Bone-Induced Expression of Tumoral Integrin beta3 Enables Targeted Nanotherapy of Breast Cancer Metastases

NASA Astrophysics Data System (ADS)

Ross, Michael H.

Breast cancer is the most common cancer for women worldwide, representing approximately 25% of all new cancer cases in this population. While early detection and removal of breast cancer still confined to the primary site results in a good prognosis, approximately one- third of patients will develop distant metastases. In these patients, overall survival is markedly reduced. Of the common sites for breast cancer metastasis, the skeletal system is the most frequent. Treating breast cancer bone metastases has proven particularly difficult for several reasons, such as dissemination of metastases throughout the skeleton, poor drug localization to sites of interest, a lack of tumor-specific targets expressed across breast cancer subtypes, and the chemo-protective nature of the bone microenvironment. This dissertation is focused on investigating a potential tumor-target expressed on breast cancer bone metastases, and to improve drug treatment efficacy against tumor cells in the bone microenvironment. Integrins are heterodimeric cell surface receptors, composed of an alpha and beta subunit from a large family of selectively-compatible integrin subunits. As a heterodimeric complex, integrins can bind to components of the extracellular matrix or to other cells. One particular integrin complex, integrin alphavbeta3, is composed of the tightly regulated integrin subunit beta3 and the more widely expressed alphav subunit. I examined the expression of integrin beta3 on primary breast cancer as compared to metastases in murine cancer models, and observed that integrin expression is significantly elevated on bone metastases as compared to the primary tumors or visceral metastases. In addition, I evaluated tumor-associated integrin beta3 expression on a tissue microarray (TMA) composed of primary breast cancer and patient-matched bone metastatic tissue from 42 patients. Across nearly all patients, tumor-associated integrin beta3 expression was significantly elevated on bone

Cryoablation of Bone Metastases from Renal Cell Carcinoma for Local Tumor Control.

PubMed

Gardner, Carly S; Ensor, Joe E; Ahrar, Kamran; Huang, Steven Y; Sabir, Sharjeel H; Tannir, Nizar M; Lewis, Valerae O; Tam, Alda L

2017-11-15

Patients with bone metastases from renal cell carcinoma often are not surgical candidates and have a poor prognosis. There are limited data on the use of cryoablation as a locoregional therapy for bone metastases. Our objective was to assess the local tumor-control rate following cryoablation of bone metastases in the setting of renal cell carcinoma. We retrospectively reviewed the medical records of patients with metastatic renal cell carcinoma who underwent cryoablation for bone metastases between 2007 and 2014. We excluded patients if the intent of treatment was for pain palliation only, if cryoablation was performed without an attempt for complete tumor control (cytoreduction), or if the patient had no further follow-up beyond the cryoablation procedure. We recorded patient demographics, procedural variables, and complications. Cross-sectional imaging and clinical follow-up were reviewed to determine disease recurrence. The median overall survival and recurrence-free survival were determined using the Kaplan-Meier method. Forty patients (30 male and 10 female) with 50 bone metastases were included for analysis. The mean patient age was 62 years (range, 47 to 82 years). The median follow-up was 35 months (95% confidence interval [CI], 22.7 to 74.4 months). Twenty-five (62.5%) of the 40 patients had oligometastatic disease, defined as ≤5 metastases at the time of ablation. The mean tumor size was 3.4 ± 1.5 cm. Metastases in the pelvic region represented 68% of the treated tumors (34 of 50). The overall local tumor-control rate per lesion was 82% (41 of 50). Patients with oligometastatic disease experienced better local tumor control (96% [24 of 25]) compared with patients who had >5 metastases (53.3% [8 of 15]) (p = 0.001). The local tumor-control rate was better for lesions for which a larger mean difference between maximum ice-ball diameter and maximum lesion diameter was achieved (2.2 ± 0.9 cm for those without recurrence versus 1.35 ± 1.2 cm for those

Paradoxical expression of E-cadherin in prostatic bone metastases.

PubMed

Bryden, A A; Freemont, A J; Clarke, N W; George, N J

1999-12-01

To determine whether the calcium-dependent cell adhesion molecule E-cadherin is expressed in metastatic deposits of prostate cancer in bone. Ten bone biopsies containing metastatic deposits of untreated prostatic cancer were obtained and immunohistochemically stained for E-cadherin with the monoclonal antibody HECD-1, using the streptavidin-biotin complex technique. Benign prostatic tissue was used as the control. Of the 10 specimens, nine showed positive expression of E-cadherin, graded as strong in four. E-cadherin expression was strongest in well-differentiated metastases and decreased with increasing tumour grade. In some specimens there were mixed patterns of expression. E-cadherin is strongly expressed in prostatic bone metastases and the degree of expression appears to reflect local tumour grade. This suggests that loss of E-cadherin expression may not be critically linked to metastatic potential.

Detection of bone metastases in breast cancer patients in the PET/CT era: Do we still need the bone scan?

PubMed

Caglar, M; Kupik, O; Karabulut, E; Høilund-Carlsen, P F

2016-01-01

To examine the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of bone metastasis in breast cancer patients and assess whether whole body bone scan (BS) with (99m)Tc-methylene diphosphonate provides any additional information. Study group comprised 150 patients, mean age 52 years (range 27-85) with breast cancer, suspected of having bone metastases. All patients had undergone both FDG-PET/CT and BS with or without single photon emission tomography/computed tomography (SPECT/CT) within a period of 6 weeks. The final diagnosis of bone metastasis was established by histopathological findings, additional imaging, or clinical follow-up longer than 10 months. Cancer antigen 15-3 (CA15-3) and carcinoembryogenic antigen (CEA) were measured in all patients. Histologically 83%, 7% and 10% had infiltrating ductal, lobular and mixed carcinoma respectively. Confirmed bone metastases were present in 86 patients (57.3%) and absent in 64 (42.7%). Mean CA15-3 and CEA values in patients with bone metastases were 74.6ng/mL and 60.4U/mL respectively, compared to 21.3ng/mL and 3.2U/mL without metastases (p<0.001). The sensitivity of FDG-PET/CT for the detection of bone metastases was 97.6% compared to 89.5% with SPECT/CT. In 57 patients, FDG-PET/CT correctly identified additional pulmonary, hepatic, nodal and other soft tissue metastases, not detected by BS. Our findings suggest that FDG-PET/CT is superior to BS with or without SPECT/CT. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

E-cadherin and beta-catenin are down-regulated in prostatic bone metastases.

PubMed

Bryden, A A G; Hoyland, J A; Freemont, A J; Clarke, N W; Schembri Wismayer, D; George, N J R

2002-03-01

To determine the E-cadherin and beta-catenin expression phenotype in untreated primary prostate cancer and corresponding bone metastases. Paired bone metastasis and primary prostate specimens were obtained from 14 men with untreated metastatic prostate carcinoma. The tumours were histologically graded by an independent pathologist. Expression of mRNA for E-cadherin and beta-catenin was detected within the tumour cells using in-situ hybridization with a 35S-labelled cDNA probe. The expression of E-cadherin and beta-catenin were graded as uniform, heterogeneous or negative. The mRNA for E-cadherin was expressed in 13 of 14 primary carcinomas and 11 bone metastases; beta-catenin was expressed by 13 and nine, respectively. Of the primary tumours, nine expressed E-cadherin and beta-catenin uniformly; in contrast, all metastases had down-regulated E-cadherin and/or beta-catenin. The down-regulation of E-cadherin and beta-catenin are a feature of the metastatic phenotype, which may be a significant factor in the genesis of bone metastases. However, this does not appear to be reflected in the expression of these molecules in the primary tumours.

EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides.

PubMed

Handkiewicz-Junak, Daria; Poeppel, Thorsten D; Bodei, Lisa; Aktolun, Cumali; Ezziddin, Samer; Giammarile, Francesco; Delgado-Bolton, Roberto C; Gabriel, Michael

2018-05-01

The skeleton is the most common metastatic site in patients with advanced cancer. Pain is a major healthcare problem in patients with bone metastases. Bone-seeking radionuclides that selectively accumulate in the bone are used to treat cancer-induced bone pain and to prolong survival in selected groups of cancer patients. The goals of these guidelines are to assist nuclear medicine practitioners in: (a) evaluating patients who might be candidates for radionuclide treatment of bone metastases using beta-emitting radionuclides such as strontium-89 ( 89 Sr), samarium-153 ( 153 Sm) lexidronam ( 153 Sm-EDTMP), and phosphorus-32 ( 32 P) sodium phosphate; (b) performing the treatments; and ©) understanding and evaluating the treatment outcome and side effects.

Osteoclast-targeting small molecules for the treatment of neoplastic bone metastases.

PubMed

Kawatani, Makoto; Osada, Hiroyuki

2009-11-01

Osteoclasts are highly specialized cells that resorb bone, and their abnormal activity is implicated in a variety of human bone diseases. In neoplastic bone metastasis, the bone destruction caused by osteoclasts is not only associated with the formation and progression of metastatic lesions, but also could contribute to frequent complications such as severe pain and pathological fractures, which greatly diminish the quality of life of patients. Bisphosphonates, potent antiresorptive drugs, have been shown to have efficacy for treating bone metastases in many types of cancer, and the development of various molecularly targeted agents is currently proceeding. Thus, inhibition of osteoclast function is now established as an important treatment strategy for bony metastases. This review focuses on promising small molecules that disrupt osteoclast function and introduces our chemical/biological approach for identifying osteoclast-targeting small molecular inhibitors.

Therapeutic Strategies for Bone Metastases and Their Clinical Sequelae in Prostate Cancer

PubMed Central

Autio, Karen A.; Scher, Howard I.

2013-01-01

Opinion statement Skeletal metastases threaten quality of life, functionality, and longevity in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapeutic strategies for bone metastases in prostate cancer can palliate pain, delay/prevent skeletal complications, and prolong survival. Pharmacologic agents representing several drug classes have demonstrated the ability to achieve these treatment goals in men with mCRPC. Skeletal-related events such as fracture and the need for radiation can be delayed using drugs that target the osteoclast/osteoblast pathway. Cancer-related bone pain can be palliated using beta-emitting bone-seeking radiopharmaceuticals such as samarium-153 EDTMP and strontium-89. Also, prospective randomized studies have demonstrated that cytotoxic chemotherapy can palliate bone pain. For the first time, bone-directed therapy has been shown to prolong survival using the novel alpha-emitting radiopharmaceutical radium-223. Given these multifold clinical benefits, treatments targeting bone metabolism, tumor-bone stromal interactions, and bone metastases themselves are now central elements of routine clinical care. Decisions about which agents, alone or in combination, will best serve the patient’s and clinician’s clinical goals is contingent on the treatment history to date, present disease manifestations, and symptomatology. Clinical trials exploring novel agents such as those targeting c-Met and Src are under way, using endpoints that directly address how patients feel, function, and survive. PMID:22528368

AR Expression in Breast Cancer CTCs Associates with Bone Metastases.

PubMed

Aceto, Nicola; Bardia, Aditya; Wittner, Ben S; Donaldson, Maria C; O'Keefe, Ryan; Engstrom, Amanda; Bersani, Francesca; Zheng, Yu; Comaills, Valentine; Niederhoffer, Kira; Zhu, Huili; Mackenzie, Olivia; Shioda, Toshi; Sgroi, Dennis; Kapur, Ravi; Ting, David T; Moy, Beverly; Ramaswamy, Sridhar; Toner, Mehmet; Haber, Daniel A; Maheswaran, Shyamala

2018-04-01

Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER) + breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER + breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients. Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. Mol Cancer Res; 16(4); 720-7. ©2018 AACR . ©2018 American Association for Cancer Research.

Excess TGF-β mediates muscle weakness associated with bone metastases in mice

PubMed Central

Reiken, Steven; Xie, Wenjun; Andersson, Daniel C.; John, Sutha; Chiechi, Antonella; Wright, Laura E.; Umanskaya, Alisa; Niewolna, Maria; Trivedi, Trupti; Charkhzarrin, Sahba; Khatiwada, Pooja; Wronska, Anetta; Haynes, Ashley; Benassi, Maria Serena; Witzmann, Frank A.; Zhen, Gehua; Wang, Xiao; Cao, Xu; Roodman, G. David; Marks, Andrew R.; Guise, Theresa A.

2015-01-01

Cancer-associated muscle weakness is poorly understood and there is no effective treatment. Here, we find that seven different mouse models of human osteolytic bone metastases, representing breast, lung and prostate cancers, as well as multiple myeloma exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that TGF-β, released from the bone surface as a result of metastasis-induced bone destruction upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor/calcium (Ca2+) release channel (RyR1). The oxidized RyR1 channels leaked Ca2+, resulting in lower intracellular signaling required for proper muscle contraction. We found that inhibiting RyR1 leak, TGF-β signaling, TGF-β release from bone or Nox4 all improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast cancer- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, higher levels of Nox4 protein and Nox4 binding to RyR1, and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a non-malignant metabolic bone disorder associated with increased TGF-β activity. Thus, metastasis-induced TGF-β release from bone contributes to muscle weakness by decreasing Ca2+-induced muscle force production. PMID:26457758

High neuropeptide Y release associates with Ewing sarcoma bone dissemination - in vivo model of site-specific metastases

PubMed Central

Hong, Sung-Hyeok; Tilan, Jason U.; Galli, Susana; Izycka-Swieszewska, Ewa; Polk, Taylor; Horton, Meredith; Mahajan, Akanksha; Christian, David; Jenkins, Shari; Acree, Rachel; Connors, Katherine; Ledo, Phuong; Lu, Congyi; Lee, Yi-Chien; Rodriguez, Olga; Toretsky, Jeffrey A.; Albanese, Chris; Kitlinska, Joanna

2015-01-01

Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics. PMID:25714031

Micro-CT evaluation of bone defects: applications to osteolytic bone metastases, bone cysts, and fracture.

PubMed

Buie, Helen R; Bosma, Nick A; Downey, Charlene M; Jirik, Frank R; Boyd, Steven K

2013-11-01

Bone defects can occur in various forms and present challenges to performing a standard micro-CT evaluation of bone quality because most measures are suited to homogeneous structures rather than ones with spatially focal abnormalities. Such defects are commonly associated with pain and fragility. Research involving bone defects requires quantitative approaches to be developed if micro-CT is to be employed. In this study, we demonstrate that measures of inter-microarchitectural bone spacing are sensitive to the presence of focal defects in the proximal tibia of two distinctly different mouse models: a burr-hole model for fracture healing research, and a model of osteolytic bone metastases. In these models, the cortical and trabecular bone compartments were both affected by the defect and were, therefore, evaluated as a single unit to avoid splitting the defects into multiple analysis regions. The burr-hole defect increased mean spacing (Sp) by 27.6%, spacing standard deviation (SpSD) by 113%, and maximum spacing (Spmax) by 72.8%. Regression modeling revealed SpSD (β=0.974, p<0.0001) to be a significant predictor of the defect volume (R(2)=0.949) and Spmax (β=0.712, p<0.0001) and SpSD (β=0.271, p=0.022) to be significant predictors of the defect diameter (R(2)=0.954). In the mice with osteolytic bone metastases, spacing parameters followed similar patterns of change as reflected by other imaging technologies, specifically bioluminescence data which is indicative of tumor burden. These data highlight the sensitivity of spacing measurements to bone architectural abnormalities from 3D micro-CT data and provide a tool for quantitative evaluation of defects within a bone. Copyright © 2013 IPEM. Published by Elsevier Ltd. All rights reserved.

[Efficacy of Radiation Therapy for Esophageal Cancer with Bone Metastases].

PubMed

Katayanagi, So; Watanabe, Takafumi; Makuuchi, Yosuke; Shigoka, Masatoshi; Sumi, Tetsuo; Takagaki, Shinichi; Okubo, Mitsuru; Tachibana, Shingo; Oosaka, Yoshiaki; Tsuchida, Akihiko; Kawachi, Shigeyuki

2015-11-01

We retrospectively considered the validity of radiotherapy for patients with bone metastases from esophageal cancer. Eight patients have received radiotherapy in our hospital since 2007. The median age of the patients was 63 years, with 5 men and 3 women. Bone metastatic sites were 4 to the vertebrae, 3 to the ribs, 3 to the femur and 1 each to the humerus, ulna, and radius, respectively. All of the patients had other unresectable sites of metastasis. Radiotherapy reduced pain of 3 patients of PS 1 clearly. Median survival time from the start of radiation therapy was 50 days. When PS was relatively good, the possibility of easing pain and improving QOL was suggested by our data. There is a possibility that radiation therapy for patients with bone metastases from esophageal cancer can improve the QOL and alleviate pain.

Bone metastases from breast cancer at the time or radical mastectomy as detected by bone scan. Eight-year follow-up.

PubMed

Sklaroff, R B; Sklaroff, D M

1976-07-01

Sixty-four women with Stage II breast cancer who had Sr85 bone scans at the time of radical mastectomy were followed for 8 years in a prospective study. Those women with positive scans had a slight, but statistically significant, increased incidence of metastic disease, particularly for metastases to bone.However, 40% of those women with positive bone scans and negative roentgenograms survived 8 years without evidence of any metastatic disease. Therefore, it has not been shown at this time that bone scans should be obtained in order to exclude bone metastasis before regional therapy for breast cancer is instituted. Also, a significant percentage of women with negative bone scans developed both bone and soft tissue metastases. As many as 30% of asymptomatic women with a history of breast cancer and positive bone scans and negative bone roentgenograms may still harbor disease in bone after 8 years.

Diagnostic role of (99)Tc(m)-MDP SPECT/CT combined SPECT/MRI Multi modality imaging for early and atypical bone metastases.

PubMed

Chen, Xiao-Liang; Li, Qian; Cao, Lin; Jiang, Shi-Xi

2014-01-01

The bone metastasis appeared early before the bone imaging for most of the above patients. (99)Tc(m)-MDP ((99)Tc(m) marked methylene diphosphonate) bone imaging could diagnosis the bone metastasis with highly sensitivity, but with lower specificity. The aim of this study is to explore the diagnostic value of (99)Tc(m)-MDP SPECT/CT combined SPECT/MRI Multi modality imaging for the early period atypical bone metastases. 15 to 30 mCi (99)Tc(m)-MDP was intravenously injected to the 34 malignant patients diagnosed as doubtful early bone metastases. SPECT, CT and SPECT/CT images were captured and analyzed consequently. For the patients diagnosed as early period atypical bone metastases by SPECT/CT, combining the SPECT/CT and MRI together as the SPECT/MRI integrated image. The obtained SPECT/MRI image was analyzed and compared with the pathogenic results of patients. The results indicated that 34 early period doubtful metastatic focus, including 34 SPECT positive focus, 17 focus without special changes by using CT method, 11 bone metastases focus by using SPECT/CT method, 23 doubtful bone metastases focus, 8 doubtful bone metastases focus, 14 doubtful bone metastases focus and 2 focus without clear image. Totally, SPECT/CT combined with SPECT/MRI method diagnosed 30 bone metastatic focus and 4 doubtfully metastatic focus. In conclusion, (99)Tc(m)-MDP SPECT/CT combined SPECT/MRI Multi modality imaging shows a higher diagnostic value for the early period bone metastases, which also enhances the diagnostic accuracy rate.

Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells.

PubMed

Li, Qinlong; Yin, Lijuan; Jones, Lawrence W; Chu, Gina C-Y; Wu, Jason B-Y; Huang, Jen-Ming; Li, Quanlin; You, Sungyong; Kim, Jayoung; Lu, Yi-Tsung; Mrdenovic, Stefan; Wang, Ruoxiang; Freeman, Michael R; Garraway, Isla; Lewis, Michael S; Chung, Leland W K; Zhau, Haiyen E

2016-12-20

Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.

An interdisciplinary consensus on the management of bone metastases from renal cell carcinoma.

PubMed

Grünwald, Viktor; Eberhardt, Berit; Bex, Axel; Flörcken, Anne; Gauler, Thomas; Derlin, Thorsten; Panzica, Martin; Dürr, Hans Roland; Grötz, Knut Achim; Giles, Rachel H; von Falck, Christian; Graser, Anno; Muacevic, Alexander; Staehler, Michael

2018-06-14

Bone is a major site of haematogenous tumour cell spread in renal cell carcinoma (RCC), and most patients with RCC will develop painful and functionally disabling bone metastases at advanced disease stages. The prognosis of these patients is generally poor and the treatment is, therefore, aimed at palliation. However, RCC-associated bone metastases can be curable in select patients. Current data support a multimodal management strategy that includes wide resection of lesions, radiotherapy, systemic therapy, and other local treatment options, which can improve quality of life and survival. Nevertheless, the optimal approach for metastatic bone disease in RCC has not yet been defined and practical recommendations are rare. To improve the management and outcomes of patients with RCC and bone metastases, the International Kidney Cancer Coalition and the interdisciplinary working group on renal tumours of the German Cancer Society convened a meeting of experts with a global perspective to perform an unstructured review and elaborate on current treatment strategies on the basis of published data and expertise. The panel formulated recommendations for the diagnosis and treatment of patients with RCC and metastasis to the bone. Furthermore, the experts summarized current challenges and unmet patient needs that should be addressed in the future.

[Benign metastasizing leiomyoma: An unusual cause of aggressive femoral bone tumor].

PubMed

Alexandre, L; Taillieu, F; Arlet, J-B; Passeron, A; Michon, A; Bats, A-S; Pouchot, J; Ranque, B

2018-06-01

Benign metastasizing leiomyoma (BML) is a rare condition characterized by histologically benign "metastatic" smooth muscle tumors, which can affect women with history of uterine surgery. We report the case of a patient with bone metastases of BML. A 78-year-old woman who had undergone uterine surgery six years before hospital admission, was diagnosed with large pulmonary and pleural metastases that necessitated surgical removal. Pathological examination allowed the diagnosis of BML with positive staining for estrogen and progesterone receptors. Three years later, a BML metastasis in the right femoral diaphysis was unexpectedly discovered and treated by osteosynthesis because of a high risk of fracture. Despite an aromatase-inhibitor treatment, new lungs lesions appeared in the next few months. BML is a potential cause of aggressive, although histologically benign, bone tumor in women with a history of uterine surgery. Copyright © 2018. Published by Elsevier SAS.

The role of whole-body bone scanning and clinical factors in detecting bone metastases in patients with non-small cell lung cancer.

PubMed

Erturan, Serdar; Yaman, Mustafa; Aydin, Günay; Uzel, Isil; Müsellim, Benan; Kaynak, Kamil

2005-02-01

Correct detection of bone metastases in patients with non-small cell lung cancer (NSCLC) is crucial for prognosis and selection of an appropriate treatment regimen. The aim of this study was to investigate the role of whole-body bone scanning (WBBS) and clinical factors in detecting bone metastases in NSCLC. One hundred twenty-five patients with a diagnosis made between 1998 and 2002 were recruited (squamous cell carcinoma, 54.4%; adenocarcinoma, 32.8%; non-small cell carcinoma, 8.8%; large cell carcinoma, 4%). Clinical factors suggesting bone metastasis (skeletal pain, elevated alkaline phosphatase, hypercalcemia) were evaluated. WBBS was performed in all patients, and additional MRI was ordered in 10 patients because of discordance between clinical factors and WBBS findings. Bone metastases were detected in 53% (n = 21) of 39 clinical factor-positive patients, 5.8% (n = 5) of 86 clinical factor-negative patients, and 20.8% of total patients. The existence of bone-specific clinical factors as indicators of metastasis presented 53.8% positive predictive value (PPV), 94.2% negative predictive value (NPV), and 81.6% accuracy. However, the findings of WBBS showed 73.5% PPV, 97.8% NPV, and 91.2% accuracy. Adenocarcinoma was the most common cell type found in patients with bone metastasis (39%). The routine bone scanning prevented two futile thoracotomies (8%) in 25 patients with apparently operable lung cancer. In spite of the high NPV of the bone-specific clinical factors and the high value obtained in the false-positive findings in the bone scan, the present study indicates that in patients for whom surgical therapy is an option, preoperative staging using WBBS can be helpful to avoid misstaging due to asymptomatic bone metastases.

Esophageal squamous cell carcinoma with dural and bone marrow metastases.

PubMed

Chen, Yen-Hao; Huang, Cheng-Hua

2014-09-21

Patients with esophageal squamous cell carcinoma generally present at an advanced stage at the time of diagnosis. The most common sites of visceral metastasis are the lung, liver and bone, but brain and bone marrow involvement is exceedingly rare. Herein, we report a 62-year-old man with a 4-wk history of progressive low back pain with radiation to bilateral lower legs, dysphagia and body weight loss. Esophageal squamous cell carcinoma with regional lymph node, liver and bone metastases was diagnosed. He underwent concurrent chemoradiotherapy and got a partial response. Four months later, he complained of headache, diplopia and severe hearing impairment in the left ear. There was no evidence for bacterial, fungal, tuberculous infection or neoplastic infiltration. Magnetic resonance imaging of the brain demonstrated thickening and enhancement of bilateral pachymeninges and multiple enhancing masses in bilateral skull. Dural metastasis was diagnosed and he received whole brain irradiation. In addition, laboratory examination revealed severe thrombocytopenia and leucopenia, and bone marrow study confirmed the diagnosis of metastatic squamous cell carcinoma. This is the first described case of esophageal squamous cell carcinoma with dural and bone marrow metastases. We also discuss the pathogenesis of unusual metastatic diseases and differential diagnosis of pachymeningeal thickening.

