Piccirillo M, Granata V, Albino V, et al.
Can hepatocellular carcinoma (HCC) produce unconventional metastases? Four cases of extrahepatic HCC.
Tumori. 2013 Jan-Feb; 99(1):e19-23 [PubMed]

AIMS AND BACKGROUND: Extrahepatic spread of hepatocellular carcinoma (HCC) diagnosed during the clinical course of the disease is not frequent; however, with the prolonged survival of HCC patients, the incidence of extrahepatic metastases seems to be increasing.
METHODS AND STUDY DESIGN: We present four unusual cases of extrahepatic metastasis from HCC: the first concerns a patient who underwent a liver transplantation for HCC with cirrhosis and three years later developed metastases in the lung and the left orbit; the second is that of a patient who developed an extraperitoneal pararectal metastasis; in the third case a large osteolytic lesion developed on the left iliac bone, and in the fourth case we found an isolated metastasis in the left mandible.
RESULTS AND CONCLUSIONS: These cases offer important information related to the unusual biology of isolated metastases from HCC after successful treatment of the primary cancer.

Ibrahim T, Farolfi A, Mercatali L, et al.
Metastatic bone disease in the era of bone-targeted therapy: clinical impact.
Tumori. 2013 Jan-Feb; 99(1):1-9 [PubMed]

Advances in the diagnosis and treatment of tumors by surgery, chemotherapy, biotherapy, radiotherapy and other modalities have increased the survival of cancer patients over the last 20 years. As a consequence, bone now represents the third most common site of metastatic involvement after the lung and liver. Approximately 20-25% of patients with neoplastic disease develop clinically evident bone metastases (BMs) during the natural course of their illness, with a further 50% of such lesions being identified during autopsy. BMs are the major cause of morbidity in cancer patients because of their epidemiological and clinical impact. Pain is the most frequent symptom in about 75% of patients but other serious complications can also occur, such as pathological fractures, spinal cord compression, hypercalcemia and bone marrow suppression. These complications worsen the patient's general condition and reduce patients' mobility, facilitating the development of lung infections, skin ulcers, deep vein thrombosis, etc., and ultimately reducing prognosis and quality of life. The frequency of serious complications depends on the site and type of lesions and the treatment administered. Over the last 10 years, the introduction of bisphosphonates for the treatment of patients with BMs has led to a marked decrease in the frequency of complications, thus improving quality of life and clinical outcome. Furthermore, progress in understanding the pathophysiology of bone metastases has resulted in the development of new bone-targeted molecules such as denosumab. We therefore felt it would be useful to report on the epidemiological, clinical and economic impact of bone disease in a cancer setting.

Lamb MR, Gertsen E, Middlemas E
Metaplastic breast cancer: a presentation of two cases and a review of the literature.
Tenn Med. 2013; 106(2):39-41 [PubMed]

Metaplastic breast cancer has been difficult to diagnose and classify for a number of reasons. Its rarity prevents any important conclusions to be made, such as factors determining prognosis, immunohistochemistry patterns and successful treatment regimens. Here a number of studies of metaplastic breast cancer are discussed, along with the presentation of two cases.

Klingler JH, Sircar R, Deininger MH, et al.
Vesselplasty: a new minimally invasive approach to treat pathological vertebral fractures in selected tumor patients - preliminary results.
Rofo. 2013; 185(4):340-50 [PubMed]

PURPOSE: To evaluate the effectiveness and safety of percutaneous vesselplasty in pathological vertebral fractures of the thoracolumbar spine in selected tumor patients.
MATERIALS AND METHODS: Eleven pathological vertebral fractures in nine patients were treated with vesselplasty (Vessel-X®, MAXXSPINE). Nine of eleven vertebras (81.8 %) had major posterior wall deficiency (> 30 %). Clinical and radiological (CT) measures were obtained before and 3 months after the procedure.
RESULTS: The mean VAS improved significantly from preoperative to postoperative (6.9 ± 2.2 to 3.7 ± 2.3; p < 0.05), as did the ODI (59.7 %± 19.2 % to 40.3 %± 24.0 %; p < 0.05). The physical component summary of the SF-36 was significantly improved by the operation (19.2 ± 8.0 to 31.0 ± 16.5; p < 0.05). Symptomatic cement leakage or other operation-associated complications were not observed. Three patients were primarily treated with concomitant minimally invasive stabilization via fixateur interne. One patient had to undergo minimally invasive stabilization via fixateur interne 4 months after vesselplasty due to further collapse of the treated vertebral body.
CONCLUSION: From these preliminary results, vesselplasty appears to be a treatment option worth considering in pathological vertebral fractures, even in the case of posterior wall deficiency. Selected tumor patients might benefit from vesselplasty as a minimally invasive procedure for stabilization of the fractured vertebra, pain control, and improvement in body function and quality of life. Long-term prospective studies with a larger sample size are required to validate these results.

