for Bone and Mineral Research.

  7. Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow?

    Directory of Open Access Journals (Sweden)

    Mary C. Farach-Carson

    2017-08-01

    Full Text Available Sex-associated differences in bone metastasis formation from breast, lung, and prostate cancer exist in clinical studies, but have not been systematically reviewed. Differences in the bone marrow niche can be attributed to sexual dimorphism, to genetic variations that affect sex hormone levels, or to the direct effects of sex hormones, natural or exogenously delivered. This review describes the present understanding of sex-associated and sex hormone level differences in the marrow niche and in formation of bone metastasis during the transition of these three cancers from treatable disease to an often untreatable, lethal metastatic one. Our purpose is to provide insight into some underlying molecular mechanisms for hormonal influence in bone metastasis formation, and to the potential influence of sexual dimorphism, genetic differences affecting sex assignment, and sex hormone level differences on the bone niche and its favorability for metastasis formation. We reviewed publications in PubMed and EMBASE, including full length manuscripts, case reports, and clinical studies of relevance to our topic. We focused on bone metastasis formation in breast, lung, and prostate cancer because all three commonly present with bone metastases. Several clear observations emerged. For breast cancer bone metastasis formation, estrogen receptor (ER signaling pathways indicate a role for ER beta (ERβ. Estrogen influences the bone microenvironment, creating and conditioning a favorable niche for colonization and breast cancer progression. For lung cancer, studies support the hypothesis that females have a more favorable bone microenvironment for metastasis formation. For prostate cancer, a decrease in the relative androgen to estrogen balance or a “feminization” of bone marrow favors bone metastasis formation, with a potentially important role for ERβ that may be similar to that in breast cancer. Long-term estrogen administration or androgen blockade in males

  8. Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow?

    Science.gov (United States)

    Farach-Carson, Mary C; Lin, Sue-Hwa; Nalty, Theresa; Satcher, Robert L

    2017-01-01

    Sex-associated differences in bone metastasis formation from breast, lung, and prostate cancer exist in clinical studies, but have not been systematically reviewed. Differences in the bone marrow niche can be attributed to sexual dimorphism, to genetic variations that affect sex hormone levels, or to the direct effects of sex hormones, natural or exogenously delivered. This review describes the present understanding of sex-associated and sex hormone level differences in the marrow niche and in formation of bone metastasis during the transition of these three cancers from treatable disease to an often untreatable, lethal metastatic one. Our purpose is to provide insight into some underlying molecular mechanisms for hormonal influence in bone metastasis formation, and to the potential influence of sexual dimorphism, genetic differences affecting sex assignment, and sex hormone level differences on the bone niche and its favorability for metastasis formation. We reviewed publications in PubMed and EMBASE, including full length manuscripts, case reports, and clinical studies of relevance to our topic. We focused on bone metastasis formation in breast, lung, and prostate cancer because all three commonly present with bone metastases. Several clear observations emerged. For breast cancer bone metastasis formation, estrogen receptor (ER) signaling pathways indicate a role for ER beta (ERβ). Estrogen influences the bone microenvironment, creating and conditioning a favorable niche for colonization and breast cancer progression. For lung cancer, studies support the hypothesis that females have a more favorable bone microenvironment for metastasis formation. For prostate cancer, a decrease in the relative androgen to estrogen balance or a "feminization" of bone marrow favors bone metastasis formation, with a potentially important role for ERβ that may be similar to that in breast cancer. Long-term estrogen administration or androgen blockade in males may feminize the bone

  9. Inhibition of breast cancer-cell glutamate release with sulfasalazine limits cancer-induced bone pain.

    Science.gov (United States)

    Ungard, Robert G; Seidlitz, Eric P; Singh, Gurmit

    2014-01-01

    Cancer in bone is frequently a result of metastases from distant sites, particularly from the breast, lung, and prostate. Pain is a common and often severe pathological feature of cancers in bone, and is a significant impediment to the maintenance of quality of life of patients living with bone metastases. Cancer cell lines have been demonstrated to release significant amounts of the neurotransmitter and cell-signalling molecule l-glutamate via the system xC(-) cystine/glutamate antiporter. We have developed a novel mouse model of breast cancer bone metastases to investigate the impact of inhibiting cancer cell glutamate transporters on nociceptive behaviour. Immunodeficient mice were inoculated intrafemorally with the human breast adenocarcinoma cell line MDA-MB-231, then treated 14days later via mini-osmotic pumps inserted intraperitoneally with sulfasalazine, (S)-4-carboxyphenylglycine, or vehicle. Both sulfasalazine and (S)-4-carboxyphenylglycine attenuated in vitro cancer cell glutamate release in a dose-dependent manner via the system xC(-) transporter. Animals treated with sulfasalazine displayed reduced nociceptive behaviours and an extended time until the onset of behavioural evidence of pain. Animals treated with a lower dose of (S)-4-carboxyphenylglycine did not display this reduction in nociceptive behaviour. These results suggest that a reduction in glutamate secretion from cancers in bone with the system xC(-) inhibitor sulfasalazine may provide some benefit for treating the often severe and intractable pain associated with bone metastases. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  10. Cannabinoids attenuate cancer pain and proliferation in a mouse model.

    Science.gov (United States)

    Saghafi, Negin; Lam, David K; Schmidt, Brian L

    2011-01-25

    We investigated the effects of cannabinoid receptor agonists on (1) oral cancer cell viability in vitro and (2) oral cancer pain and tumor growth in a mouse cancer model. We utilized immunohistochemistry and Western blot to show that human oral cancer cells express CBr1 and CBr2. When treated with WIN55,212-2 (non-selective), ACEA (CBr1-selective) or AM1241 (CBr2-selective) agonists in vitro, oral cancer cell proliferation was significantly attenuated in a dose-dependent manner. In vivo, systemic administration (0.013M) of WIN55,212-2, ACEA, or AM1241 significantly attenuated cancer-induced mechanical allodynia. Tumor growth was also significantly attenuated with systemic AM1241 administration. Our findings suggest a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  11. Macrophage Efferocytosis and Prostate Cancer Bone Metastasis

    Science.gov (United States)

    2016-10-01

    mass and alter bone remodeling. 15. SUBJECT TERMS Macrophages, Efferocytosis, Prostate Cancer, Bone 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...cytokines, interfering with HIF-1 also promotes the generation of a specialized tumor- killing class of T cells - the so-called “cytotoxic T lymphocytes...cells possess higher killing capacity compared to WT cells (data not shown). 6 Summary: In summary, we have made considerable progress in our

  12. Bone Cancer: Questions and Answers

    Science.gov (United States)

    ... often in the knee and upper arm ( 1 ). Chondrosarcoma , which begins in cartilaginous tissue. Cartilage pads the ends of bones and lines the joints. Chondrosarcoma occurs most often in the pelvis (located between ...

  13. Attenuation of postmenopausal bone loss in patients with transient hypoparathyroidism after total thyroidectomy.

    Science.gov (United States)

    Takamura, Yuuki; Miyauchi, Akira; Yabuta, Tomonori; Kihara, Minoru; Ito, Yasuhiro; Miya, Akihiro

    2013-12-01

    Increased bone mineral density (BMD) has been reported in patients with postsurgical permanent hypoparathyroidism. Hypoparathyroidism may attenuate the high-turnover bone loss in postmenopausal women. We reported previously that patients who had transient hypoparathyroidism postoperatively were at subclinical hypoparathyroid (hP) status even 5 years after surgery. We hypothesized that patients with transient hypoparathyroidism (ThP) may have altered BMD. A total of 140 women who underwent total thyroidectomy had BMD measurements of the lumbar spine, femoral neck, and radius 3 years after surgery. At surgery, 99 patients were ≥50 years and 41 were 0 were significantly associated only with the presence of ThP postoperatively. In the patients attenuation of the high-turnover bone loss in postmenopausal women.

  14. Could Cancer Initiate From Bone Marrow Progenitors?

    OpenAIRE

    Ben Nasr, Hmed; Hammami, Serria Turky; Zeghal, Khaled

    2013-01-01

    Background Defining cancer stem cells and their origins is of much controversy,and constitutes a challenged knockout for cell targeting- anticancer drugs. Herein,we put forward a hypothetic model for cancer stem cells initiation from bone marrow stem cells. These later, will differentiate into an ancestral progenitor that activates a memorial program - the black box cassette- that is responsible of abnormal neo-organogenesis in the form of tumors and metastases. To approve this model, we assu...

  15. Numerical and experimental study on the wave attenuation in bone--FDTD simulation of ultrasound propagation in cancellous bone.

    Science.gov (United States)

    Nagatani, Yoshiki; Mizuno, Katsunori; Saeki, Takashi; Matsukawa, Mami; Sakaguchi, Takefumi; Hosoi, Hiroshi

    2008-11-01

    In cancellous bone, longitudinal waves often separate into fast and slow waves depending on the alignment of bone trabeculae in the propagation path. This interesting phenomenon becomes an effective tool for the diagnosis of osteoporosis because wave propagation behavior depends on the bone structure. Since the fast wave mainly propagates in trabeculae, this wave is considered to reflect the structure of trabeculae. For a new diagnosis method using the information of this fast wave, therefore, it is necessary to understand the generation mechanism and propagation behavior precisely. In this study, the generation process of fast wave was examined by numerical simulations using elastic finite-difference time-domain (FDTD) method and experimental measurements. As simulation models, three-dimensional X-ray computer tomography (CT) data of actual bone samples were used. Simulation and experimental results showed that the attenuation of fast wave was always higher in the early state of propagation, and they gradually decreased as the wave propagated in bone. This phenomenon is supposed to come from the complicated propagating paths of fast waves in cancellous bone.

  16. Tumor Tissue-Derived Formaldehyde and Acidic Microenvironment Synergistically Induce Bone Cancer Pain

    Science.gov (United States)

    Yang, Fei; Han, Ying; Li, Hui; Luo, Hongjun; Duan, Bo; Xu, Tianle; Maoying, Qiliang; Tan, Huangying; Wang, Jun; Zhao, Hongmei; Liu, Fengyu; Wan, You

    2010-01-01

    Background There is current interest in understanding the molecular mechanisms of tumor-induced bone pain. Accumulated evidence shows that endogenous formaldehyde concentrations are elevated in the blood or urine of patients with breast, prostate or bladder cancer. These cancers are frequently associated with cancer pain especially after bone metastasis. It is well known that transient receptor potential vanilloid receptor 1 (TRPV1) participates in cancer pain. The present study aims to demonstrate that the tumor tissue-derived endogenous formaldehyde induces bone cancer pain via TRPV1 activation under tumor acidic environment. Methodology/Principal Findings Endogenous formaldehyde concentration increased significantly in the cultured breast cancer cell lines in vitro, in the bone marrow of breast MRMT-1 bone cancer pain model in rats and in tissues from breast cancer and lung cancer patients in vivo. Low concentrations (1∼5 mM) of formaldehyde induced pain responses in rat via TRPV1 and this pain response could be significantly enhanced by pH 6.0 (mimicking the acidic tumor microenvironment). Formaldehyde at low concentrations (1 mM to 100 mM) induced a concentration-dependent increase of [Ca2+]i in the freshly isolated rat dorsal root ganglion neurons and TRPV1-transfected CHO cells. Furthermore, electrophysiological experiments showed that low concentration formaldehyde-elicited TRPV1 currents could be significantly potentiated by low pH (6.0). TRPV1 antagonists and formaldehyde scavengers attenuated bone cancer pain responses. Conclusions/Significance Our data suggest that cancer tissues directly secrete endogenous formaldehyde, and this formaldehyde at low concentration induces metastatic bone cancer pain through TRPV1 activation especially under tumor acidic environment. PMID:20422007

  17. Acupuncture for Cancer-Induced Bone Pain?

    Directory of Open Access Journals (Sweden)

    Carole A. Paley

    2011-01-01

    Full Text Available Bone pain is the most common type of pain in cancer. Bony metastases are common in advanced cancers, particularly in multiple myeloma, breast, prostate or lung cancer. Current pain-relieving strategies include the use of opioid-based analgesia, bisphosphonates and radiotherapy. Although patients experience some pain relief, these interventions may produce unacceptable side-effects which inevitably affect the quality of life. Acupuncture may represent a potentially valuable adjunct to existing strategies for pain relief and it is known to be relatively free of harmful side-effects. Although acupuncture is used in palliative care settings for all types of cancer pain the evidence-base is sparse and inconclusive and there is very little evidence to show its effectiveness in relieving cancer-induced bone pain (CIBP. The aim of this critical review is to consider the known physiological effects of acupuncture and discuss these in the context of the pathophysiology of malignant bone pain. The aim of future research should be to produce an effective protocol for treating CIBP with acupuncture based on a sound, evidence-based rationale. The physiological mechanisms presented in this review suggest that this is a realistic objective.

  18. Regulation of Prostate Cancer Bone Metastasis by DKK1

    Science.gov (United States)

    2012-09-01

    blocks the formation of osteoblastic bone lesions in animal models of bone metastasis. We have now shown that human prostate cancer cell lines...that produce osteolytic, but not osteoblastic, bone lesions in animal models of bone metastasis express significant amounts of DKK1 and this expression...cancer bone metastasis typically results in massive osteolysis from the secretion of osteoclast-activating factors, such as parathyroid hormone-related

  19. BRMS1 Suppresses Breast Cancer Metastasis to Bone via Its Regulation of MicroRNA-125b and Downstream Attenuation of TNF-alpha and HER2 Signaling Pathways

    Science.gov (United States)

    2013-10-01

    pharmacologic means [12]. Since AMPK activating compounds, such as 2-DG and Metformin , are being tested in pre-clinical applications as potential anti-cancer...family receptors and interleukin-6. Br J Cancer 79: 707-717. 4. Meehan WJ, Samant RS, Hopper JE, Carrozza MJ, Shevde LA , et al. (2004) Breast cancer...transmigration across the endothelial barrier. J Cancer Res Clin Oncol 2002;128:533–538. 65. Krishnan V, Shuman LA , Sosnoski DM, et al. Dynamic

  20. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Megan N. Thobe

    2011-01-01

    Full Text Available Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1 characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2 chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3 current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies.

  1. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Thobe, Megan N. [Section of Urology, Department of Surgery, The University of Chicago, Chicago, IL 60637 (United States); Clark, Robert J. [Department of Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, IL 60637 (United States); Bainer, Russell O. [Department of Human Genetics, The University of Chicago, Chicago, IL 60637 (United States); Prasad, Sandip M.; Rinker-Schaeffer, Carrie W., E-mail: crinkers@uchicago.edu [Section of Urology, Department of Surgery, The University of Chicago, Chicago, IL 60637 (United States)

    2011-01-27

    Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies.

  2. Targeting A-type K(+) channels in primary sensory neurons for bone cancer pain in a rat model.

    Science.gov (United States)

    Duan, Kai-Zheng; Xu, Qian; Zhang, Xiao-Meng; Zhao, Zhi-Qi; Mei, Yan-Ai; Zhang, Yu-Qiu

    2012-03-01

    Cancer pain is one of the most severe types of chronic pain, and the most common cancer pain is bone cancer pain. The treatment of bone cancer pain remains a clinical challenge. Here, we report firstly that A-type K(+) channels in dorsal root ganglion (DRG) are involved in the neuropathy of rat bone cancer pain and are a new target for diclofenac, a nonsteroidal anti-inflammatory drug that can be used for therapy for this distinct pain. There are dynamically functional changes of the A-type K(+) channels in DRG neurons during bone cancer pain. The A-type K(+) currents that mainly express in isolectin B4-positive small DRG neurons are increased on post-tumor day 14 (PTD 14), then faded but still remained at a higher level on PTD 21. Correspondingly, the expression levels of A-type K(+) channel Kv1.4, Kv3.4, and Kv4.3 showed time-dependent changes during bone cancer pain. Diclofenac enhances A-type K(+) currents in the DRG neurons and attenuates bone cancer pain in a dose-dependent manner. The analgesic effect of diclofenac can be reversed or prevented by A-type K(+) channel blocker 4-AP or pandinotoxin-Kα, also by siRNA targeted against rat Kv1.4 or Kv4.3. Repeated diclofenac administration decreased soft tissue swelling adjacent to the tumor and attenuated bone destruction. These results indicate that peripheral A-type K(+) channels were involved in the neuropathy of rat bone cancer pain. Targeting A-type K(+) channels in primary sensory neurons may provide a novel mechanism-based therapeutic strategy for bone cancer pain. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  3. Hearing protection: Surpassing the limits to attenuation imposed by the bone-conduction pathways

    Science.gov (United States)

    Berger, Elliott H.; Kieper, Ronald W.; Gauger, Dan

    2003-10-01

    With louder and louder weapon systems being developed and military personnel being exposed to steady noise levels approaching and sometimes exceeding 150 dB, a growing interest in greater amounts of hearing protection is evident. When the need for communications is included in the equation, the situation is even more extreme. New initiatives are underway to design improved hearing protection, including active noise reduction (ANR) earplugs and perhaps even active cancellation of head-borne vibration. With that in mind it may be useful to explore the limits to attenuation, and whether they can be approached with existing technology. Data on the noise reduction achievable with high-attenuation foam earplugs, as a function of insertion depth, will be reported. Previous studies will be reviewed that provide indications of the bone-conduction (BC) limits to attenuation that, in terms of mean values, range from 40 to 60 dB across the frequencies from 125 Hz to 8 kHz. Additionally, new research on the effects of a flight helmet on the BC limits, as well as the potential attenuation from deeply inserted passive foam earplugs, worn with passive earmuffs, or with active-noise reduction (ANR) earmuffs, will be examined. The data demonstrate that gains in attenuation exceeding 10 dB above the head-not-covered limits can be achieved if the head is effectively shielded from acoustical stimulation.

  4. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    OpenAIRE

    Thobe, Megan N.; Rinker-Schaeffer, Carrie W.; Clark, Robert J.; Bainer, Russell O; Prasad, Sandip M.

    2011-01-01

    Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules ...

  5. BRMS1 Suppresses Breast Cancer Metastasis to Bone via Its Regulation of microRNA-125b and Downstream Attenuation of TNF-Alpha and HER2 Signaling Pathways

    Science.gov (United States)

    2014-04-01

    April 2014 TYPE OF REPORT: Annual Summary PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort...Materiel Command Fort Detrick, Maryland 21702-5012 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION / AVAILABILITY...related transcrip- tion factor; SRF, serum response factor; BRMS1, breast cancer metastasis suppressor 1; CTC, circulating tumor cells; DTC , dissemi

  6. High dose compressive loads attenuate bone mineral loss in humans with spinal cord injury

    Science.gov (United States)

    Dudley-Javoroski, S.; Saha, P. K.; Liang, G.; Li, C.; Gao, Z.

    2012-01-01

    Summary People with spinal cord injury (SCI) lose bone and muscle integrity after their injury. Early doses of stress, applied through electrically induced muscle contractions, preserved bone density at high-risk sites. Appropriately prescribed stress early after the injury may be an important consideration to prevent bone loss after SCI. Introduction Skeletal muscle force can deliver high compressive loads to bones of people with spinal cord injury (SCI). The effective osteogenic dose of load for the distal femur, a chief site of fracture, is unknown. The purpose of this study is to compare three doses of bone compressive loads at the distal femur in individuals with complete SCI who receive a novel stand training intervention. Methods Seven participants performed unilateral quadriceps stimulation in supported stance [150% body weight (BW) compressive load—“High Dose” while opposite leg received 40% BW—“Low Dose”]. Five participants stood passively without applying quadriceps electrical stimulation to either leg (40% BW load—“Low Dose”). Fifteen participants performed no standing (0% BW load—“Untrained”) and 14 individuals without SCI provided normative data. Participants underwent bone mineral density (BMD) assessment between one and six times over a 3-year training protocol. Results BMD for the High Dose group significantly exceeded BMD for both the Low Dose and the Untrained groups (p0.05), indicating that BMD for participants performing passive stance did not differ from individuals who performed no standing. High-resolution CT imaging of one High Dose participant revealed 86% higher BMD and 67% higher trabecular width in the High Dose limb. Conclusion Over 3 years of training, 150% BW compressive load in upright stance significantly attenuated BMD decline when compared to passive standing or to no standing. High-resolution CT indicated that trabecular architecture was preserved by the 150% BW dose of load. PMID:22187008

  7. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis.

    Science.gov (United States)

    Zhen, Gehua; Wen, Chunyi; Jia, Xiaofeng; Li, Yu; Crane, Janet L; Mears, Simon C; Askin, Frederic B; Frassica, Frank J; Chang, Weizhong; Yao, Jie; Carrino, John A; Cosgarea, Andrew; Artemov, Dmitri; Chen, Qianming; Zhao, Zhihe; Zhou, Xuedong; Riley, Lee; Sponseller, Paul; Wan, Mei; Lu, William Weijia; Cao, Xu

    2013-06-01

    Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor β1 (TGF-β1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-β1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-β1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-β1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-β activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-β type II receptor (TβRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-β1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.

  8. Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis.

    Science.gov (United States)

    Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi; Harazono, Yosuke; Hogan, Victor; Chen, Wei; Ali-Fehmi, Rouba; Mehra, Rohit; Raz, Avraham

    2016-03-15

    Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158-175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche. ©2016 American Association for Cancer Research.

  9. Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice.

    Science.gov (United States)

    Hara, Toshiro; Murakami, Yoshinori; Seiki, Motoharu; Sakamoto, Takeharu

    2017-08-26

    Breast cancer is one of the most common cancers in women in the world. Although breast cancer is well treatable at the early stage, patients with distant metastases show a poor prognosis. Data from recent studies using transplantation models indicate that Mint3/APBA3 might promote breast cancer malignancy. However, whether Mint3 indeed contributes to tumor development, progression, or metastasis in vivo remains unclear. To address this, here we examined whether Mint3 depletion affects tumor malignancy in MMTV-PyMT breast cancer model mice. In MMTV-PyMT mice, Mint3 depletion did not affect tumor onset and tumor growth, but attenuated lung metastases. Experimental lung metastasis of breast cancer Met-1 cells derived from MMTV-PyMT mice also decreased in Mint3-depleted mice, indicating that host Mint3 expression affected lung metastasis of MMTV-PyMT-derived breast cancer cells. Further bone marrow transplant experiments revealed that Mint3 in bone marrow-derived cells promoted lung metastasis in MMTV-PyMT mice. Thus, targeting Mint3 in bone marrow-derived cells might be a good strategy for preventing metastasis and improving the prognosis of breast cancer patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Treatment with bone-seeking radionuclides for painful bone metastases in patients with lung cancer

    DEFF Research Database (Denmark)

    Zacho, Helle D; Karthigaseu, Nita Nishanthiny; Fuglsang, Randi

    2017-01-01

    Treatment with bone-seeking radionuclides may provide palliation from pain originating from bone metastases. However, most studies have been conducted in patients with prostate cancer and patients with breast cancer. We aimed to perform a systematic review of the use of radionuclide treatment in ...

  11. Noninvasive Femur Bone Volume Estimation Based on X-Ray Attenuation of a Single Radiographic Image and Medical Knowledge

    Science.gov (United States)

    Kiattisin, Supaporn; Chamnongthai, Kosin

    Bone Mineral Density (BMD) is an indicator of osteoporosis that is an increasingly serious disease, particularly for the elderly. To calculate BMD, we need to measure the volume of the femur in a noninvasive way. In this paper, we propose a noninvasive bone volume measurement method using x-ray attenuation on radiography and medical knowledge. The absolute thickness at one reference pixel and the relative thickness at all pixels of the bone in the x-ray image are used to calculate the volume and the BMD. First, the absolute bone thickness of one particular pixel is estimated by the known geometric shape of a specific bone part as medical knowledge. The relative bone thicknesses of all pixels are then calculated by x-ray attenuation of each pixel. Finally, given the absolute bone thickness of the reference pixel, the absolute bone thickness of all pixels is mapped. To evaluate the performance of the proposed method, experiments on 300 subjects were performed. We found that the method provides good estimations of real BMD values of femur bone. Estimates shows a high linear correlation of 0.96 between the volume Bone Mineral Density (vBMD) of CT-SCAN and computed vBMD (all PCT-SCAN.

  12. Bone Cancer Rates in Dinosaurs Compared with Modern Vertebrates

    CERN Document Server

    Natarajan, L C; Rothschild, B M; Martin, L D

    2007-01-01

    Data on the prevalence of bone cancer in dinosaurs is available from past radiological examination of preserved bones. We statistically test this data for consistency with rates extrapolated from information on bone cancer in modern vertebrates, and find that there is no evidence of a different rate. Thus, this test provides no support for a possible role of ionizing radiation in the K-T extinction event.

  13. Survival after bone metastasis by primary cancer type

    DEFF Research Database (Denmark)

    Svensson, Elisabeth; Christiansen, Christian F; Ulrichsen, Sinna P

    2017-01-01

    between 1994 and 2010, subsequently diagnosed with BM until 2012. We followed patients from date of bone metastasis diagnosis until death, emigration or 31 December 2012, whichever came first. We computed 1-year, 3-year and 5-year survival (%) and the corresponding 95% CIs stratified on primary cancer...... type. Comparing patients with bone metastasis only and patients with other synchronous metastases, we estimated crude and adjusted HRs and corresponding 95% CI for mortality. RESULTS: We included 17 251 patients with bone metastasis. The most common primary cancer types with bone metastasis were...... prostate (34%), breast (22%) and lung (20%). One-year survival after bone metastasis diagnosis was lowest in patients with lung cancer (10%, 95% CI 9% to 11%) and highest in patients with breast cancer (51%, 50% to 53%). At 5 years of follow-up, only patients with breast cancer had over 10% survival (13...

  14. The Breast Cancer to Bone (B2B) Metastases Research Program: a multi-disciplinary investigation of bone metastases from breast cancer

    National Research Council Canada - National Science Library

    Brockton, Nigel T; Gill, Stephanie J; Laborge, Stephanie L; Paterson, Alexander H G; Cook, Linda S; Vogel, Hans J; Shemanko, Carrie S; Hanley, David A; Magliocco, Anthony M; Friedenreich, Christine M

    2015-01-01

    .... The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases...

  15. Lithium attenuates lead induced toxicity on mouse non-adherent bone marrow cells.

    Science.gov (United States)

    Banijamali, Mahsan; Rabbani-Chadegani, Azra; Shahhoseini, Maryam

    2016-07-01

    Lead is a poisonous heavy metal that occurs in all parts of environment and causes serious health problems in humans. The aim of the present study was to investigate the possible protective effect of lithium against lead nitrate induced toxicity in non-adherent bone marrow stem cells. Trypan blue and MTT assays represented that exposure of the cells to different concentrations of lead nitrate decreased viability in a dose dependent manner, whereas, pretreatment of the cells with lithium protected the cells against lead toxicity. Lead reduced the number and differentiation status of bone marrow-derived precursors when cultured in the presence of colony stimulating factor (CSF), while the effect was attenuated by lithium. The cells treated with lead nitrate exhibited cell shrinkage, DNA fragmentation, anion superoxide production, but lithium prevented lead action. Moreover, apoptotic indexes such as PARP cleavage and release of HMGB1 induced by lead, were protected by lithium, suggesting anti-apoptotic effect of lithium. Immunoblot analysis of histone H3K9 acetylation indicated that lithium overcame lead effect on acetylation. In conclusion, lithium efficiently reduces lead toxicity suggesting new insight into lithium action which may contribute to increased cell survival. It also provides a potentially new therapeutic strategy for lithium and a cost-effective approach to minimize destructive effects of lead on bone marrow stem cells. Copyright © 2016 Elsevier GmbH. All rights reserved.

  16. Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain.

    Science.gov (United States)

    Hansen, Rikke R; Vacca, Valentina; Pitcher, Thomas; Clark, Anna K; Malcangio, Marzia

    2016-03-01

    Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber sprouting in the bone was associated with an increase in CGRP content in sensory neuron cell bodies in the dorsal root ganglia (DRG) and increased basal and activity-evoked release of CGRP from their central terminals in the dorsal horn. Intrathecal administration of a peptide antagonist (α-CGRP8-37) attenuated referred allodynia in the hind paw ipsilateral to bone cancer. CGRP receptor components (CLR and RAMP1) were up-regulated in dorsal horn neurons and expressed by reactive astrocytes. In primary cultures of astrocytes, CGRP incubation led to a concentration-dependent increase of forskolin-induced cAMP production, which was attenuated by pretreatment with CGRP8-37. Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP.

  17. Esophageal Cancer with Bone Marrow Hyperplasia Mimicking Bone Metastasis: Report of a Case.

    Science.gov (United States)

    Yasuda, Hiromi; Shimura, Tadanobu; Okigami, Masato; Yoshiyama, Shigeyuki; Ohi, Masaki; Tanaka, Koji; Mohri, Yasuhiko; Kusunoki, Masato

    2016-01-01

    A 63-year-old man visited the clinic with numbness in the right hand. Magnetic resonance imaging demonstrated multiple low-intensity lesions in the cervical vertebrae and sacrum, which was suspicious of cervical bone metastasis. Fluorodeoxyglucose positron emission tomography/computed tomography revealed areas of increased fluorodeoxyglucose uptake in the thoracic esophagus, sternum and sacrum. A flat, elevated esophageal cancer was identified by upper gastrointestinal endoscopy, and the macroscopic appearance indicated early-stage disease. From the cervical, thoracic and abdominal computed tomography images, there were no metastatic lesions except for the bone lesions. To confirm whether the bone lesions were metastatic, we performed bone biopsy. The histopathological diagnosis was bone marrow hyperplasia. It was crucial for treatment planning to establish whether the lesions were distant metastases. Here, we report a case of esophageal cancer with bone marrow hyperplasia mimicking bone metastasis.

  18. Esophageal Cancer with Bone Marrow Hyperplasia Mimicking Bone Metastasis: Report of a Case

    Directory of Open Access Journals (Sweden)

    Hiromi Yasuda

    2016-11-01

    Full Text Available A 63-year-old man visited the clinic with numbness in the right hand. Magnetic resonance imaging demonstrated multiple low-intensity lesions in the cervical vertebrae and sacrum, which was suspicious of cervical bone metastasis. Fluorodeoxyglucose positron emission tomography/computed tomography revealed areas of increased fluorodeoxyglucose uptake in the thoracic esophagus, sternum and sacrum. A flat, elevated esophageal cancer was identified by upper gastrointestinal endoscopy, and the macroscopic appearance indicated early-stage disease. From the cervical, thoracic and abdominal computed tomography images, there were no metastatic lesions except for the bone lesions. To confirm whether the bone lesions were metastatic, we performed bone biopsy. The histopathological diagnosis was bone marrow hyperplasia. It was crucial for treatment planning to establish whether the lesions were distant metastases. Here, we report a case of esophageal cancer with bone marrow hyperplasia mimicking bone metastasis.

  19. Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Yibin Kang

    2016-06-01

    Full Text Available Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1 in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.

  20. Bone Marrow Microenvironmental Control of Prostate Cancer Skeletal Localization

    Science.gov (United States)

    2011-05-01

    implicate PTHrP derived from prostate cancer in the pathogenesis of prostate cancer metastasis to bone. This aspect of the project is complete...presented initial findings as an invited speaker at the Cancer Induced Bone Disease meeting in Chicago (abstract appended). There was a statistically...Affiliations: 1 Department of Periodontics and Oral Medicine, the University of Michigan School of Dentistry, Ann Arbor, MI; 2 Departments of

  1. Discoidin Domain Receptors: Novel Targets in Breast Cancer Bone Metastasis

    Science.gov (United States)

    2017-02-01

    AWARD NUMBER: W81XWH-16-1-0046 TITLE: Discoidin Domain Receptors: Novel Targets in Breast Cancer Bone Metastasis PRINCIPAL INVESTIGATOR: Dr...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Discoidin Domain Receptors: Novel Targets in Breast Cancer Bone Metastasis 5b. GRANT NUMBER W81XWH-16-1-0046 5c...14. ABSTRACT Here we report major findings for our project aimed at studying the expression of Discoidin Domain Receptors (DDRs) in breast cancer

  2. A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone.

    Science.gov (United States)

    Halvorson, Kyle G; Kubota, Kazufumi; Sevcik, Molly A; Lindsay, Theodore H; Sotillo, Julio E; Ghilardi, Joseph R; Rosol, Thomas J; Boustany, Leila; Shelton, David L; Mantyh, Patrick W

    2005-10-15

    Prostate cancer is unique in that bone is often the only clinically detectable site of metastasis. Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and some neuropathic pain states in animal models, an NGF-sequestering antibody was administered in a prostate model of bone cancer where significant bone formation and bone destruction occur simultaneously in the mouse femur. Administration of a blocking antibody to NGF produced a significant reduction in both early and late stage bone cancer pain-related behaviors that was greater than or equivalent to that achieved with acute administration of 10 or 30 mg/kg of morphine sulfate. In contrast, this therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. One rather unique aspect of the sensory innervation of bone, that may partially explain the analgesic efficacy of anti-NGF therapy in relieving prostate cancer-induced bone pain, is that nearly all nerve fibers that innervate the bone express trkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors. The present results suggest that anti-NGF therapy may be effective in reducing pain and enhancing the quality of life in patients with prostate tumor-induced bone cancer pain.

  3. Unexpected Bone Metastases from Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    Sandra Gibiezaite

    2015-01-01

    Full Text Available Objective. To present a complicated case of differentiated thyroid carcinoma (DTC with metastases to the skull that was evident on I-131 whole body scan (WBS but negative on other imaging modalities in a low risk patient. Methods. We will discuss clinical course, imaging, pathological findings, and treatment of the patient with skull metastasis from DTC. Pertinent literature on imaging and pathology findings as well as radioactive iodine (RAI treatment impact on quality of life and survival in patients with bone metastases from DTC will be reviewed. Results. The patient is a 37-year-old woman with a diagnosis of DTC who had focal areas of increased uptake in the head on WBS with no correlative findings on CT and MRI. Initially, false positive findings were suspected since patient had a low risk for developing metastases. However, the persistent findings on post-RAI treatment WBS, following two courses of treatment, were highly concerning for metastatic bone disease. WBC performed 6 months following the second RAI treatment revealed resolution of the findings. Conclusions. False positive findings in WBS are frequent and may be due to contamination, perspiration, or folliculitis of the scalp as well as benign lesions such as meningioma, hematoma, cavernous angioma, and metallic sutures. However, metastatic disease should always be considered even if the patient has low risk of distant metastatic disease and correlative images do not support the diagnosis. RAI therapy appears to improve the survival rates and quality of life of thyroid cancer patients with bone metastases based on retrospective studies.

  4. Calibration of cone beam CT using relative attenuation ratio for quantitative assessment of bone density: a small animal study.

    Science.gov (United States)

    Liu, Yifei; Bäuerle, Tobias; Pan, Leyun; Dimitrakopoulou-Strauss, Antonia; Strauss, Ludwig G; Heiss, Christian; Schnettler, Reinhard; Semmler, Wolfhard; Cao, Liji

    2013-09-01

    Cone beam computed tomography (CBCT) has the disadvantage of providing non-quantitative results for bone density determination. The aim of this study is to calibrate CBCT results by using an internal reference (such as muscle) for quantitatively assessing bone density. We developed a new method using the relative attenuation ratio between two nearby materials (such as bone and muscle) for systemic error correction in CBCT that depends on the relative object position in the image volume. Phantom calibration was performed to calculate the acquired attenuation ratio in Hounsfield units (HU), comparable to the results from clinical multislice spiral computed tomography (MSCT). In addition, a small animal study with an osteoporotic rat model was evaluated to show the feasibility of this presented method to quantitatively assess bone density using a CBCT system. The phantom study results showed that the calibration process successfully corrected the systemic inaccuracy from CBCT, and the calibrated HU values agreed with the values measured from MSCT. In the small animal study, the quantitative bone densities assessed from the calibrated CBCT results were consistent with the results from MSCT data. A practical method to quantitatively estimate attenuation (HU) values for bone tissues from CBCT scans that are comparable to MSCT scans is proposed. The method may improve the quantification ability of CBCT scanning without any additional hardware requirements.

  5. Is non-attenuation-corrected PET inferior to body attenuation-corrected PET or PET/CT in lung cancer?

    Energy Technology Data Exchange (ETDEWEB)

    Maintas, Dimitris [CMN, Hopital Pneumocardiologique de Lyon, 69394 Lyon Cedex (France)]. E-mail: maintas@otenet.gr; Houzard, Claire [CMN, Hopital Pneumocardiologique de Lyon, 69394 Lyon Cedex (France); Ksyar, Rachid [CMN, Hopital Pneumocardiologique de Lyon, 69394 Lyon Cedex (France); Mognetti, Thomas [Anticancer Center Leon Berard, Nuclear Medicine Department, Lyon (France); Maintas, Catherine [Institute of Isotopic Studies, Distomou 5-7, Maroussi (Greece); Scheiber, Christian [CMN, Hopital Pneumocardiologique de Lyon, 69394 Lyon Cedex (France); Itti, Roland [CMN, Hopital Pneumocardiologique de Lyon, 69394 Lyon Cedex (France)

    2006-12-20

    It is considered that one of the great strengths of PET imaging is the ability to correct for body attenuation. This enables better lesion uptake quantification and quality of PET images. The aim of this work is to compare the sensitivity of non-attenuation-corrected (NAC) PET images, the gamma photons (GPAC) and CT attenuation-corrected (CTAC) images in detecting and staging of lung cancer. We have studied 66 patients undergoing PET/CT examinations for detecting and staging NSC lung cancer. The patients were injected with 18-FDG; 5 MBq/kg under fasting conditions and examination was started 60 min later. Transmission data were acquired by a spiral CT X-ray tube and by gamma photons emitting Cs-137l source and were used for the patient body attenuation correction without correction for respiratory motion. In 55 of 66 patients we performed both attenuation correction procedures and in 11 patients only CT attenuation correction. In seven patients with solitary nodules PET was negative and in 59 patients with lung cancer PET/CT was positive for pulmonary or other localization. In the group of 55 patients we found 165 areas of focal increased 18-FDG uptake in NAC, 165 in CTAC and 164 in GPAC PET images.In the patients with only CTAC we found 58 areas of increased 18-FDG uptake on NAC and 58 areas lesions on CTAC. In the patients with positive PET we found 223 areas of focal increased uptake in NAC and 223 areas in CTAC images. The sensitivity of NAC was equal to the sensitivity of CTAC and GPAC images. The visualization of peripheral lesions was better in NAC images and the lesions were better localized in attenuation-corrected images. In three lesions of the thorax the localization was better in GPAC and fused images than in CTAC images.

  6. Review of Animal Models of Prostate Cancer Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Jessica K. Simmons

    2014-06-01

    Full Text Available Prostate cancer bone metastases are associated with a poor prognosis and are considered incurable. Insight into the formation and growth of prostate cancer bone metastasis is required for development of new imaging and therapeutic strategies to combat this devastating disease. Animal models are indispensable in investigating cancer pathogenesis and evaluating therapeutics. Multiple animal models of prostate cancer bone metastasis have been developed, but few effectively model prostatic neoplasms and osteoblastic bone metastases as they occur in men. This review discusses the animal models that have been developed to investigate prostate cancer bone metastasis, with a focus on canine models and also includes human xenograft and rodent models. Adult dogs spontaneously develop benign prostatic hyperplasia and prostate cancer with osteoblastic bone metastases. Large animal models, such as dogs, are needed to develop new molecular imaging tools and effective focal intraprostatic therapy. None of the available models fully reflect the metastatic disease seen in men, although the various models have provided important insight into the metastatic process. As additional models are developed and knowledge from the different models is combined, the molecular mechanisms of prostate cancer bone metastasis can be deciphered and targeted for development of novel therapies and molecular diagnostic imaging.

  7. SURGICAL TREATMENT FOR BONE METASTASES OF KIDNEY CANCER

    Directory of Open Access Journals (Sweden)

    A. S. Semkov

    2010-01-01

    Full Text Available The data of 67 kidney cancer (KC patients with bone metastases, who had been treated at Moscow City Cancer Hospital Sixty-Two in 2002 to 2009 and had undergone skeletal bone surgery, were retrospectively analyzed. The role of surgical treatment for bone metastases from KC was assessed and the factors influencing the patients survival were determined. Surgical treatment for bone metastases from KC was ascertained to yield satisfactory results in improving the quality of life and increasing survival rates in the patients.

  8. SURGICAL TREATMENT FOR BONE METASTASES OF KIDNEY CANCER

    Directory of Open Access Journals (Sweden)

    A. S. Semkov

    2014-08-01

    Full Text Available The data of 67 kidney cancer (KC patients with bone metastases, who had been treated at Moscow City Cancer Hospital Sixty-Two in 2002 to 2009 and had undergone skeletal bone surgery, were retrospectively analyzed. The role of surgical treatment for bone metastases from KC was assessed and the factors influencing the patients survival were determined. Surgical treatment for bone metastases from KC was ascertained to yield satisfactory results in improving the quality of life and increasing survival rates in the patients.

  9. Modern Detection of Prostate Cancer's Bone Metastasis: Is the Bone Scan Era Over?

    Directory of Open Access Journals (Sweden)

    Bertrand Tombal

    2012-01-01

    Full Text Available Prostate cancer cells have an exquisite tropism for bone, which clinically translates into the highest rate of bone metastases amongst male cancers. Although in the latest years there has been an active development of new “bone targeted” therapies, modern diagnostic techniques for bone metastases still relies mostly on 99mTc bone scanning (BS and plain X-ray. BS dramatically lacks specificity and sensitivity. Recent publications using modern imaging technologies have clearly pinpointed that BS grossly underestimates the true prevalence of bone metastasis. In addition BS does not allow tumour measurement and is, therefore, not appropriate to monitor response to therapy. This might be extremely important in patients harbouring high-risk localized disease that are eventually candidate for local therapy. Here we reviewed what are the emerging imaging strategies that are likely to supplant BS and to what extent they can be used in the clinic already.

  10. Continuous MR bone density measurement using water- and fat-suppressed projection imaging (WASPI) for PET attenuation correction in PET-MR

    Science.gov (United States)

    Huang, C.; Ouyang, J.; Reese, T. G.; Wu, Y.; El Fakhri, G.; Ackerman, J. L.

    2015-10-01

    Due to the lack of signal from solid bone in normal MR sequences for the purpose of MR-based attenuation correction, investigators have proposed using the ultrashort echo time (UTE) pulse sequence, which yields signal from bone. However, the UTE-based segmentation approach might not fully capture the intra- and inter-subject bone density variation, which will inevitably lead to bias in reconstructed PET images. In this work, we investigated using the water- and fat-suppressed proton projection imaging (WASPI) sequence to obtain accurate and continuous attenuation for bones. This approach is capable of accounting for intra- and inter-subject bone attenuation variations. Using data acquired from a phantom, we have found that that attenuation correction based on the WASPI sequence is more accurate and precise when compared to either conventional MR attenuation correction or UTE-based segmentation approaches.

  11. CCR2 elimination in mice results in larger and stronger tibial bones but bone loss is not attenuated following ovariectomy or muscle denervation.

    Science.gov (United States)

    Mader, Tara L; Novotny, Susan A; Lin, Angela S; Guldberg, Robert E; Lowe, Dawn A; Warren, Gordon L

    2014-11-01

    Bone loss due to age and disuse contributes to osteoporosis and increases fracture risk. It has been hypothesized that such bone loss can be attenuated by modulation of the C-C chemokine receptor 2 (CCR2) and/or its ligands. The objectives of this study were to examine the effects of genetic elimination of CCR2 on cortical and trabecular bones in the mouse tibia and how bone loss was impacted following disuse and estrogen loss. Female CCR2 knockout (CCR2(-/-)) and wildtype mice underwent ovariectomy (OVX) or denervation of musculature adjacent to the tibia (DEN) to induce bone loss. Cortical and trabecular structural properties as well as mechanical properties (i.e., strength) of tibial bones were measured. Compared to wildtype mice, CCR2(-/-) mice had tibiae that were up to 9% larger and stronger; these differences could be explained mainly by the 17% greater body mass (P bone loss per se. These findings indicate that while CCR2(-/-) mice do have larger and stronger bones than do wildtype mice, there is minimal evidence that CCR2 elimination provides protection against bone loss during disuse and estrogen loss.

  12. Fractal dimension of bone texture in radiographs correlates to ultrasound broadband attenuation T-score.

    Science.gov (United States)

    Bianciardi, Giorgio; Bisogno, Stefania; Bertoldi, Ilaria; Laurini, Lorella; Coviello, Giuseppe; Frediani, Bruno

    2013-01-01

    We aimed to measure the fractal dimension on x-ray images and ultrasonographic parameters of the os calcis of bone from 4 districts in osteoporotic patients and in control subjects, in order to test the hypothesis that ultrasonographic parameters correlate to the fractal dimension obtained on x-ray images. Fractal analysis on radiological images from 4 bone districts (proximal femur, calcaneus, metacarpus and 3rd phalanx) was performed in a study comparing ultrasonographic evaluation of the os calcis in severe osteoporotic patients and in control cases. We studied 86 x-ray-views from patients with severe reduction of ultrasound Stiffness Index and in healthy women. Ultrasound measurements of left os calcis were performed using the Lunar Achilles-Plus instrument. Fractal analysis was performed using the box-counting method. In healthy subjects, fractal dimension, D, measure of structural complexity, resulted close to the topological dimension (no fractal structure), TD, in femur (1.99±0.03)and phalanx (1.96±0.03), D differed significantly from TD in calcaneus (D=1.90±0.02; pfractal dimension and ultrasound broadband attenuation T-score correlated significantly in calcaneus and metacarpus (pfractal analysis on radiographic images may add useful structural information regarding the patients' skeleton using non invasive procedures.

  13. Bone marrow-derived innate macrophages attenuate oxazolone-induced colitis.

    Science.gov (United States)

    Cheng, Zhao; Peng, Hong-Ling; Zhang, Rong; Fu, Xian-Ming; Zhang, Guang-Sen

    2017-01-01

    Previous studies have shown that a subpopulation of granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent F4/80(high) CD11b(high) innate macrophages could be derived from bone marrow cells by continuous in vitro culturing. These cells could be induced to differentiate into M1 or M2 macrophages in vitro. In the current study, we sought to determine whether bone marrow cell-derived innate macrophages (BMIMs) could be used to fulfill an anti-inflammatory purpose by intravenous transplantation in vivo after being stimulated to differentiate into M2 macrophages. Because Th2 cytokines, such as interleukin IL-4 and IL-13, can induce macrophage polarization into M2 macrophages, we treated the BMIMs with IL-4 and IL-13 in vitro. Next, the M2 macrophages were intravenously transplanted into a typical Th2-mediated inflammatory disease model, oxazolone (OXZ)-induced colitis, to assess the anti-inflammatory activity of BMIM-derived M2 macrophages (BMIM-M2Ms) in vivo. After transplantation, the severity of intestinal inflammation was attenuated. In addition, colon lengths and mouse body weights were noticeably improved. F4/80(+) CD206(+) double-positive cells (displaying the markers of M2 macrophages) had accumulated in the colon tissue of BMIM-M2M-transplanted mice. This evidence demonstrated that bone marrow-derived BMIM-M2Ms could be used to alleviate OXZ-induced Th2-mediated inflammation in a mouse model in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Influence of IV Contrast Administration on CT Measures of Muscle and Bone Attenuation: Implications for Sarcopenia and Osteoporosis Evaluation.

    Science.gov (United States)

    Boutin, Robert D; Kaptuch, Justin M; Bateni, Cyrus P; Chalfant, James S; Yao, Lawrence

    2016-11-01

    The objective of our study was to characterize enhancement of muscle and bone that occurs on standardized four-phase contrast-enhanced CT. Two musculoskeletal radiologists reviewed standardized four-phase abdominal CT scans obtained with IV contrast material. The psoas area was measured, and the mean attenuation (in Hounsfield units) was recorded for the aorta, psoas muscles, posterior paraspinal muscles, and L4 vertebral body. CT attenuation measures were compared between anatomic regions and imaging phases with the paired t test; associations between measures were examined with the Pearson correlation coefficient (R). The study included 201 patients (97 men, 104 women; mean age, 57.7 ± 12.5 [SD] years). Subject age was inversely correlated with unenhanced attenuation in the psoas muscles, posterior paraspinal muscles, and L4 (p muscles, posterior paraspinal muscles, and L4 enhanced significantly (p muscle enhancement was observed on delayed phase scans, whereas the greatest enhancement in L4 was seen on portal phase imaging. The unenhanced attenuation of the psoas muscles was significantly and negatively correlated with enhancement of the psoas muscles at the portal and delayed phases (p muscles. Age was positively correlated with posterior paraspinal muscle enhancement at the portal and delayed phases in men (p muscle and bone regions is routinely observed and should be considered when using CT attenuation values as biomarkers of sarcopenia and osteoporosis. Furthermore, CT enhancement may be significantly influenced by age, sex, and unenhanced tissue attenuation.

  15. Ca2 Receptor, Prostate Cancer, and Bone Metastases

    National Research Council Canada - National Science Library

    Brown, Edward M

    2006-01-01

    14. ABSTRACT While bony metastases of prostate cancer are often osteoblastic, excessive bone resorption also occurs in the sites of metastases, which contributes to skeletal complications (e.g., pain, fractures...

  16. Ca2+ Receptor, Prostate Cancer, and Bone Metastases

    National Research Council Canada - National Science Library

    Brown, Edward M

    2005-01-01

    While bony metastases of prostate cancer are often osteoblastic, excessive bone resorption also occurs in the sites of metastases, which contributes to skeletal complications (e.g., pain, fractures...

  17. A Case of Maxillary Bone Metastasis from Lung Cancer

    National Research Council Canada - National Science Library

    Kusunoki, Takeshi; Homma, Hirotomo; Kidokoro, Yoshinobu; Yanai, Aya; Ikeda, Katsuhisa; Wada, Ryo

    2015-01-01

    We experienced a very rare case of maxillary bone metastasis from lung cancer. The patient was a 77-year-old Japanese man with 1-month history of right alar swelling with hard pain as his chief complaint...

  18. Prevention and Treatment of Bone Metastases in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ripamonti Carla

    2013-09-01

    Full Text Available In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression. Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach.

  19. Bone Talk: Activated Osteoblasts Promote Lung Cancer Growth.

    Science.gov (United States)

    Bružas, Emilis; Egeblad, Mikala

    2018-02-02

    Cancer cells can directly stimulate the generation and recruitment of tumor-supportive bone marrow-derived cells (BMDCs), including neutrophils, via secreted factors. A new study demonstrates that lung tumors also remotely activate bone-residing osteoblasts, which in turn promote neutrophil production. This is a multistep mechanism of establishing a supportive tumor microenvironment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Bone marrow micrometastasis detected by flow cytometry is associated bone, bone marrow, lung macrometastasis in breast cancer

    Directory of Open Access Journals (Sweden)

    Mustafa Salih Akin

    2014-04-01

    Material and Methods: Bone marrow samples were obtained from 52 breast cancer patients and 16 control patients via aspiration from the iliac spine at the time of first diagnosis after the surgery. Epithelial cells were identified with anti-cytokeratin monoclonal antibody, and double-staining with propidium iodide and CD45using flow cytometry. Results: In all, 2 (12.5% of the 16 control patients and 11 (21% of the 52 breast cancer patients had cytokeratin-18 positive cells in their bone marrow. A relationship between the presence of occult metastatic cells in bone marrow, and the presence/absence of lymph node metastases, tumor size, stage, menopausal status, hormone receptor status, histological grade, c-erb-B2 expression, tumor subtype, lymphovascular invasion, Ductal carcinoma in situ (DCIS component, and gender was not observed. Significant positive relationships were observed between bone marrow micrometastasis, and age, and bone, bone marrow, lung, and liver metastases. Conclusion: Bone marrow micrometastasis was associated with age, bone, bone marrow, lung, and liver metastases at the time of diagnosis.. [Cukurova Med J 2014; 39(2.000: 305-314

  1. Targeting RANKL in the management of bone loss in patient with breast cancer

    National Research Council Canada - National Science Library

    Nicolin, Vanessa; Valentini, Roberto

    2014-01-01

    .... RANKL in bone has also been shown to serve as a chemoattractant for cancer cells, thu explaining the tropism of certain cancers such as breast and prostate cancer to preferentially metastasize to bone...

  2. Risk factors and characteristics of prostate cancer bone metastases

    Directory of Open Access Journals (Sweden)

    Jun-ming LIN

    2017-10-01

    Full Text Available Objective To analyze the risk factors and characteristics of bone metastases in patients with prostate cancer. Methods Patients who were diagnosed as prostate cancer by biopsy and histopathologic analysis between June 2006 and June 2016 were included in this study. The clinical data of the patients were reviewed, and the demographic data, laboratory examination results and Gleason score were recorded. The correlations between clinical factors and bone metastasis were analyzed, and the risk factors of bone metastasis were identified. Results A total of 585 patients were recruited in this study, including 228 with bone metastasis and 357 without bone metastasis. Of the patients with bone metastasis, the incidence of pelvic metastasis was the highest, accounting for 81.58%, followed by spin (63.16% and rib (58.33%, and the incidence of clavicle metastasis was the lowest (14.47%. Logistic regression analysis showed that age 85.5U/L, prostate-specific antigen >79.88μg/L and Gleason score >7.5 were the risk factors of bone metastasis in prostate cancer. ROC curve analysis showed that the sensitivity of diagnosing bone metastasis was 56.1%, 66.7%, 68.4% and 56.1%, and the specificity was 56.6%, 81.8%, 70.0% and 65.3%, respectively for above 4 factors. Conclusions The most common site of bone metastasis in patients with prostate cancer is pelvis. Patients' age, concentrations of plasma ALP and PSA, and Gleason score are the risk factors for bone metastasis in patients with prostate cancer. DOI: 10.11855/j.issn.0577-7402.2017.08.09

  3. Bone-Targeted Agents for the Management of Breast Cancer Patients with Bone Metastases

    Directory of Open Access Journals (Sweden)

    Demetrios Simos

    2013-08-01

    Full Text Available Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related complications. Bone metastases predispose patients to reduced survival, pain, impaired quality of life and the development of skeletal-related events. With an increased understanding of the pathophysiology of bone metastasis, effective treatments for their management have evolved and are now in widespread clinical use. This article will discuss the pathogenesis of bone metastases and review the key clinical evidence for the efficacy and safety of currently available systemic bone-targeted therapies in breast cancer patients with an emphasis on bisphosphonates and the receptor activator of nuclear factor kappa B ligand (RANKL inhibitors. We will also discuss novel strategies and therapies currently in development.

  4. Prevention and treatment of bone fragility in cancer patient

    Science.gov (United States)

    Ottanelli, Silva

    2015-01-01

    Summary It is well known that fractures increase the risk of morbidity and mortality. The various mechanisms responsible for bone loss in cancer patients may have a different impact depending on the characteristics of the clinical case and correlates with the therapies used, or caused by the therapies used against cancer. Some hormonal treatments cause hypogonadism, event which contributes to the progressive loss of bone mass. This is detectable in patients with breast cancer receiving determines that estrogen-deprivation and in men with prostate cancer with therapies that determine androgen deprivation. Chemotherapy treatments used in cancer patients have reduced bone mass. In addition, low bone mass is detectable in patients with lymphoma treated with corticosteroids or radiation or alkylating agents. In premenopausal patients suffering from breast cancer, treatment with cytotoxic therapy or ablation of ovarian function, can lead to an 8% reduction in bone mineral density at the spine and 4% in the femur. With a chemotherapy regimen in CMF, the reduction of BMD is 6.5%; this bone loss is not recovered after discontinuation of therapy. Tamoxifen given for five years reduces bone remodeling and cause a 32% increase in the risk of osteoporotic fractures when used in premenopausal. After menopause, tamoxifen has a protective effect on bone mass, with a reduced risk of new fractures. Aromatase inhibitors in post-menopausal women, depending on the formulation can cause different effects on the reduction of BMD and fracture risk. We have in fact steroids, exemestane and nonsteroidal, letrozole and anastrozole. Patients at increased risk of fragility fractures should undergo preventive therapies as soon as possible after tests performed for the study of bone health. They can be used DEXA and the FRAX algorithm, which can define a secondary osteoporosis. Prevention and treatment of the increased risk of osteoporotic fracture is to maintain adequate levels of calcium and

  5. Selaginellatamariscina attenuates metastasis via Akt pathways in oral cancer cells.

    Directory of Open Access Journals (Sweden)

    Jia-Sin Yang

    Full Text Available BACKGROUND: Crude extracts of Selaginellatamariscina, an oriental medicinal herb, have been evidenced to treat several human diseases. This study investigated the mechanisms by which Selaginellatamariscina inhibits the invasiveness of human oral squamous-cell carcinoma (OSCC HSC-3 cells. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we demonstrate that Selaginellatamariscina attenuated HSC-3 cell migration and invasion in a dose-dependent manner. The anti-metastatic activities of Selaginellatamariscina occurred at least partially because of the down-regulation of matrix metalloproteinases (MMP-2 and MMP-9 gelatinase activity and the down-regulation of protein expression. The expression and function of both MMP-2 and MMP-9 were regulated by Selaginellatamariscina at a transcriptional level, as shown by quantitative real-time PCR and reporter assays. Chromatin immunoprecipitation (ChIP data further indicated that binding of the cAMP response element-binding (CREB protein and activating protein-1 (AP-1 to the MMP-2 promoter diminished at the highest dosage level of Selaginellatamariscina. The DNA-binding activity of specificity protein 1 (SP-1 to the MMP-9 promoter was also suppressed at the same concentration. Selaginellatamariscina did not affect the mitogen-activated protein kinase signaling pathway, but did inhibit the effects of gelatinase by reducing the activation of serine-threonine kinase Akt. CONCLUSIONS: These results demonstrate that Selaginellatamariscina may be a potent adjuvant therapeutic agent in the prevention of oral cancer.

  6. Quantitative assessment of bone marrow attenuation values at MDCT: An objective tool for the detection of bone bruise related to occult sacral insufficiency fractures

    Energy Technology Data Exchange (ETDEWEB)

    Henes, F.O.; Groth, M.; Bley, T.A.; Regier, M.; Ittrich, H.; Adam, G.; Bannas, P. [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Nuechtern, J.V. [University Medical Center Hamburg-Eppendorf, Department of Trauma, Hand and Reconstructive Surgery, Hamburg (Germany); Treszl, A. [University Medical Center Hamburg-Eppendorf, Center for Experimental Medicine, Department of Medical Biometry and Epidemiology, Hamburg (Germany)

    2012-10-15

    To prove the feasibility of using Hounsfield attenuation values at MDCT to detect bone bruises related to sacral insufficiency fractures. Twenty-two patients with acute sacrum trauma and no fracture findings at MDCT were included in our prospective study. Two observers independently reviewed CTs regarding visual signs of bone bruises in 132 defined regions of the sacral alae. Interobserver agreement was tested by {kappa} statistics. Subsequently, HU values were obtained in the same regions, and attenuation differences between the two sides were calculated. Validity and reliability were assessed by intraclass correlation coefficient and Bland-Altman analysis. HU differences were subjected to ROC curve analysis to determine sensitivity, specificity, PPV and NPV. MRI served as standard reference. MRI revealed 19 regions with bone bruises and associated sacral insufficiency fractures. HU measurements demonstrated good validity and reliability (r = 0.989). ROC curve analysis exhibited an ideal cutoff value of 35.7 HU density difference between affected and non-affected regions. Visual evaluation revealed moderate agreement ({kappa} = 0.48); diagnostic accuracy was inferior to objective evaluation. Assessment of differences in bone marrow density by HU measurements is an objective and reliable tool for detection of bone bruises associated with occult sacral insufficiency fractures. (orig.)

  7. Optimal bone health management strategies in patients with prostate cancer

    Directory of Open Access Journals (Sweden)

    Gagan Prakash

    2013-01-01

    Full Text Available Bone health is affected in patients with prostate cancer, both by the disease and its treatment. Metastases to bone leads to pain, fractures, and spinal cord compression; bone loss due to androgen deprivation therapy (ADT leads to osteoporosis and its complications. Both these scenarios are a major cause of morbidity and adversely affect the quality of life of these patients. Maintaining an optimum bone health throughout the natural course of prostate cancer is an important aspect in the management of this disease. An understanding of the complex interplay between osteoclasts, osteoblasts, receptor activator of nuclear factor κB (RANK, and various other tyrosine kinases involved in the pathophysiology of bone metastases is essential. Zoledronic acid (ZA, an intravenously administered bisphosphonate, and Denosumab, a subcutaneously administered inhibitor of nuclear factor B ligand (RANKL, have already been approved by Food and Drug Administration (FDA for their use in treatment of bone metastases. This article discusses the pathophysiology of bone metastases and bone loss due to ADT in prostate cancer, role of biomarkers, newer modalities of imaging, World Health Organization (WHO/FRAX nomogram in evaluation of these patients, utility of currently available drugs and evidence supporting their use, and newer therapeutic agents like alpha-emitting Radium-223, endothelin-A receptor antagonists (Atrasentan and Zibotentan and the proto-oncogene tyrosine-protein kinase (SRC inhibitor, Dasatinib.

  8. Bone Marrow Mesenchymal Stem Cells Attenuate Mitochondria Damage Induced by Hypoxia in Mouse Trophoblasts.

    Directory of Open Access Journals (Sweden)

    Lingjuan Wang

    Full Text Available We aimed to observe the change of mitochondrial function and structure as well as the cell function induced by hypoxia in mouse trophoblasts, and moreover, to validate the restoration of these changes after co-culture with bone marrow mesenchymal stem cells (hereinafter referred to as "MSCs". Further, we explored the mechanism of MSCs attenuating the functional damage of trophoblasts caused by hypoxia.Cells were divided into two groups, trophoblasts and MSCs+trophoblasts respectively, and the two groups of cells were incubated with normoxia or hypoxia. Chemiluminescence was used to assay the β-HCG and progesterone in cell culture supernatants quantitatively. Western blotting and PCR were applied to detect the expression of Mfn2, MMP-2, MMP-9 and integrin β1 in the two groups. The mitochondrial membrane potential of each group of cells was detected with JC-1 dye and the ATP content was measured by the phosphomolybdic acid colorimetric method. We utilized transmission electron microscopy for observing the ultrastructure of mitochondria in trophoblasts. Finally, we assessed the cell apoptosis with flow cytometry (FCM and analyzed the expression of the apoptosis related genes-Bcl-2, Bax, Caspase3 and Caspase9 by western blotting.The results showed that the Mfn2 expression was reduced after 4 h in hypoxia compared with that in normoxia, but increased in the co-culture group when compared with that in the separated-culture group (p<0.05. In addition, compared with the separated-culture group, theβ-HCG and progesterone levels in the co-culture group were significantly enhanced (p<0.05, and so were the expressions of MMP-2, MMP-9 and integrin β1 (p<0.05. Moreover, it exhibited significantly higher in ATP levels and intensified about the mitochondrial membrane potential in the co-culture group. TEM revealed disorders of the mitochondrial cristae and presented short rod-like structure and spheroids in hypoxia, however, in the co-culture group, the

  9. Urothelial Cancer With Occult Bone Marrow Metastases and Isolated Thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Ajjai Alva

    2015-07-01

    Full Text Available Bladder cancer rarely presents clinically with a myelophthisic picture from diffuse bone marrow infiltration especially in the absence of detectable skeletal metastases. A 75-year old man presented with newly diagnosed urothelial cell carcinoma of the bladder. Pathology from transurethral resection of bladder tumor demonstrated muscle-invasive disease. Pre-therapy imaging including CT abdomen/pelvis, CXR and bone scan demonstrated liver lesions concerning for metastatic disease but no skeletal metastases. Labs were notable for isolated thrombocytopenia, hypercalcemia and acute kidney injury prompting hospitalization. Hematologic work-up including bone marrow aspiration and biopsy revealed diffuse infiltration of the bone marrow by urothelial cancer. The case illustrates the importance of fully investigating otherwise unexplained clinical findings in patients with clinically localized urothelial cancer prior to curative intent surgery.

