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Old 01-05-2010, 11:07 AM   #1
Rich66
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Bone mets




Medscape bone metastasis overview:
http://www.medscape.com/viewarticle/714362_5
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Cancer Network Bone Metastasis section: http://www.cancernetwork.com/bone-metastases



J Clin Oncol. 2010 Jun 1. [Epub ahead of print]
Integrated Positron Emission Tomography/Computed Tomography May Render Bone Scintigraphy Unnecessary to Investigate Suspected Metastatic Breast Cancer.

Morris PG, Lynch C, Feeney JN, Patil S, Howard J, Larson SM, Dickler M, Hudis CA, Jochelson M, McArthur HL.
Memorial Sloan-Kettering Cancer Center, New York, NY.



Abstract

PURPOSE Although the accurate detection of osseous metastases in the evaluation of patients with suspected metastatic breast cancer (MBC) has significant prognostic and therapeutic implications, the ideal diagnostic approach is uncertain. In this retrospective, single-institution study, we compare the diagnostic performance of integrated positron emission tomography/computed tomography (PET/CT) and bone scintigraphy (BSc) in women with suspected MBC. PATIENTS AND METHODS Women with suspected MBC evaluated with PET/CT and BSc (within 30 days) between January 1, 2003 and June 30, 2008, were identified through institutional databases. Electronic medical records were reviewed, and radiology reports were classified as positive/negative/equivocal for osseous metastases. A nuclear medicine radiologist (blinded to correlative and clinical end points) reviewed all equivocal PET/CT and BSc images and reclassified some reports. Final PET/CT and BSc classifications were compared. Baseline patient/tumor characteristics and bone pathology were recorded and compared to the final imaging results. Results We identified 163 women who had a median age of 52 years (range, 30 to 90 years); 32% had locally advanced breast cancer, 42% had been diagnosed with breast cancer less than 12 weeks before identification. Twenty studies were originally deemed equivocal (five with PET/CT, and 15 with BSc), and 13 (65%) of these studies were reclassified after radiology review. Overall, PET/CT and BSc were highly concordant for reporting osseous metastases with 132 paired studies (81%); 32 (20%) were positive, and 100 (61%) were negative. Thirty-one occurrences (19%) were discordant. Twelve of these (39%) had pathology confirming osseous metastases: nine (of 18) were PET/CT positive and BSc negative; one (of three) was PET/CT positive and BSc equivocal; and two (of two) were PET/CT equivocal and BSc negative. CONCLUSION This study supports the use of PET/CT in detecting osseous metastases for suspected MBC. Whether PET/CT may supplant BSc in this setting is unknown.

PMID: 20516453 [PubMed - as supplied by publisher]


Supplementary editorial provided by OncologySTAT
TAKE-HOME MESSAGE

Bone metastases were more likely to be detected with combined PET/CT imaging than with bone scintigraphy in women with suspected metastatic breast cancer.


This study, based at Memorial Sloan-Kettering Cancer Center, compared the diagnostic performance of PET/CT with BSc for bone metastases in women being evaluated for suspected metastatic breast cancer.


This is the largest study reported to date comparing PET/CT and BSc in women with suspected metastatic breast cancer. The results of this study suggest that PET/CT may be superior to BSc in detecting bone metastases in such women.










See Zoledronic Acid thread: http://her2support.org/vbulletin/showthread.php?t=39563



http://carcin.oxfordjournals.org/cgi...act/30/11/1941
Selenium modifies the osteoblast inflammatory stress response to bone metastatic breast cancer
Department of Biochemistry and Molecular Biology, 431 South Frear Building, Penn State University, University Park, PA 16802, USA Email: ksp4@psu.edu
Breast cancer frequently metastasizes to the skeleton resulting in bone degradation due to osteoclast activation. Metastases also downregulate differentiation and the bone-rebuilding function of osteoblasts. Moreover, cancer cells trigger osteoblast inflammatory stress responses. ...
our data indicate that the osteoblast response to metastatic breast cancer cells is regulated by NF-B activation, which can be effectively suppressed by MSA either through short-lived active metabolites and/or selenoproteins. Thus, Se supplementation may prevent the osteoblast inflammatory response or dampen the vicious cycle established when breast cancer cells, osteoblasts and osteoclasts interact.
Received February 13, 2009; revised September 10, 2009; accepted September 12, 2009.