Drudge-Coates L, Turner B
Cancer-induced bone disease.
Nurs Stand. 2013 Jan 9-15; 27(19):48-56; quiz 57 [PubMed]

A diagnosis of bone metastases may be devastating for patients with cancer because it suggests that the cancer is incurable and that patients are at increased risk of developing skeletal-related events. The optimal goal for these patients should be to maintain quality of life. Nurses have an important role in the care of patients with cancer-induced bone disease and need to have a good understanding of the effects of bone metastases to ensure prompt management of this condition.

Kuwata T, Iwata T, Iwanami T, Kawaguchi M
Surgical resection of a metastatic skull tumor from lung cancer.
Tumori. 2012; 98(6):169e-71e [PubMed]

We present an interesting case of a metastatic skull tumor from a non-small cell lung cancer that was successfully resected. At present, 1 year after the surgery, the patient is alive with chemotherapy and has not shown any evidence of tumor recurrence.

Froehner M, Abolmaali N, Wirth MP
Prostate-specific antigen-negative prostate cancer recurrence?
Urology. 2013; 81(2):e17-8 [PubMed]

We describe a patient with bone metastases occurring shortly after radical prostatectomy for organ-confined prostate cancer. The medical history and immunohistochemical findings suggested prostate cancer recurrence to the skeleton. Undetectable serum prostate-specific antigen levels, however, raised doubts about this diagnosis. A whole body (18)F-fluorodeoxyglucose positron emission tomography-computed tomography scan was obtained and revealed a right-sided breast cancer as the primary site of metastatic spread.

Balain B, Jaiswal A, Trivedi JM, et al.
The Oswestry Risk Index: an aid in the treatment of metastatic disease of the spine.
Bone Joint J. 2013; 95-B(2):210-6 [PubMed]

The revised Tokuhashi, Tomita and modified Bauer scores are commonly used to make difficult decisions in the management of patients presenting with spinal metastases. A prospective cohort study of 199 consecutive patients presenting with spinal metastases, treated with either surgery and/or radiotherapy, was used to compare the three systems. Cox regression, Nagelkerke's R(2) and Harrell's concordance were used to compare the systems and find their best predictive items. The three systems were equally good in terms of overall prognostic performance. Their most predictive items were used to develop the Oswestry Spinal Risk Index (OSRI), which has a similar concordance, but a larger coefficient of determination than any of these three scores. A bootstrap procedure was used to internally validate this score and determine its prediction optimism. The OSRI is a simple summation of two elements: primary tumour pathology (PTP) and general condition (GC): OSRI = PTP + (2 - GC). This simple score can predict life expectancy accurately in patients presenting with spinal metastases. It will be helpful in making difficult clinical decisions without the delay of extensive investigations.

Cody JJ, Rivera AA, Lyons GR, et al.
Expression of osteoprotegerin from a replicating adenovirus inhibits the progression of prostate cancer bone metastases in a murine model.
Lab Invest. 2013; 93(3):268-78 [PubMed] Article available free on PMC after 01/09/2013

Metastatic involvement of the skeleton is a frequent consequence of advanced prostate cancer. These skeletal metastases cause a number of debilitating complications and are refractory to current treatments. New therapeutic options are being explored, including conditionally replicating adenoviruses (CRAds). CRAds are engineered to selectively replicate in and destroy tumor cells and can be 'armed' with exogenous transgenes for enhanced potency. We hypothesized that a CRAd armed with osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, would inhibit the progression of prostate cancer bone metastases by directly lysing tumor cells and by reducing osteoclast activity. Although prostate cancer bone metastases are predominantly osteoblastic in nature, increased osteoclast activity is critical for the growth of these lesions. Ad5-Δ24-sOPG-Fc-RGD is a CRAd that carries a fusion of the ligand-binding domains of OPG and the Fc region of human IgG1 in place of the viral E3B genes. To circumvent low tumor cell expression of the native adenoviral receptor, an arginine-glycine-aspartic acid (RGD) peptide insertion within the viral fiber knob allows infection of cells expressing α(v) integrins. A 24-base pair deletion (Δ24) within viral E1A limits replication to cells with aberrant retinoblastoma cell cycle regulator/tumor suppressor expression. We have confirmed that Ad5-Δ24-sOPG-Fc-RGD replicates within and destroys prostate cancer cells and, in both murine and human coculture models, that infection of prostate cancer cells inhibits osteoclastogenesis in vitro. In a murine model, progression of advanced prostate cancer bone metastases was inhibited by treatment with Ad5-Δ24-sOPG-Fc-RGD but not by an unarmed control CRAd.