Bone sialoprotein is predictive of bone metastases in resectable non-small-cell lung cancer: a retrospective case-control study.

PubMed

Papotti, Mauro; Kalebic, Thea; Volante, Marco; Chiusa, Luigi; Bacillo, Elisa; Cappia, Susanna; Lausi, Paolo; Novello, Silvia; Borasio, Piero; Scagliotti, Giorgio V

2006-10-20

Bone metastases (BM) in non-small-cell lung cancer (NSCLC) may be detected at diagnosis or during the course of the disease, and are associated with a worse prognosis. Currently, there are no predictive or diagnostic markers to identify high-risk patients for metastatic bone dissemination. Thirty patients with resected NSCLC who subsequently developed BM were matched for clinicopathologic parameters to 30 control patients with resected NSCLC without any metastases and 26 patients with resected NSCLC and non-BM lesions. Primary tumors were investigated by immunohistochemistry for 10 markers involved in bone resorption or development of metastases. Differences among groups were estimated by chi2 test, whereas the prognostic impact of clinicopathologic parameters and marker expression was evaluated by univariate (Wilcoxon and Mantel-Cox tests) and multivariate (Cox proportional hazards regression model) analyses. The presence of bone sialoprotein (BSP) was strongly associated with bone dissemination (P < .001) and, independently, with worse outcome (P = .02, Mantel-Cox test), as defined by overall survival. To evaluate BSP protein expression in nonselected NSCLC, a series of 120 consecutive resected lung carcinomas was added to the study, and BSP prevalence reached 40%. No other markers showed a statistically significant difference among the three groups or demonstrated a prognostic impact, in terms of both overall survival and time interval to metastases. BSP protein expression in the primary resected NSCLC is strongly associated with BM progression and could be useful in identifying high-risk patients who could benefit from novel modalities of surveillance and preventive treatment.

Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guerra Liberal, Francisco D. C., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, Adriana Alexandre S., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, João Manuel R. S., E-mail: tavares@fe.up.pt

Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bonemore » metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium-170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of

Utility of bone scanning in detecting occult skeletal metastases from cervical carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katz, R.D.; Alderson, P.O.; Rosenshein, N.B.

1979-11-01

Bone scans were obtained in 100 patients with carcinoma of the cervix in order to search for occult skeletal metastases. Scans revealed metastases in 4 patients with advanced stages of disease, but the scans in 79 patients with Stage 0, I, or II disease were negative. The scans in 14 patients showed renal asymmetry; 11 of these had obstructive uropathy due to tumor invasion or radiation therapy. Bone scanning does not seem warranted as a screening test in asymptomatic patients with Stage 0, I, or II carcinoma. If the test is done, renal symmetry should be carefully evaluated.

Computational modeling of radiobiological effects in bone metastases for different radionuclides.

PubMed

Liberal, Francisco D C Guerra; Tavares, Adriana Alexandre S; Tavares, João Manuel R S

2017-06-01

Computational simulation is a simple and practical way to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aimed to evaluate and compare cellular effects modelled for different radioisotopes currently in use or under research for treatment of bone metastases using computational methods. Computational models were used to estimate the radiation-induced cellular effects (Virtual Cell Radiobiology algorithm) post-irradiation with selected particles emitted by Strontium-89 ( 89 Sr), Samarium-153 ( 153 Sm), Lutetium-177 ( 177 Lu), and Radium-223 ( 223 Ra). Cellular kinetics post-irradiation using 89 Sr β - particles, 153 Sm β -  particles, 177 Lu β -  particles and 223 Ra α particles showed that the cell response was dose- and radionuclide-dependent. 177 Lu beta minus particles and, in particular, 223 Ra alpha particles, yielded the lowest survival fraction of all investigated particles. 223 Ra alpha particles induced the highest cell death of all investigated particles on metastatic prostate cells in comparison to irradiation with β -  radionuclides, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice. Moreover, the data obtained suggest that the used computational methods might provide some perception about cellular effects following irradiation with different radionuclides.

The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases

PubMed Central

Boucharaba, Ahmed; Serre, Claire-Marie; Guglielmi, Julien; Bordet, Jean-Claude; Clézardin, Philippe; Peyruchaud, Olivier

2006-01-01

Platelet-derived lysophosphatidic acid (LPA) supports the progression of breast and ovarian cancer metastasis to bone. The mechanisms through which LPA promotes bone metastasis formation are, however, unknown. Here we report that silencing of the type 1 LPA receptor (LPA1) in cancer cells blocks the production of tumor-derived cytokines that are potent activators of osteoclast-mediated bone destruction and significantly reduces the progression of osteolytic bone metastases. Moreover, functional blockade of LPA action on its cognate receptor LPA1 using a pharmacological antagonist mimics the effects of silencing LPA1 in tumor cells in vitro and substantially reduces bone metastasis progression in animals. Overall, these results suggest that inhibition of platelet-derived LPA action on LPA1 expressed by tumor cells may be a promising therapeutic target for patients with bone metastases. PMID:16769891

Gastrointestinal Stromal Tumour with Synchronous Bone Metastases: A Case Report and Literature Review.

PubMed

Rochigneux, Philippe; Mescam-Mancini, Lénaig; Perrot, Delphine; Bories, Erwan; Moureau-Zabotto, Laurence; Sarran, Anthony; Guiramand, Jérôme; Bertucci, François

2017-01-01

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours of the digestive tract, derived from Cajal interstitial cells. Bone metastases are very rare, and there is no consensus regarding their treatment. Here, we present the unusual case of a 66-year-old man with a gastric GIST with synchronous bone and liver metastases, fully documented at the pathological and molecular levels with a KIT exon 11 mutation. After 9 months of imatinib, the scanner showed a 33% partial response of target lesions. We also review the literature and describe the characteristics, treatment, and outcome of all cases previously reported.

Gastrointestinal Stromal Tumour with Synchronous Bone Metastases: A Case Report and Literature Review

PubMed Central

Rochigneux, Philippe; Mescam-Mancini, Lénaig; Perrot, Delphine; Bories, Erwan; Moureau-Zabotto, Laurence; Sarran, Anthony; Guiramand, Jérôme; Bertucci, François

2017-01-01

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours of the digestive tract, derived from Cajal interstitial cells. Bone metastases are very rare, and there is no consensus regarding their treatment. Here, we present the unusual case of a 66-year-old man with a gastric GIST with synchronous bone and liver metastases, fully documented at the pathological and molecular levels with a KIT exon 11 mutation. After 9 months of imatinib, the scanner showed a 33% partial response of target lesions. We also review the literature and describe the characteristics, treatment, and outcome of all cases previously reported. PMID:28203166

Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma receiving external beam radiotherapy.

PubMed

He, Jian; Zeng, Zhao-Chong; Tang, Zhao-You; Fan, Jia; Zhou, Jian; Zeng, Meng-Su; Wang, Jian-Hua; Sun, Jing; Chen, Bing; Yang, Ping; Pan, Bai-Sheng

2009-06-15

The current study was performed to identify clinical features and independent predictors of survival in patients with bone metastases from hepatocellular carcinoma (HCC). Patients (n = 205) with bone metastases from HCC received external beam radiotherapy (EBRT) between 1997 and 2007. Demographic variables, laboratory values, tumor characteristics, and treatment modalities were determined before EBRT. The total radiation dose ranged from 32 to 66 grays (Gy) (median, 50 Gy) and was focused on the involved bone. In 80 of 205 (39.0%) patients with bone metastasis from HCC, tumors were characterized by osteolytic, expansile soft-tissue masses. Overall pain relief from EBRT occurred in 204 patients (99.5%). No consistent dose-response relation was found for palliation of bone metastases with doses between 32 and 66 Gy (P = .068), but the retreatment rate was higher in patients with expansile soft tissue. On univariate analysis, shorter survival was associated with poorer Karnofsky performance status (KPS), higher gamma-glutamyltransferase and alpha-fetoprotein levels, tumor size >5 cm, uncontrolled intrahepatic tumors, multifocal bone lesions, involvement of spinal vertebrae, extraosseous metastases, and a shorter disease-free interval after an initial diagnosis of HCC. On multivariate analysis, pretreatment-unfavorable predictors were associated with lower KPS, higher tumor markers, and uncontrolled intrahepatic tumor when KPS was considered. The median survival was 7.4 months. The results of the current study provide detailed information regarding clinical features, survival outcomes, and prognostic factors for HCC with bone metastases in a relatively large cohort of patients treated with EBRT. These prognostic factors will help in determining which dose and fraction are appropriate. (c) 2009 American Cancer Society.

Quality of Life in Relation to Pain Response to Radiation Therapy for Painful Bone Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Westhoff, Paulien G., E-mail: p.g.westhoff@umcutrecht.nl; Graeff, Alexander de; Monninkhof, Evelyn M.

Purpose: To study quality of life (QoL) in responders and nonresponders after radiation therapy for painful bone metastases; and to identify factors predictive for a pain response. Patients and Methods: The prospectively collected data of 956 patients with breast, prostate, and lung cancer within the Dutch Bone Metastasis Study were used. These patients, irradiated for painful bone metastases, rated pain, QoL, and overall health at baseline and weekly afterward for 12 weeks. Using generalized estimating equations analysis, the course of QoL was studied, adjusted for primary tumor. To identify predictive variables, proportional hazard analyses were performed, taking into account death asmore » a competing risk, and C-statistics were calculated for discriminative value. Results: In total, 722 patients (76%) responded to radiation therapy. During follow-up, responders had a better QoL in all domains compared with nonresponders. Patients with breast or prostate cancer had a better QoL than patients with lung cancer. In multivariate analysis, baseline predictors for a pain response were breast or prostate cancer as primary tumor, younger age, good performance status, absence of visceral metastases, and using opioids. The discriminative ability of the model was low (C-statistic: 0.56). Conclusions: Responding patients show a better QoL after radiation therapy for painful bone metastases than nonresponders. Our model did not have enough discriminative power to predict which patients are likely to respond to radiation therapy. Therefore, radiation therapy should be offered to all patients with painful bone metastases, aiming to decrease pain and improve QoL.« less

An Easy Tool to Predict Survival in Patients Receiving Radiation Therapy for Painful Bone Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Westhoff, Paulien G., E-mail: p.g.westhoff@umcutrecht.nl; Graeff, Alexander de; Monninkhof, Evelyn M.

2014-11-15

Purpose: Patients with bone metastases have a widely varying survival. A reliable estimation of survival is needed for appropriate treatment strategies. Our goal was to assess the value of simple prognostic factors, namely, patient and tumor characteristics, Karnofsky performance status (KPS), and patient-reported scores of pain and quality of life, to predict survival in patients with painful bone metastases. Methods and Materials: In the Dutch Bone Metastasis Study, 1157 patients were treated with radiation therapy for painful bone metastases. At randomization, physicians determined the KPS; patients rated general health on a visual analogue scale (VAS-gh), valuation of life on amore » verbal rating scale (VRS-vl) and pain intensity. To assess the predictive value of the variables, we used multivariate Cox proportional hazard analyses and C-statistics for discriminative value. Of the final model, calibration was assessed. External validation was performed on a dataset of 934 patients who were treated with radiation therapy for vertebral metastases. Results: Patients had mainly breast (39%), prostate (23%), or lung cancer (25%). After a maximum of 142 weeks' follow-up, 74% of patients had died. The best predictive model included sex, primary tumor, visceral metastases, KPS, VAS-gh, and VRS-vl (C-statistic = 0.72, 95% CI = 0.70-0.74). A reduced model, with only KPS and primary tumor, showed comparable discriminative capacity (C-statistic = 0.71, 95% CI = 0.69-0.72). External validation showed a C-statistic of 0.72 (95% CI = 0.70-0.73). Calibration of the derivation and the validation dataset showed underestimation of survival. Conclusion: In predicting survival in patients with painful bone metastases, KPS combined with primary tumor was comparable to a more complex model. Considering the amount of variables in complex models and the additional burden on patients, the simple model is preferred for daily use. In addition, a risk table for survival is

Stromal Gene Expression and Function in Primary Breast Tumors that Metastasize to Bone Cancer

DTIC Science & Technology

2004-07-01

by quantitative RT-QPCR. Further analysis of epithelium from matched spine metastases revealed some genes that were up-regulated further at the...9-fold in matched bone metastases. The expression in spine metastases was verified by in situ hybridisation whilst the expression of stefin Al in...growth in the mammary gland of Balb/c mice. Fresh resected tissue (normal fat pad, primary tumor tissue or the metastatic sites spine , femur and lung) was

‘Who’, ‘when’ and ‘how’ in re-irradiation of recurrent painful bone metastases

PubMed Central

Mok, Florence; Li, Kenneth; Yeung, Rebecca; Wong, Kam-Hung; Yu, Brian; Wong, Erin; Bedard, Gillian; Chow, Edward

2013-01-01

Re-irradiation of painful bony metastases is increasingly performed since patients are receiving better systemic treatments and having longer life expectancy, and may also be due to the increase use of initial single fraction radiotherapy. However, randomized control trial on the efficacy of re-irradiation is lacking. A recent meta-analysis concluded with a 58% response rate for pain relief by re-irradiation of symptomatic bone metastases. In this review, the effectiveness of re-irradiation in terms of clinical and economical aspects, and clinical questions on who, when, and how to re-irradiate would be discussed. A brief review of other treatment options and comparison with re-irradiation of bone metastases would be performed. PMID:26909270

Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases

PubMed Central

Hardaway, Aimalie L.; Herroon, Mackenzie K.; Rajagurubandara, Erandi

2014-01-01

Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease. PMID:24398857

Use of corticosteroids for pain control in cancer patients with bone metastases: a comprehensive literature review.

PubMed

Lim, Fiona M Y; Bobrowski, Adam; Agarwal, Arnav; Silva, Mauricio F

2017-06-01

Despite a limited understanding of the exact mechanism, corticosteroids are commonly employed for pain control in patients with bone metastases. The aim of this review was to evaluate the efficacy of corticosteroid-mediated pain control in patients with bone metastases associated with solid cancers. A literature search was conducted using OVID MEDLINE and Embase databases (from 1946 up to July 19, 2016). Studies involving patients with bone metastases receiving corticosteroids as the primary means of pain control were included. Screening and data extraction were conducted by paired reviewers, with consensus established by discussion, or a third adjudicator. A total of 12 studies were included. Rates of pain relief achieved with corticosteroid use varied from 30 to 70%, but generally reflected moderate pain control. Corticosteroid use significantly reduced the incidence of pain flare alongside radiotherapy, reportedly by almost half of baseline pain severity. Adverse events were not documented consistently across studies, though grade two to three hyperglycemia was noted in approximately 2% of patients by some studies. Recent evidence suggests that short-term corticosteroid use may provide moderate pain and pain flare control with radiotherapy for patients with bone metastases. The risk of developing adverse effects should be carefully considered prior to therapy initiation on a case-by-case basis.

Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca; Hoskin, Peter; Mitera, Gunita

2012-04-01

Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadianmore » Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis.« less

Feasibility of volumetric MRI-guided high intensity focused ultrasound (MR-HIFU) for painful bone metastases.

PubMed

Huisman, Merel; Lam, Mie K; Bartels, Lambertus W; Nijenhuis, Robbert J; Moonen, Chrit T; Knuttel, Floor M; Verkooijen, Helena M; van Vulpen, Marco; van den Bosch, Maurice A

2014-01-01

Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) has recently emerged as an effective treatment option for painful bone metastases. We describe here the first experience with volumetric MR-HIFU for palliative treatment of painful bone metastases and evaluate the technique on three levels: technical feasibility, safety, and initial effectiveness. In this observational cohort study, 11 consecutive patients (7 male and 4 female; median age, 60 years; age range, 53-86 years) underwent 13 treatments for 12 bone metastases. All patients exhibited persistent metastatic bone pain refractory to the standard of care. Patients were asked to rate their worst pain on an 11-point pain scale before treatment, 3 days after treatment, and 1 month after treatment. Complications were monitored. All data were prospectively recorded in the context of routine clinical care. Response was defined as a ≥2-point decrease in pain at the treated site without increase in analgesic intake. Baseline pain scores were compared to pain scores at 3 days and 1 month using the Wilcoxon signed-rank test. For reporting, the STROBE guidelines were followed. No treatment-related major adverse events were observed. At 3 days after volumetric MR-HIFU ablation, pain scores decreased significantly (p = 0.045) and response was observed in a 6/11 (55%) patients. At 1-month follow-up, which was available for nine patients, pain scores decreased significantly compared to baseline (p = 0.028) and 6/9 patients obtained pain response (overall response rate 67% (95% confidence interval (CI) 35%-88%)). This is the first study reporting on the volumetric MR-HIFU ablation for painful bone metastases. No major treatment-related adverse events were observed during follow-up. The results of our study showed that volumetric MR-HIFU ablation for painful bone metastases is technically feasible and can induce pain relief in patients with metastatic bone pain refractory to the standard of

Effectiveness of Reirradiation for Painful Bone Metastases: A Systematic Review and Meta-Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huisman, Merel, E-mail: m.huisman-7@umcutrecht.nl; Bosch, Maurice A.A.J. van den; Wijlemans, Joost W.

2012-09-01

Purpose: Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases. Methods and Materials: A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated formore » overall pain response for reirradiation of metastatic bone pain. Results: Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49-0.67). There was a substantial between-study heterogeneity (I{sup 2} = 63.3%, p = 0.01) because of clinical and methodological differences between studies. Conclusions: Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date.« less

Cancer Pain Management and Bone Metastases: An Update for the Clinician

PubMed Central

Schneider, Guido; Voltz, Raymond; Gaertner, Jan

2012-01-01

Breast cancer patients with bone metastases often suffer from cancer pain. In general, cancer pain treatment is far from being optimal for many patients. To date, morphine remains the gold standard as first-line therapy, but other pure μ agonists such as hydromorphone, fentanyl, or oxycodone can be considered. Transdermal opioids are an important option if the oral route is impossible. Due to its complex pharmacology, methadone should be restricted to patients with difficult pain syndromes. The availability of a fixed combination of oxycodone and naloxone is a promising development for the reduction of opioid induced constipation. Especially bone metastases often result in breakthrough pain episodes. Thus, the provision of an on-demand opioid (e.g., immediate-release morphine or rapid-onset fentanyl) in addition to the baseline (regular) opioid therapy (e.g., sustained-release morphine tablets) is mandatory. Recently, rapid onset fentanyls (buccal or nasal) have been strongly recommended for breakthrough cancer pain due to their fast onset and their shorter duration of action. If available, metamizole is an alternative non-steroid-anti-inflammatory-drug. The indication for bisphosphonates should always be checked early in the disease. In advanced cancer stages, glucocorticoids are an important treatment option. If bone metastases lead to neuropathic pain, coanalgetics (e.g., pregabalin) should be initiated. In localized bone pain, radiotherapy is the gold standard for pain reduction in addition to pharmacologic pain management. In diffuse bone pain radionuclids (such as samarium) can be beneficial. Invasive measures (e.g., neuroaxial blockage) are rarely necessary but are an important option if patients with cancer pain syndromes are refractory to pharmacologic management and radiotherapy as described above. Clinical guidelines agree that cancer pain management in incurable cancer is best provided as part of a multiprofessional palliative care approach and all

Diagnostic performance of 18F-FDG PET/CT and whole-body diffusion-weighted imaging with background body suppression (DWIBS) in detection of lymph node and bone metastases from pediatric neuroblastoma.

PubMed

Ishiguchi, Hiroaki; Ito, Shinji; Kato, Katsuhiko; Sakurai, Yusuke; Kawai, Hisashi; Fujita, Naotoshi; Abe, Shinji; Narita, Atsushi; Nishio, Nobuhiro; Muramatsu, Hideki; Takahashi, Yoshiyuki; Naganawa, Shinji

2018-06-01

Recent many studies have shown that whole body "diffusion-weighted imaging with background body signal suppression" (DWIBS) seems a beneficial tool having higher tumor detection sensitivity without ionizing radiation exposure for pediatric tumors. In this study, we evaluated the diagnostic performance of whole body DWIBS and 18 F-FDG PET/CT for detecting lymph node and bone metastases in pediatric patients with neuroblastoma. Subjects in this retrospective study comprised 13 consecutive pediatric patients with neuroblastoma (7 males, 6 females; mean age, 2.9 ± 2.0 years old) who underwent both 18 F-FDG PET/CT and whole-body DWIBS. All patients were diagnosed as neuroblastoma on the basis of pathological findings. Eight regions of lymph nodes and 17 segments of skeletons in all patients were evaluated. The images of 123 I-MIBG scintigraphy/SPECT-CT, bone scintigraphy/SPECT, and CT were used to confirm the presence of lymph node and bone metastases. Two radiologists trained in nuclear medicine evaluated independently the uptake of lesions in 18 F-FDG PET/CT and the signal-intensity of lesions in whole-body DWIBS visually. Interobserver difference was overcome through discussion to reach a consensus. The sensitivities, specificities, and overall accuracies of 18 F-FDG PET/CT and whole-body DWIBS were compared using McNemer's test. Positive predictive values (PPVs) and negative predictive values (NPVs) of both modalities were compared using Fisher's exact test. The total numbers of lymph node regions and bone segments which were confirmed to have metastasis in the total 13 patients were 19 and 75, respectively. The sensitivity, specificity, overall accuracy, PPV, and NPV of 18 F-FDG PET/CT for detecting lymph node metastasis from pediatric neuroblastoma were 100, 98.7, 98.9, 95.0, and 100%, respectively, and those for detecting bone metastasis were 90.7, 73.1, 80.3, 70.1, and 91.9%, respectively. In contrast, the sensitivity, specificity, overall accuracy, PPV

Tumor Response After Stereotactic Body Radiation Therapy to Nonspine Bone Metastases: An Evaluation of Response Criteria

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDonald, Rachel; Probyn, Linda; Poon, Ian

Purpose: To evaluate the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and University of Texas MD Anderson (MDA) Cancer Center criteria in the setting of stereotactic body radiation therapy (SBRT) to nonspine bone metastases. Methods: Patients who were treated with SBRT to nonspine bone metastases were identified by retrospective chart review. An independent musculoskeletal radiologist evaluated response to treatment using computed tomography (CT) scans. Results: Thirty-three patients were treated to 42 nonspine bone metastases. The most common primary cancer cites were renal cell carcinoma (RCC) (33.3%), lung (24.2%), and prostate (18.2%). Bone metastases were either mainlymore » lytic (57.1%), mainly sclerotic (28.6%), or mixed (14.3%). When lytic and sclerotic lesions were evaluated according to RECIST 1.1, local control (LC) was 83%, 85%, 88%, and 80% for those with CT imaging between months 1 to 3, 4 to 6, 7 to 9, and 10 to 12, respectively. When evaluated by the MDA criteria by density, LC within each time period was slightly greater. Overall LC decreased considerably when evaluated by MDA in terms of size. Conclusions: Consensus definitions of response are required as they have implications on clinical trials and disease management. Without consistent response criteria, outcomes from clinical trials cannot be compared and treatment efficacy remains undetermined.« less

Gastric cancer bone metastases together with osteopoikilosis diagnosed using bone scintigraphy and 18F-FDG PET/CT.

PubMed

Prado Wohlwend, S; Sánchez Vaño, R; Sopena Novales, P; Uruburu García, E; Aparisi Rodríguez, F; Martínez Carsí, C

The coexistence of different bone diseases in the same patient involves a complex differential diagnosis. A patient is presented who was studied due to a renal mass that showed many sclerotic lesions in spine and limbs in conventional radiology and CT. These lesions were evaluated with 99m TC-HDP bone scintigraphy and 18 F-FDG PET/CT, which helped to obtain the definitive pathological diagnosis of osteopoikilosis (OP) co-existing with gastric cancer bone metastases. Of the different imaging scans performed, bone scintigraphy was particularly relevant due to its ability to discriminate between benign and metastatic bone disease. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

Cost of skeletal complications from bone metastases in six European countries.