Overview of ablation techniques: http://www.cancerablation.com/procedures.html





Mol Pharmacol. 2010 Jan;77(1):17-25. Epub 2009 Oct 14.
Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-kappaB signal.

Lee JH, Jin H, Shim HE, Kim HN, Ha H, Lee ZH.
Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, 28 Yeongon-Dong, Jongro-Gu, Seoul 110-749, Republic of Korea.
Epigallocatechin-3-gallate (EGCG), the major anti-inflammatory compound in green tea, has been shown to suppress osteoclast differentiation. However, the precise molecular mechanisms underlying the inhibitory action of EGCG in osteoclastogenesis and the effect of EGCG on inflammation-mediated bone destruction remain unclear. In this study, we found that EGCG inhibited osteoclast formation induced by osteoclastogenic factors in bone marrow cell-osteoblast cocultures but did not affect the ratio of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) to osteoprotegerin induced by osteoclastogenic factors in osteoblasts. We also found that EGCG inhibited osteoclast formation from bone marrow macrophages (BMMs) induced by macrophage colony-stimulating factor plus RANKL in a dose-dependent manner without cytotoxicity. Pretreatment with EGCG significantly inhibited RANKL-induced the gene expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. EGCG suppressed RANKL-induced activation of c-Jun N-terminal protein kinase (JNK) pathway, among the three well known mitogen-activated protein kinases and also inhibited RANKL-induced phosphorylation of the NF-kappaB p65 subunit at Ser276 and NF-kappaB transcriptional activity without affecting the degradation of IkappaBalpha and NF-kappaB DNA-binding in BMMs. The inhibitory effect of EGCG on osteoclast formation was somewhat reversed by retroviral c-Fos overexpression, suggesting that c-Fos is a downstream target for antiosteoclastogenic action of EGCG. In addition, EGCG treatment reduced interleukin-1-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo. Taken together, our data suggest that EGCG has an antiosteoclastogenic effect by inhibiting RANKL-induced the activation of JNK/c-Jun and NF-kappaB pathways, thereby suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.

PMID: 19828731 [PubMed - indexed for MEDLINE]






Br J Cancer. 2007 May 21;96(10):1526-31. Epub 2007 Apr 17.
Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer.

FULL TEXT (free)





Duivenvoorden WC, Vukmirović-Popović S, Kalina M, Seidlitz E, Singh G.
Juravinski Cancer Centre, Hamilton, Ontario, Canada L8V 5C2.
Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline- and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.

PMID: 17437017 [PubMed - indexed for MEDLINE]



Minireview
Epidermal growth factor signalling and bone metastasis
FULL TEXT

X Lu1 and Y Kang*,1,2
1Department of Molecular Biology, Princeton University, Princeton, NJ, USA; 2Breast Cancer Program, Cancer Institute of New Jersey, New Brunswick,
NJ 08903, USA
Epidermal growth factor (EGF) signalling is well known for its multifaceted functions in development and tissue homoeostasis. The EGF family of ligands and receptors (ERBB family) have also been extensively investigated for their roles in promoting tumourigenesis and metastasis in a variety of cancer types. Recent findings indicate that EGF signalling is an important mediator of bone metastasis in breast, prostate and kidney cancers. The EGF signalling stimulates the growth of bone metastasis directly by increasing tumour cell proliferation and indirectly by engaging bone stromal cell in metastasis-promoting activities. Therefore, molecular targeting of ERBB receptors may benefit patients with bone metastasis and should be evaluated in clinical trials.
British Journal of Cancer (2010) 102, 457–461. doi:10.1038/sj.bjc.6605490 www.bjcancer.com
Published online 15 December 2009
& 2010 Cancer Research UK




PLoS One. 2009 Sep 3;4(9):e6896.
Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment.