Laufer I, Iorgulescu JB, Chapman T, et al.
Local disease control for spinal metastases following "separation surgery" and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients.
J Neurosurg Spine. 2013; 18(3):207-14 [PubMed]

OBJECT: Decompression surgery followed by adjuvant radiotherapy is an effective therapy for preservation or recovery of neurological function and achieving durable local disease control in patients suffering from metastatic epidural spinal cord compression (ESCC). The authors examine the outcomes of postoperative image-guided intensity-modulated radiation therapy delivered as single-fraction or hypofractionated stereotactic radiosurgery (SRS) for achieving long-term local tumor control.
METHODS: A retrospective chart review identified 186 patients with ESCC from spinal metastases who were treated with surgical decompression, instrumentation, and postoperative radiation delivered as either single-fraction SRS (24 Gy) in 40 patients (21.5%), high-dose hypofractionated SRS (24-30 Gy in 3 fractions) in 37 patients (19.9%), or low-dose hypofractionated SRS (18-36 Gy in 5 or 6 fractions) in 109 patients (58.6%). The relationships between postoperative adjuvant SRS dosing and fractionation, patient characteristics, tumor histology-specific radiosensitivity, grade of ESCC, extent of surgical decompression, response to preoperative radiotherapy, and local tumor control were evaluated by competing risks analysis.
RESULTS: The total cumulative incidence of local progression was 16.4% 1 year after SRS. Multivariate Gray competing risks analysis revealed a significant improvement in local control with high-dose hypofractionated SRS (4.1% cumulative incidence of local progression at 1 year, HR 0.12, p = 0.04) as compared with low-dose hypofractionated SRS (22.6% local progression at 1 year, HR 1). Although univariate analysis demonstrated a trend toward greater risk of local progression for patients in whom preoperative conventional external beam radiation therapy failed (22.2% local progression at 1 year, HR 1.96, p = 0.07) compared with patients who did not receive any preoperative radiotherapy (11.2% local progression at 1 year, HR 1), this association was not confirmed with multivariate analysis. No other variable significantly correlated with progression-free survival, including radiation sensitivity of tumor histology, grade of ESCC, extent of surgical decompression, or patient sex.
CONCLUSIONS: Postoperative adjuvant SRS following epidural spinal cord decompression and instrumentation is a safe and effective strategy for establishing durable local tumor control regardless of tumor histology-specific radiosensitivity. Patients who received high-dose hypofractionated SRS demonstrated 1-year local progression rates of less than 5% (95% CI 0%-12.2%), which were superior to the results of low-dose hypofractionated SRS. The local progression rate after single-fraction SRS was less than 10% (95% CI 0%-19.0%).

Tangpatanasombat C, Sanpakit S, Suratkarndawadee S, et al.
Surgical management of spinal metastases: the postoperative quality of life.
J Med Assoc Thai. 2012; 95 Suppl 9:S87-94 [PubMed]

OBJECTIVE: The surgical treatment of spinal metastases remains controversial. Increasing life expectancy has resulted in greater interest in overall quality of life, pain and neurologic improvements. There are few prospective studies on functional and quality of life outcomes in patients with vertebral metastases. Therefore, the authors conducted the prospective study evaluating the clinical, neurologic function and quality of life after surgery in these patients.
MATERIAL AND METHOD: Fifty-two patients undergoing surgical treatment for spinal metastases during October 2007 to October 2009 were prospectively evaluated. Surgical intervention included neurological decompression,fusion and spinal instrumentation. Pre- and post-operative assessments at 1st month, 3rd month and 6th month were performed using a visual analog scale, the modified Frankel grade classification and a Shortform-36 (SF-36).
RESULTS: Pain scores were improved significantly at all post-operative time points (p < 0.001). The neurological functions were improved at 1st month (p < 0.001), 3rd month (p < 0.001) and 6th month (p = 0.260) postoperatively. At 1st month after surgery, 40 patients (76.9%) had improvement in quality of life. However, at 3rd month postoperatively, there were 31 patients (59.6%) improved. At 6th month postoperatively, only 15 patients (28.8%) were improved. Internal organ metastases was the only factor that related to the reduction of quality of life at 1 month, 3rd month (p < 0.001) and 6th month (p < 0.05).
CONCLUSION: Patients with spinal metastases will have benefit from palliative surgery in significant pain reduction and neurological recovery. As the global assessment in the quality of life, the patients may have the improvement at 1st month postoperatively but after 3 months and 6 months postoperatively, selected patients may have benefit from the surgery and the factors such as internal organ metastases and primary site of cancer have great effects on the improvement in the quality of life. This data may be useful for counseling the patients and relatives about the prognosis and expected surgical outcome before surgical intervention is decided.

