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Secondary Bone Cancer (bone metastasis)

Secondary bone cancer is where malignant cells have spread to the bones from other parts of the body. This is different to cancer that actually started in the bones (primary bone cancer). Virtually all types of cancer can spread to bone. Bone metastases are particularly common in people with breast, lung or prostate cancer. Bone metastases are usually multiple, they cause pain and can can lead to other symptoms such as hypercalcemia (abnormally high levels of calcium in the blood).

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    MeSH term: Bone Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Cox TR, Rumney RM, Schoof EM, et al.
The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase.
Nature. 2015; 522(7554):106-10 [PubMed] Related Publications
Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.

Shukla P, Mathur V, Kumar A, et al.
Nanoemulsion based concomitant delivery of curcumin and etoposide: impact on cross talk between prostate cancer cells and osteoblast during metastasis.
J Biomed Nanotechnol. 2014; 10(11):3381-91 [PubMed] Related Publications
An attempt has been made to use curcumin (CUR) in combination with Etoposide (ETP) by encapsulating in nanoemulsion, as two tier approach i.e., to evaluate improvement in efficacy of ETP on prostate cancer cells (PC3 and DU145) and to assess their effect on cross-talk between osteoblast and tumor cells leading to metastatic cascade in bones. Nanoemulsion was developed and evaluated for size, charge, in-vitro drug release and anticancer activity, effect on cross talk between osteoblast and prostate cancer cells and pharmacokinetics in rats. The entrapment efficiency of both ETP and CUR in nanoemulsion was more than 98% while the globule size was less than 150 nm with zeta potential - 29.8 mV. The percent inhibition in case of ETP and ETP: CUR (1:3 w/w) was 55.92 ± 1.2 and 41.13 ± 2.4% (at 5 μM) respectively when tested in PC3 cells. DU-145 seemed to be less responsive in comparison to PC3 cells both in respect of ETP and their mixture (ETP+ CUR). Our data shows that CUR and ETP after encapsulation in nanoemulsion (F5) were effectively delivered intracellularly in PC3 cells and the cytotoxicity of F5 was enhanced by 1.5 fold as compared to ETP + CUR at 5 μM concentration. It has also been observed that mice calvarial osteoblasts cultured and incubated with PC-3 and DU-145 cells conditioned media induces inhibition of osteoblast differentiation event. While this inhibition was significantly reversed by F5 at 5 μM concentration over other treated groups, the pharmacokinetic profile of both ETP and CUR was also significantly improved when administered in nanoemulsion.

Pilanci KN, Alco G, Ordu C, et al.
Is administration of trastuzumab an independent risk factor for developing osteonecrosis of the jaw among metastatic breast cancer patients under zoledronic acid treatment?
Medicine (Baltimore). 2015; 94(18):e671 [PubMed] Related Publications
One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect.Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients' ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits.Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13-82) and the mean number of ZA infusions was 38 (range: 15-56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively).The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab.

Catalano OA, Nicolai E, Rosen BR, et al.
Comparison of CE-FDG-PET/CT with CE-FDG-PET/MR in the evaluation of osseous metastases in breast cancer patients.
Br J Cancer. 2015; 112(9):1452-60 [PubMed] Article available free on PMC after 28/04/2016 Related Publications
BACKGROUND: Despite improvements in treatments, metastatic breast cancer remains difficult to cure. Bones constitute the most common site of first-time recurrence, occurring in 40-75% of cases. Therefore, evaluation for possible osseous metastases is crucial. Technetium 99 ((99)Tc) bone scintigraphy and fluorodexossyglucose (FDG) positron emission tomography (PET)-computed tomography (PET-CT) are the most commonly used techniques to assess osseous metastasis. PET magnetic resonance (PET-MR) imaging is an innovative technique still under investigation. We compared the capability of PET-MR to that of same-day PET-CT to assess osseous metastases in patients with breast cancer.
METHODS: One hundred and nine patients with breast cancer, who underwent same-day contrast enhanced (CE)-PET-CT and CE-PET-MR, were evaluated. CE-PET-CT and CE-PET-MR studies were interpreted by consensus by a radiologist and a nuclear medicine physician. Correlations with prior imaging and follow-up studies were used as the reference standard. Binomial confidence intervals and a χ(2) test were used for categorical data, and paired t-test was used for the SUVmax data; a non-informative prior Bayesian approach was used to estimate and compare the specificities.
RESULTS: Osseous metastases affected 25 out 109 patients. Metastases were demonstrated by CE-PET-CT in 22 out of 25 patients (88%±7%), and by CE-PET-MR in 25 out of 25 patients (100%). CE-PET-CT revealed 90 osseous metastases and CE-PET-MR revealed 141 osseous metastases (P<0.001). The estimated sensitivity of CE-PET-CT and CE-PET-MR were 0.8519 and 0.9630, respectively. The estimated specificity for CE-FDG-PET-MR was 0.9884. The specificity of CE-PET-CT cannot be determined from patient-level data, because CE-PET-CT yielded a false-positive lesion in a patient who also had other, true metastases.
CONCLUSIONS: CE-PET-MR detected a higher number of osseous metastases than did same-day CE-PET-CT, and was positive for 12% of the patients deemed osseous metastasis-negative on the basis of CE-PET-CT.

