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Cancer

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Supplement: Skeletal Complications of Malignancy

1 February 2003

Volume 97, Issue S3

Pages xi–xi, 719–892

  1. Preface

    1. Top of page
    2. Preface
    3. Introduction
    4. Articles from the Symposium
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  2. Introduction

    1. Top of page
    2. Preface
    3. Introduction
    4. Articles from the Symposium
    1. Introduction

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      Third North American symposium on skeletal complications of malignancy : Summary of the scientific sessions (pages 719–725)

      Suresh Mohla, Katherine N. Weilbacher, Michael L. Cher, Babatunde O. Oyajobi, Catherine Van Poznak and Dennis R. Clohisy

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11136

      The introduction summarizes the five scientific sessions to provide an overview of the proceedings for the readers. Details of most of the talks are presented as full length papers in the current volume.

  3. Articles from the Symposium

    1. Top of page
    2. Preface
    3. Introduction
    4. Articles from the Symposium
    1. Bone Marrow Microenvironment and Animal Models of Bone Metastasis

      Bone Marrow Microenvironment and Animal Models of Bone Metastasis
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      The development and function of the skeleton and bone metastases (pages 726–732)

      Gideon A. Rodan

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11147

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      To fulfill its functions in calcium homeostasis and mechanical support, bone undergoes continuous destruction and rebuilding. Tumor cells most likely subvert these physiologic processes to lodge in bone and cause metastases.

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      Role of stromal-derived cytokines and growth factors in bone metastasis (pages 733–738)

      G. David Roodman

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11148

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      Adhesive interactions between tumor cells in the bone microenvironment induce expression of growth factors, chemokines, and cytokines that enhance tumor cell homing and growth. This interplay between the bone microenvironment and tumor cells plays an important role in the development of bone metastases.

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      Stromal factors involved in prostate carcinoma metastasis to bone (pages 739–747)

      Carlton R. Cooper, Christopher H. Chay, James D. Gendernalik, Hyung-Lae Lee, Jasmine Bhatia, Russell S. Taichman, Laurie K. McCauley, Evan T. Keller and Kenneth J. Pienta

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11181

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      The authors present data supporting the role of stromal factors in the metastasis of prostate carcinoma to bone marrow. Stromal factors can regulate local tumor cell invasion, act as chemoattractants, modulate tumor cell adhesion to bone marrow endothelium, facilitate extravasation, and regulate tumor cell growth in the bone microenvironment.

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      Animal models of bone metastasis (pages 748–757)

      Thomas J. Rosol, Sarah H. Tannehill-Gregg, Bruce E. LeRoy, Stefanie Mandl and Christopher H. Contag

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11150

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      Spontaneous bone metastases in animals with cancer are uncommon. Most animal models of bone metastasis were developed from syngeneic transplantation of rare rodent cancers or xenografts of spontaneous human neoplasms in immunodeficient mice. New models are being developed using neoplasms from transgenic mice. Current and future animal models will continue to be important tools to investigate the pathogenesis and treatment of bone metastases in humans.

    5. Prostate Cancer

      Prostate Cancer
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      Prostate carcinoma : Defining therapeutic objectives and improving overall outcomes (pages 758–771)

      Howard I. Scher

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11151

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      The author discusses the management of patients with prostate carcinoma in terms of defining therapeutic objectives over the course of a disease that may span a decade or more, gauging the efficacy of currently available treatments, treating disease that has spread to the skeleton, and improving patient outcomes using clinical insights as well as recent developments in tumor biology.

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      Prostate carcinoma bone-stroma interaction and its biologic and therapeutic implications (pages 772–778)

      Leland W. K. Chung

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11140

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      Currently, there is no therapy for patients with the lethal phenotypes of bone metastasis from prostate carcinoma. Understanding the multistep process of bone metastasis and targeting the interaction of tumor cells and bone stroma may improve the prognosis, reduce the suffering, and increase the survival of patients with bone metastases as a consequence of advanced prostate carcinoma.

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      Role of endothelin-1 in osteoblastic bone metastases (pages 779–784)

      Theresa A. Guise, Juan Juan Yin and Khalid S. Mohammad

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11129

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      The molecular mechanisms responsible for osteoblastic metastases are complex and involve bidirectional interactions between tumor and bone. This review provides evidence to support a role for tumor-produced endothelin-1 in the pathogenesis of osteoblastic metastases.