Usmani SZ, Mitchell A, Waheed S, et al.
Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3.
Blood. 2013; 121(10):1819-23 [PubMed] Article available free on PMC after 07/03/2014

Prognostic implications of 3 imaging tools, metastatic bone survey, magnetic resonance imaging, and positron emission tomography (PET), were evaluated in 2 consecutive Total Therapy 3 trials for newly diagnosed myeloma. Data including PET at baseline and on day 7 of induction as well as standard prognostic factors were available in 302 patients of whom 277 also had gene expression profiling (GEP)-derived risk information. According to multivariate analysis, more than 3 focal lesions on day 7 imparted inferior overall survival and progression-free survival, overall and in the subset with GEP-risk data. GEP high-risk designation retained independent significance for all 3 end points examined. Thus, the presence of > 3 focal lesions on day 7 PET follow-up may be exploited toward early therapy change, especially for the 15% of patients with GEP-defined high-risk disease with a median overall survival expectation of 2 years. This trial was registered at www.clinicaltrials.gov as #NCT00081939 and # NCT00572169.

Padhani AR, van Ree K, Collins DJ, et al.
Assessing the relation between bone marrow signal intensity and apparent diffusion coefficient in diffusion-weighted MRI.
AJR Am J Roentgenol. 2013; 200(1):163-70 [PubMed]

OBJECTIVE: The purposes of this study were to observe the relation between signal intensity (SI) on MR images with a high b value and the apparent diffusion coefficient (ADC) of bone marrow on body diffusion-weighted MR images, to determine cutoff values that enable separation of malignant and normal bone marrow, and to identify the upper ADC values of untreated multiple myeloma lesions and bone metastatic lesions of breast cancer.
MATERIALS AND METHODS: Retrospective evaluations of 16 patients without bone disease, 21 patients with untreated metastases of breast cancer, and 12 patients with myeloma undergoing body diffusion-weighted MRI were performed (b values, 50 s/mm(2) and 800 or 900 s/mm(2)). Normal yellow and red bone marrow regions were compared with metastatic breast and myeloma bone marrow lesions (one to five regions of interest per patient). SI values were normalized to kidney, muscle, and spinal cord SI. Signal-to-noise ratio and ADC for each lesion were recorded. Nonparametric, receiver operating characteristic, and nonlinear regression analyses were performed.
RESULTS: Yellow bone marrow and red bone marrow ADC values were lower than the tumor values (p < 0.001; area under the curve, 0.94; cutoff, 774 μm(2)/s). Tissue-normalized SI and the signal-to-noise ratio of normal bone marrow were also lower than those in tumor regions (p < 0.001; area under the curve, 0.86-0.88). Second-order polynomial curve fitting between SI and ADC was observed (muscle normalized SI, R(2) = 0.4). The 95th percentile and maximum values for mean tumor ADC distribution were 1209 μm(2)/s and 1433 μm(2)/s.
CONCLUSION: Both tissue-normalized SI and ADC measurements allow differentiation between normal bone marrow and tumors of myeloma and breast cancer. The presence of a nonlinear relation between bone marrow SI and ADC values enables definition of an upper limit of ADC value for untreated myeloma lesions and metastatic lesions of breast cancer.

Sawant A, Deshane J, Jules J, et al.
Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer.
Cancer Res. 2013; 73(2):672-82 [PubMed] Article available free on PMC after 15/01/2014

Enhanced bone destruction is a hallmark of various carcinomas such as breast cancer, where osteolytic bone metastasis is associated with increased morbidity and mortality. Immune cells contribute to osteolysis in cancer growth, but the factors contributing to aggressive bone destruction are not well understood. In this study, we show the importance of myeloid-derived suppressor cells (MDSC) in this process at bone metastatic sites. Because MDSC originate from the same myeloid lineage as macrophages, which are osteoclast precursors, we hypothesized that MDSC may undergo osteoclast differentiation and contribute to enhanced bone destruction and tumor growth. Using an immunocompetent mouse model of breast cancer bone metastasis, we confirmed that MDSC isolated from the tumor-bone microenvironment differentiated into functional osteoclasts both in vitro and in vivo. Mechanistic investigations revealed that nitric oxide signaling was critical for differentiation of MDSC into osteoclasts. Remarkably, osteoclast differentiation did not occur in MDSC isolated from control or tumor-bearing mice that lacked bone metastasis, signifying the essential cross-talk between tumor cells and myeloid progenitors in the bone microenvironment as a requirement for osteoclast differentiation of MDSC. Overall, our results identify a wholly new facet to the multifunctionality of MDSC in driving tumor progression, in this case as a novel osteoclast progenitor that specifically drives bone metastasis during cancer progression.