Sugimoto S, Tanaka M, Suzawa K, et al.
Pneumocephalus and chylothorax complicating vertebrectomy for lung cancer.
Ann Thorac Surg. 2015; 99(4):1425-8 [PubMed] Related Publications
Pneumocephalus is a rare, but potentially fatal complication of thoracic surgery. We describe a case of successful management of pneumocephalus complicated by persistent chylothorax developing after en bloc partial vertebrectomy performed after induction chemoradiotherapy for lung cancer invading the spine. Surgical treatment should be considered for pneumocephalus complicated by any condition requiring persistent chest drainage.

Bowers B
Recognising metastatic spinal cord compression.
Br J Community Nurs. 2015; 20(4):162-5 [PubMed] Related Publications
Metastatic spinal cord compression (MSCC) is a potentially life changing oncological emergency. Neurological function and quality of life can be preserved if patients receive an early diagnosis and rapid access to acute interventions to prevent or reduce nerve damage. Symptoms include developing spinal pain, numbness or weakness in arms or legs, or unexplained changes in bladder and bowel function. Community nurses are well placed to pick up on the 'red flag' symptoms of MSCC and ensure patients access prompt, timely investigations to minimise damage.

Chan HP, Hu C, Yu CC, et al.
Added value of using a cocktail of F-18 sodium fluoride and F-18 fluorodeoxyglucose in positron emission tomography/computed tomography for detecting bony metastasis: a case report.
Medicine (Baltimore). 2015; 94(13):e687 [PubMed] Related Publications
Current nuclear imaging of the skeletal system is achieved using technetium-99m (Tc-99m) methylene diphosphonate (MDP), F-18 sodium fluoride (NaF), or F-18 fluorodeoxyglucose (FDG). However, comparisons of these are rare in the literature. We present a case of a 51-year-old female with suspicious lung cancer due to main symptoms of dyspnea, nonproductive cough, and pleural pain. Tc-99m MDP whole-body bone scan (WBBS) showed multiple bony metastases. Five days later, positron emission tomography/computed tomography (PET/CT) images using both F-18 NaF and a cocktail of F-18 NaF and F-18 FDG were obtained on the same day 2 hours apart. The former showed more foci and precisely showed bony lesions compared to those obtained using Tc-99m MDP WBBS. However, the latter demonstrated more extensive radiotracer uptake, especially in osteolytic lesions, and additional soft tissue lesions in the left axillary and surpraclavicular nodes as well as the left pleura. Surgical biopsy was performed in left axillary nodes, and the metastatic carcinoma was found to be of breast origin. This case demonstrated that a cocktail of F-18 NaF and F-18 FDG could be useful in PET/CT for not only detecting more skeletal lesions but also guiding biopsies accurately to the affected tissue.

Tseng CL, Sussman MS, Atenafu EG, et al.
Magnetic resonance imaging assessment of spinal cord and cauda equina motion in supine patients with spinal metastases planned for spine stereotactic body radiation therapy.
Int J Radiat Oncol Biol Phys. 2015; 91(5):995-1002 [PubMed] Related Publications
PURPOSE: To assess motion of the spinal cord and cauda equina, which are critical neural tissues (CNT), which is important when evaluating the planning organ-at-risk margin required for stereotactic body radiation therapy.
METHODS AND MATERIALS: We analyzed CNT motion in 65 patients with spinal metastases (11 cervical, 39 thoracic, and 24 lumbar spinal segments) in the supine position using dynamic axial and sagittal magnetic resonance imaging (dMRI, 3T Verio, Siemens) over a 137-second interval. Motion was segregated according to physiologic cardiorespiratory oscillatory motion (characterized by the average root mean square deviation) and random bulk shifts associated with gross patient motion (characterized by the range). Displacement was evaluated in the anteroposterior (AP), lateral (LR), and superior-inferior (SI) directions by use of a correlation coefficient template matching algorithm, with quantification of random motion measure error over 3 separate trials. Statistical significance was defined according to P<.05.
RESULTS: In the AP, LR, and SI directions, significant oscillatory motion was observed in 39.2%, 35.1%, and 10.8% of spinal segments, respectively, and significant bulk motions in all cases. The median oscillatory CNT motions in the AP, LR, and SI directions were 0.16 mm, 0.17 mm, and 0.44 mm, respectively, and the maximal statistically significant oscillatory motions were 0.39 mm, 0.41 mm, and 0.77 mm, respectively. The median bulk displacements in the AP, LR, and SI directions were 0.51 mm, 0.59 mm, and 0.66 mm, and the maximal statistically significant displacements were 2.21 mm, 2.87 mm, and 3.90 mm, respectively. In the AP, LR, and SI directions, bulk displacements were greater than 1.5 mm in 5.4%, 9.0%, and 14.9% of spinal segments, respectively. No significant differences in axial motion were observed according to cord level or cauda equina.
CONCLUSIONS: Oscillatory CNT motion was observed to be relatively minor. Our results support the importance of controlling bulk patient motion and the practice of applying a planning organ-at-risk margin.