  10. Urothelial Cancer With Occult Bone Marrow Metastases and Isolated Thrombocytopenia.

    Science.gov (United States)

    Alva, Ajjai; Davis, Elizabeth; Chinnaiyan, Arul M; Dhanasekaran, Saravana; Mehra, Rohit

    2015-07-01

    Bladder cancer rarely presents clinically with a myelophthisic picture from diffuse bone marrow infiltration especially in the absence of detectable skeletal metastases. A 75-year old man presented with newly diagnosed urothelial cell carcinoma of the bladder. Pathology from transurethral resection of bladder tumor demonstrated muscle-invasive disease. Pre-therapy imaging including CT abdomen/pelvis, CXR and bone scan demonstrated liver lesions concerning for metastatic disease but no skeletal metastases. Labs were notable for isolated thrombocytopenia, hypercalcemia and acute kidney injury prompting hospitalization. Hematologic work-up including bone marrow aspiration and biopsy revealed diffuse infiltration of the bone marrow by urothelial cancer. The case illustrates the importance of fully investigating otherwise unexplained clinical findings in patients with clinically localized urothelial cancer prior to curative intent surgery.

  11. Detection of occult vertebral fractures by quantitative assessment of bone marrow attenuation values at MDCT

    Energy Technology Data Exchange (ETDEWEB)

    Henes, Frank Oliver, E-mail: f.henes@uke.de [Department of Diagnostic and Interventional Radiology, Center for Radiology and Endoscopy, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany); Groth, Michael [Department of Diagnostic and Interventional Neuroradiology, Center for Radiology and Endoscopy, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany); Kramer, Harald [Department of Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistr. 15, 81377 Munich (Germany); Department of Radiology, University of Wisconsin – Madison, Clinical Science Center, 600 Highland Avenue, Madison, WI 53792 (United States); Schaefer, Christian [Department of Trauma-, Hand- and Reconstructive Surgery, Spine Center, Center for Surgical Sciences, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg (Germany); Regier, Marc; Derlin, Thorsten; Adam, Gerhard; Bannas, Peter [Department of Diagnostic and Interventional Radiology, Center for Radiology and Endoscopy, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany)

    2014-01-15

    Objectives: To determine a cut-off value of Hounsfield attenuation units (HU) at multidetector computed tomography (MDCT) for valid and reliable detection of bone marrow oedema (BME) related to occult vertebral fractures. Methods: 36 patients underwent both MDCT and Magnetic Resonance Imaging (MRI) for evaluation of vertebral fractures of the thoracolumbar spine and were included in this retrospective study. Two readers independently assessed HU values at MDCT in a total of 196 vertebrae. Reliability was assessed by intraclass correlation coefficient and Bland–Altman analysis. For each patient we determined the vertebra with the lowest HU value and calculated the HU-difference to each other vertebral body. HU-differences were subjected to receiver operating characteristic (ROC) curve analysis to determine the diagnostic accuracy for detection of BME as determined by MRI, which served as the reference standard. Results of HU-measurements were compared with standard visual evaluation of MDCT. Results: HU measurements demonstrated a high interrater reliability (ICC = 0.984). ROC curve analysis (AUC = 0.978) exhibited an ideal cut-off value of 29.6 HU for detection of BME associated with vertebral fractures with an accuracy of 97.4% as compared to 93.4% accuracy of visual evaluation. Particularly, HU-measurements increased the sensitivity for detection of vertebral fractures from 78.0% to 92.7% due to the detection of 7 of 9 occult fractures that were missed by visual evaluation alone. Conclusions: Assessing bone marrow density by HU measurements using the cut-off of 29.6 HU is a valid and reliable tool for detection of BME related to occult vertebral fractures in MDCT. The introduced technique may allow more accurate treatment decisions and may make further diagnostic work-up with MRI unnecessary.

  12. Characterizing the inorganic/organic interface in cancer bone metastasis

    Science.gov (United States)

    Wu, Fei

    Bone metastasis frequently occurs in patients with advanced breast cancer and remains a major source of mortality. At the molecular level, bone is a nanocomposite composed of inorganic bone mineral deposited within an organic extracellular matrix (ECM). Although the exact mechanisms of bone metastasis remain unclear, the nanoscale materials properties of bone mineral have been implicated in this process. Bone apatite is closely related to synthetic hydroxyapatite (HAP, Ca10(PO4)6(OH)2) in terms of structural and mechanical properties. Additionally, although the primary protein content of bone is collagen I, the glycoprotein fibronectin (Fn) is essential in maintaining the overall integrity of the bone matrix. Importantly, in vivo, neither breast cancer cells nor normal bone cells interact directly with the bone mineral but rather with the protein film adsorbed onto the mineral surface. Therefore, we hypothesized that breast cancer cell functions were regulated by differential fibronectin adsorption onto hydroxyapatite, which led to pathological remodeling of the bone matrix and sustained bone metastasis. Three model systems containing HAP and Fn were developed for this thesis. In model system I, a library of synthetic HAP nanoparticles were utilized to investigate the effect of mineral size, shape, and crystallinity on Fn conformation, using Forster resonance energy transfer (FRET) spectroscopy. In model system II, Fn-functionalized large geologic HAP crystals were used instead of HAP nanoparticles to avoid cellular uptake when investigating subsequent cell functions. Overall our FRET analysis (models I and II) revealed that Fn conformation depended on size, surface chemistry, and roughness of underlying HAP. When breast cancer cells were seeded on the Fn-coated HAP crystal facets (model II), our data indicated high secretion levels of proangiogenic and proinflammatory factors associated with the presence of unfolded Fn conformations, likely caused by differential

  13. P2X7 receptor-mediated analgesia in cancer-induced bone pain.

    Science.gov (United States)

    Falk, S; Schwab, S D; Frøsig-Jørgensen, M; Clausen, R P; Dickenson, A H; Heegaard, A-M

    2015-04-16

    Pain is a common and debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of molecular events, including mechanisms observed in inflammatory and neuropathic pain states, but also changes unique for cancer-induced bone pain. The P2X7 receptor (P2X7R) is involved in a variety of cellular functions and has been linked to both inflammatory and neuropathic pain. Here we study the analgesic potential of P2X7R antagonism in a rat model of cancer-induced bone pain. In cancer-bearing animals, the P2X7R antagonist A839977 attenuated dorsal horn neuronal responses in a modality and intensity-specific way. Spinal application of 0.4-mg/kg and 1.2-mg/kg A839977 significantly reduced the evoked responses to high-intensity mechanical and thermal stimulation, whereas no effect was seen in response to low-intensity or electrical stimulation. In contrast, A839977 had no effect on the tested parameters in naïve or sham animals. In awake animals, 40-mg/kg A839977 (i.p.) significantly reduced both early- and late-stage pain behavior. In contrast, no effect was observed in sham or vehicle-treated animals. The results suggest that the P2X7R is involved in the mechanisms of cancer-induced bone pain, and that P2X7R antagonism might be a useful analgesic target. No effect was observed in sham or naïve animals, indicating that the P2X7R-mediated effect is state-dependent, and might therefore be an advantageous target compared to traditional analgesics. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. MRI-guided attenuation correction in whole-body PET/MR : assessment of the effect of bone attenuation

    NARCIS (Netherlands)

    Akbarzadeh, A.; Ay, M. R.; Ahmadian, A.; Alam, N. Riahi; Zaidi, H.

    Hybrid PET/MRI presents many advantages in comparison with its counterpart PET/CT in terms of improved soft-tissue contrast, decrease in radiation exposure, and truly simultaneous and multi-parametric imaging capabilities. However, the lack of well-established methodology for MR-based attenuation

  15. Bone tumor

    Science.gov (United States)

    Tumor - bone; Bone cancer; Primary bone tumor; Secondary bone tumor; Bone tumor - benign ... The cause of bone tumors is unknown. They often occur in areas of the bone that grow rapidly. Possible causes include: Genetic defects passed down ...

  16. Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Yardley DA

    2016-05-01

    Full Text Available Denise A Yardley1,2 1Sarah Cannon Research Institute, Nashville, TN, USA; 2Tennessee Oncology, Nashville, TN, USA Abstract: There is a high risk for bone loss and skeletal-related events, including bone metastases, in postmenopausal women with hormone receptor-positive breast cancer. Both the disease itself and its therapeutic treatments can negatively impact bone, resulting in decreases in bone mineral density and increases in bone loss. These negative effects on the bone can significantly impact morbidity and mortality. Effective management and minimization of bone-related complications in postmenopausal women with hormone receptor-positive breast cancer remain essential. This review discusses the current understanding of molecular and biological mechanisms involved in bone turnover and metastases, increased risk for bone-related complications from breast cancer and breast cancer therapy, and current and emerging treatment strategies for managing bone metastases and bone turnover in postmenopausal women with hormone receptor-positive breast cancer. Keywords: breast cancer, bone metastases, hormone receptor-positive, bone-related complications, interventions, management and management strategies, estrogen receptor-positive

  17. Predicting the risk of bone metastasis in prostate cancer.

    Science.gov (United States)

    Briganti, Alberto; Suardi, Nazareno; Gallina, Andrea; Abdollah, Firas; Novara, Giacomo; Ficarra, Vincenzo; Montorsi, Francesco

    2014-02-01

    The ability to identify prostate cancer patients at 'high risk' for bone metastasis development could allow early selection of those most likely to benefit from interventions to prevent or delay bone metastasis. This review is aimed to identify potential predictors of risk for bone metastasis in newly diagnosed patients and in those who have already received treatment. At diagnosis, established predictors of prostate cancer aggressiveness (e.g. PSA level, clinical stage, Gleason score) can identify patients at risk for bone metastasis. Following treatment of the disease, increasing evidence suggests that absolute PSA levels and other measures of PSA kinetics are useful to aid prediction of bone metastasis risk in patients both with and without a history of ADT. However, which PSA parameter most accurately predicts risk and the cut-off values that should be employed are unclear. Inclusion of PSA parameters to identify a high risk population may be beneficial in whom bone-modifying treatments are being considered. Other novel (but unvalidated) biomarkers that potentially predict the development of bone metastases have been identified, although it is unclear whether they will have value as independent markers or when combined with other parameters (e.g. measures of PSA kinetics). Further prospective studies of PSA kinetics and other predictive markers are, therefore, required to define the optimal criteria for identifying patients at high risk of bone metastases and those who are most likely to benefit from intensive monitoring and therapeutic intervention. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Subject-specific bone attenuation correction for brain PET/MR: can ZTE-MRI substitute CT scan accurately?

    Science.gov (United States)

    Khalifé, Maya; Fernandez, Brice; Jaubert, Olivier; Soussan, Michael; Brulon, Vincent; Buvat, Irène; Comtat, Claude

    2017-10-01

    In brain PET/MR applications, accurate attenuation maps are required for accurate PET image quantification. An implemented attenuation correction (AC) method for brain imaging is the single-atlas approach that estimates an AC map from an averaged CT template. As an alternative, we propose to use a zero echo time (ZTE) pulse sequence to segment bone, air and soft tissue. A linear relationship between histogram normalized ZTE intensity and measured CT density in Hounsfield units (HU ) in bone has been established thanks to a CT-MR database of 16 patients. Continuous AC maps were computed based on the segmented ZTE by setting a fixed linear attenuation coefficient (LAC) to air and soft tissue and by using the linear relationship to generate continuous μ values for the bone. Additionally, for the purpose of comparison, four other AC maps were generated: a ZTE derived AC map with a fixed LAC for the bone, an AC map based on the single-atlas approach as provided by the PET/MR manufacturer, a soft-tissue only AC map and, finally, the CT derived attenuation map used as the gold standard (CTAC). All these AC maps were used with different levels of smoothing for PET image reconstruction with and without time-of-flight (TOF). The subject-specific AC map generated by combining ZTE-based segmentation and linear scaling of the normalized ZTE signal into HU was found to be a good substitute for the measured CTAC map in brain PET/MR when used with a Gaussian smoothing kernel of 4~mm corresponding to the PET scanner intrinsic resolution. As expected TOF reduces AC error regardless of the AC method. The continuous ZTE-AC performed better than the other alternative MR derived AC methods, reducing the quantification error between the MRAC corrected PET image and the reference CTAC corrected PET image.

  19. A comparison between the patella and the calcaneus using ultrasound velocity and attenuation as predictors of bone mineral density

    Science.gov (United States)

    Han, S. M.; Davis, J.

    1997-10-01

    The bone mineral density (BMD), ultrasound velocity (UV) and attenuation were examined in sixteen matched sets of human patellae and calcanei. For the sixteen calcanei, BMD was strongly correlated with all ultrasound parameters. Calcaneal UV appeared to be inferior to attenuation in the ability to predict BMD. For the sixteen patellae, the average UV was found to be greater in the superior/inferior direction than in the anterior/posterior and medial/lateral directions. It was found that patella BMD was significantly correlated with each of three directional ultrasound velocities. The relationship between BMD and ultrasound attenuation parameters was not significant in the patella. A comparative study of the two different bone sets demonstrated that the BMDs of the patella and calcaneus were significantly correlated with each other. Ultrasound velocity of calcaneus, measured in the medial/lateral direction, was not significantly associated with any of three directional ultrasound velocities in the patella. Similarly, ultrasound attenuation parameters of calcaneus were not significantly correlated with those of patella. The present study also demonstrated evidence that when predicting BMDs at their respective sites using ultrasound, the calcaneus appeared to be superior to the patella.

  20. Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis.

    Science.gov (United States)

    Siclari, Valerie A; Mohammad, Khalid S; Tompkins, Douglas R; Davis, Holly; McKenna, C Ryan; Peng, Xianghong; Wessner, Lisa L; Niewolna, Maria; Guise, Theresa A; Suvannasankha, Attaya; Chirgwin, John M

    2014-12-02

    Adrenomedullin (AM) is secreted by breast cancer cells and increased by hypoxia. It is a multifunctional peptide that stimulates angiogenesis and proliferation. The peptide is also a potent paracrine stimulator of osteoblasts and bone formation, suggesting a role in skeletal metastases-a major site of treatment-refractory tumor growth in patients with advanced disease. The role of adrenomedullin in bone metastases was tested by stable overexpression in MDA-MB-231 breast cancer cells, which cause osteolytic bone metastases in a standard animal model. Cells with fivefold increased expression of AM were characterized in vitro, inoculated into immunodeficient mice and compared for their ability to form bone metastases versus control subclones. Bone destruction was monitored by X-ray, and tumor burden and osteoclast numbers were determined by quantitative histomorphometry. The effects of AM overexpression on tumor growth and angiogenesis in the mammary fat pad were determined. The effects of AM peptide on osteoclast-like multinucleated cell formation were tested in vitro. A small-molecule AM antagonist was tested for its effects on AM-stimulated ex vivo bone cell cultures and co-cultures with tumor cells, where responses of tumor and bone were distinguished by species-specific real-time PCR. Overexpression of AM mRNA did not alter cell proliferation in vitro, expression of tumor-secreted factors or cell cycle progression. AM-overexpressing cells caused osteolytic bone metastases to develop more rapidly, which was accompanied by decreased survival. In the mammary fat pad, tumors grew more rapidly with unchanged blood vessel formation. Tumor growth in the bone was also more rapid, and osteoclasts were increased. AM peptide potently stimulated bone cultures ex vivo; responses that were blocked by small-molecule adrenomedullin antagonists in the absence of cellular toxicity. Antagonist treatment dramatically suppressed tumor growth in bone and decreased markers of

  1. Radium-223 Therapy of Bone Metastases in Prostate Cancer.

    Science.gov (United States)

    Nilsson, Sten

    2016-11-01

    Metastatic castration-resistant prostate cancer frequently metastasizes to the bone, often resulting in painful skeletal events, reduced quality of life, and reduced survival. Radium-223 is a first-in-class alpha-emitting radiopharmaceutical that has proven to prolong overall survival, delay time to symptomatic skeletal events, and improve quality of life in patients with castration-resistant prostate cancer and symptomatic bone metastases and no visceral metastases. Radium-223 provides survival benefit to patients with castration-resistant prostate cancer and symptomatic bone metastases, regardless of prior docetaxel use. This article gives an overview of the development of radium-223 from the first-in-human trial to current status. Copyright © 2016. Published by Elsevier Inc.

  2. Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor.

    Science.gov (United States)

    Majuta, Lisa A; Longo, Geraldine; Fealk, Michelle N; McCaffrey, Gwen; Mantyh, Patrick W

    2015-01-01

    The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain-related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti-nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains.

  3. Whole-body bone segmentation from MRI for PET/MRI attenuation correction using shape-based averaging

    DEFF Research Database (Denmark)

    Arabi, Hossein; Zaidi, H.

    2016-01-01

    PET-CT images. Conclusions: The performance of SBA was enhanced through application of local atlas weighting or regularization schemes (L-STAPLE and L-Shp). Bone recognition, fragmentation of the contiguous structures, and quantitative PET uptake recovery improved dramatically using these methods...... in less than 3% SUV mean relative error and 6% SUV mean absolute error in bony structures owing to superior bone identification accuracy. The quantitative analysis using joint histograms revealed good correlation between PET-MRAC images using the proposed L-Shp algorithm and the corresponding reference......Purpose: The authors evaluate the performance of shape-based averaging (SBA) technique for whole-body bone segmentation from MRI in the context of MRI-guided attenuation correction (MRAC) in hybrid PET/MRI. To enhance the performance of the SBA scheme, the authors propose to combine...

  4. How MMPs Impact Bone Responses to Metastatic Prostate Cancer

    Science.gov (United States)

    2011-04-30

    Washington Note: Sup Cancer Res Correspon and Rehab Tower, Sui Fax: 615-3 doi: 10.115 ©2010 Am www.aacrIn human prostate to bone metastases and in a...threshold. The number of osteolytic lesions that completely penetrated the cortical bone, as seen in the virtual reconstruction, were counted. MicroCT...at the time of their death [1–3]. Bone metastases are often termed as either osteolytic or osteogenic but in reality , the lesions contain areas of

  5. Tanshinone IIA Exerts an Antinociceptive Effect in Rats with Cancer-induced Bone Pain.

    Science.gov (United States)

    Hao, Wei; Chen, Lei; Wu, Li-Fang; Yang, Fan; Niu, Jian-Xiang; Kaye, Alan D; Xu, Shi-Yuan

    2016-01-01

    Cancer-induced bone pain (CIBP) is a common chronic pain characterized by 2 components, ongoing pain and breakthrough pain. Tanshinone IIA (TSN IIA) is a bioactive constituent of the traditional Chinese medicine Danshen, which has been reported to have an antinociceptive effect on neuropathic and inflammatory pain through downregulation of the late proinflammatory cytokine high-mobility group protein B1 (HMGB1). To assess the antinociceptive effect of TSN IIA on CIBP. A randomized, double-blind, controlled animal trial was performed. University lab in China. A rat CIBP model was established by injecting Walker 256 mammary gland carcinoma cells into the intramedullary cavity of the tibia. Both ongoing pain, e.g., flinching and guarding, and breakthrough pain, e.g., limb use and von Frey threshold, were evaluated. The effects of intraperitoneally administered TSN IIA on pain behavior and the expression levels of spinal HMGB1, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 were determined. The effect of TSN IIA on the electrically evoked response of spinal wide-dynamic range (WDR) neurons was performed in vivo. TSN IIA dose-dependently inhibited cancer-induced ongoing pain and breakthrough pain. The expression levels of spinal HMGB1 and other inflammatory factors (IL-1beta, TNF-alpha, and IL-6) were increased in the rat model, but they were suppressed by TSN IIA in a dose-dependent manner. Moreover, TSN IIA significantly inhibited the neuronal responses of WDR neurons in spinal deep layers. Further studies are warranted to ascertain how TSN IIA attenuates cancer-induced ongoing pain. Our results indicate that TSN IIA attenuates cancer-induced ongoing pain and breakthrough pain, possibly via suppression of central sensitization in CIBP rats. Therefore, we have provided strong evidence supporting TSN IIA as a potential and effective therapy for relieving CIBP. Cancer-induced bone pain, high-mobility group protein B1, Tanshinone IIA, ongoing pain

  6. Wnt Signaling in Prostate Cancer Bone Metastases

    Science.gov (United States)

    2016-11-01

    Pten, Estrous Cycle MCB - 11 THE EFFECT OF HDACI (AR-42) ON CANINE PROSTATE CANCER METASTASIS. S. Elshafae1, N. Kohart1, L... canine prostate cancer overexpressing Dkk-1 was used in this study to investigate how enhanced Wnt/JNK signaling could alter tumor growth, metastasis and...metastatic phenotype of prostate cancer. Ace-1-Dkk-1, a canine prostate cancer overexpressing human Dkk-1, previously developed in our lab was used in

  7. Peri-Implant Tissue Findings in Bone Grafted Oral Cancer Patients Compared to non Bone Grafted Patients without Oral Cancer

    OpenAIRE

    Jan Wolff; Hideki Agata; Sándor, George K.; Suvi Haimi

    2012-01-01

    ABSTRACT Objectives The aim of this study was to compare microbiological, histological, and mechanical findings from tissues around osseointergrated dental implants in patients who had undergone tumour resection and subsequent bone grafting with non bone grafted patients without a history of oral cancer and to develop an effective tool for the monitoring of the peri-implant tissues. A third aim was to assess and compare the masticatory function of the two patient groups after reconstruction w...

  8. How I do it: managing bone health in patients with prostate cancer.

    Science.gov (United States)

    Barkin, Jack

    2014-08-01

    Urologists have two scenarios where they have to address bone loss or increased risk of fractures in men with prostate cancer. In the first setting, a patient who has been started on androgen deprivation therapy may develop cancer-treatment-induced bone loss. In the second setting, a patient's prostate cancer may have metastasized to the bone. This article describes six steps to manage bone health in patients diagnosed with prostate cancer in a community practice.

  9. Mechanisms of Radiation-Induced Bone Loss and Effects on Prostate Cancer Bone Metastases

    Science.gov (United States)

    2013-06-01

    skeletal sites. Indeed, within five years of radiation treatment at the pelvic region ( cervical , rectal or anal cancer), the risk of hip fracture ...radiation-induced effects at skeletal sites, including bone loss and increased fracture risk at the hip [2-4]. Indeed, the risk of hip fracture within...general population [5-7]. Hip fracture causes considerable morbidity and mortality to cancer patients during the course of treatment and poses a

  10. Multiparametric Magnetic Resonance Imaging of Prostate Cancer Bone Disease

    Science.gov (United States)

    Perez-Lopez, Raquel; Nava Rodrigues, Daniel; Figueiredo, Ines; Mateo, Joaquin; Collins, David J.; Koh, Dow-Mu; de Bono, Johann S.; Tunariu, Nina

    2018-01-01

    Objectives The aim of this study was to correlate magnetic resonance imaging (MRI) of castration-resistant prostate cancer (CRPC) bone metastases with histological and molecular features of bone metastases. Materials and Methods Forty-three bone marrow biopsies from 33 metastatic CRPC (mCRPC) patients with multiparametric MRI and documented bone metastases were evaluated. A second cohort included 10 CRPC patients with no bone metastases. Associations of apparent diffusion coefficient (ADC), normalized b900 diffusion-weighted imaging (nDWI) signal, and signal-weighted fat fraction (swFF) with bone marrow biopsy histological parameters were evaluated using Mann-Whitney U test and Spearman correlations. Univariate and multivariate logistic regression models were analyzed. Results Median ADC and nDWI signal was significantly higher, and median swFF was significantly lower, in bone metastases than nonmetastatic bone (P < 0.001). In the metastatic cohort, 31 (72.1%) of 43 biopsies had detectable cancer cells. Median ADC and swFF were significantly lower and median nDWI signal was significantly higher in biopsies with tumor cells versus nondetectable tumor cells (898 × 10−6 mm2/s vs 1617 × 10−6 mm2/s; 11.5% vs 62%; 5.3 vs 2.3, respectively; P < 0.001). Tumor cellularity inversely correlated with ADC and swFF, and positively correlated with nDWI signal (P < 0.001). In serial biopsies, taken before and after treatment, changes in multiparametric MRI parameters paralleled histological changes. Conclusions Multiparametric MRI provides valuable information about mCRPC bone metastases. These data further clinically qualify DWI as a response biomarker in mCRPC. PMID:28906339

  11. Combined PET/MR imaging in neurology: MR-based attenuation correction implies a strong spatial bias when ignoring bone.

    Science.gov (United States)

    Andersen, Flemming Littrup; Ladefoged, Claes Nøhr; Beyer, Thomas; Keller, Sune Høgild; Hansen, Adam Espe; Højgaard, Liselotte; Kjær, Andreas; Law, Ian; Holm, Søren

    2014-01-01

    Combined PET/MR systems have now become available for clinical use. Given the lack of integrated standard transmission (TX) sources in these systems, attenuation and scatter correction (AC) must be performed using the available MR-images. Since bone tissue cannot easily be accounted for during MR-AC, PET quantification can be biased, in particular, in the vicinity of the skull. Here, we assess PET quantification in PET/MR imaging of patients using phantoms and patient data. Nineteen patients referred to our clinic for a PET/CT exam as part of the diagnostic evaluation of suspected dementia were included in our study. The patients were injected with 200MBq [(18)F]FDG and imaged with PET/CT and PET/MR in random sequence within 1h. Both, PET/CT and PET/MR were performed as single-bed acquisitions without contrast administration. PET/CT and PET/MR data were reconstructed following CT-based and MR-based AC, respectively. MR-AC was performed based on: (A) standard Dixon-Water-Fat segmentation (DWFS), (B) DWFS with co-registered and segmented CT bone values superimposed, and (C) with co-registered full CT-based attenuation image. All PET images were reconstructed using AW-OSEM, with neither resolution recovery nor time-of-flight option employed. PET/CT (D) or PET/MR (A-C) images were decay-corrected to the start time of the first examination. PET images following AC were evaluated visually and quantitatively using 10 homeomorphic regions of interest drawn on a transaxial T1w-MR image traversing the central basal ganglia. We report the relative difference (%) of the mean ROI values for (A)-(C) in reference to PET/CT (D). In a separate phantom experiment a 2L plastic bottle was layered with approximately 12mm of Gypsum plaster to mimic skull bone. The phantom was imaged on PET/CT only and standard MR-AC was performed by replacing hyperdense CT attenuation values corresponding to bone (plaster) with attenuation values of water. PET image reconstruction was performed with CT

  12. Does colon cancer ever metastasize to bone first? a temporal analysis of colorectal cancer progression

    Directory of Open Access Journals (Sweden)

    Gayed Isis W

    2009-08-01

    Full Text Available Abstract Background It is well recognized that colorectal cancer does not frequently metastasize to bone. The aim of this retrospective study was to establish whether colorectal cancer ever bypasses other organs and metastasizes directly to bone and whether the presence of lung lesions is superior to liver as a better predictor of the likelihood and timing of bone metastasis. Methods We performed a retrospective analysis on patients with a clinical diagnosis of colon cancer referred for staging using whole-body 18F-FDG PET and CT or PET/CT. We combined PET and CT reports from 252 individuals with information concerning patient history, other imaging modalities, and treatments to analyze disease progression. Results No patient had isolated osseous metastasis at the time of diagnosis, and none developed isolated bone metastasis without other organ involvement during our survey period. It took significantly longer for colorectal cancer patients to develop metastasis to the lungs (23.3 months or to bone (21.2 months than to the liver (9.8 months. Conclusion: Metastasis only to bone without other organ involvement in colorectal cancer patients is extremely rare, perhaps more rare than we previously thought. Our findings suggest that resistant metastasis to the lungs predicts potential disease progression to bone in the colorectal cancer population better than liver metastasis does.

  13. Bone morphogenetic protein 6 expression in oral cavity squamous cell cancer is associated with bone invasion.

    Science.gov (United States)

    Kejner, Alexandra E; Burch, M Benjamin; Sweeny, Larissa; Rosenthal, Eben L

    2013-12-01

    To evaluate bone invasion, survival, and expression of bone morphogenetic protein-6 (BMP-6) in oral cavity cancer in the context of known biomarkers indicative of poor prognosis. Molecular expression study combined with retrospective chart review of corresponding patients at a tertiary care center. Between 2000 and 2009, a total of 197 patients underwent resection for oral cavity squamous cell carcinoma. Of these, 30 pathologic specimens were chosen for further molecular analysis. These 30 patients were separated into three groups (10 per group) based on American Joint Committee on Cancer (AJCC) staging and staging based on size alone (TAJCC /SIZE ). The first group consisted of tumors staged as T2 /2 based on size less than 4 cm and that had no evidence of bone invasion. The T2 /4 group consisted of tumors that were upstaged from T2 based on bone invasion. The T4 /4 group consisted of tumors that were large with and without bone invasion. The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), BMP-6, and epidermal growth factor receptor (EGFR) was examined using immunohistochemistry techniques. Patient demographics, tumor characteristics, survival, and recurrence were compared. Average follow-up was 21 months. Expression of BMP-6 was significantly higher in the T2 /4 cohort (tumor less than 4 cm with bony invasion) than the larger tumors without bone invasion (T4 /4 cohort, P = .05). In addition, increased BMP-6 expression correlated with aggressive behavior in the smaller tumors. Furthermore, increased EGFR expression positively correlated with increased levels of BMP-6. Increased expression of BMP-6 in oral cavity cancer may affect bone invasion. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

  14. Modeling selective elimination of quiescent cancer cells from bone marrow.

    Science.gov (United States)

    Cavnar, Stephen P; Rickelmann, Andrew D; Meguiar, Kaille F; Xiao, Annie; Dosch, Joseph; Leung, Brendan M; Cai Lesher-Perez, Sasha; Chitta, Shashank; Luker, Kathryn E; Takayama, Shuichi; Luker, Gary D

    2015-08-01

    Patients with many types of malignancy commonly harbor quiescent disseminated tumor cells in bone marrow. These cells frequently resist chemotherapy and may persist for years before proliferating as recurrent metastases. To test for compounds that eliminate quiescent cancer cells, we established a new 384-well 3D spheroid model in which small numbers of cancer cells reversibly arrest in G1/G0 phase of the cell cycle when cultured with bone marrow stromal cells. Using dual-color bioluminescence imaging to selectively quantify viability of cancer and stromal cells in the same spheroid, we identified single compounds and combination treatments that preferentially eliminated quiescent breast cancer cells but not stromal cells. A treatment combination effective against malignant cells in spheroids also eliminated breast cancer cells from bone marrow in a mouse xenograft model. This research establishes a novel screening platform for therapies that selectively target quiescent tumor cells, facilitating identification of new drugs to prevent recurrent cancer. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  15. The Anabolic Effect of PTH on Bone is Attenuated by Simultaneous Glucocorticoid Treatment

    DEFF Research Database (Denmark)

    Oxlund, Hans; Ørtoft, Gitte; Thomsen, Jesper Skovhus

    2006-01-01

    Glucocorticoids (GC) are used for the treatment of a wide spectrum of diseases because of their potent anti-inflammatory and immunosuppressive effects, and they are serious and common causes of secondary osteoporosis. Administration of intermittent parathyroid hormone (PTH) may induce formation...... of new bone and may counteract the bone loss induced by GC treatment. Effects of simultaneous PTH and GC treatment were investigated on bone biomechanics, static and dynamic histomorphometry, and bone metabolism. Twenty-seven-month-old female rats were divided randomly into the following groups: baseline...... injections resulted in a 5-fold increase in cancellous bone volume. At the proximal tibia, PTH induced a pronounced formation of new cancellous bone which originated from the endocortical bone surfaces and from thin trabeculae. Formation and modeling of connections between trabeculae were observed. Similar...

  16. A combination of soy isoflavones and cello-oligosaccharides changes equol/O-desmethylangolensin production ratio and attenuates bone fragility in ovariectomized mice.

    Science.gov (United States)

    Fujii, Shungo; Takahashi, Nobuyuki; Inoue, Hirofumi; Katsumata, Shin-Ichi; Kikkawa, Yuji; Machida, Makoto; Ishimi, Yoshiko; Uehara, Mariko

    2016-08-01

    We examined the cooperative effects of isoflavones and cello-oligosaccharides on daidzein metabolism and bone fragility in ovariectomized mice. Cello-oligosaccharides increased urinary equol and decreased O-desmethylangolensin. A combination of isoflavones and cello-oligosaccharides attenuated decreases in bone breaking force and stiffness caused by ovariectomy. Combination treatment with isofalvones and cello-oligosaccharides increases urinary equol/O-desmethylangolensin production ratio and prevents ovariectomy-induced abnormalities in bone strength.

  17. Inhibition of SDF-1α/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Yonghui Dong

    2016-06-01

    Full Text Available Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA. Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process. Post-traumatic osteoarthritis (PTOA mice models were prepared by transecting the anterior cruciate ligament (ACLT, or a sham surgery was performed, in a total of 30 mice. Mice were treated with phosphate buffer saline (PBS or AMD3100 (an inhibitor of CXCR4 and sacrificed at 30 days post ACLT or sham surgery. Tibial subchondral bone status was quantified by micro-computed tomography (μCT. Knee-joint histology was analysed to examine the articular cartilage and joint degeneration. The levels of SDF-1α and collagen type I c-telopeptidefragments (CTX-I were quantified by ELISA. Bone marrow mononuclear cells (BMMCs were used to clarify the effects of SDF-1α on osteoclast formation and activity in vivo. μCT analysis revealed significant loss of trabecular bone from tibial subchondral bone post-ACLT, which was effectively prevented by AMD3100. AMD3100 could partially prevent bone loss and articular cartilage degeneration. Serum biomarkers revealed an increase in SDF-1α and bone resorption, which were also reduced by AMD3100. SDF-1α can promote osteoclast formation and the expression oftartrate resistant acid phosphatase (TRAP, cathepsin K (CK, and matrix metalloproteinase (MMP-9 in osteoclasts by activating the MAPK pathway, including ERK and p38, but not JNK. In conclusion, inhibition of SDF-1α/CXCR4signalling was able to prevent trabecular bone loss and attenuated cartilage

  18. Role of Adrenomedullin in Breast Cancer Bone Metastasis and Chemoresistance

    Science.gov (United States)

    2007-05-01

    calvarial osteoblast proliferation and cranial suture fusion. Cleft Palate Craniofacial Journal, 39, 487–496. 86. Chikazu, D., Katagiri, M., Ogasawara, T...and lung cancer models. These observations identify AM as a significant target for therapeutic intervention in bone metastasis. Small molecules

  19. Macrophage Efferocytosis and Prostate Cancer Bone Metastasis

    Science.gov (United States)

    2015-10-01

    efferocytosis. The translation of this functional role during pathophysiological states such as tumor metastasis to the skeleton is unknown. The purpose of this...COLLABORATING ORGANIZATIONS What individuals have worked on the project? Name: L.C. Hofbauer Institution: Department of Endocrinology, Diabetes , and Bone

  20. [Predictive factors for bone metastases of prostate cancer].

    Science.gov (United States)

    Chen, Ye-Hui; Nie, Pin; Jiang, Wen; Zhao, Shi-Jia; Zhang, Zhi; Lin, Hua-Xin; Li, Miao-Yuan; Liu, Yan-Qing; Li, Peng-Hui; Zhu, Xu-Sheng

    2016-02-01

    To investigate the correlation between a diverse of clinical factors and bone metastases of prostate cancer. The clinical data of 80 patients with prostate cancer were collected and analyzed. The correlations of age, alkaline phosphotase (ALP), prostate specific antigen (PSA), erythrocyte sedimentation rate (ESR), Gleason score, and expressions of androgen receptor (AR) and Ki-67 with bone metastases were analyzed by one-way ANOVA and Logistic regression analysis. The cutoff value, sensitivity and specificity of the independent correlation factors were calculated. Forty-five of the 80 patients (56%) were found to have bone metastasis, who had significantly older age and higher levels of ALP, PSA, ESR, Gleason score, and expressions of AR and Ki-67 than those without bone metastasis (PGleason score and AR expression as independent factors correlated with bone metastasis with OR (95% CI) of 1.005 (1.001, 1.009) (P=0.008), 5.356 (1.431, 20.039) (P=0.013), and 18.594 (2.460, 140.524) (P=0.005), respectively. The cutoff values of PSA, Gleason Score and AR were 67.1 ng/ml, 7.5, and 2.5, respectively; their sensitivities were 55.6%, 75.6%, and 84.0% for predicting bone metastasis with specificities of 97.1%, 82.9%, and 91.4%, respectively. Of the factors analyzed, PSA, Gleason score and AR expression, but not age, ALP, PSA, ESR, or Ki-67 expression, are the predictive factors of bone metastasis of prostate cancer.

  1. Impact of denosumab on bone mass in cancer patients

    Directory of Open Access Journals (Sweden)

    Brown-Glaberman U

    2013-07-01

    Full Text Available Ursa Brown-Glaberman, Alison T StopeckUniversity of Arizona Cancer Center, Tucson, AZ, USAAbstract: Cancer therapy-induced bone loss (CTIBL is a form of secondary osteoporosis associated with systemic chemotherapy and hormonal ablation therapy. The monitoring and treatment of CTIBL is an important component of comprehensive cancer care, especially for patients with curable disease and long life expectancies. Whereas oral bisphosphonates remain the most commonly used therapeutic option for CTIBL, additional treatment options may be required for patients who do not respond adequately or are intolerant to bisphosphonates, have renal insufficiency, or are receiving treatment with nephrotoxic medications. For these patients, denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand (RANKL, offers an effective and well-tolerated alternative. Several recent randomized trials have examined the use of denosumab as treatment for CTIBL associated with hormone ablation therapy for breast and prostate cancer. Recent data suggest a possible role for RANKL inhibitors in both chemoprevention and the prevention of cancer recurrence through direct effects on breast tissue and breast cancer stem cells. The outcomes of several international Phase III clinical trials currently underway will help clarify the role of denosumab in patients undergoing cancer therapy.Keywords: denosumab, osteoporosis, osteopenia, hormone ablation therapy, cancer therapy-induced bone loss, chemotherapy

  2. Bone Metastasis

    Science.gov (United States)

    ... help reduce pain and other symptoms of bone metastases. Symptoms Sometimes, bone metastasis causes no signs and ... cancers most likely to cause bone metastasis include: Breast cancer Kidney cancer Lung cancer Lymphoma Multiple myeloma Prostate ...

  3. [Serum osteoprotegerin as a novel marker of bone metastasis in prostate cancer].

    Science.gov (United States)

    Chen, Hai-xin; Li, Han-zhong; Li, Hong-jun; Shi, Bing-bing; Jin, Wei; Cheng, Xin-qi

    2007-03-15

    To evaluate the diagnostic usefulness of serum osteoprotegerin (OPG) in prostate cancer bone metastasis. Serum osteoprotegerin were measured by ELISA assay in 30 healthy men, 30 patients with benign prostatic hyperplasia, 66 patients with prostate cancer including 36 without bone metastasis (30 with localized cancer, 6 with lymph node metastasis) and 30 with bone metastasis. The results associated with clinical data were calculated statistically. Serum osteoprotegerin were significantly increased in patients with bone metastasis compared with others (PGleason score or grade (r=0.427, 0.277; Pbone metastasis in prostate cancer. Serum osteoprotegerin could be used as a marker for diagnosis of bone metastasis in prostate cancer.

  4. Assessment of the relationship between broadband ultrasound attenuation and bone mineral density at the calcaneus using BUA imaging and DXA.

    Science.gov (United States)

    Chappard, C; Laugier, P; Fournier, B; Roux, C; Berger, G

    1997-01-01

    The purposes of this study was to determine the relationship between broadband ultrasound attenuation (BUA) and bone mineral density (BMD) measured at different regions of the calcaneus with identical site-matched regions of interest (ROIs). Dual-energy X-ray absorptiometry (DXA) measurements of the calcaneus and BUA imaging were performed in 30 women (15 premenopausal and 15 postmenopausal). Four square ROIs were located in the great tuberosity and one square ROI in the foramen calcaneus. A ROI adapted to the shape and size of the whole calcaneus was also considered. All ROIs were analyzed three times with both techniques to minimize intra-observer variability. The correlation coefficient between attenuation and frequency was used as an index of BUA measurement error. Before accepting a measurement of BUA in inhomogeneous material, it could be useful to map the spatial variations of the measurement error. In all ROIs we found the BUA and BMD were strongly related (r = 0.78-0.91, p < 0.001). The correlation between BUA and BMD was slightly higher in the inferior part of the posterior tuberosity than in the superior part and in the foramen calcaneus. The very high correlation between attenuation and frequency found in all ROIs (r = 0.99) suggests that measurement errors of propagation were probably not significant. Ultrasound imaging yields the opportunity for studying the spatial acoustic properties in the calcaneus and their relation to bone mass or structural parameters provided by independent imaging techniques. BUA measured with current transmission techniques reflects mainly bone mass, and microarchitecture to a smaller extent.

  5. Metastatic Prostate Cancer and the Bone: Significance and Therapeutic Options.

    Science.gov (United States)

    Gartrell, Benjamin A; Coleman, Robert; Efstathiou, Eleni; Fizazi, Karim; Logothetis, Christopher J; Smith, Matthew R; Sonpavde, Guru; Sartor, Oliver; Saad, Fred

    2015-11-01

    Skeletal involvement is common in metastatic prostate cancer (PCa) and is associated with skeletal-related events (SREs). The interaction of PCa with the bone microenvironment contributes to self-perpetuating progression of cancer in bone. Bone-targeted agents (BTAs) are available for use in metastatic castration-resistant prostate cancer (mCRPC). To review the biology of bone metastases in PCa and to review the clinical trial data for BTAs in PCa. A literature search was conducted in October 2014. Keywords included clinical trial, prostate cancer, denosumab, bisphosphonates, zoledronic acid, radium-223, bone turnover markers, skeletal-related events, and symptomatic skeletal events. The biology of bone metastases in PCa is summarized. Data supporting the use of BTAs in PCa are reviewed, and issues related to the combination and sequencing of available agents are discussed. The osteoclast-targeted agents zoledronic acid and denosumab decrease SREs in mCRPC, and the α-emitting radiopharmaceutical agent radium-223 improves survival and decreases symptomatic skeletal events. Limited data are available to guide the sequence and combination of BTAs with disease-modifying agents, although data support the use of osteoclast-targeted drugs with chemotherapy, androgen-targeted agents, and radium-223. Zoledronic acid does not reduce SREs when started prior to castration resistance, although osteoclast-targeted agents do improve outcomes when used in patients with asymptomatic to minimally symptomatic chemotherapy-naive mCRPC. The optimal sequence of radium-223 with chemotherapy is uncertain, although data suggest the efficacy and tolerability of radium-223 is similar with either sequence. Clinical trials evaluating the combination of BTAs with other agents are under way. The optimization of sequence and combination strategies will guide the best use of available agents. The literature pertaining to bone metastases in prostate cancer (PCa) was reviewed, and the current

  6. Effect of Bone Reading CT software on radiologist performance in detecting bone metastases from breast cancer.

    Science.gov (United States)

    Ha, Ji Y; Jeon, Kyung N; Bae, Kyungsoo; Choi, Bong H

    2017-04-01

    To evaluate the effect of CT software that generates rib unfolding images and automatically numbers ribs and thoracic spines on radiologist performance in detecting thoracic bone metastases from breast cancer. A total of 126 patients with breast cancer who underwent chest CT and fludeoxyglucose (FDG)-positron emission tomography (PET)/CT and/or bone scans were retrospectively reviewed. One board-certified radiologist (R1) and one radiology resident (R2) independently assessed the original chest CT and rib unfolding images using a commercially available post-processing software (Bone Reading) application to evaluate metastasis in the ribs and thoracic spines. Results were compared with reference standard based on CT, FDG-PET/CT and/or bone scan with follow-up. Based on reference standard, 78 metastatic bone lesions in 26 patients were identified. On per-patient-based analysis, Bone Reading assessed by R1/R2 had a sensitivity of 84.6%/80.8% and a specificity of 94.0%/94.0% with an accuracy of 92.1%/91.3%. The original CT reading yielded a sensitivity of 73.1%/57.7% and a specificity of 95.0%/94.0% with an accuracy of 90.5%/86.5%. The sensitivity and accuracy of Bone Reading were significantly higher than those of CT reading, as assessed by R2 (both p = 0.031). On per-lesion-based analysis, Bone Reading assessed by R1/R2 yielded a sensitivity of 84.6%/82.1% and a specificity of 99.7%/99.6% with an accuracy of 99.4%/99.3%, while the original CT reading yielded a sensitivity of 71.8%/62.8% and a specificity of 99.6%/99.5% with an accuracy of 99.2%/98.9%. The sensitivity and accuracy with Bone Reading application were significantly higher than those with CT reading by both readers (R1, p = 0.006 and p = 0.036, respectively; R2, both p reading time needed for Bone Reading application was significantly shorter than that for original chest CT reading (p Reading application helped readers find small and sclerotic lesions missed in original CT reading. In

  7. Vitamin D, Breast Cancer, and Bone Health

    Science.gov (United States)

    2011-05-01

    canned in oil 3 oz 200 50 Eel, cooked 15 oz 200 50 Egg One whole 20 5 Milk, vitamin D fortified 1 cup 98 25 Orange juice, fortified 1 cup 98 25...an initial clinical laboratory assessment: serum calcium, phosphorus, creatinine, albumin , 25(OH)D, parathyroid hormone (PTH), bone-specific alkaline...events will be recorded. Blood will be collected for serum calcium, albumin , and urine calcium and creatinine will be also measured (fasting). At the 4

  8. Prevention of Bone Metastases in Breast Cancer Patients. Therapeutic Perspectives

    Directory of Open Access Journals (Sweden)

    Philippe Beuzeboc

    2014-05-01

    Full Text Available One in four breast cancer patients is at risk of developing bone metastases in her life time. The early prevention of bone metastases is a crucial challenge. It has been suggested that the use of zoledronic acid (ZOL in the adjuvant setting may reduce the persistence of disseminated tumor cells and thereby might improve outcome, specifically in a population of patients with a low estrogen microenvironment. More recently, the results of a large meta-analysis from 41 randomized trials comparing a bisphosphonate (BP to placebo or to an open control have been presented at the 2013 San Antonio Breast Cancer Meeting. Data on 17,016 patients confirm that adjuvant BPs, irrespective of the type of treatment or the treatment schedule and formulation (oral or intra-venously (IV, significantly reduced bone recurrences and improved breast cancer survival in postmenopausal women. No advantage was seen in premenopausal women. BPs are soon likely to become integrated into standard practice. Published data on the mechanisms involved in tumor cell seeding from the primary site, in homing to bone tissues and in the reactivation of dormant tumor cells will be reviewed; these might offer new ideas for innovative combination strategies.

  9. Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice.

    Science.gov (United States)

    Motyl, Katherine J; DeMambro, Victoria E; Barlow, Deborah; Olshan, David; Nagano, Kenichi; Baron, Roland; Rosen, Clifford J; Houseknecht, Karen L

    2015-07-01

    Atypical antipsychotic (AA) drugs cause significant metabolic side effects, and clinical data are emerging that demonstrate increased fracture risk and bone loss after treatment with the AA, risperidone (RIS). The pharmacology underlying the adverse effects on bone is unknown. However, RIS action in the central nervous system could be responsible because the sympathetic nervous system (SNS) is known to uncouple bone remodeling. RIS treatment in mice significantly lowered trabecular bone volume fraction (bone volume/total volume), owing to increased osteoclast-mediated erosion and reduced osteoblast-mediated bone formation. Daytime energy expenditure was also increased and was temporally associated with the plasma concentration of RIS. Even a single dose of RIS transiently elevated expression of brown adipose tissue markers of SNS activity and thermogenesis, Pgc1a and Ucp1. Rankl, an osteoclast recruitment factor regulated by the SNS, was also increased 1 hour after a single dose of RIS. Thus, we inferred that bone loss from RIS was regulated, at least in part, by the SNS. To test this, we administered RIS or vehicle to mice that were also receiving the nonselective β-blocker propranolol. Strikingly, RIS did not cause any changes in trabecular bone volume/total volume, erosion, or formation while propranolol was present. Furthermore, β2-adrenergic receptor null (Adrb2(-/-)) mice were also protected from RIS-induced bone loss. This is the first report to demonstrate SNS-mediated bone loss from any AA. Because AA medications are widely prescribed, especially to young adults, clinical studies are needed to assess whether β-blockers will prevent bone loss in this vulnerable population.

  10. Intrathecal injection of lentivirus-mediated glial cell line-derived neurotrophic factor RNA interference relieves bone cancer-induced pain in rats.

    Science.gov (United States)

    Meng, Fu-Fen; Xu, Yang; Dan, Qi-Qin; Wei, La; Deng, Ying-Jie; Liu, Jia; He, Mu; Liu, Wei; Xia, Qing-Jie; Zhou, Fiona H; Wang, Ting-Hua; Wang, Xi-Yan

    2015-04-01

    Bone cancer pain is a common symptom in cancer patients with bone metastases and the underlying mechanisms are largely unknown. The aim of this study is to explore the endogenous analgesic mechanisms to develop new therapeutic strategies for bone-cancer induced pain (BCIP) as a result of metastases. MRMT-1 tumor cells were injected into bilateral tibia of rats and X-rays showed that the area suffered from bone destruction, accompanied by an increase in osteoclast numbers. In addition, rats with bone cancer showed apparent mechanical and thermal hyperalgesia at day 28 after intratibial MRMT-1 inoculation. However, intrathecal injection of morphine or lentivirus-mediated glial cell line-derived neurotrophic factor RNAi (Lvs-siGDNF) significantly attenuated mechanical and thermal hyperalgesia, as shown by increases in paw withdrawal thresholds and tail-flick latencies, respectively. Furthermore, Lvs-siGDNF interference not only substantially downregulated GDNF protein levels, but also reduced substance P immunoreactivity and downregulated the ratio of pERK/ERK, where its activation is crucial for pain signaling, in the spinal dorsal horn of this model of bone-cancer induced pain. In this study, Lvs-siGDNF gene therapy appeared to be a beneficial method for the treatment of bone cancer pain. As the effect of Lvs-siGDNF to relieve pain was similar to morphine, but it is not a narcotic, the use of GDNF RNA interference may be considered as a new therapeutic strategy for the treatment of bone cancer pain in the future. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  11. Induced Pluripotent Stem Cell Derived Mesenchymal Stem Cells for Attenuating Age-Related Bone Loss

    Science.gov (United States)

    2012-07-01

    Mesenchymal stem cell (MSC) differentiation towards the bone forming osteoblastic lineage decreases as a function of age and may contribute to age-related...problem of age-related reduced availability of MSC we propose to examine the bone anabolic potential of induced pluripotent stem cell (iPS) derived MSC

  12. Green tea polyphenols attenuate deterioration of bone microarchitecture in female rats with systemic chronic inflammation

    Science.gov (United States)

    Introduction: Our previous study demonstrated that green tea polyphenols (GTP) benefit bone health in female rats with chronic inflammation, because of GTP’s antioxidant capacity. The current study further evaluates whether GTP can restore bone microstructure along with related mechanism in rats wit...

  13. Attenuated Wnt/β-catenin signalling mediates methotrexate chemotherapy-induced bone loss and marrow adiposity in rats.

    Science.gov (United States)

    Georgiou, Kristen R; King, Tristan J; Scherer, Michaela A; Zhou, Hong; Foster, Bruce K; Xian, Cory J

    2012-06-01

    Cancer chemotherapy often causes significant bone loss, marrow adiposity and haematopoietic defects, yet the underlying mechanisms and recovery potential remain unclear. Wnt/β-catenin signalling is integral to the regulation of osteogenesis, adipogenesis and haematopoiesis; using a rat model, the current study investigated roles of this signalling pathway in changes to bone marrow stromal and haematopoietic cell differentiation after chemotherapy with methotrexate (MTX), a commonly used antimetabolite. MTX treatment in rats (5 daily administrations at 0.75 mg/kg) has previously been found to decrease bone volume and increase marrow fat, which was associated with increased osteoclastogenesis in haematopoietic cells and with an osteogenesis to adipogenesis switch in bone marrow stromal cells of treated rats. In the current study, on day 6 after the first MTX dose we found that accompanying these changes as well as a suppressed haematopoietic cellularity but increased granulocyte/macrophage differentiation potential, there was an increase in mRNA expression of Wnt antagonists sFRP-1 and Dkk-1 in bone, a reduction in nuclear β-catenin protein in bone marrow stromal cells, and decreased mRNA levels of β-catenin target genes lef-1, cyclin D1 and survivin, suggesting reduced activation of Wnt/β-catenin signalling in the bone during MTX-induced damage. Concurrent administration of BIO, a GSK-3β inhibitor that stabilises β-catenin, partially abrogated the MTX-induced transient changes in osteogenic/adipogenic commitment, granulocyte/macrophage lineage differentiation and osteoclast number. These findings demonstrate a potentially important role of Wnt/β-catenin signalling in MTX chemotherapy-induced cellular changes to the bone marrow microenvironment. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. [Bone metabolism, renal function and immune structure in prostate cancer. Our experience].

    Science.gov (United States)

    Di Francesco, Simona; Tenaglia, Raffaele Lanfranco

    2013-01-01

    Relation studies between bone and immune system converge in recent years in osteoimmunology chapter. It has been suggested that prostate cancer cells may alter bone homeostasis, renal function and the immune system. The aim of this paper is to evaluate bone metabolism, renal function and immune process in prostate cancer patients versus control. Patients with prostate malignancy and bone metastases showed a condition of hypocalcemia and hypophosphatemia associated with increased bone anabolism and lymphopenia, suggesting a possible correlation between bone metabolism and immune context in prostate cancer.

  15. Role of nitric oxide synthase in the development of bone cancer pain and effect of L-NMMA.

    Science.gov (United States)

    Yang, Yan; Zhang, Juan; Liu, Yue; Zheng, Yaguo; Bo, Jinhua; Zhou, Xiaofang; Wang, Junhua; Ma, Zhengliang

    2016-02-01

    Spinal nitric oxide is involved in the mechanisms of pain generation and transmission during inflammatory and neuropathic pain. The aim of the present study was to explore the role of spinal nitric oxide in the development of bone cancer pain. 2 x 10(5) osteosarcoma cells were implanted into the intramedullary space of right femurs of C3H/HeJ mice to induce a model of ongoing bone cancer. Polymerase chain reaction and immunohistochemical analyses were performed to assess the expression of neuronal nitric oxide synthase (nNOS) and inducible (i)NOS in the spinal cord following inoculation. The results showed that inoculation of osteosarcoma cells induced progressive bone cancer, accompanied with pain-associated behavior. The levels of nNOS mRNA in the spinal cord of tumor mice began to increase at day 10 and then decreased to the level in sham mice at day 14, while iNOS mRNA markedly increased in the tumor group at days 10 and 14. Immunohistochemical analysis showed that nNOS- and iNOS-positive neurons were mainly located in the superficial dorsal horn and around the central canal of the L3-L5 spinal cord. Intrathecal injection of 50 µg NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) attenuated cancer-evoked pain behaviors at day 14. These findings indicated that an upregulation of nNOS and iNOS in the spinal cord is associated with bone cancer pain and suggests that exogenously administered L-NMMA may have beneficial effects to alleviate bone cancer pain.

  16. Dependences of the attenuation and the backscatter coefficients on the frequency and the porosity in bovine trabecular bone: application of the binary mixture model

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Kang Il [Kangwon National University, Chuncheon (Korea, Republic of)

    2012-02-15

    The present study aims to investigate the dependences of the attenuation and the backscatter coefficients on the frequency and the porosity in bovine trabecular bone in vitro. The frequency dependent attenuation and backscatter coefficients were measured in 22 bovine femoral trabecular bone samples over a frequency range from 1.4 to 3.0 MHz by using a pair of transducers with a diameter of 12.7 mm and a center frequency of 2.25 MHz. The binary mixture model for ultrasonic scattering in trabecular bone, in which trabecular bone is assumed to be an isotropic binary mixture composed of a bone matrix and marrow, was applied to predict the measurements. The experimental results showed that the attenuation and the backscatter coefficients increased with increasing frequency from 1.4 to 3.0 MHz and decreased with increasing porosity from 66.9 to 91.5%. The predictions of the binary mixture model showed good agreements with the measurements, suggesting that scattering may be the dominant attenuation mechanism in dense bovine trabecular bone at frequencies from 1.4 to 3.0 MHz.

  17. Correction of quantification errors in pelvic and spinal lesions caused by ignoring higher photon attenuation of bone in [{sup 18}F]NaF PET/MR

    Energy Technology Data Exchange (ETDEWEB)

    Schramm, Georg, E-mail: georg.schramm@kuleuven.be; Maus, Jens; Hofheinz, Frank; Petr, Jan; Lougovski, Alexandr [Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden 01328 (Germany); Beuthien-Baumann, Bettina; Oehme, Liane [Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Dresden 01307 (Germany); Platzek, Ivan [Department of Radiology, University Hospital Carl Gustav Carus, Dresden 01307 (Germany); Hoff, Jörg van den [Helmholtz-Zentrum Dresden-Rossendorf, Institute for Radiopharmaceutical Cancer Research, Dresden 01328 (Germany); Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Dresden 01307 (Germany)

    2015-11-15

    Purpose: MR-based attenuation correction (MRAC) in routine clinical whole-body positron emission tomography and magnetic resonance imaging (PET/MRI) is based on tissue type segmentation. Due to lack of MR signal in cortical bone and the varying signal of spongeous bone, standard whole-body segmentation-based MRAC ignores the higher attenuation of bone compared to the one of soft tissue (MRAC{sub nobone}). The authors aim to quantify and reduce the bias introduced by MRAC{sub nobone} in the standard uptake value (SUV) of spinal and pelvic lesions in 20 PET/MRI examinations with [{sup 18}F]NaF. Methods: The authors reconstructed 20 PET/MR [{sup 18}F]NaF patient data sets acquired with a Philips Ingenuity TF PET/MRI. The PET raw data were reconstructed with two different attenuation images. First, the authors used the vendor-provided MRAC algorithm that ignores the higher attenuation of bone to reconstruct PET{sub nobone}. Second, the authors used a threshold-based algorithm developed in their group to automatically segment bone structures in the [{sup 18}F]NaF PET images. Subsequently, an attenuation coefficient of 0.11 cm{sup −1} was assigned to the segmented bone regions in the MRI-based attenuation image (MRAC{sub bone}) which was used to reconstruct PET{sub bone}. The automatic bone segmentation algorithm was validated in six PET/CT [{sup 18}F]NaF examinations. Relative SUV{sub mean} and SUV{sub max} differences between PET{sub bone} and PET{sub nobone} of 8 pelvic and 41 spinal lesions, and of other regions such as lung, liver, and bladder, were calculated. By varying the assigned bone attenuation coefficient from 0.11 to 0.13 cm{sup −1}, the authors investigated its influence on the reconstructed SUVs of the lesions. Results: The comparison of [{sup 18}F]NaF-based and CT-based bone segmentation in the six PET/CT patients showed a Dice similarity of 0.7 with a true positive rate of 0.72 and a false discovery rate of 0.33. The [{sup 18}F]NaF-based bone

  18. Endothelial Cells as Precursors for Osteoblasts in the Metastatic Prostate Cancer Bone

    Directory of Open Access Journals (Sweden)

    Ana E. Paiva

    2017-11-01

    Full Text Available Prostate cancer cells metastasize to the bones, causing ectopic bone formation, which results in fractures and pain. The cellular mechanisms underlying new bone production are unknown. In a recent study, Lin and colleagues, by using state-of-the-art techniques, including prostate cancer mouse models in combination with sophisticated in vivo lineage-tracing technologies, revealed that endothelial cells form osteoblasts induced by prostate cancer metastasis in the bone. Strikingly, genetic deletion of osteorix protein from endothelial cells affected prostate cancer–induced osteogenesis in vivo. Deciphering the osteoblasts origin in the bone microenvironment may result in the development of promising new molecular targets for prostate cancer therapy.

  19. SURGICAL TREATMENT FOR KIDNEY CANCER METASTASES TO THE LONG TUBULAR BONES

    Directory of Open Access Journals (Sweden)

    S. V. Kostritsky

    2014-07-01

    Full Text Available The data of 35 kidney cancer patients with metastases in long bones, who had been operated, were retrospectively analyzed. The role of surgery in patients with long bones metastases of kidney cancer was assessed and application of surgical treatment was ascertained to yield satisfactory results in improving the quality of life and duration of life in patients with solitary bone metastases.

  20. SURGICAL TREATMENT FOR KIDNEY CANCER METASTASES TO THE LONG TUBULAR BONES

    Directory of Open Access Journals (Sweden)

    S. V. Kostritsky

    2013-01-01

    Full Text Available The data of 35 kidney cancer patients with metastases in long bones, who had been operated, were retrospectively analyzed. The role of surgery in patients with long bones metastases of kidney cancer was assessed and application of surgical treatment was ascertained to yield satisfactory results in improving the quality of life and duration of life in patients with solitary bone metastases.

  1. Esophageal Cancer with Bone Marrow Hyperplasia Mimicking Bone Metastasis: Report of a Case

    OpenAIRE

    Yasuda, Hiromi; Shimura, Tadanobu; Okigami, Masato; Yoshiyama, Shigeyuki; Ohi, Masaki; Tanaka, Koji; Mohri, Yasuhiko; Kusunoki, Masato

    2016-01-01

    A 63-year-old man visited the clinic with numbness in the right hand. Magnetic resonance imaging demonstrated multiple low-intensity lesions in the cervical vertebrae and sacrum, which was suspicious of cervical bone metastasis. Fluorodeoxyglucose positron emission tomography/computed tomography revealed areas of increased fluorodeoxyglucose uptake in the thoracic esophagus, sternum and sacrum. A flat, elevated esophageal cancer was identified by upper gastrointestinal endoscopy, and the macr...

  2. High-fat Diet Enhances and Plasminogen Activator Inhibitor-1 Deficiency Attenuates Bone Loss in Mice with Lewis Lung Carcinoma.

    Science.gov (United States)

    Yan, Lin; Nielsen, Forrest H; Sundaram, Sneha; Cao, Jay

    2015-07-01

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (Pai1(-/-)) on the bone structure in male C57BL/6 mice bearing Lewis lung carcinoma (LLC) in lungs. Significant reduction in bone volume fraction (BV/TV), trabecular number (Tb.N) and bone mineral density (BMD) in femurs and vertebrae were found in LLC-bearing mice compared to non-tumor-bearing mice. In LLC-bearing mice, the high-fat diet compared to the AIN93G control diet significantly reduced BV/TV, Tb.N and BMD in femurs and BV/TV in vertebrae. The high-fat diet significantly reduced BMD in vertebrae in wild-type mice but not in Pai1(-/-) mice. Compared to wild-type mice, PAI1 deficiency significantly increased BV/TV and Tb.N in femurs. The plasma concentration of osteocalcin was significantly lower and that of tartrate-resistant acid phosphatase 5b (TRAP5b) was significantly higher in LLC-bearing mice. The high-fat diet significantly reduced plasma osteocalcin and increased TRAP5b. Deficiency in PAI1 prevented the high-fat diet-induced increases in plasma TRAP5b. These findings demonstrate that a high-fat diet enhances, whereas PAI1 deficiency, attenuates metastasis-associated bone loss, indicating that a high-fat diet and PAI1 contribute to metastasis-associated bone deterioration. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  3. Atractylenolide I-mediated Notch pathway inhibition attenuates gastric cancer stem cell traits

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Li; Mao, Rurong; Shen, Ke; Zheng, Yuanhong; Li, Yueqi [State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237 (China); Liu, Jianwen, E-mail: liujian@ecust.edu.cn [State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237 (China); Ni, Lei, E-mail: nilei625@yahoo.com [Department of Respiration, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Road II, Shanghai 200025 (China)

    2014-07-18

    Highlights: • This paper supports the anti-tumor effects of AT-I on gastric cancer in vitro. • AT-I attenuates gastric cancer stem cell traits. • It is the systematic study regarding AT-I suppression of Notch pathway in GC and GCSLCs. - Abstract: Atractylenolide I (AT-I), one of the main naturally occurring compounds of Rhizoma Atractylodis Macrocephalae, has remarkable anti-cancer effects on various cancers. However, its effects on the treatment of gastric cancer remain unclear. Via multiple cellular and molecular approaches, we demonstrated that AT-I could potently inhibit cancer cell proliferation and induce apoptosis through inactivating Notch pathway. AT-I treatment led to the reduction of expressions of Notch1, Jagged1, and its downstream Hes1/ Hey1. Our results showed that AT-I inhibited the self-renewal capacity of gastric stem-like cells (GCSLCs) by suppression of their sphere formation capacity and cell viability. AT-I attenuated gastric cancer stem cell (GCSC) traits partly through inactivating Notch1, leading to reducing the expressions of its downstream target Hes1, Hey1 and CD44 in vitro. Collectively, our results suggest that AT-I might develop as a potential therapeutic drug for the treatment of gastric cancer.