Akbas T, Ugurluer G, Arpaci T
Solitary sternal metastasis of nasopharyngeal carcinoma: a case report.
Eur Rev Med Pharmacol Sci. 2012; 16(14):1947-50 [PubMed]

Solitary sternal metastasis of nasopharyngeal carcinoma (NPC) is rare. At the time of diagnosis, distant metastases are found in about 5 to 7% of NPC patients. We report a case of isolated sternal metastasis of nasopharyngeal carcinoma in a 23 year-old man.

Cheng K, Chen Y, Zhao F, et al.
Collecting duct carcinoma presenting uncommon metastatic features.
Tumori. 2012 Sep-Oct; 98(5):135e-138e [PubMed]

Collecting duct carcinoma (CDC) is a relatively rare subtype of renal cell carcinoma (RCC) which has an aggressive course with an extremely poor prognosis. Here we report on a case of CDC in a 29-year-old woman who showed rapid disease progression with some uncommon clinical features including extensive vertebral metastases and invasion of the spinal meninges. The patient developed paraplegia and died 9 months after the diagnosis of CDC. The features of the fulminant clinical course with the lesions of the meninges, although rare, are important for the accumulation of experience of this rare disease.

Kischel P, Bellahcene A, Deux B, et al.
Overexpression of CD9 in human breast cancer cells promotes the development of bone metastases.
Anticancer Res. 2012; 32(12):5211-20 [PubMed]

BACKGROUND: Bone is a preferred target for circulating metastatic breast cancer cells. We found that the CD9 protein was up-regulated in the B02 osteotropic cell line, derived from the aggressive parental MDA-MB-231 breast cancer cell line. Here, we investigated the putative relationship between CD9 expression and the osteotropic phenotype.
MATERIALS AND METHODS: Overexpression of CD9 was analyzed by immunoblotting in different cell lines. Immunohistochemistry was used to assess CD9 expression in primary tumors and metastatic lesions. In vivo experiments were conducted in mice using a monoclonal antibody against CD9.
RESULTS: CD9 overexpression was confirmed in osteotropic cells. CD9 was significantly overexpressed in bone metastases versus primary tumors and visceral metastatic lesions. Finally, in vivo experiments showed that an antibody against CD9 delays homing of B02 cells in bone marrow, slowing down bone destruction.
CONCLUSION: Our study reveals a potential implication of CD9 in the formation of bony metastases from breast cancer cells.

Hauer K, Calzada-Wack J, Steiger K, et al.
DKK2 mediates osteolysis, invasiveness, and metastatic spread in Ewing sarcoma.
Cancer Res. 2013; 73(2):967-77 [PubMed]

Ewing sarcoma, an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in Ewing sarcoma compared with corresponding normal tissues. Using RNA interference, we showed that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to Ewing sarcoma invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Furthermore, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2, and TGFβ1 that are associated with homing, invasion, and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1α, JAG1, IL6, and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in Ewing sarcoma cells, DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in Ewing sarcoma invasion and osteolysis and also in the differential phenotype of Ewing sarcoma cells.

Segal E, Felder S, Haim N, et al.
Vitamin D deficiency in oncology patients--an ignored condition: impact on hypocalcemia and quality of life.
Isr Med Assoc J. 2012; 14(10):607-12 [PubMed]