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      Targeting prostate cancer bone metastases (pages 785–788)

      Christopher Logothetis, Shi-Ming Tu and Nora Navone

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11130

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      Bone metastases are reported to account for a substantial portion of the symptoms from prostate carcinoma. Thus, many investigators have targeted this site of metastases in the hopes of achieving palliation of symptoms. These efforts have included the use of androgen ablation, radiopharmaceuticals, focal radiation, and chemotherapy. Preliminary clinical data support the fact that bone-targeting therapy can be beneficial using multiple modalities. In the current study, the authors observed that selected patients with advanced androgen-independent prostate carcinoma who received consolidation bone-targeted therapy comprised of strontium-89 with weekly doxorubicin after induction chemotherapy had a longer survived compared with those who did not receive bone-targeted therapy.

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      Diagnosis and management of treatment-related osteoporosis in men with prostate carcinoma (pages 789–795)

      Matthew R. Smith

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11149

      Osteoporosis is a complication of androgen deprivation therapy in men with prostate carcinoma. The author reviews the pathophysiology, diagnosis, clinical manifestations, and management of treatment-related osteoporosis in men with prostate carcinoma.

    10. Multiple Myeloma

      Multiple Myeloma
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      Moving disease biology from the lab to the clinic (pages 796–801)

      Kenneth C. Anderson

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11137

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      Multiple myeloma (MM) cells home to and adhere to extracellular matrix proteins and to bone marrow stromal cells. Novel therapies that target not only the MM cells but also the bone marrow microenvironment can overcome drug resistance in vitro and in vivo in murine human MM models. Future studies should examine and define these novel therapies.

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      RANK-Fc: A therapeutic antagonist for RANK-L in myeloma (pages 802–812)

      Emilia Mia Sordillo and Roger Niles Pearse

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11134

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      Myeloma-associated bone destruction reflects heightened osteoclastogenesis in conjunction with impaired osteogenesis. Myeloma triggers osteoclastogenesis by disrupting the balance between the receptor activator of nuclear factor κB ligand (RANK-L) and its natural antagonist, osteoprotegerin. In the SCID-hu-MM mouse model of human myeloma, administration of RANK-Fc, a recombinant RANK-L antagonist formed by the fusion of the extra cellular domain of RANK to the Fc portion of human immunoglobulin G1, both prevents myeloma-induced bone destruction and limits myeloma progression.

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      Receptor activator of NF-κB ligand, macrophage inflammatory protein-1α, and the proteasome : Novel therapeutic targets in myeloma (pages 813–817)

      Babatunde O. Oyajobi and Gregory R. Mundy

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11133

      Even when chemotherapy regimens reduce tumor burden, the underlying bone disease in myeloma patients frequently remains refractory to treatment. There is a compelling need for continuing development of novel biologically based therapies that may impact both tumor burden and osteolysis. Recent studies have implicated the receptor activator of NF-κB ligand (RANKL), macrophage inflammatory protein (MIP)-1α, and proteasomal function in myelomagenesis and associated osteolysis. The dual antitumor and antiosteolytic efficacy of antagonists of RANKL and MIP-1α bioactivities, as well as proteasome inhibitors in in vivo preclinical myeloma models, identify these two cytokines and the proteasome as valid molecular targets in developing novel therapeutics for myeloma patients.

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      Bisphosphonates and osteoprotegerin as inhibitors of myeloma bone disease (pages 818–824)

      Peter I. Croucher, Claire M. Shipman, Ben Van Camp and Karin Vanderkerken

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11125

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      The development of osteolytic bone disease is a major cause of morbidity in patients with myeloma. Inhibiting osteoclast activity with bisphosphonates or targeting the receptor activator of NFkB ligand system with osteoprotegerin are effective mechanisms for preventing the development of myeloma bone disease.

    14. Breast Cancer

      Breast Cancer
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      The biology of breast carcinoma (pages 825–833)

      Judith Clancy Keen and Nancy E. Davidson

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11126

      Breast carcinoma is a complex disease with multiple factors contributing to its development and progression. This review focuses on the role of several critical genes including estrogen receptor, progesterone receptor, retinoic acid receptor-β, epidermal growth factor receptor family members, p53, BRCA1, and BRCA2 as risk factors for the development of disease, predictors of prognosis and response to therapy, and as therapeutic targets.