  4. Combined Treatment with Exendin-4 and Metformin Attenuates Prostate Cancer Growth.

    Directory of Open Access Journals (Sweden)

    Yoko Tsutsumi

    Full Text Available Recently, the pleiotropic benefits of incretin-based therapy have been reported. We have previously reported that Exendin-4, a glucagon-like peptide-1 (GLP-1 receptor agonist, attenuates prostate cancer growth. Metformin is known for its anti-cancer effect. Here, we examined the anti-cancer effect of Exendin-4 and metformin using a prostate cancer model.Prostate cancer cells were treated with Exendin-4 and/or metformin. Cell proliferation was quantified by growth curves and 5-bromo-2'-deoxyuridine (BrdU assay. TUNEL assay and AMP-activated protein kinase (AMPK phosphorylation were examined in LNCaP cells. For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin. TUNEL assay and immunohistochemistry were performed on tumors.Exendin-4 and metformin additively decreased the growth curve, but not the migration, of prostate cancer cells. The BrdU assay revealed that both Exendin-4 and metformin significantly decreased prostate cancer cell proliferation. Furthermore, metformin, but not Exendin-4, activated AMPK and induced apoptosis in LNCaP cells. The anti-proliferative effect of metformin was abolished by inhibition or knock down of AMPK. In vivo, Exendin-4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment. Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin, and that metformin increased phospho-AMPK expression and the apoptotic cell number.These data suggest that Exendin-4 and metformin attenuated prostate cancer growth by inhibiting proliferation, and that metformin inhibited proliferation by inducing apoptosis. Combined treatment with Exendin-4 and metformin attenuated prostate cancer growth more than separate treatments.

  5. Combined Treatment with Exendin-4 and Metformin Attenuates Prostate Cancer Growth.

    Science.gov (United States)

    Tsutsumi, Yoko; Nomiyama, Takashi; Kawanami, Takako; Hamaguchi, Yuriko; Terawaki, Yuichi; Tanaka, Tomoko; Murase, Kunitaka; Motonaga, Ryoko; Tanabe, Makito; Yanase, Toshihiko

    2015-01-01

    Recently, the pleiotropic benefits of incretin-based therapy have been reported. We have previously reported that Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, attenuates prostate cancer growth. Metformin is known for its anti-cancer effect. Here, we examined the anti-cancer effect of Exendin-4 and metformin using a prostate cancer model. Prostate cancer cells were treated with Exendin-4 and/or metformin. Cell proliferation was quantified by growth curves and 5-bromo-2'-deoxyuridine (BrdU) assay. TUNEL assay and AMP-activated protein kinase (AMPK) phosphorylation were examined in LNCaP cells. For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin. TUNEL assay and immunohistochemistry were performed on tumors. Exendin-4 and metformin additively decreased the growth curve, but not the migration, of prostate cancer cells. The BrdU assay revealed that both Exendin-4 and metformin significantly decreased prostate cancer cell proliferation. Furthermore, metformin, but not Exendin-4, activated AMPK and induced apoptosis in LNCaP cells. The anti-proliferative effect of metformin was abolished by inhibition or knock down of AMPK. In vivo, Exendin-4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment. Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin, and that metformin increased phospho-AMPK expression and the apoptotic cell number. These data suggest that Exendin-4 and metformin attenuated prostate cancer growth by inhibiting proliferation, and that metformin inhibited proliferation by inducing apoptosis. Combined treatment with Exendin-4 and metformin attenuated prostate cancer growth more than separate treatments.

  6. [Paget's disease mimicking metastatic prostate cancer on bone scan image : a case report].

    Science.gov (United States)

    Fukushi, Ken; Koie, Takuya; Yamamoto, Hayato; Okamoto, Akiko; Imai, Atsushi; Hatakeyama, Shingo; Yoneyama, Takahiro; Hashimoto, Yasuhiro; Ohyama, Chikara

    2013-04-01

    A 61-year-old man was referred to our hospital complaining of elevated serum prostate-specific antigen (PSA) (5.1 ng/ml). Histopathologic diagnosis with trans-rectal prostate biopsy specimen was adenocarcinoma, Gleason score 4+5 = 9. Bone scintigraphy revealed an abnormal uptake on left coxal bone. The patient was diagnosed with prostate cancer with bone metastasis. He received androgen deprivation therapy for two years. Serum PSA decreased to an undetected level. However, the abnormal activity of left coxal bone lesion was not changed on bone scintigraphy. Coxal bone biopsy was performed. The bone lesion was histopathologically diagnosed as Paget's disease of bone.

  7. A 3D printed nano bone matrix for characterization of breast cancer cell and osteoblast interactions

    Science.gov (United States)

    Zhu, Wei; Castro, Nathan J.; Cui, Haitao; Zhou, Xuan; Boualam, Benchaa; McGrane, Robert; Glazer, Robert I.; Zhang, Lijie Grace

    2016-08-01

    Bone metastasis is one of the most prevalent complications of late-stage breast cancer, in which the native bone matrix components, including osteoblasts, are intimately involved in tumor progression. The development of a successful in vitro model would greatly facilitate understanding the underlying mechanism of breast cancer bone invasion as well as provide a tool for effective discovery of novel therapeutic strategies. In the current study, we fabricated a series of in vitro bone matrices composed of a polyethylene glycol hydrogel and nanocrystalline hydroxyapatite of varying concentrations to mimic the native bone microenvironment for the investigation of breast cancer bone metastasis. A stereolithography-based three-dimensional (3D) printer was used to fabricate the bone matrices with precisely controlled architecture. The interaction between breast cancer cells and osteoblasts was investigated in the optimized bone matrix. Using a Transwell® system to separate the two cell lines, breast cancer cells inhibited osteoblast proliferation, while osteoblasts stimulated breast cancer cell growth, whereas, both cell lines increased IL-8 secretion. Breast cancer cells co-cultured with osteoblasts within the 3D bone matrix formed multi-cellular spheroids in comparison to two-dimensional monolayers. These findings validate the use of our 3D printed bone matrices as an in vitro metastasis model, and highlights their potential for investigating breast cancer bone metastasis.

  8. Peri-Implant Tissue Findings in Bone Grafted Oral Cancer Patients Compared to non Bone Grafted Patients without Oral Cancer

    Directory of Open Access Journals (Sweden)

    Jan Wolff

    2011-08-01

    Full Text Available Objectives: The aim of this study was to compare microbiological, histological, and mechanical findings from tissues around osseointergrated dental implants in patients who had undergone tumour resection and subsequent bone grafting with non bone grafted patients without a history of oral cancer and to develop an effective tool for the monitoring of the peri-implant tissues. A third aim was to assess and compare the masticatory function of the two patient groups after reconstruction with dental implants.Material and Methods: A total of 20 patients were divided into 2 groups. The first group was edentulous and treated with dental implants without the need for bone grafting. The second edentulous group, with a history of oral cancer involving the mandible, received onlay bone grafts with concurrent placement of dental implants. Microbiological, histological, mechanical and biochemical assessment methods, crevicular fluid flow rate, hygiene-index, implant mobility, and the masticatory function were analysed and compared in both patient groups.Results: The microbiological examinations showed no evidence of the three most common pathogenic bacteria: Porphyromonas gingivalis, Prevotella intermedius, Actinobacillus actinomycetencomitans. A causal relationship between specific microbes and peri-implant inflammation could not be found. All biopsies in both patient groups revealed early signs of soft tissue peri-implant inflammation.Conclusions: The crevicular fluid volume and grade of gingival inflammation around the dental implants were related. Peri-implant tissue findings were similar in the two patient groups despite the history of oral cancer and the need for bone grafting at the time of dental implant placement.

  9. Denosumab: a new option in the treatment of bone metastases from urological cancers

    Directory of Open Access Journals (Sweden)

    Yonese J

    2012-09-01

    Full Text Available Takeshi Yuasa, Shinya Yamamoto, Shinji Urakami, Iwao Fukui, Junji YoneseDepartment of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Tokyo, JapanAbstract: Bone metastases often create serious clinical problems: they lead to poor performance status due to pathologic fractures, spinal cord compression and intractable pain, commonly referred to as skeletal-related events. The receptor activator of nuclear factor-κB (RANK, the RANK ligand (RANKL, and osteoprotegerin, a decoy receptor for RANK, regulate osteoclastogenesis and may play a key role in bone metastasis. Denosumab (XGEVA; Amgen, Thousand Oaks, CA, a fully human monoclonal antibody that binds to and neutralizes RANKL, inhibits osteoclast function, prevents generalized bone resorption and local bone destruction, and has become a therapeutic option for preventing or delaying first on-study skeletal-related events in various malignancies. In the context of urological cancer, three main Phase III clinical studies have been published in prostate cancer. This article provides a brief overview of the characteristics of bone metastasis in urological cancers, reviews the mechanisms of bone metastasis, including the RANK/RANKL/osteoprotegerin axis, the current standard of care, zoledronic acid, and describes the efficacy of the novel bone-targeted agent denosumab in bone metastasis. Denosumab is emerging as a key therapeutic option in the treatment of bone metastases from urological cancers.Keywords: bone metastasis, denosumab, prostate cancer, renal cell cancer, urothelial cancer, zoledronic acid

  10. Methoxsalen supplementation attenuates bone loss and inflammatory response in ovariectomized mice.

    Science.gov (United States)

    Ham, Ju Ri; Choi, Ra-Yeong; Yee, Sung-Tae; Hwang, Yun-Ho; Kim, Myung-Joo; Lee, Mi-Kyung

    2017-12-25

    Methoxsalen (MTS) is a natural bioactive compound found in a variety of plants that has many known biofunctions; however, its effects on osteoporosis and related mechanisms are not clear. This study examined whether MTS exhibited preventive effects against postmenopausal osteoporosis. Female C3H/HeN mice were divided into four groups: Sham, ovariectomy (OVX), OVX with MTS (0.02% in diet), and OVX with estradiol (0.03 μg/day, s.c). After 6 weeks, MTS supplementation significantly increased femur bone mineral density and bone surface along with bone surface/total volume. MTS significantly elevated the levels of serum formation markers (estradiol, osteocalcin and bone-alkaline phosphatase) such as estradiol in OVX mice. Tartrate resistant acid phosphatase staining revealed that MTS suppressed osteoclast numbers and formation in femur tissues compared with the OVX group. Supplementation of MTS slightly up-regulated osteoblastogenesis-related genes (Runx-2, osterix, osteocalcin, and Alp) expression, whereas it significantly down-regulated inflammatory genes (Nfκb and Il6) expression in femur tissue compared with the OVX group. These results indicate that MTS supplementation effectively prevented OVX-induced osteoporosis via enhancement of bone formation and suppression of inflammatory response in OVX mice. Our study provides valid scientific information regarding the development and application of MTS as a food ingredient, a food supplement or an alternative agent for preventing postmenopausal osteoporosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage

    Directory of Open Access Journals (Sweden)

    Jie Deng

    2018-04-01

    Full Text Available Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX. However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (β-alanyl-l-histidine, a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200 mg/kg, i.p. significantly inhibited the generation of reactive oxygen species (ROS and 8-hydroxy-2′-deoxyguanosine (8-oxo-dG, and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20 mg/kg, i.v., 24 h. Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity. Keywords: Carnosine, Cyclophosphamide, Oxidative DNA damage, Sister chromatid exchange, Apoptosis, Cell cycle arrest

  12. Does increased local bone resorption secondary to breast and prostate cancer result in increased cartilage degradation?

    DEFF Research Database (Denmark)

    Leeming, Diana J; Byrjalsen, Inger; Qvist, Per

    2008-01-01

    BACKGROUND: Breast and prostate cancer patients often develop lesions of locally high bone turnover, when the primary tumor metastasizes to the bone causing an abnormal high bone resorption at this site. The objective of the present study was to determine whether local increased bone turnover...... experiments revealed that osteoclasts released CTXI fragments but not CTXII from bone specimens. The same was observed for cathepsin K. CONCLUSION: Data suggest that an uncoupling between bone resorption and cartilage degradation occurs in breast and lung cancer patient....

  13. Cost of palliative radiation to the bone for patients with bone metastases secondary to breast or prostate cancer

    Directory of Open Access Journals (Sweden)

    Hess Gregory

    2012-10-01

    Full Text Available Abstract Background To estimate the costs (paid amounts of palliative radiation episodes of care (REOCs to the bone for patients with bone metastases secondary to breast or prostate cancer. Methods Claims-linked medical records from patients at 98 cancer treatment centers in 16 US states were analyzed. Inclusion criteria included a primary neoplasm of breast or prostate cancer with a secondary neoplasm of bone metastases; ≥2 visits to ≥1 radiation center during the study period (1 July 2008 through 31 December 2009 on or after the metastatic cancer diagnosis date; radiation therapy to ≥1 bone site; and ≥1 complete REOC as evidenced by a >30-day gap pre- and post-radiation therapy. Results The total number of REOCs was 220 for 207 breast cancer patients and 233 for 213 prostate cancer patients. In the main analysis (which excluded records with unpopulated costs the median number of fractions per a REOC for treatment of metastases was 10. Mean total radiation costs (i.e., radiation direct cost + cost of radiation-related procedures and visits per REOC were $7457 for patients with breast cancer and $7553 for patients with prostate cancer. Results were consistent in sensitivity analyses excluding patients with unpopulated costs. Conclusions In the US, current use of radiation therapy for bone metastases is relatively costly and the use of multi-fraction schedules remains prevalent.

  14. The Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development

    Science.gov (United States)

    2015-09-01

    AWARD NUMBER: W81XWH-12-1-0271 TITLE: The Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development PRINCIPAL...31Aug 2015 4. TITLE AND SUBTITLE The Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development 5a. CONTRACT NUMBER...initiate prostate cancer (PCa), promote PCa progression, and facilitate the development of mixed osteoblastic/osteolytic bone lesions . However, the

  15. Dixon Sequence with Superimposed Model-Based Bone Compartment Provides Highly Accurate PET/MR Attenuation Correction of the Brain.

    Science.gov (United States)

    Koesters, Thomas; Friedman, Kent P; Fenchel, Matthias; Zhan, Yiqiang; Hermosillo, Gerardo; Babb, James; Jelescu, Ileana O; Faul, David; Boada, Fernando E; Shepherd, Timothy M

    2016-06-01

    Simultaneous PET/MR of the brain is a promising technology for characterizing patients with suspected cognitive impairment or epilepsy. Unlike CT, however, MR signal intensities do not correlate directly with PET photon attenuation correction (AC), and inaccurate radiotracer SUV estimation can limit future PET/MR clinical applications. We tested a novel AC method that supplements standard Dixon-based tissue segmentation with a superimposed model-based bone compartment. We directly compared SUV estimation between MR-based AC and reference CT AC in 16 patients undergoing same-day PET/CT and PET/MR with a single (18)F-FDG dose for suspected neurodegeneration. Three Dixon-based MR AC methods were compared with CT: standard Dixon 4-compartment segmentation alone, Dixon with a superimposed model-based bone compartment, and Dixon with a superimposed bone compartment and linear AC optimized specifically for brain tissue. The brain was segmented using a 3-dimensional T1-weighted volumetric MR sequence, and SUV estimations were compared with CT AC for whole-image, whole-brain, and 91 FreeSurfer-based regions of interest. Modifying the linear AC value specifically for brain and superimposing a model-based bone compartment reduced the whole-brain SUV estimation bias of Dixon-based PET/MR AC by 95% compared with reference CT AC (P < 0.05), resulting in a residual -0.3% whole-brain SUVmean bias. Further, brain regional analysis demonstrated only 3 frontal lobe regions with an SUV estimation bias of 5% or greater (P < 0.05). These biases appeared to correlate with high individual variability in frontal bone thickness and pneumatization. Bone compartment and linear AC modifications result in a highly accurate MR AC method in subjects with suspected neurodegeneration. This prototype MR AC solution appears equivalent to other recently proposed solutions and does not require additional MR sequences and scanning time. These data also suggest that exclusively model-based MR AC

  16. Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes.

    Science.gov (United States)

    Krings, A; Rahman, S; Huang, S; Lu, Y; Czernik, P J; Lecka-Czernik, B

    2012-02-01

    Fat occupies a significant portion of bone cavity however its function is largely unknown. Marrow fat expands during aging and in conditions which affect energy metabolism, indicating that fat in bone is under similar regulatory mechanisms as other fat depots. On the other hand, its location may determine specific functions in the maintenance of the environment for bone remodeling and hematopoiesis. We have demonstrated that marrow fat has a distinctive phenotype, which resembles both, white and brown adipose tissue (WAT and BAT, respectively). Marrow adipocytes express gene markers of brown adipocytes at levels characteristic for the BAT, including transcription factor Prdm16, and regulators of thermogenesis such as deiodinase 2 (Dio2) and PGC1α. The levels of expression of BAT-specific gene markers are decreased in bone of 24 mo old C57BL/6 and in diabetic yellow agouti A(vy)/a mice implicating functional changes of marrow fat occurring with aging and diabetes. Administration of antidiabetic TZD rosiglitazone, which sensitizes cells to insulin and increases adipocyte metabolic functions, significantly increased both, BAT (UCP1, PGC1α, Dio2, β3AR, Prdm16, and FoxC2) and WAT (adiponectin and leptin) gene expression in marrow of normoglycemic C57BL/6 mice, but failed to increase the expression of BAT, but not WAT, gene markers in diabetic mice. In conclusion, the metabolic phenotype of marrow fat combines both BAT and WAT characteristics. Decrease in BAT-like characteristics with aging and diabetes may contribute to the negative changes in the marrow environment supporting bone remodeling and hematopoiesis. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Topical Treatment with Xiaozheng Zhitong Paste (XZP Alleviates Bone Destruction and Bone Cancer Pain in a Rat Model of Prostate Cancer-Induced Bone Pain by Modulating the RANKL/RANK/OPG Signaling

    Directory of Open Access Journals (Sweden)

    Yanju Bao

    2015-01-01

    Full Text Available To explore the effects and mechanisms of Xiaozheng Zhitong Paste (XZP on bone cancer pain, Wistar rats were inoculated with vehicle or prostate cancer PC-3 into the tibia bone and treated topically with inert paste, XZP at 15.75, 31.5, or 63 g/kg twice per day for 21 days. Their bone structural damage, nociceptive behaviors, bone osteoclast and osteoblast activity, and the levels of OPG, RANL, RNAK, PTHrP, IGF-1, M-CSF, IL-8, and TNF-α were examined. In comparison with that in the placebo group, significantly reduced numbers of invaded cancer cells, decreased levels of bone damage and mechanical threshold and paw withdrawal latency, lower levels of serum TRACP5b, ICTP, PINP, and BAP, and less levels of bone osteoblast and osteoclast activity were detected in the XZP-treated rats (P<0.05. Moreover, significantly increased levels of bone OPG but significantly decreased levels of RANL, RNAK, PTHrP, IGF-1, M-CSF, IL-8, and TNF-α were detected in the XZP-treated rats (P<0.05 for all. Together, XZP treatment significantly mitigated the cancer-induced bone damage and bone osteoclast and osteoblast activity and alleviated prostate cancer-induced bone pain by modulating the RANKL/RANK/OPG pathway and bone cancer-related inflammation in rats.

  18. Radiotherapy Results of Breast Cancer Patients with Metastatic Bone Disease

    Directory of Open Access Journals (Sweden)

    Ahmet Dirier

    2006-01-01

    Full Text Available Breast cancer patients with bone metastasis who had admitted to Dicle University Department of Radiation Oncology for palliative radiation therapy between September 2001 and December 2003 were evaluated. There were 31 patients (26 female, 5 male. Median age was 43 years (range 23-79. Histopathological subtypes were infiltrating ductal carcinoma (88%, tubulolobuler carcinoma (6% and inflammatory carcinoma (6%. Loci of bone metastasis were vertebra only in twelve patients (39%, non-vertebral bones only in 8 patients (26% and both vertebral and nonvertebral bones in 11 patients (35%. Two patients had refused radiotherapy. Radiation doses were 3000 cGy with 10 fractions in 15 patients, 2000 cGy with 5 fractions in 6 patients and 800 cGy single fraction in eight patients. Complete palliation of pain was achieved in 18 patients (62% and partial palliation was achieved in 11 patients (38%. Treatment related toxicity was grade I-II dermatitis. In conclusion; same respons rates in terms of palliation can be achieved in the three radiotherapy schedules.

  19. High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity.

    Science.gov (United States)

    Lecka-Czernik, B; Stechschulte, L A; Czernik, P J; Dowling, A R

    2015-07-15

    Obesity is generally recognized as a condition which positively influences bone mass and bone mineral density (BMD). Positive effect of high body mass index (BMI) on bone has been recognized as a result of increased mechanical loading exerted on the skeleton. However, epidemiologic studies indicate that obesity is associated with increased incidence of fractures. The results presented here offer a new perspective regarding the mechanisms which may be responsible for the increase of bone mass and concurrent decrease in bone quality. Two groups of 12 week old C57BL/6 males were fed either high fat diet (HFD) or regular diet (RD) for 11 weeks. Metabolic profile, bone parameters and gene expression were assessed in these groups at the end of the experiment. Additionally, bone status was evaluated in a third group of 12 week old animals corresponding to animals at the start of the feeding period. Administration of HFD resulted in development of a diet-induced obesity (DIO), glucose intolerance, alteration in energy metabolism, and impairment in WAT function, as compared to the age-matched control animals fed RD. The expression of adiponectin, FABP4/aP2, DIO2 and FoxC2 were decreased in WAT of DIO animals, as well as transcript levels for IGFBP2, the cytokine regulating both energy metabolism and bone mass. At the end of experiment, DIO mice had higher bone mass than both control groups on RD, however they had decreased bone formation, as assessed by calcein labeling, and increased marrow adipocyte content. This study suggests that the bone mass acquired in obesity is a result of a two-phase process. First phase would consist of either beneficial effect of fat expansion to increase bone mass by increased mechanical loading and/or increased production of bone anabolic adipokines and/or nutritional effect of fatty acids. This is followed by a second phase characterized by decreased bone formation and bone turnover resulting from development of metabolic impairment

  20. When to perform bone scintigraphy in patients with newly diagnosed prostate cancer? a retrospective study.

    Science.gov (United States)

    Lin, Yiwei; Mao, Qiqi; Chen, Bin; Wang, Liujiang; Liu, Ben; Zheng, Xiangyi; Xie, Liping

    2017-06-12

    To determine when a bone scintigraphy investigation is appropriate in patients with newly diagnosed prostate cancer (PCa). We retrospectively reviewed 703 newly diagnosed PCa patients who were referred for bone scintigraphy. The association between age, prostate specific antigen (PSA), Gleason score (GS) and bone scintigraphy result were investigated by series of crude or stratified analysis. Overall, 15.08% (106/703) patients had bone metastases. PSA and GS between positive bone scan group and negative bone scan group were significantly different, while age was not. The incidence of bone metastasis in patient with PSA bone scan. Patients with PSA ≥ 20 ng/ml or GS ≥ 8 were in higher risk of bone metastasis, bone scintigraphy was recommended. But a bone scintigraphy is of limited value in PCa patients with PSA ≤ 20 ng/ml and GS ≤ 7.

  1. Porous tantalum seeded with bone marrow mesenchymal stem cells attenuates steroid-associated osteonecrosis.

    Science.gov (United States)

    Fu, W-M; Yang, L; Wang, B-J; Xu, J-K; Wang, J-L; Qin, L; Zhao, D-W

    2016-08-01

    Bone marrow mesenchymal stem cells (BMMSCs) have been widely applied in osteonecrosis. However, lack of biomechanical support limited application of BMMSCs. And porous tantalum (PTA) has been identified as a cell-friendly scaffold for bone regeneration. Herein, we aimed to investigate the efficacy of PTA seeded with BMMSCs in the treatment of osteonecrosis. After the production of PTA seeded with BMMSCs, MTT and GFP were performed to identify the proliferation and adhesion of BMMSCs respectively, which was further examined by scanning electron microscopy (SEM). And real-time PCR was also used to determine mRNA level of osteogenic markers, including Alp, OCN, OPN, Col I and Runx-2 in BMMSCs. Nineteen adult rabbits were applied for building steroid-associated osteonecrosis (SAON) models. Bone formation rate (BFR) and mineral apposition rate (MAR) were determined. And Goldner Trichrome Staining was used in these SAON models, which further confirmed the efficacy of PTA seeded with BMMSCs in SAON. PTA seeded with BMMSCs showed excellent biocompatibility. Additionally, SEM assay showed that BMMSCs adhered tightly and spread fully in the pores of PTA. Next, the expression of ALP and OPN mRNA in BMMSCs were significantly (p < 0.05) higher in the PTA-treated group compared to those in the PTA-untreated group. Furthermore, compared to those treated by only PTA, the dynamic bone formation in rabbits treated by PTA seeded with BMMSCs was significantly increased (p < 0.001) at both week 3rd and week 6th. The product, PTA seeded with BMMSCs, was successfully produced, and was determined as high efficacy for treatment of steroid-associated osteonecrosis. PTA seeded with BMMSCs may afford a promising option for treating osteonecrosis.

  2. Cancer-Induced Bone Pain Management Through Buddhist Beliefs.

    Science.gov (United States)

    Cheng, Fung Kei

    2017-04-24

    Dealing with physical pain represents a huge public health expenditure, especially for cancer-induced bone pain, one of the most difficult health issues, which impairs appetite, sleep, and mobility, negatively impacting quality of life and evoking mental problems. Although some literature has reported positive correlation between religion and pain management, there is a dearth of research examining the effectiveness of Buddhism on this topic. This study investigates the usefulness of Buddhist beliefs in managing cancer-induced bone pain through a case example. It illustrates how an advanced cancer patient, with the assistance of a counsellor, perceived pain and coped with it and pain-induced mental problems via Buddhist teachings and practices, including the four noble truths, the law of dependent origination, and karma. It offers alternative perspectives for helping professionals (such as physicians, nurses, counsellors, social workers, hospice and palliative service providers, and pain management practitioners) who are keen to equip themselves with a wider worldview and life view to better serve their clients.

  3. Monocyte chemotactic protein-1 attenuates and high-fat diet exacerbates bone loss in mice with pulmonary metastasis of Lewis lung carcinoma

    Science.gov (United States)

    Bone can be adversely affected by obesity and cancer-associated complications including wasting. The objective of this study was to determine whether a high-fat diet and a deficiency in monocyte chemotactic protein-1 (MCP-1) altered bone structural defects found in male C57BL/6 mice with Lewis lung...

  4. Inhibition of Decay-Accelerating Factor (CD55 Attenuates Prostate Cancer Growth and Survival In Vivo

    Directory of Open Access Journals (Sweden)

    Robert D. Loberg

    2006-01-01

    Full Text Available Decay-accelerating factor (CD55 is a member of membrane-bound complement-regulatory proteins. CD55 expression correlates with poor survival in patients with colorectal cancer and has been implicated in the survival and tumorigenesis of blood-borne malignancies. Histologic analysis of clinical specimens from patients with advanced prostate cancer revealed an increase in CD55 expression in prostate tumor epithelial cells. CD55 was shown to be functionally active and to inhibit complement-mediated lysis in PC-3 and DU145 cells. The percentage of lysis was correlative with the CD55 expression profile observed in these prostate cancer cell lines. These data suggest that CD55 is an important regulator of prostate cancer cell survival. As a result, we have hypothesized that CD55 expression on prostate cancer cells promotes cell survival and contributes to the metastatic potential of prostate cancer cells. To determine the role of CD55 in prostate cancer tumorigenesis and metastasis, we generated PC-3Luc prostate cancer cells with CD55 siRNA-targeted disruption. We found that PC-3Luc/CD55 siRNA constructs in SCID mice resulted in a significant attenuation of overall tumor burden. Further investigation into the mechanisms of CD55-mediated tumor cell/microenvironment interaction is necessary to understand the role of CD55 in tumor cell survival and metastatic lesion formation.

  5. Integrin alpha V beta 3 expression by bone-residing breast cancer metastases.

    Science.gov (United States)

    Liapis, H; Flath, A; Kitazawa, S

    1996-06-01

    Breast cancer metastasis to bone is a multistep process requiring attachment of tumor cells to the bone and bone marrow environment. The precise adhesion molecules involved in skeletal homing of breast cancer to bone are unknown but likely include integrins. We investigated the expression of vitronectin receptor (alpha V beta 3) by breast cancer cells residing in bone because this heterodimer mediates osteoclast-bone recognition. We used immunohistochemistry and in situ hybridization in a systematic study of 22 bone biopsies containing breast cancer metastases and available samples of corresponding primary tumors and normal breast and compared alpha V beta 3, alpha 2 beta 1, and alpha B beta 5 integrin expression. The results showed that alpha V beta 3 was strongly expressed by normal breast epithelium and was decreased in some and strongly expressed in other primary invasive breast carcinomas. In contrast, this integrin heterodimer was abundant in all breast cancer cells metastatic to bone. In situ hybridization revealed high levels of steady-state mRNA corresponding to sites of protein expression; alpha 2 beta 1 was weakly expressed in both primary and metastatic tumors, and alpha V beta 5 was not detected. Our results showed an overexpression of alpha V beta 3 by bone-residing breast cancer cells and suggest either subclonal selection of alpha V beta 3-expressing tumor cell populations or upregulation of alpha V beta 3 in the bone microenvironment.

  6. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain

    NARCIS (Netherlands)

    Schweizerhof, Matthias; Stösser, Sebastian; Kurejova, Martina; Njoo, Christian; Gangadharan, Vijayan; Agarwal, Nitin; Schmelz, Martin; Bali, Kiran Kumar; Michalski, Christoph W.; Brugger, Stefan; Dickenson, Anthony; Simone, Donald A.; Kuner, Rohini

    2009-01-01

    Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves.

  7. PPARα inhibition modulates multiple reprogrammed metabolic pathways in kidney cancer and attenuates tumor growth.

    Science.gov (United States)

    Abu Aboud, Omran; Donohoe, Dallas; Bultman, Scott; Fitch, Mark; Riiff, Tim; Hellerstein, Marc; Weiss, Robert H

    2015-06-01

    Kidney cancer [renal cell carcinoma (RCC)] is the sixth-most-common cancer in the United States, and its incidence is increasing. The current progression-free survival for patients with advanced RCC rarely extends beyond 1-2 yr due to the development of therapeutic resistance. We previously identified peroxisome proliferator-activating receptor-α (PPARα) as a potential therapeutic target for this disease and showed that a specific PPARα antagonist, GW6471, induced apoptosis and cell cycle arrest at G0/G1 in RCC cell lines associated with attenuation of cell cycle regulatory proteins. We now extend that work and show that PPARα inhibition attenuates components of RCC metabolic reprogramming, capitalizing on the Warburg effect. The specific PPARα inhibitor GW6471, as well as a siRNA specific to PPARα, attenuates the enhanced fatty acid oxidation and oxidative phosphorylation associated with glycolysis inhibition, and PPARα antagonism also blocks the enhanced glycolysis that has been observed in RCC cells; this effect did not occur in normal human kidney epithelial cells. Such cell type-specific inhibition of glycolysis corresponds with changes in protein levels of the oncogene c-Myc and has promising clinical implications. Furthermore, we show that treatment with GW6471 results in RCC tumor growth attenuation in a xenograft mouse model, with minimal obvious toxicity, a finding associated with the expected on-target effects on c-Myc. These studies demonstrate that several pivotal cancer-relevant metabolic pathways are inhibited by PPARα antagonism. Our data support the concept that targeting PPARα, with or without concurrent inhibition of glycolysis, is a potential novel and effective therapeutic approach for RCC that targets metabolic reprogramming in this tumor.

  8. Loss of TGF-β signaling in osteoblasts increases basic-FGF and promotes prostate cancer bone metastasis.

    Science.gov (United States)

    Meng, Xiangqi; Vander Ark, Alexandra; Daft, Paul; Woodford, Erica; Wang, Jie; Madaj, Zachary; Li, Xiaohong

    2018-04-01

    TGF-β plays a central role in prostate cancer (PCa) bone metastasis, and it is crucial to understand the bone cell-specific role of TGF-β signaling in this process. Thus, we used knockout (KO) mouse models having deletion of the Tgfbr2 gene specifically in osteoblasts (Tgfbr2 Col1CreERT KO) or in osteoclasts (Tgfbr2 LysMCre KO). We found that PCa-induced bone lesion development was promoted in the Tgfbr2 Col1CreERT KO mice, but was inhibited in the Tgfbr2 LysMCre KO mice, relative to their respective control Tgfbr2 FloxE2 littermates. Since metastatic PCa cells attach to osteoblasts when colonized in the bone microenvironment, we focused on the mechanistic studies using the Tgfbr2 Col1CreERT KO mouse model. We found that bFGF was upregulated in osteoblasts from PC3-injected tibiae of Tgfbr2 Col1CreERT KO mice and correlated with increased tumor cell proliferation, angiogenesis, amounts of cancer-associated fibroblasts and osteoclasts. In vitro studies showed that osteoblastogenesis was inhibited, osteoclastogenesis was stimulated, but PC3 viability was not affected, by bFGF treatments. Lastly, the increased PC3-induced bone lesions in Tgfbr2 Col1CreERT KO mice were significantly attenuated by blocking bFGF using neutralizing antibody, suggesting bFGF is a promising target inhibiting bone metastasis. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Bone mineral density in postmenopausal breast cancer survivors.

    Science.gov (United States)

    Twiss, J J; Waltman, N; Ott, C D; Gross, G J; Lindsey, A M; Moore, T E

    2001-06-01

    The overall purpose of this longitudinal 18-month study was to test the feasibility and effectiveness of a multicomponent intervention for prevention and treatment of osteoporosis. The purpose of this article is to describe the baseline bone mineral density (BMD) findings for 30 postmenopausal women and to compare these BMD findings to time since menopause, body mass index, and tamoxifen use. Baseline data of BMD findings for 30 postmenopausal women, who have had a variety of treatments including surgery, adjuvant chemotherapy and or tamoxifen, and are enrolled in the 18-month longitudinal study. A demographic questionnaire and a three day dietary record were used to collect baseline data. Eighty percent of the women with breast cancer history had abnormal BMDs at baseline (t-scores below -1.00 SD). Thinner women showed a greater risk for accelerated trabecular bone loss at the spine and hip. These findings suggest the need for early BMD assessments and for aggressive health promotion intervention strategies that include a multifaceted protocol of drug therapy for bone remodeling, 1500 mg of daily calcium, 400 IU vitamin D and a strength weight training program that is implemented immediately following chemotherapy treatment and menopause in this high risk population of women.

  10. Prognostic significance of global grading system of Gleason score in patients with prostate cancer with bone metastasis

    National Research Council Canada - National Science Library

    Kambara, Tsunehito; Oyama, Tetsunari; Segawa, Atsuki; Fukabori, Yoshitatsu; Yoshida, Ken-Ichiro

    2010-01-01

    ...) on prediction of prognosis for patients with prostate cancer with bone metastasis. PATIENTS AND METHODS Prostatic needle biopsy specimens from 113 patients with prostate cancer with bone metastasis were scored using the conventional GGS (CGGS...

  11. Improving radionuclide therapy in prostate cancer patients with metastatic bone pain

    NARCIS (Netherlands)

    Lam, M.G.E.H.

    2009-01-01

    Bone seeking radiopharmaceuticals are indicated in cancer patients with multiple painful skeletal metastases. The majority of these patients are hormone-refractory prostate cancer patients in an advanced stage of their disease. Bone seeking radiopharmaceuticals relieve pain and improve the patients

  12. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

    OpenAIRE

    Pollari, Sirkku; Kakonen, Sanna-Maria; Edgren, Henrik; Wolf, Maija; Kohonen, Pekka; Sara, Henri; Guise, Theresa,; Nees, Matthias; Kallioniemi, Olli

    2010-01-01

    Abstract Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, an understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidences for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic...

  13. Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases.

    Science.gov (United States)

    Nishimukai, Arisa; Higuchi, Tomoko; Ozawa, Hiromi; Yanai, Ayako; Miyagawa, Yoshimasa; Murase, Keiko; Imamura, Michiko; Takatsuka, Yuichi; Miyoshi, Yasuo

    2017-03-01

    Bone-modifying agents are effective for treatment of breast cancer patients with bone metastases. Since their action is mediated through suppression of the osteoclast function, their efficacy can be determined by monitoring bone turnover markers. However, the clinical significance of these markers is yet to be compared. For this study, 52 breast cancer patients with bone metastases treated with zoledronic acid (n = 36) or denosumab (n = 22) were enrolled (6 patients were treated sequentially with both agents). Serum tartrate-resistant acid phosphatase-5b (TRACP-5b), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), N-terminal cross-linking telopeptides of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) were measured at pretreatment and 1, 3 and 6 months after treatment. Serum TRACP-5b (p agents reduced the baseline levels of TRACP-5b, NTX and BAP significantly, the reduction patterns differed. TRACP-5b appears to affect levels most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings suggest that the efficacy of TRACP-5b is clinically significant when considering which bone-modifying agents to use for breast cancer patients with bone metastases.

  14. The intrabody targeting of hTERT attenuates the immortality of cancer cells.

    Science.gov (United States)

    Zhu, Xiangying; Yang, Nan; Cai, Jianguo; Yang, Guimei; Liang, Shenghua; Ren, Daming

    2010-01-01

    hTERT (human telomerase reverse transcriptase) plays a key role in the process of cell immortalization. Overexpression of hTERT has been implicated in 85% of malignant tumors and offers a specific target for cancer therapy. In this paper, we describe an effective approach using a single-chain variable fragment (scFv) intrabody derived from monoclonal hybridoma directed against hTERT to attenuate the immortalization of human uterine cervix and hepatoma cells. The scFv we constructed had a high affinity to hTERT, and specifically neutralized over 70% of telomere synthesis activity, thereby inhibiting the viability and proliferation of the cancer cells. Our results indicate that this anti-hTERT intrabody is a promising tool to target hTERT and intervene in the immortalization process of cancer cells.

  15. Assessment of bone metastasis using nuclear medicine imaging in breast cancer: comparison between PET/CT and bone scan

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Dae Hyoun; Ahn, Byeong Cheol; Kang, Sung Min [Kyungpook National University Medical School, Daegu (Korea, Republic of)] (and others)

    2007-02-15

    Bone metastasis in breast cancer patients are usually assessed by conventional Tc-99m methylene diphosphonate whole-body bone scan, which has a high sensitivity but a poor specificity. However, positron emission tomography with {sup 18}F-2-deoxyglucose (FDG-PET) can offer superior spatial resolution and improved specificity. FDG-PET/CT can offer more information to assess bone metastasis than PET alone, by giving a anatomical information of non-enhanced CT image. We attempted to evaluate the usefulness of FDG-PET/CT for detecting bone metastasis in breast cancer and to compare FDG-PET/CT results with bone scan findings. The study group comprised 157 women patients (range: 28 {approx} 78 years old, mean {+-} SD = 49.5 {+-}8.5) with biopsy-proven breast cancer who underwent bone scan and FDG-PET/CT within 1 week interval. The final diagnosis of bone metastasis was established by histopathological findings, radiological correlation, or clinical follow-up. Bone scan was acquired over 4 hours after administration of 740 MBq Tc-99m MDP. Bone scan image was interpreted as normal, low, intermediate or high probability for osseous metastasis. FDG PET/CT was performed after 6 hours fasting. 370 MBq F-18 FDG was administered intravenously 1 hour before imaging. PET data was obtained by 3D mode and CT data, used as transmission correction database, was acquired during shallow respiration. PET images were evaluated by visual interpretation, and quantification of FDG accumulation in bone lesion was performed by maximal SUV(SUVmax) and relative SUV(SUVrel). Six patients (4.4%) showed metastatic bone lesions. Four (66.6%) of 6 patients with osseous metastasis was detected by bone scan and all 6 patients (100%) were detected by PET/CT. A total of 135 bone lesions found on either FDG-PET or bone scan were consist of 108 osseous metastatic lesion and 27 benign bone lesions. Osseous metastatic lesion had higher SUVmax and SUVrel compared to benign bone lesion (4.79 {+-} 3.32 vs 1

  16. Bisphosphonate-functionalized coordination polymer nanoparticles for the treatment of bone metastatic breast cancer.

    Science.gov (United States)

    He, Yuanfeng; Huang, Yanjuan; Huang, Ziyuan; Jiang, Yali; Sun, Xiaoqi; Shen, Yifeng; Chu, Weijing; Zhao, Chunshun

    2017-10-28

    Bone is the most common organ affected by metastatic breast cancer. Targeting cancers within the bone remains a great challenge due to the inefficient delivery of therapeutic to bone. In this study, a polyethylene glycol (PEG) coated nanoparticles (NPs) made of a Zn2+ coordination polymer was linked with a bone seeking moiety, alendronate (ALN), to deliver cisplatin prodrug (DSP) to the bone. The particle sizes of this novel system, DSP-Zn@PEG-ALN NPs, were regulated by adjusting the volume ratio of water phase to oil phase in microemulsion. It was small enough (about 55nm) to extravasate through the clefts (80nm) of the bone's sinusoidal capillaries and localize into metastatic bones. DSP-Zn@PEG-ALN NPs showed much higher affinity for hydroxyapatite in vitro and bone in vivo than non-targeted DSP-Zn@PEG NPs and cisplatin. In addition, the in vivo biodistribution studies demonstrated that about 4-fold of platinum was delivered to the bone metastatic lesions than that in healthy bones by DSP-Zn@PEG-ALN NPs intravenously. Finally, DSP-Zn@PEG-ALN NPs not only inhibited the tumor growth efficiently but also reduced the osteocalastic bone destruction. Besides, DSP-Zn@PEG-ALN NPs showed significantly reduced toxicity of cisplatin. These results indicate that the DSP-Zn@PEG-ALN NPs have a great potential in enhancing chemotherapeutic efficacy for the treatment of bone metastatic breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential

    Directory of Open Access Journals (Sweden)

    Kun-Chun Chiang

    2016-04-01

    Full Text Available Regarding breast cancer treatment, triple negative breast cancer (TNBC is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl-1α,25(OH2D3, the newly-synthesized 1α,25(OH2D3 analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH2D3 and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH2D3 and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH2D3 induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH2D3 and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9 activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH2D3 and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC.

  18. Using (31)P-MRI of hydroxyapatite for bone attenuation correction in PET-MRI: proof of concept in the rodent brain.

    Science.gov (United States)

    Lebon, Vincent; Jan, Sébastien; Fontyn, Yoann; Tiret, Brice; Pottier, Géraldine; Jaumain, Emilie; Valette, Julien

    2017-12-01

    The correction of γ-photon attenuation in PET-MRI remains a critical issue, especially for bone attenuation. This problem is of great importance for brain studies due to the density of the skull. Current techniques for skull attenuation correction (AC) provide indirect estimates of cortical bone density, leading to inaccurate estimates of brain activity. The purpose of this study was to develop an alternate method for bone attenuation correction based on NMR. The proposed approach relies on the detection of hydroxyapatite crystals by zero echo time (ZTE) MRI of (31)P, providing individual and quantitative assessment of bone density. This work presents a proof of concept of this approach. The first step of the method is a calibration experiment to determine the conversion relationship between the (31)P signal and the linear attenuation coefficient μ. Then (31)P-ZTE was performed in vivo in rodent to estimate the μ-map of the skull. (18)F-FDG PET data were acquired in the same animal and reconstructed with three different AC methods: (31)P-based AC, AC neglecting the bone and the gold standard, CT-based AC, used to comparison for the other two methods. The calibration experiment provided a conversion factor of (31)P signal into μ. In vivo (31)P-ZTE made it possible to acquire 3D images of the rat skull. Brain PET images showed underestimation of (18)F activity in peripheral regions close to the skull when AC neglected the bone (as compared with CT-based AC). The use of (31)P-derived μ-map for AC leads to increased peripheral activity, and therefore a global overestimation of brain (18)F activity. In vivo (31)P-ZTE MRI of hydroxyapatite provides μ-map of the skull, which can be used for attenuation correction of (18)F-FDG PET images. This study is limited by several intrinsic biases associated with the size of the rat brain, which are unlikely to affect human data on a clinical PET-MRI system.

  19. Concurrent antitumor and bone-protective effects of everolimus in osteotropic breast cancer.

    Science.gov (United States)

    Browne, Andrew J; Kubasch, Marie L; Göbel, Andy; Hadji, Peyman; Chen, David; Rauner, Martina; Stölzel, Friedrich; Hofbauer, Lorenz C; Rachner, Tilman D

    2017-08-09

    The mammalian target of rapamycin inhibitor everolimus is approved as an antitumor agent in advanced estrogen receptor-positive breast cancer. Surrogate bone marker data from clinical trials suggest effects on bone metabolism, but the mode of action of everolimus in bone biology remains unclear. In this study, we assessed potential bone-protective effects of everolimus in the context of osteotropic tumors. The effects of everolimus on cancer cell viability in vitro and on tumor growth in vivo were assessed. Everolimus-regulated osteoclastogenesis and osteoblastogenesis were also assessed in vitro before we assessed the bone-protective effect of everolimus in a model where bone loss was induced in ovariectomized (OVX) mice. Finally, the role of everolimus in the progression of osteolytic bone disease was assessed in an intracardiac model of breast cancer bone metastases. At low concentrations (1 nM) in vitro, everolimus reduced the viability of human and murine cancer cell lines and impaired the osteoclastogenesis of osteoclast progenitors as assessed by quantitative real-time polymerase chain reaction and counting tartrate-resistant acid phosphatase-positive, multinucleated osteoclasts (p < 0.001). Everolimus had little or no deleterious effect on osteoblastogenesis in vitro, with concentrations of 1 and 10 nM increasing the messenger RNA expression of osteoblast marker genes (p ≤ 0.05) and leaving mineralization in differentiated human mesenchymal stem cells unchanged. Everolimus treatment (1 mg/kg body weight/day) prevented the bone loss observed in OVX mice and concurrently inhibited the metastatic growth of MDA-MB-231 cells by 70% (p < 0.002) while preserving bone mass in an intracardiac model of bone metastasis. These results underline the antitumor effects of everolimus and highlight its bone-protective efficacy, warranting further research on the potential implications on bone health in populations prone to osteoporosis and bone metastases

  20. Sinomenine hydrochloride inhibits breast cancer metastasis by attenuating inflammation-related epithelial-mesenchymal transition and cancer stemness.

    Science.gov (United States)

    Li, Xiao; Li, Pingping; Liu, Chao; Ren, Yu; Tang, Xiaojiang; Wang, Ke; He, Jianjun

    2017-02-21

    Sinomenine hydrochloride (SH) has been investigated for its anti-tumor growth effect. We have previously reported that SH inhibited breast cancer cell proliferation via MAPKs signaling. However, whether SH could inhibit tumor metastasis has not been fully explored. In this study, we found that SH suppressed the metastasis potential of breast cancer cells. The wound healing and transwell assays showed that SH inhibited the migration and invasion ability of both 4T1 and MDA-MB-231 breast cancer cells. The orthotopic mouse model of 4T1 and the experimental mouse model of MDA-MB-231-luc (MDA-MB-231 cell line expressing firefly luciferase) demonstrated that SH treatment inhibited breast cancer metastasis by inhibiting epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties without obvious hepatotoxicity and renal toxicity. We also found that SH decreased spleen volume and weight in both mouse models, especially in the 4T1 mouse model. IL-6, a strong inflammatory factor causing EMT, was remarkably reduced. Overall, this anti-metastasis effect of SH could be possibly caused by attenuating inflammatory reaction, which led to inhibition of EMT and CSC characteristics of breast cancer cells. This study, together with our previous one, provides more evidence of SH as a potential drug for breast cancer therapy.

  1. SPARC inhibits breast cancer bone metastasis and may be a clinical therapeutic target.

    Science.gov (United States)

    Ma, Jingjing; Gao, Sheng; Xie, Xiju; Sun, Erhu; Zhang, Min; Zhou, Qian; Lu, Cheng

    2017-11-01

    Breast cancer is one of the most common types of cancer in females worldwide, and metastasis to bone is an important characteristic of malignancy. The present study aimed to investigate the molecular mechanism of breast cancer to bone metastasis of secreted protein acidic and rich in cysteine (SPARC). Immunohistochemistry was performed to examine the expression of SPARC in primary breast tumors and bone metastatic foci. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the expression level of SPARC in several types of breast cancer cell. A Transwell filter assay was used to assess the effect of SPARC on breast cancer cell invasion ability, and an osteoblast differentiation assay was employed to analyze the effect of SPARC on the differentiation ability of mesenchymal stem cells. Clinical data revealed that decreased stromal SPARC expression is associated with breast cancer to bone metastasis. Gain- and loss-of-function studies reveal that SPARC inhibits the migration and invasion of breast cancer cells, and suppresses osteoclast activation in the breast cancer microenvironment. SPARC serves an important role in breast cancer bone metastasis and may be a promising therapeutic target for the treatment of breast cancer bone metastasis.

  2. Prostate Cancer Metastases to Bone: Role of High Bone Turnover Induced by Androgen Deprivation

    National Research Council Canada - National Science Library

    Padalecki, Susan

    2002-01-01

    .... Treatment with androgen deprivation therapy leads to an increase in bone turnover as indicated by the loss of bone mineral density and the increase in markers of bone turnover in patients on treatment...

  3. Is retention of zoledronic acid onto bone different in multiple myeloma and breast cancer patients with bone metastasis?

    DEFF Research Database (Denmark)

    Søe, Kent; Plesner, Torben; Jakobsen, Erik H

    2013-01-01

    or more previous administrations). On average, 62% of the administered Zol was retained in the skeleton of both MM and BC patients and independently of the number of treatments. WBrt of Zol did not correlate with cross-linked C-telopeptide (CTX) levels, but linear regression analyses showed that WBrt...... with the extent of bone disease (p = 0.028). Multivariate linear regression analyses of the entire cohort pointed out that WBrt of Zol was best predicted by age (p ......Zoledronic acid (Zol) is used to treat bone disease in both multiple myeloma (MM) and breast cancer patients with bone metastasis (BC). However, bones of MM and BC patients show a difference in retention of the bisphosphonate used for bone scintigraphy. Therefore, we hypothesized that disease...

  4. Emerging Lung Cancer Therapeutic Targets Based on the Pathogenesis of Bone Metastases

    Directory of Open Access Journals (Sweden)

    Moses O. Oyewumi

    2014-01-01

    Full Text Available Lung cancer is the second most common cancer and the leading cause of cancer related mortality in both men and women. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. It is widely accepted that tumor metastasis is a formidable barrier to effective treatment of lung cancer. The bone is one of the frequent metastatic sites for lung cancer occurring in a large number of patients. Bone metastases can cause a wide range of symptoms that could impair quality of life of lung cancer patients and shorten their survival. We strongly believe that molecular targets (tumor-related and bone microenvironment based that have been implicated in lung cancer bone metastases hold great promise in lung cancer therapeutics. Thus, this paper discusses some of the emerging molecular targets that have provided insights into the cascade of metastases in lung cancer with the focus on bone invasion. It is anticipated that the information gathered might be useful in future efforts of optimizing lung cancer treatment strategies.

  5. Pyrrolidine Dithiocarbamate (PDTC Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

    Directory of Open Access Journals (Sweden)

    Chunxiao Miao

    2017-12-01

    Full Text Available Cancer cachexia is a kind of whole body metabolic disorder syndrome accompanied with severe wasting of muscle and adipose tissue. NF-κB signaling plays an important role during skeletal muscle atrophy and fat lipolysis. As an inhibitor of NF-κB signaling, Pyrrolidine dithiocarbamate (PDTC was reported to relieve cancer cachexia; however, its mechanism remains largely unknown. In our study, we showed that PDTC attenuated cancer cachexia symptom in C26 tumor bearing mice models in vivo without influencing tumor volume. What’s more, PDTC inhibited muscle atrophy and lipolysis in cells models in vitro induced by TNFα and C26 tumor medium. PDTC suppressed atrophy of myotubes differentiated from C2C12 by reducing MyoD and upregulating MuRF1, and preserving the expression of perilipin as well as blocking the activation of HSL in 3T3-L1 mature adipocytes. Meaningfully, we observed that PDTC also inhibited p38 MAPK signaling besides the NF-κB signaling in cancer cachexia in vitro models. In addition, PDTC also influenced the protein synthesis of skeletal muscle by activating AKT signaling and regulated fat energy metabolism by inhibiting AMPK signaling. Therefore, PDTC primarily influenced different pathways in different tissues. The study not only established a simple and reliable screening drugs model of cancer cachexia in vitro but also provided new theoretical basis for future treatment of cancer cachexia.

  6. Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain

    Directory of Open Access Journals (Sweden)

    Ya-Qun Zhou

    2018-04-01

    Full Text Available Cancer-induced bone pain (CIBP is a frequent complication in patients suffering from bone metastases. Previous studies have demonstrated a pivotal role of reactive oxygen species (ROS in inflammatory and neuropathic pain, and ROS scavengers exhibited potent antinociceptive effect. However, the role of spinal ROS remains unclear. In this study, we investigated the analgesic effect of two ROS scavengers in a well-established CIBP model. Our results found that intraperitoneal injection of N-tert-Butyl-α-phenylnitrone (PBN, 50 and 100 mg/kg and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol, 100 and 200 mg/kg significantly suppressed the established mechanical allodynia in CIBP rats. Moreover, repeated injection of PBN and Tempol showed cumulative analgesic effect without tolerance. However, early treatment with PBN and Tempol failed to prevent the development of CIBP. Naive rats received repetitive injection of PBN and Tempol showed no significant change regarding the nociceptive responses. Finally, PBN and Tempol treatment notably suppressed the activation of spinal microglia in CIBP rats. In conclusion, ROS scavengers attenuated established CIBP by suppressing the activation of microglia in the spinal cord. Keywords: Cancer-induced bone pain, Reactive oxygen species, PBN, Tempol

  7. C-C motif ligand 5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment.

    Science.gov (United States)

    Urata, Satoko; Izumi, Kouji; Hiratsuka, Kaoru; Maolake, Aerken; Natsagdorj, Ariunbold; Shigehara, Kazuyoshi; Iwamoto, Hiroaki; Kadomoto, Suguru; Makino, Tomoyuki; Naito, Renato; Kadono, Yoshifumi; Lin, Wen-Jye; Wufuer, Guzailinuer; Narimoto, Kazutaka; Mizokami, Atsushi

    2017-12-30

    Chemokines and their receptors have key roles in cancer progression. The present study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when C-C motif ligand 5 (CCL5) neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  8. Green Tea Modulates Cytokine Expression in the Periodontium and Attenuates Alveolar Bone Resorption in Type 1 Diabetic Rats.

    Science.gov (United States)

    Gennaro, Gabriela; Claudino, Marcela; Cestari, Tania Mary; Ceolin, Daniele; Germino, Patrícia; Garlet, Gustavo Pompermaier; de Assis, Gerson Francisco

    2015-01-01

    Diabetes mellitus comprises a heterogeneous group of disorders with the main feature of hyperglycemia. Chronic hyperglycemia increases the severity of periodontal disease via an exacerbated inflammatory response, activated by advanced glycation end products and their receptor, RAGE. Therefore, anti-inflammatory agents represent potential inhibitors of this pathological interaction. In particular, green tea has been shown to possess anti-inflammatory properties mediated by its polyphenol content. This study investigated the mechanisms by which green tea attenuates the spontaneous onset of diabetes-induced periodontitis. Diabetes was induced in rats via a single intraperitoneal injection of streptozotocin (STZ). Diabetic and control animals were divided into water-treated and green tea-treated subgroups and were analyzed at 15, 30, 60 and 90 days after diabetes induction. Immunohistochemistry was performed to quantitatively evaluate tumor necrosis factor-α (TNF-α), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), interleukin-10 (IL-10) and runt-related transcription factor 2 (RUNX-2) expression in serial sections of each hemimaxilla. Morphometric measurements of the distance from the cementum-enamel junction (CEJ) of the superior distal root of the first molar to the alveolar bone crest (ABC) were performed to assess bone loss. Diabetes resulted in significant bone loss and alterations in the number of cells that stained positive for inflammatory mediators. In the diabetic rats treated with green tea, we observed a decreased number of cells expressing RANKL and TNF-α compared with that observed in the diabetic rats treated with water. Additionally, green tea increased the numbers of cells that stained positive for OPG, RUNX-2 and IL-10 in the diabetic rats. Green tea intake reduces expression of the pro-inflammatory cytokine TNF-α and the osteoclastogenic mediator RANKL to normal levels while increasing expression of the anti

  9. Response of Bone Resorption Markers to Aristolochia longa Intake by Algerian Breast Cancer Postmenopausal Women

    OpenAIRE

    Bachir Benarba; Boumedienne Meddah; Aicha Tir Touil

    2014-01-01

    Aristolochia longa is widely used in traditional medicine in Algeria to treat breast cancer. The aim of the present study was to investigate the response of bone resorption markers to A. longa intake by Algerian breast cancer postmenopausal women. According to the A. longa intake, breast cancer patients were grouped into A. longa group (Al) (n = 54) and non-A. longa group (non-Al) (n = 24). 32 women constituted the control group. Bone resorption markers (from urine) pyridinoline (PYD) and deo...

  10. Bone-targeted cabazitaxel nanoparticles for metastatic prostate cancer skeletal lesions and pain.

    Science.gov (United States)

    Gdowski, Andrew S; Ranjan, Amalendu; Sarker, Marjana R; Vishwanatha, Jamboor K

    2017-09-01

    The aim of this study was to develop a novel cabazitaxel bone targeted nanoparticle (NP) system for improved drug delivery to the bone microenvironment. Nanoparticles were developed using poly(D,L-lactic-co-glycolic acid) and cabazitaxel as the core with amino-bisphosphonate surface conjugation. Optimization of nanoparticle physiochemical properties, in vitro evaluation in prostate cancer cell lines and in vivo testing in an intraosseous model of metastatic prostate cancer was performed. This bone targeted cabazitaxel nanocarrier system showed significant reduction in tumor burden, while at the same time maintaining bone structure integrity and reducing pain in the mouse tumor limb. This bone microenvironment targeted nanoparticle system and clinically relevant approach of evaluation represents a promising advancement for treating bone metastatic cancer.

  11. A retrospective study of incidence of bone metastasis in head and neck cancer.

    Science.gov (United States)

    Bhandari, Virendra; Jain, Ravi Kant

    2013-01-01

    The incidence of bone metastasis in head and neck Squamous cell carcinoma is very uncommon. This retrospective study was done to identify the frequency, clinical presentation, and the clinical course of the metastatic disease to bone from head and neck primary. Out of 624 patients of head and neck cancers seen in our clinic 6 patients developed metastasis to solitary or multiple bones during the course of the disease. Postoperative patients had multiple bone involvement whereas others had solitary bone involvement. Main bones involved were parietal bone of skull, shaft of humerus and femur, sacrum, and ribs. All the patients had survival of few months only after developing metastasis. Improvement in technology has resulted in improved results in advanced head and neck cancer patients; hence measures should be taken for complete responders to diagnose this metastasis early and treat them appropriately.

  12. A retrospective study of incidence of bone metastasis in head and neck cancer

    Directory of Open Access Journals (Sweden)

    Virendra Bhandari

    2013-01-01

    Full Text Available The incidence of bone metastasis in head and neck Squamous cell carcinoma is very uncommon. Aim: This retrospective study was done to identify the frequency, clinical presentation, and the clinical course of the metastatic disease to bone from head and neck primary. Material and Methods: Out of 624 patients of head and neck cancers seen in our clinic 6 patients developed metastasis to solitary or multiple bones during the course of the disease. Results: Postoperative patients had multiple bone involvement whereas others had solitary bone involvement. Main bones involved were parietal bone of skull, shaft of humerus and femur, sacrum, and ribs. All the patients had survival of few months only after developing metastasis. Conclusion: Improvement in technology has resulted in improved results in advanced head and neck cancer patients; hence measures should be taken for complete responders to diagnose this metastasis early and treat them appropriately.

  13. Use of bone scan during initial prostate cancer workup, downstream procedures, and associated Medicare costs.

    Science.gov (United States)

    Falchook, Aaron D; Salloum, Ramzi G; Hendrix, Laura H; Chen, Ronald C

    2014-06-01

    For patients with a high likelihood of having metastatic disease (high-risk prostate cancer), bone scan is the standard, guideline-recommended test to look for bony metastasis. We quantified the use of bone scans and downstream procedures, along with associated costs, in patients with high-risk prostate cancer, and their use in low- and intermediate-risk patients for whom these tests are not recommended. Patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database diagnosed with prostate cancer from 2004 to 2007 were included. Prostate specific antigen (PSA), Gleason score, and clinical T stage were used to define D'Amico risk categories. We report use of bone scans from the date of diagnosis to the earlier of treatment or 6 months. In patients who underwent bone scans, we report use of bone-specific x-ray, computed tomography (CT), and magnetic resonance imaging (MRI) scans, and bone biopsy within 3 months after bone scan. Costs were estimated using 2012 Medicare reimbursement rates. In all, 31% and 48% of patients with apparent low- and intermediate-risk prostate cancer underwent a bone scan; of these patients, 21% underwent subsequent x-rays, 7% CT, and 3% MRI scans. Bone biopsies were uncommon. Overall, bone scans and downstream procedures was $11,300,000 for low- and intermediate-risk patients. For patients with apparent high-risk disease, only 62% received a bone scan, of whom 14% were found to have metastasis. There is overuse of bone scans in patients with low- and intermediate-risk prostate cancers, which is unlikely to yield clinically actionable information and results in a potential Medicare waste. However, there is underuse of bone scans in high-risk patients for whom metastasis is likely. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Use of Bone Scan During Initial Prostate Cancer Workup, Downstream Procedures, and Associated Medicare Costs

    Energy Technology Data Exchange (ETDEWEB)

    Falchook, Aaron D. [Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Salloum, Ramzi G. [Department of Health Services Policy and Management, University of South Carolina, Columbia, South Carolina (United States); Hendrix, Laura H. [Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Chen, Ronald C., E-mail: ronald_chen@med.unc.edu [Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States)

    2014-06-01

    Purpose: For patients with a high likelihood of having metastatic disease (high-risk prostate cancer), bone scan is the standard, guideline-recommended test to look for bony metastasis. We quantified the use of bone scans and downstream procedures, along with associated costs, in patients with high-risk prostate cancer, and their use in low- and intermediate-risk patients for whom these tests are not recommended. Methods and Materials: Patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database diagnosed with prostate cancer from 2004 to 2007 were included. Prostate specific antigen (PSA), Gleason score, and clinical T stage were used to define D'Amico risk categories. We report use of bone scans from the date of diagnosis to the earlier of treatment or 6 months. In patients who underwent bone scans, we report use of bone-specific x-ray, computed tomography (CT), and magnetic resonance imaging (MRI) scans, and bone biopsy within 3 months after bone scan. Costs were estimated using 2012 Medicare reimbursement rates. Results: In all, 31% and 48% of patients with apparent low- and intermediate-risk prostate cancer underwent a bone scan; of these patients, 21% underwent subsequent x-rays, 7% CT, and 3% MRI scans. Bone biopsies were uncommon. Overall, <1% of low- and intermediate-risk patients were found to have metastatic disease. The annual estimated Medicare cost for bone scans and downstream procedures was $11,300,000 for low- and intermediate-risk patients. For patients with apparent high-risk disease, only 62% received a bone scan, of whom 14% were found to have metastasis. Conclusions: There is overuse of bone scans in patients with low- and intermediate-risk prostate cancers, which is unlikely to yield clinically actionable information and results in a potential Medicare waste. However, there is underuse of bone scans in high-risk patients for whom metastasis is likely.

  15. The Breast Cancer to Bone (B2B) Metastases Research Program: a multi-disciplinary investigation of bone metastases from breast cancer.