BACKGROUND: Vitamin D status is not evaluated routinely in cancer patients with bone metastasis who are treated with bisphosphonates.
OBJECTIVES: To assess the effect of vitamin D status on risk of hypocalcemia and quality of life in these patients.
METHODS: We performed laboratory tests for routine serum biochemistry, 25(OH)D, plasma parathyroid hormone (PTH) and bone turnover markers (CTX, P1NP) in 54 patients aged 57.5 +/- 13 years treated with intravenous bisphosphonates.
RESULTS: Most of the patients (n = 44, 77.8%) did not receive calcium and vitamin D supplementation. Their mean serum 25(OH)D levels (12.83 +/- 6.86 ng/ml) correlated with vitamin D daily intake (P = 0.002). In 53 patients (98.1%) 25(OH) D levels were suboptimal (< 30 ng/ml). Albumin-corrected calcium levels correlated with plasma PTH (P = 0.001). No correlation was observed between daily calcium intake and serum calcium (P = 0.45). Hypocalcemia was observed in one patient. Mean plasma PTH was 88.5 - 65 ng/L. Plasma PTH correlated negatively with 25(OH)D serum levels (P = 0.003) and positively with P1NP (P = 0.004). Albumin-corrected calcium correlated negatively with P1NP (mean 126.9 +/- 191 ng/ml) but not with CTX levels (mean 0.265 +/- 0.1 ng/ml) (P < 0.001). There was no correlation among quality of life parameters, yearly sun exposure and 25(OH)D levels (P = 0.99).
CONCLUSIONS: Vitamin D deficiency is frequent in oncology patients with bone metastasis treated with bisphosphonates and might increase bone damage. Our results indicate a minor risk for the development of severe hypocalcemia in vitamin D-deficient patients receiving bisphosphonate therapy. Although vitamin D deficiency might have some effect on the quality of life in these patients, it was not proven significant.

Kanayama T, Mabuchi S, Fujita M, Kimura T
Calcaneal metastasis in uterine cervical cancer: a case report and a review of the literature.
Eur J Gynaecol Oncol. 2012; 33(5):524-5 [PubMed]

A 64-year-old woman with FIGO Stage IB2 cervical cancer was treated with radical surgery. Six months after her initial surgery, the patient developed calcaneal metastasis. Significant relief in bone pain was achieved with palliative radiotherapy followed by platinum-based combination chemotherapy, and the patient is currently alive with disease at eight months after the development of recurrence. Bone metastasis from uterine cervical cancer is uncommon, especially in the distal appendicular skeleton. Currently, and to the best of the authors' knowledge, calcaneal metastasis derived from cervical cancer has never been reported in English literature. As the prognosis of patients with bone metastasis is dismal and most patients die within a year, treatment should be directed towards improving the patient's quality of life and palliating their symptoms.

Fang Y, Chen Y, Yu L, et al.
Inhibition of breast cancer metastases by a novel inhibitor of TGFβ receptor 1.
J Natl Cancer Inst. 2013; 105(1):47-58 [PubMed]

BACKGROUND: Transforming growth factor beta (TGFβ), which is implicated in metastasis to various organs in breast cancer, is a potential target for new antitumor metastasis drugs.
METHODS: To identify specific inhibitors of TGFβ receptor 1 (TGFβR1) in breast cancer metastasis, a virtual library of more than 400000 different compounds was screened by molecular docking modeling and confirmed with Smad-binding element luciferase and TGFβR1 kinase assays. Affymetrix GeneChip expression analysis of mRNA levels and real-time polymerase chain reaction were performed to determine expression changes of TGFβ-mediated, metastasis-associated genes in breast cancer cells after treatment with the small-molecule inhibitor YR-290. YR-290 was also examined for its effects on breast cancer migration, invasion, and metastasis using transwell and epithelial-to-mesenchymal transition (EMT) assays in vitro and three different mouse (BALB/c and NU/NU nude) models (n = 10 per group). Kaplan-Meier analyses were used to assess survival. All statistical tests were two-sided.
RESULTS: YR-290 interacted with the kinase domain of TGFβR1, abrogated kinase activity (half maximal inhibitory concentration = 137nM, 95% confidence interval = 126.4 to 147.6nM) and inhibited the TGFβ-mediated downstream signaling pathway and metastasis-associated genes in breast cancer cells. YR-290 inhibited TGFβ-modulated breast cancer cell migration and invasion. In tumor metastasis mouse models, YR-290 almost completely blocked cancer metastasis. Numbers of lung tumor nodules of mice treated with 1mg/kg and 5mg/kg YR-290 were reduced by 74.93% (95% confidence interval = 61.45% to 88.41%) and 94.93% (95% confidence interval = 82.13% to 100%), respectively, compared with control mice. Treatment with YR-290 also statistically significantly prolonged the survival of tumor-bearing mice.
CONCLUSIONS: YR-290 is a novel inhibitor of tumor metastasis that works by blocking TGFβ signaling pathways.

Figueroa-Magalhães MC, Miller RS
Bone-modifying agents as adjuvant therapy for early-stage breast cancer.
Oncology (Williston Park). 2012; 26(10):955-62 [PubMed]

The development of effective systemic therapies to reduce the risk of disease recurrence or metastases in early-stage breast cancer remains an important challenge. The use of bone-modifying agents (BMAs), including the bisphosphonates (BPs) and the monoclonal antibody denosumab (Xgeva), is well established for metastatic bone disease. In the adjuvant setting, some studies have shown provocative findings with some of these agents for the prevention of future breast cancer-related events, with improved survival in some subgroups. The most compelling results have been seen with clodronate and zoledronic acid. In this review we describe the current evidence for use of BPs as part of the adjuvant treatment of patients with early-stage breast cancer.