Dunn LK, Mohammad KS, Fournier PG, McKenna CR, Davis HW, Niewolna M, Peng XH, Chirgwin JM, Guise TA.
Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
BACKGROUND: Most patients with advanced breast cancer develop bone metastases, which cause pain, hypercalcemia, fractures, nerve compression and paralysis. Chemotherapy causes further bone loss, and bone-specific treatments are only palliative. Multiple tumor-secreted factors act on the bone microenvironment to drive a feed-forward cycle of tumor growth. Effective treatment requires inhibiting upstream regulators of groups of prometastatic factors. Two central regulators are hypoxia and transforming growth factor (TGF)- beta. We asked whether hypoxia (via HIF-1alpha) and TGF-beta signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed interactions between HIF-1alpha and TGF-beta pathways in MDA-MB-231 breast cancer cells. Only vascular endothelial growth factor (VEGF) and the CXC chemokine receptor 4 (CXCR4), of 16 genes tested, were additively increased by both TGF-beta and hypoxia, with effects on the proximal promoters. We inhibited HIF-1alpha and TGF-beta pathways in tumor cells by shRNA and dominant negative receptor approaches. Inhibition of either pathway decreased bone metastasis, with no further effect of double blockade. CONCLUSIONS/SIGNIFICANCE: We tested pharmacologic inhibitors of the pathways, which target both the tumor and the bone microenvironment. Unlike molecular blockade, combined drug treatment decreased bone metastases more than either alone, with effects on bone to decrease osteoclastic bone resorption and increase osteoblast activity, in addition to actions on tumor cells. Hypoxia and TGF-beta signaling in parallel drive tumor bone metastases and regulate a common set of tumor genes. In contrast, small molecule inhibitors, by acting on both tumor cells and the bone microenvironment, additively decrease tumor burden, while improving skeletal quality. Our studies suggest that inhibitors of HIF-1alpha and TGF-beta may improve treatment of bone metastases and increase survival.

PMID: 19727403 [PubMed - indexed for MEDLINE]



Cancer. 1997 Oct 15;80(8 Suppl):1572-80.
Parathyroid hormone-related protein and bone metastases.

Guise TA.
Department of Medicine, University of Texas Health Science Center at San Antonio, 78284-7877, USA.
Parathyroid hormone-related protein (PTH-rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH-rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH-rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastatic to bone expresses PTH-rP in >90% of cases, compared with only 17% of metastasis to nonbone sites. These observations suggest that PTH-rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor-beta (TGF-beta), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH-rP expression and tumor cell growth. To investigate the role of PTH-rP in the pathophysiology of breast carcinoma metastasis to bone, the human breast carcinoma cell line MDA-MB-231 was studied in a murine model of human breast carcinoma metastasis to bone. A series of experiments were performed in which 1) PTH-rP secretion was altered, 2) the effects of PTH-rP were neutralized, or 3) the responsiveness to TGF-beta was abolished in MDA-MB-231 cells. Cultured MDA-MB-231 cells secreted low amounts of PTH-rP that increased fivefold in response to TGF-beta. Tumor cells inoculated into the left cardiac ventricle of nude mice caused osteolytic metastasis similar to that observed in humans with breast carcinoma. When PTH-rP was overexpressed in the tumor cells, bone metastases were increased. MDA-MB-231 cells transfected with the cDNA for human preproPTH-rP secreted a tenfold greater amount of PTH-rP and caused significantly greater bone metastases when inoculated into the left cardiac ventricle of female nude mice compared with parental cells. In contrast, when the biologic effects of PTH-rP were neutralized or its production was suppressed, such metastases were decreased. Treatment of mice with a neutralizing monoclonal antibody to human PTH-rP resulted in a decrease in the development and progression of bone metastasis due to the parental MDA-MB-231 cells. Similar results were observed when mice were treated with dexamethasone, a potent glucocorticoid that suppresses production of PTH-rP by the MDA-MB-231 cells in vitro. The role of bone-derived TGF-beta in the development and progression of bone metastasis was studied by transfecting MDA-MB-231 cells with a cDNA encoding a TGF-beta type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF-beta. Stable clones expressing this mutant receptor (MDA/TbetaRIIdeltacyt) did not increase PTH-rP secretion in response to TGF-beta stimulation compared with controls of untransfected MDA-MB-231 or those transfected with the empty vector. Mice inoculated into the left cardiac ventricle with MDA/TbetaRIIdeltacyt had fewer and smaller bone metastases as assessed radiographically and histomorphometrically compared with controls. Taken together, these data suggest that PTH-rP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Furthermore, TGF-beta responsiveness of breast carcinoma cells may be important for the expression of PTH-rP in bone and the development of osteolytic bone metastasis in vivo. These interactions define a critical feedback loop between breast carcinoma cells and the bone microenvironment that may be responsible for the alacrity with which breast carcinoma grows in bone.