    Science.gov (United States)

    Brockton, Nigel T; Gill, Stephanie J; Laborge, Stephanie L; Paterson, Alexander H G; Cook, Linda S; Vogel, Hans J; Shemanko, Carrie S; Hanley, David A; Magliocco, Anthony M; Friedenreich, Christine M

    2015-07-10

    Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone. The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood samples are collected and detailed epidemiologic data is collected by in-person interview and self-administered questionnaires. Additional self-administered questionnaires and blood samples are completed at specified follow-up intervals (24, 48 and 72 months). Vital status is obtained prior to each follow-up through record linkages with the Alberta Cancer Registry. Recurrences are identified through medical chart abstractions. Each of the four projects applies specific methods and analyses to assess the impact of serum vitamin D and cytokine concentrations, tumour transcript and protein expression, serum metabolomic profiles and in vitro cell signalling on breast cancer bone metastases. The B2B Research Program will address key issues in breast cancer bone metastases including the association between lifestyle factors (particularly a comprehensive assessment of vitamin D status) inflammation and bone metastases, the significance or primary tumour gene expression in tissue tropism, the

  16. miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer.

    Science.gov (United States)

    Mody, Hardik R; Hung, Sau Wai; Pathak, Rakesh K; Griffin, Jazmine; Cruz-Monserrate, Zobeida; Govindarajan, Rajgopal

    2017-08-01

    Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFβ-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs to regulate endogenous TGFβ1 levels via miR-663/4787-mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016) (1). Although DZNep also attenuates exogenous TGFβ-induced EMT response, the mechanism of this inhibition was unclear. Here, DZNep induced miR-202-5p to target both TGFβ receptors, TGFBR1 and TGFBR2, for RNA interference and thereby contributes to the suppression of exogenous TGFβ-induced EMT in pancreatic cancer cells. Lentiviral overexpression of miR-202 significantly reduced the protein levels of both TGFβ receptors and suppressed TGFβ signaling and EMT phenotypic characteristics of cultured parenchymal pancreatic cancer cells. Consistently, transfection of anti-miRNAs against miR-202-5p resulted in increased TGFBR1 and TGFBR2 protein expressions and induced EMT characteristics in these cells. In stellate pancreatic cells, miR-202 overexpression slowed growth as well as reduced stromal extracellular membrane matrix protein expression. In orthotopic pancreatic cancer mouse models, both immunodeficient and immunocompetent, miR-202 reduced tumor burden and metastasis. Together, these findings demonstrate an alternative mechanism of DZNep in suppressing TGFβ signaling at the receptor level and uncover the EMT-suppressing role of miR-202 in pancreatic cancer.Implications: These findings support the possibility of combining small molecule-based (e.g., DZNep analogs) or large molecule-based (e.g., miRNAs) epigenetic modifiers with conventional nucleoside analogs (e.g., gemcitabine, capecitabine) to improve the antimetastatic potential of current pancreatic cancer therapy. Mol Cancer Res; 15(8); 1029-39. ©2017 AACR. ©2017 American Association for Cancer

  17. Clinical characteristics and risk factors for developing bone metastases in patients with breast cancer

    OpenAIRE

    Chen, Wen-Zhao; Shen, Jun-Feng; Zhou, Yang; Xuan-yin CHEN; Liu, Jia-Ming; Liu, Zhi-Li

    2017-01-01

    The risk factors for predicting bone metastases in patients with breast cancer are still controversial. Here, a total of 2133 patients with breast cancer, including 327 with bone metastases (15.33%) and 1806 without bone metastases (84.67%) were retrospective reviewed from January 2005 to December 2015. The spine was found to be the most common site for bone metastases, followed by ribs (57.5%), pelvis (54.1%) and sternum (44.3%). The results indicated that axillary lymph node metastases and ...

  18. Influence of sex differences on the progression of cancer-induced bone pain

    DEFF Research Database (Denmark)

    Falk, Sarah; Uldall, Maria; Appel, Camilla

    2013-01-01

    on the progression of cancer-induced bone pain. Materials and Methods: 4T1-luc2 mammary cancer cells were introduced into the femoral cavity of female and male BALB/cJ mice. Bioluminescence tumor signal, pain-related behavior and bone degradation were monitored for 14 days. Results: Female mice demonstrated...... a significantly greater bioluminescence signal on day 2 compared to male mice and, in addition, a significant earlier onset of pain-related behavior was observed in the females. No sex difference was observed for bone degradation. Finally, a strong correlation between pain-related behavior and bone degradation...

  19. k-space sampling optimization for ultrashort TE imaging of cortical bone: Applications in radiation therapy planning and MR-based PET attenuation correction

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Lingzhi, E-mail: hlingzhi@gmail.com, E-mail: raymond.muzic@case.edu; Traughber, Melanie [Philips Healthcare, Cleveland, Ohio 44143 (United States); Su, Kuan-Hao; Pereira, Gisele C.; Grover, Anu; Traughber, Bryan; Muzic, Raymond F. Jr., E-mail: hlingzhi@gmail.com, E-mail: raymond.muzic@case.edu [University Hospitals Case Medical Center, Cleveland, Ohio 44106 (United States)

    2014-10-15

    Purpose: The ultrashort echo-time (UTE) sequence is a promising MR pulse sequence for imaging cortical bone which is otherwise difficult to image using conventional MR sequences and also poses strong attenuation for photons in radiation therapy and PET imaging. The authors report here a systematic characterization of cortical bone signal decay and a scanning time optimization strategy for the UTE sequence through k-space undersampling, which can result in up to a 75% reduction in acquisition time. Using the undersampled UTE imaging sequence, the authors also attempted to quantitatively investigate the MR properties of cortical bone in healthy volunteers, thus demonstrating the feasibility of using such a technique for generating bone-enhanced images which can be used for radiation therapy planning and attenuation correction with PET/MR. Methods: An angularly undersampled, radially encoded UTE sequence was used for scanning the brains of healthy volunteers. Quantitative MR characterization of tissue properties, including water fraction and R2{sup ∗} = 1/T2{sup ∗}, was performed by analyzing the UTE images acquired at multiple echo times. The impact of different sampling rates was evaluated through systematic comparison of the MR image quality, bone-enhanced image quality, image noise, water fraction, and R2{sup ∗} of cortical bone. Results: A reduced angular sampling rate of the UTE trajectory achieves acquisition durations in proportion to the sampling rate and in as short as 25% of the time required for full sampling using a standard Cartesian acquisition, while preserving unique MR contrast within the skull at the cost of a minimal increase in noise level. The R2{sup ∗} of human skull was measured as 0.2–0.3 ms{sup −1} depending on the specific region, which is more than ten times greater than the R2{sup ∗} of soft tissue. The water fraction in human skull was measured to be 60%–80%, which is significantly less than the >90% water fraction in

  20. Survival of cancer patients after radiotherapy for bone metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Matsubayashi, Takashi; Murata, Koichiro; Ikeda, Toshiaki; Tadokoro, Katsumi; Nishimaki, Hiroshi; Ohta, Akishige

    1988-12-01

    From January 1972 through April 1985, a total of 270 patients were treated with palliative radiation therapy for bone metastases. The lung and breast accounted for 52 % of the primary sites. A single target volume, in principle, receieved 1.7 to 2.5 Gy daily 6 times a week to a total dosage of 40-50 Gy. When there were two or more target volumes, a total of 20-30 Gy was delivered synchronously or metachronously to each irradiation field. According to the primary sites, median survivals after the beginning of radiation therapy were short for the lung (3.3 mo), stomach (2.1 mo), and uterine cervix (4.8 mo), in contrast to the breast (26.9 mo), thyroid (23.5 mo), and salivary gland (14.0 mo). Seven patients with breast cancer and one patient with thyroid cancer were alive 5 years or more after palliative radiation therapy. For these patients, the time of radiation therapy ranged from 6 mo before surgery to 88.6 mo after surgery. Four patients had one target volume, 3 had 2 volumes, and one had 4 volumes. Histological comparison for lung cancer revealed no significant difference in survivals between adenocarcinoma and squamous cell carcinoma. The primary site of cancer seems to be a contributing factor to the probability of longer survivals after palliative radiation therapy. In maintaining quality of life for long-term survivors, not only pain relief but also prevention of pathologic fracture and delayed radiation effects should be taken into account. (N.K.).

  1. Multiparametric Magnetic Resonance Imaging of Prostate Cancer Bone Disease: Correlation With Bone Biopsy Histological and Molecular Features.

    Science.gov (United States)

    Perez-Lopez, Raquel; Nava Rodrigues, Daniel; Figueiredo, Ines; Mateo, Joaquin; Collins, David J; Koh, Dow-Mu; de Bono, Johann S; Tunariu, Nina

    2018-02-01

    The aim of this study was to correlate magnetic resonance imaging (MRI) of castration-resistant prostate cancer (CRPC) bone metastases with histological and molecular features of bone metastases. Forty-three bone marrow biopsies from 33 metastatic CRPC (mCRPC) patients with multiparametric MRI and documented bone metastases were evaluated. A second cohort included 10 CRPC patients with no bone metastases. Associations of apparent diffusion coefficient (ADC), normalized b900 diffusion-weighted imaging (nDWI) signal, and signal-weighted fat fraction (swFF) with bone marrow biopsy histological parameters were evaluated using Mann-Whitney U test and Spearman correlations. Univariate and multivariate logistic regression models were analyzed. Median ADC and nDWI signal was significantly higher, and median swFF was significantly lower, in bone metastases than nonmetastatic bone (P < 0.001). In the metastatic cohort, 31 (72.1%) of 43 biopsies had detectable cancer cells. Median ADC and swFF were significantly lower and median nDWI signal was significantly higher in biopsies with tumor cells versus nondetectable tumor cells (898 × 10 mm/s vs 1617 × 10 mm/s; 11.5% vs 62%; 5.3 vs 2.3, respectively; P < 0.001). Tumor cellularity inversely correlated with ADC and swFF, and positively correlated with nDWI signal (P < 0.001). In serial biopsies, taken before and after treatment, changes in multiparametric MRI parameters paralleled histological changes. Multiparametric MRI provides valuable information about mCRPC bone metastases. These data further clinically qualify DWI as a response biomarker in mCRPC.

  2. WNT5A and Its Receptors in the Bone-Cancer Dialogue.

    Science.gov (United States)

    Thiele, Stefanie; Rachner, Tilman D; Rauner, Martina; Hofbauer, Lorenz C

    2016-08-01

    Wnt signaling is critical for tumorigenesis and skeletal remodeling. However, its contribution to the formation of metastatic bone lesions remains poorly defined. One major challenge of unraveling its role in cancer progression is the high complexity of Wnt signaling, which includes numerous ligands, receptors, and inhibitors, with intricate biological effects and specific signaling pathways depending on the cellular context. In this perspective, we summarize the role of the noncanonical Wnt ligand WNT5A in the development and metastatic process of osteotropic cancer entities. We focus on its tumor-suppressive function in breast cancer, tumor promoting effects in melanoma, and ambiguous role in prostate cancer, and discuss potential challenges and opportunities that may be associated with targeting Wnt signaling for cancer therapy and treatment of bone metastases. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

  3. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

    Science.gov (United States)

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2015-12-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

  4. Reductions in heel bone quality across gestation are attenuated in pregnant adolescents with higher prepregnancy weight and greater increases in PTH across gestation.

    Science.gov (United States)

    Whisner, Corrie M; Young, Bridget E; Witter, Frank R; Harris, Zena Leah; Queenan, Ruth A; Cooper, Elizabeth M; O'Brien, Kimberly O

    2014-09-01

    Few studies have examined the effect of maternal calcium intake and vitamin D status on bone health across gestation in pregnant adolescents. This study aimed to characterize maternal bone quality and determinants of bone-quality change across gestation in pregnant adolescents. Healthy pregnant adolescents (n = 156; aged 13 to 18 years) with singleton pregnancies and at 12 to 30 weeks gestation at enrollment were recruited from two urban maternity clinics in Baltimore, MD, and Rochester, NY, for this prospective longitudinal study. Maternal serum was collected at midgestation and at delivery for assessment of bone biomarkers and calcitropic hormones. Maternal bone quality (assessed by heel ultrasound) and sonographic fetal biometry were measured up to three times across pregnancy. Racially diverse teens (64.7% African American, 35.3% white) were followed from 21.0 (interquartile range [IQR] 17.3, 27.0) weeks of gestation until delivery at 40.0 (IQR 39.0, 40.7) weeks. Significant decreases in calcaneal speed of sound (SOS), broadband ultrasound attenuation (BUA), and quantitative ultrasound index (QUI) (-9.2 ± 16.1 m/s, -3.2 (-8.0, 2.1) dB/MHz and -5.3 ± 8.8, respectively) were evident across pregnancy. Multivariate analysis controlling for baseline measures and measurement intervals was used to identify independent predictors of normalized (per week) calcaneal bone loss. Weekly decreases in bone quality were not significantly associated with maternal calcium intake or 25(OH)D concentration. Greater weekly reductions in calcaneal bone quality were evident in teens with lower prepregnancy weight (BUA, p = 0.006 and QUI, p = 0.012) and among those with lower weekly increase in PTH (SOS, p = 0.046). Overall, significant decreases in calcaneal bone quality occurred across pregnancy in adolescents, but the magnitude of this loss was attenuated in those with greater prepregnancy weight and weekly increases in PTH. Further studies are needed to

  5. Allogeneic Compact Bone-Derived Mesenchymal Stem Cell Transplantation Attenuates the Severity of Idiopathic Pneumonia Syndrome in a Murine Bone Marrow Transplantation Model

    Directory of Open Access Journals (Sweden)

    Shu-kai Qiao

    2016-12-01

    Full Text Available Background/Aims: Idiopathic pneumonia syndrome (IPS is a serious and life-threatening lung complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT and currently no effective therapies exist. This study was designed to determine whether transplantation of allogeneic murine compact bone derived- mesenchymal stem cells (CB-MSCs could prevent the development of IPS. Methods: We tested the effects of CB-MSCs transplantation on IPS using an established murine model of C57BL/6 (H-2b→BALB/c (H-2d. Survival rates, body weight change, clinical GVHD scores, lung histological changes were assessed after IPS induction. Mechanistically, concentrations of cytokines (TNF-α, IFN-γ and IL-4 and chemokines (CCL5, CXCL9 and CXCL10 in bronchoalveolar lavage fluid (BALF from the recipient mice were measured at different time point post-transplantation. CD4+CD25+Foxp3+ regulatory T cell (Treg percentage, CCR5, CXCR3 and CCR7 expression on CD3+ T cells, and lung CXCR3, CCR5, CCR7, T-bet and GATA-3 mRNA levels were also evaluated at different time point post-transplantation. Results: Co-transplantation of CB-MSCs significantly attenuated the severity of lung injuries and increased survival rate of mice compared to non-cotransplanted mice. A higher Treg percentage, reduction of TNF-α, IFN-γ, CCL5, CXCL9 and CXCL10 levels, down-regulation of CXCR3 and CCR5, as well as up-regulation of CCR7, were observed in MSCs co-transplantation mice. Also, the prophylactic effect of CB-MSCs was associated with a shift of Th1/Th2 balance toward anti-inflammatory Th2 polarization. Conclusions: Allogeneic CB-MSCs effectively controlled the occurrence of IPS due to its profound immunomodulatory capacity. This may offer a novel prophylactic approach for IPS after allo-HSCT.

  6. Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice

    OpenAIRE

    Miwa, Shinji; Yano, Shuya; Zhang, Yong; Matsumoto,Yasunori; Uehara, Fuminari; Yamamoto, Mako; Hiroshima, Yukihiko; Kimura, Hiroaki; Hayashi, Katsuhiro; Yamamoto, Norio; Bouvet, Michael; Tsuchiya, Hiroyuki; Hoffman, Robert M.; Zhao, Ming

    2014-01-01

    Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely...

  7. Influence of sex differences on the progression of cancer-induced bone pain

    DEFF Research Database (Denmark)

    Falk, Sarah; Uldall, Maria Schmidt; Appel, Camilla

    2013-01-01

    Pain caused by bone metastases has a severe impact on the quality of life for many patients with cancer. Good translational in vivo models are required to understand the molecular mechanism and develop better treatment. In the current study we evaluated the influence of sex differences on the pro......Pain caused by bone metastases has a severe impact on the quality of life for many patients with cancer. Good translational in vivo models are required to understand the molecular mechanism and develop better treatment. In the current study we evaluated the influence of sex differences...... on the progression of cancer-induced bone pain....

  8. The incidence of bone metastasis after early-stage breast cancer in Canada.

    Science.gov (United States)

    Liede, Alexander; Jerzak, Katarzyna J; Hernandez, Rohini K; Wade, Sally W; Sun, Ping; Narod, Steven A

    2016-04-01

    Current information on the incidence and prevalence of bone metastases in women with breast cancer is scarce. This study examined the occurrence and predictors of bone metastases, as well as post-metastasis survival in a prospective cohort of Canadian women with breast cancer. We included women treated for early-stage (stage I, II, or III) breast cancer at the Henrietta Banting Breast Centre (HBBC) in Toronto, Canada between 1987 and 2000. Data were abstracted from medical records and pathology reports in the HBBC database; follow-up extended to end of data availability or August 31, 2015. Actuarial survival analyses provided cumulative incidence of bone metastases at 5, 10, and 15 years after breast cancer diagnosis. Kaplan-Meier curves describe breast cancer mortality. Regression models assessed patient, tumor, and treatment characteristics as predictors of bone metastases with all-cause mortality as a competing risk. Among 2097 women studied, the 5-, 10-, and 15-year probability of bone metastasis was 6.5, 10.3, and 11.3 % for the first recurrence, and 8.4, 12.5, and 13.6 % for any bone recurrence. At median follow-up (12.5 years), 13.2 % of patients had bone metastases. Median survival was 1.6 years following bone metastasis, and shorter if both bone and visceral metastases occurred. Advanced age and adjuvant treatment with tamoxifen were protective against bone metastasis. In this representative cohort of women diagnosed with early-stage breast cancer in Ontario, Canada, with long follow-up, the incidence of bone metastases was consistent with longitudinal studies from the United Kingdom, Denmark, and the US.

  9. Skeletal-related events due to bone metastases from differentiated thyroid cancer.

    Science.gov (United States)

    Farooki, Azeez; Leung, Vivien; Tala, Hernan; Tuttle, R Michael

    2012-07-01

    In oncology, the clinical impact of metastatic bone disease is conveyed via a composite end point termed skeletal-related events (SRE), which encompasses spinal cord compression, pathological fracture, a need for external beam radiation or surgery to bone, and hypercalcemia of malignancy. An appreciation for the high incidence of SRE in other advanced cancers involving the bone has led to the approval of potent antiresorptive agents because they delay the time to the first SRE and decrease the incidence of SRE. The risk and rate of SRE after diagnosis of bone metastasis have not been described in thyroid cancer; antiresorptive agents are not routinely used. This was a retrospective review of 245 differentiated thyroid cancer patients with bone metastases identified as part of routine clinical care at Memorial Sloan-Kettering Cancer Center between 1960 and 2011. The occurrence of SRE was recorded from the initial diagnosis of bone metastasis until final follow-up or death. Seventy-eight percent of patients (192 of 245) either presented with or developed at least one SRE after the diagnosis of metastatic bone disease. The median time from identification of bone metastasis to first SRE was 5 months (excluding the 97 patients in whom first SRE occurred at the time of the bone metastasis diagnosis). Of the patients who sustained an initial SRE, 65% (120 of 192) went on to sustain a second SRE at a median of 10.7 months after the first event. SRE were frequently multiple; 39% (74 of 192) sustained three or more discrete SRE. Thyroid cancer bone metastases identified as part of routine clinical follow-up frequently cause significant and recurrent morbidity. The incidence of SRE and median time to first SRE in metastatic thyroid cancer to bone are similar to those reported in other solid tumors. Prospective clinical trials to assess the efficacy of antiresorptive agents in this population are needed.

  10. Breast Cancer Cell Colonization of the Human Bone Marrow Adipose Tissue Niche

    Directory of Open Access Journals (Sweden)

    Zach S. Templeton

    2015-12-01

    Full Text Available BACKGROUND/OBJECTIVES: Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche. METHODS: Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry. RESULTS: Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014 and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006 and IL-1β (P = .001 in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment. CONCLUSIONS: Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche.

  11. The value of a baseline bone scan in patients with newly diagnosed prostate cancer.

    Science.gov (United States)

    Lin, K; Szabo, Z; Chin, B B; Civelek, A C

    1999-08-01

    This study evaluated the role of bone scans in managing newly diagnosed, untreated prostate cancer. Two hundred seventy consecutive staging bone scans in patients (mean age, 69 years) with newly diagnosed prostate cancer who had serum prostate-specific antigen (PSA) determinations and biopsies between January 1995 and October 1997 were evaluated retrospectively. The bone scans were positive for metastatic bone disease in 24 patients and negative in 246. Serum PSA levels, the number of positive biopsy cores, the extent of tumor in the prostate gland, and Gleason scores were all significantly correlated with scintigraphic bone metastases (P bone metastases. Bone metastases were found in 2 of 34 patients with PSA levels of 10.1 to 20 ng/ml, in 3 of 29 patients with PSA values of 20.1 to 50 ng/ml, and in 16 of 30 patients with PSA levels greater than 50.1 ng/ml. Only one patient had a bone metastasis when the prostate cancer involved fewer than 2 biopsy cores (1 of 135) or when disease was confined to one lobe (1 of 131), but the incidence increased significantly when the malignancy involved three or more biopsy cores (20 of 114) or disease was present in both prostate lobes (20 of 118). Four of 160 patients with Gleason scores less than 6 had bone metastases, whereas 20 of 110 patients with Gleason scores greater than 7 had bone metastases. The likelihood of bone metastases is low in patients with newly diagnosed, untreated prostate cancer when the initial PSA level was less than 10 ng/ml, the number of positive biopsy cores was less than 2, tumor was confined to one lobe, or the Gleason score was less than 6. However, none of these criteria can be used to exclude metastatic bone disease. A baseline bone scan is an important staging procedure and should be obtained to provide maximum data for clinical management of the disease.

  12. The diagnostic and prognostic value of serum bone Gla protein (osteocalcin) in patients with recurrent breast cancer

    DEFF Research Database (Denmark)

    Kamby, C; Egsmose, C; Söletormos, G

    1993-01-01

    Serum bone Gla protein (S-BGP), a marker of bone metabolism, was measured in 60 patients included in a staging programme for recurrent breast cancer. Other diagnostic procedures comprised S-alkaline phosphatase (S-AP), bone scan (B-scan), bilateral iliac crest bone marrow biopsies, and radiological...... bone survey. The sites of recurrence were bone (61%), bone marrow (46%), soft tissue (52%), lung (13%), pleura (11%), liver (4%), and brain (2%). Radiology and bone biopsy served as key diagnoses as to the presence or absence of bone metastases. The diagnostic efficiency of B-scan and S-AP was greater...

  13. Do all patients with newly diagnosed prostate cancer need staging radionuclide bone scan? A retrospective study.

    Science.gov (United States)

    Al-Ghazo, Mohammed A; Ghalayini, Ibrahim F; Al-Azab, Rami S; Bani-Hani, Ibrahim; Barham, Alaa; Haddad, Yazan

    2010-01-01

    Define a group of patients with newly diagnosed prostate cancer, whose risk of bone metastasis is low enough to omit a bone scan staging study. From 2003 to 2009, the medical records of patients who were newly diagnosed with prostate cancer were retrospectively reviewed. The data collected included: age, digital rectal examination, serum prostate specific antigen (PSA), Gleason score, clinical T stage, and bone isotope scan. Patients were divided into two groups according to the results of bone isotope scan; positive group and negative group. A univariate and multivariate binary logistic regression was used to analyze the results. Of the 106 patients, 98 had a complete data collection and were entered into the study. The median age of the patients was 70.5 years and patients with a positive bone scan was 74 years, significantly higher than for patients with negative scans (69 years) (p=0.02). Bone metastasis was detected in 39 cases (39.7%). In all patients with clinical T1-2 stage, a Gleason score of bone isotope scans were negative. In univariate analysis, PSA (>20 ng/mL) and Gleason score (>7) were independently predictive of positive bone scan, while clinical stage was not. Staging bone scans can be omitted in patients with a PSA level of ≤20 ng/mL, and Gleason scoreGleason score and PSA, a larger proportion of patients with prostate cancer could avoid a staging bone scan.

  14. Prognostic value of the bone scan index using a computer-aided diagnosis system for bone scans in hormone-naive prostate cancer patients with bone metastases.

    Science.gov (United States)

    Miyoshi, Yasuhide; Yoneyama, Shuko; Kawahara, Takashi; Hattori, Yusuke; Teranishi, Jun-ichi; Kondo, Keiichi; Moriyama, Masatoshi; Takebayashi, Shigeo; Yokomizo, Yumiko; Yao, Masahiro; Uemura, Hiroji; Noguchi, Kazumi

    2016-02-19

    The bone scan index (BSI) using a computer-aided diagnosis system for bone scans is expected to be an objective and quantitative clinical tool for evaluating bone metastatic prostate cancer. This study aimed to evaluate the pretreatment BSI as a prognostic factor in hormone-naive prostate cancer patients with bone metastases. The study included 60 patients with hormone-naive, bone metastatic prostate cancer that was initially treated with combined androgen blockade therapy. The BONENAVI system was used for calculating the BSI. We evaluated the correlation between overall survival (OS) and pretreatment clinicopathological characteristics, including patients' age, initial prostate-specific antigen (PSA) value, Gleason scores, clinical TNM stage, and the BSI. Cox proportional hazards regression models were used for statistical analysis. The median follow-up duration was 21.4 months. Clinical or PSA progression occurred in 37 (61.7%) patients and 18 (30.0%) received docetaxel. Death occurred in 16 (26.7%) patients. Of these deaths, 15 (25.0%) were due to prostate cancer. The median OS was not reached. In multivariate analysis, age and the BSI were independent prognostic factors for OS. We evaluated the discriminatory ability of our models, including or excluding BSI by quantifying the C-index. The BSI improved the C-index from 0.751 to 0.801 for OS. Median OS was not reached in patients with a BSI ≤ 1.9 and median OS was 34.8 months in patients with a BSI >1.9 (p = 0.039). The pretreatment BSI and patients' age are independent prognostic factors for patients with hormone-naive, bone metastatic prostate cancer.

  15. PREVENTION OF COMPLICATIONS IN CASTRATE-REFRACTORY PROSTATE CANCER PATIENTS WITH BONE METASTASES

    Directory of Open Access Journals (Sweden)

    K. M. Nushko

    2015-01-01

    Full Text Available Abstract:Prostate cancer (PC is one of the most urgent problems in modern oncourology. Every year the world is recording more than 900 thousands new cases of prostate cancer. For this reason, the diagnosis and treatment of this disease has recently been given more attention, both abroad and in the Russian Federation. Despite improvements in diagnostic methods and implementation of programs for active detection of the disease in its early stages, the number of patients suffering from advanced forms of prostate cancer remains high. Currently, the main method of treatment in patients with metastatic prostate cancer remains the hormone therapy (HT. Patients with metastatic prostate cancer most frequently have localization of metastatic lesions in the lymph nodes and bones. Frequent localization of metastatic lesions in the bones is due to tumor cell tropism of prostate cancer to the bone. Metastatic bone disease, as well as long-term HT conducted in patients with metastatic prostate cancer, leads to irreversible disruption of bone remodeling, which may be accompanied by osteoporosis and fragility fractures. Bone metastases in patients with PC are the most common cause of complications and significantly impair the quality of life of patients. Therapy underlying the prevention of bone complications can be specific, aimed directly at the tumor tissue and non-specific, to strengthen bones and decrease its resorption processes. The article provides an overview of the literature covering the effectiveness of modern drugs, aimed at non-specific prevention of bone complications in patients with metastatic prostate cancer, such as bisphosphonates, and inhibitors of the ligand RANKL, as well as an overview of studies to assess the effectiveness of domestic analogue zolendronovoy acid preparation Resorba in the prevention of osteoporosis.

  16. Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression.

    Science.gov (United States)

    Thackeray, James T; Pietzsch, Stefan; Stapel, Britta; Ricke-Hoch, Melanie; Lee, Chun-Wei; Bankstahl, Jens P; Scherr, Michaela; Heineke, Jörg; Scharf, Gesine; Haghikia, Arash; Bengel, Frank M; Hilfiker-Kleiner, Denise

    2017-05-18

    Advanced cancer induces fundamental changes in metabolism and promotes cardiac atrophy and heart failure. We discovered systemic insulin deficiency in cachectic cancer patients. Similarly, mice with advanced B16F10 melanoma (B16F10-TM) or colon 26 carcinoma (C26-TM) displayed decreased systemic insulin associated with marked cardiac atrophy, metabolic impairment, and function. B16F10 and C26 tumors decrease systemic insulin via high glucose consumption, lowering pancreatic insulin production and producing insulin-degrading enzyme. As tumor cells consume glucose in an insulin-independent manner, they shift glucose away from cardiomyocytes. Since cardiomyocytes in both tumor models remained insulin responsive, low-dose insulin supplementation by subcutaneous implantation of insulin-releasing pellets improved cardiac glucose uptake, atrophy, and function, with no adverse side effects. In addition, by redirecting glucose to the heart in addition to other organs, the systemic insulin treatment lowered glucose usage by the tumor and thereby decreased tumor growth and volume. Insulin corrected the cancer-induced reduction in cardiac Akt activation and the subsequent overactivation of the proteasome and autophagy. Thus, cancer-induced systemic insulin depletion contributes to cardiac wasting and failure and may promote tumor growth. Low-dose insulin supplementation attenuates these processes and may be supportive in cardio-oncologic treatment concepts.

  17. Reporting and Handling of Indeterminate Bone Scan Results in the Staging of Prostate Cancer

    DEFF Research Database (Denmark)

    Petersen, Lars J; Strandberg, Jesper; Stenholt, Louise

    2018-01-01

    Bone scintigraphy is key in imaging skeletal metastases in newly diagnosed prostate cancer. Unfortunately, a notable proportion of scans are not readily classified as positive or negative but deemed indeterminate. The extent of reporting of indeterminate bone scans and how such scans are handled ...... of prostate cancer was insufficiently reported in clinical trials. In the case of indeterminate scans, most studies provided adequate measures to obtain the final status of the patients.......Bone scintigraphy is key in imaging skeletal metastases in newly diagnosed prostate cancer. Unfortunately, a notable proportion of scans are not readily classified as positive or negative but deemed indeterminate. The extent of reporting of indeterminate bone scans and how such scans are handled...... in clinical trials are not known. A systematic review was conducted using electronic databases up to October 2016. The main outcome of interest was the reporting of indeterminate bone scans, analyses of how such scans were managed, and exploratory analyses of the association of study characteristics...

  18. Study on 41Ca-AMS for diagnosis and assessment of cancer bone metastasis in rats

    Science.gov (United States)

    Shen, Hongtao; Pang, Fangfang; Jiang, Shan; He, Ming; Dong, Kejun; Dou, Liang; Pang, Yijun; Yang, Xianlin; Ruan, Xiangdong; Liu, Manjun; Xia, Chunbo

    2015-10-01

    The annual incidence of new cancer patients in China is about 2 million, 30-40% of which will end up with bone metastasis. Profound study on the preclinical model and early diagnosis of cancer bone metastasis in rats are very significant for the drug development, better understanding and treatment of bone metastases. In order to monitor the process of bone metabolism and early detection of bone metastasis of cancer cells, a technique of 41Ca isotope tracer combined with AMS has been developed and applied in the study on the bone metastasis of cancer cells by rat model. In this work, 3-month-old female Sprague-Dawley (SD) rats were randomly divided into different groups, and tumor cells injected respectively into the tail vein, femoral artery, femoral cavity and the thigh muscle to establish the rat models for bone metastases. The most appropriate model, i.e., the thigh muscle group, was finally adopted in our real metastases experiment. Each rat in this group was intramuscularly (i.m.) injected with 250 μl CaCl2 solution (containing 1.4 mg Ca and 5nCi 41Ca). About 40 days later, the rat mammary gland carcinoma cells (Walker 256) were injected into these rats following the established protocol. After bone metastasis, medicine interventions were performed. The sequential urine and blood samples were collected and analyzed for 41Ca (by AMS) and N-terminal telopeptide (Ntx), respectively. Bone Mineral Density (BMD) values in the femur and the tibia were measured by CT scan. The results of 41Ca/Ca in longitudinal urinary samples can sensitively reveal the skeletal perturbations caused by bone metastasis of rats, suggests that 41Ca might be similarly developed for human use and improve clinical management through the assessment of the curative effect and non-invasive detection of the earliest stages of cancer growth in bone.

  19. Potentiation of ghrelin signaling attenuates cancer anorexia–cachexia and prolongs survival

    Science.gov (United States)

    Fujitsuka, N; Asakawa, A; Uezono, Y; Minami, K; Yamaguchi, T; Niijima, A; Yada, T; Maejima, Y; Sedbazar, U; Sakai, T; Hattori, T; Kase, Y; Inui, A

    2011-01-01

    Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia. PMID:22832525

  20. Propofol attenuates pancreatic cancer malignant potential via inhibition of NMDA receptor.

    Science.gov (United States)

    Chen, Xiangyuan; Wu, Qichao; You, Li; Chen, Sisi; Zhu, Minmin; Miao, Changhong

    2017-01-15

    Propofol is a commonly used intravenous anesthetic, and could attenuate cancer cells malignant potential via inhibiting hypoxia-inducible factor-1α (HIF-1α) expression. However, the mechanism is still inclusive. In the present study, we mainly focus on the mechanism by which propofol down-regulated HIF-1α expression and malignant potential in pancreatic cancer cells. Human pancreatic cancer cells (Miapaca-2 and Panc-1) in vitro and murine pancreatic cancer cell (Panc02) in vivo were used to assess the effect of propofol on vascular endothelial growth factor (VEGF) expression and migration of pancreatic cancer cells. Propofol inhibited cells migration, expression of VEGF and HIF-1α, phosphorylation of extracellular regulated protein kinases (ERK), AKT, Ca2+/calmodulin dependent protein kinases II (CaMK II), and Ca2+ concentration in a concentration-dependent manner (5, 25, 50, 100μM). Furthermore, MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMK II, could inhibit the expression of VEGF, HIF-1a, p-AKT, p-ERK, p-CaMK II in vitro, growth of tumor and VEGF expression in vivo, which were similar to the effect of propofol. In addition, the anti-tumor effect of propofol could be counteracted by rapastinel, an activator of NMDA receptor. Our study indicated that propofol suppressed VEGF expression and migration ability of pancreatic cancer cells in vitro and in vivo, probably via inhibiting NMDA receptor. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Biochemical markers for assessment of bone metastases in patients with breast cancer.

    Science.gov (United States)

    Hou, M F; Tsai, L Y; Tsai, S M; Huang, C J; Huang, Y S; Hsieh, J S; Chan, H M; Wang, J Y; Chuang, C H; Chen, F M; Huang, T J

    1999-08-01

    Breast cancer commonly metastasizes to bones, producing both osteolytic and osteoblastic deposits. Different markers for quantitative determination of bone turnover have been developed to evaluate bone metastases of breast cancer. The urinary deoxypyridinoline (Dpd), a crosslink product of collagen molecules found in bone and excreted in urine during bone degradation, and bone specific alkaline phosphatase (B-ALP), an isoenzyme localized in the membrane of osteoblasts and released in circulation during bone formation, were recently described as a group of markers of bone turnover in metastatic cancer. The urinary Dpd/creatinine (Cre) ratios and the serum B-ALP activity were determined in the samples from 148 patients who suffered from breast cancer (BC patients) with or without bone metastases, and 42 healthy women. For comparison, other biochemical markers, e.g. carcinoembryonic antigen (CEA), CA15-3, tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPSA), and total alkaline phosphatase (T-ALP) in these samples were also evaluated. The results showed that there was a significant difference in urinary Dpd/Cre ratio between the control group and the patients with breast cancer (BC group) (mean +/- S.D., 5.69 +/- 1.26 vs. 8.19 +/- 3.95 nM/mM, P markers, the best diagnostic efficiency of biochemical markers, analyzed by step wise discriminate analysis, was provided by CEA followed by Dpd/Cre ratio, CA15-3, TPA, TPSA, B-ALP and T-ALP. We conclude that showed the urinary Dpd/Cre ratio was a useful tumor marker to evaluate breast cancer with bone metastases.

  2. The Role of Osteoblast-Derived Cytokines in Bone Metastatic Breast Cancer

    Science.gov (United States)

    2009-01-01

    MDA-MB-231 human metastatic breast cancer cell variants retained a rounded shape , as opposed to a thin, spindle-like shape (Figure 3.1) [5]. Thus...of both cell popu- lations decreased so that the ratio of osteoblasts to osteo- clasts decreased from an average of 40 to only 4 by 4 weeks...bone marrow and lead to osteolysis. Activation of osteo- clasts and bone resorption far exceed bone deposition in this disease. Whether the lesions

  3. Alterations of the Bone Marrow Microenvironment Contribute to Prostate Cancer Skeletal Metastasis

    Science.gov (United States)

    2012-05-01

    megakaryocytes promote osteoblast synthesis of type I collagen, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (RANKL), all of...clinical benefits of anti-platelet agents (such as aspirin and heparin) in cancer patients [56]. Macrophages Promote Tumor Growth and Metastasis in Bone...2005) Megakaryocytes modulate osteoblast synthesis of type- l collagen, osteoprotegerin, and RANKL. Bone 36(5):812–819. doi:10.1016/j.bone.2004.12.006

  4. Denosumab Reduces Risk of Bone Side Effects in Advanced Prostate Cancer

    Science.gov (United States)

    The biological agent denosumab (Xgeva) is more effective than zoledronic acid at decreasing the risk of bone fractures and other skeletal-related events (SRE) in men with castration-resistant metastatic prostate cancer, according to results from a randomi

  5. Slit2/Robo1 Mediation of Synaptic Plasticity Contributes to Bone Cancer Pain.

    Science.gov (United States)

    Ke, Changbin; Gao, Feng; Tian, Xuebi; Li, Caijuan; Shi, Dai; He, Wensheng; Tian, Yuke

    2017-01-01

    Synaptic plasticity is fundamental to spinal sensitivity of bone cancer pain. Here, we have shown that excitatory synaptogenesis contributes to bone cancer pain. New synapse formation requires neurite outgrowth and an interaction between axons and dendrites, accompanied by the appositional organization of presynaptic and postsynaptic specializations. We have shown that Slit2, Robo1, and RhoA act as such cues that promote neurite outgrowth and guide the axon for synapse formation. Sarcoma inoculation induces excitatory synaptogenesis and bone cancer pain which are reversed by Slit2 knockdown but aggravated by Robo1 knockdown. Synaptogenesis of cultured neurons are inhibited by Slit2 knockdown but enhanced by Robo1 knockdown. Sarcoma implantation induces an increase in Slit2 and decreases Robo1 and RhoA, while Slit2 knockdown results in an increase of Robo1 and RhoA. These results have demonstrated a molecular mechanism of synaptogenesis in bone cancer pain.

  6. Hepatocyte Growth Factor and Interleukin-6 in Prostate Cancer Bone Metastasis

    National Research Council Canada - National Science Library

    Knudsen, Beatrice

    2004-01-01

    The hypothesis of this grant proposal is that androgen-ablative therapy paradoxically increases growth factor secretion from bone stromal cells and that this may stimulate the growth of prostate cancer metastases...

  7. Hepatocyte Growth Factor and Interleukin-6 in Prostate Cancer Bone Metastasis

    National Research Council Canada - National Science Library

    Knudsen, Beatrice S

    2006-01-01

    The hypothesis of this grant proposal is that androgen-ablative therapy paradoxically increases growth factor secretion from bone stromal cells and that this may stimulate the growth of prostate cancer metastases...

  8. A narrowing range of bone scan in newly diagnosed prostate cancer patients: A retrospective comparative study

    Directory of Open Access Journals (Sweden)

    Berat Cem Özgür

    2015-01-01

    Conclusions: A bone scan seems to be impractical in newly diagnosed prostate cancer patients with serum PSA level <20 ng/ml and GS up to seven and pre-treatment PSA is the best predictor of the need for the bone scan according to results of this study.

  9. TGF-Beta Induction of PMEPA1: Role in Bone Metastasis Due to Prostate Cancer

    Science.gov (United States)

    2009-01-01

    ASBMR John Haddad Young Investigator award, American Society for Bone and Mineral Research. 2008 Noa Siris Schwartz Research Award, Bone and Cancer...Riggins for their technical assistance . 40 Funding Disclosure This work was supported by a Department of Defense (DoD) predoctoral fellowship

  10. Radium-223 treatment of bone metastases from castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Mortensen, Jann; Højgaard, Liselotte

    2014-01-01

    The alpha emitter Radium-223 ((22)3Ra-Cl2) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone refractory prostate cancer. More than 1,000 patients have been included in clinical phase I-III tests showing significant reduction in alkaline...

  11. Application of bone scans for prostate cancer staging: Which guideline shows better result?

    Science.gov (United States)

    Chong, Ari; Hwang, Insang; Ha, Jung-min; Yu, Seong Hyeon; Hwang, Eu Chang; Yu, Ho Song; Kim, Sun Ouck; Jung, Seung-Il; Kang, Taek Won; Kwon, Dong Deuk; Park, Kwangsung

    2014-01-01

    Introduction: We evaluated the accuracy of current guidelines by analyzing bone scan results and clinical parameters of patients with prostate cancer to determine the optimal guideline for predicting bone metastasis. Methods: We retrospectively analyzed patients who were diagnosed with prostate cancer and who underwent a bone scan. Bone metastasis was confirmed by bone scan results with clinical and radiological follow-up. Serum prostate-specific antigen, Gleason score, percent of positive biopsy core, clinical staging and bone scan results were analyzed. We analyzed diagnostic performance in predicting bone metastasis of the guidelines of the European Association of Urology (EAU), American Urological Association (AUA), and the National Comprehensive Cancer Network (NCCN) guidelines as well as Briganti’s classification and regression tree (CART). We also compared the percent of positive biopsy core between patients with and without bone metastases. Results: A total 167 of 806 patients had bone metastases. Receiver operating curve analysis revealed that the AUA and EAU guidelines were better for detecting bone metastases than were Briganti’s CART and NCCN. No significant difference was observed between AUA and EAU guidelines. Patients with bone metastases had a higher percent positive core than did patients without metastasis (the cut-off value >55.6). Conclusion: The EAU and AUA guidelines showed better results than did Briganti’s CART and NCCN for predicting bone metastasis in the enrolled patients. A bone scan is strongly recommended for patients who have a higher percent positive core and who meet the EAU and AUA guidelines. PMID:25210554

  12. Prostate Cancer Metastases Alter Bone Mineral and Matrix Composition Independent of Effects on Bone Architecture in Mice A Quantitative Study Using microCT and Raman Spectroscopy

    Science.gov (United States)

    Bi, Xiaohong; Sterling, Julie A.; Merkel, Alyssa R.; Perrien, Daniel S.; Nyman, Jeffry; Mahadevan-Jansen, Anita

    2013-01-01

    Prostate cancer is the most common primary tumor and the second leading cause of cancer-related deaths in men in the United States. Prostate cancer bone metastases are characterized by abnormal bone remodeling processes and result in a variety of skeletal morbidities. Prevention of skeletal complications is a crucial element in prostate cancer management. This study investigated prostate cancer-induced alterations in the molecular composition and morphological structure of metastasis-bearing bones in a mouse model of prostate cancer using Raman spectroscopy and micro-computed tomography (microCT). LNCaP C4-2B prostate cancer cells were injected into the right tibiae of 5-week old male SCID mice. Upon sacrifice at 8 weeks post tumor inoculation, two out of the ten tumor-bearing tibiae showed only osteoblastic lesions in the radiographs, 4 osteolytic lesions only and 4 mixed with osteoblastic and osteolytic lesions.. Carbonate substitution was significantly increased while there was a marked reduction in the level of collagen mineralization, mineral crystallinity, and carbonate:matrix ratio in the cortex of the intact tumor-bearing tibiae compared to contralateral controls. MicroCT analysis revealed a significant reduction in bone volume/total volume, trabecular number and trabecular thickness, as well as significant increase in bone surface/volume ratio in tibiae with osteolytic lesions, suggesting active bone remodeling and bone loss. None of the changes in bone compositional properties were correlated with lesion area from radiographs or the changes in bone architecture from microCT. This study indicates that LNCaP C4-2B prostate cancer metastases alter bone tissue composition independent of changes in architecture, and altered bone quality may be an important contributor to fracture risk in these patients. Raman spectroscopy may provide a new avenue of investigation into interactions between tumor and bone microenvironment. PMID:23867219

  13. Management of bone metastases in refractory prostate cancer – role of denosumab

    Directory of Open Access Journals (Sweden)

    Paller CJ

    2012-09-01

    Full Text Available Channing J Paller,1 Michael A Carducci,1 George K Philips21Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 2Georgetown Lombardi Comprehensive Cancer Center, Washington DC, USAAbstract: This article reviews the problem of bone disease in prostate cancer and the evolving role of the novel agent denosumab, a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor-ΚB ligand, in suppressing bone resorption and offering bone protection in this disease. Prostate cancer frequently metastasizes to bone, and additionally its treatment with androgen deprivation leads to accelerated bone loss resulting in clinically relevant skeletal complications associated with disabling symptoms. Among the bone-targeting therapeutic strategies investigated for the prevention of bone complications, the potent bisphosphonate zoledronic acid has been the most widely used agent for bone protection in the past decade. Denosumab is the first among a new class of osteoclast-targeting agents to show superior efficacy in several clinical scenarios in both prostate and breast cancer, as well as in osteoporosis, but the focus of this review will be on its role in prostate cancer. The safety and efficacy of denosumab versus zoledronic acid was established in a randomized trial, demonstrating a delay in skeletal-related events in metastatic castration-resistant prostate cancer patients. This study led to the approval of denosumab in the US. The chief risks of denosumab were hypocalcemia and osteonecrosis of the jaw. Denosumab was also approved for fracture risk reduction in patients on androgen-deprivation therapy for nonmetastatic prostate cancer. Although denosumab extended bone metastasis-free survival in a Phase III trial in men with castration-resistant nonmetastatic prostate cancer to a statistically significant degree, a Food and Drug Administration committee found that the effect was not sufficiently clinically

  14. Do all patients with newly diagnosed prostate cancer need staging radionuclide bone scan? a retrospective study

    Directory of Open Access Journals (Sweden)

    Mohammed A. Al-Ghazo

    2010-12-01

    Full Text Available PURPOSE: Define a group of patients with newly diagnosed prostate cancer, whose risk of bone metastasis is low enough to omit a bone scan staging study. MATERIALS AND METHODS: From 2003 to 2009, the medical records of patients who were newly diagnosed with prostate cancer were retrospectively reviewed. The data collected included: age, digital rectal examination, serum prostate specific antigen (PSA, Gleason score, clinical T stage, and bone isotope scan. Patients were divided into two groups according to the results of bone isotope scan; positive group and negative group. A univariate and multivariate binary logistic regression was used to analyze the results. RESULTS: Of the 106 patients, 98 had a complete data collection and were entered into the study. The median age of the patients was 70.5 years and patients with a positive bone scan was 74 years, significantly higher than for patients with negative scans (69 years (p = 0.02. Bone metastasis was detected in 39 cases (39.7%. In all patients with clinical T1-2 stage, a Gleason score of 20 ng/mL and Gleason score (> 7 were independently predictive of positive bone scan, while clinical stage was not. CONCLUSION: Staging bone scans can be omitted in patients with a PSA level of = 20 ng/mL, and Gleason score < 8. Our results suggest that by considering the Gleason score and PSA, a larger proportion of patients with prostate cancer could avoid a staging bone scan.

  15. [Disseminated carcinomatosis of the bone marrow in two patients with prostate cancer].

    Science.gov (United States)

    Kato, Takuma; Yamamoto, Norihito; Matsuoka, Yuuki; Kuwata, Yoshihiro; Taoka, Teruhisa; Kazuki, Naomi; Kushida, Yoshio; Kakehi, Yoshiyuki

    2011-01-01

    Disseminated carcinomatosis of the bone marrow is caused by metastasis to the bone marrow and can cause disseminated intravascular coagulation (DIC), leucoerythroblastosis, and microangiopathic hemolytic anemia (MHA). The prognosis of this syndrome is poor. We report herein two rare cases of disseminated carcinomatosis of the bone marrow in association with prostate cancer. Case 1 involved a 61-year-old man admitted to our department with elevated prostate-specific antigen (PSA) levels. Prostate biopsy revealed prostate cancer, and imaging studies were performed. Under a diagnosis of prostate cancer (T3N1Mx), the patient was treated using hormonotherapy, but died 2 months after admission due to gastrointestinal bleeding of unknown cause, refractory DIC, and cachexia. Bone marrow biopsy after his death revealed metastasis of the prostate cancer to the bone marrow. Case 2 involved a 68-year-old man admitted to our department with gross hematuria. Cystoscopy revealed non-papillary tumor in the prostatic urethra. Transurethral biopsy was performed and histology identified prostate cancer. Treatment was initiated with hormonotherapy and zoledronate. After 8 months, he complained of general fatigue and blood testing identified anemia and thrombocytopenia. Bone marrow biopsy revealed adenocarcinoma in the bone marrow. Alternative androgen therapy and chemotherapy with docetaxel was started, and the patient recovered from pancytopenia and general fatigue.

  16. MO-G-17A-03: MR-Based Cortical Bone Segmentation for PET Attenuation Correction with a Non-UTE 3D Fast GRE Sequence

    Energy Technology Data Exchange (ETDEWEB)

    Ai, H; Pan, T [The University of Texas MD Anderson Cancer Center, Houston, TX (United States); The University of Texas Graduate School of Biomedical Science, Houston, TX (United States); Hwang, K [GE Healthcare, Houston, TX (United States)

    2014-06-15

    Purpose: To determine the feasibility of identifying cortical bone on MR images with a short-TE 3D fast-GRE sequence for attenuation correction of PET data in PET/MR. Methods: A water-fat-bone phantom was constructed with two pieces of beef shank. MR scans were performed on a 3T MR scanner (GE Discovery™ MR750). A 3D GRE sequence was first employed to measure the level of residual signal in cortical bone (TE{sub 1}/TE{sub 2}/TE{sub 3}=2.2/4.4/6.6ms, TR=20ms, flip angle=25°). For cortical bone segmentation, a 3D fast-GRE sequence (TE/TR=0.7/1.9ms, acquisition voxel size=2.5×2.5×3mm{sup 3}) was implemented along with a 3D Dixon sequence (TE{sub 1}/TE{sub 2}/TR=1.2/2.3/4.0ms, acquisition voxel size=1.25×1.25×3mm{sup 3}) for water/fat imaging. Flip angle (10°), acquisition bandwidth (250kHz), FOV (480×480×144mm{sup 3}) and reconstructed voxel size (0.94×0.94×1.5mm{sup 3}) were kept the same for both sequences. Soft tissue and fat tissue were first segmented on the reconstructed water/fat image. A tissue mask was created by combining the segmented water/fat masks, which was then applied on the fast-GRE image (MRFGRE). A second mask was created to remove the Gibbs artifacts present in regions in close vicinity to the phantom. MRFGRE data was smoothed with a 3D anisotropic diffusion filter for noise reduction, after which cortical bone and air was separated using a threshold determined from the histogram. Results: There is signal in the cortical bone region in the 3D GRE images, indicating the possibility of separating cortical bone and air based on signal intensity from short-TE MR image. The acquisition time for the 3D fast-GRE sequence was 17s, which can be reduced to less than 10s with parallel imaging. The attenuation image created from water-fat-bone segmentation is visually similar compared to reference CT. Conclusion: Cortical bone and air can be separated based on intensity in MR image with a short-TE 3D fast-GRE sequence. Further research is required

  17. Current Studies of Acupuncture in Cancer-Induced Bone Pain Animal Models

    OpenAIRE

    Ryu, Hee Kyoung; Baek, Yong-Hyeon; Park, Yeon-Cheol; Seo, Byung-Kwan

    2014-01-01

    Acupuncture is generally accepted as a safe and harmless treatment option for alleviating pain. To explore the pain mechanism, numerous animal models have been developed to simulate specific human pain conditions, including cancer-induced bone pain (CIBP). In this study, we analyzed the current research methodology of acupuncture for the treatment of CIBP. We electronically searched the PubMed database for animal studies published from 2000 onward using these search terms: (bone cancer OR can...

  18. High-fat diet enhances and plasminogen activator inhibitor-1 deficiency attenuates bone loss in mice with Lewis Lung carcinoma

    Science.gov (United States)

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (PAI-1-/-) on bone structure in mice bearing Lewis lung carcinoma (LLC) in lungs. Reduction in bone volume fraction (BV/TV) by 22% and 21%, trabecular number (Tb.N) by 8% and 4% and bone mineral de...

  19. Targeting Bone Metabolism in Patients with Advanced Prostate Cancer: Current Options and Controversies

    Directory of Open Access Journals (Sweden)

    Tilman Todenhöfer

    2015-01-01

    Full Text Available Maintaining bone health remains a clinical challenge in patients with prostate cancer (PC who are at risk of developing metastatic bone disease and increased bone loss due to hormone ablation therapy. In patients with cancer-treatment induced bone loss (CTIBL, antiresorptive agents have been shown to improve bone mineral density (BMD and to reduce the risk of fractures. For patients with bone metastases, both zoledronic acid and denosumab delay skeletal related events (SREs in the castration resistant stage of disease. Novel agents targeting the Wnt inhibitors dickkopf-1 and sclerostin are currently under investigation for the treatment of osteoporosis and malignant bone disease. New antineoplastic drugs such as abiraterone, enzalutamide, and Radium-223 are capable of further delaying SREs in patients with advanced PC. The benefit of antiresorptive treatment for patients with castration sensitive PC appears to be limited. Recent trials on the use of zoledronic acid for the prevention of bone metastases failed to be successful, whereas denosumab delayed the occurrence of bone metastases by a median of 4.1 months. Currently, the use of antiresorptive drugs to prevent bone metastases still remains a field of controversies and further trials are needed to identify patient subgroups that may profit from early therapy.

  20. Bone mineral density deficits in childhood cancer survivors: Pathophysiology, prevalence, screening, and management

    Directory of Open Access Journals (Sweden)

    Min Jae Kang

    2013-02-01

    Full Text Available As chemotherapy and other sophisticated treatment strategies evolve and the number of survivors of long-term childhood cancer grows, the long-term complications of treatment and the cancer itself are becoming ever more important. One of the most important but often neglected complications is osteoporosis and increased risk of fracture during and after cancer treatment. Acquisition of optimal peak bone mass and strength during childhood and adolescence is critical to preventing osteoporosis later in life. However, most childhood cancer patients have multiple risk factors for bone mineral loss. Cancer itself, malnutrition, decreased physical activity during treatment, chemotherapeutic agents such as steroids, and radiotherapy cause bone mineral deficit. Furthermore, complications such as growth hormone deficiency and musculoskeletal deformity have negative effects on bone metabolism. Low bone mineral density is associated with fractures, skeletal deformity, pain, and substantial financial burden not only for childhood cancer survivors but also for public health care systems. Thus, it is important to monitor bone health in these patients and minimize their risk of developing osteoporosis and fragility fractures later in life.

  1. Inhibition of the RANK/RANKL signaling with osteoprotegerin prevents castration-induced acceleration of bone metastasis in castration-insensitive prostate cancer.

    Science.gov (United States)

    Takayama, Koichiro; Inoue, Takamitsu; Narita, Shintaro; Maita, Shinya; Huang, Mingguo; Numakura, Kazuyuki; Tsuruta, Hiroshi; Saito, Mitsuru; Maeno, Atsushi; Satoh, Shigeru; Tsuchiya, Norihiko; Habuchi, Tomonori

    2017-07-01

    Androgen deprivation therapy (ADT) for patients with metastatic or locally advanced prostate cancer reduces bone mineral density by stimulating receptor activator of nuclear factor kappa-B (RANK) signaling in osteoclasts. The involvement of the RANK/RANKL signaling in ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer was examined in a murine model using osteoprotegerin (OPG). Male Balb/c nude mice were divided into three groups: the non-castration, castration, and castration + OPG groups. PC-3M-luc-C6 was injected into the left ventricle of the mice. Recombinant OPG was injected intravenously twice weekly in the castration + OPG group. In-vivo imaging system (IVIS ® ) determined that the prevalence and photon counts of bone metastasis in the castration group were significantly higher than that in the non-castration and castration + OPG groups. The mean number of RANKL-positive osteoblasts and the mean serum RANKL level in the castration group were significantly higher than those in the non-castration group. RANKL-enhanced activation of osteoclasts was attenuated in the castration + OPG group. These results suggest that the mechanisms of RANK/RANKL signaling are involved in the ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Scutellarein inhibits cancer cell metastasis in vitro and attenuates the development of fibrosarcoma in vivo.

    Science.gov (United States)

    Shi, Xiujuan; Chen, Guangfeng; Liu, Xiaoqiang; Qiu, Yu; Yang, Shuzhang; Zhang, Yan; Fang, Xuexun; Zhang, Chen; Liu, Xiaoqing

    2015-01-01

    Fibrosarcoma is an aggressive and highly metastatic cancer of the connective tissue, for which effective therapeutic methods are limited. Recently, there has been a renewed interest in small molecular compounds from natural products in the treatment of cancer. In the present study, we investigated the compound, scutellarein, extracted from the perennial herb Scutellaria lateriflora, and it was found to possess anticancer potential. Cell proliferation assay and cell cycle analysis revealed that the proliferation rate of HT1080 human fibrosarcoma cells was significantly suppressed by treatment with scutellarein through the induction of apoptosis. Moreover, an in vivo experiment using Balb/c nude mice revealed that the volume and weight of the tumors were markedly reduced following treatment with scutellarein. We also analyzed the effects of scutellarein on the markers of metastasis, using the HT1080 cells. The results indicated that scutellarein potently inhibited cell migration, invasion and the expression and activity of matrix metalloproteinase (MMP)-2, -9 and -14. Furthermore, MMP activation and cell survival were suppressed due to the scutellarein-mediated downregulation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation. In conclusion, our data suggest that scutellarein has the ability to attenuate the development of fibrosarcoma and inhibit cancer cell metastasis.

  3. Fulvic Acid Attenuates Resistin-Induced Adhesion of HCT-116 Colorectal Cancer Cells to Endothelial Cells.

    Science.gov (United States)

    Huang, Wen-Shih; Yang, Jen-Tsung; Lu, Chien-Chang; Chang, Shun-Fu; Chen, Cheng-Nan; Su, Yu-Ping; Lee, Ko-Chao

    2015-12-09

    A high level of serum resistin has recently been found in patients with a number of cancers, including colorectal cancer (CRC). Hence, resistin may play a role in CRC development. Fulvic acid (FA), a class of humic substances, possesses pharmacological properties. However, the effect of FA on cancer pathophysiology remains unclear. The aim of this study was to investigate the effect of resistin on the endothelial adhesion of CRC and to determine whether FA elicits an antagonistic mechanism to neutralize this resistin effect. Human HCT-116 (p53-negative) and SW-48 (p53-positive) CRC cells and human umbilical vein endothelial cells (HUVECs) were used in the experiments. Treatment of both HCT-116 and SW-48 cells with resistin increases the adhesion of both cells to HUVECs. This result indicated that p53 may not regulate this resistin effect. A mechanistic study in HCT-116 cells further showed that this resistin effect occurs via the activation of NF-κB and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Co-treating cells with both FA and resistin revealed that FA significantly attenuated the resistin-increased NF-κB activation and ICAM-1/VCAM-1 expression and the consequent adhesion of HCT-116 cells to HUVECs. These results demonstrate the role of resistin in promoting HCT-116 cell adhesion to HUVECs and indicate that FA might be a potential candidate for the inhibition of the endothelial adhesion of CRC in response to resistin.

  4. [Bone-specific therapy with radium-223 dichloride : Castration-resistant prostate cancer with symptomatic bone metastases].

    Science.gov (United States)

    Tauber, R; Gschwend, J; Scheidhauer, K; Eiber, M; Krönke, M

    2017-01-01

    Radium-223 dichloride (Xofigo®, Alpharadin) is approved for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. As a calcium mimetic, it is integrated into osteoplastic bone lesions and emits alpha particles with high energy which leads to local destruction of tumor cells. In the 2013 published ALSYMPCA trial, a significant advantage for overall survival and quality of life in comparison to placebo was found. Recent data suggest an increased potential in combination with next generation hormonal treatment.

  5. Involvement of chemokine CXCL11 in the development of morphine tolerance in rats with cancer-induced bone pain.

    Science.gov (United States)

    Guo, Genhua; Peng, Yawen; Xiong, Bingrui; Liu, Daiqiang; Bu, Huilian; Tian, Xuebi; Yang, Hui; Wu, Zhen; Cao, Fei; Gao, Feng

    2017-05-01

    Morphine is viewed as one of the classical treatments for intractable pain, but its role is limited by side effects, including analgesic tolerance. A few chemokines have been reported to be engaged in the mechanisms of morphine tolerance. However, the exact roles of CXC chemokine 11 (CXCL11) in chronic morphine tolerance remain unknown. In this study, Walker 256 mammary gland carcinoma cells were inoculated into the tibia of rats to provoke cancer-induced bone pain. Then, morphine was intrathecally administered twice daily for seven consecutive days to induce drug tolerance. We found that the level of CXCL11 in lumbar spinal cord was increased during the development of morphine tolerance in cancer-induced bone pain rats. Meanwhile, CXCL11 was co-localized with markers of astrocytes and neurons in the spinal cord. Inhibition of CXCL11 by neutralizing antibodies could remarkably attenuate the degree of morphine tolerance and decrease the activation of astrocytes. Moreover, blocking astrocyte activation by d, l-Fluorocitric acid could distinctly alleviate morphine tolerance and reduce the expression of CXCL11. Finally, morphine stimulation could induce the release of CXCL11 by cultured astrocytes and neurons in vitro. In summary, our results provide evidence that spinal CXCL11 plays a powerful modulatory role in the development of morphine tolerance through cross-talking between astrocytes and neurons. Read the Review series "Pain". © 2016 International Society for Neurochemistry.

  6. Osteoclasts Are Active in Bone Forming Metastases of Prostate Cancer Patients

    Science.gov (United States)

    Gorassini, Eva; Grimaldi, Anastasia; Bonello, Lisa; Fiori, Cristian; Delsedime, Luisa; Tizzani, Alessandro; De Libero, Alfredo; Isaia, Giancarlo; Ferracini, Riccardo

    2008-01-01

    Background Bone forming metastases are a common and disabling consequence of prostate cancer (CaP). The potential role of osteoclast activity in CaP bone metastases is not completely explained. In this study, we investigated ex vivo whether the osteolytic activity is present and how it is ruled in CaP patients with bone forming metastases. Methodology Forty-six patients affected by newly diagnosed CaP and healthy controls were enrolled. At diagnosis, 37 patients had a primary tumour only, while 9 had primary tumour and concomitant bone forming metastases. In all patients there was no evidence of metastasis to other non-bone sites. For all patients and controls we collected blood and urinary samples. We evaluated patients' bone homeostasis; we made peripheral blood mononuclear cell (PBMC) cultures to detect in vitro osteoclastogenesis; we dosed serum expression of molecules involved in cancer induced osteoclatogenesis, such as RANKL, OPG, TNF-alpha, DKK-1 and IL-7. By Real-Time PCR, we quantified DKK-1 and IL-7 gene expression on micro-dissected tumour and healthy tissue sections. Principal Findings CaP bone metastatic patients showed bone metabolism disruption with increased bone resorption and formation compared to non-bone metastatic patients and healthy controls. The CaP PBMC cultures showed an enhanced osteoclastogenesis in bone metastatic patients, due to an increase of RANKL/OPG ratio. We detected increased DKK-1 serum levels and tissue gene expression in patients compared to controls. IL-7 resulted high in patients' sera, but its tissue gene expression was comparable in patients and controls. Conclusions We demonstrated ex vivo that osteoclastogenesis is an active mechanism in tumour nesting of bone forming metastatic cancer and that serum DKK-1 levels are increased in CaP patients, suggesting to deeply investigate its role as tumour marker. PMID:18978943

  7. Genomic Copy Number Imbalances Associated with Bone and Non-bone Metastasis of Early-Stage Breast Cancer

    Science.gov (United States)

    Liu, Yanhong; Zhou, Renke; Baumbusch, Lars O.; Tsavachidis, Spyros; Brewster, Abenaa M.; Do, Kim-Anh; Sahin, Aysegul; Hortobagyi, Gabriel N.; Taube, Joseph H.; Mani, Sendurai A.; Aarøe, Jørgen; Wärnberg, Fredrik; Børresen-Dale, Anne-Lise; Mills, Gordon B.; Thompson, Patricia A.; Bondy, Melissa L.