Humm JL, Sartor O, Parker C, et al.
Radium-223 in the treatment of osteoblastic metastases: a critical clinical review.
Int J Radiat Oncol Biol Phys. 2015; 91(5):898-906 [PubMed] Related Publications
The element radium (Ra) was discovered by the Curies in 1898 and within a decade was in broad scientific testing for the management of several forms of cancer. The compound was known to give rise to a series of both high-energy particulate and penetrating γ-emissions. The latter found an important role in early 20th century brachytherapy applications, but the short-range α-particles seemed much less useful. Although highly cytotoxic when released within a few cell diameters of critical cell nuclei, the dense double-strand break damage was poorly repaired, and concerns regarding treatment-related toxicities and secondary malignancies halted clinical development. Moreover, the most common isotope of Ra has an exceptionally long half-life (>1600 years for (226)Ra) that proved daunting when aiming for a systemic cancer therapy. Fortunately, other radium isotopes have more convenient half-lives while still producing cytotoxic α particles. Radium-223 dichloride has a half-life of 11.4 days, and this isotope was identified as an excellent candidate for radionuclide therapy of cancers metastatic to bone. The calcium-mimetic chemical properties of the radium allowed intravenous infusion with rapid uptake to sites of new bone formation. The highly efficient bone localization suggested a potential therapeutic role for osteoblastic bone metastases, and a series of phase 1, 2, and 3 clinical trials was undertaken to explore this possibility. This series of clinical explorations culminated in the ALSYMPCA trial, an international, placebo-controlled, phase 3 study that accrued 921 symptomatic men with bone-metastatic, castrate-resistant prostate cancer. Results of this trial demonstrated a prolongation of overall survival, and regulatory agencies around the world have now approved this product as a treatment for advanced prostate cancer.

Liu YN, Yin J, Barrett B, et al.
Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis.
Mol Cell Biol. 2015; 35(11):1940-51 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes.

Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I
Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer.
Clin Exp Metastasis. 2015; 32(4):353-68 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Increased bone marrow adiposity is a common feature of advanced age, obesity and associated metabolic pathologies. Augmented numbers of marrow adipocytes positively correlate with dysregulated bone remodeling, also a well-established complication of metastatic disease. We have shown previously that marrow adiposity accelerates prostate tumor progression in the skeleton and promotes extensive destruction of the bone; however, the factors behind adipocyte-driven osteolysis in the skeletal tumor microenvironment are not currently known. In this study, utilizing in vivo diet-induced models of bone marrow adiposity, we reveal evidence for positive correlation between increased marrow fat content, bone degradation by ARCaP(M) and PC3 prostate tumors, and augmented levels of host-derived CXCL1 and CXCL2, ligands of CXCR2 receptor. We show by in vitro osteoclastogenesis assays that media conditioned by bone marrow adipocytes is a significant source of CXCL1 and CXCL2 proteins. We also demonstrate that both the adipocyte-conditioned media and the recombinant CXCL1 and CXCL2 ligands efficiently accelerate osteoclast maturation, a process that can be blocked by neutralizing antibodies to each of the chemokines. We further confirm the contribution of CXCR2 signaling axis to adiposity-driven osteoclastogenesis by blocking fat cell-induced osteoclast differentiation with CXCR2 antagonist or neutralizing antibodies. Together, our results link CXCL1 and CXCL2 chemokines with bone marrow adiposity and implicate CXCR2 signaling in promoting effects of marrow fat on progression of skeletal tumors in bone.

Dibekoglu C, Turanli S, Karaman N, et al.
Bone fracture in breast cancer patients with isolated bone metastasis.
Chirurgia (Bucur). 2015 Jan-Feb; 110(1):43-8 [PubMed] Related Publications
AIM: 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?"
METHODS: 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.
RESULTS: 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).
CONCLUSION: 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.

Soni A, Ren Z, Hameed O, et al.
Breast cancer subtypes predispose the site of distant metastases.
Am J Clin Pathol. 2015; 143(4):471-8 [PubMed] Related Publications
OBJECTIVES: The distant organs to which breast cancer preferentially metastasizes are of significant clinical importance.
METHODS: We explored the relationship between the clinicopathologic factors and the common sites of distant metastasis in 531 consecutive patients with advanced breast cancer.
RESULTS: Breast cancer subtype as a variable was significantly associated with all five common sites of relapse by multivariate analysis. The luminal tumors were remarkable for their significant bone-seeking phenotype and were less frequently observed in lung, brain, and pleural metastases and less likely to be associated with multiorgan relapse. The HER2 subtype demonstrated a significant liver-homing characteristic. African Americans were significantly less likely to have brain-only metastasis in patients with brain relapse.
CONCLUSIONS: These findings further articulate that breast cancer subtypes differ not only in tumor characteristics but also in their metastatic behavior, thus raising the possibility that this knowledge could potentially be used in determining the appropriate strategy for follow-up of patients with newly diagnosed breast cancer.