PMID: 9362424 [PubMed - indexed for MEDLINE]






Blood. 2007 Apr 15;109(8):3424-31. Epub 2006 Dec 27.
Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner.

Hirbe AC, Uluçkan O, Morgan EA, Eagleton MC, Prior JL, Piwnica-Worms D, Trinkaus K, Apicelli A, Weilbaecher K.
Department of Medicine and Division of Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Inhibition of osteoclast (OC) activity has been associated with decreased tumor growth in bone in animal models. Increased recognition of factors that promote osteoclastic bone resorption in cancer patients led us to investigate whether increased OC activation could enhance tumor growth in bone. Granulocyte colony-stimulating factor (G-CSF) is used to treat chemotherapy-induced neutropenia, but is also associated with increased markers of OC activity and decreased bone mineral density (BMD). We used G-CSF as a tool to investigate the impact of increased OC activity on tumor growth in 2 murine osteolytic tumor models. An 8-day course of G-CSF alone (without chemotherapy) significantly decreased BMD and increased OC perimeter along bone in mice. Mice administered G-CSF alone demonstrated significantly increased tumor growth in bone as quantitated by in vivo bioluminescence imaging and histologic bone marrow tumor analysis. Short-term administration of AMD3100, a CXCR4 inhibitor that mobilizes neutrophils with little effect on bone resorption, did not lead to increased tumor burden. However, OC-defective osteoprotegerin transgenic (OPG(Tg)) mice and bisphosphonate-treated mice were resistant to the effects of G-CSF administration upon bone tumor growth. These data demonstrate a G-CSF-induced stimulation of tumor growth in bone that is OC dependent.

PMID: 17192391 [PubMed - indexed for MEDLINE]



J Immunol. 2004 May 15;172(10):5940-7.
Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis.


FULL TEXT



Bharti AC, Takada Y, Aggarwal BB.
Cytokine Research Section, Department of Bioimmunotherapy, Unit 143, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with cancers and other diseases. Gene deletion studies have shown that receptor activator of NF-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. How RANKL mediates osteoclastogenesis is not fully understood, but an agent that suppresses RANKL signaling has potential to inhibit osteoclastogenesis. In this report, we examine the ability of curcumin (diferuloylmethane), a pigment derived from turmeric, to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and preexposure of the cells to curcumin completely suppressed RANKL-induced NF-kappaB activation. Curcumin inhibited the pathway leading from activation of IkappaBalpha kinase and IkappaBalpha phosphorylation to IkappaBalpha degradation. RANKL induced osteoclastogenesis in these monocytic cells, and curcumin inhibited both RANKL- and TNF-induced osteoclastogenesis and pit formation. Curcumin suppressed osteoclastogenesis maximally when added together with RANKL and minimally when it was added 2 days after RANKL. Whether curcumin inhibits RANKL-induced osteoclastogenesis through suppression of NF-kappaB was also confirmed independently, as RANKL failed to activate NF-kappaB in cells stably transfected with a dominant-negative form of IkappaBalpha and concurrently failed to induce osteoclastogenesis. Thus overall these results indicate that RANKL induces osteoclastogenesis through the activation of NF-kappaB, and treatment with curcumin inhibits both the NF-kappaB activation and osteoclastogenesis induced by RANKL.

PMID: 15128775 [PubMed - indexed for MEDLINE]




Planta Med. 2010 Feb 15. [Epub ahead of print]
Inhibition of Bone Metastasis from Breast Carcinoma by Rosmarinic Acid.

Xu Y, Jiang Z, Ji G, Liu J.
State Key Laboratory of Bioreactor Engineering & School of Pharmacy, East China University of Science and Technology, Shanghai, P. R. China.
Skeletal disorders are a common complication of breast cancer and will be found in the vast majority of women with metastatic disease. Our study showed that rosmarinic acid (RA) could inhibit the migration of MDA-MB-231BO human bone-homing breast cancer cells dose-dependently. Furthermore, in ST-2 murine bone marrow stromal cells cultured with RA there was a significant and dose-dependent increase in alkaline phosphatase (ALP) activity, with the number and size of mineralized nodules increasing. According to Western blot and quantitative real-time PCR assay, RA may inhibit bone metastasis from breast carcinoma mainly via the pathway of the receptor activator of NF kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) and by simultaneously suppressing the expression of interleukin-8 (IL-8). RA may thus be a good candidate for a new therapeutic approach in bone metastasis from breast carcinoma. © Georg Thieme Verlag KG Stuttgart · New York.