    2014-01-01

    Purpose To identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis. Patients and Methods Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model. Results Gains at 1q41 and 1q42.12 and losses at 1p13.3, 8p22, and Xp11.3 were significantly associated with bone metastasis. Gains at 2p11.2, 3q21.3–22.2, 3q27.1, 10q23.1, and 14q13.2–3 and loss at 7q21.11 were associated with non-bone metastasis. To examine the joint effect of CNIs and clinical predictors, patients were stratified into three risk groups (low, intermediate, and high) based on the sum of predicted linear hazard ratios (HRs). For bone metastasis, the hazard (95% confidence interval) for the low-risk group was 0.32 (0.11–0.92) compared to the intermediate-risk group and 2.99 (1.74–5.11) for the high-risk group. For non-bone metastasis, the hazard for the low-risk group was 0.34 (0.17–0.66) and 2.33 (1.59–3.43) for the high-risk group. The prognostic value of loss at 8p22 for bone metastasis and gains at 10q23.1 for non-bone metastasis, and gain at 11q13.5 for both bone and non-bone metastases were externally validated in 335 breast tumors pooled from four independent cohorts. Conclusions Distinct CNIs are independently associated with bone and non-bone metastasis for early-stage breast cancer patients across cohorts. These data warrant consideration for tailoring surveillance and management of metastasis risk. PMID:24305980

  8. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, Rikke Rie; Nielsen, Christian K.; Nasser, Arafat

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice...... were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. Furthermore, acute treatment with the selective P2X7 receptor antagonist, A-438079, failed to alleviate pain-related behaviours in models of bone cancer pain...... with and without astrocyte activation (BALB/cJ or C3H mice inoculated with 4T1 mammary cancer cells or NCTC 2472 osteosarcoma cells, respectively), suggesting that astrocytic P2X7 receptors play a negligible role in bone cancer pain. The results support the hypothesis that bone cancer pain is a separate pain state...

  9. Bone Health in Patients with Breast Cancer: Recommendations from an Evidence-Based Canadian Guideline

    Directory of Open Access Journals (Sweden)

    Alexander H. G. Paterson

    2013-12-01

    Full Text Available Bone loss is common in patients with breast cancer. Bone modifying agents (BMAs, such as bisphosphonates and denosumab, have been shown to reverse or stabilize bone loss and may be useful in the primary and metastatic settings. The purpose of this review is to provide clear evidence-based strategies for the management of bone loss and its symptoms in breast cancer. A systematic review of clinical trials and meta-analyses published between 1996 and 2012 was conducted of MEDLINE and EMBASE. Reference lists were hand-searched for additional publications. Recommendations were developed based on the best available evidence. Zoledronate, pamidronate, clodronate, and denosumab are recommended for metastatic breast cancer patients; however, no one agent can be recommended over another. Zoledronate or any oral bisphosphonate and denosumab should be considered in primary breast cancer patients who are postmenopausal on aromatase inhibitor therapy and have a high risk of fracture and/or a low bone mineral density and in premenopausal primary breast cancer patients who become amenorrheic after therapy. No one agent can be recommended over another. BMAs are not currently recommended as adjuvant therapy in primary breast cancer for the purpose of improving survival, although a major Early Breast Cancer Cooperative Trialists’ Group meta-analysis is underway which may impact future practice. Adverse events can be managed with appropriate supportive care.

  10. Natural History of Malignant Bone Disease in Gastric Cancer: Final Results of a Multicenter Bone Metastasis Survey

    Science.gov (United States)

    Silvestris, Nicola; Pantano, Francesco; Ibrahim, Toni; Gamucci, Teresa; De Vita, Fernando; Di Palma, Teresa; Pedrazzoli, Paolo; Barni, Sandro; Bernardo, Antonio; Febbraro, Antonio; Satolli, Maria Antonietta; Bertocchi, Paola; Catalano, Vincenzo; Giommoni, Elisa; Comandone, Alessandro; Maiello, Evaristo; Riccardi, Ferdinando; Ferrara, Raimondo; Trogu, Antonio; Berardi, Rossana; Leo, Silvana; Bertolini, Alessandro; Angelini, Francesco; Cinieri, Saverio; Russo, Antonio; Pisconti, Salvatore; Brunetti, Anna Elisabetta; Azzariti, Amalia; Santini, Daniele

    2013-01-01

    Background Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature, few data on the natural history of bone disease in GC are available. Patients and Methods Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. Results Median time to bone metastasis was 8 months (CI 95%, 6.125–9.875 months) considering all included patients. Median number of SREs/patient was one. Less than half of the patients (31%) experienced at least one and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid before the first SRE, the median time to appearance of first SRE was significantly prolonged compared to control (7 months vs 4 months for control; P: 0.0005). Conclusions To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Indeed, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis. Taken together, these data may support the beneficial effects of ZOL in GC patients. PMID:24204569

  11. Natural history of malignant bone disease in gastric cancer: final results of a multicenter bone metastasis survey.

    Science.gov (United States)

    Silvestris, Nicola; Pantano, Francesco; Ibrahim, Toni; Gamucci, Teresa; De Vita, Fernando; Di Palma, Teresa; Pedrazzoli, Paolo; Barni, Sandro; Bernardo, Antonio; Febbraro, Antonio; Satolli, Maria Antonietta; Bertocchi, Paola; Catalano, Vincenzo; Giommoni, Elisa; Comandone, Alessandro; Maiello, Evaristo; Riccardi, Ferdinando; Ferrara, Raimondo; Trogu, Antonio; Berardi, Rossana; Leo, Silvana; Bertolini, Alessandro; Angelini, Francesco; Cinieri, Saverio; Russo, Antonio; Pisconti, Salvatore; Brunetti, Anna Elisabetta; Azzariti, Amalia; Santini, Daniele

    2013-01-01

    Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature, few data on the natural history of bone disease in GC are available. Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. Median time to bone metastasis was 8 months (CI 95%, 6.125-9.875 months) considering all included patients. Median number of SREs/patient was one. Less than half of the patients (31%) experienced at least one and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid before the first SRE, the median time to appearance of first SRE was significantly prolonged compared to control (7 months vs 4 months for control; P: 0.0005). To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Indeed, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis. Taken together, these data may support the beneficial effects of ZOL in GC patients.

  12. Natural history of malignant bone disease in gastric cancer: final results of a multicenter bone metastasis survey.

    Directory of Open Access Journals (Sweden)

    Nicola Silvestris

    Full Text Available BACKGROUND: Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC as disease-related survival improves. In literature, few data on the natural history of bone disease in GC are available. PATIENTS AND METHODS: Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs, and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. RESULTS: Median time to bone metastasis was 8 months (CI 95%, 6.125-9.875 months considering all included patients. Median number of SREs/patient was one. Less than half of the patients (31% experienced at least one and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid before the first SRE, the median time to appearance of first SRE was significantly prolonged compared to control (7 months vs 4 months for control; P: 0.0005. CONCLUSIONS: To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Indeed, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis. Taken together, these data may support the beneficial effects of ZOL in GC patients.

  13. Current role of bone scan with phosphonates in the follow-up of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Maffioli, Lorenzo; Florimonte, Luigia; Pagani, Luca; Butti, Ivana [Division of Nuclear Medicine, Ospedale ' ' A. Manzoni' ' , Via dell' Eremo 9/11, 23900, Lecco (Italy); Roca, Isabel [Division of Nuclear Medicine, Hospital Universitari Vall Hebron, 08035, Barcelona (Spain)

    2004-06-01

    A number of studies have demonstrated that bone scintigraphy has high sensitivity and efficacy in the early detection of bone metastases from several tumours, including breast cancer. Bone scintigraphy is the most definitive tool for diagnosing and monitoring metastatic spread of breast cancer. However, in the past decade there has been a wide debate on its impact on survival time, morbidity and quality of life. Worldwide economic restrictions and these studies have led to the adoption of an almost minimalist policy for breast cancer follow-up using evidence-based guidelines. The recommended breast cancer surveillance testing includes only a few procedures (history, physical and breast self-examination, patient education on symptoms, pelvic examination). The routine use of additional tests, such as blood cell count, tumour markers, liver ultrasonography, bone scan and chest X-rays, is not recommended. Accordingly, scintigraphy should be reserved for a limited number of patients. On the other hand, early diagnosis of bone involvement may reduce the risk of skeletal related events, thus leading to a significant improvement in quality of life. Furthermore, new drugs (e.g. bisphosphonates) can now delay the onset of bone metastasis and reduce the number of patients who experience skeletal complications. In conclusion, the evidence of the clinical usefulness of bone scintigraphy (to allow early planning of new treatments in advanced disease) has to be re-evaluated, possibly by large randomised prospective trials. (orig.)

  14. Silibinin attenuates ionizing radiation-induced pro-angiogenic response and EMT in prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Nambiar, Dhanya K. [Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi (India); School of Environmental Sciences, Jawaharlal Nehru University, New Delhi (India); Rajamani, Paulraj [School of Environmental Sciences, Jawaharlal Nehru University, New Delhi (India); Singh, Rana P., E-mail: rana_singh@mail.jnu.ac.in [Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi (India); School of Life Sciences, Central University of Gujarat, Gandhinagar (India)

    2015-01-02

    Graphical abstract: Potential model showing mechanism of silibinin-mediated attenuation of IR-induced angiogenic phenotype and EMT in tumor cells. Silibinin counters radiation induced invasive and migratory phenotype of cancer cells by down-regulating mitogenic pathways activated by IR, leading to inhibition of molecules including VEGF, iNOS, MMPs and N-cadherin. Silibinin also reverses IR mediated E-cadherin down-regulation, inhibiting EMT in tumor cells. Silibinin also radiosensitizes endothelial cells, reduces capillary tube formation by targeting various pro-angiogenic molecules. Further, silibinin may inhibit autocrine and paracrine signaling between tumor and endothelial cells by decreasing the levels of VEGF and other signaling molecules activated in response to IR. - Highlights: • Silibinin radiosensitizes endothelial cells. • Silibinin targets ionization radiation (IR)-induced EMT in PCa cells. • Silibinin is in phase II clinical trial in PCa patients, hence clinically relevant. - Abstract: Radiotherapy of is well established and frequently utilized in prostate cancer (PCa) patients. However, recurrence following therapy and distant metastases are commonly encountered problems. Previous studies underline that, in addition to its therapeutic effects, ionizing radiation (IR) increases the vascularity and invasiveness of surviving radioresistant cancer cells. This invasive phenotype of radioresistant cells is an upshot of IR-induced pro-survival and mitogenic signaling in cancer as well as endothelial cells. Here, we demonstrate that a plant flavonoid, silibinin can radiosensitize endothelial cells by inhibiting expression of pro-angiogenic factors. Combining silibinin with IR not only strongly down-regulated endothelial cell proliferation, clonogenicity and tube formation ability rather it strongly (p < 0.001) reduced migratory and invasive properties of PCa cells which were otherwise marginally affected by IR treatment alone. Most of the pro

  15. Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children

    OpenAIRE

    Chiaming Fan; Kristen R. Georgiou; King, Tristan J.; Xian, Cory J.

    2011-01-01

    The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX), the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical obs...

  16. Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children

    Directory of Open Access Journals (Sweden)

    Chiaming Fan

    2011-01-01

    Full Text Available The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX, the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy-induced skeletal damage. These models revealed that high-dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy-induced skeletal toxicities.

  17. Thermographic image analysis as a pre-screening tool for the detection of canine bone cancer

    Science.gov (United States)

    Subedi, Samrat; Umbaugh, Scott E.; Fu, Jiyuan; Marino, Dominic J.; Loughin, Catherine A.; Sackman, Joseph

    2014-09-01

    Canine bone cancer is a common type of cancer that grows fast and may be fatal. It usually appears in the limbs which is called "appendicular bone cancer." Diagnostic imaging methods such as X-rays, computed tomography (CT scan), and magnetic resonance imaging (MRI) are more common methods in bone cancer detection than invasive physical examination such as biopsy. These imaging methods have some disadvantages; including high expense, high dose of radiation, and keeping the patient (canine) motionless during the imaging procedures. This project study identifies the possibility of using thermographic images as a pre-screening tool for diagnosis of bone cancer in dogs. Experiments were performed with thermographic images from 40 dogs exhibiting the disease bone cancer. Experiments were performed with color normalization using temperature data provided by the Long Island Veterinary Specialists. The images were first divided into four groups according to body parts (Elbow/Knee, Full Limb, Shoulder/Hip and Wrist). Each of the groups was then further divided into three sub-groups according to views (Anterior, Lateral and Posterior). Thermographic pattern of normal and abnormal dogs were analyzed using feature extraction and pattern classification tools. Texture features, spectral feature and histogram features were extracted from the thermograms and were used for pattern classification. The best classification success rate in canine bone cancer detection is 90% with sensitivity of 100% and specificity of 80% produced by anterior view of full-limb region with nearest neighbor classification method and normRGB-lum color normalization method. Our results show that it is possible to use thermographic imaging as a pre-screening tool for detection of canine bone cancer.

  18. Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

    Directory of Open Access Journals (Sweden)

    Xiaoyan Jiao

    2017-12-01

    Full Text Available Background/Aims: Cisplatin-induced acute kidney injury (AKI involves damage to tubular cells via excess reactive oxygen species (ROS generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC-derived conditioned medium (CM against cisplatin-induced AKI. Methods: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. Results: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data

  19. Radiation therapy for metastatic lesions from breast cancer. Breast cancer metastasis to bone

    Energy Technology Data Exchange (ETDEWEB)

    Hayashi, Shinya; Hoshi, Hiroaki [Gifu Univ. (Japan). School of Medicine

    2000-10-01

    This paper summarizes radiation therapy in the treatment of bone metastases from breast cancer. Bone metastasis occurs in approximately 70% of breast cancer patients, and the goals of radiation therapy for bone metastasis are: palliation of pain, prevention and treatment of neuropathic symptoms, and prevention of pathologic fractures. The prognosis of bone metastasis from breast cancer is known to be better than that of bone metastasis from other solid tumors. Local-field radiation, hemibody (or wide-field) radiation, and systemic radionuclide treatment are the major methods of radiation therapy for pain palliation. Although many studies have shown that breast cancer is more responsive to radiation therapy for pain palliation than other solid tumors, some studies found no significant difference. Local-field radiation therapy, which includes multi-fraction irradiation and single-fraction irradiation, is currently the most generally used method of radiotherapy for pain palliation. Pain palliation has been reported to be achieved in approximately 80% to 90% of patients treated with local-field external beam irradiation. Three types of multi-fraction irradiation therapy are administered depending on the prognosis: high-dose fraction irradiation (36-50 Gy/12-25 Fr/2.4-5 wk), short-course irradiation (20-30 Gy/10-15 Fr/2-3 wk), and ultra-short-course irradiation (15-25 Gy/2-5 Fr/1 wk). The most common irradiation schedule is 30 Gy/10 Fr/2 wk. Although many reports indicate no significant difference in pain palliation according to the dose, the percentage of patients who show a complete cure is significantly higher in those treated with doses of 30 Gy or more, and thus the total irradiation dose should be at least 30 Gy. High-dose fraction irradiation is indicated for patients with an expected survival time of 6 months or more while short-course or single-fraction irradiation is indicated for those with an expected survival time of 3 months or more. Single

  20. Utilization of bone densitometry for prediction and administration of bisphosphonates to prevent osteoporosis in patients with prostate cancer without bone metastases receiving antiandrogen therapy

    Science.gov (United States)

    Holt, Abby; Khan, Muhammad A; Gujja, Swetha; Govindarajan, Rangaswmy

    2015-01-01

    Background Prostate cancer subjects with prostate-specific antigen (PSA) relapse who are treated with androgen deprivation therapy (ADT) are recommended to have baseline and serial bone densitometry and receive bisphosphonates. The purpose of this community population study was to assess the utilization of bone densitometry and bisphosphonate therapy in men receiving ADT for non-metastatic prostate cancer. Methods A cohort study of men aged 65 years or older with non-metastatic incident diagnoses of prostate cancer was obtained from the Surveillance Epidemiology End Results (SEER)-linked Medicare claims between 2004 and 2008. Claims were used to assess prescribed treatment of ADT, bone densitometry, and bisphosphonates. Results A total of 30,846 incident prostate cancer cases receiving ADT and aged 65 years or older had no bone metastases; 87.3% (n=26,935) on ADT did not receive either bone densitometry or bisphosphonate therapy. Three percent (n=931) of the cases on ADT received bisphosphonate therapy without ever receiving bone densitometry, 8.8% (n=2,702) of the cases on ADT received bone densitometry without receiving intravenous bisphosphonates, while nearly 1% (0.90%, n=278) of the cases on ADT received both bone densitometry and bisphosphonates. Analysis showed treatment differed by patient characteristics. Conclusion Contrary to the recommendations, bone densitometry and bisphosphonate therapy are underutilized in men receiving ADT for non-metastatic prostate cancer. PMID:25565887

  1. RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth.

    Science.gov (United States)

    Yao, Ke; Peng, Cong; Zhang, Yuwen; Zykova, Tatyana A; Lee, Mee-Hyun; Lee, Sung-Young; Rao, Enyu; Chen, Hanyong; Ryu, Joohyun; Wang, Lei; Zhang, Yi; Gao, Ge; He, Wei; Ma, Wei-Ya; Liu, Kangdong; Bode, Ann M; Dong, Ziming; Li, Bing; Dong, Zigang

    2017-11-13

    Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNγ secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNγ in the RSK2 KO mice compared with the WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate Ifnγ gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNγ expression, because knockdown of RSK2 expression or overexpression of mutant T-bet reduces IFNγ mRNA expression. To verify the function of the phosphorylation sites, we overexpressed a constitutively active mutant T-bet (S498E/S502E) in bone marrow. Mutant T-bet restored the IFNγ mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for the inhibition of colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNγ signaling. Published under the PNAS license.

  2. Decibel attenuation of pulsed electromagnetic field (PEMF) in blood and cortical bone determined experimentally and from the theory of ohmic losses.

    Science.gov (United States)

    Zborowski, Maciej; Kligman, Boris; Midura, Ronald J; Wolfman, Alan; Patterson, Thomas E; Ibiwoye, Michael; Grabiner, Mark

    2006-06-01

    We studied the PEMF power attenuation in tissues representative of clinical applications (blood and cortical bone) to determine the amount of power available for PEMF purported biological effects. The experimental system consisted of a pair of nearly circular, parallel and coaxial coils separated by a distance of one coil diameter. The power attenuation was measured using a small search coil connected to a digital oscilloscope. The coils were powered by a voltage switch operating at two different frequencies (3.8 and 63 kHz) producing bursts of pulses (numbering 21 and 1619) and triggered at two different frequencies (1.5 and 15 Hz, respectively). The tissue samples were placed inside the coils so as to expose them to either transverse electric field (at the center of coils) or the transverse magnetic field (at the coil wire). The cylindrical coil geometry yielded closed-form expressions for power attenuation based on magnetic diffusion equation and ohmic losses due to bulk tissue magnetic permeability and electrical conductivity. The measured power attenuation at these PEMF frequencies of not more than one decibel (1 dB) was well explained by the theory for the 3.8 kHz but less so for the 63 kHz frequency PEMF. The results provide important insights regarding physical mechanism of weak PEMF power dissipation in tissues.

  3. Response of Bone Resorption Markers to Aristolochia longa Intake by Algerian Breast Cancer Postmenopausal Women.

    Science.gov (United States)

    Benarba, Bachir; Meddah, Boumedienne; Tir Touil, Aicha

    2014-01-01

    Aristolochia longa is widely used in traditional medicine in Algeria to treat breast cancer. The aim of the present study was to investigate the response of bone resorption markers to A. longa intake by Algerian breast cancer postmenopausal women. According to the A. longa intake, breast cancer patients were grouped into A. longa group (Al) (n = 54) and non-A. longa group (non-Al) (n = 24). 32 women constituted the control group. Bone resorption markers (from urine) pyridinoline (PYD) and deoxypyridinoline (DPD) were determined by HPLC. Serum and urinary creatinine, uric acid, and urea were measured. 1 g of A. longa intake resulted in significant rise of renal serum markers and a pronounced increase of bone resorption markers. The intake of A. longa roots is detrimental for kidney function and resulted in high bone resorption, maybe due to the reduction in renal function caused by the aristolochic acids contained in the roots.

  4. Dystrophic Cutaneous Calcification and Metaplastic Bone Formation due to Long Term Bisphosphonate Use in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ali Murat Tatlı

    2013-01-01

    Full Text Available Bisphosphonates are widely used in the treatment of breast cancer with bone metastases. We report a case of a female with breast cancer presented with a rash around a previous mastectomy site and a discharge lesion on her right chest wall in August 2010. Biopsy of the lesion showed dystrophic calcification and metaplastic bone formation. The patient’s history revealed a long term use of zoledronic acid for the treatment of breast cancer with bone metastasis. We stopped the treatment since we believed that the cutaneous dystrophic calcification could be associated with her long term bisphosphonate therapy. Adverse cutaneous events with bisphosphonates are very rare, and dystrophic calcification has not been reported previously. The dystrophic calcification and metaplastic bone formation in this patient are thought to be due to long term bisphosphonate usage.

  5. Response of Bone Resorption Markers to Aristolochia longa Intake by Algerian Breast Cancer Postmenopausal Women

    Directory of Open Access Journals (Sweden)

    Bachir Benarba

    2014-01-01

    Full Text Available Aristolochia longa is widely used in traditional medicine in Algeria to treat breast cancer. The aim of the present study was to investigate the response of bone resorption markers to A. longa intake by Algerian breast cancer postmenopausal women. According to the A. longa intake, breast cancer patients were grouped into A. longa group (Al (n=54 and non-A. longa group (non-Al (n=24. 32 women constituted the control group. Bone resorption markers (from urine pyridinoline (PYD and deoxypyridinoline (DPD were determined by HPLC. Serum and urinary creatinine, uric acid, and urea were measured. 1 g of A. longa intake resulted in significant rise of renal serum markers and a pronounced increase of bone resorption markers. The intake of A. longa roots is detrimental for kidney function and resulted in high bone resorption, maybe due to the reduction in renal function caused by the aristolochic acids contained in the roots.

  6. Retrospective study of predictors of bone metastasis in prostate cancer cases.

    Science.gov (United States)

    Ho, Christopher Chee Kong; Seong, Poh Keat; Zainuddin, Zulkifli Md; Abdul Manaf, Mohd Rizal; Parameswaran, Muhilan; Razack, Azad H A

    2013-01-01

    The purpose of this study was to identify clinical profiles of patients with low risk of having bone metastases, for which bone scanning could be safely eliminated. This retrospective cross sectional study looked at prostate cancer patients seen in the Urology Departments in 2 tertiary centres over the 11 year period starting from January 2000 to May 2011. Patient demographic data, levels of PSA at diagnosis, Gleason score for the biopsy core, T-staging as well as the lymph node status were recorded and analysed. 258 men were included. The mean age of those 90 men (34.9%) with bone metastasis was 69.2 ± 7.3 years. Logistic regression found that PSA level (P=0.000) at diagnosis and patient's nodal-stage (P=0.02) were the only two independent variables able to predict the probability of bone metastasis among the newly diagnosed prostate cancer patients. Among those with a low PSA level less than 20 ng/ml, and less than 10 ng/ml, bone metastasis were detected in 10.3% (12 out of 117) and 9.7% (7 out of 72), respectively. However, by combining PSA level of 10 ng/ml or lower, and nodal negative as the two criteria to predict negative bone scan, a relatively high negative predictive value of 93.8% was obtained. The probability of bone metastasis in prostate cancer can be calculated with this formula: -1.069+0.007(PSA value, ng/ml) +1.021(Nodal status, 0 or 1)=x Probability of bone metastasis=2.718 x/1+2.718 x. Newly diagnosed prostate cancer patients with a PSA level of 10 ng/ml or lower and negative nodes have a very low risk of bone metastasis (negative predictive value 93.8%) and therefore bone scans may not be necessary.

  7. Whole-Body PET/MR Imaging: Quantitative Evaluation of a Novel Model-Based MR Attenuation Correction Method Including Bone.

    Science.gov (United States)

    Paulus, Daniel H; Quick, Harald H; Geppert, Christian; Fenchel, Matthias; Zhan, Yiqiang; Hermosillo, Gerardo; Faul, David; Boada, Fernando; Friedman, Kent P; Koesters, Thomas

    2015-07-01

    In routine whole-body PET/MR hybrid imaging, attenuation correction (AC) is usually performed by segmentation methods based on a Dixon MR sequence providing up to 4 different tissue classes. Because of the lack of bone information with the Dixon-based MR sequence, bone is currently considered as soft tissue. Thus, the aim of this study was to evaluate a novel model-based AC method that considers bone in whole-body PET/MR imaging. The new method ("Model") is based on a regular 4-compartment segmentation from a Dixon sequence ("Dixon"). Bone information is added using a model-based bone segmentation algorithm, which includes a set of prealigned MR image and bone mask pairs for each major body bone individually. Model was quantitatively evaluated on 20 patients who underwent whole-body PET/MR imaging. As a standard of reference, CT-based μ-maps were generated for each patient individually by nonrigid registration to the MR images based on PET/CT data. This step allowed for a quantitative comparison of all μ-maps based on a single PET emission raw dataset of the PET/MR system. Volumes of interest were drawn on normal tissue, soft-tissue lesions, and bone lesions; standardized uptake values were quantitatively compared. In soft-tissue regions with background uptake, the average bias of SUVs in background volumes of interest was 2.4% ± 2.5% and 2.7% ± 2.7% for Dixon and Model, respectively, compared with CT-based AC. For bony tissue, the -25.5% ± 7.9% underestimation observed with Dixon was reduced to -4.9% ± 6.7% with Model. In bone lesions, the average underestimation was -7.4% ± 5.3% and -2.9% ± 5.8% for Dixon and Model, respectively. For soft-tissue lesions, the biases were 5.1% ± 5.1% for Dixon and 5.2% ± 5.2% for Model. The novel MR-based AC method for whole-body PET/MR imaging, combining Dixon-based soft-tissue segmentation and model-based bone estimation, improves PET quantification in whole-body hybrid PET/MR imaging, especially in bony tissue and

  8. Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone.

    Directory of Open Access Journals (Sweden)

    Renjie Jin

    Full Text Available Patients with advanced prostate cancer almost invariably develop osseous metastasis. Although many studies indicate that the activation of NF-κB signaling appears to be correlated with advanced cancer and promotes tumor metastasis by influencing tumor cell migration and angiogenesis, the influence of altered NF-κB signaling in prostate cancer cells within boney metastatic lesions is not clearly understood. While C4-2B and PC3 prostate cancer cells grow well in the bone, LNCaP cells are difficult to grow in murine bone following intraskeletal injection. Our studies show that when compared to LNCaP, NF-κB activity is significantly higher in C4-2B and PC3, and that the activation of NF-κB signaling in prostate cancer cells resulted in the increased expression of the osteoclast inducing genes PTHrP and RANKL. Further, conditioned medium derived from NF-κB activated LNCaP cells induce osteoclast differentiation. In addition, inactivation of NF-κB signaling in prostate cancer cells inhibited tumor formation in the bone, both in the osteolytic PC3 and osteoblastic/osteoclastic mixed C4-2B cells; while the activation of NF-κB signaling in LNCaP cells promoted tumor establishment and proliferation in the bone. The activation of NF-κB in LNCaP cells resulted in the formation of an osteoblastic/osteoclastic mixed tumor with increased osteoclasts surrounding the new formed bone, similar to metastases commonly seen in patients with prostate cancer. These results indicate that osteoclastic reaction is required even in the osteoblastic cancer cells and the activation of NF-κB signaling in prostate cancer cells increases osteoclastogenesis by up-regulating osteoclastogenic genes, thereby contributing to bone metastatic formation.

  9. Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung Cancer Patients with Bone Metastasis

    DEFF Research Database (Denmark)

    Fabian, Katalin; Puskás, Rita; Kakuk, Tímea

    2017-01-01

    Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for chan...

  10. Trolox inhibits osteolytic bone metastasis of breast cancer through both PGE2-dependent and independent mechanisms.

    Science.gov (United States)

    Lee, Jong-Ho; Kim, Bongjun; Jin, Won Jong; Kim, Jung-Wook; Kim, Hong-Hee; Ha, Hyunil; Lee, Zang Hee

    2014-09-01

    Bone is a preferred site of metastasis from breast cancer, and increased osteoclast activity is implicated in breast cancer outgrowth in the bone microenvironment. Our previous observation of an anti-osteoclastic activity of Trolox, a vitamin E analog, led us to investigate whether Trolox inhibits bone metastasis and osteolysis caused by breast cancer. Administration of Trolox markedly inhibited osteolytic bone metastasis in an experimental metastasis model by intracardiac injection of 4T1 breast cancer cells. Trolox inhibited proliferation of 4T1 cells in the bone marrow but not in the mammary fat pad. In addition, Trolox could reduce tumor burden, osteolysis, and prostaglandin E2 (PGE2) production induced by direct inoculation of 4T1 cells into the marrow cavity of the tibia. Trolox decreased the migratory and invasive activities of 4T1 cells via PGE2-dependent and independent mechanisms. It also inhibited the ability of 4T1 cells to stimulate the expression of receptor activator of nuclear factor-κB ligand (RANKL), a key cytokine for osteoclast differentiation factor, in osteoblasts. In addition, Trolox suppressed RANKL expression in osteoblasts induced by soluble factors from 4T1 cells. Furthermore, Trolox suppressed 4T1 cell-induced osteoclast differentiation in the co-culture of bone marrow cells and osteoblasts via both PGE2-dependent and independent mechanisms. Taken together, these results suggest that Trolox inhibits breast cancer cell-induced osteoclast differentiation and the invasive behavior of cancer cells through PGE2-dependent and independent mechanisms, thereby suppressing osteolytic bone metastasis of breast cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. At the crossroads: EGFR and PTHrP signaling in cancer-mediated diseases of bone.

    Science.gov (United States)

    Foley, John; Nickerson, Nicole; Riese, David J; Hollenhorst, Peter C; Lorch, Gwendolen; Foley, Anne M

    2012-07-01

    The epidermal growth factor receptor is a well-established cancer therapeutic target due to its stimulation of proliferation, motility, and resistance to apoptosis. Recently, additional roles for the receptor have been identified in growth of metastases. Similar to development, metastatic spread requires signaling interactions between epithelial-derived tumor cells and mesenchymal derivatives of the microenvironment. This necessitates reactivation of developmental signaling molecules, including the hypercalcemia factor parathyroid hormone-related protein. This review covers the variations of epidermal growth factor receptor signaling in cancers that produce bone metastases, regulation of parathyroid hormone-related protein, and evidence that the two molecules drive cancer-mediated diseases of bone.

  12. Bone metastasis in prostate cancer: Recurring mitochondrial DNA mutation reveals selective pressure exerted by the bone microenvironment.

    Science.gov (United States)

    Arnold, Rebecca S; Fedewa, Stacey A; Goodman, Michael; Osunkoya, Adeboye O; Kissick, Haydn T; Morrissey, Colm; True, Lawrence D; Petros, John A

    2015-09-01

    Cancer progression and metastasis occur such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell's description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis. We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary tumor and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation. Somatic mutations were significantly more numerous in the bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (n.p.) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in the bone. Other notable somatic mutations that occurred in more than one patient

  13. Targeted Therapies for Myeloma and Metastatic Bone Cancers

    National Research Council Canada - National Science Library

    Vail, Neal

    2008-01-01

    ... done. Quantified functional groups available for ligand conjugation using S35-labeled ligands. Developed alternative assay to confirm affinity of bone-targeting nanoparticles to hydroxyapatite substrates...

  14. Contribution of bone tissue modulus to breast cancer metastasis to bone.

    Science.gov (United States)

    Guelcher, Scott A; Sterling, Julie A

    2011-12-01

    Certain tumors, such as breast, frequently metastasize to bone where they can induce bone destruction. Currently, it is well-accepted that the tumor cells are influenced by other cells and growth factors present in the bone microenvironment that lead to tumor-induced bone disease. Over the past 20 years, many groups have studied this process and determined the major contributing factors; however, these results do not fully explain the changes in gene expression and cell behavior that occur when tumor cells metastasize to bone. More recently, groups studying metastasis from soft tissue sites have determined that the rigidity of the microenvironment, which increases during tumor progression in soft tissue, can regulate tumor cell behavior and gene expression. Therefore, we began to investigate the role of the rigid bone extracellular matrix in the regulation of genes that stimulate tumor-induced bone disease. We found that the rigidity of bone specifically regulates parathyroid hormone-related protein (PTHrP) and Gli2 expression in a transforming growth factor β (TGF-β) and mechanotransduction-dependent mechanism. In this review, we summarize the mechanotransduction signaling pathway and how this influences TGF-β signaling and osteolytic gene expression.

  15. Genistein suppresses Prevotella intermedia lipopolysaccharide-induced inflammatory response in macrophages and attenuates alveolar bone loss in ligature-induced periodontitis.

    Science.gov (United States)

    Choi, Eun-Young; Bae, Seung Han; Ha, Min Hee; Choe, So-Hui; Hyeon, Jin-Yi; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

    2016-02-01

    Genistein is a major isoflavone subclass of flavonoids found in soybean and a potent tyrosine kinase inhibitor. The present study aimed to assess the effect of genistein on the production of proinflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) isolated from Prevotella intermedia, a pathogen associated with different forms of periodontal disease, and to evaluate its possible influence on alveolar bone loss in ligature-induced periodontitis using micro-computed tomography (micro-CT) analysis as well. LPS was isolated from P. intermedia ATCC 25611 by using the standard hot phenol-water method. Culture supernatants were analyzed for nitric oxide (NO) and interleukin-6 (IL-6). Inducible NO synthase (iNOS) protein expression was evaluated by immunoblot analysis. Real-time PCR was carried out to measure iNOS and IL-6 mRNA expression. In addition, effect of genistein on alveolar bone loss was evaluated in a rat model of experimental periodontitis using micro-CT analysis. Genistein significantly attenuated P. intermedia LPS-induced production of iNOS-derived NO and IL-6 with attendant decrease in their mRNA expression in RAW264.7 cells. In addition, when genistein was administered to rats, decreases in alveolar bone height and bone volume fraction induced by ligature placement were significantly inhibited. Genistein administration also prevented ligature-induced alterations in the microstructural parameters of trabecular bone, including trabecular thickness, trabecular separation, bone mineral density and structure model index. While additional studies are required, we suggest that genistein could be utilized for the therapy of human periodontitis in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Development of Raman spectral markers to assess metastatic bone in breast cancer

    Science.gov (United States)

    Ding, Hao; Nyman, Jeffry S.; Sterling, Julie A.; Perrien, Daniel S.; Mahadevan-Jansen, Anita; Bi, Xiaohong

    2014-11-01

    Bone is the most common site for breast cancer metastases. One of the major complications of bone metastasis is pathological bone fracture caused by chronic bone loss and degeneration. Current guidelines for the prediction of pathological fracture mainly rely on radiographs or computed tomography, which are limited in their ability to predict fracture risk. The present study explored the feasibility of using Raman spectroscopy to estimate pathological fracture risk by characterizing the alterations in the compositional properties of metastatic bones. Tibiae with evident bone destruction were investigated using Raman spectroscopy. The carbonation level calculated by the ratio of carbonate/phosphate ν1 significantly increased in the tumor-bearing bone at all the sampling regions at the proximal metaphysis and diaphysis, while tumor-induced elevation in mineralization and crystallinity was more pronounced in the metaphysis. Furthermore, the increased carbonation level is positively correlated to bone lesion size, indicating that this parameter could serve as a unique spectral marker for tumor progression and bone loss. With the promising advances in the development of spatially offset Raman spectroscopy for deep tissue measurement, this spectral marker can potentially be used for future noninvasive evaluation of metastatic bone and prediction of pathological fracture risk.

  17. When is a bone scan study appropriate in asymptomatic men diagnosed with prostate cancer?

    Science.gov (United States)

    Pal, Raj P; Thiruudaian, Thivyaan; Khan, Masood A

    2008-11-01

    To determine when a bone scan investigation is appropriate in asymptomatic men diagnosed with prostate cancer. Between November 2005 and July 2006, 317 men with prostate cancer underwent a bone scan study; 176 men fulfilled the inclusion criteria. Prostate-specific antigen (PSA) cut-offs as well as univariate and multivariate logistic regression analyses using digital rectal examination finding, biopsy Gleason scores and age were performed to determine when a bone scan study is likely to be of value. Only 1/61 men (1.6%) with a serum PSA 20 ng/mL had a positive bone scan. However, 2/38 men (4.7%) with a serum PSA 20.1-40.0 ng/mL, 3/20 men (15%) with a serum PSA 40.1-60.0 ng/mL, 7/19 men (36.8%) with a serum PSA 60.1-100.0 ng/mL and 19/38 men (50%) with a serum PSA > 100.0 ng/mL had positive bone scans. Univariate and multivariate logistic regression analyses were uninformative in these groups. Based on our findings, a bone scan is of limited value in asymptomatic prostate cancer patients presenting PSA =orGleason score and age are unhelpful in predicting those who might harbor bone metastasis. (c) 2008, Asian Journal of Andrology, SIMM and SJTU. All rights reserved.

  18. Exercise improves body fat, lean mass and bone mass in breast cancer survivors

    OpenAIRE

    Irwin, Melinda L; Alvarez-Reeves, Marty; Cadmus, Lisa; Mierzejewski, Eileen; Mayne, Susan T.; Yu, Herbert; Chung, Gina G.; Jones, Beth; Knobf, M. Tish; DiPietro, Loretta

    2009-01-01

    Given the negative effects of a breast cancer diagnosis and its treatments on body weight and bone mass, we investigated the effects of a 6-month randomized controlled aerobic exercise intervention vs. usual care on body composition in breast cancer survivors. Secondary aims were to examine the effects stratified by important prognostic and physiologic variables. Seventy-five physically inactive postmenopausal breast cancer survivors were recruited through the Yale-New Haven Hospital Tumor Re...

  19. F-8 sodium fluoride position emission tomography/computed tomography for detection of thyroid cancer bone metastasis compared with bone scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hyun Jong; Lee, Won Woo; Park, So Yeon; Kim, Sang Eun [Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2016-04-15

    The aim of the study was to compare the diagnostic performances of F-18 sodium fluoride positron emission tomography/computed tomography (bone PET/CT) and bone scintigraphy (BS) for the detection of thyroid cancer bone metastasis. We retrospectively enrolled 6 thyroid cancer patients (age = 44.7 ± 9.8 years, M:F = 1:5, papillary:follicular = 2:4) with suspected bone metastatic lesions in the whole body iodine scintigraphy or BS, who subsequently underwent bone PET/CT. Pathologic diagnosis was conducted for 4 lesions of 4 patients. Of the 17 suspected bone lesions, 10 were metastatic and 7 benign. Compared to BS, bone PET/CT exhibited superior sensitivity (10/10 = 100% vs. 2/10 = 20%, p = 0.008), and accuracy (14/17 = 82.4% vs. 7/17 = 41.2%, p < 0.025). The specificity (4/7 = 57.1%) of bone PET/CT was not significantly different from that of BS (5/7 = 71.4%, p > 0.05). Bone PET/CT may be more sensitive and accurate than BS for the detection of thyroid cancer bone metastasis.

  20. Fulvic Acid Attenuates Resistin-Induced Adhesion of HCT-116 Colorectal Cancer Cells to Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Wen-Shih Huang

    2015-12-01

    Full Text Available A high level of serum resistin has recently been found in patients with a number of cancers, including colorectal cancer (CRC. Hence, resistin may play a role in CRC development. Fulvic acid (FA, a class of humic substances, possesses pharmacological properties. However, the effect of FA on cancer pathophysiology remains unclear. The aim of this study was to investigate the effect of resistin on the endothelial adhesion of CRC and to determine whether FA elicits an antagonistic mechanism to neutralize this resistin effect. Human HCT-116 (p53-negative and SW-48 (p53-positive CRC cells and human umbilical vein endothelial cells (HUVECs were used in the experiments. Treatment of both HCT-116 and SW-48 cells with resistin increases the adhesion of both cells to HUVECs. This result indicated that p53 may not regulate this resistin effect. A mechanistic study in HCT-116 cells further showed that this resistin effect occurs via the activation of NF-κB and the expression of intercellular adhesion molecule-1 (ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1. Co-treating cells with both FA and resistin revealed that FA significantly attenuated the resistin-increased NF-κB activation and ICAM-1/VCAM-1 expression and the consequent adhesion of HCT-116 cells to HUVECs. These results demonstrate the role of resistin in promoting HCT-116 cell adhesion to HUVECs and indicate that FA might be a potential candidate for the inhibition of the endothelial adhesion of CRC in response to resistin.

  1. Fulvic Acid Attenuates Resistin-Induced Adhesion of HCT-116 Colorectal Cancer Cells to Endothelial Cells

    Science.gov (United States)

    Huang, Wen-Shih; Yang, Jen-Tsung; Lu, Chien-Chang; Chang, Shun-Fu; Chen, Cheng-Nan; Su, Yu-Ping; Lee, Ko-Chao

    2015-01-01

    A high level of serum resistin has recently been found in patients with a number of cancers, including colorectal cancer (CRC). Hence, resistin may play a role in CRC development. Fulvic acid (FA), a class of humic substances, possesses pharmacological properties. However, the effect of FA on cancer pathophysiology remains unclear. The aim of this study was to investigate the effect of resistin on the endothelial adhesion of CRC and to determine whether FA elicits an antagonistic mechanism to neutralize this resistin effect. Human HCT-116 (p53-negative) and SW-48 (p53-positive) CRC cells and human umbilical vein endothelial cells (HUVECs) were used in the experiments. Treatment of both HCT-116 and SW-48 cells with resistin increases the adhesion of both cells to HUVECs. This result indicated that p53 may not regulate this resistin effect. A mechanistic study in HCT-116 cells further showed that this resistin effect occurs via the activation of NF-κB and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Co-treating cells with both FA and resistin revealed that FA significantly attenuated the resistin-increased NF-κB activation and ICAM-1/VCAM-1 expression and the consequent adhesion of HCT-116 cells to HUVECs. These results demonstrate the role of resistin in promoting HCT-116 cell adhesion to HUVECs and indicate that FA might be a potential candidate for the inhibition of the endothelial adhesion of CRC in response to resistin. PMID:26690142

  2. Bone scanning--who needs it among patients with newly diagnosed prostate cancer?

    Science.gov (United States)

    Hirobe, Megumi; Takahashi, Atsushi; Hisasue, Shin-Ichi; Kitamura, Hiroshi; Kunishima, Yasuharu; Masumori, Naoya; Iwasawa, Akihiko; Fujimori, Kenji; Hasegawa, Tadashi; Tsukamoto, Taiji

    2007-10-01

    We evaluated the relationship between serum PSA and clinical variables to eliminate bone scanning in patients with prostate cancer having a low probability of bone metastasis. The study included 366 patients with newly diagnosed prostate cancer between 1999 and 2005. Bone metastasis was studied for its correlation with various clinical and pathological variables in these patients. Bone metastasis was found in 28 (7.7%) of 366 patients. Fourteen patients had skeletal symptoms related to bone metastasis. The risk for bone metastases increased considerably with increases of PSA level, clinical T stage and Gleason score. The metastasis was not found in 161 patients with serum PSA concentration of 10 ng/ml or lower. In 95 patients with the concentration between 10 and 20 ng/ml only two had the metastasis. These two patients had T2 disease and Gleason scores of 7 or greater. In 204 patients with clinical stage T1 disease, one (0.5%) had the metastasis. In 117 patients with Gleason scores of 6 or less, the metastasis was found in two (1.7%). For patients with serum PSA levels of 10 ng/ml or lower, bone scanning may be eliminated because of the negligible risk of bone metastases. In addition, scanning may not be necessary for those with PSA levels between 10 and 20 ng/ml, when they have T1 disease and Gleason scores of 6 or lower.

  3. High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice.

    Science.gov (United States)

    Carvalho, Adriana Lelis; DeMambro, Victoria E; Guntur, Anyonya R; Le, Phuong; Nagano, Kenichi; Baron, Roland; de Paula, Francisco José Albuquerque; Motyl, Katherine J

    2018-02-01

    There is a growing and alarming prevalence of obesity and the metabolic syndrome in type I diabetic patients (T1DM), particularly in adolescence. In general, low bone mass, higher fracture risk, and increased marrow adipose tissue (MAT) are features of diabetic osteopathy in insulin-deficient subjects. On the other hand, type 2 diabetes (T2DM) is associated with normal or high bone mass, a greater risk of peripheral fractures, and no change in MAT. Therefore, we sought to determine the effect of weight gain on bone turnover in insulin-deficient mice. We evaluated the impact of a 6-week high-fat (HFD) rich in medium chain fatty acids or low-fat diet (LFD) on bone mass and MAT in a streptozotocin (STZ)-induced model using male C57BL/6J mice at 8 weeks of age. Dietary intervention was initiated after diabetes confirmation. At the endpoint, lower non-fasting glucose levels were observed in diabetic mice fed with high fat diet compared to diabetic mice fed the low fat diet (STZ-LFD). Compared to euglycemic controls, the STZ-LFD had marked polydipsia and polyphagia, as well as reduced lean mass, fat mass, and bone parameters. Interestingly, STZ-HFD mice had higher bone mass, namely less cortical bone loss and more trabecular bone than STZ-LFD. Thus, we found that a HFD, rich in medium chain fatty acids, protects against bone loss in a T1DM mouse model. Whether this may also translate to T1DM patients who are overweight or obese in respect to maintenance of bone mass remains to be determined through longitudinal studies. © 2017 Wiley Periodicals, Inc.

  4. Integrated PET/MR breast cancer imaging: Attenuation correction and implementation of a 16-channel RF coil.

    Science.gov (United States)

    Oehmigen, Mark; Lindemann, Maike E; Lanz, Titus; Kinner, Sonja; Quick, Harald H

    2016-08-01

    This study aims to develop, implement, and evaluate a 16-channel radiofrequency (RF) coil for integrated positron emission tomography/magnetic resonance (PET/MR) imaging of breast cancer. The RF coil is designed for optimized MR imaging performance and PET transparency and attenuation correction (AC) is applied for accurate PET quantification. A 16-channel breast array RF coil was designed for integrated PET/MR hybrid imaging of breast cancer lesions. The RF coil features a lightweight rigid design and is positioned with a spacer at a defined position on the patient table of an integrated PET/MR system. Attenuation correction is performed by generating and applying a dedicated 3D CT-based template attenuation map. Reposition accuracy of the RF coil on the system patient table while using the positioning frame was tested in repeated measurements using MR-visible markers. The MR, PET, and PET/MR imaging performances were systematically evaluated using modular breast phantoms. Attenuation correction of the RF coil was evaluated with difference measurements of the active breast phantoms filled with radiotracer in the PET detector with and without the RF coil in place, serving as a standard of reference measurement. The overall PET/MR imaging performance and PET quantification accuracy of the new 16-channel RF coil and its AC were then evaluated in first clinical examinations on ten patients with local breast cancer. The RF breast array coil provides excellent signal-to-noise ratio and signal homogeneity across the volume of the breast phantoms in MR imaging and visualizes small structures in the phantoms down to 0.4 mm in plane. Difference measurements with PET revealed a global loss and thus attenuation of counts by 13% (mean value across the whole phantom volume) when the RF coil is placed in the PET detector. Local attenuation ranging from 0% in the middle of the phantoms up to 24% was detected in the peripheral regions of the phantoms at positions closer to

  5. Inhibitory Effects of Megakaryocytes in Prostate Cancer Bone Metastasis

    Science.gov (United States)

    2010-04-01

    modulate osteoblast synthesis of type-l collagen, osteoprotegerin, and RANKL. Bone 36(5):812-9. 15. Kacena MA, Gundberg CM, Horowitz MC 2006 A...Jeong SS, Chen R, Weilbaecher K 2008 APT102, a novel adpase, cooperates with aspirin to disrupt bone metastasis in mice. J Cell Biochem 104(4):1311-23

  6. Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment

    Energy Technology Data Exchange (ETDEWEB)

    Park, Se Young; Kim, Hyun-Jeong; Kim, Ki Rim; Lee, Sun Kyoung; Lee, Chang Ki; Park, Kwang-Kyun, E-mail: biochelab@yuhs.ac; Chung, Won-Yoon, E-mail: wychung@yuhs.ac

    2014-03-01

    Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulated with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatment-induced estrogen deficiency. - Highlights: • Betulinic acid reduced PTHrP production in human metastatic breast cancer cells. • Betulinic acid blocked RANKL/OPG ratio in PTHrP-stimulated human osteoblastic cells. • Betulinic

  7. Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal proinflammatory cytokines

    Directory of Open Access Journals (Sweden)

    Hu Shan

    2012-12-01

    Full Text Available Abstract Background The neuroinflammatory responses in the spinal cord following bone cancer development have been shown to play an important role in cancer-induced bone pain (CIBP. Lipoxins (LXs, endogenous lipoxygenase-derived eicosanoids, represent a unique class of lipid mediators that possess a wide spectrum of anti-inflammatory and pro-resolving actions. In this study, we investigated the effects of intrathecal injection with lipoxin and related analogues on CIBP in rats. Methods The CIBP model was induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Mechanical thresholds were determined by measuring the paw withdrawal threshold to probing with a series of calibrated von Frey filaments. Lipoxins and analogues were administered by intrathecal (i.t. or intravenous (i.v. injection. The protein level of LXA4 receptor (ALX was tested by western blot. The localization of lipoxin receptor in spinal cord was assessed by fluorescent immunohistochemistry. Real-time PCR was carried out for detecting the expression of pro-inflammatory cytokines. Results Our results demonstrated that: 1 i.t. injection with the same dose (0.3 nmol of lipoxin A4 (LXA4, lipoxin B4 (LXB4 or aspirin-triggered-15-epi-lipoxin A4 (ATL could alleviate the mechanical allodynia in CIBP on day 7 after surgery. ATL showed a longer effect than the others and the effect lasted for 6 hours. ATL administered through i.v. injection could also attenuate the allodynia in cancer rats. 2 The results from western blot indicate that there is no difference in the expression of ALX among the naive, sham or cancer groups. 3 Immunohistochemistry showed that the lipoxin receptor (ALX-like immunoreactive substance was distributed in the spinal cord, mainly co-localized with astrocytes, rarely co-localized with neurons, and never co-localized with microglia. 4 Real-time PCR analysis revealed that, compared with vehicle, i.t. injection with ATL could significantly

  8. Dried Plum Protects From Radiation-Induced Bone Loss by Attenuating Pro-Osteoclastic and Oxidative Stress Responses

    Science.gov (United States)

    Globus, Ruth

    2015-01-01

    Future space explorations beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure plays a major role in progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Our long-term goals are to define the mechanisms and risk of bone loss in the spaceflight environment and to facilitate the development of effective countermeasures. We had previously reported that exposure to low or high-LET radiation correlates with an acute increase in the expression of pro-osteoclastic and oxidative stress genes in bone during the early response to radiation followed by pathological changes in skeletal structure. We then conducted systematic screening for potential countermeasures against bone loss where we tested the ability of various antioxidants to mitigate the radiation-induced increase in expression of these markers. For the screen, 16-week old C57Bl6J mice were treated with a dietary antioxidant cocktail, injectable DHLA or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs radiation and one day later, marrow cells were collected and the relevant genes analyzed for expression levels. Among the candidate countermeasures tested, DP was most effective in reducing the expression of genes associated with bone loss. Furthermore, analysis of skeletal structure by microcomputed tomography (microCT) revealed that DP also prevents the radiation-induced deterioration in skeletal microarchitecture as indicated by parameters such as percent bone volume (BVTV), trabecular spacing and trabecular number. We also found that DP has similar protective effects on skeletal structure in a follow-up study using 1 Gy of

  9. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.

    Science.gov (United States)

    Price, Trevor T; Burness, Monika L; Sivan, Ayelet; Warner, Matthew J; Cheng, Renee; Lee, Clara H; Olivere, Lindsey; Comatas, Karrie; Magnani, John; Kim Lyerly, H; Cheng, Qing; McCall, Chad M; Sipkins, Dorothy A

    2016-05-25

    Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease. Copyright © 2016, American Association for the Advancement of Science.

  10. Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.

    Directory of Open Access Journals (Sweden)

    Katsuya Morita

    Full Text Available Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2 protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.

  11. Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement

    Energy Technology Data Exchange (ETDEWEB)

    Kraeber-Bodere, F.; Campion, L.; Rousseau, C.; Bourdin, S.; Chatal, J.-F.; Resche, I. [Rene Gauducheau Cancer Center, Nantes (France)

    2000-10-01

    This retrospective study evaluated the toxicity and efficacy of strontium-89 chloride (Metastron, Amersham) in 94 patients with painful bone metastases of prostate cancer (117 injections of 150 MBq) and compared the efficacy of treatment in patients with moderate and extensive bone involvement. The predictive value of flare response with regard to analgesic response was also studied. High-grade leukothrombopenians were observed after only 5% of injections. An improvement in quality of life was obtained in 65% of cases, a decrease in pain in 78% (31% complete response) and a reduction of analgesics in 60%. Efficacy was significantly better for pain decrease (P=0.005) and reduction of analgesics (P=0.018), and response was significantly longer (P<0.0035) in patients with moderate than in patients with extensive bone involvement. The flare response observed in 23% of cases was not predictive of pain response (P=0.919) or reduction of analgesics (P=0.353). A second dose prolonged analgesia in three-quarters of cases without any apparent increase in toxicity. These results confirm the benefit of {sup 89}Sr chloride for the treatment of metastatic bone pain and suggest that internal radiotherapy should be started earlier. A bone scan could be proposed at the time of hormonal escape resulting in bone pain, and internal radiotherapy could be initiated when several metastatic foci exist, even if only one is painful. In this way, pain-free follow-up could be prolonged, and the transition to other therapeutic approaches, particularly opioids, delayed. (orig.)

  12. Impact of improved attenuation correction featuring a bone atlas and truncation correction on PET quantification in whole-body PET/MR.

    Science.gov (United States)

    Oehmigen, Mark; Lindemann, Maike E; Gratz, Marcel; Kirchner, Julian; Ruhlmann, Verena; Umutlu, Lale; Blumhagen, Jan Ole; Fenchel, Matthias; Quick, Harald H

    2017-11-09

    Recent studies have shown an excellent correlation between PET/MR and PET/CT hybrid imaging in detecting lesions. However, a systematic underestimation of PET quantification in PET/MR has been observed. This is attributable to two methodological challenges of MR-based attenuation correction (AC): (1) lack of bone information, and (2) truncation of the MR-based AC maps (μmaps) along the patient arms. The aim of this study was to evaluate the impact of improved AC featuring a bone atlas and truncation correction on PET quantification in whole-body PET/MR. The MR-based Dixon method provides four-compartment μmaps (background air, lungs, fat, soft tissue) which served as a reference for PET/MR AC in this study. A model-based bone atlas provided bone tissue as a fifth compartment, while the HUGE method provided truncation correction. The study population comprised 51 patients with oncological diseases, all of whom underwent a whole-body PET/MR examination. Each whole-body PET dataset was reconstructed four times using standard four-compartment μmaps, five-compartment μmaps, four-compartment μmaps + HUGE, and five-compartment μmaps + HUGE. The SUVmax for each lesion was measured to assess the impact of each μmap on PET quantification. All four μmaps in each patient provided robust results for reconstruction of the AC PET data. Overall, SUVmax was quantified in 99 tumours and lesions. Compared to the reference four-compartment μmap, the mean SUVmax of all 99 lesions increased by 1.4 ± 2.5% when bone was added, by 2.1 ± 3.5% when HUGE was added, and by 4.4 ± 5.7% when bone + HUGE was added. Larger quantification bias of up to 35% was found for single lesions when bone and truncation correction were added to the μmaps, depending on their individual location in the body. The novel AC method, featuring a bone model and truncation correction, improved PET quantification in whole-body PET/MR imaging. Short reconstruction times, straightforward

  13. Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis

    Science.gov (United States)

    Liang, Yajun; Wu, Heng; Lei, Rong; Chong, Robert A.; Wei, Yong; Lu, Xin; Tagkopoulos, Ilias; Kung, Sun-Yuan; Yang, Qifeng; Hu, Guohong; Kang, Yibin

    2012-01-01

    The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes. PMID:22875853

  14. 177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment

    OpenAIRE

    Bergmann, Ralf; Meckel, Marian; Kub??ek, Vojt?ch; Pietzsch, Jens; Steinbach, J?rg; Hermann, Petr; R?sch, Frank

    2016-01-01

    Background Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents...

  15. Cold metastases detected by bone scintigraphy in aggressive lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Martinez Carsi, C.; Perales Vila, A. [Servei de Medicina Nuclear de l`Hospital 9 d`Octubre, Valencia (Spain); Ruiz Hernandez, G. [Servei de Medicina Nuclear de l`Hospital Clinic Universitari, Valencia (Spain); Sanchez Marchori, C.; Oro Camps, J. [Servei de Traumatologia de l`Hospital 9 d`Octubre, Valencia (Spain)

    1998-12-31

    A case of a 55-year-old man was remitted to Traumatology Department to present back pain of two weeks of evolution. The results of bone scintigraphy and the patient`s evolution allowed the diagnosis. This case report and a literature review showed the importance of using a routine bone scan in diagnosis of bone metastases. (orig.) [Deutsch] Ein 55jaehriger Mann mit seit zwei Wochen andauernden lumbalen Schmerzen wurde in der orthopaedischen Klinik untersucht. Die Evolution des klinischen Bildes und eine Knochenszintigraphie ermoeglichten die Diagnose. Dieser klinische Fall und das wissenschaftliche Schrifttum zeigten, wie wichtig eine routinemaessige Knochenszintigraphie in der Diagnostik von Knochenmetastasen ist. (orig.)

  16. Targeting a novel bone degradation pathway in primary bone cancer by inactivation of the collagen receptor uPARAP/Endo180

    DEFF Research Database (Denmark)

    Engelholm, Lars H; Carlsen Melander, Eva Maria; Hald, Andreas

    2016-01-01

    In osteosarcoma, a primary mesenchymal bone cancer occurring predominantly in younger patients, invasive tumour growth leads to extensive bone destruction. This process is insufficiently understood, cannot be efficiently counteracted and calls for novel means of treatment. The endocytic collagen ...... neoadjuvant therapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd....

  17. ABL kinases promote breast cancer osteolytic metastasis by modulating tumor-bone interactions through TAZ and STAT5 signaling.

    Science.gov (United States)

    Wang, Jun; Rouse, Clay; Jasper, Jeff S; Pendergast, Ann Marie

    2016-02-02

    Bone metastases occur in up to 70% of advanced breast cancer. For most patients with breast cancer, bone metastases are predominantly osteolytic. Interactions between tumor cells and stromal cells in the bone microenvironment drive osteolytic bone metastasis, a process that requires the activation of osteoclasts, cells that break down bone. We report that ABL kinases promoted metastasis of breast cancer cells to bone by regulating the crosstalk between tumor cells and the bone microenvironment. ABL kinases protected tumor cells from apoptosis induced by TRAIL (TNF-related apoptosis-inducing ligand), activated the transcription factor STAT5, and promoted osteolysis through the STAT5-dependent expression of genes encoding the osteoclast-activating factors interleukin-6 (IL-6) and matrix metalloproteinase 1 (MMP1). Furthermore, in breast cancer cells, ABL kinases increased the abundance of the Hippo pathway mediator TAZ and the expression of TAZ-dependent target genes that promote bone metastasis. Knockdown of ABL kinases or treatment with ABL-specific allosteric inhibitor impaired osteolytic metastasis of breast cancer cells in mice. These findings revealed a role for ABL kinases in regulating tumor-bone interactions and provide a rationale for using ABL-specific inhibitors to limit breast cancer metastasis to bone. Copyright © 2016, American Association for the Advancement of Science.

  18. Glucocorticoids induce CCN5/WISP-2 expression and attenuate invasion in oestrogen receptor-negative human breast cancer cells.

    Science.gov (United States)

    Ferrand, Nathalie; Stragier, Emilien; Redeuilh, Gérard; Sabbah, Michèle

    2012-10-01

    CCN5 (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed 5)/WISP-2 [WNT1 (wingless-type MMTV integration site family, member 1)-inducible signalling pathway protein 2] is an oestrogen-regulated member of the CCN family. CCN5 is a transcriptional repressor of genes associated with the EMT (epithelial-mesenchymal transition) and plays an important role in maintenance of the differentiated phenotype in ER (oestrogen receptor)-positive breast cancer cells. In contrast, CCN5 is undetectable in more aggressive ER-negative breast cancer cells. We now report that CCN5 is induced in ER-negative breast cancer cells such as MDA-MB-231 following glucocorticoid exposure, due to interaction of the endogenous glucocorticoid receptor with a functional glucocorticoid-response element in the CCN5 gene promoter. Glucocorticoid treatment of MDA-MB-231 cells is accompanied by morphological alterations, decreased invasiveness and attenuated expression of mesenchymal markers, including vimentin, cadherin 11 and ZEB1 (zinc finger E-box binding homeobox 1). Interestingly, glucocorticoid exposure did not increase CCN5 expression in ER-positive breast cancer cells, but rather down-regulated ER expression, thereby attenuating oestrogen pathway signalling. Taken together, our results indicate that glucocorticoid treatment of ER-negative breast cancer cells induces high levels of CCN5 expression and is accompanied by the appearance of a more differentiated and less invasive epithelial phenotype. These findings propose a novel therapeutic strategy for high-risk breast cancer patients.

  19. ADJUVANT TREATMENT WITH BIPHOSPONATES IN COMPLEX THERAPY OF PAPILLARY THYROID CANCER BONE METASTASES

    Directory of Open Access Journals (Sweden)

    A. D. Kaprin

    2017-01-01

    Full Text Available Distant metastasis of thyroid cancer are founded in 10% of all metastases. Bone metastases are founded in 23% of distant metastasis. Complications associated with metastatic skeletal involvement often lead to a deterioration in the overall condition and a decrease in the quality of life of patients. Surgical treatment, chemotherapy are less effective, provide a higher injury rate and toxicity. This is a reason of increasing of cost of treatment. Bisphosphonates are a class of drugs that prevent the loss of bone mass, which can prolong the time to releasing bone complications: bone fracture, spine column fracture with spinal medulla compression, which decrease the QoL. Surgical treatment and chemotherapy have worse outcomes, higher injury rate, toxicity and increase cost of treatment. Bisphosphonates decrease the level of pain syndrome. Bisphosphonates are used in treatment of oncological patients since 1990. First medication was Fosamax (Aledronat. Later more medications with better efficacy and more useful were synthesised. The last one was Zoledronic acid. Rezorba (zoledronic acid was synthesised in 2006 in Russia. Rezorba has a same efficacy with other bisphosphonates, it was shown in clinical studies with groups of breast cancer and prostatic cancer. Clinical case of 67 y.o. male patient with diagnosis: Thyroid cancer IV c st pT1bN1bM1, right neck, paratraсheal, bone and lung metastasis. Complex treatment (surgery + radioiodine therapy + 5 courses of Rezorba was presented. After 3 courses the level of pain was decreased from 3 to 1,5. After 5 courses the ECOQ score was decreased from 2 to 1 point. Inclusion of Resorba in complex treatment of patients with bone metastasis after thyroid cancer at all stages of treatment decreases the score of pain syndrome and bone tissue reparation.

  20. Role of sympathetic nerves in the establishment of metastatic breast cancer cells in bone

    Directory of Open Access Journals (Sweden)

    Florent Elefteriou

    2016-09-01

    Full Text Available The bone marrow microenvironment is characterized by its multicellular nature, and perhaps less obviously by the high mobility of multiple transient and stationary cell lineages present in this environment. The trafficking of hematopoietic and mesenchymal cells between the bone marrow and blood compartments is regulated by a number of bone marrow-derived factors. It is suspected that transformed metastatic cells “hijack” these processes to engraft into the skeleton and eventually cause the skeletal complications associated with metastatic disease. In this short review, experimental and association data supporting the contribution of a less recognized cell type of the bone marrow – the nerves of the sympathetic nervous system – to early events of the breast cancer bone metastatic process, are summarized.