Mandelin J, Cardó-Vila M, Driessen WH, et al.
Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors.
Proc Natl Acad Sci U S A. 2015; 112(12):3776-81 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgen-independent and induces a robust osteoblastic reaction in bonelike matrix and soft tissue. We found two peptides, PKRGFQD and SNTRVAP, which were enriched in the tumors, targeted the cell surface of androgen-independent prostate cancer cells in vitro, and homed to androgen receptor-null prostate cancer in vivo. Purification of tumor homogenates by affinity chromatography on these peptides and subsequent mass spectrometry revealed a receptor for the peptide PKRGFQD, α-2-macroglobulin, and for SNTRVAP, 78-kDa glucose-regulated protein (GRP78). These results indicate that GRP78 and α-2-macroglobulin are highly active in osteoblastic, androgen-independent prostate cancer in vivo. These previously unidentified ligand-receptor systems should be considered for targeted drug development against human metastatic androgen-independent prostate cancer.

Hwang YS, Han SS, Kim KR, et al.
Validating of the pre-clinical mouse model for metastatic breast cancer to the mandible.
J Appl Oral Sci. 2015 Jan-Feb; 23(1):3-8 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Metastatic breast carcinoma has a great tendency to spread to the mandible. It is concomitantly associated with bone destruction, food intake disorder, and a poorer prognosis. Appropriate animal models need to be developed for a better understanding of the mechanisms underlying the metastatic process of breast cancer cells to mandible and to test the effects of potential lead compounds. Here, we assessed the metastasis model of intracardiac injection using luciferase-transfected metastatic breast cancer cells (MDA-MB-231Luc+) by determining the incidences of metastasis, mCT images, and histopathological results. A high bioluminescence signal mainly detected mandibular lesions with less frequent distal femora and proximal tibiae lesions. Extensive mandibular bone destruction occurred in nude mice grafted with metastatic breast cancer cells. This type of animal model might be a useful tool in assessing therapeutic implications and the efficacy of anti-cancer drugs for osteolytic cancers.

Luedders DW, Steinhoff J, Thill M, et al.
Lack of difference in acute nephrotoxicity of intravenous bisphosphonates zoledronic acid and ibandronate in women with breast cancer and bone metastases.
Anticancer Res. 2015; 35(3):1797-802 [PubMed] Related Publications
BACKGROUND: More than 50% of patients with advanced breast cancer develop bone metastases that may lead to multiple complications such as pathological fractures, bone pain or hypercalcaemia. The standard treatment, besides endocrine, targeted-therapy or chemotherapy, is the use of bisphosphonates. However, one of their main adverse side-effects is bisphosphonate-induced nephrotoxicity. The mechanism by which the latter occurs is not well-understood, although emerging evidence suggests that the effect of bisphosphonates on the kidney may differ between agents.
PATIENTS AND METHODS: The aim of this evaluation was to compare the renal toxicity of 6 mg ibandronate i.v. versus 4 mg zoledronic acid i.v. over a period of six months in women with breast cancer and bone metastases. A prospective randomized trial was carried out to examine specific kidney and other parameters (α1- and β2-microglobulin, albumin, α2-macroglobulin, IgG and C-reactive protein (CRP) generated from spontaneous urine samples from 17 patients of each group.
RESULTS: We were unable to find any significant difference between the two treatment groups with regard to renal toxicity. All patients, independently of the applied bisphosphonate, experienced only temporary renal dysfunction without any evidence of irreversible damage in terms of acute nephrotoxicity during the study period. α1-Microglobulin, a marker for proximal tubular damage, in particular, was not differently elevated in either group.
CONCLUSION: Both applied bisphosphonates were found to be well-tolerated and safe with regard to renal toxicity during a six-month treatment period in patients with otherwise healthy kidneys having advanced breast cancer and bone metastases.

Sosnoski DM, Norgard RJ, Grove CD, et al.
Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment.
Clin Exp Metastasis. 2015; 32(4):335-44 [PubMed] Related Publications
Breast cancer can reoccur, often as bone metastasis, many years if not decades after the primary tumor has been treated. The factors that stimulate dormant metastases to grow are not known, but bone metastases are often associated with skeletal trauma. We used a dormancy model of MDA-MB-231BRMS1, a metastasis-suppressed human breast cancer cell line, co-cultured with MC3T3-E1 osteoblasts in a long term, three dimensional culture system to test the hypothesis that bone remodeling cytokines could stimulate dormant cells to grow. The cancer cells attached to the matrix produced by MC3T3-E1 osteoblasts but grew slowly or not at all until the addition of bone remodeling cytokines, TNFα and IL-β. Stimulation of cell proliferation by these cytokines was suppressed with indomethacin, an inhibitor of cyclooxygenase and of prostaglandin production, or a prostaglandin E2 (PGE2) receptor antagonist. Addition of PGE2 directly to the cultures also stimulated cell proliferation. MCF-7, non-metastatic breast cancer cells, remained dormant when co-cultured with normal human osteoblast and fibroblast growth factor. Similar to the MDA-MB-231BRMS1 cells, MCF-7 proliferation increased in response to TNFα and IL-β. These findings suggest that changes in the bone microenvironment due to inflammatory cytokines associated with bone repair or excess turnover may trigger the occurrence of latent bone metastasis.