PubMed

Pereira, J; Body, J-J; Gunther, O; Sleeboom, H; Hechmati, G; Maniadakis, N; Terpos, E; Acklin, Y P; Finek, J; von Moos, R

2016-06-01

Objective Patients with bone metastases or lesions secondary to solid tumors or multiple myeloma often experience bone complications (skeletal-related events [SREs]-radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression); however, recent data that can be used to assess the value of treatments to prevent SREs across European countries are limited. This study aimed to provide estimates of health resource utilization (HRU) and cost associated with all SRE types in Europe. HRU data were reported previously; cost data are reported herein. Methods Eligible patients from 49 centers across Austria (n = 57), the Czech Republic (n = 59), Finland (n = 60), Greece (n = 59), Portugal (n = 59), and Sweden (n = 62) had bone metastases or lesions secondary to breast, lung, or prostate cancer, or multiple myeloma, and ≥1 index SRE (a SRE preceded by a SRE-free period of ≥ 6.5 months). SRE-related costs were estimated from a payer perspective using health resource utilization data from patient charts (before and after the index SRE diagnosis). Country-specific unit costs were from 2010 and local currencies were converted to 2010 euros. Results The mean costs across countries were €7043, €5242, €11,101, and €11,509 per radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression event, respectively. Purchasing power parity (PPP)-adjusted mean cost ratios were similar in most countries, with the exception of radiation to bone. Limitations The overall burden of SREs may have been under-estimated owing to home visits and evaluations outside the hospital setting not being reported here. Conclusions All SREs were associated with substantial costs. Variation in SRE-associated costs between countries was most likely driven by differences in treatment practices and unit costs.

An evaluation of bone scans as screening procedures for occult metastases in primary breast cancer.

PubMed Central

Baker, R R; Holmes, E R; Alderson, P O; Khouri, N F; Wagner, H N

1977-01-01

Preoperative bone scans were obtained in 104 patients with operable breast cancer. Areas of increased radioactivity detected by the bone scan were correlated with appropriate radiographs. One of 64 patients (1.5%) with clinical Stage I and Stage II breast cancer had a metastatic lesion detected by the preoperative bone scan. In contrast, 10 of 41 patients (24%) with Stage III breast cancer had occult metastatic lesions detected by the preoperative bone scan. The majority of patients with abnormal bone scans and no radiographic evidence of a benign lesion to explain the cause of the increased radioactivity proved to have metastatic breast cancer on follow-examination. Even though 20% of patients with operable breast cancer will eventually develop bone metastases, our results indicate that preoperative bone scans are not an effective means of predicting which patients with Stage I and Stage II disease will develop metastatic breast cancer. Because of the considerably increased frequency of detection of occult metastases in patients with Stage III breast cancer, bone scans should be obtained routinely in the preoperative assessment of these patients. Images Figs. 1a and b. Figs. 2a and b. Figs. 3a-d. PMID:889378

Integrated approach to pain management for a patient with multiple bone metastases of uterine cervical cancer.

PubMed

Qin, De-An; Song, Jie-Fu; Song, Li-Ping; Feng, Gui-Sheng

2018-05-01

Background Pain management for multiple bone metastases is complex and often requires multidisciplinary treatment. We herein describe patient-centered multidisciplinary pain management for metastatic cancer. A 61-year-old woman with multiple bone metastases of uterine cervical cancer developed intractable low back pain. After external beam radiotherapy failed, we performed lumbar spinal intralesional curettage, pedicle screw fixation, and nerve decompression. However, the neuralgia persisted. We then percutaneously injected epirubicin into the intervertebral foramina under computed tomography guidance for L5 dorsal root ganglion destruction. Osteoplasty was performed under C-arm X-ray guidance; however, the sacrum was mistaken for the ilium, and treatment was ineffective. We administered zoledronic acid and strontium-89. The last resort was outpatient implantation of an epidural bupivacaine-morphine infusion system. A visual analog scale (VAS) was used for pain evaluation. Lumbar spinal intralesional curettage and fixation, epirubicin-induced ganglion destruction, and administration of zoledronic acid and strontium-89 decreased her VAS pain score from 7-8 to 3-4. Radiotherapy and nerve decompression and release were ineffective, as was osteoplasty because of the location error. The epidural infusion system decreased the VAS score from 7-8 to 2-3 and was highly efficient. Conclusions Multidisciplinary integrated treatment for metastatic cancer can be effective.

Validation of International Classification of Diseases coding for bone metastases in electronic health records using technology-enabled abstraction.

PubMed

Liede, Alexander; Hernandez, Rohini K; Roth, Maayan; Calkins, Geoffrey; Larrabee, Katherine; Nicacio, Leo

2015-01-01

The accuracy of bone metastases diagnostic coding based on International Classification of Diseases, ninth revision (ICD-9) is unknown for most large databases used for epidemiologic research in the US. Electronic health records (EHR) are the preferred source of data, but often clinically relevant data occur only as unstructured free text. We examined the validity of bone metastases ICD-9 coding in structured EHR and administrative claims relative to the complete (structured and unstructured) patient chart obtained through technology-enabled chart abstraction. Female patients with breast cancer with ≥1 visit after November 2010 were identified from three community oncology practices in the US. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of bone metastases ICD-9 code 198.5. The technology-enabled abstraction displays portions of the chart to clinically trained abstractors for targeted review, thereby maximizing efficiency. We evaluated effects of misclassification of patients developing skeletal complications or treated with bone-targeting agents (BTAs), and timing of BTA. Among 8,796 patients with breast cancer, 524 had confirmed bone metastases using chart abstraction. Sensitivity was 0.67 (95% confidence interval [CI] =0.63-0.71) based on structured EHR, and specificity was high at 0.98 (95% CI =0.98-0.99) with corresponding PPV of 0.71 (95% CI =0.67-0.75) and NPV of 0.98 (95% CI =0.98-0.98). From claims, sensitivity was 0.78 (95% CI =0.74-0.81), and specificity was 0.98 (95% CI =0.98-0.98) with PPV of 0.72 (95% CI =0.68-0.76) and NPV of 0.99 (95% CI =0.98-0.99). Structured data and claims missed 17% of bone metastases (89 of 524). False negatives were associated with measurable overestimation of the proportion treated with BTA or with a skeletal complication. Median date of diagnosis was delayed in structured data (32 days) and claims (43 days) compared with technology-assisted EHR. Technology

A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer

PubMed Central

Hutton, Brian; Addison, Christina L.; Campbell, Kaitryn; Fergusson, Dean; Mazarello, Sasha; Clemons, Mark

2013-01-01

Background Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3–4 weeks. Less frequent (‘de-escalated’) treatment may provide similar benefits with improved safety and reduced cost. Methods To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.e. every 12–16 weeks) to standard treatment (i.e. every 3–4 weeks), a formal systematic review of the literature was performed. Two individuals independently screened citations and full text articles. Random effects meta-analyses of clinically important outcomes were planned provided homogeneous studies were identified. Results Five relevant studies (n=1287 patients) were identified. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targeted agents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de-escalated treatment may provide similar benefits compared to 3–4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective. Conclusions Studies comparing standard and de-escalated treatment with bone-targeted agents in breast cancer are rare. The benefits of standard treatment compared to de-escalated therapy on important clinical outcomes remain unclear. Future pragmatic studies must be conducted to determine the merits of this approach. PMID:26909282

The SK-N-AS human neuroblastoma cell line develops osteolytic bone metastases with increased angiogenesis and COX-2 expression

PubMed Central

Tsutsumimoto, Takahiro; Williams, Paul; Yoneda, Toshiyuki

2014-01-01

Neuroblastoma (NB), which arises from embryonic neural crest cells, is the most common extra-cranial solid tumor of childhood. Approximately half of NB patients manifest bone metastasis accompanied with bone pain, fractures and bone marrow failure, leading to disturbed quality of life and poor survival. To study the mechanism of bone metastasis of NB, we established an animal model in which intracardiac inoculation of the SK-N-AS human NB cells in nude mice developed osteolytic bone metastases with increased osteoclastogenesis. SK-N-AS cells induced the expression of receptor activator of NF-κB ligand and osteoclastogenesis in mouse bone marrow cells in the co-culture. SK-N-AS cells expressed COX-2 mRNA and produced substantial amounts of prostaglandin E2 (PGE2). In contrast, the SK-N-DZ and SK-N-FI human NB cells failed to develop bone metastases, induce osteoclastogenesis, express COX-2 mRNA and produce PGE2. Immunohistochemical examination of SK-N-AS bone metastasis and subcutaneous tumor showed strong expression of COX-2. The selective COX-2 inhibitor NS-398 inhibited PGE2 production and suppressed bone metastases with reduced osteoclastogenesis. NS-398 also inhibited subcutaneous SK-N-AS tumor development with decreased angiogenesis and vascular endothelial growth factor-A expression. Of interest, metastasis to the adrenal gland, a preferential site for NB development, was also diminished by NS-398. Our results suggest that COX2/PGE2 axis plays a critical role in the pathophysiology of osteolytic bone metastases and tumor development of the SK-NS-AS human NB. Inhibition of angiogenesis by suppressing COX-2/PGE2 may be an effective therapeutic approach for children with NB. PMID:26909300

Temporal Subtraction of Serial CT Images with Large Deformation Diffeomorphic Metric Mapping in the Identification of Bone Metastases.

PubMed

Sakamoto, Ryo; Yakami, Masahiro; Fujimoto, Koji; Nakagomi, Keita; Kubo, Takeshi; Emoto, Yutaka; Akasaka, Thai; Aoyama, Gakuto; Yamamoto, Hiroyuki; Miller, Michael I; Mori, Susumu; Togashi, Kaori

2017-11-01

Purpose To determine the improvement of radiologist efficiency and performance in the detection of bone metastases at serial follow-up computed tomography (CT) by using a temporal subtraction (TS) technique based on an advanced nonrigid image registration algorithm. Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. CT image pairs (previous and current scans of the torso) in 60 patients with cancer (primary lesion location: prostate, n = 14; breast, n = 16; lung, n = 20; liver, n = 10) were included. These consisted of 30 positive cases with a total of 65 bone metastases depicted only on current images and confirmed by two radiologists who had access to additional imaging examinations and clinical courses and 30 matched negative control cases (no bone metastases). Previous CT images were semiautomatically registered to current CT images by the algorithm, and TS images were created. Seven radiologists independently interpreted CT image pairs to identify newly developed bone metastases without and with TS images with an interval of at least 30 days. Jackknife free-response receiver operating characteristics (JAFROC) analysis was conducted to assess observer performance. Reading time was recorded, and usefulness was evaluated with subjective scores of 1-5, with 5 being extremely useful and 1 being useless. Significance of these values was tested with the Wilcoxon signed-rank test. Results The subtraction images depicted various types of bone metastases (osteolytic, n = 28; osteoblastic, n = 26; mixed osteolytic and blastic, n = 11) as temporal changes. The average reading time was significantly reduced (384.3 vs 286.8 seconds; Wilcoxon signed rank test, P = .028). The average figure-of-merit value increased from 0.758 to 0.835; however, this difference was not significant (JAFROC analysis, P = .092). The subjective usefulness survey response showed a median score of 5 for use of the technique

Patterns of Care Among Patients Receiving Radiation Therapy for Bone Metastases at a Large Academic Institution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellsworth, Susannah G.; Alcorn, Sara R., E-mail: salcorn2@jhmi.edu; Hales, Russell K.

Purpose: This study evaluates outcomes and patterns of care among patients receiving radiation therapy (RT) for bone metastases at a high-volume academic institution. Methods and Materials: Records of all patients whose final RT course was for bone metastases from April 2007 to July 2012 were identified from electronic medical records. Chart review yielded demographic and clinical data. Rates of complicated versus uncomplicated bone metastases were not analyzed. Results: We identified 339 patients whose final RT course was for bone metastases. Of these, 52.2% were male; median age was 65 years old. The most common primary was non-small-cell lung cancer (29%). Most patientsmore » (83%) were prescribed ≤10 fractions; 8% received single-fraction RT. Most patients (52%) had a documented goals of care (GOC) discussion with their radiation oncologist; hospice referral rates were higher when patients had such discussions (66% with vs 50% without GOC discussion, P=.004). Median life expectancy after RT was 96 days. Median survival after RT was shorter based on inpatient as opposed to outpatient status at the time of consultation (35 vs 136 days, respectively, P<.001). Hospice referrals occurred for 56% of patients, with a median interval between completion of RT and hospice referral of 29 days and a median hospice stay of 22 days. Conclusions: These data document excellent adherence to American Society for Radiation Oncolology Choosing Wisely recommendation to avoid routinely using >10 fractions of palliative RT for bone metastasis. Nonetheless, single-fraction RT remains relatively uncommon. Participating in GOC discussions with a radiation oncologist is associated with higher rates of hospice referral. Inpatient status at consultation is associated with short survival.« less

TU-A-12A-08: Computing Longitudinal Material Changes in Bone Metastases Using Dual Energy Computed Tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schmidtlein, CR; Hwang, S; Veeraraghavan, H

Purpose: This study demonstrates a methodology for tracking changes in metastatic bone disease using trajectories in material basis space in serial dual energy computed tomography (DECT) studies. Methods: This study includes patients with bone metastases from breast cancer that had clinical surveillance CT scans using a General Electric CT750HD in dual energy mode. A radiologist defined regions-of-interested (ROI) for bone metastasis, normal bone, and marrow across the serial DECT scans. Our approach employs a Radon transform to forward-projection the basis images, namely, water and iodine, into sinogram space. This data is then repartitioned into fat/bone and effective density/Z image pairsmore » using assumed energy spectrums for the x-ray energies. This approach both helps remove negative material densities and avoids adding spectrum-hardening artifacts. These new basis data sets were then reconstructed via filtered back-projection to create new material basis pair images. The trajectories of these pairs were then plotted in the new basis space providing a means to both visualize and quantitatively measure changes in the material properties of the tumors. Results: ROI containing radiologist defined metastatic bone disease showed well-defined trajectories in both fat/bone and effective density/Z space. ROI that contained radiologist defined normal bone and marrow did not exhibit any discernible trajectories and were stable from scan to scan. Conclusions: The preliminary results show that changes in material composition and effective density/Z image pairs were seen primarily in metastasis and not in normal tissue. This study indicates that by using routine clinical DECT it may be possible to monitor therapy response of bone metastases because healing or worsening bone metastases change material composition of bone. Additional studies are needed to further validate these results and to test for their correlation with outcome.« less

Repeatability of quantitative parameters of 18F-fluoride PET/CT and biochemical tumour and specific bone remodelling markers in prostate cancer bone metastases.

PubMed

Wassberg, Cecilia; Lubberink, Mark; Sörensen, Jens; Johansson, Silvia

2017-12-01

18F-fluoride PET/CT exhibits high sensitivity to delineate and measure the extent of bone metastatic disease in patients with prostate cancer. 18F-fluoride PET/CT could potentially replace traditional bone scintigraphy in clinical routine and trials. However, more studies are needed to assess repeatability and biological uptake variation. The aim of this study was to perform test-retest analysis of quantitative PET-derived parameters and blood/serum bone turnover markers at the same time point. Ten patients with prostate cancer and verified bone metastases were prospectively included. All underwent two serial 18F-fluoride PET/CT at 1 h post-injection. Up to five dominant index lesions and whole-body 18F-fluoride skeletal tumour burden were recorded per patient. Lesion-based PET parameters were SUVmax, SUVmean and functional tumour volume applying a VOI with 50% threshold (FTV 50% ). The total skeletal tumour burden, total lesion 18F-fluoride (TLF), was calculated using a threshold of SUV of ≥15. Blood/serum biochemical bone turnover markers obtained at the time of each PET were PSA, ALP, S-osteocalcin, S-beta-CTx, 1CTP and BAP. A total of 47 index lesions and a range of 2-122 bone metastases per patient were evaluated. Median time between 18F-fluoride PET/CT was 7 days (range 6-8 days). Repeatability coefficients were for SUVmax 26%, SUVmean 24%, FTV 50% for index lesions 23% and total skeletal tumour burden (TLF) 35%. Biochemical bone marker repeatability coefficients were for PSA 19%, ALP 23%, S-osteocalcin 18%, S-beta-CTx 22%, 1CTP 18% and BAP 23%. Quantitative 18F-fluoride uptake and simultaneous biochemical bone markers measurements are reproducible for prostate cancer metastases and show similar magnitude in test-retest variation.

Novel Radiolabeled Bisphosphonates for PET Diagnosis and Endoradiotherapy of Bone Metastases.

PubMed

Pfannkuchen, Nina; Meckel, Marian; Bergmann, Ralf; Bachmann, Michael; Bal, Chandrasekhar; Sathekge, Mike; Mohnike, Wolfgang; Baum, Richard P; Rösch, Frank

2017-05-18

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99m Tc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68 Ge/ 68 Ga generator, an analog to the established 99m Tc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the β-emitter 177 Lu. This overview describes the possibility of diagnosing bone metastases using [ 68 Ga]Ga-BPAMD ( 68 Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [ 177 Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68 Ga- and 177 Lu-labeled bisphosphonates offering improved pharmacological properties.

Comparison of [68Ga]Ga-PSMA-11 PET/CT with [18F]NaF PET/CT in the evaluation of bone metastases in metastatic prostate cancer patients prior to radionuclide therapy.

PubMed

Uprimny, Christian; Svirydenka, Anna; Fritz, Josef; Kroiss, Alexander Stephan; Nilica, Bernhard; Decristoforo, Clemens; Haubner, Roland; von Guggenberg, Elisabeth; Buxbaum, Sabine; Horninger, Wolfgang; Virgolini, Irene Johanna

2018-05-16

The purpose of this study was to investigate the diagnostic performance of 68 Ga-PSMA-11 PET/CT in the evaluation of bone metastases in metastatic prostate cancer (PC) patients scheduled for radionuclide therapy in comparison to [ 18 F]sodium fluoride ( 18 F-NaF) PET/CT. Sixteen metastatic PC patients with known skeletal metastases, who underwent both 68 Ga-PSMA-11 PET/CT and 18 F-NaF PET/CT for assessment of metastatic burden prior to radionuclide therapy, were analysed retrospectively. The performance of both tracers was calculated on a lesion-based comparison. Intensity of tracer accumulation of pathologic bone lesions on 18 F-NaF PET and 68 Ga-PSMA-11 PET was measured with maximum standardized uptake values (SUV max ) and compared to background activity of normal bone. In addition, SUV max values of PET-positive bone lesions were analysed with respect to morphologic characteristics on CT. Bone metastases were either confirmed by CT or follow-up PET scan. In contrast to 468 PET-positive lesions suggestive of bone metastases on 18 F-NaF PET, only 351 of the lesions were also judged positive on 68 Ga-PSMA-11 PET (75.0%). Intensity of tracer accumulation of pathologic skeletal lesions was significantly higher on 18 F-NaF PET compared to 68 Ga-PSMA-11 PET, showing a median SUV max of 27.0 and 6.0, respectively (p < 0.001). Background activity of normal bone was lower on 68 Ga-PSMA-11 PET, with a median SUV max of 1.0 in comparison to 2.7 on 18 F-NaF PET; however, tumour to background ratio was significantly higher on 18 F-NaF PET (9.8 versus 5.9 on 68 Ga-PSMA-11 PET; p = 0.042). Based on morphologic lesion characterisation on CT, 18 F-NaF PET revealed median SUV max values of 23.6 for osteosclerotic, 35.0 for osteolytic, and 19.0 for lesions not visible on CT, whereas on 68 Ga-PSMA-11 PET median SUV max values of 5.0 in osteosclerotic, 29.5 in osteolytic, and 7.5 in lesions not seen on CT were measured. Intensity of tracer accumulation between 18 F-NaF PET

68Ga-PSMA PET/CT in the evaluation of bone metastases in prostate cancer.

PubMed

Sachpekidis, Christos; Bäumer, P; Kopka, K; Hadaschik, B A; Hohenfellner, M; Kopp-Schneider, A; Haberkorn, U; Dimitrakopoulou-Strauss, A

2018-06-01

The aims of this retrospective analysis were to compare 68 Ga-PSMA PET findings and low-dose CT findings (120 kV, 30 mA), and to obtain semiquantitative and quantitative 68 Ga-PSMA PET data in patients with prostate cancer (PC) bone metastases. In total, 152 PET/CT scans from 140 patients were evaluated. Of these patients, 30 had previously untreated primary PC, and 110 had biochemical relapse after treatment of primary PC. All patients underwent dynamic PET/CT scanning of the pelvis and lower abdomen as well as whole-body PET/CT with 68 Ga-PSMA-11. The PET/CT scans were analysed qualitatively (visually), semiquantitatively (SUV), and quantitatively based on a two-tissue compartment model and a noncompartmental approach leading to the extraction of the fractal dimension. Differences were considered significant for p values <0.05. In total, 168 68 Ga-PSMA-positive and 113 CT-positive skeletal lesions were detected in 37 patients (8 with primary PC, 29 with biochemical recurrence). Of these 168 lesions, 103 were both 68 Ga-PSMA PET-positive and CT-positive, 65 were only 68 Ga-PSMA-positive, and 10 were only CT-positive. The Yang test showed that there were significantly more 68 Ga-PSMA PET-positive lesions than CT-positive lesions. Association analysis showed that PSA plasma levels were significantly correlated with several 68 Ga-PSMA-11-associated parameters in bone metastases, including the degree of tracer uptake (SUV average and SUV max ), its transport rate from plasma to the interstitial/intracellular compartment (K 1 ), its rate of binding to the PSMA receptor and its internalization (k 3 ), its influx rate (K i ), and its distribution heterogeneity. 68 Ga-PSMA PET/CT is a useful diagnostic tool in the detection of bone metastases in PC. 68 Ga-PSMA PET visualizes more bone metastases than low-dose CT. PSA plasma levels are significantly correlated with several 68 Ga-PSMA PET parameters.

TU-G-204-02: Automatic Sclerotic Bone Metastases Detection in the Pelvic Region From Dual Energy CT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fehr, D; Schmidtlein, C; Hwang, S

Purpose: To automatically detect sclerotic bone metastases in the pelvic region using dual energy computed tomography (DECT). Methods: We developed a two stage algorithm to automatically detect sclerotic bone metastases in the pelvis from DECT for patients with multiple bone metastatic lesions and with hip implants. The first stage consists of extracting the bone and marrow regions by using a support vector machine (SVM) classifier. We employed a novel representation of the DECT images using multi-material decomposition, which represents each voxel as a mixture of different physical materials (e.g. bone+water+fat). Following the extraction of bone and marrow, in the secondmore » stage, a bi -histogram equalization method was employed to enhance the contrast to reveal the bone metastases. Next, meanshift segmentation was performed to separate the voxels by their intensity levels. Finally, shape-based filtering was performed to extract the possible locations of the metastatic lesions using multiple shape criteria. We used the following shape parameters: area, eccentricity, major and minor axis, perimeter and skeleton. Results: A radiologist with several years of experience with DECT manually labeled 64 regions consisting of metastatic lesions from 10 different patients. However, the patients had many more metastasic lesions throughout the pelvis. Our method correctly identified 46 of the marked 64 regions (72%). In addition, our method also identified several other lesions, which can then be validated by the radiologist. The missed lesions were typically very large elongated regions consisting of several islands of very small (<4mm) lesions. Conclusion: We developed an algorithm to automatically detect sclerotic lesions in the pelvic region from DECT. Preliminary assessment shows that our algorithm generated lesions agreeing with the radiologist generated candidate regions. Furthermore, our method reveals additional lesions that can be inspected by the radiologist

Patterns of Practice in Palliative Radiotherapy for Painful Bone Metastases: Impact of a Regional Rapid Access Clinic on Access to Care

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Jackson S.Y., E-mail: jackson.wu@cancerboard.ab.c; Kerba, Marc; Wong, Rebecca K.S.

2010-10-01

Purpose: External beam radiotherapy (RT) is commonly indicated for the palliation of symptomatic bone metastases, but there is evidence of underutilization of this treatment modality in palliative care for cancer populations. This study was conducted to investigate factors that influenced the use of palliative RT services at a regional comprehensive cancer center. Methods and Materials: A cohort of patients with radiographically confirmed bone metastases and first-time users of palliative RT between 2003 and 2005 was retrospectively reviewed from the time of initial diagnosis of bone metastases to death or last follow-up. Type of radiation treatment service provider used (rapid accessmore » or routine access) and patient-, tumor-, and treatment-related factors were analyzed for their influences on the number of treatment courses given over the duration of disease. Results: A total of 887 patients received 1,354 courses of palliative RT for bone metastases at a median interval of 4.0 months between courses. Thirty-three percent of patients required more than one RT course. Increased age and travel distance reduced the likelihood and number of treatment courses, while service through a rapid access clinic was independently associated with an increase in subsequent use of palliative RT. Conclusions: A rapid access service model for palliative RT facilitated access to RT. Travel distance and other factors remained substantial barriers to use of palliative RT services. The pattern of practice suggests an unmet need for symptom control in patients with bone metastases.« less

Diagnostic performance of 11C-choline PET/CT and bone scintigraphy in the detection of bone metastases in patients with prostate cancer.