  1. Testing an alternative high-throughput tool for investigating bone diagenesis: FTIR in attenuated total reflection (ATR) mode

    NARCIS (Netherlands)

    Hollund, H.I.; Ariese, F.; Fernandes, R.; Jans, M.M.E.; Kars, H.

    2012-01-01

    Archaeological bone undergoes alterations after burial (diagenesis) that constitute a problem for the survival of archaeological information. A common method to assess this alteration is Fourier transform infrared spectrometry (FTIR). However, the commonly applied method (FTIR-KBr) is destructive

  2. Use of Animal Models in Understanding Cancer-induced Bone Pain

    Directory of Open Access Journals (Sweden)

    Lauren M. Slosky

    2015-01-01

    Full Text Available Many common cancers have a propensity to metastasize to bone. Although malignancies often go undetected in their native tissues, bone metastases produce excruciating pain that severely compromises patient quality of life. Cancer-induced bone pain (CIBP is poorly managed with existing medications, and its multifaceted etiology remains to be fully elucidated. Novel analgesic targets arise as more is learned about this complex and distinct pain state. Over the past two decades, multiple animal models have been developed to study CIBP's unique pathology and identify therapeutic targets. Here, we review animal models of CIBP and the mechanistic insights gained as these models evolve. Findings from immunocompromised and immunocompetent host systems are discussed separately to highlight the effect of model choice on outcome. Gaining an understanding of the unique neuromolecular profile of cancer pain through the use of appropriate animal models will aid in the development of more effective therapeutics for CIBP.

  3. Bisphosphonate-related atypical femoral fracture with bone metastasis of breast cancer: case report and review.

    Science.gov (United States)

    Hayashi, Kazunori; Aono, Masanari; Shintani, Kousuke; Kazuki, Kenichi

    2014-03-01

    Intravenous bisphosphonates (BPs) have been used to reduce the frequency of skeletal-related events due to bone metastases of several kinds of cancers. Although many studies on BP-related atypical fractures (BRAFs) due to the use of BP for osteoporosis treatment have been reported, few reports on BRAFs arising as a complication of long-term BP use for bone metastasis of cancer are available. A 62-year-old woman with a history of breast cancer presented with right thigh pain after she had a fall. Radiographs indicated a transverse fracture in the shaft of the right femur. She had been on zoledronate treatment for six years. Based on radiographic and histopathological findings, we concluded that the fracture was not a pathological fracture associated with metastasis but was a complication of long-term BP treatment. Clinical oncologists should consider the possibility of BRAFs in patients on long-term zoledronate treatment for bone metastases.

  4. Breast cancer osteomimicry and its role in bone specific metastasis; an integrative, systematic review of preclinical evidence.

    Science.gov (United States)

    Awolaran, Olugbenga; Brooks, Susan A; Lavender, Verna

    2016-12-01

    Metastasis accounts for most of the deaths from breast cancer and the preference of invasive breast cancer metastasising to bone has been widely reported. However, the biological basis of breast cancer osteotropism is not fully understood. This paper provides, for the first time, an integrative, systematic review of evidence of molecular factors that have functional roles in the homing of metastatic breast cancer to the bone. Pubmed, Web of Science and EBSCOhost were searched using keywords and synonyms for molecular, metastasis, breast cancer and bone to identify articles published between January 2004 and August 2016. 4491 potentially relevant citations were retrieved. 63 articles met the inclusion criteria, which were primary studies reporting evidence of molecular factors that have functional roles in predisposing breast cancer bone metastasis in vivo. 12 of those 63 articles that additionally met quality criteria were included in the review. Extracted data were tabulated and key findings that indicated biological mechanisms involved in breast cancer metastasis to bone were synthesised. 15 proteins expressed by breast cancer cells were identified as factors that mediate breast cancer bone metastasis: ICAM-1, cadherin-11, osteoactivin, bone sialoprotein, CCN3, IL-11, CCL2, CITED2, CXCR4, CTGF, OPN, CX3CR1, TWIST1, adrenomedullin and Enpp1. Upregulation or overexpression of one or more of them by breast cancer cells resulted in increased breast cancer metastasis to bone in vivo, except for CCL2 where bone-metastatic cells showed a reduced expression of this factor. All factors identified, here expressed by breast cancer cells, are proteins that are normally expressed in the bone microenvironment and linked to physiologic bone functions. All have a functional role in one of more of the following: cell proliferation and differentiation, bone mineralization and remodelling, cell adhesion and/or chemokine signalling. Six of them (cadherin-11, ICAM-1, OPN, CX3CR1

  5. Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor

    OpenAIRE

    Majuta, Lisa A.; Longo, Geraldine; Fealk, Michelle N.; McCaffrey, Gwen; Mantyh, Patrick W.

    2015-01-01

    The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nons...

  6. Can surgical management of bone metastases improve quality of life among women with gynecologic cancer?

    Science.gov (United States)

    Ji, Tao; Eskander, Ramez; Wang, Yifei; Sun, Kunkun; Hoang, Bang H; Guo, Wei

    2014-08-05

    The evaluation, counseling, and management of gynecologic patients with bone metastasis remain a challenge for clinicians. In order to critically evaluate the role of surgery, we retrospectively analyzed the records of 18 patients surgically treated for metastatic gynecologic tumors of bone, focusing on quality of life, local tumor control, and survival. Eighteen patients underwent surgical procedures for the treatment of bone metastases secondary to gynecologic cancer between September 2003 and April 2012. The primary cancer sites included the uterus (n = 10), the cervix (n = 5), and an ovary (n = 3). Patients were followed for an average period of 13.8 months (range, 2 to 34 months). A visual analog pain scale (VAS) and Eastern Cooperative Oncology Group (ECOG) performance status were evaluated both pre- and postoperatively. The median survival time following diagnosis of bone metastasis was 10.0 months. The mean VAS score was 5.8 preoperatively compared with 2.1, 3 months after surgery. The mean pre and postoperative ECOG performance status grades were 3.1 and 2.3, respectively. The prognosis of gynecological cancer patients with bone metastasis is poor. Some patients had improvement in their quality of life after surgical intervention for bone metastases; however, novel integrated treatment modalities should be investigated.

  7. Toward better use of bone scans among men with early-stage prostate cancer

    Science.gov (United States)

    Merdan, Selin; Womble, Paul R.; Miller, David C.; Barnett, Christine; Ye, Zaojun; Linsell, Susan M.; Montie, James E.; Denton, Brian T.

    2016-01-01

    Objective To evaluate the performance of published guidelines compared to current practice for radiographic staging of men with newly-diagnosed prostate cancer. Materials and Methods Using data from the Michigan Urological Surgery Improvement Collaborative (MUSIC) clinical registry, we identified 1,509 men diagnosed with prostate cancer from March 2012 through June 2013. Clinical data included age, prostate-specific antigen (PSA), Gleason score (GS), clinical T-stage, number of biopsy cores and bone scan (BS) results. We then fit a multivariable logistic regression model to examine the association between clinical variables and the occurrence of bone metastases. Because some patients did not undergo BS, we used established methods to correct for verification bias and estimate the diagnostic accuracy of published guidelines. Results Among 416 men who received a BS, 48 (11.5%) had evidence of bone metastases. Patients with bone metastases were older, with higher PSA and GS (all p Guidelines from the American Urology Association (AUA) and the National Comprehensive Cancer Network (NCCN) demonstrated similar performance in detecting bone metastases in our population, with fewer negative studies than the European Association of Urology (EAU) guideline. Applying the AUA recommendations (i.e., image when PSA >20 or GS ≥8) to current clinical practice, we estimate that guidelines would ensure that BS is performed for almost all men with bone metastases, while avoiding many negative imaging studies. PMID:25096341

  8. Bone scintigraphy predicts the risk of spinal cord compression in hormone-refractory prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Soerdjbalie-Maikoe, Vidija; Pelger, Rob C.M.; Nijeholt, Guus A.B. Lycklama [Department of Urology, Leiden University Medical Center, Leiden (Netherlands); Arndt, Jan-Willem [Department of Nuclear Medicine, Leiden University Medical Center, Leiden (Netherlands); Zwinderman, Aeilko H. [Department of Medical Statistics, Leiden University Medical Center, Leiden (Netherlands); Bril, Herman [Department of Pathology, Reinier de Graaf Hospital, Delft (Netherlands); Papapoulos, Socrates E.; Hamdy, Neveen A.T. [Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden (Netherlands)

    2004-07-01

    In prostate cancer, confirmation of metastatic involvement of the skeleton has traditionally been achieved by bone scintigraphy, although the widespread availability of prostate-specific antigen (PSA) measurements has tended to eliminate the need for this investigation. The potential of bone scintigraphy to predict skeletal-related events, particularly spinal cord compression, after the onset of hormone refractoriness has never been investigated. The aim of this study was to establish whether a new method of evaluating bone scintigraphy would offer a better predictive value for this complication of the metastatic process than is achieved with currently available grading methods. We studied 84 patients with hormone-refractory prostate cancer who had undergone bone scintigraphy at the time of hormone escape. Tumour grading and parameters of tumour load (PSA and alkaline phosphatase activity) were available in all patients. The incidence of spinal cord compression was documented and all patients were followed up until death. Bone scintigraphy was evaluated by the conventional Soloway grading and by an additional analysis determining total or partial involvement of individual vertebrae. In contrast to the Soloway method, the new method was able to predict spinal cord compression at various spinal levels. Our data suggest that there is still a place for bone scintigraphy in the management of hormone-refractory prostate cancer. (orig.)

  9. MMP-8, A Breast Cancer Bone Metastasis Suppressor Gene

    National Research Council Canada - National Science Library

    Selvamurugan, Nagarajan

    2006-01-01

    .... But the expression level of MMP-8 was not detected by Western blot analysis. The molecular mechanisms of how TGF-BetaI mediates stimulation of invasion and formation of bone metastasis have yet to be completely determined. ATF-3...

  10. Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis.

    Science.gov (United States)

    Suominen, Mari I; Rissanen, Jukka P; Käkönen, Rami; Fagerlund, Katja M; Alhoniemi, Esa; Mumberg, Dominik; Ziegelbauer, Karl; Halleen, Jussi M; Käkönen, Sanna-Maria; Scholz, Arne

    2013-06-19

    Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis. We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis. A single dose of radium-223 dichloride was used in three different settings mimicking the prevention or treatment of bone metastasis. Disease progression was monitored using fluorescence and radiographic imaging and histological analyses. The effect of radium-223 dichloride alone and in combination with doxorubicin or zoledronic acid on survival of mice was analyzed by Kaplan-Meier methods. All statistical tests used were two-sided. Radium-223 dichloride incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values radium-223 dichloride prevented tumor-induced cachexia (0/14 vs 7/14 control mice) and decreased osteolysis by 56% and tumor growth by 43% (all P values Radium-223 dichloride induced double-strand DNA breaks in cancer cells in vivo. Finally, radium-223 dichloride extended survival as a monotherapy (29.2 days, 95% confidence interval [CI] = 26.6 to 31.8 days, P = .039) and in combination with zoledronic acid (31.4 days, 95% CI = 28.8 to 34.0 days, P = .004) or doxorubicin (31.5 days, 95% CI = 29.5 to 33.5 days, P radium-223 dichloride was administered in a preventive or micrometastatic setting. Our findings strongly support the development of radium-223 dichloride for the treatment of breast cancer patients with or at high risk of developing bone metastases.

  11. Discoidin Domain Receptors: Novel Targets in Breast Cancer Bone Metastasis

    Science.gov (United States)

    2017-02-01

    within the skeletal niche and consequently represent promising targets for intervention in BrCa patients with bone metastasis. The scope of research...subtypes with comprehensive clinical and pathological information, including the presence of distant metastasis. Sixteen cases had presence of bone...of association between DDR1 expression levels and age , race, menopausal status, estrogen receptor (ER), progesterone receptor (PR), HER2-neu

  12. Anti-Osteoclastic Activity of Artemisia capillaris Thunb. Extract Depends upon Attenuation of Osteoclast Differentiation and Bone Resorption-Associated Acidification Due to Chlorogenic Acid, Hyperoside, and Scoparone.

    Science.gov (United States)

    Lee, Sang-Hyun; Lee, Jung-Yun; Kwon, Young-In; Jang, Hae-Dong

    2017-02-04

    The present study attempts to elucidate the anti-osteoporotic activity of Artemisia capillaris Thunb. in the form of anti-osteoclastic effect and responsible bioactive compounds. The contents of chlorogenic acid, caffeic acid, hyperoside, isoquercitrin, isochlorogenic acid A, and scoparone in Artemisia capillaris hydroethanolic extract (ACHE) were 38.53, 0.52, 4.07, 3.03, 13.90, and 6.59 mg/g, respectively. ACHE diminished osteoclast differentiation and bone resorption due to chlorogenic acid, hyperoside, and scoparone. In addition, ACHE attenuated acidification as well as reducing tumor necrosis factor receptor-associated factor 6 (TRAF6) expression and its association with vacuolar H⁺-adenosine triphosphatase (V-ATPase). Furthermore, chlorogenic acid, hyperoside, and scoparone from A. capillaris abrogated the association of V-ATPase with TRAF6, suggesting that the blockage of bone resorption by A. capillaris was partially mediated by reducing acidification through down-regulating interaction of V-ATPase with TRAF6 due to scoparone as well as chlorogenic acid and hyperoside. These results imply that the anti-osteoclastic effect of A. capillaris through down-regulating osteoclast differentiation and bone resorption may contribute to its anti-osteoporotic effect.

  13. 18F-NaF Positive Bone Metastases of Non 18F-FDG Avid Mucinous Gastric Cancer

    OpenAIRE

    Çiğdem Soydal; Elgin Özkan; Özlem Nuriye Küçük

    2015-01-01

    Detection of gastric cancer bone metastasis is crucial since its presence is an independent prognostic factor. In this case report, we would like to present 18F-NaF positive bone metastases of non 18F-FDG avid gastric mucinous cancer.

  14. Avascular necrosis of bone in childhood cancer patients: a possible role of genetic susceptibility.

    Science.gov (United States)

    Geczova, L; Soltysova, A; Gecz, J; Sufliarska, S; Horakova, J; Mladosievicova, B

    2015-01-01

    With the increasing number of paediatric cancer patients and with their prolonged survival, the evidence of a number of serious complications induced by anticancer therapy is rising. Osteonecrosis (ON) of bone is one of these treatment-related effects with a multifactorial pathogenesis. In the past few years, several polymorphisms of candidate genes with possible role in development of this disorder were studied.We summarized potential risk factors leading to increased susceptibility to osteonecrosis of bone development in cancer patients during childhood and to present current knowledge in the field of genetic aspects of this condition (Ref. 86).

  15. Utilization of bone densitometry for prediction and administration of bisphosphonates to prevent osteoporosis in patients with prostate cancer without bone metastases receiving antiandrogen therapy

    Directory of Open Access Journals (Sweden)

    Holt A

    2014-12-01

    Full Text Available Abby Holt,1 Muhammad A Khan,2 Swetha Gujja,3 Rangaswmy Govindarajan31Arkansas Department of Health, Little Rock, 2White River Health System, Batesville, 3Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USABackground: Prostate cancer subjects with prostate-specific antigen (PSA relapse who are treated with androgen deprivation therapy (ADT are recommended to have baseline and serial bone densitometry and receive bisphosphonates. The purpose of this community population study was to assess the utilization of bone densitometry and bisphosphonate therapy in men receiving ADT for non-metastatic prostate cancer.Methods: A cohort study of men aged 65 years or older with non-metastatic incident diagnoses of prostate cancer was obtained from the Surveillance Epidemiology End Results (SEER-linked Medicare claims between 2004 and 2008. Claims were used to assess prescribed treatment of ADT, bone densitometry, and bisphosphonates.Results: A total of 30,846 incident prostate cancer cases receiving ADT and aged 65 years or older had no bone metastases; 87.3% (n=26,935 on ADT did not receive either bone densitometry or bisphosphonate therapy. Three percent (n=931 of the cases on ADT received bisphosphonate therapy without ever receiving bone densitometry, 8.8% (n=2,702 of the cases on ADT received bone densitometry without receiving intravenous bisphosphonates, while nearly 1% (0.90%, n=278 of the cases on ADT received both bone densitometry and bisphosphonates. Analysis showed treatment differed by patient characteristics.Conclusion: Contrary to the recommendations, bone densitometry and bisphosphonate therapy are underutilized in men receiving ADT for non-metastatic prostate cancer.Keywords: prostatic neoplasms, androgen antagonists, bone densitometry, gonadotropin-releasing hormone, osteoporosis

  16. SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis.

    Science.gov (United States)

    Tseng, Ruo-Chia; Lee, Shih-Hua; Hsu, Han-Shui; Chen, Ben-Han; Tsai, Wan-Ching; Tzao, Ching; Wang, Yi-Ching

    2010-01-15

    Chromosome 4p15.3 is frequently deleted in late-stage lung cancer. We investigated the significance of the SLIT2 gene located in this region to lung cancer progression. SLIT2 encodes an extracellular glycoprotein that can suppress breast cancer by regulating beta-catenin. In this study, we examined alterations in the structure or expression of SLIT2, its receptor ROBO1, and beta-catenin, along with the AKT/glycogen synthase kinase 3beta (GSK3beta)/beta-transducin repeat-containing protein (betaTrCP) pathway in lung cancer cell lines and patients. Low SLIT2 expression correlated with an upward trend of pathological stage and poorer survival in lung cancer patients. Importantly, SLIT2, betaTrCP, and beta-catenin expression levels predicted postoperative recurrence of lung cancer in patients. Stimulating SLIT2 expression by various methods increased the level of E-cadherin caused by attenuation of its transcriptional repressor SNAI1. Conversely, knocking down SLIT2 expression increased cell migration and reduced cell adhesion through coordinated deregulation of beta-catenin and E-cadherin/SNAI1 in the AKT/GSK3beta/betaTrCP pathway. Our findings indicate that SLIT2 suppresses lung cancer progression, defining it as a novel "theranostic" factor with potential as a therapeutic target and prognostic predictor in lung cancer. Cancer Res; 70(2); 543-51.

  17. Metastatic Prostate Cancer Diagnosed by Bone Marrow Aspiration in an Elderly Man Not Undergoing PSA Screening

    Directory of Open Access Journals (Sweden)

    Ridwan Alam

    2017-02-01

    Full Text Available Prostate cancer screening by PSA testing remains controversial, particularly in the elderly. Practice guidelines from most clinical societies suggest discontinuing PSA screening at age 70 while the USPSTF recommends against screening at any age. Recent reports have demonstrated an increased incidence of metastatic prostate cancer, with men aged 75 or older accounting for roughly half of those newly diagnosed at an incurable stage. We herein describe the case of an elderly gentleman with no history of prostate cancer screening who presented with anorexia and back pain of unclear etiology. Evaluation with bone marrow aspiration revealed a diagnosis of metastatic prostate cancer.

  18. A novel 3-D mineralized tumor model to study breast cancer bone metastasis.

    Directory of Open Access Journals (Sweden)

    Siddharth P Pathi

    2010-01-01

    Full Text Available Metastatic bone disease is a frequent cause of morbidity in patients with advanced breast cancer, but the role of the bone mineral hydroxyapatite (HA in this process remains unclear. We have developed a novel mineralized 3-D tumor model and have employed this culture system to systematically investigate the pro-metastatic role of HA under physiologically relevant conditions in vitro.MDA-MB231 breast cancer cells were cultured within non-mineralized or mineralized polymeric scaffolds fabricated by a gas foaming-particulate leaching technique. Tumor cell adhesion, proliferation, and secretion of pro-osteoclastic interleukin-8 (IL-8 was increased in mineralized tumor models as compared to non-mineralized tumor models, and IL-8 secretion was more pronounced for bone-specific MDA-MB231 subpopulations relative to lung-specific breast cancer cells. These differences were pathologically significant as conditioned media collected from mineralized tumor models promoted osteoclastogenesis in an IL-8 dependent manner. Finally, drug testing and signaling studies with transforming growth factor beta (TGFbeta confirmed the clinical relevance of our culture system and revealed that breast cancer cell behavior is broadly affected by HA.Our results indicate that HA promotes features associated with the neoplastic and metastatic growth of breast carcinoma cells in bone and that IL-8 may play an important role in this process. The developed mineralized tumor models may help to reveal the underlying cellular and molecular mechanisms that may ultimately enable more efficacious therapy of patients with advanced breast cancer.

  19. Bone resorption deficiency affects tooth root development in RANKL mutant mice due to attenuated IGF-1 signaling in radicular odontoblasts.

    Science.gov (United States)

    Huang, Hong; Wang, Jue; Zhang, Yan; Zhu, Guochun; Li, Yi-Ping; Ping, Ji; Chen, Wei

    2017-12-29

    The tooth root is essential for normal tooth physiological function. Studies on mice with mutations or targeted gene deletions revealed that osteoclasts (OCs) play an important role in tooth root development. However, knowledge on the cellular and molecular mechanism underlying how OCs mediate root formation is limited. During bone formation, growth factors (e.g. Insulin-like growth factor-1, IGF-1) liberated from bone matrix by osteoclastic bone resorption stimulate osteoblast differentiation. Thus, we hypothesize that OC-osteoblast coupling may also apply to OC-odontoblast coupling; therefore OCs may have a direct impact on odontoblast differentiation through the release of growth factor(s) from bone matrix, and consequently regulate tooth root formation. To test this hypothesis, we used a receptor activator of NF-κB ligand (RANKL) knockout mouse model in which OC differentiation and function was entirely blocked. We found that molar root formation and tooth eruption were defective in RANKL-/- mice. Disrupted elongation and disorganization of Hertwig's epithelial root sheath (HERS) was observed in RANKL-/- mice. Reduced expression of nuclear factor I C (NFIC), osterix, and dentin sialoprotein, markers essential for radicular (root) odontogenic cell differentiation indicated that odontoblast differentiation was disrupted in RANKL deficient mice likely contributing to the defect in root formation. Moreover, down-regulation of IGF/AKT/mTOR activity in odontoblast indicated that IGF signaling transduction in odontoblasts of the mutant mice was impaired. Treating odontoblast cells in vitro with conditioned medium from RANKL-/- OCs cultured on bone slices resulted in inhibition of odontoblast differentiation. Moreover, depletion of IGF-1 in bone resorption-conditioned medium (BRCM) from wild-type (WT) OC significantly compromised the ability of WT osteoclastic BRCM to induce odontoblast differentiation while addition of IGF-1 into RANKL-/- osteoclastic BRCM rescued

  20. Management of bone loss in postmenopausal breast cancer patients treated with aromatase inhibitors

    Directory of Open Access Journals (Sweden)

    Margarida Cepa

    2015-10-01

    Full Text Available Breast cancer is the most commonly diagnosed cancer among women, but despite survival rates improvement, it is still the second major cause of cancer related death. In postmenopausal women with estrogen receptor (ER dependent breast cancer, hormone therapy is an option, either by direct inhibition of ER using tamoxifen or by aromatase inhibition, resulting in decreased estrogen production. In this paper these two endocrine therapy approaches are compared in terms of their impact on bone health. Guidance for the prevention of bone loss and occurrence of fractures in postmenopausal women receiving AIs is also proposed. Despite intervention strategies to maintain bone health in AI-treated patients are not well established, recommendations by international societies to identify women with high risk of fracture and advice on the preventive anti-fracture therapy are exposed. Finally, available therapeutic options for management of bone loss in patients receiving AIs are presented. The search strategy for this literature review was conducted by using the key words “aromatase inhibitor*” and “bone loss” OR “aromatase inhibitor*” and “osteoporosis” in the MEDLINE/PubMed database. Nowadays, hormone-responsive breast cancer in postmenopausal women is preferably being treated with AIs instead of tamoxifen, due to clear benefits in disease-free survival and reduced recurrence. AIs have an advantageous side effect profile compared to tamoxifen, however all AIs have detrimental long-term effects on bone, due to nearly complete depletion of estrogens, resulting in increased bone loss and increased risk of fracture. Current recommendations state that all women treated with AIs should be evaluated for their fracture risk prior to initiation of AI-treatment, taking in consideration individual bone mineral density and several risk factors. The thresholds to introduce preventive therapy and drugs proposed differ among the available recommendations

  1. Management of bone loss in postmenopausal breast cancer patients treated with aromatase inhibitors.

    Science.gov (United States)

    Cepa, M; Vaz, C

    2015-01-01

    Breast cancer is the most commonly diagnosed cancer among women, but despite survival rates improvement, it is still the second major cause of cancer related death. In postmenopausal women with estrogen receptor (ER) dependent breast cancer, hormone therapy is an option, either by direct inhibition of ER using tamoxifen or by aromatase inhibition, resulting in decreased estrogen production. In this paper these two endocrine therapy approaches are compared in terms of their impact on bone health. Guidance for the prevention of bone loss and occurrence of fractures in postmenopausal women receiving AIs is also proposed. Despite intervention strategies to maintain bone health in AI-treated patients are not well established, recommendations by international societies to identify women with high risk of fracture and advice on the preventive anti-fracture therapy are exposed. Finally, available therapeutic options for management of bone loss in patients receiving AIs are presented. The search strategy for this literature review was conducted by using the key words "aromatase inhibitor*" and "bone loss" OR "aromatase inhibitor*" and "osteoporosis" in the MEDLINE/PubMed database. Nowadays, hormone-responsive breast cancer in postmenopausal women is preferably being treated with AIs instead of tamoxifen, due to clear benefits in disease-free survival and reduced recurrence. AIs have an advantageous side effect profile compared to tamoxifen, however all AIs have detrimental long-term effects on bone, due to nearly complete depletion of estrogens, resulting in increased bone loss and increased risk of fracture. Current recommendations state that all women treated with AIs should be evaluated for their fracture risk prior to initiation of AI-treatment, taking in consideration individual bone mineral density and several risk factors. The thresholds to introduce preventive therapy and drugs proposed differ among the available recommendations. Lifestyle modifications and adequate

  2. Identification of bone and liver metastases from breast cancer by measurement of plasma alkaline phosphatase isoenzyme activity.

    OpenAIRE

    Mayne, P D; Thakrar, S; Rosalki, S B; Foo, A Y; Parbhoo, S

    1987-01-01

    Plasma alkaline phosphatase isoenzyme activities were determined in patients with breast cancer to diagnose and monitor bone and liver metastases. Bone alkaline phosphatase activity was increased in 21 of 50 patients (42%) with radiologically confirmed bone metastases, while total alkaline phosphatase activity was increased in only 10 of 50 (20%); liver alkaline phosphatase activity was raised in 12 of 25 patients (48%) with liver metastases. All patients with liver metastases had bone metast...

  3. Evaluation of clinical parameters influencing the development of bone metastasis in breast cancer.

    Science.gov (United States)

    Diessner, Joachim; Wischnewsky, Manfred; Stüber, Tanja; Stein, Roland; Krockenberger, Mathias; Häusler, Sebastian; Janni, Wolfgang; Kreienberg, Rolf; Blettner, Maria; Schwentner, Lukas; Wöckel, Achim; Bartmann, Catharina

    2016-05-12

    The development of metastases is a negative prognostic parameter for the clinical outcome of breast cancer. Bone constitutes the first site of distant metastases for many affected women. The purpose of this retrospective multicentre study was to evaluate if and how different variables such as primary tumour stage, biological and histological subtype, age at primary diagnosis, tumour size, the number of affected lymph nodes as well as grading influence the development of bone-only metastases. This retrospective German multicentre study is based on the BRENDA collective and included 9625 patients with primary breast cancer recruited from 1992 to 2008. In this analysis, we investigated a subgroup of 226 patients with bone-only metastases. Association between bone-only relapse and clinico-pathological risk factors was assessed in multivariate models using the tree-building algorithms "exhausted CHAID (Chi-square Automatic Interaction Detectors)" and CART(Classification and Regression Tree), as well as radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression. Multivariate analysis demonstrated that breast cancer subtypes have the strongest influence on the development of bone-only metastases (χ2 = 28). 29.9 % of patients with luminal A or luminal B (ABC-patients) and 11.4 % with triple negative BC (TNBC) or HER2-overexpressing tumours had bone-only metastases (p bottom line of different mathematical models is the prior importance of subcategories of breast cancer and the age at primary diagnosis for the appearance of osseous metastases. The primary tumour stage, histological subtype, tumour size, the number of affected lymph nodes, grading and NPI seem to have only a minor influence on the development of bone-only metastases.

  4. β-Elemene-Attenuated Tumor Angiogenesis by Targeting Notch-1 in Gastric Cancer Stem-Like Cells

    Directory of Open Access Journals (Sweden)

    Bing Yan

    2013-01-01

    Full Text Available Emerging evidence suggests that cancer stem cells are involved in tumor angiogenesis. The Notch signaling pathway is one of the most important regulators of these processes. β-Elemene, a naturally occurring compound extracted from Curcumae Radix, has been used as an antitumor drug for various cancers in China. However, its underlying mechanism in the treatment of gastric cancer remains largely unknown. Here, we report that CD44+ gastric cancer stem-like cells (GCSCs showed enhanced proliferation capacity compared to their CD44− counterparts, and this proliferation was accompanied by the high expression of Notch-1 (in vitro. These cells were also more superior in spheroid colony formation (in vitro and tumorigenicity (in vivo and positively associated with microvessel density (in vivo. β-Elemene was demonstrated to effectively inhibit the viability of GCSCs in a dose-dependent manner, most likely by suppressing Notch-1 (in vitro. β-Elemene also contributed to growth suppression and attenuated the angiogenesis capacity of these cells (in vivo most likely by interfering with the expression of Notch-1 but not with Dll4. Our findings indicated that GCSCs play an important role in tumor angiogenesis, and Notch-1 is one of the most likely mediators involved in these processes. β-Elemene was effective at attenuating angiogenesis by targeting the GCSCs, which could be regarded as a potential mechanism for its efficacy in gastric cancer management in the future.

  5. Simultaneous screening for osteoporosis at CT colonography: bone mineral density assessment using MDCT attenuation techniques compared with the DXA reference standard.

    Science.gov (United States)

    Pickhardt, Perry J; Lee, Lawrence J; del Rio, Alejandro Muñoz; Lauder, Travis; Bruce, Richard J; Summers, Ron M; Pooler, B Dustin; Binkley, Neil

    2011-09-01

    The purpose of this study was to evaluate the utility of lumbar spine attenuation measurement for bone mineral density (BMD) assessment at screening computed tomographic colonography (CTC) using central dual-energy X-ray absorptiometry (DXA) as the reference standard. Two-hundred and fifty-two adults (240 women and 12 men; mean age 58.9 years) underwent CTC screening and central DXA BMD measurement within 2 months (mean interval 25.0 days). The lowest DXA T-score between the spine and hip served as the reference standard, with low BMD defined per World Health Organization as osteoporosis (DXA T-score ≤ -2.5) or osteopenia (DXA T-score between -1.0 and -2.4). Both phantomless quantitative computed tomography (QCT) and simple nonangled region-of-interest (ROI) multi-detector CT (MDCT) attenuation measurements were applied to the T(12) -L(5) levels. The ability to predict osteoporosis and low BMD (osteoporosis or osteopenia) by DXA was assessed. A BMD cut-off of 90 mg/mL at phantomless QCT yielded 100% sensitivity for osteoporosis (29 of 29) and a specificity of 63.8% (143 of 224); 87.2% (96 of 110) below this threshold had low BMD and 49.6% (69 of 139) above this threshold had normal BMD at DXA. At L(1) , a trabecular ROI attenuation cut-off of 160 HU was 100% sensitive for osteoporosis (29 of 29), with a specificity of 46.4% (104 of 224); 83.9% (125 of 149) below this threshold had low BMD and 57.5% (59/103) above had normal BMD at DXA. ROI performance was similar at all individual T(12) -L(5) levels. At ROC analysis, AUC for osteoporosis was 0.888 for phantomless QCT [95% confidence interval (CI) 0.780-0.946] and ranged from 0.825 to 0.853 using trabecular ROIs at single lumbar levels (0.864; 95% CI 0.752-0.930 at multivariate analysis). Supine-prone reproducibility was better with the simple ROI method compared with QCT. It is concluded that both phantomless QCT and simple ROI attenuation measurements of the lumbar spine are effective for BMD screening at CTC

  6. Solitary bone metastasis to the tibia from colorectal cancer- A case report

    Directory of Open Access Journals (Sweden)

    Abdulsalam Alnajjar

    2014-12-01

    Full Text Available The onset of osseous metastases during the course of colorectal cancer is not common. Although rare, they usually appear in the axial skeleton. In our report, we refer to the case of a 48-year-old patient who presented with colon cancer and eventually developed a solitary bone metastasis in the upper end of left tibia. At the time of diagnosis and staging investigations, the patient had only a primary disease.------------------------------------------------Cite this article as:Alnajjar A, Mohanty AK. Solitary bone metastasis to the tibia from colorectal cancer- A case report. Int J Cancer Ther Oncol 2014; 2(4:02045. DOI: 10.14319/ijcto.0204.5

  7. Bone complications among prostate cancer survivors: long-term follow-up from the prostate cancer outcomes study.

    Science.gov (United States)

    Morgans, A K; Fan, K-H; Koyama, T; Albertsen, P C; Goodman, M; Hamilton, A S; Hoffman, R M; Stanford, J L; Stroup, A M; Penson, D F

    2014-12-01

    To assess the relationship between androgen deprivation therapy (ADT) exposure and self-reported bone complications among men in a population-based cohort of prostate cancer survivors followed for 15 years after diagnosis. The Prostate Cancer Outcomes Study enrolled 3533 patients diagnosed with prostate cancer between 1994 and 1995. This analysis included participants with non-metastatic disease at the time of diagnosis who completed 15-year follow-up surveys to report development of fracture, and use of bone-related medications. The relationship between ADT duration and bone complications was assessed using multivariable logistic regression models. Among 961 surviving men, 157 (16.3%) received prolonged ADT (>1 year), 120 (12.5%) received short-term ADT (⩽ 1 year) and 684 (71.2%) did not receive ADT. Men receiving prolonged ADT had higher odds of fracture (OR 2.5; 95% confidence interval (CI): 1.1-5.7), bone mineral density testing (OR 5.9; 95% CI: 3.0-12) and bone medication use (OR 4.3; 95% CI: 2.3-8.0) than untreated men. Men receiving short-term ADT reported rates of fracture similar to untreated men. Half of men treated with prolonged ADT reported bone medication use. In this population-based cohort study with long-term follow-up, prolonged ADT use was associated with substantial risks of fracture, whereas short-term use was not. This information should be considered when weighing the advantages and disadvantages of ADT in men with prostate cancer.

  8. Periportal low attenuation associated with liver metastasis from colorectal cancer: evaluation using multi-detector-row CT with pathological correlation.

    Science.gov (United States)

    Takaji, Ryo; Matsumoto, Shunro; Kiyonaga, Maki; Yamada, Yasunari; Mori, Hiromu; Iwashita, Yukio; Ohta, Masayuki; Inomata, Masafumi; Hijiya, Naoki; Moriyama, Masatsugu; Takaki, Hajime; Fukuzawa, Kengo; Yonemasu, Hirotoshi

    2017-01-01

    Periportal low attenuation (PPLA) associated with metastatic liver cancer is occasionally seen on multi-detector-row CT (MDCT). The purpose of this study was to investigate the MDCT patterns of the PPLA and to correlate it with pathological findings. We retrospectively reviewed the MDCT images of 63 patients with metastatic liver cancers from colorectal adenocarcinoma. On MDCT scans, PPLA associated with liver metastasis was visualized in six patients with colorectal cancer. In these six patients who had undergone surgical resection, the radiologic-pathologic correlation was analyzed. All patients underwent a single contrast-enhanced MDCT within 1 month before surgical resection. The six liver cancers were pathologically proven to be moderately differentiated adenocarcinoma. We assessed the PPLA on MDCT concerning the distribution patterns and contrast enhancement with pathological correlation. In five of the patients, the PPLA extended to the hilar side from metastatic liver cancer. Pathologically, there was no cancer invasion into the intra-hepatic periportal area; however, massive lymphedema and fibrosis occurred in all six cases. PPLA on the hilar and peripheral sides of hepatic metastasis from colorectal cancer may be present suggesting lymphedema and fibrosis of portal tracts not always indicating cancer infiltration.

  9. Comparison of bone mineral density in young patients with breast cancer and healthy women

    Directory of Open Access Journals (Sweden)

    Sousan Kolahi

    2014-05-01

    Full Text Available BACKGROUND: Almost 1 in 8 women will have breast cancer during their lifetime. Several risk factors were identified; however, 70% of females with breast cancer have no risk factors. Many risk factors are associated with sex steroid hormones. Some studies have been focused on identification of the indices of cumulative exposures to estrogen during the patients’ life. One of these indicators is bone mineral density (BMD. Our aim was the comparison of BMD in young patients with and without breast cancer, and finding a relationship between breast cancer and bone density. METHODS: In this case-control study, 120 people were enrolled; 40 patients with breast cancer and 80 normal healthy persons as control group. Measurement of BMD was performed in both groups and compared. RESULTS: Both groups were matched in age, weight, age at menarche, age at first marriage and first pregnancy, number of pregnancies over 32 weeks and lactation period, and taking supplemental calcium and vitamin D. However, there was a significant difference between the two groups in terms of estrogen intake, family history of breast cancer, and history of breast masses (P = 0.03, P = 0.03, P ≤ 0.01, respectively. A significant difference was found between BMD, bone mineral content (BMC, and t-scores of lumbar spine of the two groups; they were higher in the control group (P = 0.08, P ≤ 0.01, P = 0.06, respectively. CONCLUSIONS: This study shows that bone mineral density of young patients with breast cancer is not higher than normal similar age females; thus, BMD is not directly a risk factor for breast cancer.

  10. Bone pain palliation with Strontium-89 in cancer patients with bone metastases

    Energy Technology Data Exchange (ETDEWEB)

    Giammarile, F. [Centre Leon Berard, Dept. of Nuclear Medicine, Lyon (France); Mognetti, T. [Centre Hospitalier Universitaire Edouard Herriot, Lyon (France); Resche, I. [Centre Rene Gauducheau, Nantes (France)

    2001-03-01

    Strontium-89 is s pure {beta}-emitting radioisotope, a chemical analogue of calcium, and it is therefore avidly concentrated by areas of high osteoblastic activity. Selective uptake and prolonged retention at sites of increased bone mineral turnover provide precise bone lesions targeting. {sup 89}Sr chloride (commercialised as Metastron(R)) is typically administered in a single 150 MBq parenteral dose. Its radioactive emission poses very little radioprotection concerns. Overall, studies show pain relief in up to 80% of patients, of which 10 to 40% became effectively pain free. The mean duration of palliation was 3-4 months. The mechanism of pain relief is controversial; it is probably, but not only, related to the absorbed dose in the tumor and bone. There is no clear dose-response relationship. The only reported toxicity is temporary myelosuppression. WBC and platelets should be monitored at least on a weekly basis until they return to baseline. It seems that only patients with a reasonably good general condition stand to benefit from this treatment. In conclusion, systemic radionuclide therapy using {sup 89}Sr represents a feasible, safe, effective, well tolerated and cost-effective palliative treatment in patients with refractory bone pain.

  11. The diagnostic and prognostic value of serum bone Gla protein (osteocalcin) in patients with recurrent breast cancer

    DEFF Research Database (Denmark)

    Kamby, C; Egsmose, C; Söletormos, G

    1993-01-01

    Serum bone Gla protein (S-BGP), a marker of bone metabolism, was measured in 60 patients included in a staging programme for recurrent breast cancer. Other diagnostic procedures comprised S-alkaline phosphatase (S-AP), bone scan (B-scan), bilateral iliac crest bone marrow biopsies, and radiological....... S-alkaline phosphatase (S-AP) and S-BGP were the only significant, independent prognostic factors....... bone survey. The sites of recurrence were bone (61%), bone marrow (46%), soft tissue (52%), lung (13%), pleura (11%), liver (4%), and brain (2%). Radiology and bone biopsy served as key diagnoses as to the presence or absence of bone metastases. The diagnostic efficiency of B-scan and S-AP was greater...

  12. Breast cancer bone metastases: an epidemiologic study in selected radiation departments.

    Science.gov (United States)

    Runco, Raffaele; Laganà, Simona; Marino, Giacomo; Di Grazia, Alfio; Marino, Lorenza; Umina, Vincenza; Girlando, Andrea; Ricottone, Nicola; D'Agostino, Antonino; Marletta, Francesco; Tamburo, Maria; Corsaro, Giuseppe; Rallo, Francesco; Santacaterina, Anna; Acquaviva, Grazia; Crispi, Manuela; Palazzolo, Carmela; Platania, Angelo; Spatola, Corrado; Privitera, Giuseppe; Frosina, Pasquale; Garufi, Giuseppe; Bonanno, Salvatore; Rosso, Alberto; Barone, Vincenzo; Corallo, Anna; Sansotta, Giuseppe; Delia, Pietro; Donato, Valentino; Lopes, Salvatore; Pisana, Michele; Borzì, Francesca; Iatì, Giuseppe; Potami, Antonio; Messina, Giovanna; Parisi, Silvana; Frosina, Luciano; Marletta, Dario; De Renzis, Costantino; Pontoriero, Antonio; Pergolizzi, Stefano

    2014-01-01

    To quantify radiation treatments for bone metastases from breast cancer in three Sicilian provinces (Messina, Catania, Ragusa) with respect to the general population and the incidence and prevalence of breast cancer in this macro-area in a 8-year period. All bone metastasis patients treated using radiotherapy in 8 radiation departments operating in the provinces of Messina, Catania and Ragusa were collected. Among these, metastases from breast carcinoma were analyzed according to year of irradiation. An analysis of breast cancer incidence and prevalence with respect to inhabitants in this macro-area was conducted using literature and census data. From January 2004 to December 2011, irradiation was delivered in 4419 bone metastasis patients. Among these, 1617 had a primary breast cancer with a median treatment per year of 206.5 (range, 164-251); 211 patients were treated in 2004 and 206 in 2011. In 2004, there were 1,048,957 female residents in the three provinces and 1,065,422 in 2011. The reported breast cancer incidence and prevalence in Sicily was respectively 100.79/100,000 and 908.54/100,000 in 2004 and 108.41/100,000 and 1091.29/100,000 in 2010. There has been an increase in both incidence and prevalence of breast cancer in Sicily. Nevertheless, it seems that there was no increment in skeletal-related events requiring irradiation in such patients in eastern Sicily radiation departments.

  13. Glycinol Enhances Osteogenic Differentiation and Attenuates the Effects of Aging on Bone Marrow-derived Mesenchymal Stem Cells

    Science.gov (United States)

    Osteoporosis is characterized by decreased bone mineral density and increased risk of fractures. It is most prevalent in the elderly population, leading to significant morbidity and mortality. Recently, phytoestrogens have gained significant attention as an alternative therapy due to their structura...

  14. Detection and correlation analysis of serum cytokines in non-small-cell lung cancer patients with bone and non-bone metastases

    Directory of Open Access Journals (Sweden)

    Sun Y

    2015-08-01

    Full Text Available Yingjia Sun, Xinghao Ai, Shengping Shen, Linping Gu, Shun Lu Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China Objective: To detect and analyze 13 cytokines that may be related to bone metastasis in the serum of non-small-cell lung cancer (NSCLC patients with bone metastases and NSCLC patients with non-bone metastases.Patients and methods: The Luminex LiquiChip system was used to detect the concentration of 13 cytokines that may be related to bone metastasis in the serum of 30 NSCLC patients with bone metastases and 30 with non-bone metastases.Results: The concentration of insulin-like growth factor binding protein-3 (IGFBP-3 in the serum of NSCLC patients with bone metastases was obviously higher than in non-bone metastasis patients (P=0.014. The serum concentration of other cytokines showed no significant difference (P>0.05 between the two groups. The concentration of IGFBP-3 in the serum of the bone metastasis group was positively correlated to VEGF concentration (r=0.804, P=0.009 and monocyte chemotactic protein 1 (MCP-1 concentration (r=0.785, P=0.012, but had no correlation to other factors (P>0.05. No correlation was found between serum concentrations of cytokines in bone metastasis. Concentration of IGFBP-3 in the serum of bone metastasis patients was positively correlated to the presence or absence of pain at diagnosis (r=0.701, P=0.036 and performance status (PS score (r=0.670, P=0.048, and correlated with the number of bone metastases, sex, age, pathological characteristics, T stage, and N stage (P>0.05.Conclusion: The findings of this study suggest important clinical implications to detect the concentration of IGFBP-3 in the serum of lung cancer patients so as to evaluate the diagnosis and degree of bone metastasis. Concentration of IGFBP-3 in the serum of bone metastasis patients was positively correlated to concentration of VEGF and MCP-1, which may be

  15. Cross-linked type I collagen C- and N-telopeptides in women with bone metastases from breast cancer.

    Science.gov (United States)

    Ulrich, U; Rhiem, K; Schmolling, J; Flaskamp, C; Paffenholz, I; Sälzer, H; Bauknecht, T; Schlebusch, H

    2001-01-01

    This study documents values of biochemical markers of bone remodeling in 106 patients with breast cancer. Based on scintigraphic and radiological findings, patients were divided into 3 groups: 19 patients with bone metastases, 65 patients without bone metastases and normal bone scintigrams, and 22 patients with pathological, non-malignant findings on scintigraphy without proof of bone metastases. Urinary cross-linked type I collagen N-telopeptides (NTx) and serum cross-linked type I collagen C-telopeptides (ICTP) were assessed as markers of bone resorption. Bone alkaline phosphatase (BAP) was assessed as a marker of bone formation. All three markers were significantly higher in patients with bone metastases compared to both patients without skeletal recurrence and those with pathological, non-malignant scintigraphic findings (p < 0.01). There were no statistically significant differences between the latter two groups. The clinical sensitivity for diagnosing bone metastases was 44% for NTx, 65% for ICTP, and 26% for BAP, respectively. The clinical specificitiy for discriminating patients with bone disease from those without were 79%, 91%, and 92% for NTx, ICTP, and BAP, respectively. In conclusion, markers of bone remodeling are increased in patients with breast cancer metastatic to the skeleton. The sensitivity of the markers presented in this paper did not seem to be sufficient enough for early identification of patients with subclinical bone recurrence in a clinical practice setting.

  16. [Analysis of risk factors for bone metastasis after radical resection of colorectal cancer within 5 years].

    Science.gov (United States)

    Li, Ang; Tan, Zhen; Fu, Chuangang; Wang, Hao; Yuan, Jie

    2017-01-25

    To investigate the risk factors of metachronous bone metastasis after radical resection of colorectal cancer within 5 years. Clinical data of 1 749 patients with colorectal cancer, of whom 50(2.8%) patients developed metastasis to bone after operation, in the Department of Colorectal Surgery, Changhai Hospital of The Second Military Medical University from January 2001 to December 2010 were analyzed retrospectively. Univariate and multivariate analysis were performed to find the risk factors of metachronous bone metastasis from colorectal cancer using Chi square test and Logistic regression, respectively. Of 50 colorectal cancer cases with bone metastasis, 29 were male and 21 were female. The age was ≥ 60 years old in 28 cases. Tumors of 36 cases were located in the rectum and of 14 cases located in the colon. Pathology examination showed 43 cases were adenocarcinomas, 7 cases were mucinous adenocarcinoma. Forty-two cases had T3-4 stage lesions, 30 cases had lymph node metastasis, 14 cases had pulmonary metastasis, and 5 cases had liver metastasis. Univariate Chi square test indicated that factors associated with the metachronous bone metastasis of colorectal cancer within 5 years were tumor site (χ2=4.932, P=0.026), preoperative carbohydrate antigen 199 (CA199) level (χ2=4.266, P=0.039), lymph node metastasis (χ2=13.054, P=0.000) and pulmonary metastasis(χ2=35.524, P=0.000). The incidence of bone metastasis in patients with rectal cancer (3.6%, 36/991) was higher compared to those with colon cancer (1.8%, 14/758). The incidence of bone metastasis in patients with higher(> 37 kU/L) preoperative serum CA199 level (4.9%, 12/245) was higher compared to those with lower serum CA199 level (2.5%, 38/1504). The incidence of bone metastasis in patients with lymph node metastasis(4.8%,30/627) and pulmonary metastasis (11.6%, 14/121) was significantly higher compared to those without lymph node metastasis (1.8%, 20/1122) and pulmonary metastasis(2.2%, 36

  17. Perilipin1 deficiency in whole body or bone marrow-derived cells attenuates lesions in atherosclerosis-prone mice.

    Directory of Open Access Journals (Sweden)

    Xiaojing Zhao

    Full Text Available The objective of this study is to determine the role of perilipin 1 (Plin1 in whole body or bone marrow-derived cells on atherogenesis.Accumulated evidence have indicated the role of Plin1 in atherosclerosis, however, these findings are controversial. In this study, we showed that Plin1 was assembled and colocalized with CD68 in macrophages in atherosclerotic plaques of ApoE-/- mice. We further found 39% reduction of plaque size in the aortic roots of Plin1 and ApoE double knockout (Plin1-/-ApoE-/- females compared with ApoE-/- female littermates. In order to verify whether this reduction was macrophage-specific, the bone marrow cells from wild-type or Plin1 deficient mice (Plin1-/- were transplanted into LDL receptor deficient mice (LDLR-/-. Mice receiving Plin1-/- bone marrow cells showed also 49% reduction in aortic atherosclerotic lesions compared with LDLR-/- mice received wild-type bone marrow cells. In vitro experiments showed that Plin1-/- macrophages had decreased protein expression of CD36 translocase and an enhanced cholesterol ester hydrolysis upon aggregated-LDL loading, with unaltered expression of many other regulators of cholesterol metabolism, such as cellular lipases, and Plin2 and 3. Given the fundamental role of Plin1 in protecting LD lipids from lipase hydrolysis, it is reasonably speculated that the assembly of Plin1 in microphages might function to reduce lipolysis and hence increase lipid retention in ApoE-/- plaques, but this pro-atherosclerotic property would be abrogated on inactivation of Plin1.Plin1 deficiency in bone marrow-derived cells may be responsible for reduced atherosclerotic lesions in the mice.

  18. The role of purinergic receptors in cancer-induced bone pain

    DEFF Research Database (Denmark)

    Falk, Sarah; Uldall, Maria; Heegaard, Anne-Marie

    2012-01-01

    Cancer-induced bone pain severely compromises the quality of life of many patients suffering from bone metastasis, as current therapies leave some patients with inadequate pain relief. The recent development of specific animal models has increased the understanding of the molecular and cellular...... mechanisms underlying cancer-induced bone pain including the involvement of ATP and the purinergic receptors in the progression of the pain state. In nociception, ATP acts as an extracellular messenger to transmit sensory information both at the peripheral site of tissue damage and in the spinal cord....... Several of the purinergic receptors have been shown to be important for the development and maintenance of neuropathic and inflammatory pain, and studies have demonstrated the importance of both peripheral and central mechanisms. We here provide an overview of the current literature on the role...

  19. Evaluation of Bone Cancer Pain Induced by Different Doses of Walker 256 Mammary Gland Carcinoma Cells.

    Science.gov (United States)

    Dong, Changsheng; Wu, RuiXin; Wu, Jing; Guo, Jing; Wang, Fangyuan; Fu, Yanli; Wang, Qing; Xu, Ling; Wang, Juyong

    2016-01-01

    Cancer pain is a complex medical syndrome. Understanding its underlying mechanisms relies on the use of animal models which can mimic the human condition. A crucial component of this model is the quantity of tumor cells; however, the exact relationship between the doses of tumor cells on bone cancer pain is yet unknown. We explored the relationship of different doses of Walker 256 carcinoma cells using a bone cancer pain model in rats, and evaluated its success and stability. Experimental animal study using a comparative design. Experimental Animal Center and Tumor Institute of Traditional Chinese Medicine. We constructed the bone cancer pain model by implanting Walker 256 carcinoma cells into the right tibia of Sprague-Dawley (SD) rats (150 - 170 g). Spontaneous pain, mechanical threshold, and paw withdrawal latency (PWL) were measured and x-ray, bone mineral density (BMD), histological, interleukin-1 beta (IL-1beta) mRNA, carboxyterminal telopeptide of type I collagen (ICTP), and bone alkaline phosphatase (BAP) were analyzed for bone pain model evaluation. The results showed that: (1) the 3 doses (3×105, 3.5×105, 4×105) of Walker 256 carcinoma cells can induce bone cancer pain from day 7 to day 21 after implantation into the right tibia of SD rats; (2) compared to the control group, 3×105, 3.5×105, and 4×105 Walker 256 carcinoma cells produced different pain manifestations, where the 3.5×105 dose of Walker 256 carcinoma cells resulted in the greatest bone cancer pain response; (3) the 3.5×105 dose induced the lowest mortality rate in rats; (4) Walker 256 carcinoma cells (3×105, 3.5×105, and 4×105) resulted in a significant decrease in the general condition and body weight of rats, where the 3.5×105 and 4×105 doses of carcinoma cells produced a greater effect than 3×105 dose of carcinoma cells; (5) progressive spontaneous pain, PWL, and mechanical threshold were exacerbated by 3.5×105 and 4×105 doses of carcinoma cells; (6) implantation of 3.5×105

  20. Specific Inhibition of the Nuclear Exporter Exportin-1 Attenuates Kidney Cancer Growth

    Science.gov (United States)

    Wettersten, Hiromi I.; Landesman, Yosef; Friedlander, Sharon; Shacham, Sharon; Kauffman, Michael; Weiss, Robert H.

    2014-01-01

    Purpose Despite the advent of FDA-approved therapeutics to a limited number of available targets (kinases and mTOR), PFS of kidney cancer (RCC) has been extended only one to two years due to the development of drug resistance. Here, we evaluate a novel therapeutic for RCC which targets the exportin-1 (XPO1) inhibitor. Materials and Methods RCC cells were treated with the orally available XPO1 inhibitor, KPT-330, and cell viability and Annexin V (apoptosis) assays, and cell cycle analyses were performed to evaluate the efficacy of KPT-330 in two RCC cell lines. Immunoblotting and immunofluorescence analysis were performed to validate mechanisms of XPO1 inhibition. The efficacy and on-target effects of KPT-330 were further analyzed in vivo in RCC xenograft mice, and KPT-330-resistant cells were established to evaluate potential mechanisms of KPT-330 resistance. Results KPT-330 attenuated RCC viability through growth inhibition and apoptosis induction both in vitro and in vivo, a process in which increased nuclear localization of p21 by XPO1 inhibition played a major role. In addition, KPT-330 resistant cells remained sensitive to the currently approved for RCC multi-kinase inhibitors (sunitinib, sorafenib) and mTOR inhibitors (everolimus, temsirolimus), suggesting that these targeted therapeutics would remain useful as second line therapeutics following KPT-330 treatment. Conclusion The orally-available XPO1 inhibitor, KPT-330, represents a novel target for RCC whose in vivo efficacy approaches that of sunitinib. In addition, cells resistant to KPT-330 retain their ability to respond to available RCC therapeutics suggesting a novel approach for treatment in KPT-330-naïve as well as -resistant RCC patients. PMID:25461627

  1. Specific inhibition of the nuclear exporter exportin-1 attenuates kidney cancer growth.

    Directory of Open Access Journals (Sweden)

    Hiromi I Wettersten

    Full Text Available PURPOSE: Despite the advent of FDA-approved therapeutics to a limited number of available targets (kinases and mTOR, PFS of kidney cancer (RCC has been extended only one to two years due to the development of drug resistance. Here, we evaluate a novel therapeutic for RCC which targets the exportin-1 (XPO1 inhibitor. MATERIALS AND METHODS: RCC cells were treated with the orally available XPO1 inhibitor, KPT-330, and cell viability and Annexin V (apoptosis assays, and cell cycle analyses were performed to evaluate the efficacy of KPT-330 in two RCC cell lines. Immunoblotting and immunofluorescence analysis were performed to validate mechanisms of XPO1 inhibition. The efficacy and on-target effects of KPT-330 were further analyzed in vivo in RCC xenograft mice, and KPT-330-resistant cells were established to evaluate potential mechanisms of KPT-330 resistance. RESULTS: KPT-330 attenuated RCC viability through growth inhibition and apoptosis induction both in vitro and in vivo, a process in which increased nuclear localization of p21 by XPO1 inhibition played a major role. In addition, KPT-330 resistant cells remained sensitive to the currently approved for RCC multi-kinase inhibitors (sunitinib, sorafenib and mTOR inhibitors (everolimus, temsirolimus, suggesting that these targeted therapeutics would remain useful as second line therapeutics following KPT-330 treatment. CONCLUSION: The orally-available XPO1 inhibitor, KPT-330, represents a novel target for RCC whose in vivo efficacy approaches that of sunitinib. In addition, cells resistant to KPT-330 retain their ability to respond to available RCC therapeutics suggesting a novel approach for treatment in KPT-330-naïve as well as -resistant RCC patients.

  2. An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis.

    Directory of Open Access Journals (Sweden)

    Shikha Vashisht

    Full Text Available Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.

  3. p53 Regulates Bone Differentiation and Osteosarcoma Formation | Center for Cancer Research

    Science.gov (United States)

    Osteosarcoma is an uncommon cancer that usually begins in the large bones of the arm or leg, but is the second leading cause of cancer-related death in children and young adults. The tumor suppressor protein, p53, appears to be an important player in osteosarcomagenesis in part because these cancers are one of the most common to develop in patients with Li-Fraumeni syndrome, which is caused by an inherited mutation in p53. However, the precise role of p53 in osteosarcoma development has not been established. To begin investigating its importance to the formation of normal bone and osteosarcomas, Jing Huang, Ph.D., of CCR’s Laboratory of Cancer Biology and Genetics, and his colleagues, isolated bone marrow-derived mesenchymal stem cells (BMSCs) from p53 wild type (WT) and knock out (KO) mice using a recently validated approach. Because BMSCs are one of the cells-of-origin of osteosarcoma, they serve as a useful model system. BMSCs contain a subset of multipotent stem cells that can differentiate into several cell types, including osteoblasts, and are important mediators of bone homeostasis.

  4. Factors predicting skeletal-related events in patients with bone metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Klaassen, Zachary; Howard, Lauren E; de Hoedt, Amanda; Amling, Christopher L; Aronson, William J; Cooperberg, Matthew R; Kane, Christopher J; Terris, Martha K; Freedland, Stephen J

    2017-05-01

    Skeletal-related events (SREs) are common complications of bone metastatic castration-resistant prostate cancer (mCRPC). To the authors' knowledge, there are limited data regarding which factors predict SREs. The authors identified risk factors for SREs in men with bone mCRPC using characteristics commonly available in the medical record. Data from 454 patients with nonmetastatic CRPC were identified from 2 Veteran Affairs Medical Centers from 2000 through 2013. Among these men, 233 (51%) developed bone metastases during follow-up and represented the study cohort. First occurrence of an SRE was abstracted from the medical records. A stepwise multivariable Cox model was used to select the strongest predictors of time to SRE. The median age of the patients at the time of diagnosis of bone mCRPC was 75 years (interquartile range, 68-81 years), and there were 153 nonblack patients (66%). During follow-up (median, 7.8 months [interquartile range, 2.9-18.3 months]), 88 patients (38%) had an SRE. On univariable analysis, more recent year of metastasis (hazard ratio [HR], 0.91), prostate-specific antigen doubling time of ≥9 months versus Cancer 2017;123:1528-1535. © 2017 American Cancer Society. © 2016 American Cancer Society.

  5. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, RR; Nielsen, CK; Nasser, A

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice ...

  6. A Rare Colon Cancer with Ossification: Pathogenetic Analysis of Bone Formation.

    Science.gov (United States)

    Noh, Byeong-Joo; Kim, Youn Wha; Park, Yong-Koo

    2016-07-01

    Heterotopic ossification occurring in colon cancer is an exceedingly rare event. The pathogenetic mechanism of tumor-related heterotopic bone formation remains unclear. Herein, we describe a rare case of colon cancer with ossification in a 76-year-old woman. We also highlight the etiology of heterotopic ossification by immunohistochemical evaluation of novel markers such as bone morphogenetic protein 9 (BMP9), osteocalcin, osteopontin, and β-catenin. BMP9 is one of the most potent osteogenetic BMPs. However, no previous research has been performed concerning BMP9 in heterotopic ossification arising in colon cancer. Subsequently, we suggest a hypothesis of tumor-associated heterotopic bone formation through this case. When osteoblastic indicators including BMP9, osteocalcin, and osteopontin are upregulated in tumor cells, osteoblast-like transformation of such tumor cells occurs. These tumor cells augment the release of interactive osteogenetic factors (BMP9, osteocalcin, and osteopontin) and stimulate uncommitted mesenchymal stromal cells into specific osteoblastic differentiation, contributing to heterotopic bone formation. This transformation of tumor cells is considered a type of epithelial-mesenchymal transition (EMT) because of overexpression of BMP9 and β-catenin. Patients should be followed closely because EMT has a tendency toward local recurrence. Our findings provide insight into the pathogenetic etiology of heterotopic ossification in colon cancer. © 2016 by the Association of Clinical Scientists, Inc.

  7. Regenerative Stem Cell Therapy for Breast Cancer Bone Metastasis

    Science.gov (United States)

    2015-11-01

    Small Animal Bone Phenotyping Core, respectively. The authors thank Enid Keyser for technical assistance in flow cytometry and sorting and the...Receptor. Structure 2012;20:1971–82. 40. Cummings SR, SanMartin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in

  8. Bone Microenvironment Modulates Expression and Activity of Cathepsin B in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Izabela Podgorski

    2005-03-01

    Full Text Available Prostate cancers metastasize to bone leading to osteolysis. Here we assessed proteolysis of DOcollagen I (a bone matrix protein and, for comparison, DO-collagen IV, by living human prostate carcinoma cells in vitro. Both collagens were degraded, this degradation was reduced by inhibitors of matrix metallo, serine, cysteine proteases. Because secretion of the cysteine protease cathepsin B is increased in human breast fibroblasts grown on collagen I gels, we analyzed cathepsin B levels and secretion in prostate cells grown on collagen I gels. Levels and secretion were increased only in DU145 cells-cells that expressed the highest baseline levels of cathepsin B. Secretion of cathepsin B was also elevated in DU145 cells grown in vitro on human bone fragments. We further investigated the effect of the bone microenvironment on cathepsin B expression and activity in vivo in a SCID-human model of prostate bone metastasis. High levels of cathepsin B protein and activity were found in DU145, PC3, LNCaP bone tumors, although the PC3 and LNCaP cells had exhibited low cathepsin B expression in vitro. Our results suggest that tumor-stromal interactions in the context of the bone microenvironment can modulate the expression of the cysteine protease cathepsin B.

  9. Animal models of bone cancer pain: systematic review and meta-analyses.

    Science.gov (United States)

    Currie, Gillian L; Delaney, Ada; Bennett, Michael I; Dickenson, Anthony H; Egan, Kieren J; Vesterinen, Hanna M; Sena, Emily S; Macleod, Malcolm R; Colvin, Lesley A; Fallon, Marie T

    2013-06-01

    Pain can significantly decrease the quality of life of patients with advanced cancer. Current treatment strategies often provide inadequate analgesia and unacceptable side effects. Animal models of bone cancer pain are used in the development of novel pharmacological approaches. Here we conducted a systematic review and meta-analysis of publications describing in vivo modelling of bone cancer pain in which behavioural, general health, macroscopic, histological, biochemical, or electrophysiological outcomes were reported and compared to appropriate controls. In all, 150 publications met our inclusion criteria, describing 38 different models of bone cancer pain. Reported methodological quality was low; only 31% of publications reported blinded assessment of outcome, and 11% reported random allocation to group. No publication reported a sample size calculation. Studies that reported measures to reduce bias reported smaller differences in behavioural outcomes between tumour-bearing and control animals, and studies that presented a statement regarding a conflict of interest reported larger differences in behavioural outcomes. Larger differences in behavioural outcomes were reported in female animals, when cancer cells were injected into either the tibia or femur, and when MatLyLu prostate or Lewis Lung cancer cells were used. Mechanical-evoked pain behaviours were most commonly reported; however, the largest difference was observed in spontaneous pain behaviours. In the spinal cord astrocyte activation and increased levels of Substance P receptor internalisation, c-Fos, dynorphin, tumor necrosis factor-α and interleukin-1β have been reported in bone cancer pain models, suggesting several potential therapeutic targets. However, the translational impact of animal models on clinical pain research could be enhanced by improving methodological quality. Copyright © 2013. Published by Elsevier B.V.