Nagasawa M, Johnin K, Hanada E, et al.
Advanced childhood testicular yolk sac tumor with bone metastasis: a case report.
Urology. 2015; 85(3):671-3 [PubMed] Related Publications
We report a case of advanced childhood testicular yolk sac tumor with bone metastasis, which was successfully treated by multimodal treatment. Optimal management of bone metastases from testicular yolk sac tumor in childhood is discussed.

Miscusi M, Polli FM, Forcato S, et al.
Comparison of minimally invasive surgery with standard open surgery for vertebral thoracic metastases causing acute myelopathy in patients with short- or mid-term life expectancy: surgical technique and early clinical results.
J Neurosurg Spine. 2015; 22(5):518-25 [PubMed] Related Publications
OBJECT Spinal metastasis is common in patients with cancer. About 70% of symptomatic lesions are found in the thoracic region of the spine, and cord compression presents as the initial symptom in 5%-10% of patients. Minimally invasive spine surgery (MISS) has recently been advocated as a useful approach for spinal metastases, with the aim of decreasing the morbidity associated with more traditional open spine surgery; furthermore, the recovery time is reduced after MISS, such that postoperative chemotherapy and radiotherapy can begin sooner. METHODS Two series of oncological patients, who presented with acute myelopathy due to vertebral thoracic metastases, were compared in this study. Patients with complete paraplegia for more than 24 hours and with a modified Bauer score greater than 2 were excluded from the study. The first group (n = 23) comprised patients who were prospectively enrolled from May 2010 to September 2013, and who were treated with minimally invasive laminotomy/laminectomy and percutaneous stabilization. The second group (n = 19) comprised patients from whom data were retrospectively collected before May 2010, and who had been treated with laminectomy and stabilization with traditional open surgery. Patient groups were similar regarding general characteristics and neurological impairment. Results were analyzed in terms of neurological recovery (American Spinal Injury Association grade), complications, pain relief (visual analog scale), and quality of life (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and EORTC QLQ-BM22 scales) at the 30-day follow-up. Operation time, postoperative duration of bed rest, duration of hospitalization, intraoperative blood loss, and the need and length of postoperative opioid administration were also evaluated. RESULTS There were no significant differences between the 2 groups in terms of neurological recovery and complications. Nevertheless, the MISS group showed a clear and significant improvement in terms of blood loss, operation time, and bed rest length, which is associated with a more rapid functional recovery and discharge from the hospital. Postoperative pain and the need for opioid administration were also significantly less pronounced in the MISS group. Results from the EORTC QLQ-C30 and QLQ-BM22 scales showed a more pronounced improvement in quality of life at follow-up in the MISS group. CONCLUSIONS In the authors' opinion, MISS techniques should be considered the first choice for the treatment for patients with spinal metastasis and myelopathy. MISS is as safe and effective for spinal cord decompression and spine fixation as traditional surgery, and it also reduces the impact of surgery in critical patients. However, further studies are needed to confirm these findings.

Gurrieri L, Longhi A, Braghetti A
Lung cancer presenting as a metastasis to the tibial bones: a case report.
Tumori. 2015 Jan-Feb; 101(1):e18-20 [PubMed] Related Publications
AIMS AND BACKGROUND: Bone metastasis below the knee from primary lung cancer is rare. Discussion of such cases in a multidisciplinary team is important to establish the correct treatment approach.
CASE REPORT: We analyzed the diagnostic pathway of a 53-year-old female patient with a 5-month history of pain in the right foot. The patient underwent several radiological examinations for the pain. An initial diagnosis of osteoporotic syndrome was made, followed by a diagnosis of primary sarcoma. Only when the patient continued to have pain were other radiological examinations performed and a biopsy of the right ankle taken. This revealed a metastasis from undifferentiated pulmonary adenocarcinoma. A total-body computed tomography scan did not show any tumor locations apart from the primary lung cancer. The patient underwent chemotherapy and palliative therapies. This case has been reported for its rarity.