PubMed

Kitajima, Kazuhiro; Fukushima, Kazuhito; Yamamoto, Shingo; Kato, Takashi; Odawara, Soichi; Takaki, Haruyuki; Fujiwara, Masayuki; Yamakado, Koichiro; Nakanishi, Yukako; Kanematsu, Akihiro; Nojima, Michio; Hirota, Shozo

2017-08-01

The aim of this study was to compare 11C-choline PET/CT and bone scintigraphy (BS) for detection of bone metastases in patients with prostate cancer. Twenty-one patients with histologically proven prostate cancer underwent 11C-choline PET/CT and BS before (n = 4) or after (n = 17) treatment. Patient-, region-, and lesion-based diagnostic performances of bone metastasis of both 11C-choline PET/CT and BS were evaluated using a five-point scale by two experienced readers. Bone metastases were present in 11 (52.4%) of 21 patients and 48 (32.7%) of 147 regions; 111 lesions were found to have bone metastases. Region-based analysis showed that the sensitivity, specificity, accuracy, and area under the receiver-operating-characteristic curves (AUC) of 11C-choline PET/CT were 97.9%, 99.0%, 98.6%, and 0.9989, respectively; those of BS were 72.9%, 99.0%, 90.5%, and 0.8386, respectively. Sensitivity, accuracy, and AUC significantly differed between the two methods (McNemar test, p = 0.0015, p = 0.0015, and p < 0.0001, respectively). 11C-choline PET/CT detected 110/111 metastatic lesions (99.1%); BS detected 85 (76.6%) (p < 0.0001). According to the CT morphological type, the visualization rates of 11C-choline-PET/BS were 100%/90.3% for the blastic type, 91.7%/8.3% for the lytic type, 100%/100% for the mixed type, and 100%/53.3% for the invisible type, respectively. Significant differences in blastic, lytic, and invisible types were observed between the two methods (p = 0.013, p = 0.0044, and p = 0.023, respectively). In conclusion, 11C-choline PET/CT had greater sensitivity and accuracy than BS for detection of bone involvement in patients with prostate cancer.

Change in urinary markers of osteoclast activity following palliative radiotherapy for bone metastases.

PubMed

Chow, E; Hird, A; Zhang, Liying; Sinclair, E; Danjoux, C; Barnes, E; Tsao, M; Barbera, L; Wong, Shun; Vieth, R

2009-05-01

To examine the effect of radiotherapy for bone metastases on urinary markers of osteoclast activity. Patients with radiological evidence of bone metastases planned for palliative radiotherapy were eligible for the study. A urine specimen was collected before and 1 month after radiotherapy to assess levels of calcium, creatinine, magnesium, phosphate, N-telopeptide and pyridinoline. The Brief Pain Inventory was completed in person at baseline and by telephone follow-up at 1 month after radiotherapy. Patients were classified as responders (complete or partial pain response) or non-responders (stable or progressive pain) to radiotherapy based on the International Bone Metastases Consensus Criteria for end point measurements. Absolute values of urine markers were compared between responders and non-responders, or between responders and patients with progression. Our study population consisted of 74 men and 51 women. A single 8 Gy or 20 Gy in five daily fractions were commonly employed. At the 1 month follow-up, all Brief Pain Inventory functional interference scores showed a highly significant decrease from baseline (P<0.01). From our study population, 58 (64%) were classified as responders and 57 (46%) as non-responders to radiotherapy. We compared the urinary markers between the responders and the non-responders. There were no statistically significant differences between the two groups either in terms of baseline markers or in terms of month 1 follow-up markers. There was no significant change from baseline to the 1 month follow-up in responders or in non-responders to radiotherapy. Baseline levels of urinary markers could not predict which patient would benefit from palliative radiotherapy.

Multiple bone metastases from glioblastoma multiforme without local brain relapse: a case report and review of the literature.

PubMed

Takanen, Silvia; Bangrazi, Caterina; Caiazzo, Rossella; Raffetto, Nicola; Tombolini, Vincenzo

2013-01-01

Extracranial metastases from glioblastoma multiforme (GBM) are a very rare event, even if an increasing incidence has been documented. We report the case of a young woman with primary GBM who developed bone metastases without local brain relapse. Because of persistent headache and visual disturbances, in March 2011 the patient underwent magnetic resonance imaging (MRI) evidencing a temporoparietal mass, which was surgically resected. Histology revealed GBM. She was given concomitant chemoradiotherapy according to the Stupp regimen. After a 4-week break, the patient received 6 cycles of adjuvant temozolomide according to the standard 5-day schedule every 28 days. In December 2011 she complained of progressive low back pain, and MRI showed multiple bone metastases from primary GBM, confirmed by histology. Cases of metastatic GBM in concurrence with a primary brain tumor or local relapse are more common in the literature; only a few cases have been reported where extracranial metastases from GBM occurred without any relapse in the brain. Here we report our experience.

Modeling invasion of metastasizing cancer cells to bone marrow utilizing ecological principles.

PubMed

Chen, Kun-Wan; Pienta, Kenneth J

2011-10-03

The invasion of a new species into an established ecosystem can be directly compared to the steps involved in cancer metastasis. Cancer must grow in a primary site, extravasate and survive in the circulation to then intravasate into target organ (invasive species survival in transport). Cancer cells often lay dormant at their metastatic site for a long period of time (lag period for invasive species) before proliferating (invasive spread). Proliferation in the new site has an impact on the target organ microenvironment (ecological impact) and eventually the human host (biosphere impact). Tilman has described mathematical equations for the competition between invasive species in a structured habitat. These equations were adapted to study the invasion of cancer cells into the bone marrow microenvironment as a structured habitat. A large proportion of solid tumor metastases are bone metastases, known to usurp hematopoietic stem cells (HSC) homing pathways to establish footholds in the bone marrow. This required accounting for the fact that this is the natural home of hematopoietic stem cells and that they already occupy this structured space. The adapted Tilman model of invasion dynamics is especially valuable for modeling the lag period or dormancy of cancer cells. The Tilman equations for modeling the invasion of two species into a defined space have been modified to study the invasion of cancer cells into the bone marrow microenvironment. These modified equations allow a more flexible way to model the space competition between the two cell species. The ability to model initial density, metastatic seeding into the bone marrow and growth once the cells are present, and movement of cells out of the bone marrow niche and apoptosis of cells are all aspects of the adapted equations. These equations are currently being applied to clinical data sets for verification and further refinement of the models.

Palliative radiation therapy for bone metastases: Update of an ASTRO Evidence-Based Guideline.

PubMed

Lutz, Stephen; Balboni, Tracy; Jones, Joshua; Lo, Simon; Petit, Joshua; Rich, Shayna E; Wong, Rebecca; Hahn, Carol

The purpose is to provide an update the Bone Metastases Guideline published in 2011 based on evidence complemented by expert opinion. The update will discuss new high-quality literature for the 8 key questions from the original guideline and implications for practice. A systematic PubMed search from the last date included in the original Guideline yielded 414 relevant articles. Ultimately, 20 randomized controlled trials, 32 prospective nonrandomized studies, and 4 meta-analyses/pooled analyses were selected and abstracted into evidence tables. The authors synthesized the evidence and reached consensus on the included recommendations. Available literature continues to support pain relief equivalency between single and multiple fraction regimens for bone metastases. High-quality data confirm single fraction radiation therapy may be delivered to spine lesions with acceptable late toxicity. One prospective, randomized trial confirms both peripheral and spine-based painful metastases can be successfully and safely palliated with retreatment for recurrence pain with adherence to published dosing constraints. Advanced radiation therapy techniques such as stereotactic body radiation therapy lack high-quality data, leading the panel to favor its use on a clinical trial or when results will be collected in a registry. The panel's conclusion remains that surgery, radionuclides, bisphosphonates, and kyphoplasty/vertebroplasty do not obviate the need for external beam radiation therapy. Updated data analysis confirms that radiation therapy provides excellent palliation for painful bone metastases and that retreatment is safe and effective. Although adherence to evidence-based medicine is critical, thorough expert radiation oncology physician judgment and discretion regarding number of fractions and advanced techniques are also essential to optimize outcomes when considering the patient's overall health, life expectancy, comorbidities, tumor biology, anatomy, previous treatment

Non-invasive assessment of inter-and intrapatient variability of integrin expression in metastasized prostate cancer by PET.

PubMed

Beer, Ambros J; Schwarzenböck, Sarah M; Zantl, Niko; Souvatzoglou, Michael; Maurer, Tobias; Watzlowik, Petra; Kessler, Horst; Wester, Hans-Jürgen; Schwaiger, Markus; Krause, Bernd Joachim

2016-05-10

Due to the high expression of the integrin αvβ3 not only on endothelial cells, but also on mature osteoclasts and prostate cancer cells, imaging of osseous metastases with αvβ3-targeted tracers seems promising. However, little is known about the patterns of αvβ3-expression in metastasized prostate cancer lesions in-vivo. Thus we evaluated the uptake of the αvβ3-specific PET tracer [18F]Galacto-RGD for assessment of bone metastases in prostate cancer patients. [18F]Galacto-RGD PET identified 58/74 bone-lesions (detection rate of 78.4%) and lymph node metastases in 2/5 patients. The SUVmean was 2.12+/-0.94 (range 0.70-4.38; tumor/blood 1.36+/-0.53; tumor/muscle 2.82+/-1.31) in bone-lesions and 2.21+/-1.18 (range 0.75-3.56) in lymph node metastases. Good visualization and detection of bone metastases was feasible due to a low background activity of the surrounding normal bone tissue. 12 patients with known metastasized prostate cancer according to conventional staging (including bone-scintigraphy and contrast-enhanced CT; median PSA 68.63 ng/ml, range 3.72-1935) were examined with PET after i.v.-injection of [18F]Galacto-RGD. Two blinded nuclear-medicine physicians evaluated the PET-scans in consensus concerning lesion detectability. Volumes-of-interest were drawn in the PET-scans over all metastases defined by conventional staging (maximum of 11 lesions/patient), over the left ventricle, liver and muscle and standardized-uptake-values (SUVs) were calculated. Our data show generally elevated uptake of [18F]Galacto-RGD in bone metastases from prostate cancer with a marked inter- and intrapatient variability. While [18F]Galacto-RGD PET is inferior to bone scintigraphy for detection of osseous metastases, it might be valuable in patient screening and monitoring of αvβ3-targeted therapies due to the high variability of αvβ3-expression.

Novel Radiolabeled Bisphosphonates for PET Diagnosis and Endoradiotherapy of Bone Metastases

PubMed Central

Pfannkuchen, Nina; Meckel, Marian; Bergmann, Ralf; Bachmann, Michael; Bal, Chandrasekhar; Sathekge, Mike; Mohnike, Wolfgang; Baum, Richard P.; Rösch, Frank

2017-01-01

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the β-emitter 177Lu. This overview describes the possibility of diagnosing bone metastases using [68Ga]Ga-BPAMD (68Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [177Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68Ga- and 177Lu-labeled bisphosphonates offering improved pharmacological properties. PMID:28524118

Functional Interference Clusters in Cancer Patients With Bone Metastases: A Secondary Analysis of RTOG 9714

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chow, Edward, E-mail: Edward.Chow@sunnybrook.c; James, Jennifer; Barsevick, Andrea

Purpose: To explore the relationships (clusters) among the functional interference items in the Brief Pain Inventory (BPI) in patients with bone metastases. Methods: Patients enrolled in the Radiation Therapy Oncology Group (RTOG) 9714 bone metastases study were eligible. Patients were assessed at baseline and 4, 8, and 12 weeks after randomization for the palliative radiotherapy with the BPI, which consists of seven functional items: general activity, mood, walking ability, normal work, relations with others, sleep, and enjoyment of life. Principal component analysis with varimax rotation was used to determine the clusters between the functional items at baseline and the follow-up.more » Cronbach's alpha was used to determine the consistency and reliability of each cluster at baseline and follow-up. Results: There were 448 male and 461 female patients, with a median age of 67 years. There were two functional interference clusters at baseline, which accounted for 71% of the total variance. The first cluster (physical interference) included normal work and walking ability, which accounted for 58% of the total variance. The second cluster (psychosocial interference) included relations with others and sleep, which accounted for 13% of the total variance. The Cronbach's alpha statistics were 0.83 and 0.80, respectively. The functional clusters changed at week 12 in responders but persisted through week 12 in nonresponders. Conclusion: Palliative radiotherapy is effective in reducing bone pain. Functional interference component clusters exist in patients treated for bone metastases. These clusters changed over time in this study, possibly attributable to treatment. Further research is needed to examine these effects.« less

Detection of extensive melorheostosis on bone scintigram performed for suspected metastases.

PubMed

Sonoda, Luke I; Halim, Mohamed Y; Balan, Kottekkattu K

2011-03-01

Melorheostosis is a rare but benign disorder characterized by asymmetric osteosclerotic dysplasia. Radiographic appearances are characteristic and described as "melting wax flowing down a candle." This disorder may involve more than one bone contiguously across the joints following a sclerotomal distribution. It is often asymptomatic but occasionally presents with pain and contractures. The authors report accidental detection of bilateral upper and lower limb melorheostosis in an elderly woman with the history of breast cancer and recent onset of low back pain, which was referred for a bone scintigram for suspected metastases. The images showed bilateral femoral and tibial melorheostosis, which was subsequently confirmed on plain radiograph and by clinical follow-up.

[Chemoembolization of symptomatic bone metastases: technical considerations and therapeutic effectiveness].

PubMed

Clarençon, F; Cormier, E; Di Maria, F; Sourour, N-A; Szatmary, Z; Rose, M; Chiras, J

2011-09-01

Chemoembolization of bone metastases is defined by the intraarterial perfusion of a chemotherapy agent followed by microparticles embolization to improve tissue impregnation. This technique increases the local concentration of the chemotherapy agent. Tumor response (stable or reduced tumor size) is achieved in 30-80% of cases with symptomatic relief in over 80% of cases. The indications, technical considerations, and effectiveness of this procedure will be reviewed. Copyright © 2011 Elsevier Masson SAS and Éditions françaises de radiologie. All rights reserved.

Efficacy of Magnetic Resonance-guided Focused Ultrasound Surgery for Bone Metastases Pain Palliation

NASA Astrophysics Data System (ADS)

Kawasaki, Motohiro; Nanba, Hirofumi; Kato, Tomonari; Tani, Toshikazu; Ushida, Takahiro

2011-09-01

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a novel treatment method that achieves non-invasive thermal ablation by focusing many ultrasound waves on a target tissue with real-time monitoring of the location and temperature of the target during the procedure. We investigated the palliative effect on pain and safety of MRgFUS in painful bone metastases. Six patients (mean age, 65.8 years) who met eligibility criteria for the clinical study approved by our Institutional Ethics Committee based on the cooperative protocol were treated with MRgFUS. Targeted sites included the sacrum (n = 1), ilium (n = 2), scapula (n = 2), and femur (n = 1). The mean follow-up period was 9.2 months. All procedures were performed as a single-session treatment using the treatment system that is integrated into the patient table of a magnetic resonance image (MRI) scanner. Endpoints were change in the intensity of pain due to bone metastases from before to after the treatment, as measured on a numerical rating scale, pain interference with daily activities as determined by the Brief pain inventory (BPI), change in images, and safety. Pain relief was obtained in all patients early after treatment, with a reduction in the mean pain score from 6.0±1.3 at baseline to 1.2±1.0 at the end of follow-up as well as in pain interference with daily activities. The mean time required for a single-session treatment was 83.7±37.0 min, with a mean number of sonications required of 13.3±3.7 and mean energy applied of 846.4±273.5 J. No significant growth of tumors was observed, nor were there treatment-related adverse events. These results suggest that MRgFUS has a non-invasive palliative effect on the localized pain in patients with bone metastasis. MRgFUS could become an option in treatment strategies for painful bone metastases in the future.

11C-Choline PET/CT based Helical Tomotherapy as Treatment Approach for Bone Metastases in Recurrent Prostate Cancer Patients.

PubMed

Incerti, Elena; Gangemi, Vincenzo; Mapelli, Paola; Deantoni, Chiara Lucrezia; Giovacchini, Giampiero; Fallanca, Federico; Fodor, Andrei; Ciarmiello, Andrea; Baldari, Sergio; Gianolli, Luigi; Di Muzio, Nadia; Picchio, Maria

2017-11-10

To evaluate the efficacy of 11C-choline PET/CT (CHO-PET/CT) based helical tomotherapy (HTT) as a therapeutic approach for bone metastases in recurrent prostate cancer (PCa) patients. This retrospective study includes 20 PCa patients (median age: 67; range: 51-80 years) presenting biochemical relapse after primary treatment who underwent CHO-PET/CT based HTT on positive bone metastases from December 2007 to June 2014. The effectiveness of HTT has been assessed with biochemical response at 3/6/12 months, biochemical relapse free survival (bRFS) and overall survival (OS) at 2 years. Toxicity has also been considered and assessed according to Common Terminology Criteria for Adverse Events (CTCAE). All patients presented a relapse at the time of CHO-PET/CT at bone level. In addition 15/20 (75%) also at lymph nodes (LNs) level (total lesions= 54). All patients underwent HTT on bone metastases and 19/20 concomitantly on prostatic bed and LNs. The median follow-up from CHO-PET/CT was 2 years (range: 1-7 years). At 3 months after the beginning of HTT treatment complete or partial biochemical response occurred in 79% of patients, at 6 months in 82% and at 12 months in 63% of patients. bRFS and OS at 2 years were 50% and 55% of patients, respectively. Patients presented mostly grade 1 or 2 toxicity according to CTCAE. The only grade 3 late toxicity has been observed in one patient. CHO-PET/CT based HTT is a suitable therapeutic approach in patients with recurrent PCa presenting bone metastases with a medium-low toxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Estrogen receptor (ESR1) mutation in bone metastases from breast cancer.

PubMed

Bartels, Stephan; Christgen, Matthias; Luft, Angelina; Persing, Sascha; Jödecke, Kai; Lehmann, Ulrich; Kreipe, Hans

2018-01-01

Activating mutations of estrogen receptor α gene (ESR1) in breast cancer can cause endocrine resistance of metastatic tumor cells. The skeleton belongs to the metastatic sides frequently affected by breast cancer. The prevalence of ESR1 mutation in bone metastasis and the corresponding phenotype are not known. In this study bone metastases from breast cancer (n=231) were analyzed for ESR1 mutation. In 27 patients (12%) (median age 73 years, range: 55-82 years) activating mutations of ESR1 were detected. The most frequent mutation was p.D538G (53%), no mutations in exon 4 (K303) or 7 (S463) were found. Lobular breast cancer was present in 52% of mutated cases (n=14) and in 49% of all samples (n=231), respectively. Mutated cancers constantly displayed strong estrogen receptor expression. Progesterone receptor was positive in 78% of the mutated cases (n=21). From 194 estrogen receptor-positive samples, 14% had ESR1 mutated. Except for one mutated case, no concurrent HER2 overexpression was noted. Metastatic breast cancer with activating mutations of ESR1 had a higher Ki67 labeling index than primary luminal cancers (median 30%, ranging from 5 to 60% with 85% of cases revealing ≥20% Ki67-positive cells). From those patients from whom information on endocrine therapy was available (n=7), two had received tamoxifen only, 4 tamoxifen followed by aromatase inhibitors and one patient had been treated with aromatase inhibitors only. We conclude that ESR1 mutation is associated with estrogen receptor expression and high proliferative activity and affects about 14% of estrogen receptor-positive bone metastases from breast cancer.

Expression of the gastrin-releasing peptide receptor, the prostate stem cell antigen and the prostate-specific membrane antigen in lymph node and bone metastases of prostate cancer.

PubMed

Ananias, Hildo J K; van den Heuvel, Marius C; Helfrich, Wijnand; de Jong, Igle J

2009-07-01

Cell membrane antigens like the gastrin-releasing peptide receptor (GRPR), the prostate stem cell antigen (PSCA), and the prostate-specific membrane antigen (PSMA), expressed in prostate cancer, are attractive targets for new therapeutic and diagnostic applications. Therefore, we investigated in this study whether these antigens are expressed in metastasized prostate cancer. Formalin-fixed, paraffin-embedded specimens of 15 patients with uni- or bilateral lymph node metastases of prostate cancer (totaling 21 cases) and 17 patient-cases of bone metastases were processed for immunohistochemistry with anti-GRPR, anti-PSCA, and anti-PSMA antibodies. A pathologist blinded to clinical and pathological data scored the immunoreactivity for these antibodies on a four-point scale (0 = no staining; 1+ = weak staining; 2+ = moderate staining; 3+ = strong staining) and documented the distribution pattern. GRPR staining in lymph node metastases was seen in 85.7% of cases (18 of 21 cases), PSCA in 95.2% (20/21), and PSMA in 100% (21/21). GRPR in bone metastases was seen in 52.9% of cases (9/17), PSCA in 94.1% (16/17), and PSMA in 100% (17/17). We have shown for the first time that GRPR is expressed in the vast majority of lymph node metastases and in 52.9% of bone metastases of prostate cancer. PSCA and PSMA are both highly expressed in lymph node and bone metastases. Although PSCA and PSMA are mostly expressed in prostate cancer metastases, GRPR offers an interesting alternative target as it can be targeted relatively easy with peptide-based (radio)pharmaceuticals. (c) 2009 Wiley-Liss, Inc.

Which metabolic imaging, besides bone scan with 99mTc-phosphonates, for detecting and evaluating bone metastases in prostatic cancer patients? An open discussion.

PubMed

Bombardieri, E; Setti, L; Kirienko, M; Antunovic, L; Guglielmo, P; Ciocia, G

2015-12-01

Prostate cancer bone metastases occur frequently in advanced cancer and this is matter of particular attention, due to the great impact on patient's management and considering that a lot of new emerging therapeutic options have been recently introduced. Imaging bone metastases is essential to localize lesions, to establish their size and number, to study characteristics and changes during therapy. Besides radiological imaging, nuclear medicine modalities can image their features and offer additional information about their metabolic behaviour. They can be classified according to physical characteristics, type of detection, mechanism of uptake, availability for daily use. The physiopathology of metastases formation and the mechanisms of tracer uptake are essential to understand the interpretation of nuclear medicine images. Therefore, radiopharmaceuticals for bone metastases can be classified in agents targeting bone (99mTc-phosphonates, 18F-fluoride) and those targeting prostatic cancer cells (18F-fluoromethylcholine, 11C-choline, 18F-fluorodeoxyglucose). The modalities using the first group of tracers are planar bone scan, SPECT or SPECT/CT with 99mTc-diphosphonates, and 18F-fluoride PET/CT, while the modalities using the second group include 18F/11C-choline derivatives PET/CT, 18F-FDG PET/CT and PET/CT scans with several other radiopharmaceuticals described in the literature, such as 18F/11C-acetate derivatives, 18F-fluoro-5α-dihydrotestosterone (FDHT), 18F-anti-1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC), 18F-2'-fluoro-5-methyl-1-β-D-arabinofuranosyluracil (FMAU) and 68Ga-labeled-prostate specific membrane antigen (PMSA) PET/TC. However, since data on clinical validation for these last novel modalities are not conclusive and/or are not still sufficient in number, at present they can be still considered as promising tools under evaluation. The present paper considers the nuclear modalities today available for the clinical routine. This overview wants

Impact of ¹⁸F-fluoride PET-CT on implementing early treatment of painful bone metastases with Sm-153 EDTMP.

PubMed

Storto, Giovanni; Gallicchio, Rosj; Pellegrino, Teresa; Nardelli, Anna; De Luca, Serena; Capacchione, Daniela; Sirignano, Cesare; Pace, Leonardo

2013-05-01

This study evaluated the diagnostic impact of using skeletal (18)F-fluoride PET/CT on patients with painful bone metastases to schedule an early palliative radionuclide treatment. The skeletal involvement from prostate cancer metastases was assessed by both (99m)Tc-diphosphonate bone scan (BS) and (18)F-fluoride PET/CT within four weeks in 24 patients (67.7 ± 5.1 years) suffering from a borderline degree of bone pain for which radionuclide palliation was not shortly planned for administration. The BS and (18)F-fluoride PET/CT results were compared, assessing the number and extension of the skeletal sites involved. Afterward, the patients were randomly assigned either to the study group (N=12) receiving radionuclide therapy (Samarium-153 EDTMP) or to the control group (N=12) not receiving radionuclide therapy. The short-term results from the radionuclide palliation group (evaluated with a visual analogue scale) were compared with the controls. Overall, at BS, 7.6 ± 1.4 sites were considered metastatic, involving at least 5 ± 1 body regions. At (18)F-fluoride PET/CT, 116 ± 19 sites presented metastatic involvement with 12/12 body regions concerned. No differences were found in regards to either the number of metastatic sites or regions at both BS and (18)F-fluoride PET/CT between the study group and controls (p=ns). At CT, 88 blastic metastases were identified, whereas 110 were mainly lytic. Most of mainly lytic lesions were not detectable at BS. The reduction in total discomfort and bone pain in the study group was significantly greater than in the controls (p<0.0001). Sm-153 EDTMP therapy should be considered for patients with early bone pain from prostate cancer even if their BS only indicates a few metastases before the initiation of a severe pain syndrome. (18)F-fluoride PET/CT may be helpful in deciding if the implementation of bone pain palliation using bone-seeking radionuclides at pain onset is necessary. Copyright © 2013 Elsevier Inc. All rights

Cost analysis of skeletal-related events in Spanish patients with bone metastases from solid tumours.