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      Mechanisms of osteolytic bone metastases in breast carcinoma (pages 834–839)

      Sanna-Maria Käkönen and Gregory R. Mundy

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11132

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      The destruction of bone by metastatic breast carcinoma cells is mediated by osteoclasts and facilitated by the bone marrow microenvironment. The complex cellular and molecular interactions involved provide multiple potential targets for drug discovery.

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      Antitumor effects of bisphosphonates (pages 840–847)

      Jonathan R. Green

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11128

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      In addition to inhibiting osteoclastic bone resorption, bisphosphonates can also exert antiproliferative and proapoptotic effects on tumor cells in vitro. In animal tumor models, bisphosphonate treatment markedly reduced the growth of bone metastases and occasionally affected visceral metastases. However, it is still unclear whether these effects were due to direct antitumor activity or indirectly to alterations in the bone microenvironment arising from osteoclast inhibition.

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      Bisphosphonates and metastatic breast carcinoma (pages 848–853)

      Allan Lipton

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11123

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      Metastasis to the skeleton frequently occurs in patients with breast carcinoma. Of the approximately 180,000 women diagnosed with breast carcinoma each year in the U.S., approximately 30% will develop bone metastases. Although patients in whom bone is the only site of spread are reported to have a better prognosis than patients with extraskeletal metastases, the complications associated with skeletal metastases affect the patients' quality of life significantly. In the current study, the author briefly reviews older trials using the bisphosphonates clodronate and pamidronate and presents information from a recently completed trial using zoledronic acid.

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      Bisphosphonate therapy for patients with breast carcinoma : Who to treat and when to stop (pages 854–858)

      Timothy A. Plunkett and Robert D. Rubens

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11146

      This article provides a review of the current indications for bisphosphonate therapy in patients with breast carcinoma and discusses the areas for further research.

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      Effectiveness and cost of bisphosphonate therapy in tumor bone disease (pages 859–865)

      Jean-Jacques Body

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11139

      The prolonged administration of bisphosphonates can reduce the skeletal morbidity rate in patients with bone metastases from breast carcinoma or in patients with multiple myeloma by approximately 25–50%. Cost-effectiveness studies currently are limited but indicate that the cost of bisphosphonate therapy exceeds the cost savings from the prevention of skeletal-related events. However, this does not take into account the marked improvement in quality of life.

    20. Preclinical and Clinical Studies on Bone Metastasis: Future Directions

      Preclinical and Clinical Studies on Bone Metastasis: Future Directions
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      Bone cancer pain (pages 866–873)

      Denis R. Clohisy and Patrick W. Mantyh

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11144

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      Bone cancer pain is common and can be difficult to treat. Neurochemical characteristics of bone cancer pain indicate that it is different from inflammatory or neuropathic pain and that it causes sensitization of the peripheral and central nervous systems.

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      Bone markers in the management of patients with skeletal metastases (pages 874–879)

      Laurence M. Demers

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11127

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      Surrogate markers that are used to manage patients with metastatic bone disease, including bone collagen breakdown products and specific factors associated with the process of osteoclastogenesis, can be useful in determining response to antiresorptive therapy, in selecting optimal dosage, and as markers of disease progression. However, questions remain whether blood measurements of surrogate markers of osteoclastogenesis will be useful in the assessment and management of patients with metastatic bone disease.

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      Current and future status of adjuvant therapy for breast cancer (pages 880–886)

      Robert E. Coleman

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11124

      Adjuvant endocrine and chemotherapy treatments have greatly improved the prognosis of women with early breast cancer. Bisphosphonates have an increasing role in early breast cancer, possibly as part of adjuvant therapy and certainly for treatment-induced bone loss.

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      A Phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases (pages 887–892)

      Jean-Jacques Body, Philip Greipp, Robert E. Coleman, Thierry Facon, Filip Geurs, Jean-Paul Fermand, Jean-Luc Harousseau, Allan Lipton, Xavier Mariette, Catherine D. Williams, Arline Nakanishi, Donna Holloway, Steven W. Martin, Colin R. Dunstan and Pirow J. Bekker

      Version of Record online: 23 JAN 2003 | DOI: 10.1002/cncr.11138

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      Osteoprotegerin (OPG) is important in the regulation of osteoclastic maturation and activation. Based on urinary levels of collagen crosslinks, a single subcutaneous dose of AMGN-0007, a recombinant OPG construct, was shown to decrease bone resorption rapidly, profoundly and in a sustained manner in patients with multiple myeloma or breast carcinoma related bone metastasis.

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