PMID: 20157877 [PubMed - as supplied by publisher]


Rosmarinic acid available as supplement HERE
(may be estrogenic..can't place where I saw that)






Support Care Cancer. 2010 Feb 12. [Epub ahead of print]
Bone pain reduction in patients with metastatic breast cancer treated with ibandronate-results from a post-marketing surveillance study.

Diel IJ, Kurth AH, Sittig HB, Meden H, Maasberg M, Sandermann A, Bergner R.
Institute for Gynaecological Oncology, CGG-Clinic, P7, 16-18, 68161, Mannheim, Germany, diel@cgg-mannheim.de.
BACKGROUND: Pain relief is an important treatment goal for breast cancer patients with metastatic bone disease and treatment should be associated with a low rate of side effects. This interim analysis of a prospective non-interventional study documents the efficacy and safety of the amino-bisphosphonate ibandronate in the treatment of metastatic bone disease under real-life conditions. PATIENTS AND METHODS: For up to 24 weeks 913 breast cancer patients received IV infusions of 6 mg ibandronate every 3-4 weeks or 50 mg of oral ibandronate once daily. Efficacy variables included pain severity, analgesic use, and skeletal-related events; the major safety parameter was renal function, assessed by serum creatinine levels. Subgroup analyses were performed according to pretreatment with bisphosphonates (none, ibandronate, or other bisphosphonates). RESULTS: At baseline, patients with ibandronate pretreatment tended to have lower mean pain scores and lower serum creatinine levels than those pre-treated with other bisphosphonates. Over the observation period, analgesic use did not increase. Among the 712 patients reporting pain at baseline, 70% achieved an improvement in pain severity during treatment with ibandronate, and there was no evidence to suggest relevant differences in mean pain reductions with IV or oral administration of ibandronate or according to prior bisphosphonate treatment. Skeletal-related events were rare (7%). Changes in serum creatinine levels during ibandronate treatment were small and both formulations of ibandronate were rated as well tolerated by physicians and patients. CONCLUSIONS: Data from this non-interventional study confirm the analgesic efficacy and safety profile of IV and oral ibandronate under real-life conditions.

PMID: 20151162 [PubMed - as supplied by publisher]



Cancer Res. 2010 Feb 16. [Epub ahead of print]
Vitamin D Deficiency Promotes Human Breast Cancer Growth in a Murine Model of Bone Metastasis.

Ooi LL, Zhou H, Kalak R, Zheng Y, Conigrave AD, Seibel MJ, Dunstan CR.
Authors' Affiliations: Bone Research Program, ANZAC Research Institute, School of Molecular and Microbial Biosciences, and Biomedical Engineering, AMME, University of Sydney, Sydney, New South Wales, Australia.
Vitamin D exerts antiproliferative, prodifferentiation, and proapoptotic effects on nonclassic target tissues such as breast. Blood levels of 25-hydroxyvitamin D [25(OH)D], the most sensitive indicator of vitamin D status, are inversely correlated with breast cancer risk; however, a causal relationship between vitamin D deficiency and breast cancer growth in bone has not been assessed. We examined the effect of vitamin D deficiency on the intraskeletal growth of the human breast cancer cell line MDA-MB-231-TxSA in a murine model of malignant bone lesions. Subsets of mice were treated concurrently with osteoprotegerin (OPG) to abrogate bone resorption. Outcomes were assessed by repeated radiographic and end-point micro-computed tomography and histologic analyses. Mice weaned onto a vitamin D-free diet developed vitamin D deficiency within 4 weeks [mean +/- SE serum 25(OH)D: 11.5 +/- 0.5 nmol/L], which was sustained throughout the study and was associated with secondary hyperparathyroidism and accelerated bone turnover. Osteolytic lesions appeared earlier and were significantly larger in vitamin D-deficient than in vitamin D-sufficient mice after 2 weeks (radiographic osteolysis: +121.5%; histologic tumor area: +314%; P < 0.05). Although OPG treatment reduced the size of radiographic osteolyses and tumor area in both groups, tumors remained larger in OPG-treated vitamin D-deficient compared with OPG-treated vitamin D-sufficient mice (0.53 +/- 0.05 mm(2) versus 0.19 +/- 0.05 mm(2); P < 0.05). We conclude that vitamin D deficiency promotes the growth of human breast cancer cells in the bones of nude mice. These effects are partly mediated through secondary changes in the bone microenvironment, along with direct effects of vitamin D on tumor growth. Cancer Res; 70(5); 1835-44.