  10. Significance of baseline bone markers on disease progression and survival in hormone-sensitive prostate cancer with bone metastasis.

    Science.gov (United States)

    Nozawa, Masahiro; Hara, Isao; Matsuyama, Hideyasu; Iki, Masayuki; Nagao, Kazuhiro; Nishioka, Tsukasa; Komura, Takahiro; Esa, Atsunobu; Uejima, Shigeya; Imanishi, Masaaki; Uekado, Yasunari; Ogawa, Takatoshi; Kajikawa, Hiroshi; Uemura, Hirotsugu

    2015-09-01

    This study evaluated the baseline patient characteristics associated with the time to biochemical progression and overall survival in patients who participated in a phase II trial on zoledronic acid combined with the initial androgen-deprivation therapy for treatment-naïve bone-metastatic prostate cancer. Patients received zoledronic acid 4 mg intravenously every 4 weeks for up to 24 months, concomitantly started with bicalutamide 80 mg orally every day and goserelin acetate 10.8 mg subcutaneously every 12 weeks. A total of 53 Japanese patients were enrolled between July 2008 and April 2010, and 52 patients were evaluable. Median follow-up period was 41.6 months. Updated median time to biochemical progression was 25.9 months (95 % confidence interval 14.5-49.9). Higher serum bone-specific alkaline phosphatase was an independent risk factor for time to biochemical progression based on multivariate analysis (hazard ratio 6.51; 95 % confidence interval 2.71-15.62; P prostate cancer treated with upfront zoledronic acid concomitantly started with androgen-deprivation therapy.

  11. Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer.

    Science.gov (United States)

    Fuady, Jerry H; Bordoli, Mattia R; Abreu-Rodríguez, Irene; Kristiansen, Glen; Hoogewijs, David; Stiehl, Daniel P; Wenger, Roland H

    2014-01-01

    Hypoxia and the hypoxia-inducible factor (HIF) signaling pathway trigger the expression of several genes involved in cancer progression and resistance to therapy. Transcriptionally active HIF-1 and HIF-2 regulate overlapping sets of target genes, and only few HIF-2 specific target genes are known so far. Here we investigated oxygen-regulated expression of Wnt-1 induced signaling protein 2 (WISP-2), which has been reported to attenuate the progression of breast cancer. WISP-2 was hypoxically induced in low-invasive luminal-like breast cancer cell lines at both the messenger RNA and protein levels, mainly in a HIF-2α-dependent manner. HIF-2-driven regulation of the WISP2 promoter in breast cancer cells is almost entirely mediated by two phylogenetically and only partially conserved functional hypoxia response elements located in a microsatellite region upstream of the transcriptional start site. High WISP-2 tumor levels were associated with increased HIF-2α, decreased tumor macrophage density, and a better prognosis. Silencing WISP-2 increased anchorage-independent colony formation and recovery from scratches in confluent cell layers of normally low-invasive MCF-7 cancer cells. Interestingly, these changes in cancer cell aggressiveness could be phenocopied by HIF-2α silencing, suggesting that direct HIF-2-mediated transcriptional induction of WISP-2 gene expression might at least partially explain the association of high HIF-2α tumor levels with prolonged overall survival of patients with breast cancer.

  12. Cancer-induced bone loss and associated pain-related behavior is reduced by risedronate but not its phosphonocarboxylate analog NE-10790

    DEFF Research Database (Denmark)

    Hald, Andreas; Hansen, Rikke Rie; Thomsen, Mette W

    2009-01-01

    Prostate, breast and lung cancers readily develop bone metastases which lead to fractures, hypercalcemia and pain. Malignant growth in the bones depends on osteoclast-mediated bone resorption and in this regard bisphosphonate compounds, which have high-bone affinity and inhibit osteoclast activity......, have been found to alleviate bone cancer symptoms. In this study, the bisphosphonate risedronate and its phosphonocarboxylate derivative NE-10790 was tested in a murine bone cancer pain model. Risedronate decreased bone cancer-related bone destruction and pain-related behavior and decreased the spinal...... that a direct toxic effect on tumor cells may also be present in vivo and be related to the efficacy of bisphosphonate compounds. In conclusion, these results suggest that risedronate treatment may lead to an increased life quality, in patient suffering from bone cancer, in terms of decreased osteolysis...

  13. Use of disodium pamidronate bisphosphonate in patients with bone metastases of lung cancer

    Directory of Open Access Journals (Sweden)

    Ranković Boško

    2002-01-01

    Full Text Available Disodium pamidronate (Aredia®, a drug of the bisphosphonate group, was administered to 20 patients with pains in the bones due to secondary deposits of lung cancer. The aim of the study was to investigate the analgesic effect of pamidronate to osteolytic metastases of lung cancer in the bone. In 16 (80% patients non-small-cell lung cancer was diagnosed, and in 4 (20% patients small-cell-lung cancer was confirmed. Intensive disseminated pains in the bones were present in all the patients. Metastases in the skeleton were confirmed by radiography and scintigraphy of the bones. Initial values of calcium in the plasma were determined in those patients. In 11 (55% patients, initial values of calcium in the serum were normal, and in 9 (45% patients, they were elevated. Patients with normal calcium values received 30 mg of pamidronate in 250 ml of normal saline, and patients with hypercalcaemia received 45-60 mg in 500 ml of normal saline. Analgesic effect of pamidronate was present in 12 (60% patients, and the completely painless state was achieved in 4 out of 12 patients. Evaluation of the pain was done by questionnaire, using a simple, descriptive scale. In all 9 (100% patients with hypercalcaemia, values of calcium in plasma were normalized. Pamidronate exerted favorable analgesic effect in the case of metastases of lung cancer in the bones in more than 50% patients. Satisfactory results were also achieved in the patients non-responsive to palliative therapy by irradiation This enables the use of opiates in lower doses.

  14. Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer.

    Science.gov (United States)

    Ryan, Christopher W; Huo, Dezheng; Demers, Laurence M; Beer, Tomasz M; Lacerna, Leo V

    2006-09-01

    Androgen deprivation therapy in patients with prostate cancer is associated with bone loss and an increased risk of fractures. Zoledronic acid protects against bone mineral density loss when initiated concurrently with androgen deprivation therapy. We evaluated the effect of zoledronic acid initiated subsequent to androgen deprivation therapy on bone mineral density and biochemical markers of bone turnover. Patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less were randomized to 4 mg zoledronic acid or placebo intravenously every 3 months for 1 year. Patients were stratified according to androgen deprivation therapy duration (less than 6 vs 6 to 12 months). The primary end point was the change in femoral neck and lumbar spine bone mineral density in the 2 groups. The secondary end point was the change in serum bone specific alkaline phosphatase and urine N-telopeptide levels. Total hip bone mineral density was also measured. The 120 patients with prostate cancer received zoledronic acid (61) or placebo (59). Compared with placebo, zoledronic acid increased femoral neck, total hip and lumbar spine bone mineral density yearly by 3.6% (p = 0.0004), 3.8% (p bone mineral density at these 3 sites were not differentiated according to androgen deprivation therapy duration. Additionally, mean bone specific alkaline phosphatase and N-telopeptide levels were decreased in the zoledronic acid group (each p bone mineral density and suppressed bone turnover markers in patients with prostate cancer without bone metastases when initiated during year 1 of androgen deprivation therapy.

  15. 15-deoxy-δ12,14-prostaglandin j2 inhibits osteolytic breast cancer bone metastasis and estrogen deficiency-induced bone loss.

    Directory of Open Access Journals (Sweden)

    Ki Rim Kim

    Full Text Available Breast cancer is the major cause of cancer death in women worldwide. The most common site of metastasis is bone. Bone metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated bone resorption, which results in osteolytic lesions. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2 is an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ that has anti-inflammatory and antitumor activity at micromolar concentrations through PPARγ-dependent and/or PPARγ-independent pathways. We investigated the inhibitory activity of 15d-PGJ2 on the bone loss that is associated with breast cancer bone metastasis and estrogen deficiency caused by cancer treatment. 15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and parathyroid hormone-related protein (PTHrP production in MDA-MB-231 breast cancer cells. 15d-PGJ2 suppressed receptor activator of nuclear factor kappa-B ligand (RANKL mRNA levels and normalized osteoprotegerin (OPG mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or PTHrP, which decreased the RANKL/OPG ratio. 15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of cathepsin K and matrix metalloproteinases, which are secreted by mature osteoclasts. 15d-PGJ2 exerted its effects on breast cancer and bone cells via PPARγ-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected 15d-PGJ2 substantially decreased metastatic progression, cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum PTHrP levels. 15d-PGJ2 prevented the destruction of femoral trabecular structures in estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore, 15d-PGJ2 may be beneficial for the prevention and treatment of breast cancer

  16. β-Glucans (Saccharomyces cereviseae) Reduce Glucose Levels and Attenuate Alveolar Bone Loss in Diabetic Rats with Periodontal Disease

    Science.gov (United States)

    2015-01-01

    The objective of this study was to assess the effects of oral ingestion of β-glucans isolated from Saccharomyces cereviseae on the metabolic profile, expression of gingival inflammatory markers and amount of alveolar bone loss in diabetic rats with periodontal disease. Diabetes mellitus was induced in 48 Wistar rats by intraperitoneal injection of streptozotocin (80 mg/kg). After confirming the diabetes diagnosis, the animals were treated with β-glucans (by gavage) for 28 days. On the 14th day of this period, periodontal disease was induced using a ligature protocol. β-glucans reduced the amount of alveolar bone loss in animals with periodontal disease in both the diabetic and non-diabetic groups (p periodontal disease (p periodontal disease (p periodontal effects in diabetic rats with periodontal disease. PMID:26291983

  17. Serum levels of PSA, ALP, ICTP, and BSP in prostate cancer patients and the significance of ROC curve in the diagnosis of prostate cancer bone metastases.

    Science.gov (United States)

    Wei, R J; Li, T Y; Yang, X C; Jia, N; Yang, X L; Song, H B

    2016-06-03

    Bone metastasis is a common complication in prostate cancer patients that can cause bone pain and pathological fracture. This study tested serum levels of prostate specific antigen (PSA), alkaline phosphatase (ALP), bone sialoprotein (BSP), collagen type I pyridine crosslinking peptide (ICTP) in prostate cancer patients and the significance of the receiver operator characteristic (ROC) curve in the diagnosis of prostate cancer bone metastases. Eighty-three prostate cancer patients were enrolled including 42 in the bone metastases group and 41 in the non-bone metastases group. Serum levels of BSP, ALP, ICTP, and PSA were highest in the bone metastases group followed by the non-bone metastases group, hyperplasia group, and then the control group (P Gleason score, serum levels were highest in the poorly differentiated group followed by moderately differentiated and well-differentiated groups (P bone metastases were 80.95, 57.14, 69.05, 71.43%, respectively, and the specificity of the same markers were 72.80, 64.80, 76.80, and 88.80%, respectively. Combined detection of the four markers improved sensitivity to 97.62% and the negative-predictive value increased to 97.60%. PSA + BSP showed the best efficiency when combining two markers. In conclusion, serum levels of BSP, ALP, ICTP, and PSA increased in patients with bone metastases, and combined detection of all markers could improve the positive-predictive value.

  18. Inducible Lentivirus-Mediated siRNA against TLR4 Reduces Nociception in a Rat Model of Bone Cancer Pain

    Directory of Open Access Journals (Sweden)

    Ruirui Pan

    2015-01-01

    Full Text Available Although bone cancer pain is still not fully understood by scientists and clinicians alike, studies suggest that toll like receptor 4 (TLR4 plays an important role in the initiation and/or maintenance of pathological pain state in bone cancer pain. A promising treatment for bone cancer pain is the downregulation of TLR4 by RNA interference; however, naked siRNA (small interference RNA is not effective in long-term treatments. In order to concoct a viable prolonged treatment for bone cancer pain, an inducible lentivirus LvOn-siTLR4 (tetracycline inducible lentivirus carrying siRNA targeting TLR4 was prepared and the antinociception effects were observed in bone cancer pain rats induced by Walker 256 cells injection in left leg. Results showed that LvOn-siTLR4 intrathecal injection with doxycycline (Dox oral administration effectively reduced the nociception induced by Walker 256 cells while inhibiting the mRNA and protein expression of TLR4. Proinflammatory cytokines as TNF-α and IL-1β in spinal cord were also decreased. These findings suggest that TLR4 could be a target for bone cancer pain treatment and tetracycline inducible lentivirus LvOn-siTLR4 represents a new potential option for long-term treatment of bone cancer pain.

  19. Changes in Cytokines of the Bone Microenvironment during Breast Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Donna M. Sosnoski

    2012-01-01

    Full Text Available It is commonly accepted that cancer cells interact with host cells to create a microenvironment favoring malignant colonization. The complex bone microenvironment produces an ever changing array of cytokines and growth factors. In this study, we examined levels of MCP-1, IL-6, KC, MIP-2, VEGF, MIG, and eotaxin in femurs of athymic nude mice inoculated via intracardiac injection with MDA-MB-231GFP human metastatic breast cancer cells, MDA-MB-231BRMS1GFP, a metastasis suppressed variant, or PBS. Animals were euthanized (day 3, 11, 19, 27 after injection to examine femoral cytokine levels at various stages of cancer cell colonization. The epiphysis contained significantly more cytokines than the diaphysis except for MIG which was similar throughout the bone. Variation among femurs was evident within all groups. By day 27, MCP-1, MIG, VEGF and eotaxin levels were significantly greater in femurs of cancer cell-inoculated mice. These pro-osteoclastic and angiogenic cytokines may manipulate the bone microenvironment to enhance cancer cell colonization.

  20. Podoplanin in cancer cells is experimentally able to attenuate prolymphangiogenic and lymphogenous metastatic potentials of lung squamoid cancer cells

    Directory of Open Access Journals (Sweden)

    Suzuki Hanako

    2010-10-01

    . Conclusions Our findings suggested that LSCC-associated podoplanin was functional and could attenuate the potential for lymph node metastasis, possibly based on the suppression of tumor lymphangiogenesis; thus, podoplanin in cancer cells may become a useful biomarker to measure the malignancy of lung SCC.

  1. Adipose Stem Cell-Based Therapeutic Targeting of Residual Androgens in African Americans With Bone-Metastatic Prostate Cancer

    Science.gov (United States)

    2014-09-01

    Hereditary prostate cancer : epidemiologic and clinical features. J Urol., 150(3):797-802, 1993. 12. Boring, C. C. Cancer StatistiAC. (1991) CA...Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer . Cancer Res 2006;66(5):2815–2825. [PubMed: 16510604]. 12 ...Adipose Stem Cell-Based Therapeutic Targeting of Residual Androgens in African Americans With Bone-Metastatic Prostate Cancer PRINCIPAL

  2. Functional Interference in the Bone Marrow Microenvironment by Disseminated Breast Cancer Cells.

    Science.gov (United States)

    Dhawan, Abhishek; von Bonin, Malte; Bray, Laura J; Freudenberg, Uwe; Pishali Bejestani, Elham; Werner, Carsten; Hofbauer, Lorenz C; Wobus, Manja; Bornhäuser, Martin

    2016-08-01

    Skeletal metastasis of breast cancer is associated with a poor prognosis and significant morbidity. Investigations in other solid tumors have revealed an impairment in hematopoietic function upon bone marrow invasion. However, the interaction between disseminated breast cancer cells and the bone marrow microenvironment which harbors them has not been addressed comprehensively. Employing advanced co-culture assays, proteomic studies, organotypic models as well as in vivo xenotransplant models, we define the consequences of this interaction on the stromal compartment of bone marrow, affected molecular pathways and subsequent effects on the hematopoietic stem and progenitor cells (HSPCs). The results showed a basic fibroblast growth factor (bFGF)-mediated, synergistic increase in proliferation of breast cancer cells and mesenchymal stromal cells (MSCs) in co-culture. The stromal induction was associated with elevated phosphoinositide-3 kinase (PI3K) signaling in the stroma, which coupled with elevated bFGF levels resulted in increased migration of breast cancer cells towards the MSCs. The perturbed cytokine profile in the stroma led to reduction in the osteogenic differentiation of MSCs via downregulation of platelet-derived growth factor-BB (PDGF-BB). Long term co-cultures of breast cancer cells, HSPCs, MSCs and in vivo studies in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl) /SzJ (NSG) mice showed a reduced support for HSPCs in the altered niche. The resultant non- conducive phenotype of the niche for HSPC support emphasizes the importance of the affected molecular pathways in the stroma as clinical targets. These findings can be a platform for further development of therapeutic strategies aiming at the blockade of bone marrow support to disseminated breast cancer cells. Stem Cells 2016;34:2224-2235. © 2016 AlphaMed Press.

  3. Trafficking of Metastatic Breast Cancer Cells in Bone

    National Research Council Canada - National Science Library

    Mastro, Andrea M

    2004-01-01

    ... metaphyses. Human breast cancer cells that express green fluorescent protein (GFP-MDA-MB 231) will be inoculated into athymic mice by intracardiac injection and femurs harvested at various times from 1 hour to 6 weeks later...

  4. Predicting bone scan positivity in non-metastatic castration-resistant prostate cancer

    Science.gov (United States)

    Moreira, Daniel M.; Howard, Lauren E.; Sourbeer, Katie N.; Amarasekara, Hiruni S.; Chow, Lydia C.; Cockrell, Dillon C.; Hanyok, Brian T.; Pratson, Connor L.; Aronson, William J.; Kane, Christopher J.; Terris, Martha K.; Amling, Christopher L.; Cooperberg, Matthew R.; Liede, Alexander; Freedland, Stephen J.

    2015-01-01

    Objectives To evaluate PSA levels and kinetic cutoffs to predict positive bone scans for men with non-metastatic castrate resistant prostate cancer (CRPC) from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort. Methods Retrospective analysis of 531 bone scans of 312 clinically CRPC patients with no known metastases at baseline treated with a variety of primary treatment types in the SEARCH database. The association of patients’ demographics, pathological features, PSA levels and kinetics with risk of a positive scan was tested using generalized estimating equations. Results A total of 149 (28%) scans were positive. Positive scans were associated with younger age (OR=0.98; P=0.014), higher Gleason scores (relative to Gleason 2-6, Gleason 3+4: OR=2.03, P=0.035; Gleason 4+3 and 8-10: OR=1.76, P=0.059), higher pre-scan PSA (OR=2.11; Pbone scan. Conclusions PSA levels and kinetics were associated with positive bone scans. We developed tables to predict the risk of positive bone scans by PSA and PSADT. Combining PSA levels and kinetics may help select patients with CRPC for bone scans. PMID:26171882

  5. Radium-223 chloride: Extending life in prostate cancer patients by treating bone metastases.

    Science.gov (United States)

    Wissing, Michel D; van Leeuwen, Fijs W B; van der Pluijm, Gabri; Gelderblom, Hans

    2013-11-01

    The treatment scope for patients with metastatic castrate-resistant prostate cancer (mCRPC) is rapidly expanding. On May 15, 2013, the U.S. Food and Drug Administration (FDA) approved radium-223 chloride ((223)RaCl2) for the treatment of mCRPC patients whose metastases are limited to the bones. Radium-223 is an α-emitting alkaline earth metal ion, which, similar to calcium ions, accumulates in the bone. In a phase III study (ALSYMPCA), mCRPC patients with bone metastases received best standard-of-care treatment with placebo or (223)RaCl2. At a prespecified interim analysis, the primary endpoint of median overall survival was significantly extended by 3.6 months in patients treated with radium-223 compared with placebo (P < 0.001). The radioisotope was well tolerated and gave limited bone marrow suppression. (223)RaCl2 is the first bone-targeting antitumor therapy that received FDA approval based on a significant extended median overall survival. Further studies are required to optimize its dosing and to confirm its efficacy and safety in cancer patients.

  6. RGD Peptide Cell-Surface Display Enhances the Targeting and Therapeutic Efficacy of Attenuated Salmonella-mediated Cancer Therapy.

    Science.gov (United States)

    Park, Seung-Hwan; Zheng, Jin Hai; Nguyen, Vu Hong; Jiang, Sheng-Nan; Kim, Dong-Yeon; Szardenings, Michael; Min, Jung Hyun; Hong, Yeongjin; Choy, Hyon E; Min, Jung-Joon

    2016-01-01

    Bacteria-based anticancer therapies aim to overcome the limitations of current cancer therapy by actively targeting and efficiently removing cancer. To achieve this goal, new approaches that target and maintain bacterial drugs at sufficient concentrations during the therapeutic window are essential. Here, we examined the tumor tropism of attenuated Salmonella typhimurium displaying the RGD peptide sequence (ACDCRGDCFCG) on the external loop of outer membrane protein A (OmpA). RGD-displaying Salmonella strongly bound to cancer cells overexpressing αvβ3, but weakly bound to αvβ3-negative cancer cells, suggesting the feasibility of displaying a preferential homing peptide on the bacterial surface. In vivo studies revealed that RGD-displaying Salmonellae showed strong targeting efficiency, resulting in the regression in αvβ3-overexpressing cancer xenografts, and prolonged survival of mouse models of human breast cancer (MDA-MB-231) and human melanoma (MDA-MB-435). Thus, surface engineering of Salmonellae to display RGD peptides increases both their targeting efficiency and therapeutic effect.

  7. The Utilization of Gleason Grade as the Primary Criterion for Ordering Nuclear Bone Scan in Newly Diagnosed Prostate Cancer Patients

    Directory of Open Access Journals (Sweden)

    Chad W. M. Ritenour

    2009-01-01

    Full Text Available Utilization of nuclear bone scans for staging newly diagnosed prostate cancer has decreased dramatically due to PSA-driven stage migration. The current criteria for performing bone scans are based on limited historical data. This study evaluates serum PSA and Gleason grade in predicting positive scans in a contemporary large series of newly diagnosed prostate cancer patients. Eight hundred consecutive cases of newly diagnosed prostate cancer over a 64-month period underwent a staging nuclear scan. All subjects had histologically confirmed cancer. The relationship between PSA, Gleason grade, and bone scan was examined by calculating series of crude, stratified, and adjusted odds ratios with corresponding 95% confidence intervals. Four percent (32/800 of all bone scans were positive. This proportion was significantly lower in patients with Gleason score ≤7 (1.9% vs. Gleason score ≥8 (18.8%, p 30 ng/ml compared to ≤30 ng/ml (p 10 ng/ml compared to ≤10 ng/ml (p = 0.002. The combination of Gleason score and PSA enhances predictability of bone scans in newly diagnosed prostate cancer patients. The PSA threshold for ordering bone scans should be adjusted according to Gleason score. For patients with Gleason scores ≤7, we recommend a bone scan if the PSA is >30 ng/ml. However, for patients with a high Gleason score (8–10, we recommend a bone scan if the PSA is >10 ng/ml.

  8. Treatment patterns in patients with prostate cancer and bone metastasis among US community-based urology group practices.

    Science.gov (United States)

    Freedland, Stephen J; Richhariya, Akshara; Wang, Huei; Chung, Karen; Shore, Neal D

    2012-08-01

    To evaluate a cohort of United States-based urology practices for patterns related to screening, diagnosis, and treatment of bone metastases in men with castration-resistant prostate cancer. Chart audits at 15 community-based urology group practices were conducted in the United States. Patient charts were eligible for study inclusion and review if they had documented bone metastasis secondary to castration-resistant prostate cancer. Data abstracted include site and patient demographics, diagnosis patterns, and bone metastases treatment between July 2006 and July 2009. A sample of approximately 10 charts per practice was used, starting with the most recent patient who met eligibility requirements. Eligible patients (n = 147) from 15 practices had a mean (SD) age of 67.8 (9.3) years at prostate cancer diagnosis and 72.5 (8.6) years at diagnosis of bone metastasis. Bone metastasis occurred 31.3 months (median) after cancer diagnosis. Seventy-three percent (n = 108) of patients had multiple bone metastases, and 82% (n = 120) had bone metastases in weight-bearing bones at last follow-up. Intravenous bisphosphonates were administered to 49% (72/147) of patients, with 97% (70/72) receiving zoledronic acid. Among patients with castration-resistant prostate cancer and documented bone metastases, approximately one half received intravenous zoledronic acid. This suggests that the other half of patients with bone metastases from prostate cancer remained undertreated for the prevention of skeletal complications based on National Comprehensive Cancer Network guidelines during the study time period. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. The intake of yam (Dioscorea bulbifera Linn) attenuated the hyperglycemia and the bone fragility in female diabetic rats.

    Science.gov (United States)

    Rêgo, Thaís de Salgado; Ash, Louise da Silva; Pessoa, Letícia; Feijó, Márcia Barreto da Silva; Leite, Juliana; dos Santos, Aline de Sousa; da Costa, Carlos Alberto Soares; Boaventura, Gilson Teles

    2014-02-01

    Diabetic patients have a higher risk to osteoporotic fractures. Foods, such as yam, to oppose hyperglycemia, has been used to treatment of diabetes. The goal was assess the role of Brazilian yam (Dioscorea bulbifera) on glycemia and bone parameters of female diabetic rats. Female Wistar rats with 3 months age were allocated in three groups. Control group (C, n = 6), treated with normal fat diet. Diabetic rats treated with high-fat diet without (DM, n = 8) and with (DMY, n = 8) liofilized yam flour. After 5 weeks of the experiment, serum glucose and insulin, pancreas mass, number and area of pancreas islets were quantified. And femur parameters were analyzed by dual-energy X-ray absorptiometry (DXA) and computed tomography (CT). Differences were considered significant if P<0.05. Diabetic groups showed lower (P < 0.05): femur and pancreas mass, area of the pancreatic islets and insulin. However, DMY showed lower (-10%, P < 0.05) concentrations of glucose to DM group. Femur, by DXA, showed lower bone mineral density, content and area in the DM group. While the DMY group showed greater (+27%, P < 0.05) radiodensity of femoral head when compared to DM group. Brazilian yam flour supplement did not fix a defect, but alleviated the consequences of the experimental diabetic disease. It showed results to control the rise in blood glucose levels in diabetic rats, suggesting protection in oxidative agents and postpone harm in the bone. Considering all the findings of the present study, our results suggest that yam flour does act producing benefits in the experimental diabetes. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  10. Polyurethane foam scaffold as in vitro model for breast cancer bone metastasis.

    Science.gov (United States)

    Angeloni, Valentina; Contessi, Nicola; De Marco, Cinzia; Bertoldi, Serena; Tanzi, Maria Cristina; Daidone, Maria Grazia; Farè, Silvia

    2017-11-01

    Breast cancer (BC) represents the most incident cancer case in women (29%), with high mortality rate. Bone metastasis occurs in 20-50% cases and, despite advances in BC research, the interactions between tumor cells and the metastatic microenvironment are still poorly understood. In vitro 3D models gained great interest in cancer research, thanks to the reproducibility, the 3D spatial cues and associated low costs, compared to in vivo and 2D in vitro models. In this study, we investigated the suitability of a poly-ether-urethane (PU) foam as 3D in vitro model to study the interactions between BC tumor-initiating cells and the bone microenvironment. PU foam open porosity (>70%) appeared suitable to mimic trabecular bone structure. The PU foam showed good mechanical properties under cyclic compression (E=69-109kPa), even if lower than human trabecular bone. The scaffold supported osteoblast SAOS-2 cell line proliferation, with no cytotoxic effects. Human adipose derived stem cells (ADSC) were cultured and differentiated into osteoblast lineage on the PU foam, as shown by alizarin red staining and RT-PCR, thus offering a bone biomimetic microenvironment to the further co-culture with BC derived tumor-initiating cells (MCFS). Tumor aggregates were observed after three weeks of co-culture by e-cadherin staining and SEM; modification in CaP distribution was identified by SEM-EDX and associated to the presence of tumor cells. In conclusion, we demonstrated the suitability of the PU foam to reproduce a bone biomimetic microenvironment, useful for the co-culture of human osteoblasts/BC tumor-initiating cells and to investigate their interaction. 3D in vitro models represent an outstanding alternative in the study of tumor metastases development, compared to traditional 2D in vitro cultures, which oversimplify the 3D tissue microenvironment, and in vivo studies, affected by low reproducibility and ethical issues. Several scaffold-based 3D in vitro models have been proposed

  11. Lung Cancer Onset in Wild Type Mice Following Bone Marrow Reconstitution with krasv12 Cells

    Science.gov (United States)

    Belloni, Elena; Martin Padura, Ines; Gerbino, Elvira; Orecchioni, Stefania; Fusar Imperatore, Fulvia; Marighetti, Paola; Bertalot, Giovanni; Giuseppe Pelicci, Pier; Bertolini, Francesco

    2015-01-01

    A role for bone-marrow-derived cells (BMDCs) in tissue repair and malignancy onset has been proposed, but their contribution is still debated. We tested the ability of BMDCs containing the inducible krasV12 oncogene to initiate lung adenocarcinoma. For our experimental strategy, we reconstituted lethally irradiated wild type mice with BMDCs carrying inducible krasV12 and subsequently induced oncogene expression by 4-OHT administration. Epithelial lung lesions, from adenoma to adenocarcinomas, appeared at successive time points. These results show that lung tumors were derived from donor BMDCs and indicate a direct involvement of bone marrow cells in the development of epithelial cancers. PMID:26267334

  12. [Radium-223 treatment of bone metastases from castration-resistant prostate cancer].

    Science.gov (United States)

    Mortensen, Jann; Højgaard, Liselotte

    2014-07-21

    The alpha emitter Radium-223 ((22)3Ra-Cl2) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone refractory prostate cancer. More than 1,000 patients have been included in clinical phase I-III tests showing significant reduction in alkaline phosphatase- and PSA level and prolonged survival. Adverse events are usually mild to moderate and comprise gastrointestinal and myelotoxic symptoms. Intravenously administered (22)3Ra-Cl2 (half-life 11.4 days) will likely be given every four weeks for six treatments to out-patients.

  13. [A case of prostate cancer with disseminated carcinomatosis of bone marrow which responded to Zoledronic acid].

    Science.gov (United States)

    Kato, Keiji; Nagahama, Kanji; Yagibashi, Yusuke; Yamamoto, Masakazu; Kanamaru, Hiroshi; Hirata, Hirokazu

    2011-06-01

    A 76-year-old man underwent radical prostatectomy under the diagnosis of stage C prostate cancer (cT3bN0M0, Gleason score 3+4) in 1999. Endocrine treatment for postoperative biochemical failure started in 2001. He was admitted to our hospital because of general fatigue and multiple bone pain with a prostate specific antigen (PSA) level of 1,141 ng/ml in August 2009. On admission, no metastasis was detected on bone scintigraphy or computed tomography. Bone marrow biopsy was finally performed for the assessment of bone metastasis after PSA further increased to 8,679 ng/ml with the manifestation of severe anemia and thrombocytopenia. The biopsy findings disclosed disseminated carcinomatosis of bone marrow (DCBM). Treatment with Zoledronic acid (ZA) not only mitigated bone pain, but also rapidly improved of PSA and hematological findings. Although the prognosis of a patient with DCBM is generally considered to be very poor, ZA contributed to the improvement for the survival of the patient in the present case.

  14. [Effect of intravenous treatment with OK-432 on the bone marrow in patients with lung cancer].

    Science.gov (United States)

    Fujii, M; Ishikawa, M; Toki, H

    1984-03-01

    We studied effects of OK-432 on the bone marrow and peripheral blood cells of lung cancer patients. The nuclear cell count of bone marrow increased in 5 to 7 patients upon intravenous treatment with OK-432 compared with 3 of 6 patients who were intramuscularly treated with OK-432. Serial neutrophil counts of bone marrow increased in all 7 patients treated intravenously compared with 3 of 6 patients treated intramuscularly. The mean nuclear cell count or the serial neutrophil count of bone marrow in intravenously treated patients was significantly higher than the pretreatment values (p less than 0.001). In the peripheral blood picture, the difference in white blood cells or neutrophils before and after intravenous treatment was also statistically significant (p less than 0.01). There was no change in the erythrocytic series count of bone marrow and the hemoglobin count. Our results support the superiority of intravenous OK-432 treatment over intramuscular treatment in the growth-accelerating effect on bone marrow cells, especially regarding the neutrophil series.

  15. Formoterol attenuates increased oxidative stress and myosin protein loss in respiratory and limb muscles of cancer cachectic rats

    Directory of Open Access Journals (Sweden)

    Anna Salazar-Degracia

    2017-12-01

    Full Text Available Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Therapeutic options are still scarce. We hypothesized that cachexia-induced muscle oxidative stress may be attenuated in response to treatment with beta2-adrenoceptor-selective agonist formoterol in rats. In diaphragm and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally with and without treatment with formoterol (0.3 mg/kg body weight/day for seven days, daily subcutaneous injection, redox balance (protein oxidation and nitration and antioxidants and muscle proteins (1-dimensional immunoblots, carbonylated proteins (2-dimensional immunoblots, inflammatory cells (immunohistochemistry, and mitochondrial respiratory chain (MRC complex activities were explored. In the gastrocnemius, but not the diaphragm, of cancer cachectic rats compared to the controls, protein oxidation and nitration levels were increased, several functional and structural proteins were carbonylated, and in both study muscles, myosin content was reduced, inflammatory cell counts were greater, while no significant differences were seen in MRC complex activities (I, II, and IV. Treatment of cachectic rats with formoterol attenuated all the events in both respiratory and limb muscles. In this in vivo model of cancer-cachectic rats, the diaphragm is more resistant to oxidative stress. Formoterol treatment attenuated the rise in oxidative stress in the limb muscles, inflammatory cell infiltration, and the loss of myosin content seen in both study muscles, whereas no effects were observed in the MRC complex activities. These findings have therapeutic implications as they demonstrate beneficial effects of the beta2 agonist through decreased protein oxidation and inflammation in cachectic muscles, especially the gastrocnemius.

  16. Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion.

    LENUS (Irish Health Repository)

    Cooke, Niamh M

    2015-09-09

    Platelet-cancer cell interactions play a key role in successful haematogenous metastasis. Disseminated malignancy is the leading cause of death among ovarian cancer patients. It is unknown why different ovarian cancers have different metastatic phenotypes. To investigate if platelet-cancer cell interactions play a role, we characterized the response of ovarian cancer cell lines to platelets both functionally and at a molecular level.

  17. Osteoblast-Derived PTHRP and Breast Cancer Bone Metastasis

    Science.gov (United States)

    2004-11-01

    pep6de gene. Genes Dev. 1994;8(3):277-289. 10. Wysolmerskijj, Philbrick WM, Dunbar ME, La.nske B, Kronwberg H, Broadus AE. Rescue of the para- thyroid ...mechanism for stem cell homing. Bone.l006;38(4):497-508. 63. Guise TA, et al. Evidence for a causal role of para- thyroid hormone-related protein in...proliferative capacity and increased apoptosis in multiple tissues, retarded growth, early senescence and malnutrition leading to an early death [53]. In

  18. Evaluation of imaging technologies to correct for photon attenuation in the overlying tissue for in vivo bone strontium measurements.

    Science.gov (United States)

    Heirwegh, C M; Chettle, D R; Pejović-Milić, A

    2010-02-21

    The interpretation of measurements of bone strontium in vivo using energy dispersive x-ray fluorescence spectroscopy is presently hindered by overlying skin and soft-tissue absorption of the strontium x-rays. The use of imaging technologies to measure the overlying soft-tissue thickness at the index finger measuring site might allow correction of the strontium reading to estimate its concentration in bone. An examination of magnetic resonance (MR), computed tomography (CT) and high-frequency ultrasound (US) imaging technologies revealed that 55 MHz US had the smallest range of measurement uncertainty at 3.2% followed by 1 Tesla MR, 25 MHz US, 8 MHz US and CT at 4.3, 5.4, 6.6 and 7.1% uncertainty, respectively. Of these, only CT imaging appeared to underestimate total thickness (p < 0.05). Furthermore, an inter-study comparison on the accuracy of US measurements of the overlying tissue thickness at finger and ankle in nine subjects was investigated. The 8 MHz US system used in prior in vivo experiments was found to perform satisfactorily in a repeat study of ankle measurements, but indicated that finger thickness measurements may have been misread in previous studies by up to 17.7% (p < 0.025). Repeat ankle measurements were not significantly different from initial measurements at 2.2% difference.

  19. The effect of breast cancer on the Fourier transform infrared attenuated total reflection spectra of human hair

    OpenAIRE

    Lyman, Donald J.; Fay, Sheila G

    2014-01-01

    Changes in the Synchrotron x-ray diffraction pattern of scalp hair were shown to occur in patients with breast cancer. A preliminary Fourier transform infrared (FT-IR) spectroscopy study of scalp hair using attenuated total reflection (ATR) supported the concept that these changes are due to an increase in the lipid content of the hair fibre. This study was undertaken to determine whether the ATR-FT-IR spectrum obtained using a single hair fibre ATR cell could be used in the detection of brea...

  20. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang, E-mail: brilliant212@163.com; Yang, Xinghai, E-mail: cnspineyang@163.com; Xiao, Jianru, E-mail: jianruxiao83@163.com

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  1. Synthetic bone substitute material comparable with xenogeneic material for bone tissue regeneration in oral cancer patients: First and preliminary histological, histomorphometrical and clinical results

    Science.gov (United States)

    Ghanaati, Shahram; Barbeck, Mike; Lorenz, Jonas; Stuebinger, Stefan; Seitz, Oliver; Landes, Constantin; Kovács, Adorján F.; Kirkpatrick, Charles J.; Sader, Robert A.

    2013-01-01

    Background: The present study was first to evaluate the material-specific cellular tissue response of patients with head and neck cancer to a nanocrystalline hydroxyapatite bone substitute NanoBone (NB) in comparison with a deproteinized bovine bone matrix Bio-Oss (BO) after implantation into the sinus cavity. Materials and Methods: Eight patients with tumor resection for oral cancer and severely resorbed maxillary bone received materials according to a split mouth design for 6 months. Bone cores were harvested prior to implantation and analyzed histologically and histomorphometrically. Implant survival was followed-up to 2 years after placement. Results: Histologically, NB underwent a higher vascularization and induced significantly more tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated giant cells when compared with BO, which induced mainly mononuclear cells. No significant difference was observed in the extent of new bone formation between both groups. The clinical follow-up showed undisturbed healing of all implants in the BO-group, whereas the loss of one implant was observed in the NB-group. Conclusions: Within its limits, the present study showed for the first time that both material classes evaluated, despite their induction of different cellular tissue reactions, may be useful as augmentation materials for dental and maxillofacial surgical applications, particularly in patients who previously had oral cancer. PMID:24205471

  2. P2X7 receptor-mediated analgesia in cancer-induced bone pain

    DEFF Research Database (Denmark)

    Falk, Sarah; D. Schwab, Samantha; Frøsig-Jørgensen, Majbrit

    2015-01-01

    for cancer-induced bone pain. The P2X7 receptor (P2X7R) is involved in a variety of cellular functions and has been linked to both inflammatory and neuropathic pain. Here we study the analgesic potential of P2X7 receptor antagonism in a rat model of cancer-induced bone pain. In cancer-bearing animals, the P2...... to low intensity or electrical stimulation. In contrast, A839977 had no effect on the tested parameters in naïve or sham animals. In awake animals, 40mg/kg A839977 (i.p) significantly reduced both early and late stage pain behavior. In contrast, no effect was observed in sham or vehicle-treated animals....... The results suggest that the P2X7R is involved in the mechanisms of cancer-induced bone pain, and that P2X7R antagonism might be a useful analgesic target. No effect was observed in sham or naïve animals, indicating that the P2X7R-mediated effect is state-dependent, and might therefore be an advantageous...

  3. Effect of music therapy on pain behaviors in rats with bone cancer pain.

    Science.gov (United States)

    Gao, Ji; Chen, Shaoqin; Lin, Suyong; Han, Hongjing

    2016-01-01

    To investigate the effects of music therapy on the pain behaviors and survival of rats with bone cancer pain and analyze the mediating mechanism of mitogen activated protein kinase (MAPK) signal transduction pathway. Male Wistar rats aged 5-8 weeks and weighing 160-200 g were collected. The rat models of colorectal cancer bone cancer pain was successfully established. Animals were divided into experimental and control group, each with 10 rats. The animals in the observation group were given Mozart K448 sonata, sound intensity of 60 db, played the sonata once every 1 hr in the daytime, stopped playing during the night, and this cycle was kept for 2 weeks. On the other hand, rats in the control group were kept under the same environment without music. Animals in the experimental group consumed more feed and gained significant weight in comparison to the control group. The tumor volume of the experimental group was significantly smaller than that of the control group (pMusic therapy may improve the pain behaviors in rats with bone cancer pain, which might be related with low expression of p38á and p38β in the MAPK signal transduction pathway.

  4. Behavioral and neurochemical analysis of ongoing bone cancer pain in rats.

    Science.gov (United States)

    Remeniuk, Bethany; Sukhtankar, Devki; Okun, Alec; Navratilova, Edita; Xie, Jennifer Y; King, Tamara; Porreca, Frank

    2015-10-01

    Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized after intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching. Conditioned place preference (CPP) and enhanced dopamine (DA) release in the nucleus accumbens (NAc) shell was observed after peripheral nerve block (PNB) selectively in tumor-bearing rats revealing nociceptive-driven ongoing pain. Oral diclofenac reversed tumor-induced tactile hypersensitivity but did not block PNB-induced CPP or NAc DA release. Tumor-induced tactile hypersensitivity, and PNB-induced CPP and NAc DA release, was blocked by prior subcutaneous implantation of a morphine pellet. In sham rats, morphine produced a modest but sustained increase in NAc DA release. In contrast, morphine produced a transient 5-fold higher NAc DA release in tumor bearing rats compared with sham morphine rats. The possibility that this increased NAc DA release reflected the reward of pain relief was tested by irreversible blockade of rostral anterior cingulate cortex (rACC) μ-opioid receptors (MORs). The rACC MOR blockade prevented the morphine-induced transient increased NAc DA release in tumor bearing rats but did not affect morphine-induced effects in sham-operated animals. Consistent with clinical experience, ongoing cancer pain was controlled by morphine but not by a dose of diclofenac that reversed evoked hypersensitivity. Additionally, the intrinsic reward of morphine can be dissociated from the reward of relief of cancer pain by blockade of rACC MOR. This approach allows mechanistic and therapeutic assessment of ongoing cancer pain with likely translation relevance.

  5. Bone Scan Index predicts outcome in patients with metastatic hormone-sensitive prostate cancer.

    Science.gov (United States)

    Poulsen, Mads H; Rasmussen, Janne; Edenbrandt, Lars; Høilund-Carlsen, Poul F; Gerke, Oke; Johansen, Allan; Lund, Lars

    2016-05-01

    To evaluate the Bone Scan Index (BSI) for prediction of castration resistance and prostate cancer-specific survival (PCSS). In this retrospective study, we used novel computer-assisted software for automated detection/quantification of bone metastases by BSI. Patients with prostate cancer are M-staged by whole-body bone scintigraphy (WBS) and categorised as M0 or M1. Within the M1 group, there is a wide range of clinical outcomes. The BSI was introduced a decade ago providing quantification of bone metastases by estimating the percentage of bone involvement. Being too time consuming, it never gained widespread clinical use. In all, 88 patients with prostate cancer awaiting initiation of androgen-deprivation therapy due to metastases were included. WBS was performed using a two-headed γ-camera. BSI was obtained using the automated platform EXINI bone (EXINI Diagnostics AB, Lund, Sweden). In Cox proportional hazard models, time to castration-resistant prostate cancer (CRPC) and PCSS were modelled as the dependent variables, whereas prostate-specific antigen (PSA) level, Gleason score and BSI were used as explanatory factors. For Kaplan-Meier estimates, BSI groups were dichotomously split into: BSI Gleason score was 7.7 (2-10), and the mean (range) BSI was 1.0 (0-9.2). During a mean (range) follow-up of 26 (8-49) months, 48 patients became castration resistant and 15 had died; most (13) from prostate cancer. In multivariate analysis including PSA level, Gleason score and BSI, only prediction by BSI was statistically significant. This was true both for time to CRPC (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.22-1.74; C-index increase from 0.49 to 0.69) and for PCSS (HR 1.34, 95% CI 1.07-1.67; C-index increase from 0.76 to 0.95). BSI obtained using a novel automated computer-assisted algorithm appears to be a useful predictor of outcome for time to CRPC and PCSS in patients with hormone-sensitive metastatic prostate cancer. © 2015 The Authors BJU

  6. Current Studies of Acupuncture in Cancer-Induced Bone Pain Animal Models

    Directory of Open Access Journals (Sweden)

    Hee Kyoung Ryu

    2014-01-01

    Full Text Available Acupuncture is generally accepted as a safe and harmless treatment option for alleviating pain. To explore the pain mechanism, numerous animal models have been developed to simulate specific human pain conditions, including cancer-induced bone pain (CIBP. In this study, we analyzed the current research methodology of acupuncture for the treatment of CIBP. We electronically searched the PubMed database for animal studies published from 2000 onward using these search terms: (bone cancer OR cancer AND (pain OR analgesia AND (acupuncture OR pharmacopuncture OR bee venom. We selected articles that described cancer pain in animal models. We analyzed the methods used to induce cancer pain and the outcome measures used to assess the effects of acupuncture on CIBP in animal models. We reviewed articles that met our inclusion criteria. Injection of mammary cancer cells into the cavity of the tibia was the most frequently used method for inducing CIBP in the animal models. Among the eight selected studies, five studies demonstrated the effects of electroacupuncture on CIBP. The effects of acupuncture were assessed by measuring pain-related behavior. Future researches will be needed to ascertain the effectiveness of acupuncture for treating CIBP and to explore the specific mechanism of CIBP in animal models.

  7. Tumor-Host Interaction in Breast Cancer Bone Metastasis

    Science.gov (United States)

    2006-01-01

    Kallioniemi, O.-P., and Ethier, S. P. Molecular cytogenetic analysis of 11 new breast cancer cell lines. Br J Cancer, 81: 1328-1334, 1999. 26. Harris, A...1.318480186 NM_000546 TP53 Tumor protein p53 (Li-Fraumeni syndrome ) 0.875703301 NM_006670 TPBG Trophoblast glycoprotein 1.130637565 NM_003379 VIL2 Villin...primary tumors was determined according to the Richardson– Bloom grading system [17]. BM assessment BM (10 cc) was aspirated from the sternum and both

  8. Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts.

    Directory of Open Access Journals (Sweden)

    Marion David

    2010-03-01

    Full Text Available Bone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorptive agents are only palliative indicating that factors independent of bone resorption control bone metastasis progression. Autotaxin (ATX/NPP2 is a secreted protein with both oncogenic and pro-metastatic properties. Through its lysosphospholipase D (lysoPLD activity, ATX controls the level of lysophosphatidic acid (LPA in the blood. Platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. We asked whether ATX was involved in the bone metastasis process. We characterized the role of ATX in osteolytic bone metastasis formation by using genetically modified breast cancer cells exploited on different osteolytic bone metastasis mouse models.Intravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX to immunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss, tumor burden, and a higher number of active osteoclasts at the metastatic site. Mouse breast cancer 4T1 cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. These cells expressed active ATX and silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at the bone metastatic site. In vitro, osteoclast differentiation was enhanced in presence of MDA-B02/ATX cell conditioned media or recombinant autotaxin that was blocked by the autotaxin inhibitor vpc8a202. In vitro, addition of LPA to active charcoal-treated serum restored the capacity of the serum to support RANK-L/MCSF-induced osteoclastogenesis.Expression of autotaxin by cancer cells controls osteolytic bone metastasis formation. This work demonstrates a new role for LPA as a factor that stimulates directly cancer growth and metastasis, and

  9. Liensinine and Nuciferine, Bioactive Components of Nelumbo nucifera, Inhibit the Growth of Breast Cancer Cells and Breast Cancer-Associated Bone Loss

    Directory of Open Access Journals (Sweden)

    Eun Ji Kang

    2017-01-01

    Full Text Available Once breast cancer cells grow aggressively and become lodged in the skeleton through migration and invasion, they interact with bone microenvironment and accelerate much more tumor growth and bone destruction. We investigated whether liensinine and nuciferine, major active components in Nelumbo nucifera (lotus, could prevent breast cancer cell-mediated bone destruction. Liensinine and nuciferine inhibited the growth of MDA-MB-231 and MCF-7 human breast cancer cells by inducing apoptosis and inhibiting proliferation via cell cycle arrest. Liensinine treatment led to the increased Bax/Bcl-2 ratio, activation of caspase-3, and subsequent cleavage of PARP. Liensinine also displayed significant inhibition on the migration and invasion of both MDA-MB-231 and MCF-7 human breast cancer cells compared with nuciferine. In addition, liensinine and nuciferine inhibited the receptor activator of nuclear factor kappa-B ligand- (RANKL- induced osteoclast differentiation in mouse bone marrow macrophage cells and mature osteoclast-mediated bone resorption. Furthermore, oral administration of liensinine reduced the osteolysis in nude mice with intratibial injection of MDA-MB-231 cells. Collectively, liensinine and nuciferine may be promising candidates for preventing and treating breast cancer bone metastasis and the resulting osteolytic bone loss by targeting both cancer cells and osteoclasts. Liensinine has more potent anticancer and antibone resorptive activities than nuciferine.

  10. Study on {sup 41}Ca-AMS for diagnosis and assessment of cancer bone metastasis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Hongtao; Pang, Fangfang [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Jiang, Shan; He, Ming; Dong, Kejun; Dou, Liang [China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Pang, Yijun [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Yang, Xianlin [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); Ruan, Xiangdong [College of Physics, Guangxi University, Nanning 530004 (China); Liu, Manjun; Xia, Chunbo [Guiin Medical University, Guilin 541004 (China)

    2015-10-15

    The annual incidence of new cancer patients in China is about 2 million, 30–40% of which will end up with bone metastasis. Profound study on the preclinical model and early diagnosis of cancer bone metastasis in rats are very significant for the drug development, better understanding and treatment of bone metastases. In order to monitor the process of bone metabolism and early detection of bone metastasis of cancer cells, a technique of {sup 41}Ca isotope tracer combined with AMS has been developed and applied in the study on the bone metastasis of cancer cells by rat model. In this work, 3-month-old female Sprague–Dawley (SD) rats were randomly divided into different groups, and tumor cells injected respectively into the tail vein, femoral artery, femoral cavity and the thigh muscle to establish the rat models for bone metastases. The most appropriate model, i.e., the thigh muscle group, was finally adopted in our real metastases experiment. Each rat in this group was intramuscularly (i.m.) injected with 250 μl CaCl{sub 2} solution (containing 1.4 mg Ca and 5nCi {sup 41}Ca). About 40 days later, the rat mammary gland carcinoma cells (Walker 256) were injected into these rats following the established protocol. After bone metastasis, medicine interventions were performed. The sequential urine and blood samples were collected and analyzed for {sup 41}Ca (by AMS) and N-terminal telopeptide (Ntx), respectively. Bone Mineral Density (BMD) values in the femur and the tibia were measured by CT scan. The results of {sup 41}Ca/Ca in longitudinal urinary samples can sensitively reveal the skeletal perturbations caused by bone metastasis of rats, suggests that {sup 41}Ca might be similarly developed for human use and improve clinical management through the assessment of the curative effect and non-invasive detection of the earliest stages of cancer growth in bone.

  11. Robust and fast characterization of OCT-based optical attenuation using a novel frequency-domain algorithm for brain cancer detection

    Science.gov (United States)

    Yuan, Wu; Kut, Carmen; Liang, Wenxuan; Li, Xingde

    2017-03-01

    Cancer is known to alter the local optical properties of tissues. The detection of OCT-based optical attenuation provides a quantitative method to efficiently differentiate cancer from non-cancer tissues. In particular, the intraoperative use of quantitative OCT is able to provide a direct visual guidance in real time for accurate identification of cancer tissues, especially these without any obvious structural layers, such as brain cancer. However, current methods are suboptimal in providing high-speed and accurate OCT attenuation mapping for intraoperative brain cancer detection. In this paper, we report a novel frequency-domain (FD) algorithm to enable robust and fast characterization of optical attenuation as derived from OCT intensity images. The performance of this FD algorithm was compared with traditional fitting methods by analyzing datasets containing images from freshly resected human brain cancer and from a silica phantom acquired by a 1310 nm swept-source OCT (SS-OCT) system. With graphics processing unit (GPU)-based CUDA C/C++ implementation, this new attenuation mapping algorithm can offer robust and accurate quantitative interpretation of OCT images in real time during brain surgery.

  12. Trafficking of Metastatic Breast Cancer Cells in Bone

    Science.gov (United States)

    2006-08-01

    acids, 5% fetal bovine serum (Atlanta Biologicals, Norcross, GA), without antibiotics or antimycotics (cDME/ F12). All cultures were confirmed to be...32. Fidler IJ. Metastasis: quantitative analysis of distri- bution and fate of tumor emboli labeled with 125I-5- iodo -2V-deoxyuridine. J Natl Cancer

  13. Potential Role of CD68 in Breast Cancer Bone Metastasis

    Science.gov (United States)

    2013-01-01

    antibody (AB-108-C) were also obtained from R&D Systems. Animals C57BL/6 mice were purchased from Harlan Industries (Indianapolis, IN). Mice were...Sotiriou C, Lacroix M, Lagneaux L, Berchem G, Body JJ: The aspirin metabolite salicylate inhibits breast cancer cells growth and their synthesis of the

  14. Ca2+ Receptor, Prostate Cancer, and Bone Metastases

    Science.gov (United States)

    2005-03-01

    the skeletal complications of metastatic niurie hyperealcemia andother syndromes ofaltered respansive- breast cancer and on the incidence of new... dhat an hicrease in extra.ehlinlar Ca42 resulted :in delayed activation of exlracellular signal-regulated kinwse (ERK) in PC-3 cells. Pre-intcubation

  15. PKCα Attenuates Jagged-1-mediated Notch Signaling in ErbB-2 positive Breast Cancer to Reverse Trastuzumab Resistance

    Science.gov (United States)

    Pandya, Kinnari; Wyatt, Debra; Gallagher, Brian; Shah, Deep; Baker, Andrew; Bloodworth, Jeffrey; Zlobin, Andrei; Pannuti, Antonio; Green, Andrew; Ellis, Ian O.; Filipovic, Aleksandra; Sagert, Jason; Rana, Ajay; Albain, Kathy S.; Miele, Lucio; Denning, Mitchell F.; Osipo, Clodia

    2015-01-01

    Purpose Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2 positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib. We showed previously that Notch-1 is required for trastuzumab resistance in ErbB-2 positive breast cancer. Experimental Design Here, we sought to elucidate mechanisms by which ErbB-2 attenuates Notch signaling and how this is reversed by trastuzumab or lapatinib. Results The current study elucidates a novel Notch inhibitory mechanism by which PKCα downstream of ErbB-2: 1. Restricts the availability of Jagged-1 at the cell surface to trans activate Notch; 2. Restricts the critical interaction between Jagged-1 and Mindbomb-1, an E3 ligase that is required for Jagged-1 ubiquitinylation and subsequent Notch activation; 3. Reverses trastuzumab resistance in vivo; and 4. Predicts better outcome in women with ErbB-2 positive breast cancer. Conclusions The clinical impact of these studies is PKCα is potentially a good prognostic marker for low Notch activity and increased trastuzumab sensitivity in ErbB-2 positive breast cancer. Moreover, women with ErbB-2 positive breast tumors expressing high Notch activation and low PKCα expression could be the best candidates for anti-Notch therapy. PMID:26350262

  16. Opposite prognostic roles of HIF1β and HIF2β expressions in bone metastatic clear cell renal cell cancer

    DEFF Research Database (Denmark)

    Szendroi, Attila; Szász, A. Marcell; Kardos, Magdolna

    2016-01-01

    BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1β/HIF2β and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2β was lower in mRCC both at mRNA...

  17. Pretreatment levels of urinary deoxypyridinoline as a potential marker in patients with prostate cancer with or without bone metastasis

    NARCIS (Netherlands)

    Wymenga, L. F.; Groenier, K.; Schuurman, J.; Boomsma, J. H.; Elferink, R. O.; Mensink, H. J.

    2001-01-01

    OBJECTIVE: To assess the predictive role of the bone markers alkaline phosphatase (ALP) and urinary deoxypyridinoline (DPD), as indicators of bone turnover, at baseline in patients with prostate cancer. PATIENTS, SUBJECTS AND METHODS: Urinary DPD, serum ALP and prostate-specific antigen (PSA) were

  18. The effect of breast cancer on the Fourier transform infrared attenuated total reflection spectra of human hair.

    Science.gov (United States)

    Lyman, Donald J; Fay, Sheila G

    2014-01-01

    Changes in the Synchrotron x-ray diffraction pattern of scalp hair were shown to occur in patients with breast cancer. A preliminary Fourier transform infrared (FT-IR) spectroscopy study of scalp hair using attenuated total reflection (ATR) supported the concept that these changes are due to an increase in the lipid content of the hair fibre. This study was undertaken to determine whether the ATR-FT-IR spectrum obtained using a single hair fibre ATR cell could be used in the detection of breast cancer. In addition, variable angle ATR-FT-IR difference spectra were obtained to investigate the location and the molecular structure of this lipid material in the hair fibre, which appears to be an indicator of breast cancer. Patients with breast cancer showed an increase in the peak height ratio of the 1446-1456 cm(-1) C-H bending absorption bands of the ATR-FT-IR spectra of a single hair fibre. Peak height ratios > 1.0 were indicative of breast cancer. The spectra of scalp hair of subjects with breast cancer also showed a slight shift in C-H bending absorption from 1446 to 1448 cm(-1) and from 1456 to 1458 cm(-1) that could result from the formation of secondary structures by the increased lipid material. Variable angle difference spectra indicated that this increased lipid material is located in the cuticle-cortex interface area and appears to be similar to the lipids normally found here. An alteration in hair biosynthesis in the follicle caused by breast cancer signalling molecules, or biomarkers, is most likely involved. ATR-FT-IR spectral analysis of a long hair fibre containing a distal portion formed when the breast cancer was present and a proximal portion formed after the breast cancer was removed showed that hair fibre synthesis had become normal after the removal of the cancer. This study demonstrates the potential of ATR-FT-IR analysis of a hair fibre in the early detection of breast cancer and in studying how hair acts as a biosensor for breast cancer.

  19. ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway.

    Science.gov (United States)

    Li, Xiao-Qing; Du, Xin; Li, Dong-Mei; Kong, Peng-Zhou; Sun, Yan; Liu, Pei-Fang; Wang, Qing-Shan; Feng, Yu-Mei

    2015-08-15

    Bone metastasis affects more than 70% of advanced breast cancer patients, but the molecular mechanisms of this process remain unclear. Here, we present clinical and experimental evidence to clarify the role of the integrin β-like 1 (ITGBL1) as a key contributor to bone metastasis of breast cancer. In an in vivo model system and in vitro experiments, ITGBL1 expression promoted formation of osteomimetic breast cancers, facilitating recruitment, residence, and growth of cancer cells in bone microenvironment along with osteoclast maturation there to form osteolytic lesions. Mechanistic investigations identified the TGFβ signaling pathway as a downstream effector of ITGBL1 and the transcription factor Runx2 as an upstream activator of ITGBL1 expression. In support of these findings, we also found that ITGBL1 was an essential mediator of Runx2-induced bone metastasis of breast cancer. Overall, our results illuminate how bone metastasis occurs in breast cancer, and they provide functional evidence for new candidate biomarkers and therapeutic targets to identify risk, to prevent, and to treat this dismal feature of advanced breast cancer. ©2015 American Association for Cancer Research.

  20. Post-operative breast cancer patients diagnosed with skeletal metastasis without bone pain had fewer skeletal-related events and deaths than those with bone pain

    Directory of Open Access Journals (Sweden)

    Koizumi Mitsuru

    2010-08-01

    Full Text Available Abstract Background Skeletal metastases are often accompanied by bone pain. To investigate the clinical meaning of bone pain associated with skeletal metastasis in breast cancer patients after surgery, we explored whether the presence of bone pain was due to skeletal-related events (SREs or survival (cause specific death, CSD, retrospectively. Methods Consecutive breast cancer patients undergoing surgery between 1988 and 1998 were examined for signs of skeletal metastasis until December 2006. Patients who were diagnosed as having skeletal metastasis were the subjects of this study. Bone scans were performed annually for 5, 7 or 10 years; they were also conducted if skeletal metastasis was suspected. Data concerning bone pain and tumor markers at the time of skeletal metastasis diagnosis, and data relating to various factors including tumors, lymph nodes and hormone receptors at the time of surgery, were investigated. The relationships between factors such as bone pain, SRE and CSD were analyzed using the Kaplan-Meier method and Cox's analysis. Results Skeletal metastasis occurred in 668 patients but the pain status of two patients was unknown, therefore 666 patients were included in the study. At the time of skeletal metastasis diagnosis 270 patients complained of pain; however, 396 patients did not. Analysis of data using Cox's and Kaplan-Meier methods demonstrated that patients without pain had fewer SREs and better survival rates than those with pain. Hazard ratios regarding SRE (base = patients without pain were 2.331 in univariate analysis and 2.243 in multivariate analysis. Hazard ratios regarding CSD (base = patients without pain were 1.441 in univariate analysis and 1.535 in multivariate analysis. Similar results were obtained when analyses were carried out using the date of surgery as the starting point. Conclusion Bone pain at diagnosis of skeletal metastasis was an indicator of increased SRE and CSD. However, these data did not

  1. Repeatability of quantitative parameters of 18F-fluoride PET/CT and biochemical tumour and specific bone remodelling markers in prostate cancer bone metastases.

    Science.gov (United States)

    Wassberg, Cecilia; Lubberink, Mark; Sörensen, Jens; Johansson, Silvia

    2017-12-01

    18F-fluoride PET/CT exhibits high sensitivity to delineate and measure the extent of bone metastatic disease in patients with prostate cancer. 18F-fluoride PET/CT could potentially replace traditional bone scintigraphy in clinical routine and trials. However, more studies are needed to assess repeatability and biological uptake variation. The aim of this study was to perform test-retest analysis of quantitative PET-derived parameters and blood/serum bone turnover markers at the same time point. Ten patients with prostate cancer and verified bone metastases were prospectively included. All underwent two serial 18F-fluoride PET/CT at 1 h post-injection. Up to five dominant index lesions and whole-body 18F-fluoride skeletal tumour burden were recorded per patient. Lesion-based PET parameters were SUVmax, SUVmean and functional tumour volume applying a VOI with 50% threshold (FTV50%). The total skeletal tumour burden, total lesion 18F-fluoride (TLF), was calculated using a threshold of SUV of ≥15. Blood/serum biochemical bone turnover markers obtained at the time of each PET were PSA, ALP, S-osteocalcin, S-beta-CTx, 1CTP and BAP. A total of 47 index lesions and a range of 2-122 bone metastases per patient were evaluated. Median time between 18F-fluoride PET/CT was 7 days (range 6-8 days). Repeatability coefficients were for SUVmax 26%, SUVmean 24%, FTV50% for index lesions 23% and total skeletal tumour burden (TLF) 35%. Biochemical bone marker repeatability coefficients were for PSA 19%, ALP 23%, S-osteocalcin 18%, S-beta-CTx 22%, 1CTP 18% and BAP 23%. Quantitative 18F-fluoride uptake and simultaneous biochemical bone markers measurements are reproducible for prostate cancer metastases and show similar magnitude in test-retest variation.

  2. The Difficult Task of Diagnosing Prostate Cancer Metastases on Dry Bone.

    Science.gov (United States)

    Castoldi, Elisa; Cappella, Annalisa; Gibelli, Daniele; Sforza, Chiarella; Cattaneo, Cristina

    2017-08-17

    The interpretation of pathology on skeletal remains is mandatory for implementing the biological profile and for disease recognition. Prostate cancer is one of the most common tumors, with a high preference for the skeleton as a primary site of metastasis. Its diagnosis on bone is however still ambiguous, due to its "osteoblastic" and resorptive manifestation. This study investigates distribution and appearance of prostate cancer metastases on dry bone on six known cases (selected from the Milano Cemetery Skeletal Collection) and one healthy individual. A macroscopic inspection was performed highlighting the abnormalities observed, describing location, shape, dimension, and aspect. A great amount of proliferative and mixed lesions was noticed, but also cases of pure lytic lesions were displayed. The multiple appearances of the manifestations observed display the difficulty in correctly identifying such a pathology, but also the potential and advantages provided by investigating a study sample with known antemortem history. © 2017 American Academy of Forensic Sciences.