Choy WS, Kim KJ, Lee SK, et al.
Surgical treatment of pathological fractures occurring at the proximal femur.
Yonsei Med J. 2015; 56(2):460-5 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
PURPOSE: To analyze the results of surgical treatment for pathological fractures at the proximal femur.
MATERIALS AND METHODS: Nineteen patients with a pathological fracture were included. The mean age was 65.7 years old. The patients comprised 8 males and 11 females. Primary tumors, types of pathological fractures, surgical procedures, and postoperative complications were recorded. Musculoskeletal Tumor Society (MSTS) functional score was used for functional evaluation. A Kaplan-Meier survival analysis was used to determine survival rate.
RESULTS: The primary malignancies were 6 cases of breast cancer, 3 cases of lung cancer, 3 cases of renal cell carcinoma, 2 cases of cholangiocarcinoma, 2 cases of hepatocellular carcinoma, 1 case of esophageal cancer, 1 case of colon cancer, and 1 case of ovarian cancer. Pathological fractures included 8 cases of pertrochanteric fractures and 11 cases of subtrochanteric fractures. Intramedullary nailing was performed in 10 cases, and joint replacement surgery was performed in 9 cases. Postoperative complications included local recurrence in 1 case, infection in 1 case, and nail breakage in 1 case. The mean postoperative MSTS score was 21. The mean survival period was 10.6 months. Patient survival rates were 42.1% after 6 months, 26.3% after 12 months, and 10.5% after 24 months.
CONCLUSION: Surgical treatment of pathological fractures at the proximal femur provided early ambulation, and excellent pain relief. The surgery was well tolerated emotionally. Surgery is necessary for improving the quality of life in such patients; however, more cases of pathological fractures in these regions should be subjected to detailed analysis.

Kim H, Rajagopalan MS, Beriwal S, et al.
Cost-effectiveness analysis of single fraction of stereotactic body radiation therapy compared with single fraction of external beam radiation therapy for palliation of vertebral bone metastases.
Int J Radiat Oncol Biol Phys. 2015; 91(3):556-63 [PubMed] Related Publications
PURPOSE: Stereotactic body radiation therapy (SBRT) has been proposed for the palliation of painful vertebral bone metastases because higher radiation doses may result in superior and more durable pain control. A phase III clinical trial (Radiation Therapy Oncology Group 0631) comparing single fraction SBRT with single fraction external beam radiation therapy (EBRT) in palliative treatment of painful vertebral bone metastases is now ongoing. We performed a cost-effectiveness analysis to compare these strategies.
METHODS AND MATERIALS: A Markov model, using a 1-month cycle over a lifetime horizon, was developed to compare the cost-effectiveness of SBRT (16 or 18 Gy in 1 fraction) with that of 8 Gy in 1 fraction of EBRT. Transition probabilities, quality of life utilities, and costs associated with SBRT and EBRT were captured in the model. Costs were based on Medicare reimbursement in 2014. Strategies were compared using the incremental cost-effectiveness ratio (ICER), and effectiveness was measured in quality-adjusted life years (QALYs). To account for uncertainty, 1-way, 2-way and probabilistic sensitivity analyses were performed. Strategies were evaluated with a willingness-to-pay (WTP) threshold of $100,000 per QALY gained.
RESULTS: Base case pain relief after the treatment was assumed as 20% higher in SBRT. Base case treatment costs for SBRT and EBRT were $9000 and $1087, respectively. In the base case analysis, SBRT resulted in an ICER of $124,552 per QALY gained. In 1-way sensitivity analyses, results were most sensitive to variation of the utility of unrelieved pain; the utility of relieved pain after initial treatment and median survival were also sensitive to variation. If median survival is ≥11 months, SBRT cost <$100,000 per QALY gained.
CONCLUSION: SBRT for palliation of vertebral bone metastases is not cost-effective compared with EBRT at a $100,000 per QALY gained WTP threshold. However, if median survival is ≥11 months, SBRT costs ≤$100,000 per QALY gained, suggesting that selective SBRT use in patients with longer expected survival may be the most cost-effective approach.

Akram M, Baig MA, Ali S
Sister Mary Joseph nodule, a forgotten nodule.
J Ayub Med Coll Abbottabad. 2014 Jul-Sep; 26(3):416-8 [PubMed] Related Publications
Metastatic cancer of the umbilicus, known as Sister Mary Joseph nodule, is typically associated with visceral malignancy. It is an uncommon and rare presentation. It indicates disseminated disease and poor prognosis. Physicians need to be aware of this rare clinical condition so that they can promptly diagnose the primary cancer.