PubMed

Durán, I; Garzón, C; Sánchez, A; García-Carbonero, I; Pérez-Gracia, J L; Seguí-Palmer, M Á; Wei, R; Restovic, G; Gasquet, J A; Gutiérrez, L

2014-03-01

To estimate the cost per skeletal-related event (SRE) in patients with bone metastases secondary to solid tumours in the Spanish healthcare setting. Patients diagnosed with bone metastases secondary to breast, prostate or lung cancer were included in this multicentre, observational study. SREs are defined as pathologic fracture (vertebral and non-vertebral fracture), radiation to bone, spinal cord compression or surgery to bone. Health resource utilisation associated with these events (inpatient stays, outpatient, emergency room and home health visits, nursing home stays and procedures) were collected retrospectively for all SREs that occurred in the 97 days prior to enrolment and prospectively during follow-up. Unit costs were obtained from the 2010 eSalud healthcare costs database. A total of 93 Spanish patients with solid tumours were included (31 had breast cancer, 21 prostate cancer and 41 lung cancer), contributing a total of 143 SREs to this cost analysis. Inpatient stays (between 9.0 and 29.9 days of mean length of stay per inpatient stay by SRE type) and outpatient visits (between 1.7 and 6.4 mean visits per SRE type) were the most frequently reported types of health resources utilised. The mean cost per SRE was between 2,377.79 (radiation to bone) and 7,902.62 (spinal cord compression). SREs are associated with a significant consumption of healthcare resources that generate a substantial economic burden for the Spanish healthcare system.

High serum ALP level is associated with increased risk of denosumab-related hypocalcemia in patients with bone metastases from solid tumors.

PubMed

Kinoshita, Yuka; Arai, Makoto; Ito, Nobuaki; Takashi, Yuichi; Makita, Noriko; Nangaku, Masaomi; Shinoda, Yusuke; Fukumoto, Seiji

2016-05-31

Metastatic bone disease is one of the most common complications of advanced cancers. Pathological fractures, spinal cord compression, and radiotherapy or surgery to the bone are collectively called skeletal-related events (SREs), which cause severe pain, increase hospitalization rates, and impair the quality of life (QOL) of patients with bone metastases. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK pathway is critical in the progression of bone metastases. Previous studies have demonstrated that an anti-RANKL antibody (denosumab) was superior to zoledronic acid in prolonging time to first SRE in patients with bone metastases from prostate and breast cancers. However, severe hypocalcemic events occur more frequently after treatment with denosumab compared with zoledronic acid. In this study, 368 administrations of denosumab in 219 patients with metastatic bone disease from solid tumors were analyzed to clarify the risk factors for developing hypocalcemia. The results showed that grade 2/3 hypocalcemia was observed in 10.4% of the total number of denosumab administrations. Patients with higher baseline serum ALP, higher performance status (PS), or gastric cancer were at higher risk for developing hypocalcemia. The cut-off value for ALP to predict denosumab-related hypocalcemia was 587 U/L with a sensitivity of 0.77 and a specificity of 0.81. Close monitoring of serum calcium, especially after the first treatment with denosumab, is strongly recommended in these patients.

Patterns of pain and interference in patients with painful bone metastases: a brief pain inventory validation study.

PubMed

Wu, Jackson S Y; Beaton, Dorcas; Smith, Peter M; Hagen, Neil A

2010-02-01

Bone metastases are prevalent, painful, and carry a poorer prognosis for pain control compared with other cancer pain syndromes. Standard tools to measure pain have not been validated in this patient population, and particular subgroups with more challenging symptoms have yet to be identified and studied. The objectives of this study were 1) to validate the psychometric properties of the Brief Pain Inventory (BPI) and its Pain and Interference subscales in patients with clinically significant metastatic bone pain requiring palliative radiotherapy and 2) to examine differences in BPI subscales among predefined subgroups of bone metastases patients. A total of 258 patients evaluated and treated through a rapid access radiation therapy clinic between July 2002, and November 2006, were included in the analysis. High internal consistency of the BPI subscales of Pain, Activity interference, and Affect interference was demonstrated by Cronbach's alpha between 0.81 and 0.89. Removing sleep interference improved model fit in confirmatory factor analysis. The BPI revealed an alarming pattern in patients with lower body metastases, who reported substantial interference of activity even though pain levels were mild or moderate. Such patients may require prompt clinical attention to better meet their needs. Finally, the allocation of interference from sleep within the BPI framework, in our population of pain patients, requires further study. Copyright 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perk, T; Bradshaw, T; Harmon, S

2015-06-15

Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40100) numbersmore » of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.« less

Course of Quality of Life After Radiation Therapy for Painful Bone Metastases: A Detailed Analysis From the Dutch Bone Metastasis Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Westhoff, Paulien G., E-mail: p.g.westhoff@umcutrecht.nl; Department of Radiotherapy, Radboud University Medical Center, Nijmegen; Verdam, Mathilde G.E.

Purpose: To study the course of quality of life (QoL) after radiation therapy for painful bone metastases. Patients and Methods: The Dutch Bone Metastasis Study randomized 1157 patients with painful bone metastases between a single fraction of 8 Gy and 6 fractions of 4 Gy between 1996 and 1998. The study showed a comparable pain response of 74%. Patients filled out weekly questionnaires for 13 weeks, then monthly for 2 years. In these analyses, physical, psychosocial, and functional QoL domain scores and a score of general health were studied. Mixed modeling was used to model the course of QoL and to study the influence ofmore » several characteristics. Results: In general, QoL stabilized after 1 month. Psychosocial QoL improved after treatment. The level of QoL remained stable, steeply deteriorating at the end of life. For most QoL domains, a high pain score and intake of opioids were associated with worse QoL, with small effect sizes (−0.11 to −0.27). A poor performance score was associated with worse functional QoL, with a medium effect size (0.41). There is no difference in QoL between patients receiving a single fraction of 8 Gy and 6 fractions of 4 Gy, except for a temporary worsening of physical QoL after 6 fractions. Conclusion: Although radiation therapy for painful bone metastases leads to a meaningful pain response, most domains of QoL do not improve after treatment. Only psychosocial QoL improves slightly after treatment. The level of QoL is related to the actual survival, with a rather stable course of QoL for most of the remaining survival time and afterward a sharp decrease, starting only a few weeks before the end of life. Six fractions of 4 Gy lead to a temporary worse physical QoL compared with a single fraction of 8 Gy.« less

Increased expression of a set of genes enriched in oxygen binding function discloses a predisposition of breast cancer bone metastases to generate metastasis spread in multiple organs.

PubMed

Capulli, Mattia; Angelucci, Adriano; Driouch, Keltouma; Garcia, Teresa; Clement-Lacroix, Philippe; Martella, Francesco; Ventura, Luca; Bologna, Mauro; Flamini, Stefano; Moreschini, Oreste; Lidereau, Rosette; Ricevuto, Enrico; Muraca, Maurizio; Teti, Anna; Rucci, Nadia

2012-11-01

Bone is the preferential site of distant metastasis in breast carcinoma (BrCa). Patients with metastasis restricted to bone (BO) usually show a longer overall survival compared to patients who rapidly develop multiple metastases also involving liver and lung. Hence, molecular predisposition to generate bone and visceral metastases (BV) represents a clear indication of poor clinical outcome. We performed microarray analysis with two different chip platforms, Affymetrix and Agilent, on bone metastasis samples from BO and BV patients. The unsupervised hierarchical clustering of the resulting transcriptomes correlated with the clinical progression, segregating the BO from the BV profiles. Matching the twofold significantly regulated genes from Affymetrix and Agilent chips resulted in a 15-gene signature with 13 upregulated and two downregulated genes in BV versus BO bone metastasis samples. In order to validate the resulting signature, we isolated different MDA-MB-231 clonal subpopulations that metastasize only in the bone (MDA-BO) or in bone and visceral tissues (MDA-BV). Six of the signature genes were also significantly upregulated in MDA-BV compared to MDA-BO clones. A group of upregulated genes, including Hemoglobin B (HBB), were involved in oxygen metabolism, and in vitro functional analysis of HBB revealed that its expression in the MDA subpopulations was associated with a reduced production of hydrogen peroxide. Expression of HBB was detected in primary BrCa tissue but not in normal breast epithelial cells. Metastatic lymph nodes were frequently more positive for HBB compared to the corresponding primary tumors, whereas BO metastases had a lower expression than BV metastases, suggesting a positive correlation between HBB and ability of bone metastasis to rapidly spread to other organs. We propose that HBB, along with other genes involved in oxygen metabolism, confers a more aggressive metastatic phenotype in BrCa cells disseminated to bone. Copyright © 2012

A Prospective Study Comparing 99mTc-Hydroxyethylene-Diphosphonate Planar Bone Scintigraphy and Whole-Body SPECT/CT with 18F-Fluoride PET/CT and 18F-Fluoride PET/MRI for Diagnosing Bone Metastases.

PubMed

Löfgren, Johan; Mortensen, Jann; Rasmussen, Sine H; Madsen, Claus; Loft, Annika; Hansen, Adam E; Oturai, Peter; Jensen, Karl Erik; Mørk, Mette Louise; Reichkendler, Michala; Højgaard, Liselotte; Fischer, Barbara M

2017-11-01

We prospectively evaluated and compared the diagnostic performance of 99m Tc-hydroxyethylene-diphosphonate ( 99m Tc-HDP) planar bone scintigraphy (pBS), 99m Tc-HDP SPECT/CT, 18 F-NaF PET/CT, and 18 F-NaF PET/MRI for the detection of bone metastases. Methods: One hundred seventeen patients with histologically proven malignancy referred for clinical pBS were prospectively enrolled. pBS and whole-body SPECT/CT were performed followed by 18 F-NaF PET/CT within 9 d. 18 F-NaF PET/MRI was also performed in 46 patients. Results: Bone metastases were confirmed in 16 patients and excluded in 101, which was lower than expected. The number of equivocal scans was significantly higher for pBS than for SPECT/CT and PET/CT (18 vs. 5 and 6, respectively; P = 0.004 and 0.01, respectively). When equivocal readings were excluded, no statistically significant difference in sensitivity, specificity, positive predictive value, negative predictive value, or overall accuracy were found when comparing the different imaging techniques. In the per-patient analysis, equivocal scans were either assumed positive for metastases ("pessimistic analysis") or assumed negative for metastases ("optimistic analysis"). The percentages of misdiagnosed patients for the pessimistic analysis were 21%, 15%, 9%, and 7% for pBS, SPECT/CT, PET/CT, and PET/MRI, respectively. Corresponding figures for the optimistic analysis were 9%, 12%, 5%, and 7%. In those patients identified as having bone metastases according to the reference standard, SPECT/CT, 18 F-NaF PET/CT, and PET/MRI detected additional lesions compared with pBS in 31%, 63%, and 71%, respectively. Conclusion: 18 F-NaF PET/CT and whole-body SPECT/CT resulted in a significant reduction of equivocal readings compared with pBS, which implies an improved diagnostic confidence. However, the clinical benefit of using, for example, 18 F-NaF PET/CT or PET/MRI as compared with SPECT/CT and pBS in this patient population with a relatively low prevalence of bone

64Cu-Labeled Phosphonate Cross-Bridged Chelator Conjugates of c(RGDyK) for PET/CT Imaging of Osteolytic Bone Metastases.

PubMed

Ocak, Meltem; Beaino, Wissam; White, Alexander; Zeng, Dexing; Cai, Zhengxin; Anderson, Carolyn J

2018-03-01

The goal of this research was to evaluate c(RGDyK) conjugated to phosphonate-based cross-bridged chelators using Cu-free click chemistry in the 4T1 mouse mammary tumor bone metastasis model in comparison with 64 Cu-CB-TE2A-c(RGDyK), which previously showed selective binding to integrin αvβ3 on osteoclasts. Two phosphonate-based cross-bridged chelators (CB-TE1A1P and CB-TE1K1P) were conjugated to c(RGDyK) through bio-orthogonal strain-promoted alkyne-azide cycloaddition. In vitro and in vivo evaluation of the 64 Cu-labeled TE1A1P-DBCO-c(RGDyK) (AP-c(RGDyK)), TE1K1P-PEG4-DBCO-c(RGDyK) (KP-c(RGDyK)), and CB-TE2A-c(RGDyK) were compared in the 4T1 mouse model of bone metastasis. The affinities of the unconjugated and chelator-c(RGDyK) analogs for αvβ3 integrin were determined using a competitive-binding assay. For in vivo evaluation, BALB/c mice were injected with 1 × 10 5 4T1/Luc cells in the left ventricle. Formation of metastases was monitored by bioluminescence imaging (BLI) followed by small-animal PET/CT 2 h postinjection of radiotracers. The chelator-peptide conjugates showed similar affinity to integrin αvβ3, in the low nM range. PET imaging demonstrated a higher uptake in bones having metastases for all 64 Cu-labeled c(RGDyK) analogs compared with bones in nontumor-bearing mice. The correlation between uptake of 64 Cu-AP-c(RGDyK) and 64 Cu-KP-c(RGDyK) in bones with metastases based on PET/CT imaging, and osteoclast number based on histomorphometry, was improved over the previously investigated 64 Cu-CB-TE2A-c(RGDyK). These data suggest that the phosphonate chelator conjugates of c(RDGyK) peptides are promising PET tracers suitable for imaging tumor-associated osteoclasts in bone metastases.

Retrospective evaluation of the clinical benefit of long-term continuous use of zoledronic acid in patients with lung cancer and bone metastases.

PubMed

Henk, Henry J; Kaura, Satyin; Teitelbaum, April

2012-01-01

For patients with bone metastases, skeletal-related events including fracture are common, can cause considerable morbidity, and may reduce overall survival (OS). This retrospective analysis assessed the effect of Zometa (zoledronic acid, ZOL), an intravenous bisphosphonate (IV-BP), on fracture risk and OS in patients with bone metastases from lung cancer (LC). (Zometa is a registered trademark of Novartis Pharmaceuticals Corporation, USA.) A claims-based analysis using commercial and Medicare Advantage data from >45 US managed-care plans was used to evaluate the association between fracture risk and treatment persistency (31-90, 91-180, 181-365, and ≥366 days) and follow-up duration in LC patients diagnosed with bone metastases between 01/01/2001 and 12/31/2006 and treated with ZOL or without (no IV-BP). Persistency was defined as the absence of a >45-day gap between ZOL treatments. Analysis of variance tests were used to compare follow-up duration, a proxy for OS, between ZOL persistency groups. The effect of time to treatment with ZOL was also assessed. In 9874 LC patients with bone metastases (n = 1090 ZOL; n = 8784 no IV-BP) the unadjusted relative fracture risk was reduced by 40% with ZOL vs no IV-BP; fracture risk decreased consistently with increasing duration of ZOL treatment. Even short-term (31-90 days) ZOL significantly reduced fracture risk (47%) vs no IV-BP (p = 0.005) with adjustment for differences in demographic and clinical characteristics. Delaying ZOL until after bone metastases were diagnosed significantly increased fracture risk (p = 0.0017). For a sub-set of patients included in a survival analysis (n = 550 ZOL; n = 4512 no IV-BP), mortality was significantly lower (mean, 38.6 vs 46.8 deaths/100 person-years; p = 0.038) in those treated with ZOL vs no IV-BP. Interpretation of this claims-based analysis must be tempered by the inherent limitations of observational data, such as limited clinical information and the

[Magnetic resonance guided focused ultrasound surgery for pain palliation of bone metastases: early experience of clinical application in China].

PubMed

Gu, Jianjun; Wang, Han; Tang, Na; Hua, Yingqi; Yang, Haiyan; Qiu, Yimin; Ge, Renbin; Zhou, Ying; Wang, Wenwen; Zhang, Guixiang

2015-11-03

To evaluate the safety and efficacy of magnetic resonance guided focused ultrasound surgery (MRgFUS) in treatment for pain palliation of bone metastases. Eighty-one patients of painful bone metastases were volunteered to screen for this study in Shanghai General Hospital from June 2014 to February 2015. Twenty-three patients among them were treated by MRgFUS, who was more than 18-years old, having the ability to fully understand the informed consent of the research, suffering with pain of numeric rating scale (NRS) ≥ 4, non-received radiotherapy or chemotherapy for pain palliation of bone metastases in the past two weeks. The NRS, the standard question of Brief Pain Inventory (BPI-QoL), and the standard question of Europe Organization for Research and Treatment of Cancer Quality of Life Questionnaire- Bone Metastases 22 (EORTC QLQ-BM22) were respectively recorded before and 1-week, 1-month, 3-month after the treatment. The related adverse events of MRgFUS were observed and recorded in 3 months after the treatment as well. (1)Twenty-three metastatic bone tumor lesions of 23 patients were treated by MRgFUS, the treatment data was as follows: the mean treatment time was (88 ± 33) minutes, the mean sonication number was 13 ± 8. (2) Adverse events included: pain in therapy area 3/23, which spontaneous relieving within one week; numbness in lower limb (1/23), which relieved after physiotherapy. (3) The NRS of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 6.0 ± 1.5, 3.7 ± 1.7,3.1 ± 2.0, and 2.2 ± 1.0,which significantly decreased after the treatment (P<0.01). (4) The BPI-QoL score of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 39 ± 16, 27 ± 18, 26 ± 18, and 21 ± 18, which significantly decreased after the treatment (P<0.01). (5) The EORTC QLQ-BM22 score of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 52 ± 13, 44 ± 12, 42 ± 12, and 39 �

Impact of Using Audit Data to Improve the Evidence-Based Use of Single-Fraction Radiation Therapy for Bone Metastases in British Columbia.

PubMed

Olson, Robert A; Tiwana, Manpreet; Barnes, Mark; Cai, Eric; McGahan, Colleen; Roden, Kelsey; Yurkowski, Emily; Gentles, Quinn; French, John; Halperin, Ross; Olivotto, Ivo A

2016-01-01

To assess the impact of a population-based intervention to increase the consistency and use of single-fraction radiation therapy (SFRT) for bone metastases. In 2012, an audit of radiation therapy prescriptions for bone metastases in British Columbia identified significant interphysician and -center (26%-73%) variation in the use of SFRT. Anonymous physician-level and identifiable regional cancer center SFRT use data were presented to all radiation oncologists, together with published guidelines, meta-analyses, and recommendations from practice leaders. The use of SFRT for bone metastases from 2007 through 2011 was compared with use of SFRT in 2013, to assess the impact of the audit and educational intervention. Multilevel logistic regression was used to assess the relationship between the usage of SFRT and the timing of the radiation while controlling for potentially confounding variables. Physician and center were included as group effects to account for the clustered structure of the data. A total of 16,898 courses of RT were delivered from 2007 through 2011, and 3200 courses were delivered in 2013. The rates of SFRT use in 2007, 2008, 2009, 2010, 2011, and 2013 were 50.5%, 50.9%, 48.3%, 48.5%, 48.0%, and 59.7%, respectively (P<.001). Use of SFRT increased in each of 5 regional centers: A: 26% to 32%; B: 36% to 56%; C: 39% to 57%; D: 49% to 56%; and E: 73% to 85.0%. Use of SFRT was more consistent; 3 of 5 centers used SFRT for 56% to 57% of bone metastases RT courses. The regression analysis showed strong evidence that the usage of SFRT increased after the 2012 intervention (odds ratio 2.27, 95% confidence interval 2.06-2.50, P<.0001). Assessed on a population basis, an audit-based intervention increased utilization of SFRT for bone metastases. The intervention reversed a trend to decreasing SFRT use, reduced costs, and improved patient convenience. This suggests that dissemination of programmatic quality indicators in oncology can lead to increased utilization

Cost effectiveness of bisphosphonates in the management of breast cancer patients with bone metastases.

PubMed

Botteman, M; Barghout, V; Stephens, J; Hay, J; Brandman, J; Aapro, M

2006-07-01

Bisphosphonates are recommended to prevent skeletal related events (SREs) in patients with breast cancer and bone metastases (BCBM). However, their clinical and economic profiles vary from one agent to the other. Using modeling techniques, we simulated from the perspective of the UK's National Health Service (NHS) the cost and quality adjusted survival (QALY) associated with five commonly-used bisphosphonates or no therapy in this patient population. The simulation followed patients into several health states (i.e. alive or dead, experiencing an SRE or no SRE, and receiving first or second line therapy). Drugs costs, infusion costs, SREs costs, and utility values were estimated from published sources. Utilities were applied to time with and without SREs to capture the impact on quality of life. Compared to no therapy, all bisphosphonates are either cost saving or highly cost-effective (with a cost per QALY < or = 6126 pounds sterlings). Within this evaluation, zoledronic acid was more effective and less expensive than all other options. Based on our model, the use of bisphosphonates in breast cancer patients with bone metastases should lead to improved patient outcomes and cost savings to the NHS and possibly other similar entities.

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

PubMed Central

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

2013-01-01

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

Contrast-enhanced Magnetic Resonance Imaging of Pelvic Bone Metastases at 3.0 T: Comparison Between 3-dimensional T1-weighted CAIPIRINHA-VIBE Sequence and 2-dimensional T1-weighted Turbo Spin-Echo Sequence.

PubMed

Yoon, Min A; Hong, Suk-Joo; Lee, Kyu-Chong; Lee, Chang Hee

2018-06-12

This study aimed to compare 3-dimensional T1-weighted gradient-echo sequence (CAIPIRINHA-volumetric interpolated breath-hold examination [VIBE]) with 2-dimensional T1-weighted turbo spin-echo sequence for contrast-enhanced magnetic resonance imaging (MRI) of pelvic bone metastases at 3.0 T. Thirty-one contrast-enhanced MRIs of pelvic bone metastases were included. Two contrast-enhanced sequences were evaluated for the following parameters: overall image quality, sharpness of pelvic bone, iliac vessel clarity, artifact severity, and conspicuity and edge sharpness of the smallest metastases. Quantitative analysis was performed by calculating signal-to-noise ratio and contrast-to-noise ratio of the smallest metastases. Significant differences between the 2 sequences were assessed. CAIPIRINHA-VIBE had higher scores for overall image quality, pelvic bone sharpness, iliac vessel clarity, and edge sharpness of the metastatic lesions, and had less artifacts (all P < 0.05). There was no significant difference in conspicuity, signal-to-noise ratio, or contrast-to-noise ratio of the smallest metastases (P > 0.05). Our results suggest that CAIPIRINHA-VIBE may be superior to turbo spin-echo for contrast-enhanced MRI of pelvic bone metastases at 3.0 T.

EARLY COMPLICATIONS IN THE ORTHOPEDIC TREATMENT OF BONE METASTASES.

PubMed

Teixeira, Luiz Eduardo Moreira; Miranda, Ricardo Horta; Ghedini, Daniel Ferreira; Aguilar, Rafael Bazílio; Novais, Eduardo Nilo Vasconcelos; de Abreu E Silva, Guilherme Moreira; Araújo, Ivana Duval; de Andrade, Marco Antônio Percope

2009-01-01

To assess the early complications in the orthopedic treatment of metastatic bone lesions and the factors associated with these complications. There were assessed, retrospectively, 64 patients that underwent surgical treatment for bone metastases, analyzing the complications that occurred in the pre-operative and early post- operative period and associating them with the tumor origin, type of procedure done, the need of blood reposition before the surgery, the need of new surgical procedures and the mortality due to the complications. Early complications in the treatment were observed in 17 (26.6%) patients, of which six (35.2%) ended up dying due to these complications. Regarding the type, 15 (23.8%) cases were due to surgical complications, four (6.3%) clinical and three (4.7%) patients showed clinical and surgical complications. There was no significant difference in the frequency of complications or mortality when assessed the type of reconstruction or affected region. The tumors with a renal origin needed more blood reposition and showed a bigger frequency of complications. The complications occurred in 26.6%. The complications are not related to the kind of treatment performed or to the region affected. The renal origin tumors showed a higher risk of hemorrhage.