  3. Pulsed radiofrequency therapy for relieving neuropathic bone pain in cancer patients

    Directory of Open Access Journals (Sweden)

    Wei-Li Lin

    2014-01-01

    Full Text Available Metastatic bone pain is among the most commonly reported pain conditions in cancer patients and pharmacological therapy frequently fails to provide satisfactory pain relief. Pulsed radiofrequency (PRF is a minimally invasive procedure and may be an effective alternative. However, there is little published data evaluating PRF treatment of metastatic pain. PRF therapy of select lumbar dorsal root ganglia was performed on two patients suffering from uncontrolled metastatic lumbar bone pain. After PRF therapy, the patients reported markedly improved back pain, and the effect lasted for months until they deceased. No complications or adverse events were noted from this minimally invasive procedure. PRF may be considered a potential intervention in treating certain neuropathic cancer pain conditions.

  4. Diagnostic value of urinary N-telopeptide of type I collagen in prostate cancer. Comparison with bone scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Fukumitsu, Nobuyoshi; Yanada, Shuuichi; Hatano, Takashi; Igarashi, Hiroshi; Nakada, Jojiro [Jikei Univ., Chiba (Japan). Kashiwa Hospital; Uchiyama, Mayuki; Mori, Yutaka

    1999-05-01

    The usefulness of a new biochemical marker of bone resorption, N-telopeptide of type I collagen (NTx), in the diagnosis of bone metastasis was assessed in 69 prostate cancer patients. Based on the bone scintigraphy findings, the patients were divided into a bone metastasis (+) group (n=36) and a bone metastasis (-) group (n=33). The urinary NTx level was significantly higher in the bone metastasis (+) group than in the bone metastasis (-) group (95.5{+-}18.5 nM BCE/mM Cr vs. 63.3{+-}7.9 nM BCE/mM Cr). There was a tendency for greater variability in urinary NTx levels during a 2 month-period in the bone metastasis (+) group than in the bone metastasis (-) group. The urinary NTx level of the 6 patients who were clinically staged as (4+) according to the extent of disease (EOD) grading system was 211.4{+-}96.9 nM BCE/mM Cr, and was significantly higher (p<0.05) than in the (-) group. However, there was not a significant difference in urinary NTx levels between the (1+) to (3+) groups and the (-) group. In conclusion, measuring urinary NTx levels in useful in diagnosing bone metastasis in view of the fact that it is a simple and noninvasive procedure. While it is not as sensitive as bone scintigraphy, it may be used to supplement bone scintigraphy. (author)

  5. A study on staging bone scans in newly diagnosed prostate cancer.

    Science.gov (United States)

    Ayyathurai, R; Mahapatra, R; Rajasundaram, R; Srinivasan, V; Archard, N P; Toussi, H

    2006-01-01

    This study aimed to evaluate the role of bone scan as a staging investigation in newly diagnosed untreated prostate cancers. Bone scan results in patients with newly diagnosed prostate cancer were reviewed and correlated with clinical stage, prostate-specific antigen (PSA) and Gleason scores from the biopsy specimen. In all, 124 patients fulfilled inclusion criteria with an age range of 51-94 (mean 72.3) years. Pre-biopsy PSA ranged from 2.2 to 5,864 with a median of 21.1 ng/ml. Clinical stage was T0-T1c 14.5%, T2a 41.9%, T2b 17.7%, T3 16.9%, and T4 9%. A Gleason score of 7 was found in 31%. Four patients' samples were not suitable for Gleason scoring. Twenty patients (16.1%) had a positive bone scan with a mean age of 79.4 years (median 83). Two patients with PSAGleason sumGleasonbone scans as a staging investigation. Staging bone scan can be safely omitted in patients with a clinical stage of Gleason score of Gleason patternmetastasis. Copyright (c) 2006 S. Karger AG, Basel.

  6. [Bone metastasis of lung cancer in a mouse model with normal immune function].

    Science.gov (United States)

    Meng, Yue; Li, Chunyu; Hao, Song; Hu, Shaoyu; Lin, Zhen; Yuan, Liang; Li, Wei; Yan, Wenjuan; Chen, Jianting; Yang, Dehong

    2014-05-01

    To establish a model bearing human lung cancer xenograft with bone metastasis in mice with normal immune function. Forty female C57BL/6J mice were randomly allocated into 4 equal groups, including a control group and 3 immunosuppression groups treated with low, moderate, and high doses of dexamethasone (50, 100, and 150 mg, respectively). Four days after immune suppression, the mice were subjected to percutaneous injection of1.0×10(9) L(-1) A549 cells into the tibial plateau, and the bone defects were assessed radiographically 28 days after modeling. HE staining and immunohistochemical staining were used to examine the tumor tissues and bone tissue damages. In each of the 4 groups one mouse died during tumor cell injection. Only 1 mouse showed tumor formation in low-dose immunosuppression group, as compared to 7 and 4 in moderate- and high-dose immunosuppression groups. X-ray and microCT scan showed significant tibial bone destruction in moderate- and high-dose groups. The moderate- and high-dose groups showed similar ALP activities but both were significantly higher than those in the other two groups (Pdexamethasone results in longer survival time of the human lung cancer xenograft-bearing model mice as well as a higher tumor formation rate.

  7. Influence of the Different Primary Cancers and Different Types of Bone Metastasis on the Lesion-based Artificial Neural Network Value Calculated by a Computer-aided Diagnostic System,BONENAVI, on Bone Scintigraphy Images

    Directory of Open Access Journals (Sweden)

    TAKURO ISODA

    2017-01-01

    Full Text Available Objective(s: BONENAVI, a computer-aided diagnostic system, is used in bone scintigraphy. This system provides the artificial neural network (ANN and bone scan index (BSI values. ANN is associated with the possibility of bone metastasis, while BSI is related to the amount of bone metastasis. The degree of uptake on bone scintigraphy can be affected by the type of bone metastasis. Therefore, the ANN value provided by BONENAVI may be influenced by the characteristics of bone metastasis. In this study, we aimed to assess the relationship between ANN value and characteristics of bone metastasis. Methods: We analyzed 50 patients (36 males, 14 females; age range: 42–87 yrs, median age: 72.5 yrs with prostate, breast, or lung cancer who had undergone bone scintigraphy and were diagnosed with bone metastasis (32 cases of prostate cancer, nine cases of breast cancer, and nine cases of lung cancer. Those who had received systematic therapy over the past years were excluded. Bone metastases were diagnosed clinically, and the type of bone metastasis (osteoblastic, mildly osteoblastic,osteolytic, and mixed components was decided visually by the agreement of two radiologists. We compared the ANN values (case-based and lesion-based among the three primary cancers and four types of bone metastasis.Results: There was no significant difference in case-based ANN values among prostate, breast, and lung cancers. However, the lesion-based ANN values were the highest in cases with prostate cancer and the lowest in cases of lung cancer (median values: prostate cancer, 0.980; breast cancer, 0.909; and lung cancer, 0.864. Mildly osteoblastic lesions showed significantly lower ANN values than the other three types of bone metastasis (median values: osteoblastic, 0.939; mildly osteoblastic, 0.788; mixed type, 0.991; and osteolytic, 0.969. The possibility of a lesion-based ANN value below 0.5 was 10.9% for bone metastasis in prostate cancer, 12.9% for breast cancer, and 37

  8. Influence of the Different Primary Cancers and Different Types of Bone Metastasis on the Lesion-based Artificial Neural Network Value Calculated by a Computer-aided Diagnostic System, BONENAVI, on Bone Scintigraphy Images.

    Science.gov (United States)

    Isoda, Takuro; BaBa, Shingo; Maruoka, Yasuhiro; Kitamura, Yoshiyuki; Tahara, Keiichiro; Sasaki, Masayuki; Hatakenaka, Masamitsu; Honda, Hiroshi

    2017-01-01

    BONENAVI, a computer-aided diagnostic system, is used in bone scintigraphy. This system provides the artificial neural network (ANN) and bone scan index (BSI) values. ANN is associated with the possibility of bone metastasis, while BSI is related to the amount of bone metastasis. The degree of uptake on bone scintigraphy can be affected by the type of bone metastasis. Therefore, the ANN value provided by BONENAVI may be influenced by the characteristics of bone metastasis. In this study, we aimed to assess the relationship between ANN value and characteristics of bone metastasis. We analyzed 50 patients (36 males,14 females; age range: 87-42 yrs median age:72.5 yrs) with prostate, breast, or lung cancer who had undergone bone scintigraphy and were diagnosed with bone metastasis (32 cases of prostate cancer, nine cases of breast cancer, and nine cases of lung cancer). Those who had received systematic therapy over the past years were excluded. Bone metastases were diagnosed clinically, and the type of bone metastasis (osteoblastic, mildly osteoblastic, osteolytic, and mixed components) was decided visually by the agreement of two radiologists. We compared the ANN values (case-based and lesion-based) among the three primary cancers and four types of bone metastasis. There was no significant difference in case-based ANN values among prostate, breast, and lung cancers. However, the lesion-based ANN values were the highest in cases with prostate cancer and the lowest in cases of lung cancer (median values: prostate cancer, 0.980; breast cancer 0.909; and lung cancer, 0.864). Mildly osteoblastic lesions showed significantly lower ANN values than the other three types of bone metastasis (median values: osteoblastic,; 0.939 mildly osteoblastic; 0.788, mixed type; 0.991, and osteolytic. 0.969) The possibility of a lesion-based ANN value below 0.5 was %10.9 for bone metastasis in prostate cancer, %12.9 for breast cancer, and %37.2 for lung cancer. The corresponding

  9. CT Measures of Bone Mineral Density and Muscle Mass Can Be Used to Predict Noncancer Death in Men with Prostate Cancer.

    Science.gov (United States)

    McDonald, Andrew M; Swain, Thomas A; Mayhew, David L; Cardan, Rex A; Baker, Christopher B; Harris, David M; Yang, Eddy S; Fiveash, John B

    2017-02-01

    Purpose To determine if computed tomographic (CT) metrics of bone mineral density and muscle mass can improve the prediction of noncancer death in men with localized prostate cancer. Materials and Methods Institutional review board approval was obtained, with waiver of informed consent. All patients who underwent radiation therapy for localized prostate cancer between 2001 and 2012 with height, weight, and past medical history documented and who underwent CT that included the L4-5 vertebral interspace were included. On a single axial CT section obtained at the mid-L5 level, the mean CT attenuation of the trabecular bone of the L5 vertebral body (L5 HU ) was measured. The height-normalized psoas cross-sectional area (Psoas L4-5 ) was measured on a single CT section obtained at the L4-5 vertebral interface. Multivariable Cox proportional hazards models were used to assess effects on noncancer death. By using parameter estimates from an adjusted model, a prognostic index for prediction of noncancer death was generated and compared with age-adjusted Charlson Comorbidity Index (CCI) by using the Harrell c statistic. Results Six hundred fifty-three men met the inclusion criteria. Prostate cancer risk grouping, androgen deprivation, race, age-adjusted CCI, L5 HU , and Psoas L4-5 were included in a multivariable model. Age-adjusted CCI (hazard ratio [HR] = 1.36, P index yielded a c value of 0.747 for the prediction of noncancer death versus 0.718 for age-adjusted CCI alone. Conclusion L5 HU and Psoas L4-5 , which are surrogates for bone mineral density and muscle mass, respectively, were independent predictors of noncancer death. The prognostic index that incorporated these measures with the CCI was associated with improved accuracy for prediction of noncancer death. © RSNA, 2016 Online supplemental material is available for this article.

  10. Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer

    Directory of Open Access Journals (Sweden)

    Fuady JH

    2014-03-01

    Full Text Available Jerry H Fuady,1,* Mattia R Bordoli,1,* Irene Abreu-Rodríguez,1,* Glen Kristiansen,2 David Hoogewijs,1,** Daniel P Stiehl,1,** Roland H Wenger1,**1Institute of Physiology and Zurich Center for Human Physiology, University of Zurich, Zurich, Switzerland; 2University Hospital Bonn, Institute of Pathology, Bonn, Germany*,**These authors contributed equally to this workAbstract: Hypoxia and the hypoxia-inducible factor (HIF signaling pathway trigger the expression of several genes involved in cancer progression and resistance to therapy. Transcriptionally active HIF-1 and HIF-2 regulate overlapping sets of target genes, and only few HIF-2 specific target genes are known so far. Here we investigated oxygen-regulated expression of Wnt-1 induced signaling protein 2 (WISP-2, which has been reported to attenuate the progression of breast cancer. WISP-2 was hypoxically induced in low-invasive luminal-like breast cancer cell lines at both the messenger RNA and protein levels, mainly in a HIF-2α-dependent manner. HIF-2-driven regulation of the WISP2 promoter in breast cancer cells is almost entirely mediated by two phylogenetically and only partially conserved functional hypoxia response elements located in a microsatellite region upstream of the transcriptional start site. High WISP-2 tumor levels were associated with increased HIF-2α, decreased tumor macrophage density, and a better prognosis. Silencing WISP-2 increased anchorage-independent colony formation and recovery from scratches in confluent cell layers of normally low-invasive MCF-7 cancer cells. Interestingly, these changes in cancer cell aggressiveness could be phenocopied by HIF-2α silencing, suggesting that direct HIF-2-mediated transcriptional induction of WISP-2 gene expression might at least partially explain the association of high HIF-2α tumor levels with prolonged overall survival of patients with breast cancer.Keywords: invasion, metastasis, motility, oxygen, tumor, transcriptional

  11. Clearance of xenon-133 from bone marrow in patients with small-cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Petersen, L.J.; Friberg, L.; Jensen, J.; Bulow, J.; Hansen, M. (Bispebjerg Hospital, Copenhagen (Denmark)); Madsen, J. (Panum Inst., Copenhagen (Denmark). Inst. of Medical Physiology)

    1991-10-01

    The aim of this study was to estimate bone-marrow blood flow (BMBF) in man and to correlate this with myelosuppression induced by cytostatic treatment dosed as a function of surface area. Twenty-four patients suffering from small-cell lung cancer participated in the study. Blood flow was measured with the xenon-133 washout technique. The results demonstrated no correlation between {sup 133}Xe clearance from crista iliaca and leucocyte or platelet suppression. (Author).

  12. RKIP Suppresses Breast Cancer Metastasis to the Bone by Regulating Stroma-Associated Genes

    Directory of Open Access Journals (Sweden)

    Elena Bevilacqua

    2012-01-01

    genes. Conceptually, the approach we developed uses a master regulator and expression arrays from breast cancer patients to formulate hypotheses based on clinical data. Experimental validation is followed by further bioinformatic analysis to establish the clinical significance of discoveries. Using RKIP as an example we show here that this multi-step approach can be used to identify gene regulatory mechanisms that affect tumor-stroma interactions that in turn influence metastasis to the bone or other organs.

  13. Feasibility study of Transcutaneous Electrical Nerve Stimulation (TENS) for cancer bone pain.

    Science.gov (United States)

    Bennett, Michael I; Johnson, Mark I; Brown, Sarah R; Radford, Helen; Brown, Julia M; Searle, Robert D

    2010-04-01

    This multicenter study assessed the feasibility of conducting a phase III trial of transcutaneous electrical nerve stimulation (TENS) in patients with cancer bone pain recruited from palliative care services. Eligible patients received active and placebo TENS for 1 hour at site of pain in a randomized crossover design; median interval between applications 3 days. Responses assessed at 30 and 60 minutes included numerical and verbal ratings of pain at rest and on movement, and pain relief. Recruitment, tolerability, adverse events, and effectiveness of blinding were also evaluated. Twenty-four patients were randomised and 19 completed both applications. The intervention was well tolerated. Five patients withdrew: 3 due to deteriorating performance status, and 2 due to increased pain (1 each following active and placebo TENS). Confidence interval estimation around the differences in outcomes between active and placebo TENS suggests that TENS has the potential to decrease pain on movement more than pain on rest. Nine patients did not consider that a placebo was used; the remaining 10 correctly identified placebo TENS. Feasibility studies are important in palliative care prior to undertaking clinical trials. Our findings suggest that further work is required on recruitment strategies and refining the control arm before evaluating TENS in cancer bone pain. Cancer bone pain is common and severe, and partly mediated by hyperexcitability. Animal studies suggest that Transcutaneous Electrical Nerve Stimulation can reduce hyperalgesia. This study examined the feasibility of evaluating TENS in patients with cancer bone pain in order to optimize methods before a phase III trial. Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.

  14. An analysis of bone and head sinus cancers in radium dial painters using a two-mutation carcinogenesis model

    Energy Technology Data Exchange (ETDEWEB)

    Leenhouts, H.P. [National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands). E-mail: Henk.Leenhouts at rivm.nl; Brugmans, M.J.P. [National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands)

    2000-06-01

    Bone and head sinus cancer incidence after ingestion of {sup 226}Ra and {sup 228}Ra by radium dial painters is analysed using a two-mutation clonal expansion model for radiation carcinogenesis, taking into account the retention and radiation patterns of these nuclides in the body. The best fit is obtained for compact bone retention and efficient diffusion of {sup 222}Rn to the bone cavities and radiation action on both mutation rates of the cancer model, as found in a similar analysis of bone sarcomas after {sup 226}Ra injection in beagles. The model parameters of the best fit are consistent with cellular radiobiological data and a previous analysis of lung cancer in uranium miners. Due to the low background incidence of bone and head sinus cancer, the resulting dose-effect relationships for these cancers are linear-quadratic with radium ingestion and alpha radiation dose. These results do not support a threshold dose concept, but the risks at low doses calculated by the model come out to about a factor 10 lower than using a linear extrapolation of the data to low doses, a procedure currently applied by ICRP and EPA. Furthermore, the model results indicate radiation risks at low doses to be related with background cancer incidence between relative and absolute radiation risk projections. The results, which are dependent on the model assumptions, might be more generally applicable for bone seekers and will therefore need further study to arrive at better radiation risk estimations. (abstract)

  15. Anti-IL-20 Monoclonal Antibody Suppresses Prostate Cancer Growth and Bone Osteolysis in Murine Models.

    Directory of Open Access Journals (Sweden)

    Yu-Hsiang Hsu

    Full Text Available Interleukin (IL-20 is a proinflammatory cytokine in the IL-10 family. IL-20 is associated with tumor promotion in the pathogenesis of oral, bladder, and breast cancer. However, little is known about the role of IL-20 in prostate cancer. We hypothesize that IL-20 promotes the growth of prostate cancer cells. Immunohistochemical staining showed that IL-20 and its receptors were expressed in human PC-3 and LNCaP prostate cancer cell lines and in prostate tumor tissue from 40 patients. In vitro, IL-20 upregulated N-cadherin, STAT3, vimentin, fibronectin, RANKL, cathepsin G, and cathepsin K, and increased the migration and colony formation of prostate cancer cells via activated p38, ERK1/2, AKT, and NF-κB signals in PC-3 cells. We investigated the effects of anti-IL-20 monoclonal antibody 7E on prostate tumor growth in vivo using SCID mouse subcutaneous and intratibial xenograft tumor models. In vivo, 7E reduced tumor growth, suppressed tumor-mediated osteolysis, and protected bone mineral density after intratibial injection of prostate cancer cells. We conclude that IL-20 is involved in the cell migration, colony formation, and tumor-induced osteolysis of prostate cancer. Therefore, IL-20 might be a novel target for treating prostate cancer.

  16. Lactate dehydrogenase is a prognostic indicator for prostate cancer patients with bone metastasis.

    Science.gov (United States)

    Naruse, Katsuya; Yamada, Yoshiaki; Aoki, Shigeyuki; Taki, Tomohiro; Nakamura, Kogenta; Tobiume, Motoi; Zennami, Kenji; Katsuda, Remi; Sai, Shotoku; Nishio, Yoshitaka; Inoue, Yasusuke; Noguchi, Hiroshi; Hondai, Nobuaki

    2007-05-01

    We analyzed clinical data to identify prognostic indicators in prostate cancer patients with bone metastasis. The subjects were 60 patients with bone metastasis out of 165 patients diagnosed with prostate cancer at our clinic over 6 years from January 1998 to December 2003. The age at the initial diagnosis was 61 to 91 (mean: 73.7 +/- 7.5) years old. The following items were considered to be possible prognostic indicators: T (type) classification, N (node) classification, Gleason score, prostate specific antigen (PSA) value before therapy, disease grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), serum calcium (Ca), hemoglobin (Hgb), and platelet count (Plt). The 5-year overall survival rate was 45.7% in the 60 patients. Univariate analysis showed statistically significant differences in N (1), Gleason score 7 + 8/Gleason score 9 + 10, and LDH level (p = 0.0053, 0.0261, and 0.0049, respectively). Multivariate Cox proportional hazard analysis of these three items showed a statistically significant difference in LDH level and Gleason score 9 +/- 10 (p = 0.0167 and 0.0371). LDH was suggested to be an excellent prognostic indicator, because of its objectivity and convenience of measurement, in prostate cancer patients with bone metastasis.

  17. Exogenous Activation of Wnt/β-Catenin Signaling Attenuates Binge Alcohol-Induced Deficient Bone Fracture Healing

    Science.gov (United States)

    Lauing, Kristen L.; Sundaramurthy, Sumana; Nauer, Rachel K.; Callaci, John J.

    2014-01-01

    Aims: Excessive alcohol consumption is associated with fracture non-union. Canonical Wnt pathway signaling activity regulates normal fracture healing. We previously demonstrated that binge alcohol exposure modulates β-catenin levels in the fracture callus of mice. Here, we sought to determine whether exogenous enhancement β-catenin signaling activity could restore normal fracture healing to binge-exposed mice. Methods: C57BL/6 male mice were exposed to episodic alcohol or saline for 6 total days of alcohol exposure over a 2-week period. Following alcohol exposure, mice were subjected to a stabilized mid-shaft tibia fracture. Beginning 4 days post-injury, mice received daily injections of either lithium chloride or saline subcutaneously. Protein levels of activated, inactivated, and total β-catenin and GSK-3β in fracture calluses were measured at post-injury day 9. Biomechanical strength testing and histology of callus tissue was assessed at post fracture day 14. Results: Binge alcohol was associated with decreased callus biomechanical strength, and reduced cartilaginous callus formation. Alcohol decreased levels of callus-associated activated β-catenin while concomitantly increasing the levels of inactive β-catenin at post-injury day 9. Alcohol also increased callus associated activated GSK-3β at post-injury day 9. Lithium chloride (an inhibitor of GSK-3β) treatment increased activated β-catenin protein levels, significantly decreased activated GSK-3β and restored cartilaginous callus formation and endochondral ossification. Conclusion: These data link alcohol-impaired fracture healing with deregulation of Canonical Wnt signaling activity in the fracture callus. Exogenous activation of the Wnt pathway using LiCl attenuated the damaging effects of binge alcohol exposure on the fracture healing process by modulating canonical Wnt signaling activity. PMID:24627571

  18. Predictors of Positive Bone Metastasis in Newly Diagnosed Prostate Cancer Patients.

    Science.gov (United States)

    Chien, Tsu-Ming; Lu, Yen-Man; Geng, Jiun-Hung; Huang, Tsung-Yi; Ke, Hung-Lung; Huang, Chun-Nung; Li, Ching-Chia; Chou, Yii-Her; Wu, Wen-Jeng; Huang, Shu-Pin

    2016-01-01

    The prevalence of prostate cancer (PCa) has been increasing in recent years. Treatment strategies are largely based on the results of bone scan screening. Therefore, our aim was to investigate predictors of positive bone metastasis in newly diagnosed PCa patients. After extensive review, 336 consecutive patients newly diagnosed with PCa between April 2010 and November 2013 at our institution were enlisted in the study. Patients were divided into two groups according to bone scan results. Univariate analyses (Chi-square test for discrete variables and independent t-test for continuous variables) were applied to determine the potentially significant risk factors associated with distant bone metastasis. Binary logistic regression analyses were used to further investigate the influence of these factors on bone metastasis. The patient mean age was 71.9 ± 8.6 years (range: 48 to 94 years). The mean prostate specific antigen (PSA) level and biopsy Gleason score were 260.2 ± 1107.8 ng/mL and 7.4 ± 1.5, respectively. The body mass index (BMI) for the series was 24.5 ± 3.4 kg/m2. Sixty-four patients (19.0%) had a positive bone scan result. Patients with positive bone scan results had a significantly lower BMI (23.3 ± 3.5 vs. 24.8 ± 3.3; p=0.003), a higher Gleason score (8.5 ± 1.1 vs. 7.1 ± 1.5; p bone metastasis. Multivariate logistic regression analysis employing the above independent predictors demonstrated that a Gleason score of ≥7, clinical stage ≥T3, BMI ≤22 kg/m2, and an initial PSA level of ≥20 ng/mL were all independent predictors of bone metastasis. A bone scan might be necessary in newly diagnosed PCa patients with any of the following criteria: clinical stage T3 or higher, a Gleason score of 7 or higher, BMI equal to or less than 22, and a PSA level of 20 or higher.

  19. Attenuation of LDHA expression in cancer cells leads to redox-dependent alterations in cytoskeletal structure and cell migration.

    Science.gov (United States)

    Arseneault, Robert; Chien, Andrew; Newington, Jordan T; Rappon, Tim; Harris, Richard; Cumming, Robert C

    2013-09-28

    Aerobic glycolysis, the preferential use of glycolysis even in the presence of oxygen to meet cellular metabolic demands, is a near universal feature of cancer. This unique type of metabolism is thought to protect cancer cells from damaging reactive oxygen species (ROS) produced in the mitochondria. Using the cancer cell line MDA-MB-435 it is shown that shRNA mediated knockdown of lactate dehydrogenase A (LDHA), a key mediator of aerobic glycolysis, results in elevated mitochondrial ROS production and a concomitant decrease in cell proliferation and motility. Redox-sensitive proteins affected by oxidative stress associated with LDHA knockdown were identified by Redox 2D-PAGE and mass spectrometry. In particular, tropomyosin (Tm) isoforms Tm4, Tm5NM1 and Tm5NM5, proteins involved in cell migration and cytoskeletal dynamics, exhibited changes in disulfide bonding and co-localized with peri-nuclear actin aggregates in LDHA knockdown cells. In contrast, treatment with the thiol-based antioxidant N-acetylcysteine promoted the relocalization of Tms to cortical actin microfilaments and partially rescued the migration defects associated with attenuated LDHA expression. These results suggest that aerobic glycolysis and reduced mitochondrial ROS production create an environment conducive to cytoskeletal remodeling; key events linked to the high cell motility associated with cancer. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  20. Ginsenoside Rd attenuates breast cancer metastasis implicating derepressing microRNA-18a-regulated Smad2 expression.

    Science.gov (United States)

    Wang, Peiwei; Du, Xiaoye; Xiong, Minqi; Cui, Jingang; Yang, Qinbo; Wang, Wenjian; Chen, Yu; Zhang, Teng

    2016-09-19

    Metastasis remains a major cause of mortality and poor prognosis in breast cancer patients. Anti-metastatic therapies are in great need to achieve optimal clinical outcome in breast cancer patients. Panax Notoginseng Saponins (PNS) has previously been shown to inhibit breast cancer metastasis in mouse. Here the potential anti-metastatic effect of one of the chemical compounds of PNS, ginsenoside Rd (Rd), was further evaluated in mouse mammary carcinoma 4T1 cells. The results revealed that Rd treatment dose-dependently suppressed cell migration and invasion in cultured 4T1 cells. In 4T1 cell-inoculated mice, Rd treatment led to decreased number of tumor lesions in lungs in both spontaneous and experimental metastasis models. Rd treatment resulted in increased expression of Smad2 in cultured 4T1 cells and in tumors grown from inoculated 4T1 cells. Rd treatment decreased the expression of microRNA (miR)-18a in cultured 4T1 cells and in tumors derived from inoculated 4T1 cells. Smad2 was further verified to be a direct target of miR-18a in 4T1 cells. The significant impact of Rd on counteracting miR-18a-medidated downregulation of Smad2 expression was also demonstrated. Together, the current work shows for the first time that Rd treatment attenuates breast cancer metastasis in part through derepressing miR-18a-mediated Smad2 expression regulation.

  1. Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

    Science.gov (United States)

    Saldana, Sandra M; Lee, Heng-Huan; Lowery, Frank J; Khotskaya, Yekaterina B; Xia, Weiya; Zhang, Chenyu; Chang, Shih-Shin; Chou, Chao-Kai; Steeg, Patricia S; Yu, Dihua; Hung, Mien-Chie

    2013-01-01

    Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

  2. Differences in electrophysiological properties of functionally identified nociceptive sensory neurons in an animal model of cancer-induced bone pain

    Science.gov (United States)

    Zhu, Yong Fang; Ungard, Robert; Seidlitz, Eric; Zacal, Natalie; Huizinga, Jan; Henry, James L

    2016-01-01

    Background Bone cancer pain is often severe, yet little is known about mechanisms generating this type of chronic pain. While previous studies have identified functional alterations in peripheral sensory neurons that correlate with bone tumours, none has provided direct evidence correlating behavioural nociceptive responses with properties of sensory neurons in an intact bone cancer model. Results In a rat model of prostate cancer-induced bone pain, we confirmed tactile hypersensitivity using the von Frey test. Subsequently, we recorded intracellularly from dorsal root ganglion neurons in vivo in anesthetized animals. Neurons remained connected to their peripheral receptive terminals and were classified on the basis of action potential properties, responses to dorsal root stimulation, and to mechanical stimulation of the respective peripheral receptive fields. Neurons included C-, Aδ-, and Aβ-fibre nociceptors, identified by their expression of substance P. We suggest that bone tumour may induce phenotypic changes in peripheral nociceptors and that these could contribute to bone cancer pain. Conclusions This work represents a significant technical and conceptual advance in the study of peripheral nociceptor functions in the development of cancer-induced bone pain. This is the first study to report that changes in sensitivity and excitability of dorsal root ganglion primary afferents directly correspond to mechanical allodynia and hyperalgesia behaviours following prostate cancer cell injection into the femur of rats. Furthermore, our unique combination of techniques has allowed us to follow, in a single neuron, mechanical pain-related behaviours, electrophysiological changes in action potential properties, and dorsal root substance P expression. These data provide a more complete understanding of this unique pain state at the cellular level that may allow for future development of mechanism-based treatments for cancer-induced bone pain. PMID:27030711

  3. Risk Factors for Developing Skeletal-Related Events in Breast Cancer Patients With Bone Metastases Undergoing Treatment With Bone-Modifying Agents.

    Science.gov (United States)

    Tanaka, Ryota; Yonemori, Kan; Hirakawa, Akihiro; Kinoshita, Fumie; Takahashi, Naoki; Hashimoto, Jun; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Fujimoto, Manabu; Fujiwara, Yasuhiro; Tamura, Kenji

    2016-04-01

    Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well-understood. This study evaluated the number and timing of SREs from case studies to identify these factors. The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method. Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation ≥6 months after the detection of bone metastases were also significant risk factors, respectively. In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy. Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation ≥6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of

  4. Pain in castration-resistant prostate cancer with bone metastases: a qualitative study

    Directory of Open Access Journals (Sweden)

    Gater Adam

    2011-10-01

    Full Text Available Abstract Background Bone metastases are a common painful and debilitating consequence of castration-resistant prostate cancer (CPRC. Bone pain may predict patients' prognosis and there is a need to further explore CRPC patients' experiences of bone pain in the overall context of disease pathology. Due to the subjective nature of pain, assessments of pain severity, onset and progression are reliant on patient assessment. Patient reported outcome (PRO measures, therefore, are commonly used as key endpoints for evaluating the efficacy of CRPC treatments. Evidence of the content validity of leading PRO measures of pain severity used in CRPC clinical trials is, however, limited. Methods To document patients' experience of CRPC symptoms including pain, and their impact on health-related quality of life (HRQL, semi-structured in-depth qualitative interviews were conducted with 17 patients with CRPC and bone metastases. The content validity of the Present Pain Intensity (PPI scale from the McGill Pain Questionnaire (MPQ, and the 'Average Pain' and 'Worst Pain' items of the Brief Pain Inventory Short-Form (BPI-SF was also assessed. Results Patients with CRPC and bone metastases present with a constellation of symptoms that can have a profound effect on HRQL. For patients in this study, bone pain was the most prominent and debilitating symptom associated with their condition. Bone pain was chronic and, despite being generally well-managed by analgesic medication, instances of breakthrough cancer pain (BTcP were common. Cognitive debriefing of the selected PRO measures of pain severity highlighted difficulties among patients in understanding the verbal response scale (VRS of the MPQ PPI scale. There were also some inconsistencies in the way in which the BPI-SF 'Average Pain' item was interpreted by patients. In contrast, the BPI-SF 'Worst Pain' item was well understood and interpreted consistently among patients. Conclusions Study findings support the

  5. High-level activation of cyclic AMP signaling attenuates bone morphogenetic protein 2-induced sympathoadrenal lineage development and promotes melanogenesis in neural crest cultures.

    Science.gov (United States)

    Ji, Ming; Andrisani, Ourania M

    2005-06-01

    The intensity of cyclic AMP (cAMP) signaling is a differential instructive signal in neural crest (NC) cell specification. By an unknown mechanism, sympathoadrenal lineage specification is suppressed by high-level activation of cAMP signaling. In NC cultures, high-level activation of cAMP signaling mediates protein kinase A (PKA)-dependent Rap1-B-Raf-ERK1/2 activation, leading to cytoplasmic accumulation of phospho-Smad1, thus terminating bone morphogenetic protein 2 (BMP2)-induced sympathoadrenal cell development. Concurrently, cAMP signaling induces transcription of the melanocyte-determining transcription factor Mitf and melanogenesis. dnACREB and E1A inhibit Mitf expression and melanogenesis, supporting the notion that CREB activation is necessary for melanogenesis. However, constitutively active CREB(DIEDML) without PKA activation is insufficient for Mitf expression and melanogenesis, indicating PKA regulates additional aspects of Mitf transcription. Thus, high-level activation of cAMP signaling plays a dual role in NC cell differentiation: attenuation of BMP2-induced sympathoadrenal cell development and induction of melanogenesis. We conclude the intensity of activation of signal transduction cascades determines cell lineage segregation mechanisms.

  6. Inhibition of long non-coding RNA UCA1 by CRISPR/Cas9 attenuated malignant phenotypes of bladder cancer.

    Science.gov (United States)

    Zhen, Shuai; Hua, Ling; Liu, Yun-Hui; Sun, Xiao-Min; Jiang, Meng-Meng; Chen, Wei; Zhao, Le; Li, Xu

    2017-02-07

    CRISPR/Cas9 is a novel and effective genome editing technique, but its application is not widely expanded to manipulate long non-coding RNA (lncRNA) expression. The lncRNA urothelial carcinoma-associated 1 (UCA1) is upregulated in bladder cancer and promotes the progression of bladder cancer. Here, we design gRNAs specific to UCA1 and construct CRISPR/Cas9 systems targeting UCA1. Single CRISPR/Cas9-UCA1 can effectively inhibit UCA1 expression when transfected into 5637 and T24 bladder cancer cells, while the combined transfection of the two most effective CRISPR/Cas9-UCA1s can generate more satisfied inhibitory effect. CRISPR/Cas9-UCA1s attenuate UCA1 expression via targeted genome-specific DNA cleavage, resulting in the significant inhibition of cell proliferation, migration and invasion in vitro and in vivo. The mechanisms associated with the inhibitory effect of CRISPR/Cas9-UCA1 on malignant phenotypes of bladder cancer are attributed to the induction of cell cycle arrest at G1 phase, a substantial increase of apoptosis, and an enhanced activity of MMPs. Additionally, urinary UCA1 can be used as a non-invasive diagnostic marker for bladder cancer as revealed by a meta-analysis. Collectively, our data suggest that CRISPR/Cas9 technique can be used to down-modulate lncRNA expression, and urinary UCA1 may be used as a non-invasive marker for diagnosis of bladder cancer.

  7. Metastasis to Bone in Human Cancer Is Associated with Loss of Occludin Expression.

    Science.gov (United States)

    Martin, Tracey A; Jordan, Nicola; Davies, Eleri L; Jiang, Wen G

    2016-03-01

    Occludin is an integral membrane protein localised at tight junctions (TJ). There is no consensus regarding its paramount role in TJ. In previous work we showed that occludin is aberrantly expressed in both human breast tissues and cancer cell lines. This study demonstrates a link to bone metastasis in human cancer. Primary breast tumours (n=124) and matched normal tissues (n=30) were processed for quantitative polymerase chain reaction (QPCR) analysis. A hammerhead ribozyme was constructed to create occludin knockdown cell lines, MDA-MB-231(ΔOcc) and PC-3(ΔOcc). The effect of human bone matrix extract (BME) was investigated using cell growth and electric cell impedance sensing (ECIS) technology to measure changes in attachment/migration. Trans-epithelial resistance (TER) was measured for assessing changes in TJ function. Cells used were MDA-MB-231, PC-3, CORL-23, SKMES-1 and A-549 human cancer cell lines. Tumours from patients with bone metastasis had significantly lower occludin expression compared to those remaining alive/well (60.7±21 vs. 331±98, respectively, p=0.008). This was striking in ductal carcinomas, where patients alive/well had significantly higher occludin expression compared to those with bone metastasis (391±12.5 vs. 67.9±28, respectively, p=0.0014). ECIS demonstrated that MDA-MB-231(ΔOcc) showed reduced attachment to 5% BME compared to controls (84% vs. 100%) that prevented closure of wounded cell layers. Moreover, these cells had reduced growth on BME. In addition, BME changed the TER of a number of human cell lines and was able to effect changes in the growth of MDA-MB-241 and PC-3 cells, with greater effect on knockdown cells. This is the first study to demonstrate that occludin expression has a clear relationship with bone metastasis in human cancer. The discrepancy between this and the in vitro data indicating a reduction in migration/growth rate of occludin knockdown indicates that loss of occludin leads to complex changes in human

  8. Risk factors for bone loss with prostate cancer in Korean men not receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Sun-Ouck Kim

    2009-04-01

    Full Text Available PURPOSE: Preexisting bone loss in men with prostate cancer is an important issue due to the accelerated bone loss during androgen deprivation therapy (ADT. In addition, a high prostate-specific antigen (PSA level has been reported to be related to bone metabolism. This study assessed the factors associated with osteoporosis in Korean men with non-metastatic prostate cancer before undergoing ADT. MATERIAL AND METHODS: The study enrolled patients admitted for a prostate biopsy because of a high PSA or palpable nodule on a digital rectal examination. We divided the patients (n = 172 according to the results of the biopsy: group I, non-metastatic prostate cancer (n = 42 and group II, benign prostatic hypertrophy (BPH; n = 130. The lumbar bone mineral density (BMD was evaluated using quantitative computed tomography. The demographic, health status, lifestyle, body mass index (BMI, serum testosterone concentration, and disease variables in prostate cancer (Gleason score, clinical stage, and PSA were analyzed prospectively to determine their effect on the BMD. RESULTS: The estimated mean T-score was higher in group I than in group II (-1.96 ± 3.35 vs. -2.66 ± 3.20, but without statistic significance (p = 0.235. The significant factors correlated with BMD in group I were a high serum PSA (ß = -0.346, p = 0.010 and low BMI (ß = 0.345, p = 0.014 in the multiple linear regression model. Also old age (r = -0.481, p = 0.001, a high serum PSA (r = -0.571, p < 0.001, low BMI (r = 0.598, p < 0.001, and a high Gleason’s score (r = -0.319, p = 0.040 were the factors related to BMD in the correlation. The significant factors correlated with BMD in group II were old age (ß = -0.324, p = 0.001 and BMI (ß = 0.143, p = 0.014 in the multiple linear regression model. CONCLUSIONS: The risk factors for osteoporosis in men with prostate cancer include a low BMI, and elevated serum PSA. Monitoring BMD from the outset of ADT is a logical first step in the clinical

  9. Detection of bone metastases in breast cancer patients in the PET/CT era: Do we still need the bone scan?

    Science.gov (United States)

    Caglar, M; Kupik, O; Karabulut, E; Høilund-Carlsen, P F

    2016-01-01

    To examine the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of bone metastasis in breast cancer patients and assess whether whole body bone scan (BS) with (99m)Tc-methylene diphosphonate provides any additional information. Study group comprised 150 patients, mean age 52 years (range 27-85) with breast cancer, suspected of having bone metastases. All patients had undergone both FDG-PET/CT and BS with or without single photon emission tomography/computed tomography (SPECT/CT) within a period of 6 weeks. The final diagnosis of bone metastasis was established by histopathological findings, additional imaging, or clinical follow-up longer than 10 months. Cancer antigen 15-3 (CA15-3) and carcinoembryogenic antigen (CEA) were measured in all patients. Histologically 83%, 7% and 10% had infiltrating ductal, lobular and mixed carcinoma respectively. Confirmed bone metastases were present in 86 patients (57.3%) and absent in 64 (42.7%). Mean CA15-3 and CEA values in patients with bone metastases were 74.6ng/mL and 60.4U/mL respectively, compared to 21.3ng/mL and 3.2U/mL without metastases (p<0.001). The sensitivity of FDG-PET/CT for the detection of bone metastases was 97.6% compared to 89.5% with SPECT/CT. In 57 patients, FDG-PET/CT correctly identified additional pulmonary, hepatic, nodal and other soft tissue metastases, not detected by BS. Our findings suggest that FDG-PET/CT is superior to BS with or without SPECT/CT. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  10. [When should we perform a bone scintigraphy in patients with new diagnosis of asymptomatic prostate cancer in order to detect bone metastasis?].

    Science.gov (United States)

    Márquez-López, Javier; Gómez-Gómez, Enrique; Anaya-Henares, Fernando; Robles-Casilda, Rafael; Requena-Tapia, María José

    2015-03-01

    To define, based on PSA value, Gleason score (GS), clinical stage and age, those patients diagnosed with asymptomatic prostate cancer whose cases warrant further study of bone metastasis (BMet). From January 2006 to May 2010, we evaluated 263 patients diagnosed with prostate cancer who were chosen for further study of bone scintigraphy following the consensus protocol accepted by the Ministry of Health of Andalusia (Integrated Andalusian Process Prostate Cancer-BPH). All selected studies met the criteria defined in the test indications: PSA >10 or Gleason score (GS) ≥7 or positive biopsy of seminal vesicles, all without symptoms of bone pain. A multivariate analysis of potential predictive factors for positive bone scintigraphy was performed and cutoffs were determined by calculating the following diagnostic rates: sensitivity, specificity and positive and negative predictive values with their respective confidence intervals at 95% certainty. BMet were detected in 29 cases (11%). The average age of the patients with a positive bone scan was 65.5 and 68.4 years in those with a negative result (p=0.03). Multivariate analysis showed that GS OR: 2.08 [95% CI (1.34 - 3.18)] (pbone scan. The cutoffs were estimated by ROC curve analysis, resulting in a cutoff of 16.18 ng/ml for PSA value and 7 for GS (larger area under the curve: 0.864 with a sensitivity of 94.5% and specificity of 47%). In the group of patients defined in our study, diagnosed with asymptomatic prostate cancer, the assessment of BMet using a bone scan should be carried out with a PSA level ≥ 16.18 ng/ml and GS ≥7 as reference points.

  11. PET/CT with intravenous contrast can be used for PET attenuation correction in cancer patients

    DEFF Research Database (Denmark)

    Berthelsen, A K; Holm, S; Loft, A

    2005-01-01

    correction, but this may result in a bias in the attenuation factors. The clinical significance of this bias has not been established. Our aim was to perform a prospective clinical study where each patient had CT performed with and without IV contrast agent to establish whether PET/CT with IV contrast can...... be used for PET attenuation without reducing the clinical value of the PET scan. METHODS: A uniform phantom study was used to document that the PET acquisition itself is not significantly influenced by the presence of IV contrast medium. Then, 19 patients referred to PET/CT with IV contrast underwent CT...... comparison of standard uptake value (SUV) was performed, and SUVs in tumour, in non-tumour tissue and in the subclavian vein were calculated. Clinical evaluation of the number and location of lesions on all PET/CT scans was performed twice, blinded and in a different random order, by two independent nuclear...

  12. Curcumin Attenuates Gastric Cancer Induced by N-Methyl-N-Nitrosourea and Saturated Sodium Chloride in Rats

    Directory of Open Access Journals (Sweden)

    Kawiya Sintara

    2012-01-01

    Full Text Available To determine effects of curcumin on N-methyl-N-nitrosourea (MNU and saturated sodium chloride (s-NaCl-induced gastric cancer in rats. Male Wistar rats were divided into 5 groups: control (CO, control supplemented with 200 mg/kg curcumin (CC, MNU + s-NaCl, MNU + s-NaCl supplemented with 200 mg/kg curcumin daily for the first 3 weeks (MNU + s-NaCl + C3W, and MNU + s-NaCl supplemented with curcumin for 20 weeks (MNU + s-NaCl + C20W. To induce stomach cancer, rats except for CO and CC were orally treated with 100 mg/kg MNU on day 0 and 14, and s-NaCl twice-a-week for the first 3 weeks. The experiment was finished and rats were sacrificed at the end of 20 weeks. Cancers were found in forestomachs of all rats in MNU + s-NaCl. The expressions of phosphorylated inhibitor kappaB alpha (phospho-IκBα, 8-hydroxy-2′-deoxyguanosine (8-OHdG, and cyclin D1 significantly increased in MNU + s-NaCl compared with CO. Curcumin treatments for 3 and 20 weeks reduced the cancer incidence resulting in a decrease of phospho-IκBα expression in benign tumor-bearing rats compared with MNU + s-NaCl. Curcumin treatment for 20 weeks also decreased 8-OHdG expression in benign tumor-bearing rats compared with MNU + s-NaCl. Curcumin can attenuate cancer via a reduction of phospho-IκBα and 8-OHdG expressions, which may play a promising role in gastric carcinogenesis.

  13. Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells.

    Science.gov (United States)

    Pan, Xue-Yang; Guo, Hao; Han, Jing; Hao, Feng; An, Yu; Xu, Yan; Xiaokaiti, Yilixiati; Pan, Yan; Li, Xue-Jun

    2012-05-15

    Ginsenoside Rg3 (Rg3), one of the bioactive extracts found in ginseng root, was reported to have anti-cancer activity in various cancer models. The anti-proliferation effect of Rg3 on prostate cancer cells has been well reported. To test whether Rg3 has an anti-metastatic effect on prostate cancer, we treated a highly metastatic PC-3M prostate cancer cell line with Rg3. We found that Rg3 (10μM) led to remarkable inhibition of PC-3M cell migration. Simultaneously, exposure to Rg3 suppressed expression of the aquaporin 1 (AQP1) water channel protein, which has previously been reported to be involved in cell migration. Overexpression of AQP1 attenuated Rg3-induced inhibition of cell migration, and introduction of a shRNA targeting AQP1 abrogated the inhibitory effect of Rg3, although the basal level of cell migration was decreased by RNA interference. In mechanism study, estrogen receptor- and glucocorticoid receptor-dependent pathways are proved uninvolved in the AQP1 regulation by Rg3. However, Rg3 treatment triggered the activation of p38 MAPK; and SB202190, a specific inhibitor of p38 MAPK, antagonized the Rg3-induced regulation of AQP1 and cell migration, suggesting a crucial role for p38 in the regulation process. Deletion analysis of the promoter region of AQP1 was also conducted using dual-luciferase assay, which indicated that the -1000 bp to -200 bp promoter region was involved in the AQP1 regulation by Rg3. In all, we conclude that Rg3 effectively suppresses migration of PC-3M cells by down-regulating AQP1 expression through p38 MAPK pathway and some transcription factors acting on the AQP1 promoter. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Diallyl trisulfides, a natural histone deacetylase inhibitor, attenuate HIF-1α synthesis, and decreases breast cancer metastasis.

    Science.gov (United States)

    Wei, Zhonghong; Shan, Yunlong; Tao, Li; Liu, Yuping; Zhu, Zhijie; Liu, Zhaoguo; Wu, Yuanyuan; Chen, Wenxing; Wang, Aiyun; Lu, Yin

    2017-10-01

    Intratumoral hypoxia promotes the distant metastasis of cancer subclones. The clinical expression level of hypoxia-inducible factor-1α (HIF-1α) reflects the prognosis of a variety of cancers, especially breast cancer. Histone deacetylase (HDAC) inhibitors can target HIF-1α protein due to von Hippel-Lindau (VHL) protein-dependent degradation. Dietary organosulfur compounds, such as those in garlic, have been reported as HDAC inhibitors. The effects of diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) on the ratio of firefly/Renilla luciferase activity in hypoxic MDA-MB-231 cells were determined. The mRNA expressions of HIF-1α target genes ANGPTL4, LOXL4, and LOX in hypoxic MDA-MB-231 cells were significantly down-regulated by DATS. DATS attenuated the metastatic potential of MDA-MB-231 cells in hypoxia-induced embryonic zebrafish, xenograft, and orthotopic tumors. Endothelial cell-cancer cell adhesion, wound healing, transwell, and tube formation assays showed that DATS dose-dependently inhibited the migration and angiogenesis of MDA-MB-231 cells in vitro. The expressions of L1CAM, VEGF-A, and EMT-related proteins (Slug, Snail, MMP-2) were inhibited by DATS. DATS dose-dependently inhibited HIF-1α transcriptional activity and hypoxia-induced hematogenous metastasis of MDA-MB-231 cells. It reduced the protein expression of HIF-1α, which did not involve inhibition of HIF-1α mRNA expression or ubiquitin proteasome degradation. Efficient inhibition of HIF-1α expression was required for DATS to resist breast cancer. © 2017 Wiley Periodicals, Inc.

  15. The role of radiotherapy in the treatment of bone metastasis of prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Iku; Shinozaki, Jun; Nakamura, Yuhji; Takahashi, Mitsuhiro; Ikeda, Hajime; Mitsuhashi, Norio; Niibe, Hideo (Gunma Univ., Maebashi (Japan). School of Medicine)

    1992-11-01

    Pain relief is an important problem in the management of patients with prostate cancer because of the high frequency of bone metastasis. We analyzed the effects of radiotherapy on 157 sites of bone metastases in 39 patients with prostate cancer from 1970 to 1988. The radiation dose at which patients noticed some relief from pain for the first time was up to 20 Gy in 86% of the cases and up to 30 Gy in 98%. The effects of radiation in relieving pain, so that the patients could live as before pain first occurred, was recognized in 91% within the dose range of 20 Gy to 30 Gy. Fourteen patients who died within 6 months did not need re-irradiation applied to the same site, and only 12 out of a total of 80 irradiated sites (15%) that could be observed after more than 6 months needed re-irradiation due to recurring pain. The maximum number of re-irradiation treatment applied to the same site was 4 to the sacrum at intervals of 10 to 18 months. As more that 60% of the patients who needed irradiation to control bone metastases died within a year, it was thought to be very important from the viewpoint of a useful life to get pain relief by irradiation immediately and safely. (author).

  16. MRI-guided focused ultrasound robotic system for the treatment of bone cancer.

    Science.gov (United States)

    Menikou, Georgios; Yiallouras, Christos; Yiannakou, Marinos; Damianou, Christakis

    2017-03-01

    A novel MRI-conditional robot was developed that navigates a focused ultrasound (FUS) transducer. With this robotic system the transducer can access bones. The intended application is pain palliation from bone cancer using thermal ablation using FUS. The robotic system has four computer-controlled axes (three linear and one angular). The robotic system was manufactured using a digital manufacturing 3D printer, using acrylonitrile butadiene styrene (ABS) plastic. MRI-conditional optical encoders were used to accurately control the robotic system. The robotic system was successfully tested for MRI safety and compatibility, using fast-gradient pulse sequences and a liquid phantom. The robotic system has been tested for its functionality for creating discrete and multiple (overlapping) lesions in a gel phantom. An MRI-conditional FUS robotic system was developed that has the potential to create thermal lesions with the intention of treating bone cancer for the purpose of pain palliation. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  17. Radium-223 dichloride for the treatment of castration-resistant prostate cancer with symptomatic bone metastases.

    Science.gov (United States)

    Vogelzang, Nicholas J

    2017-08-01

    Castration-resistant prostate cancer (CRPC) is associated with the development of bone metastases, increased mortality, and a reduction in the patient's quality of life (QOL). The management of metastatic CRPC (mCRPC) has rapidly evolved over the past decade, with a number of available therapeutic agents improving overall survival. Radium-223 dichloride (radium-223), the first targeted alpha therapy, improves survival accompanied by QOL benefits with a favorable safety profile. It is approved in over 40 countries for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastatic disease. Areas covered: The current management of CRPC in men with bone metastases, and in particular the role of radium-223 in this setting, is reviewed and discussed. A search of bibliographic databases for peer-reviewed literature and major meetings was conducted. Expert commentary: In treating patients with mCRPC, the best sequencing and/or combination of radium-223 with other agents has yet to be fully elucidated. The role of radium-223 in treating patients with hormone-sensitive metastatic prostate cancer who are candidates for chemotherapy should also be investigated in well-designed trials. The ability to tailor radium-223 therapy to both the clinical and genetic profiles of CRPC patients would be a promising development.

  18. Clinical features and treatment strategies for older prostate cancer patients with bone metastasis.

    Science.gov (United States)

    Yang, Cheng; Qi, Gui-Sheng; Rong, Rui-Ming; He, Jian

    2013-11-01

    To identify the clinical features and independent predictors of survival in older patients with bone metastasis from prostate cancer (PCa). We retrospectively analysed 205 older patients with bone metastases from PCa between 1997 and 2012. The Kaplan-Meier method was used with the log-rank test for survival rate calculations and to evaluate each variable. Multivariate analysis was performed with the Cox regression model. The chi-squared test was used to compare survival rates between older and younger (n=197) patients. All patients were followed up. The 1-, 2-, 3- and 5-year survival rates were 95.5%, 77.5%, 68.5% and 33.7%, respectively. Gleason score, radiotherapy of the primary tumour, the number of bone metastases, the alkaline phosphatase alkaline phosphatase (ALP) level, organ metastasis and regional lymph node metastasis were associated with the survival rates. Multivariate Cox regression analysis showed that Gleason score at diagnosis of the primary tumour was a significant predictor of overall survival following the diagnosis of bone metastases. In addition, the overall survival rates of older patients were higher compared with younger patients, but older patients who underwent radiotherapy had higher mortality. These data may serve as a guide for creating clinical prediction models in further studies.

  19. Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance

    Directory of Open Access Journals (Sweden)

    Baksh Shairaz

    2007-02-01

    Full Text Available Abstract Background The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC is associated with frequent treatment failures (~90% in metastatic cases, and these tumors frequently contain PTEN abnormalities. Results Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. Conclusion Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories.

  20. Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance

    Science.gov (United States)

    Lin, Pei-Yin; Fosmire, Susan P; Park, See-Hyoung; Park, Jin-Young; Baksh, Shairaz; Modiano, Jaime F; Weiss, Robert H

    2007-01-01

    Background The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC) is associated with frequent treatment failures (~90% in metastatic cases), and these tumors frequently contain PTEN abnormalities. Results Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. Conclusion Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories. PMID:17300726

  1. Correlation between low Gleason score and prostate specific antigen levels with incidence of bone metastases in prostate cancer patients: when to omit bone scans?

    Science.gov (United States)

    Sanjaya, I Putu Gde; Mochtar, Chaidir Arief; Umbas, Rainy

    2013-01-01

    To identify correlation and incidence of bone metastases in prostate cancer patient with low Gleason scores (GS) and prostate specific antigen (PSA) levels. This descriptive restrospective study covered patients with prostate cancer in Cipto Mangunkusumo Hospital in 2006-2011. Of a total of 478, those who had PSA values, histological examination, and bone scan were included, resulting in 358 eligible cases. PSA values were measured using the sandwich electrochemiluminescent immunoassay. Histological examination was graded according to Gleason's grading system and divided into 3 categories: well differentiated (GS ≤ 6), moderately differentiated (GS 7) and poorly differentiated (GS 8-10). Bone scans were performed using a radiopharmaceutical agent (Tc 99m methylenen diphosphonate) with images captured by gamma camera. The mean age was 67.5 ± 7.8, mean GS was 7.7 ± 1.3 and median PSA was 56.9 (range: 0.48-17000 ng/ mL). There were 11 patients (3.0%) with positive bone scan with PSAbone metastasis. In our study, there were still small percentage of patients with bone metastasis even when low values of PSA (PSA<10 ng/mL) and GS (GS ≤ 6) were applied.

  2. Diagnostic performance of 11C-choline PET/CT and bone scintigraphy in the detection of bone metastases in patients with prostate cancer.

    Science.gov (United States)

    Kitajima, Kazuhiro; Fukushima, Kazuhito; Yamamoto, Shingo; Kato, Takashi; Odawara, Soichi; Takaki, Haruyuki; Fujiwara, Masayuki; Yamakado, Koichiro; Nakanishi, Yukako; Kanematsu, Akihiro; Nojima, Michio; Hirota, Shozo

    2017-08-01

    The aim of this study was to compare 11C-choline PET/CT and bone scintigraphy (BS) for detection of bone metastases in patients with prostate cancer. Twenty-one patients with histologically proven prostate cancer underwent 11C-choline PET/CT and BS before (n = 4) or after (n = 17) treatment. Patient-, region-, and lesion-based diagnostic performances of bone metastasis of both 11C-choline PET/CT and BS were evaluated using a five-point scale by two experienced readers. Bone metastases were present in 11 (52.4%) of 21 patients and 48 (32.7%) of 147 regions; 111 lesions were found to have bone metastases. Region-based analysis showed that the sensitivity, specificity, accuracy, and area under the receiver-operating-characteristic curves (AUC) of 11C-choline PET/CT were 97.9%, 99.0%, 98.6%, and 0.9989, respectively; those of BS were 72.9%, 99.0%, 90.5%, and 0.8386, respectively. Sensitivity, accuracy, and AUC significantly differed between the two methods (McNemar test, p = 0.0015, p = 0.0015, and p PET/CT detected 110/111 metastatic lesions (99.1%); BS detected 85 (76.6%) (p PET/BS were 100%/90.3% for the blastic type, 91.7%/8.3% for the lytic type, 100%/100% for the mixed type, and 100%/53.3% for the invisible type, respectively. Significant differences in blastic, lytic, and invisible types were observed between the two methods (p = 0.013, p = 0.0044, and p = 0.023, respectively). In conclusion, 11C-choline PET/CT had greater sensitivity and accuracy than BS for detection of bone involvement in patients with prostate cancer.

  3. Defects of uptake on bone scintigraphy in two patients with lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Labriolle-Vaylet, C. de; Cabane, J.; Mensch, B.; Talbot, J.N.; Lafarge, F.; Milleron, B.

    1989-01-01

    Defects of fixation can be observed on bone scintigraphy of the thorax in patients with lung cancer. One extensive form is reported in one case of Pancoast -Tobias syndrome with a complete disappearance of 3 ribs and 2 hemivertebrae due to tumoral invasion which was evident on CT scan. In the second case, a solitary defect was discovered in the right median part of the sternum, adjacent to the tumor, while the CT scan did not show any abnormality of the sternum. This observation raises the question of the mechanism of some cold lesions which may be due to compression of vessels supplying blood to the bone, rather than to tumoral invasion or metastases.

  4. Preparation and characterization of an iron oxide-hydroxyapatite nanocomposite for potential bone cancer therapy.

    Science.gov (United States)

    Sneha, Murugesan; Sundaram, Nachiappan Meenakshi

    2015-01-01

    Recently, multifunctional magnetic nanostructures have been found to have potential applications in biomedical and tissue engineering. Iron oxide nanoparticles are biocompatible and have distinctive magnetic properties that allow their use in vivo for drug delivery and hyperthermia, and as T2 contrast agents for magnetic resonance imaging. Hydroxyapatite is used frequently due to its well-known biocompatibility, bioactivity, and lack of toxicity, so a combination of iron oxide and hydroxyapatite materials could be useful because hydroxyapatite has better bone-bonding ability. In this study, we prepared nanocomposites of iron oxide and hydroxyapatite and analyzed their physicochemical properties. The results suggest that these composites have superparamagnetic as well as biocompatible properties. This type of material architecture would be well suited for bone cancer therapy and other biomedical applications.

  5. Monitoring Dynamic Interactions between Breast Cancer Cells and Human Bone Tissue in a Co-Culture Model

    Science.gov (United States)

    Contag, Christopher H.; Lie, Wen-Rong; Bammer, Marie C.; Hardy, Jonathan W.; Schmidt, Tobi L.; Maloney, William J.; King, Bonnie L.

    2015-01-01

    Purpose Bone is a preferential site of breast cancer metastasis and models are needed to study this process at the level of the microenvironment. We have used bioluminescence imaging (BLI) and multiplex biomarker immunoassays to monitor dynamic breast cancer cell behaviors in co-culture with human bone tissue. Procedures Femur tissue fragments harvested from hip replacement surgeries were co-cultured with luciferase-positive MDA-MB-231-fLuc cells. BLI was performed to quantify breast cell division and track migration relative to bone tissue. Breast cell colonization of bone tissues was assessed with immunohistochemistry. Biomarkers in co-culture supernatants were profiled with MILLIPLEX® immunoassays. Results BLI demonstrated increased MDA-MB-231-fLuc proliferation (pbones, and revealed breast cell migration toward bone. Immunohistochemistry illustrated MDA-MB-231-fLuc colonization of bone, and MILLIPLEX® profiles of culture supernatants suggested breast/bone crosstalk. Conclusions Breast cell behaviors that facilitate metastasis occur reproducibly in human bone tissue co-cultures and can be monitored and quantified using BLI and multiplex immunoassays. PMID:24008275

  6. Multidetector-computed tomography attenuation values between the tumor and aortic wall in response to induction therapy for esophageal cancer and its predictive value for aortic invasion.

    Science.gov (United States)

    Tsujimoto, Hironori; Ichikura, Takashi; Aiko, Satoshi; Yaguchi, Yoshihisa; Kumano, Isao; Takahata, Risa; Matsumoto, Yusuke; Yoshida, Kazumichi; Ono, Satoshi; Yamamoto, Junji; Hase, Kazuo

    2012-02-01

    The objective of this study was to evaluate the multidetector computed tomography (MDCT) attenuation value between the tumor and aorta in response to the induction therapy for esophageal cancer. In advanced esophageal cancer, the main reason for unresectability is the local invasion of the tumor into the aorta or trachea. Despite remarkable advances in diagnostic modalities, pre-operative assessment of pathological response and local tumor extent in esophageal cancer remains difficult. MDCT attenuation values between the tumor and aorta, and the contact angle of the tumor to the aorta (Picus' angle) were retrospectively evaluated in patients with esophageal cancer who underwent induction therapy in terms of predicting the pathological response, aortic invasion and prognosis of esophageal cancer. The induction therapy may increase the tumor-to-aorta distance and decrease the maximum tumor size and Picus' angle. When the tumor-to-aorta cut-off value was set at 1.3 mm following therapy and underwent curative resection. The assessment of the MDCT attenuation value between the esophageal tumor and the aorta is simple and objectively assesses the response to the induction therapy and aortic invasion in esophageal cancer. This method should be applied to predict the response to the induction therapy and to prevent unnecessary surgery in patients with tumors involving the aorta.

  7. Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells

    NARCIS (Netherlands)

    Cawood, R.; Chen, H.H.; Carroll, F.; Bazan-Peregrino, M.; Rooijen, van N.; Seymour, L.W.

    2009-01-01

    Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective

  8. The Effects of a Comprehensive Coping Strategy on Clinical Outcomes in Breast Cancer Bone Marrow Transplant Patients and Primary Caregiver.

    Science.gov (United States)

    1997-08-01

    27, 28. Northouse 28 presented summary empirical evidence from 19 studies that families may experience similar emotions as the breast cancer patient...REFERENCES 1. Peters , W.P. High-dose chemotherapy and autologous bone marrow support for breast cancer (1992). In V.T. DeVita, S. Hellman and S...innovations in Breast Cancer Care, (1), 75-76. 28. Northouse , L.L. (1995). The impact of cancer in women on the family. Cancer Practice. (3), 134-142. 29

  9. Comparison of choline-PET/CT, MRI, SPECT, and bone scintigraphy in the