Basit A, Siddiqui N, Hameed A, et al.
Factors affecting outcome of patients with multiple myeloma.
J Ayub Med Coll Abbottabad. 2014 Jul-Sep; 26(3):376-9 [PubMed] Related Publications
BACKGROUND: Multiple myeloma is a heterogeneous disease, with wide survival range and multiple risk factors and staging systems linked to survival. The objective of this study was to assess the overall survival of patients with multiple myeloma (MM) diagnosed and treated at Shaukat Khanum Memorial Cancer Hospital (SKMCH), Lahore with respect to various prognostic factors.
METHODS: This was a survival analysis with data collected retrospectively on 82 patients fulfilling the diagnostic criteria of multiple myeloma. Overall survival was studied in relation to International Staging System (ISS), renal failure (Serum creatinine >2 mg/dl), anaemia (Hemoglobin <10 mg/dl), bone involvement (presence of lytic lesion on skeletal survey) and hypercalcemia (serum calcium >11mg/dl) due to multiple myeloma at the time of diagnosis.
RESULTS: Mean age of patients was 61 years, including 67% males and 33% females. Median overall survival for ISS stage-I (24%), stage-II (44%) and stage-III (32%) was 58, 41 and 12 months respectively (p=0.01). Patients with renal impairment (16% of total) had median overall survival of 13 months compared to 41 months in patients without renal involvement (p=0.02). Hypercalcemia was noted in 27% patients with median overall survival of 32 months versus 38 months in patients without hypercalcemia, but its impact on survival was statistically insignificant (p=0.79). Similarly no significant impact on survival was noted in patients with bone involvement or anaemia found in 74 % and 38% of patient's respectively.
CONCLUSIONS: ISS stage and renal failure due to multiple myeloma at presentation have a significant impact on survival. However, other prognostic factors like bone involvement, anaemia and hypercalcemia were not shown to influence survival significantly.

Milojkovic N, Homsi S
Polymethylmethacrylate pulmonary embolism as a complication of percutaneous vertebroplasty in cancer patients.
J Ark Med Soc. 2014; 111(7):140-2 [PubMed] Related Publications
Percutaneous vertebroplasty is frequently used in the treatment of vertebral body fractures due to osteoporosis, vertebral body metastasis, or myeloma. Acrylic cement of polymethylmethacrylate injected into the vertebral body can leak into the paravertebral venous system and reach the pulmonary artery via the azygos vein leading to a cement pulmonary embolism. We are presenting a case of a 78 year old woman who was found to have polymethylmethacrylate pulmonary embolism as a result of vertebroplasty used for vertebral collapse from metastatic breast cancer. The appearance of new intrapulmonary artery tubular opaque density on CXR performed post procedure is highly suggestive of the diagnosis. In this case, we are exploring the importance of clinical and radiographic correlations, as well as evaluation of the hemodynamic and perfusion effect of the cement pulmonary embolism as essential steps in the management of this condition.

Kroon J, Buijs JT, van der Horst G, et al.
Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo.
Prostate. 2015; 75(8):815-24 [PubMed] Related Publications
BACKGROUND: The inflammatory tumor microenvironment, and more specifically the tumor-associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which - combined with the prolonged circulation kinetics of liposomes - leads to efficient tumor localization of these drug carriers, via the so-called enhanced permeability and retention (EPR) -effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases.
METHODS: Tumor-bearing Balb-c nu/nu mice were treated intravenously with 0.2-1.0-5.0 mg/kg/week free- and liposomal DEX for 3-4 weeks and tumor growth was monitored by bioluminescent imaging.
RESULTS: Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well-tolerated at clinically-relevant dosages that display potent anti-tumor efficacy.
CONCLUSIONS: Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation.

Shen L, Dong J, Li S, et al.
M1 stage subdivision and treatment outcome of patients with bone-only metastasis of nasopharyngeal carcinoma.
Oncologist. 2015; 20(3):291-8 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: The current M1 stage in nasopharyngeal carcinoma (NPC) does not differentiate patients based on metastatic site and number of metastases. This study aims to subdivide the M1 stage of NPC patients with bone-only metastases and to identify the patients who may benefit from combined chemoradiotherapy (CRT).
METHODS: Between 1998 and 2007, 312 patients diagnosed with bone-only metastasis at Sun Yat-sen University Cancer Center were enrolled. Various possible subdivisions of M1 stage were considered, including by the time order of metastasis (synchronous vs. metachronous), involvement of specific bone metastatic site, the number of metastatic sites, and the number of metastases. The correlation of the subdivisions of M1 stage with overall survival (OS) was determined by Cox regression.
RESULTS: The median OS was 23.4 months. Patients with more than three metastatic sites had significantly poorer OS than patients with three or fewer metastatic sites (16.2 vs. 32.4 months; p < .001). Metastasis to the spine was significantly associated with unfavorable OS (20.4 vs. 37.9 months; p < .001). Multivariate analysis showed that number of metastatic sites (more than three vs. three or fewer), spine involvement (present vs. absent), and treatment modality (CRT vs. chemotherapy or radiotherapy only) were independent prognostic factors for OS. In stratified analysis, compared with chemotherapy or radiotherapy alone, combined chemoradiotherapy could significantly benefit the patients with single bone metastasis (hazard ratio: 0.21; 95% confidence interval: 0.09-0.50).
CONCLUSION: Metastasis to the spine and having more than three bone metastatic sites are independent unfavorable predictors for OS in NPC patients with bone-only metastasis. Combined chemoradiotherapy should be considered for patients with single bone metastasis.