Fasting Enhances the Contrast of Bone Metastatic Lesions in 18F-Fluciclovine-PET: Preclinical Study Using a Rat Model of Mixed Osteolytic/Osteoblastic Bone Metastases

PubMed Central

Oka, Shuntaro; Kanagawa, Masaru; Doi, Yoshihiro; Schuster, David M.; Goodman, Mark M.; Yoshimura, Hirokatsu

2017-01-01

18F-fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid) is an amino acid positron emission tomography (PET) tracer used for cancer staging (e.g., prostate and breast). Patients scheduled to undergo amino acid-PET are usually required to fast before PET tracer administration. However, there have been no reports addressing whether fasting improves fluciclovine-PET imaging. In this study, the authors investigated the influence of fasting on fluciclovine-PET using triple-tracer autoradiography with 14C-fluciclovine, [5,6-3H]-2-fluoro-2-deoxy-d-glucose (3H-FDG), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) in a rat breast cancer model of mixed osteolytic/osteoblastic bone metastases in which the animals fasted overnight. Lesion accumulation of each tracer was evaluated using the target-to-background (muscle) ratio. The mean ratios of 14C-fluciclovine in osteolytic lesions were 4.6 ± 0.8 and 2.8 ± 0.6, respectively, with and without fasting, while those for 3H-FDG were 6.9 ± 2.5 and 5.1 ± 2.0, respectively. In the peri-tumor bone formation regions (osteoblastic), where 99mTc-HMDP accumulated, the ratios of 14C-fluciclovine were 4.3 ± 1.4 and 2.4 ± 0.7, respectively, and those of 3H-FDG were 6.2 ± 3.8 and 3.3 ± 2.2, respectively, with and without fasting. These results suggest that fasting before 18F-fluciclovine-PET improves the contrast between osteolytic and osteoblastic bone metastatic lesions and background, as well as 18F-FDG-PET. PMID:28468238

The Difficult Task of Diagnosing Prostate Cancer Metastases on Dry Bone.

PubMed

Castoldi, Elisa; Cappella, Annalisa; Gibelli, Daniele; Sforza, Chiarella; Cattaneo, Cristina

2018-05-01

The interpretation of pathology on skeletal remains is mandatory for implementing the biological profile and for disease recognition. Prostate cancer is one of the most common tumors, with a high preference for the skeleton as a primary site of metastasis. Its diagnosis on bone is however still ambiguous, due to its "osteoblastic" and resorptive manifestation. This study investigates distribution and appearance of prostate cancer metastases on dry bone on six known cases (selected from the Milano Cemetery Skeletal Collection) and one healthy individual. A macroscopic inspection was performed highlighting the abnormalities observed, describing location, shape, dimension, and aspect. A great amount of proliferative and mixed lesions was noticed, but also cases of pure lytic lesions were displayed. The multiple appearances of the manifestations observed display the difficulty in correctly identifying such a pathology, but also the potential and advantages provided by investigating a study sample with known antemortem history. © 2017 American Academy of Forensic Sciences.

[Efficacy of zoledronic acid combined with chemotherapy in treatment of skeletal metastases of non-small cell lung cancer and the bone metabolic markers].

PubMed

Hu, Xiao-ye; Zou, Qing-feng; Jin, Chuan; Li, Wei-dong; Chen, Wen-sheng; Ma, Lei

2010-06-01

To evaluate the clinical efficacy of zoledronic acid combined with chemotherapy in the management of skeletal metastasis of non-small cell lung cancer (NSCLC) and investigate the value in urine amino-terminal telopeptide of type I collagen (uNTX) and serum bone specific alkaline phosphatase (sBALP) in monitoring skeletal metastasis of NSCLC. From February, 2007 to January, 2009, 32 NSCLC patients with bone metastases received treatment with zoledronic acid at the dose of 4 mg given every 3 weeks and platinum-based chemotherapy (each cycle lasting for 3 weeks). Before and during the treatments, uNTX and sBALP were measured in these patients using ELISA and precipitation with wheat germ lectin, respectively. The patients were followed up for skeletal-related events (SREs) and status of survival. A significant decrease occurred in the pain scores and analgesic use in the patients after the therapy. SREs were not observed during the treatment. Serum creatinine and calcium levels underwent no significant variation during the treatment. Eleven patients reported 14 possible zoledronic acid-related adverse events. The concentration of uNTX and sBALP in patients with bone metastases was above the upper limit of the normal range. A positive correlation was observed between the levels of the markers and the extent of bone metastases. At the third month, uNTX and sBALP were significantly lowered, but radionuclide whole-body bone imaging showed no obvious changes. Of the 32 patients, 24 had elevated uNTX values, which became normal after the treatment in 15 patients and remained elevated in the other 9 patients. SREs occurred in these two subgroups at the rates of 53% and 89% (P=0.039), respectively. Twenty-six patients had elevated sBALP level, and 16 of them exhibited normal sBALP level after the treatment. The incidences of SREs in the patients with elevated and normal sBALP level were 50% and 90% (P=0.038), respectively. The levels of uNTX/Cr and sBALP were not correlated

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Se Young; Kim, Hyun-Jeong; Kim, Ki Rim

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

Impact of Using Audit Data to Improve the Evidence-Based Use of Single-Fraction Radiation Therapy for Bone Metastases in British Columbia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olson, Robert A., E-mail: rolson2@bccancer.bc.ca; University of Northern British Columbia, Prince George, British Columbia; University of British Columbia, Vancouver, British Columbia

Purpose: To assess the impact of a population-based intervention to increase the consistency and use of single-fraction radiation therapy (SFRT) for bone metastases. Methods and Materials: In 2012, an audit of radiation therapy prescriptions for bone metastases in British Columbia identified significant interphysician and -center (26%-73%) variation in the use of SFRT. Anonymous physician-level and identifiable regional cancer center SFRT use data were presented to all radiation oncologists, together with published guidelines, meta-analyses, and recommendations from practice leaders. The use of SFRT for bone metastases from 2007 through 2011 was compared with use of SFRT in 2013, to assess themore » impact of the audit and educational intervention. Multilevel logistic regression was used to assess the relationship between the usage of SFRT and the timing of the radiation while controlling for potentially confounding variables. Physician and center were included as group effects to account for the clustered structure of the data. Results: A total of 16,898 courses of RT were delivered from 2007 through 2011, and 3200 courses were delivered in 2013. The rates of SFRT use in 2007, 2008, 2009, 2010, 2011, and 2013 were 50.5%, 50.9%, 48.3%, 48.5%, 48.0%, and 59.7%, respectively (P<.001). Use of SFRT increased in each of 5 regional centers: A: 26% to 32%; B: 36% to 56%; C: 39% to 57%; D: 49% to 56%; and E: 73% to 85.0%. Use of SFRT was more consistent; 3 of 5 centers used SFRT for 56% to 57% of bone metastases RT courses. The regression analysis showed strong evidence that the usage of SFRT increased after the 2012 intervention (odds ratio 2.27, 95% confidence interval 2.06-2.50, P<.0001). Conclusion: Assessed on a population basis, an audit-based intervention increased utilization of SFRT for bone metastases. The intervention reversed a trend to decreasing SFRT use, reduced costs, and improved patient convenience. This suggests that dissemination of programmatic

Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases.

PubMed

Xie, Jipan; Namjoshi, Madhav; Wu, Eric Q; Parikh, Kejal; Diener, Melissa; Yu, Andrew P; Guo, Amy; Culver, Kenneth W

2011-10-01

Bone metastases are common in patients with hormone-refractory prostate cancer. In a study of autopsies of patients with prostate cancer, 65%-75% had bone metastases. Bone metastases place a substantial economic burden on payers with estimated total annual costs of $1.9 billion in the United States. Skeletal-related events (SREs), including pathologic fractures, spinal cord compression, surgery to bone, and radiation to bone, affect approximately 50% of patients with bone metastases. They are associated with a decreased quality of life and increased health care costs. Zoledronic acid is an effective treatment in preventing SREs in solid tumors and multiple myeloma. Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. A Phase 3 clinical trial (NCT00321620) demonstrated that denosumab had superior efficacy in delaying first and subsequent SREs compared with zoledronic acid. However, the economic value of denosumab has not been assessed in patients with hormone-refractory prostate cancer. To compare the cost-effectiveness of denosumab with zoledronic acid in the treatment of bone metastases in men with hormone-refractory prostate cancer. An Excel-based Markov model was developed to assess costs and effectiveness associated with the 2 treatments over a 1- and 3-year time horizon. Because the evaluation was conducted from the perspective of a U.S. third-party payer, only direct costs were included. Consistent with the primary outcome in the Phase 3 trial, effectiveness was assessed based on the number of SREs. The model consisted of 9 health states defined by SRE occurrence, SRE history, disease progression, and death. A hypothetical cohort of patients with hormone-refractory prostate cancer received either denosumab 120 mg or zoledronic acid 4 mg at the model entry and transitioned among the 9 health states at the beginning of each 13-week cycle. Transition probabilities associated with experiencing the first

Biochemical markers of bone turnover in patients with spinal metastases after resistance training under radiotherapy--a randomized trial.

PubMed

Rief, Harald; Omlor, Georg; Akbar, Michael; Bruckner, Thomas; Rieken, Stefan; Förster, Robert; Schlampp, Ingmar; Welzel, Thomas; Bostel, Tilman; Roth, Heinz Jürgen; Debus, Jürgen

2016-03-17

To compare the effects of resistance training versus passive physical therapy on bone turnover markers (BTM) in the metastatic bone during radiation therapy (RT) in patients with spinal bone metastases. Secondly, to evaluate an association of BTM to local response, skeletal-related events (SRE), and number of metastases. In this randomized trial, 60 patients were allocated from September 2011 to March 2013 into one of the two arms: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each arm during RT. Biochemical markers such as pyridinoline (PYD), desoxy-pyridinoline (DPD), bone alkaline phosphatase (BAP), total amino-terminal propeptide of type I collagen (PINP), beta-isomer of carboxy-terminal telopeptide of type I collagen (CTX-I), and cross-linked N-telopeptide of type I collagen (NTX) were analyzed at baseline, and three months after RT. Mean change values of PYD and CTX-I were significantly lower at 3 months after RT (p = 0.035 and p = 0.043) in Arm A. Importantly, all markers decreased in both arms, except of PYD and CTX-I in arm B, although significance was not reached for some biomarkers. In arm A, the local response was significantly higher (p = 0.003) and PINP could be identified as a predictor for survivors (OR 0.968, 95%CI 0.938-0.999, p = 0.043). BAP (OR 0.974, 95%CI 0.950-0.998, p = 0.034) and PINP (OR 1.025, 95%CI 1.001-1.049, p = 0.044) were related with an avoidance of SRE. In this group of patients with spinal bone metastases, we were able to show that patients with guided resistance training of the paravertebral muscles can influence BTM. PYD and CTX-I decreased significantly in arm A. PINP can be considered as a complementary tool for prediction of local response, and PINP as well as BAP for avoidance of SRE. Clinical trial identifier NCT 01409720. August 2, 2011.

Magnetic resonance guided focused ultrasound surgery (MRgFUS) of bone metastases: From primary pain palliation to local tumor control

NASA Astrophysics Data System (ADS)

Napoli, A.; Leonardi, A.; Andrani, F.; Boni, F.; Anzidei, M.; Catalano, C.

2017-03-01

Purpose: To evaluate the clinical performance of MRgFUS in primary pain palliation of painful bone metastases and in local tumor control. Materials and Methods: We enrolled 26 consecutive patients (female/male 12/14; age: 64.7±7.5yrs) with painful bone metastases. Before and 3 months after MRgFUS treatment pain severity and pain interference scores were assessed according to Brief Pain Inventory-Quality of Life (BPI-QoL) criteria and patients underwent both CT and MRI. Local tumor control was evaluated according to lesion size, density and perfusion at CT, dynamic contrast enhancement at MRI (Discovery 750HD, GE; Gd-Bopta, Bracco) and metabolic activity at PET or scintigraphy. Patients were classified as responders or non-responders. Results: No treatment-related adverse events were recorded during the study. As statistically significant difference between baseline and follow-up values for both pain severity and pain interference scores was observed (p<0.05). Increased bone density was observed in 9/26 (34.6%) patients. Non-Perfused Volume values ranged between 20% and 92%. There was no difference in NPV values between responders and non-responders (46.7±24.2% [25 - 90 %] vs. 45±24.9% [20 - 93 %]; p=0.7). In 6 patients (5 prostate and 1 breast primary cancer) there was nearly absence of metabolic activity after treatment (mean SUV=1.2). Conclusion: MRgFUS can be safely and effectively used as the primary treatment for pain palliation in patients with painful bone metastases; moreover our experience demonstrated also a potential role for the MRgFUS in local tumor control.

Management of Bone Metastases From Breast Cancer in Upper and Lower Body at the Same Time: A Case Report.

PubMed

Ciaglia, Gian Franco; Martino, Antonia; Sayad, Khadija; Scoglio, Claudio; Pezzulla, Donato; Cappabianca, Salvatore

2016-06-01

Breast cancer is by far the most common cancer in women, and it has the highest incidence rates in western Europe. At breast cancer diagnosis, approximately 5-6% of women present with distant spread with bone, representing the most common site of metastatic lesions. More than half of the women, who present with metastatic breast cancer at the primary diagnosis, will develop bone metastases. We report a clinical case of a 75-year-old woman, with a history of breast cancer who undergone surgery 7 years ago, presenting bone metastases in different areas. We tried to determinate the major areas of pain and then to quantify it with a one-dimensional scale. After that, we analyzed the images of the previous instrumental exams and the centering CT in order to compare them with what the patient reported and then to decide what we should have targeted first. The aim of our work was to try finding a methodology in order to determinate the priority in the selecting of the area to treat to apply in this kind of patients.

Management of Bone Metastases From Breast Cancer in Upper and Lower Body at the Same Time: A Case Report

PubMed Central

Ciaglia, Gian Franco; Martino, Antonia; Sayad, Khadija; Scoglio, Claudio; Pezzulla, Donato; Cappabianca, Salvatore

2016-01-01

Breast cancer is by far the most common cancer in women, and it has the highest incidence rates in western Europe. At breast cancer diagnosis, approximately 5-6% of women present with distant spread with bone, representing the most common site of metastatic lesions. More than half of the women, who present with metastatic breast cancer at the primary diagnosis, will develop bone metastases. We report a clinical case of a 75-year-old woman, with a history of breast cancer who undergone surgery 7 years ago, presenting bone metastases in different areas. We tried to determinate the major areas of pain and then to quantify it with a one-dimensional scale. After that, we analyzed the images of the previous instrumental exams and the centering CT in order to compare them with what the patient reported and then to decide what we should have targeted first. The aim of our work was to try finding a methodology in order to determinate the priority in the selecting of the area to treat to apply in this kind of patients. PMID:28983365

EARLY COMPLICATIONS IN THE ORTHOPEDIC TREATMENT OF BONE METASTASES

PubMed Central

Teixeira, Luiz Eduardo Moreira; Miranda, Ricardo Horta; Ghedini, Daniel Ferreira; Aguilar, Rafael Bazílio; Novais, Eduardo Nilo Vasconcelos; de Abreu e Silva, Guilherme Moreira; Araújo, Ivana Duval; de Andrade, Marco Antônio Percope

2015-01-01

Objective: To assess the early complications in the orthopedic treatment of metastatic bone lesions and the factors associated with these complications. Method: There were assessed, retrospectively, 64 patients that underwent surgical treatment for bone metastases, analyzing the complications that occurred in the pre-operative and early post- operative period and associating them with the tumor origin, type of procedure done, the need of blood reposition before the surgery, the need of new surgical procedures and the mortality due to the complications. Results: Early complications in the treatment were observed in 17 (26.6%) patients, of which six (35.2%) ended up dying due to these complications. Regarding the type, 15 (23.8%) cases were due to surgical complications, four (6.3%) clinical and three (4.7%) patients showed clinical and surgical complications. There was no significant difference in the frequency of complications or mortality when assessed the type of reconstruction or affected region. The tumors with a renal origin needed more blood reposition and showed a bigger frequency of complications. Conclusion: The complications occurred in 26.6%. The complications are not related to the kind of treatment performed or to the region affected. The renal origin tumors showed a higher risk of hemorrhage. PMID:27077063

Comparison of hybrid (68)Ga-PSMA PET/MRI and (68)Ga-PSMA PET/CT in the evaluation of lymph node and bone metastases of prostate cancer.

PubMed

Freitag, Martin T; Radtke, Jan P; Hadaschik, Boris A; Kopp-Schneider, A; Eder, Matthias; Kopka, Klaus; Haberkorn, Uwe; Roethke, Matthias; Schlemmer, Heinz-Peter; Afshar-Oromieh, Ali

2016-01-01

To evaluate the reproducibility of the combination of hybrid PET/MRI and the (68)Ga-PSMA-11 tracer in depicting lymph node (LN) and bone metastases of prostate cancer (PC) in comparison with that of PET/CT. A retrospective analysis of 26 patients who were subjected to (68)Ga-PSMA PET/CTlow-dose (1 h after injection) followed by PET/MRI (3 h after injection) was performed. MRI sequences included T1-w native, T1-w contrast-enhanced, T2-w fat-saturated and diffusion-weighted sequences (DWIb800). Discordant PET-positive and morphological findings were evaluated. Standardized uptake values (SUV) of PET-positive LNs and bone lesions were quantified and their morphological size and conspicuity determined. Comparing the PET components, the proportion of discordant PSMA-positive suspicious findings was very low (98.5 % of 64 LNs concordant, 100 % of 28 bone lesions concordant). Two PET-positive bone metastases could not be confirmed morphologically using CTlow-dose, but could be confirmed using MRI. In 12 of 20 patients, 47 PET-positive LNs (71.9 %) were smaller than 1 cm in short axis diameter. There were significant linear correlations between PET/MRI SUVs and PET/CT SUVs in the 64 LN metastases (p < 0.0001) and in the 28 osseous metastases (p < 0.0001) for SUVmean and SUVmax, respectively. The LN SUVs were significantly higher on PET/MRI than on PET/CT (p SUVmax < 0.0001; p SUVmean < 0.0001) but there was no significant difference between the bone lesion SUVs (p SUVmax = 0.495; p SUVmean = 0.381). Visibility of LNs was significantly higher on MRI using the T1-w contrast-enhanced fat-saturated sequence (p = 0.013), the T2-w fat-saturated sequence (p < 0.0001) and the DWI sequence (p < 0.0001) compared with CTlow-dose. For bone lesions, only the overall conspicuity was higher on MRI compared with CTlow-dose (p < 0.006). Nodal and osseous metastases of PC are accurately and reliably depicted by hybrid PET/MRI using (68)Ga

Bench to bedside development of GMP grade Rhenium-188-HEDP, a radiopharmaceutical for targeted treatment of painful bone metastases.

PubMed

ter Heine, Rob; Lange, Rogier; Breukels, Oscar B; Bloemendal, Haiko J; Rummenie, Rob G; Wakker, Antoinette M; de Graaf, Hilly; Beekman, Freek J; van der Westerlaken, Monique M L; Malingré, Mirte M; Wielders, Jos P M; van den Berg, Leo; Hendrikse, N Harry; de Klerk, John M H

2014-04-25

Bone-targeting therapeutic radiopharmaceuticals are effective agents for treatment of painful bone metastases. Rhenium-188-HEDP is such a therapeutic radiopharmaceutical and has advantages over commercially available alternatives in terms of efficacy, safety and the ability to be produced on-site, allowing rapid treatment upon presentation of patients with pain. Unlike many other radiopharmaceuticals, there are no standardized preparation methods for Rhenium-188-HEDP. It is known, however, that drug composition may not only affect stability of the final drug product, but it may also influence bone affinity and, thus, efficacy. Furthermore, for support of clinical studies with Rhenium-188-HEDP as an investigational medicinal product, preparation of this radiopharmaceutical has to be performed under GMP conditions. To our knowledge, no group has reported on the preparation of Rhenium-188-HEDP under GMP conditions or on stock production of sterile non-radioactive starting materials. We present the production of GMP grade Rhenium-188-HEDP for application of this therapeutic radiopharmaceutical in routine clinical practice and for support of clinical studies. In addition, bio-distribution data of Rhenium-188-HEDP in mice and in patients with bone metastases originating from prostate cancer are presented. Copyright © 2014 Elsevier B.V. All rights reserved.

HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition

PubMed Central

Gao, Ling; Deng, Hongju; Zhao, Haibo; Hirbe, Angela; Harding, John; Ratner, Lee; Weilbaecher, Katherine

2005-01-01

One in 20 carriers of human T-cell leukemia virus type 1 (HTLV-1) will develop adult T-cell leukemia/lymphoma (ATL), a disease frequently associated with hypercalcemia, bone destruction, and a fatal course refractory to current therapies. Overexpression of the HTLV-1–encoded Tax oncoprotein under the human granzyme B promoter causes large granular lymphocytic leukemia/lymphomas in mice. We found that Tax+ mice spontaneously developed hypercalcemia, high-frequency osteolytic bone metastases, and enhanced osteoclast activity. We evaluated Tax tumors for the production of osteoclast-activating factors. Purification of Tax+ tumor cells and nonmalignant tumor-infiltrating lymphocytes demonstrated that each of these populations expressed transcripts for distinct osteoclast-activating factors. We then evaluated the effect of osteoclast inhibition on tumor formation. Mice doubly transgenic for Tax and the osteoclast inhibitory factor, osteoprotegerin, were protected from osteolytic bone disease and developed fewer soft-tissue tumors. Likewise, osteoclast inhibition with bone-targeted zoledronic acid protected Tax+ mice from bone and soft-tissue tumors and prolonged survival. Tax+ mice represent the first animal model of high-penetrance spontaneous osteolytic bone metastasis and underscore the critical role of nonmalignant host cells recruited by tumor cells in the process of cancer progression and metastasis. PMID:16118323

Can peptide receptor radionuclide therapy be safely applied in florid bone metastases? A pilot analysis of late stage osseous involvement.

PubMed

Sabet, A; Khalaf, F; Yong-Hing, C J; Sabet, A; Haslerud, T; Ahmadzadehfar, H; Guhlke, S; Grünwald, F; Biersack, H-J; Ezziddin, S

2014-01-01

Highly advanced metastatic bone disease with extensive osseous infiltration of neuroendocrine tumours (NET) may preclude patients from treatment with peptide receptor radionuclide therapy (PRRT) in concern about haematotoxicity. This study aims to assess the safety and efficacy of PRRT with 177Lu-octreotate in a patient cohort with this condition. 41 PRRT courses were performed in 11 patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) and florid bone metastases (severely advanced widespread metastatic bone disease). A mean activity of 6.95 GBq 177Lu-octreotate was administered per treatment cycle, aimed at four courses with standard intervals of 3 months. Haematological parameters were determined prior to each treatment course, in 2-4 weeks intervals between the courses, 8-12 weeks after the last course of PRRT and in 3 monthly intervals thereafter. Toxicity was recorded using Common Terminology Criteria for Adverse Events v3.0. Restaging was performed 3 months after termination of PRRT with CT/MRI and functional imaging (modified MDA criteria). Significant (grade III-IV), reversible haematotoxicity occurred in 4 (35%) patients and after 10 (24%) administrations. It either resolved spontaneously (1 patient) or was controlled by supportive measures (3 patients), such as blood transfusions (3 patients) or deferral of the subsequent therapy cycle (1 patient). Patients returned to baseline blood values within up to 23 months after termination of PRRT. The observed treatment response of bone metastases consisted of a partial response in 2, a minor response in 1, stable disease in 7, and progressive disease in 1 patient. Of the 4 patients with metastatic bone pain, 1 experienced complete and 3 partial resolution of symptoms within 3-10 weeks after commencement of PRRT. These preliminary data indicate that PRRT with 177Lu-octreotate can be safely applied even in florid bone metastases with extensive, severely advanced osseous replacement. The higher

Animal Models of Bone Metastasis

PubMed Central

Simmons, J. K.; Hildreth, B. E.; Supsavhad, W.; Elshafae, S. M.; Hassan, B. B.; Dirksen, W. P.; Toribio, R. E.; Rosol, T. J.

2015-01-01

Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID:26021553

Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.

PubMed

Wan, Xinhai; Corn, Paul G; Yang, Jun; Palanisamy, Nallasivam; Starbuck, Michael W; Efstathiou, Eleni; Li Ning Tapia, Elsa M; Tapia, Elsa M Li-Ning; Zurita, Amado J; Aparicio, Ana; Ravoori, Murali K; Vazquez, Elba S; Robinson, Dan R; Wu, Yi-Mi; Cao, Xuhong; Iyer, Matthew K; McKeehan, Wallace; Kundra, Vikas; Wang, Fen; Troncoso, Patricia; Chinnaiyan, Arul M; Logothetis, Christopher J; Navone, Nora M

2014-09-03

Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors. Copyright © 2014, American Association for the Advancement of Science.

Meta-analysis of oral Chinese herbal medicine as an adjuvant treatment in relieving pain secondary to bone metastases.