Vashisht S, Bagler G
An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis.
PLoS One. 2012; 7(11):e49401 [PubMed] Article available free on PMC after 15/01/2014

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.

Barthel SR, Hays DL, Yazawa EM, et al.
Definition of molecular determinants of prostate cancer cell bone extravasation.
Cancer Res. 2013; 73(2):942-52 [PubMed] Article available free on PMC after 15/01/2014

Advanced prostate cancer commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. Prostate cancer cells roll on E-selectin(+) BMEC through E-selectin ligand-binding interactions under shear flow, and prostate cancer cells exhibit firm adhesion to BMEC via β1, β4, and αVβ3 integrins in static assays. However, whether these discrete prostate cancer cell-BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Here, we describe how metastatic prostate cancer cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. Prostate cancer cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic prostate cancer tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. Prostate cancer cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1, and Rap1 were constitutively active. In homing studies, prostate cancer cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin, and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases in transgenic adenoma of mouse prostate mice dramatically reduced prostate cancer incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins, and Rac/Rap1 GTPases in mediating prostate cancer cell homing and entry into bone and offer new insight into the role of α1,3 fucosylation in prostate cancer development.

Valencia K, Martín-Fernández M, Zandueta C, et al.
miR-326 associates with biochemical markers of bone turnover in lung cancer bone metastasis.
Bone. 2013; 52(1):532-9 [PubMed]

Recent evidence suggests that miRNAs could be used as serum markers in a variety of normal and pathological conditions. In this study, we aimed to identify novel miRNAs associated with skeletal metastatic disease in a preclinical model of lung cancer bone metastasis. We assessed the validity of these miRNAs as reliable serum biochemical markers to monitor the extent of disease and response to treatment in comparison to imaging techniques and standard biochemical markers of bone turnover. Using a murine model of human lung cancer bone metastasis after zoledronic acid (ZA) treatment, PINP (procollagen I amino-terminal propeptide) was the only marker that exhibited a strong correlation with osteolytic lesions and tumor burden at early and late stages of bone colonization. In contrast, BGP (osteocalcin) and CTX (carboxyterminal telopeptide) demonstrated a strong correlation only at late stages. We performed qPCR based screening of a panel of 380 human miRNAs and quantified bone metastatic burden using micro-CT scans, X-rays and bioluminescence imaging. Interestingly, levels of miR-326 strongly associated with tumor burden and PINP in vehicle-treated animals, whereas no association was found in ZA-treated animals. Only miR-193 was associated with biochemical markers PINP, BGP and CTX in ZA-treated animals. Consistently, miR-326 and PINP demonstrated a strong correlation with tumor burden. Our findings, taken together, indicate that miR-326 could potentially serve as a novel biochemical marker for monitoring bone metastatic progression.

Logothetis CJ, Basch E, Molina A, et al.
Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial.
Lancet Oncol. 2012; 13(12):1210-7 [PubMed]

BACKGROUND: Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy.
METHODS: The COU-AA-301 trial enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form questionnaire at baseline, day 15 of cycle 1, and day 1 of each treatment cycle thereafter until discontinuation. We assessed, with prospectively defined response criteria that incorporated analgesic use, clinically meaningful changes in pain intensity and interference with daily living. We measured time to first occurrence of skeletal-related events, which we defined as pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery, and regularly assessed them throughout the study. Pain palliation was assessed in patients who had clinically significant baseline pain, whereas all other analyses were done in the overall intention-to-treat population. COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690.
FINDINGS: Median follow-up was 20·2 months (IQR 18·4-22·1). In patients with clinically significant pain at baseline, abiraterone acetate and prednisone resulted in significantly more palliation (157 of 349 [45·0%] patients vs 47 of 163 [28·8%]; p=0·0005) and faster palliation (median time to palliation 5·6 months [95% CI 3·7-9·2] vs 13·7 months [5·4-not estimable]; p=0·0018) of pain intensity than did prednisone only. Palliation of pain interference (134 of 223 [60·1%] vs 38 of 100 [38·0%], p=0·0002; median time to palliation of pain interference 1·0 months [95% CI 0·9-1·9] vs 3·7 months [2·7-not estimable], p=0·0004) and median duration of palliation of pain intensity (4·2 months [95% CI 3·0-4·9] vs 2·1 months [1·4-3·7]; p=0·0056) were significantly better with abiraterone acetate and prednisone than with prednisone only. In the overall population, median time to occurrence of first skeletal-related event was significantly longer with abiraterone acetate and prednisone than with prednisone only (25·0 months [95% CI 25·0-not estimable] vs 20·3 months [16·9-not estimable]; p=0·0001).
INTERPRETATION: In patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events.
FUNDING: Janssen Research & Development and Janssen Global Services.