Taylor DR, Weaver JA
Tumor pseudoprogression of spinal metastasis after radiosurgery: a novel concept and case reports.
J Neurosurg Spine. 2015; 22(5):534-9 [PubMed] Related Publications
Radiosurgery for primary and metastatic tumors of the central nervous system is increasing in utility and intensity. Known complications in the brain include radiation necrosis and the well-documented phenomenon of pseudoprogression. Known complications of radiosurgery to spinal column tumors include radiation myelopathy and delayed vertebral compression fractures; however, the concept of pseudoprogression of spinal column tumors has not been previously described. The authors review 2 cases of spinal metastasis treated with stereotactic radiosurgery (SRS) and attempt to define the concept of spine tumor pseudoprogression. Two patients who had undergone SRS to the spine for metastatic disease presented in early follow-up (3 and 7 weeks) with symptomatic complaints consisting of axial pain, radicular pain, or evidence of cord compression. In both patients, MRI revealed evidence of tumor enlargement. In one patient, the lesion had grown by 9 mm and 7.7 mm in the axial and sagittal planes, respectively. In the other patient, the tumor growth resulted in a 5-mm decrease in spinal canal diameter with epidural compression and right foraminal encroachment. Because of the absence of progressive neurological deficit, myelopathy, mechanical symptomatology of instability, or vertebral compression fracture, the first patient was treated expectantly with a corticosteroid taper and had improvement of symptoms at 1 month and near-total radiographic resolution of the tumor. In the second patient, worsening symptoms suggested a need for surgical intervention to address presumed radiosurgical failure and tumor progression. During surgery, only necrotic tumor cells were observed, without viable tumor. Follow-up imaging over 1 year showed ongoing local control. To their knowledge, the authors report the first description of pseudoprogression involving spinal column metastasis in the literature and aim to alert the treating physician to this clinical situation. Unlike brain tumor pseudoprogression, spine tumor pseudoprogression is a relatively early posttreatment phenomenon, measured in days to 2 months. The authors believe that the acute inflammatory response associated with tumor necrosis and disruption of the tumor capillary integrity caused by radiotherapy is an important component in the development of pseudoprogression. Future studies will be fundamental in assigning clinical significance, defining the incidence and predictors, and affecting future management of this phenomenon.

Ito S, Yoshimura T, Kondo T, et al.
Long-term survival with chest wall resection and pulmonary metastasectomy for hepatocellular carcinoma.
Ann Thorac Surg. 2015; 99(2):695-8 [PubMed] Related Publications
A case of rib and pulmonary metastases of hepatocellular carcinoma (HCC) successfully treated with transcatheter arterial embolization (TAE) followed by surgery is reported. A 66-year-old male with a history of HCC treated previously with hepatectomy was admitted to our hospital for examination of a chest wall tumor. Before the admission, TAE targeting the chest wall tumor was performed. TAE followed by surgery for postresection metastases of HCC was performed and provided an excellent result with long-term survival. The combination of TAE plus salvage surgery could be an option in select patients with limited disease.

Bate BG, Khan NR, Kimball BY, et al.
Stereotactic radiosurgery for spinal metastases with or without separation surgery.
J Neurosurg Spine. 2015; 22(4):409-15 [PubMed] Related Publications
OBJECT: In patients with significant epidural spinal cord compression, initial surgical decompression and stabilization of spinal metastases, as opposed to radical oncological resection, provides a margin around the spinal cord that facilitates subsequent treatment with high-dose adjuvant stereotactic radiosurgery (SRS). If a safe margin exists between tumor and spinal cord on initial imaging, then high-dose SRS may be used as the primary therapy, eliminating the need for surgery. Selecting the appropriate approach has shown greater efficacy of tumor control, neurological outcome, and duration of response when compared with external beam radiotherapy, regardless of tumor histology. This study evaluates the efficacy of this treatment approach in a series of 57 consecutive patients.
METHODS: Patients treated for spinal metastases between 2007 and 2011 using the Varian Trilogy Linear Accelerator were identified retrospectively. Each received SRS, with or without initial surgical decompression and instrumentation. Medical records were reviewed to assess neurological outcome and surgical or radiation-induced complications. Magnetic resonance images were obtained for each patient at 3-month intervals posttreatment, and radiographic response was assessed as stability/regression or progression. End points were neurological outcome and local radiographic disease control at death or latest follow-up.
RESULTS: Fifty-seven patients with 69 lesions were treated with SRS for spinal metastases. Forty-eight cases (70%) were treated with SRS alone, and 21 (30%) were treated with surgery prior to SRS. A single fraction was delivered in 38 cases (55%), while a hypofractionated scheme was used in 31 (45%). The most common histological entities were renal cell, breast, and lung carcinomas. Radiographically, local disease was unchanged or regressed in 63 of 69 tumors (91.3%). Frankel score improved or remained stable in 68 of 69 cases (98.6%).
CONCLUSIONS: SRS, alone or as an adjunct following surgical decompression, provides durable local radiographic disease control while preserving or improving neurological function. This less-invasive alternative to radical spinal oncological resection appears to be effective regardless of tumor histology without sacrificing durability of radiographic or clinical response.

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