PubMed

Wang, Shi-Jun; Xu, Juan; Gong, Dan-Dan; Man, Chang-Feng; Fan, Yu

2013-10-14

To assess the effectiveness of oral Chinese herbal medicine (CHM) in relieving pain secondary to bone metastases in patients. The searched electronic literature databases included both English and Chinese articles published in the MEDLINE, EMBASE, Wanfang database and China National Knowledge Infrastructure (up to December 2012). The studies included randomized controlled trials (RCTs) comparing CHM plus conventional treatment with conventional treatment alone for patients with pain secondary to bone metastases. The outcomes were the odds ratio (OR) with 95% confidence intervals (CI) for the pain-relief rate and adverse events. A total of 16 RCTs involving 1,008 patients were identified and analyzed. All of the included RCTs were associated with a moderate to high risk of bias. In the metaanalysis, CHM plus conventional treatment increased the pain-relief rate compared with the conventional treatment alone (OR, 2.59; 95% CI 1.95 to 3.45). In subgroup analysis, the pooled OR of the pain-relief rate of CHM plus conventional treatment compared with conventional treatment was 3.11 (95% CI 2.01 to 4.79) for CHM plus bisphosphonates, 2.24 (95% CI 1.33 to 3.78) for CHM plus analgesics, 2.28 (95% CI 1.09 to 4.79) for CHM plus radiotherapy, and 2.22 (95% CI 0.95 to 5.15) for CHM plus analgesics and bisphosphonates. The adverse events included nausea, vomiting, dizziness, fever, and constipation. No serious adverse events were reported in any of the included studies. CHM interventions appear to have beneficial effects on pain secondary to bone metastases in patients. However, published efficacy trials are small in size to draw any firm conclusions.

A systematic review on in vitro 3D bone metastases models: A new horizon to recapitulate the native clinical scenario?

PubMed

Salamanna, Francesca; Contartese, Deyanira; Maglio, Melania; Fini, Milena

2016-07-12

While the skeleton is not the only organ where metastasis can occur, it is one of the preferred sites, with a significant impact in patients' quality of life. With the aim of delineating the cellular and molecular mechanisms of bone metastasis, numerous studies have been employed to identify any contributing factors that trigger cancer progression. One of the major limitations of studying cancer-bone metastasis is the multifaceted nature of the native bone environment and the lack of reliable, simple, and not expensive models that strictly mimic the biological processes occurring in vivo allowing a correct translation of results. Currently, with the growing acceptance of in vitro models as effective tools for studying cancer biology, three-dimensional (3D) models have emerged as a compromise between two-dimensional cultures of isolated cancer cells and the complexity of human cancer xenografts in immunocompromised animal hosts. This descriptive systematic literature review summarizes the current status of advanced and alternative 3D in vitro bone metastases models. We have also reviewed the strategies employed by researchers to set-up these models with special reference to recent promising developments trying to better replicate the complexity and heterogeneity of a human metastasis in situ, with an outlook at their use in medicine. All these aspects will greatly contribute to the existing knowledge on bone metastases, providing a specific link to clinical scenarios and thus making 3D in vitro bone metastasis models an attractive tool for multidisciplinary experts.

Diagnostic imaging to detect and evaluate response to therapy in bone metastases from prostate cancer: current modalities and new horizons.

PubMed

Evangelista, Laura; Bertoldo, Francesco; Boccardo, Francesco; Conti, Giario; Menchi, Ilario; Mungai, Francesco; Ricardi, Umberto; Bombardieri, Emilio

2016-07-01

Different therapeutic options for the management of prostate cancer (PC) have been developed, and some are successful in providing crucial improvement in both survival and quality of life, especially in patients with metastatic castration-resistant PC. In this scenario, diverse combinations of radiopharmaceuticals (for targeting bone, cancer cells and receptors) and nuclear medicine modalities (e.g. bone scan, SPECT, SPECT/CT, PET and PET/CT) are now available for imaging bone metastases. Some radiopharmaceuticals are approved, currently available and used in the routine clinical setting, while others are not registered and are still under evaluation, and should therefore be considered experimental. On the other hand, radiologists have other tools, in addition to CT, that can better visualize bone localization and medullary involvement, such as multimodal MRI. In this review, the authors provide an overview of current management of advanced PC and discuss the choice of diagnostic modality for the detection of metastatic skeletal lesions in different phases of the disease. In addition to detection of bone metastases, the evaluation of response to therapy is another critical issue, since it remains one of the most important open questions that a multidisciplinary team faces when optimizing the management of PC. The authors emphasize the role of nuclear modalities that can presently be used in clinical practice, and also look at future perspectives based on relevant clinical data with novel radiopharmaceuticals.

Prostate Cancer Cell–Stromal Cell Cross-Talk via FGFR1 Mediates Antitumor Activity of Dovitinib in Bone Metastases

PubMed Central

Wan, Xinhai; Corn, Paul G.; Yang, Jun; Palanisamy, Nallasivam; Starbuck, Michael W.; Efstathiou, Eleni; Li-Ning Tapia, Elsa M.; Zurita, Amado J.; Aparicio, Ana; Ravoori, Murali K.; Vazquez, Elba S.; Robinson, Dan R.; Wu, Yi-Mi; Cao, Xuhong; Iyer, Matthew K.; McKeehan, Wallace; Kundra, Vikas; Wang, Fen; Troncoso, Patricia; Chinnaiyan, Arul M.; Logothetis, Christopher J.; Navone, Nora M.

2015-01-01

Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell–bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors. PMID:25186177

Radium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone

PubMed Central

2014-01-01

Background Hormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo. Methods The US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer. Results A 44-year-old white woman with metastatic breast cancer who was estrogen receptor–positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in 18F-FDG PET/CT and 18F-NaF bone PET/CT. The patient derived clinical benefit from therapy. Conclusion We have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA–approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a

A Simple and Effective Daily Pain Management Method for Patients Receiving Radiation Therapy for Painful Bone Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrade, Regiane S.; UPMC Radiation Oncology Outreach Program; Proctor, Julian W., E-mail: proctorj@upmc.ed

Purpose: The incidence of painful bone metastases increases with longer survival times. Although external beam radiation therapy (EBRT) is an effective palliative treatment, it often requires several days from the start of treatment to produce a measurable reduction in pain scores and a qualitative amelioration of patient pain levels. Meanwhile, the use of analgesics remains the best approach early on in the treatment course. We investigated the role of radiation therapists as key personnel for collecting daily pain scores to supplement assessments by physician and oncology nursing staff and manage pain more effectively during radiation treatment. Methods and Materials: Dailymore » pain scores were obtained by the radiation therapists for 89 patients undertaking a total of 124 courses of EBRT for bone metastases and compared with pretreatment pain scores. The majority of patients (71%) were treated to 30 Gy (range, 20-37.5) in 10 fractions (range, 8-15 fractions). Results: One hundred nineteen treatment courses (96%) were completed. Pain scores declined rapidly to 37.5%, 50%, and 75% of the pretreatment levels by Days 2, 4, and 10, respectively. Pain was improved in 91% of patients with only 4% of worse pain at the end of treatment. Improved pain scores were maintained in 83% of patients at 1-month follow-up, but in 35% of them, the pain was worse than at the end of treatment. Conclusions: Collection of daily pain scores by radiation therapists was associated with an effective reduction in pain scores early on during EBRT of painful osseous metastases.« less

Hypofractionated Radiotherapy for Complicated Bone Metastases in Patients with Poor Performance Status: A Phase II International Trial.

PubMed

Silva, Mauricio F; Marta, Gustavo N; Lisboa, Felipe P C; Watte, Guilherme; Trippa, Fabio; Maranzano, Ernesto; da Motta, Neiro W; Popovic, Marko; Ha, Tuan; Burmeister, Bryan; Chow, Edward

2017-06-01

Purpose To evaluate the efficacy and safety of hypofractionated radiotherapy (16 Gy in 2 fractions, 1 week apart) in patients with complicated bone metastases and poor performance status. Methods A prospective single-arm phase II clinical trial was conducted from July 2014 to May 2016. The primary endpoint was pain response as defined in the International Consensus on Palliative Radiotherapy Endpoints. Secondary endpoints included quality of life as measured by quality of life questionnaire (QLQ) PAL-15 and QLQ-BM22 European Organisation for Research and Treatment of Cancer guidelines, pain flare, adverse events, re-irradiation, and skeletal complications. Results Fifty patients were enrolled. There were 23 men with a median age of 58 years (range 26-86). Of the 50 patients, 38 had an extraosseous soft tissue component, 18 needed postsurgical radiation, 3 had neuropathic pain, and 3 had an impending fracture in a weight-bearing bone. At 2 months, 33 patients were alive (66%). Four (12.5%) had a complete response and 12 (37.5%) had a partial response. A statistically significant improvement was seen in the functional interference (p = 0.01) and psychosocial aspects (p = 0.03) of the BM22. No patient had spinal cord compression. One patient required surgery for pathologic fracture, and another re-irradiation. Conclusions Hypofractionated radiotherapy (16 Gy in 2 fractions of 8 Gy 1 week apart) achieved satisfactory pain relief and safety results in patients with complicated bone metastases and poor performance status.

Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone

PubMed Central

Liu, Jinsong; Zeng, Youyun; Shi, Shuai; Xu, Lihua; Zhang, Hualin; Pathak, Janak L; Pan, Yihuai

2017-01-01

Treatment of cancer metastasized to bone is still a challenge due to hydrophobicity, instability, and lack of target specificity of anticancer drugs. Poly (ethylene glycol)-poly (ε-caprolactone) polymer (PEG-PCL) is an effective, biodegradable, and biocompatible hydrophobic drug carrier, but lacks bone specificity. Polyaspartic acid with eight peptide sequences, that is, (Asp)8, has a strong affinity to bone surface. The aim of this study was to synthesize (Asp)8-PEG-PCL nanoparticles as a bone-specific carrier of hydrophobic drugs to treat cancer metastasized to bone. 1H nuclear magnetic resonance, Fourier transform infrared spectroscopy, and transmission electron microscopy data showed that (Asp)8-PEG-PCL nanoparticles (size 100 nm) were synthesized successfully. (Asp)8-PEG-PCL nanoparticles did not promote erythrocyte aggregation. Fluorescence microscopy showed clear uptake of Nile red-loaded (Asp)8-PEG-PCL nanoparticles by cancer cells. (Asp)8-PEG-PCL nanoparticles did not show cytotoxic effect on MG63 and human umbilical vein endothelial cells at the concentration of 10–800 μg/mL. (Asp)8-PEG-PCL nanoparticles bound with hydroxyapatite 2-fold more than PEG-PCL. Intravenously injected (Asp)8-PEG-PCL nanoparticles accumulated 2.7-fold more on mice tibial bone, in comparison to PEG-PCL. Curcumin is a hydrophobic anticancer drug with bone anabolic properties. Curcumin was loaded in the (Asp)8-PEG-PCL. (Asp)8-PEG-PCL showed 11.07% loading capacity and 95.91% encapsulation efficiency of curcumin. The curcumin-loaded (Asp)8-PEG-PCL nanoparticles gave sustained release of curcumin in high dose for >8 days. The curcumin-loaded (Asp)8-PEG-PCL nanoparticles showed strong antitumorigenic effect on MG63, MCF7, and HeLa cancer cells. In conclusion, (Asp)8-PEG-PCL nanoparticles were biocompatible, permeable in cells, a potent carrier, and an efficient releaser of hydrophobic anticancer drug and were bone specific. The curcumin-loaded (Asp)8-PEG-PCL nanoparticles showed

Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone.

PubMed

Liu, Jinsong; Zeng, Youyun; Shi, Shuai; Xu, Lihua; Zhang, Hualin; Pathak, Janak L; Pan, Yihuai

2017-01-01

Treatment of cancer metastasized to bone is still a challenge due to hydrophobicity, instability, and lack of target specificity of anticancer drugs. Poly (ethylene glycol)-poly (ε-caprolactone) polymer (PEG-PCL) is an effective, biodegradable, and biocompatible hydrophobic drug carrier, but lacks bone specificity. Polyaspartic acid with eight peptide sequences, that is, (Asp) 8 , has a strong affinity to bone surface. The aim of this study was to synthesize (Asp) 8 -PEG-PCL nanoparticles as a bone-specific carrier of hydrophobic drugs to treat cancer metastasized to bone. 1 H nuclear magnetic resonance, Fourier transform infrared spectroscopy, and transmission electron microscopy data showed that (Asp) 8 -PEG-PCL nanoparticles (size 100 nm) were synthesized successfully. (Asp) 8 -PEG-PCL nanoparticles did not promote erythrocyte aggregation. Fluorescence microscopy showed clear uptake of Nile red-loaded (Asp) 8 -PEG-PCL nanoparticles by cancer cells. (Asp) 8 -PEG-PCL nanoparticles did not show cytotoxic effect on MG63 and human umbilical vein endothelial cells at the concentration of 10-800 μg/mL. (Asp) 8 -PEG-PCL nanoparticles bound with hydroxyapatite 2-fold more than PEG-PCL. Intravenously injected (Asp) 8 -PEG-PCL nanoparticles accumulated 2.7-fold more on mice tibial bone, in comparison to PEG-PCL. Curcumin is a hydrophobic anticancer drug with bone anabolic properties. Curcumin was loaded in the (Asp) 8 -PEG-PCL. (Asp) 8 -PEG-PCL showed 11.07% loading capacity and 95.91% encapsulation efficiency of curcumin. The curcumin-loaded (Asp) 8 -PEG-PCL nanoparticles gave sustained release of curcumin in high dose for >8 days. The curcumin-loaded (Asp) 8 -PEG-PCL nanoparticles showed strong antitumorigenic effect on MG63, MCF7, and HeLa cancer cells. In conclusion, (Asp) 8 -PEG-PCL nanoparticles were biocompatible, permeable in cells, a potent carrier, and an efficient releaser of hydrophobic anticancer drug and were bone specific. The curcumin-loaded (Asp) 8 -PEG

Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial.

PubMed

Fizazi, Karim; Bosserman, Linda; Gao, Guozhi; Skacel, Tomas; Markus, Richard

2009-08-01

Patients with bone metastases have high rates of RANKL driven bone resorption and an increased risk of skeletal morbidity. Osteoclast mediated bone resorption can be assessed by measuring urine N-telopeptide and can be inhibited by denosumab, a fully human antibody against RANKL. Eligible patients (111) had bone metastases from prostate cancer, other solid tumors or multiple myeloma, 1 or more bone lesions and urine N-telopeptide greater than 50 nM bone collagen equivalents per mM creatinine (urine N-telopeptide greater than 50) despite the use of intravenous bisphosphonates. Patients were stratified by cancer type and screening urine N-telopeptide, and randomized to continue intravenous bisphosphonates every 4 weeks or receive 180 mg subcutaneous denosumab every 4 weeks or 180 mg every 12 weeks. The primary end point was the proportion of patients with urine N-telopeptide less than 50 at week 13. We report the efficacy results for the subset of patients with prostate cancer. Patients with prostate cancer represented 45% (50 of 111) of the study population. At week 13, 22 of 32 (69%) patients in the denosumab arms had urine N-telopeptide less than 50 vs 3 of 16 (19%) in the intravenous bisphosphonates cohort. At week 25, 22 of 32 (69%) denosumab treated patients continued to have urine N-telopeptide less than 50 vs 5 of 16 (31%) treated with intravenous bisphosphonates. Grade 4, asymptomatic, reversible hypophosphatemia, possibly related to denosumab, was reported in 1 patient. In patients with prostate cancer related bone metastases and increased urine N-telopeptide despite intravenous bisphosphonate treatment, denosumab normalized urine N-telopeptide levels more frequently than ongoing intravenous bisphosphonates.

Metastases to bones.

PubMed

Wick, Mark R

2014-01-01

Metastatic tumors involving the bones may derive from a number of visceral primary sites, and they can assume several histological appearances. In selected instances, diagnostic confusion with some primary bone tumors may eventuate, necessitating the use of adjunctive pathologic studies to reach a final interpretation. This review considers metastatic osseous neoplasms in the small-cell, large-polygonal-cell, and spindle-cell-pleomorphic microscopic categories. The use of immunohistology and molecular analysis to study such tumors is discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

Occurrence of metastases in beagles with skeletal malignancies induced by internal irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lloyd, R.D.; Angus, W.; Taylor, G.N.

1994-03-01

Metastases from malignant bone tumors often are responsible for the fatal effects of these cancers. Characteristics of primary skeletal malignancies in beagles injected with bone-seeking radionuclides were studied by Thurman (1971) and summarized by Thurman et al. (1971). There were 212 tumors in 186 of these dogs for which we subsequently received information on bone tumor metastases. Evaluation of bone and soft tissue slides from these animals allowed us to compare parameters reported previously with the occurrence of grossly apparent bone tumor metastases. Data included growth-rate of the primary tumor, volume of the primary tumor at death, sex of themore » animal, growth period of the primary tumor, degree of calcification of the primary tumor, skeletal location of the primary tumor, cumulative radiation dose to the skeleton, dose equivalent to the skeleton, and year of death. For most of the comparisons, no significant differences could be established between dogs with and without metastases. However, tumor volume at death appeared to be correlated with probability of metastasis (p < 0.05), with the larger tumors being associated with higher rates of metastasis. Comparisons of dogs with and without metastases as a function of tumor growth-rate did not, for the most part, yield significantly different results between groups. 10 refs., 11 tabs.« less

Occipital anaplastic oligodendroglioma with multiple organ metastases after a short clinical course: a case report and literature review

PubMed Central

2014-01-01

Background It is generally believed that malignant gliomas never metastasize outside the central nervous system (CNS). However, the notion that oligodendrogliomas (OGDs) cells cannot spread outside CNS is being challenged. Methods We described in detail the clinical story of one patient with anaplastic OGD, which metastasized to lymph nodes, bone marrowand bones Genetic analyses included detection of 1p and 19q chromosomal arms, methylation status of MGMT promoter, and PTEN exon mutations. A search of worldwide literature was conducted for reports of metastatic OGDs using NCBI-PubMed, with the keywords “extracranial”, “extraneural”, “oligodendroglioma”, “oligodendrogliomas”, “metastatic”, “metastasis”, and “metastases”, in different combinations. Results An open biopsy of the infiltrated bones in our patient revealed that malignant cells had replaced the patient’s marrow. Moreover, the diagnosis of multiple-organ metastases of anaplastic OGD was confirmed based on immunohistochemical staining. Genetic analyses showed that the tumors originated from previously resected brain lesions. None of the lesions had 1p and 19q deletions, but hypermethylation of MGMT promoter, and the G → A transversion at codon 234 of PTEN exon 2 were detected. Literatures review yielded 60 reports of metastatic OGDs from 1951 to the present, which with our patient makes 61 cases. Concerning these 61 patients, there were 110 infiltrated sites correlated closely with primary OGDs. The most frequent metastatic sites were bone and bone marrow (n = 47; 42.7%), lymph nodes (n = 22; 20.0%), liver (n = 7; 6.4%), scalp (n = 6; 5.5%), lung (n = 6; 5.5%), pleura (n = 4; 3.6%), chest wall (n = 3; 2.7%), iliopsoas muscle (n = 2; 1.8%), soft tissue (n = 2; 1.8%), and parotid gland (n = 2; 1.8%). Conclusions Extracranial metastases in anaplastic OGD are very rare but they do occur; bone and bone marrow may be the most common sites. Detection of certain molecular markers

External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation

NASA Astrophysics Data System (ADS)

Naveen, T.; Supe, Sanjay S.; Ganesh, K. M.; Samuel, Jacob

2009-01-01

Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p < 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended.

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

PubMed Central

Fizazi, Karim; Carducci, Michael; Smith, Matthew; Damião, Ronaldo; Brown, Janet; Karsh, Lawrence; Milecki, Piotr; Shore, Neal; Rader, Michael; Wang, Huei; Jiang, Qi; Tadros, Sylvia; Dansey, Roger; Goessl, Carsten

2011-01-01

Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1

A Prospective Study of Bone Tumor Response Assessment in Metastatic Breast Cancer

PubMed Central

Hayashi, Naoki; Costelloe, Colleen M.; Hamaoka, Tsuyoshi; Wei, Caimiao; Niikura, Naoki; Theriault, Richard L.; Hortobagyi, Gabriel N.; Madewell, John E.; Ueno, Naoto T.

2013-01-01

In this pilot study, we prospectively compared the response of bone metastasis assessed by our MD Anderson (MDA) bone tumor response criteria (computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) with the response assessed by the World Health Organization (WHO) criteria (XR and SS). Both MDA and WHO criteria predicted progression-free survival (PFS) of patients at 6 months but not at an earlier time point. Background In our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases. Methods We prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions. Results The median follow-up period was 26.7 months (range, 6.1–53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases. Conclusion MDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA

(153)Sm-EDTMP for pain relief of bone metastases from prostate and breast cancer and other malignancies.

PubMed

Correa-González, Luis; Arteaga de Murphy, Consuelo; Pichardo-Romero, Pablo; Pedraza-López, Martha; Moreno-García, Claudia; Correa-Hernández, Luis

2014-05-01

Approximately 85% of patients with cancer suffer severe metastatic bone pain for which radionuclide therapy has been employed for pain palliation. We undertook this study to evaluate the pain relief effect of (153)Sm-EDTMP in Mexican patients with severe and painful bone metastases from mainly prostate, breast, and renal cancer and other malignancies. Patients (277) with intense sustained pain caused by bone metastases were referred to the Nuclear Medicine Department of the Oncology Hospital of the Mexican Social Security Institute. The patients had to have acceptable physical conditions, a previous positive (99m)Tc-MDP scan and blood values within normal range. (153)Sm-EDTMP was prepared at the Instituto Nacional de Investigaciones Nucleares (ININ) and 37 MBq/kg of body weight was injected intravenously. Pain palliation was evaluated with a visual analogue scale (VAS) and a verbal rating scale (VRS) before treatment and 3 and 12 weeks after treatment was started. The age interval of the patients was 24-92 years with a mean age of 64 ± 12 years. Mean values for hemoglobin, leukocyte and platelet counts did not statistically differ at zero time, 3 and 12 weeks after treatment. Pain intensity and relief assessment were statistically different: 9.1 ± 0.61 units initially; 4.2 ± 1.3 units 3 weeks later (54%) and after 12 weeks the pain diminished to 2.4 ± 1.4 units (74%) in the pain relief score scales. (153)Sm-EDTMP was readily available, safe and well tolerated. We conclude that (153)Sm-EDTMP was an adequate palliative agent and was the best option for our Mexican patients to relieve their severe metastatic bone pain. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.

Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial.

PubMed

Fizazi, Karim; Bosserman, Linda; Gao, Guozhi; Skacel, Tomas; Markus, Richard

2013-01-01

Patients with bone metastases have high rates of RANKL driven bone resorption and an increased risk of skeletal morbidity. Osteoclast mediated bone resorption can be assessed by measuring urine N-telopeptide and can be inhibited by denosumab, a fully human antibody against RANKL. Eligible patients (111) had bone metastases from prostate cancer, other solid tumors or multiple myeloma, 1 or more bone lesions and urine N-telopeptide greater than 50 nM bone collagen equivalents per mM creatinine (urine N-telopeptide greater than 50) despite the use of intravenous bisphosphonates. Patients were stratified by cancer type and screening urine N-telopeptide, and randomized to continue intravenous bisphosphonates every 4 weeks or receive 180 mg subcutaneous denosumab every 4 weeks or 180 mg every 12 weeks. The primary end point was the proportion of patients with urine N-telopeptide less than 50 at week 13. We report the efficacy results for the subset of patients with prostate cancer. Patients with prostate cancer represented 45% (50 of 111) of the study population. At week 13, 22 of 32 (69%) patients in the denosumab arms had urine N-telopeptide less than 50 vs 3 of 16 (19%) in the intravenous bisphosphonates cohort. At week 25, 22 of 32 (69%) denosumab treated patients continued to have urine N-telopeptide less than 50 vs 5 of 16 (31%) treated with intravenous bisphosphonates. Grade 4, asymptomatic, reversible hypophosphatemia, possibly related to denosumab, was reported in 1 patient. In patients with prostate cancer related bone metastases and increased urine N-telopeptide despite intravenous bisphosphonate treatment, denosumab normalized urine N-telopeptide levels more frequently than ongoing intravenous bisphosphonates. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Combined Microwave Ablation and Cementoplasty in Patients with Painful Bone Metastases at High Risk of Fracture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pusceddu, Claudio, E-mail: clapusceddu@gmail.com; Sotgia, Barbara, E-mail: barbara.sotgia@gmail.com; Fele, Rosa Maria, E-mail: rosellafele@tiscali.it

2016-01-15

PurposeTo retrospectively evaluate the effectiveness of computed tomography-guided percutaneous microwave ablation (MWA) and cementoplasty in patients with painful bone metastases at high risk of fracture.Materials and MethodsThirty-five patients with 37 metastatic bone lesions underwent computed tomography-guided MWA combined with cementoplasty (polymethylmethacrylate injection). Vertebrae, femur, and acetabulum were the intervention sites and the primary end point was pain relief. Pain severity was estimated by visual analog scale (VAS) before treatment; 1 week post-treatment; and 1, 6, and 12 months post-treatment. Functional outcome was assessed by improved patient walking ability. Radiological evaluation was performed at baseline and 3 and 12 months post-procedure.ResultsIn all patients, painmore » reduction occurred from the first week after treatment. The mean reduction in the VAS score was 84, 90, 90 % at week 1, month 1, and month 6, respectively. Improved walking ability occurred in 100 and 98 % of cases at the 1- and 6-month functional outcome evaluations, respectively. At the 1-year evaluation, 25 patients were alive, and 10 patients (28 %) had died because of widespread disease. The mean reduction in the VAS score and improvement in surviving patients’ walking ability were 90 and 100 %, respectively. No patients showed evidence of local tumor recurrence or progression and pathological fracture in the treated sites.ConclusionOur results suggest that MWA combined with osteoplasty is safe and effective when treating painful bone metastases at high risk of fracture. The number of surviving patients at the 1-year evaluation confirms the need for an effective and long-lasting treatment.« less

Bone Metastasis in Prostate Cancer: Recurring Mitochondrial DNA Mutation Reveals Selective Pressure Exerted by the Bone Microenvironment

PubMed Central

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

2015-01-01

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

Prospective comparison of 68Ga-PSMA PET/CT, 18F-sodium fluoride PET/CT and diffusion weighted-MRI at for the detection of bone metastases in biochemically recurrent prostate cancer.