Rades D, Douglas S, Schild SE
A validated survival score for breast cancer patients with metastatic spinal cord compression.
Strahlenther Onkol. 2013; 189(1):41-6 [PubMed]

BACKGROUND: To create a validated scoring system predicting survival of breast cancer patients with metastatic spinal cord compression (MSCC).
PATIENTS AND METHODS: Of 510 patients, one half were assigned to either the test or the validation group. In the test group, eight pretreatment factors (age, performance status, number of involved vertebrae, ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, time of developing motor deficits) plus the radiation regimen were retrospectively investigated. Factors significantly associated with survival in the multivariate analysis were included in the scoring system. The score for each factor was determined by dividing the 6-month survival rate (%) by ten. The total score was the sum of the scores for each factor.
RESULTS: In the multivariate analysis of the test group, performance status, ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, and time of developing motor deficits were significant for survival and included in the score. Total scores ranged from 30 to 50 points. In the test group, the 6-month survival rates were 12% for 30-35 points, 41% for 36-40 points, 74% for 41-45 points, and 98% for 46-50 points (p < 0.0001). In the validation group, the 6-month survival rates were 14%, 46%, 77%, and 99%, respectively (p < 0.0001).
CONCLUSION: The survival rates of the validation group were similar to the test group. Therefore, this score was reproducible and can help when selecting the appropriate radiotherapy regimen for each patient taking into account her survival prognosis.

Haidukewych GJ
Metastatic disease around the hip: maintaining quality of life.
J Bone Joint Surg Br. 2012; 94(11 Suppl A):22-5 [PubMed]

Many tumors metastasise to bone, therefore, pathologic fracture and impending pathologic fractures are common reasons for orthopedic consultation. Having effective treatment strategies is important to avoid complications, and relieve pain and preserve function. Thorough pre-operative evaluation is recommended for medical optimization and to ensure that the lesion is in fact a metastasis and not a primary bone malignancy. For impending fractures, various scoring systems have been proposed to determine the risk of fracture, and therefore the need for prophylactic stabilisation. Lower score lesions can often be treated with radiation, while more problematic lesions may require internal fixation. Intramedullary fixation is generally preferred due to favorable biomechanics. Arthroplasty may be required for lesions with massive bony destruction where internal fixation attempts are likely to fail. Radiation may also be useful postoperatively to minimise construct failure due to tumor progression.

Beuselinck B, Wolter P, Karadimou A, et al.
Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases.
Br J Cancer. 2012; 107(10):1665-71 [PubMed] Article available free on PMC after 06/11/2013

BACKGROUND: The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ).
METHODS: Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk.
RESULTS: Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates.
CONCLUSION: Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.

Dmuchowska DA, Krasnicki P, Obuchowska I, et al.
Ophthalmic manifestation of skull base metastasis from breast cancer.
Med Sci Monit. 2012; 18(11):CS105-8 [PubMed] Article available free on PMC after 06/11/2013

BACKGROUND: There is a vast discrepancy between the incidence of skull base metastases reported in vivo and at autopsy. Asymptomatic character or unspecific symptoms make the diagnosis difficult, particularly in patients with no history of cancer. Our case illustrates a skull base metastasis from breast cancer, detected in a diagnostic process initiated by ophthalmologic examination.
CASE REPORT: We report the case of a 53-year-old woman complaining of ptosis and diplopia, with concomitant loss of skin sensation within the right half of the forehead, and without any other worrisome symptoms or signs. Ophthalmic examination revealed impairment in eye movements, slight proptosis and corneal hypoesthesia on the right side, with normal pupillary light reflexes. The anterior and posterior segments of the eye were normal. Based on CT and MRI, an extensive tumor was detected, infiltrating the right orbit and the frontotemporal region of the skull base, and producing edema of the adjacent aspects of the brain. Aside from partial palsy of the oculomotor nerve and the ophthalmic division of the trigeminal nerve, no abnormalities were found on neurological examination. Explorative craniotomy and histopathological findings revealed a skull base metastasis from breast cancer.
CONCLUSIONS: Diplopia, ptosis, proptosis, and ophthalmic nerve sensory loss may be the only manifestation of a skull base metastasis. Careful ophthalmologic examination is crucial in early detection of this life-threatening condition.