PMID: 20160035 [PubMed - as supplied by publisher]






Clinical Study

British Journal of Cancer (2010) 102, 651–657. doi:10.1038/sj.bjc.6605546 www.bjcancer.com
Published online 26 January 2010
Tumour response interpretation with new tumour response criteria vs the World Health Organisation criteria in patients with bone-only metastatic breast cancer

T Hamaoka1,2, C M Costelloe3, J E Madewell3, P Liu4, D A Berry4, R Islam5, R L Theriault5, G N Hortobagyi5 and N T Ueno1,5
  1. 1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
  2. 2Breast Cancer, St Luke's International Hospital, Tokyo, Japan
  3. 3Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
  4. 4Department of Biostatistics and Applied Mathematics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
  5. 5Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Correspondence: Dr NT Ueno, Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail: nueno@mdanderson.org
Received 17 July 2009; Revised 7 December 2009; Accepted 18 December 2009; Published online 26 January 2010.

Top of pageAbstract

Background:

We compared the utility of a new response classification (MDA; based on computed tomography (CT), magnetic resonance imaging (MRI), plain radiography (XR), and skeletal scintigraphy (SS)) and the World Health Organisation response classification (WHO; based on XR and SS) in stratifying breast cancer patients with bone-only metastases with respect to progression-free survival (PFS), overall survival (OS), and clinical response.

Methods:

We retrospectively reviewed 41 patients with bone-only metastatic breast cancer and assigned responses according to the MDA and WHO criteria. We analysed whether the MDA or WHO response classifications correlated with PFS and OS.

Results:

With the MDA criteria, there were significant differences in PFS between patients classified as responders and those classified as nonresponders (P=0.025), but with the WHO criteria, there were not. Neither criteria distinguished responders from nonresponders in terms of OS. MDA response criteria correlated better than WHO response criteria with clinical response assessment.

Conclusions:

The MDA classification is superior to the WHO classification in differentiating between responders and nonresponders among breast cancer patients with bone-only metastases. Application of the MDA classification may allow bone lesions to be considered measurable disease. Prospective study is needed to test the MDA classification among patients with bone metastasis.
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Old 08-18-2010, 10:34 AM   #2
Rich66
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Re: Bone mets

J Biol Chem. 2010 Aug 2. [Epub ahead of print]
Tumor-supportive and osteoclastogenic changes induced by breast cancer-derived factors are reversed by inhibition of {gamma}-secretase.

Fong JE, Le Nihouannen D, Komarova SV.
McGill University, Canada.



Abstract

During breast cancer metastasis to bone, tumor cells home to bone marrow, likely targeting the stem cell niche, and stimulate osteoclasts, which mediate osteolysis required for tumor expansion. Although osteoblasts contribute to the regulation of the hematopoietic stem cell niche and control osteoclastogenesis through production of pro-resorptive cytokine RANKL, their role in cancer metastases to bone is not fully understood. C57BL/6J mouse bone marrow cells were treated for 3-12 days with ascorbic acid (AA, 50 mug/mL), in the presence or absence of 10% medium conditioned by breast carcinoma cells MDA-MB-231, 4T1, or MCF7. Treatment with cancer-derived factors resulted in a sustained 40-60% decrease in osteoblast differentiation markers, compared to treatment with AA alone, and induced an osteoclastogenic change in the RANKL/OPG ratio. Importantly, exposure of bone cells to breast cancer-derived factors stimulated the subsequent attachment of cancer cells to immature osteoblasts. Inhibition of gamma-secretase using pharmacological inhibitors DAPT and Compound E completely reversed cancer-induced osteoclastogenesis as well as cancer-induced enhancement of cancer cell attachment, identifying gamma-secretase activity as a key mediator of these effects. Thus, we have uncovered osteoblasts as critical intermediary of pre-metastatic signaling by breast cancer cells and pinpointed gamma-secretase as a robust target for developing therapeutics potentially capable of reducing both homing and progression of cancer metastases to bone.







Int J Cancer. 2010 Aug 16. [Epub ahead of print]
Increased expression and serum levels of the stromal cell-secreted protein periostin in breast cancer bone metastases.

Contié S, Voorzanger-Rousselot N, Litvin J, Clézardin P, Garnero P.
Research Unit 664, Institut National de la Santé et de la Recherche Médicale, Lyon, F-69372 France.
Abstract

Periostin, a matricellular protein, is overexpressed in the stroma of several cancers. The aim of this study was to investigate more specifically whether periostin expression is associated with bone metastases from breast cancer and to determine its source in the affected bone. Nude mice were inoculated with human MDA-B02 breast cancer cells. Bone metastases-bearing mice were treated with zoledronic acid -an antiresorptive drug- or vehicle. Bone metastases were examined for tumor- and stroma-derived periostin expression by Q-PCR with human and mouse specific primers, and immunohistochemistry. Serum periostin and conventional bone turnover markers were also measured. MDA-B02 cells did not express periostin both in vitro and in vivo. However, mouse-derived periostin was markedly overexpressed (8-fold) in metastatic legs compared to non inoculated mice. Serum periostin levels were also markedly increased in metastatic mice and correlated with in situ expression levels. Immunostaining showed that periostin derived from the environing stromal cells of bone metastasis. Bone turnover blockade by zoledronic acid markedly decreased osteolytic lesions but only slightly modulated serum periostin levels. Bone metastases from breast cancer induce overexpression of periostin by surrounding stromal cells. Periostin could be a biochemical marker of the early stromal response associated to breast cancer bone metastasis formation.

PMID: 20715172 [PubMed - as supplied by publisher]


Drug Shows Promise for Castration-Resistant Prostate Cancer

John Schieszer
September 24 2010

LINK



CHICAGO—Alpharadin, an investigational agent, may relieve pain and improve survival in men with metastatic castration-resistant prostate cancer (CRPC), according to data presented at the American Society of Clinical Oncology annual meeting.
“This is a bone-seeking agent that is a first-in-class [medication],” said principal investigator Sten Nilsson, MD, Professor of Oncology at Karolinska University in Stockholm, Sweden. “It delivers a very, very strong cell killing activity. It also kills all cells irrespective of cell cycle phase and receptor expression. So, I think this is the dramatic advantage with this new pharmaceutical.”
Alpharadin is a calcium mimetic, alpha-emitting nuclide, which has a potent and highly targeted anti-tumor effect on bone metastases.
Dr. Nilsson and his colleagues analyzed data from two open-label phase 1 trials (total of 37 patients) and three double-blind, placebo-controlled phase 2 trials (total of 255 patients). All men had CRPC with bone metastases. In these trials, patients experienced significant improvement in bone markers and decreases in PSA levels and pain. In one of the placebo-controlled trials, median overall survival was greater in the alpharadin groups compared with placebo recipients (65 vs. 46 weeks).
The uptake of alpharadin into bone metastases occurs rapidly. In a separate analysis of data from a phase 1 pharmacokinetic and biodistribution study, the researchers found that alpharadin accumulates in bone metastases as early as 10 minutes from the time of injection.
In addition, the drug exhibits minimal activity in the kidneys, liver, or other internal organs. Of the 292 patients in the phase 1 and 2 trials, fewer than 1% experienced CTC grade 4 hematological toxicity, about 4% experienced grade 3 anemia, and fewer than 3% of the patients experienced grade 3 platelets, neutrophils or white blood cells. The most common adverse events seen in all studies were nausea (33% of patients), bone pain (30%), fatigue (26%), diarrhea (26%), vomiting (20%), and constipation (20%). The researchers observed no signs of renal or hepatic toxicity.
“This pharmaceutical has proven to be very, very safe,” Dr. Nilsson said. “It has a benign side effect profile. It gives very little toxicity to the bone marrow, which is the main risk organ in this disease. It is excreted in the bile and intestines so we don't see any toxic effects on the kidneys.”
Researchers are evaluating alpharadin in a global phase 3, randomized, double-blind, multi-dose, placebo-controlled international clinical trial in men with CRPC with bone metastases.
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