PubMed

Zacho, Helle D; Nielsen, Julie B; Afshar-Oromieh, Ali; Haberkorn, Uwe; deSouza, Nandita; De Paepe, Katja; Dettmann, Katja; Langkilde, Niels C; Haarmark, Christian; Fisker, Rune V; Arp, Dennis T; Carl, Jesper; Jensen, Jørgen B; Petersen, Lars J

2018-06-06

To prospectively compare diagnostic accuracies for detection of bone metastases by 68 Ga-PSMA PET/CT, 18 F-NaF PET/CT and diffusion-weighted MRI (DW 600 -MRI) in prostate cancer (PCa) patients with biochemical recurrence (BCR). Sixty-eight PCa patients with BCR participated in this prospective study. The patients underwent 68 Ga-PSMA PET/CT, a 18 F-NaF PET/CT and a DW 600 -MRI (performed in accordance with European Society of Urogenital Radiology guidelines, with b values of 0 and 600 s/mm 2 ). Bone lesions were categorized using a three-point scale (benign, malignant or equivocal for metastases) and a dichotomous scale (benign or metastatic) for each imaging modality by at least two experienced observers. A best valuable comparator was defined for each patient based on study-specific imaging, at least 12 months of clinical follow-up and any imaging prior to the study and during follow-up. Diagnostic performance was assessed using a sensitivity analysis where equivocal lesions were handled as non-metastatic and then as metastatic. Ten of the 68 patients were diagnosed with bone metastases. On a patient level, sensitivity, specificity and the area under the curve (AUC) by receiver operating characteristic analysis were, respectively, 0.80, 0.98-1.00 and 0.89-0.90 for 68 Ga-PSMA PET/CT (n = 68 patients); 0.90, 0.90-0.98 and 0.90-0.94 for 18 NaF PET/CT (n = 67 patients); and 0.25-0.38, 0.87-0.92 and 0.59-0.62 for DW 600 -MRI (n = 60 patients). The diagnostic performance of DW 600 -MRI was significantly lower than that of 68 Ga-PSMA PET/CT and 18 NaF PET/CT for diagnosing bone metastases (p < 0.01), and no significant difference in the AUC was seen between 68 Ga-PSMA PET/CT and 18 NaF PET/CT (p = 0.65). 68 Ga-PSMA PET/CT and 18 F-NaF PET/CT showed comparable and high diagnostic accuracies for detecting bone metastases in PCa patients with BCR. Both methods performed significantly better than DW 600 -MRI, which was inadequate for diagnosing bone

Autologous Bone Marrow Stromal Cells Genetically Engineered to Secrete an IGF-I Receptor Decoy Prevent the Growth of Liver Metastases

PubMed Central

Wang, Ni; Fallavollita, Lucia; Nguyen, Long; Burnier, Julia; Rafei, Moutih; Galipeau, Jacques; Yakar, Shoshana; Brodt, Pnina

2009-01-01

Liver metastases respond poorly to current therapy and remain a frequent cause of cancer-related mortality. We reported previously that tumor cells expressing a soluble form of the insulin-like growth factor-I receptor (sIGFIR) lost the ability to metastasize to the liver. Here, we sought to develop a novel therapeutic approach for prevention of hepatic metastasis based on sustained in vivo delivery of the soluble receptor by genetically engineered autologous bone marrow stromal cells. We found that when implanted into mice, these cells secreted high plasma levels of sIGFIR and inhibited experimental hepatic metastases of colon and lung carcinoma cells. In hepatic micrometastases, a reduction in intralesional angiogenesis and increased tumor cell apoptosis were observed. The results show that the soluble receptor acted as a decoy to abort insulin-like growth factor-I receptor (IGF-IR) functions during the early stages of metastasis and identify sustained sIGFIR delivery by cell-based vehicles as a potential approach for prevention of hepatic metastasis. PMID:19367255

Texture analysis of apparent diffusion coefficient maps for treatment response assessment in prostate cancer bone metastases-A pilot study.

PubMed

Reischauer, Carolin; Patzwahl, René; Koh, Dow-Mu; Froehlich, Johannes M; Gutzeit, Andreas

2018-04-01

To evaluate whole-lesion volumetric texture analysis of apparent diffusion coefficient (ADC) maps for assessing treatment response in prostate cancer bone metastases. Texture analysis is performed in 12 treatment-naïve patients with 34 metastases before treatment and at one, two, and three months after the initiation of androgen deprivation therapy. Four first-order and 19 second-order statistical texture features are computed on the ADC maps in each lesion at every time point. Repeatability, inter-patient variability, and changes in the feature values under therapy are investigated. Spearman rank's correlation coefficients are calculated across time to demonstrate the relationship between the texture features and the serum prostate specific antigen (PSA) levels. With few exceptions, the texture features exhibited moderate to high precision. At the same time, Friedman's tests revealed that all first-order and second-order statistical texture features changed significantly in response to therapy. Thereby, the majority of texture features showed significant changes in their values at all post-treatment time points relative to baseline. Bivariate analysis detected significant correlations between the great majority of texture features and the serum PSA levels. Thereby, three first-order and six second-order statistical features showed strong correlations with the serum PSA levels across time. The findings in the present work indicate that whole-tumor volumetric texture analysis may be utilized for response assessment in prostate cancer bone metastases. The approach may be used as a complementary measure for treatment monitoring in conjunction with averaged ADC values. Copyright © 2018 Elsevier B.V. All rights reserved.

[Lymph node and distant metastases of thyroid gland cancer. Metastases in the thyroid glands].

PubMed

Schmid, K W

2015-11-01

The different biological features of the various major entities of thyroid cancer, e.g. papillary, follicular, poorly differentiated, anaplastic and medullary, depend to a large extent on their different metastatic spread. Papillary thyroid cancer (PTC) has a propensity for cervical lymphatic spread that occurs in 20-50 % of patients whereas distant metastasis occurs in < 5 % of cases. Cervical lymphadenopathy may be the first symptom particularly of (micro) PTC. In contrast follicular thyroid cancer (FTC) has a marked propensity for vascular but not lymphatic invasion and 10-20 % of FTC develop distant metastases. At the time of diagnosis approximately one third of medullary thyroid cancer (MTC) cases show lymph node metastases, in 10-15 % distant metastases and 25 % develop metastases during the course of the disease. Poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) spread via both lymphatic and vascular invasion. Thus distant metastases are relatively uncommon in DTC and when they occur, long-term stable disease is the typical clinical course. The major sites of distant metastases are the lungs and bone. Metastases to the brain, breasts, liver, kidneys, muscle and skin are relatively rare or even rare. The thyroid gland itself can be a site of metastases from a variety of other tumors. In autopsy series of patients with disseminated cancer disease, metastases to the thyroid gland were found in up to 10 % of cases. Metastases from other primary tumors to the thyroid gland have been reported in 1.4-3 % of patients who have surgery for suspected cancer of the thyroid gland. The most common primary cancers that metastasize to the thyroid gland are renal cell (48.1 %), colorectal (10.4 %), lung (8.3 %) and breast cancer (7.8 %) and surprisingly often sarcomas (4.0 %).

Paget's disease of bone resembling bone metastasis from gastric cancer.

PubMed

Shimoyama, Yasuyuki; Kusano, Motoyasu; Shimoda, Yoko; Ishihara, Shingo; Toyomasu, Yoshitaka; Ohno, Tetsuro; Mochiki, Erito; Sano, Takaaki; Hirato, Junko; Mori, Masatomo

2011-08-01

A 74-year-old man had an endoscopic type 0'-IIc tumor in the upper gastric body on the greater curvature and biopsy showed the tumor to be a well-differentiated adenocarcinoma (Group 5). He was referred to us for endoscopic submucosal dissection (ESD). Endoscopy revealed fold convergency, fold swelling, and fusion of the fold, indicating tumor invasion into the submucosa, which was outside the indications for ESD. In addition, there was an increase of serum bone-type alkaline phosphatase (ALP-III and ALP-IV) and urinary cross-linked N-terminal telopeptide of type I collagen (a bone metabolism marker), while (18)F-fluorodeoxyglucose positron emission tomography showed increased uptake in the left pelvis and Th10, suggesting bone metastases. We first diagnosed gastric cancer with bone metastases; however, the symptoms suggested pathological bone fracture and no bone pain. Therefore, a computed tomography-guided aspiration bone biopsy was performed to exclude the possibility of Paget's disease of bone. Biopsy specimens revealed no tumor and a mosaic pattern. No increased uptake of (18)F-FAMT (L-[3-(18)F] α-methyltyrosine) supported a diagnosis of no bone metastases from gastric cancer. We finally diagnosed gastric cancer accompanied by Paget's disease of bone and performed a laparoscopy-assisted proximal gastrectomy. The pathological diagnosis was U less 0-IIb, and U post 0-IIc ypT1a (M) N0H0P0M0 yp stage IA. In gastric cancer patients with suspected bone metastasis, we also need to consider Paget's disease of bone.

The botanical molecule p-hydroxycinnamic acid as a new osteogenic agent: insight into the treatment of cancer bone metastases.

PubMed

Yamaguchi, Masayoshi

2016-10-01

Bone homeostasis is maintained through a balance between osteoblastic bone formation and osteoclastic bone resorption. Bone loss with aging is induced by decreasing in osteoblastic bone formation and increasing in osteoclastic bone resorption, thereby leading to osteoporosis. Osteoporosis with its accompanying decrease in bone mass is widely recognized as a major public heath problem. Pharmacologic and nutritional factors may play a role in the prevention and treatment of bone loss with aging. p-Hydroxycinnamic acid (HCA), which stimulates bone mineralization in mouse bone tissues in vitro, has been found to be present in the leafstalk of wasabi (Wasabi japonica MATSUM) among various food and plants. Other phenolic acids including cinnamic acid, ferulic acid, caffeic acid and 3,4-dimethoxycinnamic acid did not have osteogenic effects. HCA was demonstrated to stimulate osteoblastic bone formation and suppresses osteoclastic bone resorption in vitro by antagonizing activation of the nuclear factor kappa B. Oral administration of HCA was found to exhibit restorative effects on bone loss induced by ovariectomy and diabetic states, supporting a role in the treatment of osteoporosis. Moreover, HCA was demonstrated to prevent the suppressed osteoblastic mineralization and the enhanced osteoclastogenesis in mouse bone marrow cells cocultured with bone metastatic MDA-MB-231 human breast cancer cells in vitro. The botanical molecule HCA, as a new osteogenic agent, is suggested to play a role in the treatment of cancer bone metastases. This review will discuss an advanced recent finding that HCA may be a useful agent to treat bone metabolic disorder.

Assessment of zoledronic acid treatment patterns and clinical outcomes in patients with bone metastases from genitourinary cancers.

PubMed

Henk, Henry J; Kaura, Satyin

2012-01-01

Patients with bone metastases secondary to genitourinary (GU) cancer are at risk for skeletal-related events (SREs), including bone pain requiring palliative radiotherapy, fractures or surgery to bone, spinal cord compression, and hypercalcemia of malignancy. These SREs can be debilitating and potentially life-limiting. This study examined treatment practices and the association of treatment patterns with Zometa (zoledronic acid, ZOL), an intravenous bisphosphonate (IV-BP), with SREs and fractures. (Zometa is a registered trademark of Novartis Pharmaceuticals Corporation, USA.) Retrospective analysis of commercial and Medicare Advantage enrollment and medical claims data was performed to evaluate IV-BP use and SRE patterns in adult patients with GU cancers. Criteria included diagnosis of ≥1 bone metastasis and prostate cancer (PC), renal cell carcinoma (RCC), or bladder cancer (BlC) between January 2001 and December 2006; continuous healthcare plan enrollment for ≥6 months before the index date; and no evidence of prior IV-BP use. Patients were followed until disenrollment from the healthcare plan or December 2007. Of 6347 patients (PC, n = 4976; RCC, n = 941; BlC, n = 430; mean [standard deviation] age: 68.9 [11.1] years), only approximately 23% received ZOL. The mean time between diagnosis of bone metastasis and ZOL initiation was approximately 108 days. Among patients with PC, fracture risk was significantly smaller for ZOL vs no IV-BP (incidence rate ratio = 0.70; p < 0.001), and 2-year survival was significantly longer for ZOL-treated vs no IV-BP patients (p = 0.007). Patients with longer persistency on ZOL had a smaller fracture risk than patients with shorter persistency. Sub-set analyses were not performed for RCC and BIC because the proportion of patients treated was too low. Interpretation of this claims-based analysis must be tempered by the inherent limitations of observational data, such as limited and accurate available

Value of percutaneous radiofrequency ablation with or without percutaneous vertebroplasty for pain relief and functional recovery in painful bone metastases.

PubMed

Clarençon, Frédéric; Jean, Betty; Pham, Hang-Phuong; Cormier, Evelyne; Bensimon, Gilbert; Rose, Michèle; Maksud, Philippe; Chiras, Jacques

2013-01-01

To evaluate the effectiveness of percutaneous radiofrequency (RF) ablation with or without percutaneous vertebroplasty (PV) on pain relief, functional recovery and local recurrence at 6 months' follow-up (FU), in patients with painful osseous metastases. Thirty RF ablations were performed in 24 patients (mean age: 61 years) with bone metastases. Half of the patients had an additional PV. The primary end point was pain relief evaluated by a visual analogue scale (VAS) before treatment, and at 1 and 6 months' FU. Functional outcome was assessed according to the evolution of their ability to walk at 6 months' FU. Imaging FU was available in 20 out of 24 patients with a mean delay of 4.7 months. Reduction of pain was obtained at 6 months FU in 81% of cases (15 out of 18). Mean pretreatment VAS was 6.4 (±2.7). Mean VAS was 1.9 (±2.4) at 1 month FU, and 2.3 (±2.9) at 6 months' FU. Pain was significantly reduced at 6 months FU (mean VAS reduction = 4.1; P < 0.00001). Functional improvement was obtained in 74% of the cases. Major complications rate was 12.5 % (3 out of 24) with 2 skin burns, and 1 case of myelopathy. Local tumour recurrence or progression was recorded in 5 cases. Radiofrequency ablation is an effective technique in terms of pain relief and functional recovery for the treatment of bone metastases, which provides a relatively low rate of local recurrence.

Fluorodeoxyglucose Uptake on Positron Emission Tomography Is a Useful Predictor of Long-Term Pain Control After Palliative Radiation Therapy in Patients With Painful Bone Metastases: Results of a Single-Institute Prospective Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tahara, Takatoshi, E-mail: taka.t-may7@med.Tottori-u.ac.jp; Fujii, Shinya; Ogawa, Toshihide

Purpose: To determine whether fluorodeoxyglucose positron emission tomography (FDG-PET) before and after palliative radiation therapy (RT) can predict long-term pain control in patients with painful bone metastases. Methods and Materials: Thirty-one patients with bone metastases who received RT were prospectively included. Forty painful metastatic treatment fields were evaluated. All patients had undergone pre-RT and post-RT PET/CT scanning. We evaluated the relationships between the pre-RT, post-RT, and changes in maximum standardized uptake value (SUV{sub max}) and the pain response, and between SUV{sub max} and pain relapse of the bone metastases in the treatment field. In addition, we compared the SUV{sub max}more » according to the length of time from the completion of RT to pain relapse of the bone metastases. Results: Regarding the pain response at 4 weeks after the completion of RT, there were 36 lesions of 27 patients in the responder group and 4 lesions of 4 patients in the nonresponder group. Changes in the SUV{sub max} differed significantly between the responder and nonresponder groups in both the early and delayed phases (P=.0292 and P=.0139, respectively), but no relationship was observed between the pre-RT and post-RT SUV{sub max} relative to the pain response. The responder group was evaluated for the rate of relapse. Thirty-five lesions of 26 patients in the responder group were evaluated, because 1 patient died of acute renal failure at 2 months after RT. Twelve lesions (34%) showed pain relapse, and 23 lesions (66%) did not. There were significant differences between the relapse and nonrelapse patients in terms of the pre-RT (early/delayed phases: P<.0001/P<.0001), post-RT (P=.0199/P=.0261), and changes in SUV{sub max} (P=.0004/P=.004). Conclusions: FDG-PET may help predict the outcome of pain control in the treatment field after palliative RT for painful bone metastases.« less

Pancreatic Extraskeletal Osteosarcoma Metastasizing to the Scalp.

PubMed

Kim, Young Jae; Kim, Hak Tae; Won, Chong Hyun; Chang, Sung Eun; Lee, Mi Woo; Choi, Jee Ho; Lee, Woo Jin

2018-06-01

Extraskeletal osteosarcoma (ESOS) is a rare mesenchymal soft-tissue neoplasm that accounts for approximately 1% of all soft-tissue sarcomas. Over 70% of these malignant tumor progress to local recurrence and metastasis. It commonly metastasizes to the lungs, lymph nodes, bone, and skin and has a poor survival outcome. Cutaneous metastasis is exceedingly rare and known to be a sign of widespread metastases. We present a 57-year-old woman who presented with a rapidly growing protuberant mass on the scalp that was finally diagnosed as metastatic ESOS from a primary pancreatic ESOS. To our knowledge, there has been no reported case of pancreatic ESOS metastasizing to the scalp.

[Progress in diagnosis and treatment of adrenal metastases tumor].

PubMed

Wu, Chu-jun; Qiu, Min; Ma, Lu-lin

2015-08-18

The adrenal gland is a common site of metastases, only second to pulmonary, liver and bone. The prevalence of adrenal metastases in patients with a history of cancer is between 10%-25%.The most common sites of origin are cancers of the lung, kidney, breast, gastrointestinal tract, and skin (melanoma).The mainstays of adrenal metastases diagnosis are computerized tomogramphy (CT), magnetic resonance imaging (MRI), and positron emission tomogramphy (PET). All patients should undergo complete hormonal evaluation to rule out functional adrenal tumors. Adrenal biopsy should be reserved for cases in which the results of non-invasive techniques are equivocal. In patients with isolated adrenal metastases, adrenalectomy is recommended, because of improved overall survival. For the patient with unresectable adrenal metastases tumor, radiotherapy and ablative therapy are feasible and useful methods for controlling adrenal metastases and offer patients opportunities for improved survival.

False-positive diagnosis of disease progression by magnetic resonance imaging for response assessment in prostate cancer with bone metastases: A case report and review of the pitfalls of images in the literature

PubMed Central

YU, YI-SHAN; LI, WAN-HU; LI, MING-HUAN; MENG, XUE; KONG, LI; YU, JIN-MING

2015-01-01

Bone metastases are common in prostate cancer. However, differentiating neoplastic from non-neoplastic alterations of bone on images is challenging. In the present report, a rare case of bone marrow reconversion on magnetic resonance imaging (MRI) assessment, which may lead to a false-positive diagnosis of disease progression of bone metastases in hormone-resistant prostate cancer, is presented. Furthermore, a review of the literature regarding the pitfalls of images for response assessment, including the ‘flare’ phenomenon on bone scintigraphy, computed tomography (CT), positron emission tomography/CT and marrow reconversion on MRI is also provided. These inaccuracies, which may lead to a premature termination of an efficacious treatment, should be carefully considered by the radiologists and oncologists involved in clinical trials. The case reported in the present study showed how to assess the early therapeutic response and select the appropriate treatment for the patient when these pitfalls are encountered on clinical images. PMID:26788174

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

PubMed

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

2016-04-01

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

Serum biomarkers of bone metabolism in castration resistant prostate cancer patients with skeletal metastases

USDA-ARS?s Scientific Manuscript database

Background. Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value ...

High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases.

PubMed

Djusberg, Erik; Jernberg, Emma; Thysell, Elin; Golovleva, Irina; Lundberg, Pia; Crnalic, Sead; Widmark, Anders; Bergh, Anders; Brattsand, Maria; Wikström, Pernilla

2017-05-01

The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6

Bone-Targeting Radiopharmaceuticals for the Treatment of Bone-Metastatic Castration-Resistant Prostate Cancer: Exploring the Implications of New Data

PubMed Central

Saylor, Philip J.; Everly, Jason J.; Sartor, Oliver

2014-01-01

Background. Clinical features of patients with castration-resistant prostate cancer (CRPC) are characterized by a high incidence of bone metastases, which are associated with impairment of quality of life, pain, skeletal-related events (SREs), and a negative impact on prognosis. Advances in the understanding of cancer cell-bone stroma interactions and molecular mechanisms have recently permitted the development of new agents. Purpose. We review the merits, applications, and limitations of emerging data sets on bone-metastatic CRPC with a focus on radium-223, an α-emitting radiopharmaceutical, and its use in therapy for this disease. Methods. References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Related links in the databases were reviewed, along with relevant published guidelines, recently published abstracts from major medical meetings, and transcripts from a recent round table of clinical investigators. Results. Prior to radium-223, available bone-targeted therapies demonstrated the ability to delay SREs and palliate bone pain in patients with metastatic CRPC but without evidence of improvement in overall survival (OS). In a randomized controlled phase III trial, radium-223 demonstrated the ability to improve OS and delay SREs in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC and was not associated with significantly more grade 3 or 4 adverse events than placebo. Conclusion. Radium-223 has a targeted effect on bone metastases in CRPC and has an important role in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC. PMID:25232039

What Is Breast in the Bone?

PubMed

Shemanko, Carrie S; Cong, Yingying; Forsyth, Amanda

2016-10-22

The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%-50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural "recycling" of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle.

A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.

PubMed

Body, Jean-Jacques; Facon, Thierry; Coleman, Robert E; Lipton, Allan; Geurs, Filip; Fan, Michelle; Holloway, Donna; Peterson, Mark C; Bekker, Pirow J

2006-02-15

Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.

Association between salivary α-amylase activity and pain relief scale scores in cancer patients with bone metastases treated with radiotherapy.

PubMed

Liu, Hong; Dong, Wen-yan; Wang, Jian-bo; Wang, Tao; Hu, Peng; Wei, Shu-fang; Ye, Lin; Wang, Qing-wei

2013-12-01

Subjective assessment tools such as visual analog scales (VAS) or pain scores are commonly used to evaluate the intensity of chronic cancer-induced pain. However, their value is limited in some cases. We measured changes in VAS pain scores and salivary α-amylase (sAA) concentrations in cancer patients receiving radiotherapy for bone metastases to ascertain the correlation between these measures. We enrolled 30 patients with bone metastases attending a single institution from June 2010 to March 2011. All patients with cancer-induced bone pain received radiation therapy (RT) at the same dose (30 Gy) and fractionation (3 Gy/fraction, 5 days/week) for palliative pain relief. We assessed heart rate (HR), systolic and diastolic blood pressures (DBP/SBP) and VAS pain scores before (d0) and after five (d5) and ten fractions (d10) of irradiation. sAA and salivary cortisol (SC) concentrations were measured using a portable analyzer and automated chemiluminescence analyzer, respectively. Radiotherapy markedly decreased VAS scores from (82.93 ± 9.29) to (31.43 ± 16.73) mm (P < 0.001) and sAA concentrations from (109.40 ± 26.38) to (36.03 ± 19.40) U/ml (P <0.001). Moreover, there was a significant correlation between these two indices (P <0.01, r = 0.541). HR decreased by 6.5% after radiotherapy, but did not correlate with VAS scores (P >0.05). SC concentrations and BP did not change significantly during the study (P >0.05). The significant correlation between sAA concentrations and VAS pain scores identified in these preliminary results suggests that this biomarker may be a valuable, noninvasive and sensitive index for the objective assessment of pain intensity in patients with cancer-induced bone pain.

A quantification strategy for missing bone mass in case of osteolytic bone lesions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fränzle, Andrea, E-mail: a.fraenzle@dkfz.de; Giske, Kristina; Bretschi, Maren

Purpose: Most of the patients who died of breast cancer have developed bone metastases. To understand the pathogenesis of bone metastases and to analyze treatment response of different bone remodeling therapies, preclinical animal models are examined. In breast cancer, bone metastases are often bone destructive. To assess treatment response of bone remodeling therapies, the volumes of these lesions have to be determined during the therapy process. The manual delineation of missing structures, especially if large parts are missing, is very time-consuming and not reproducible. Reproducibility is highly important to have comparable results during the therapy process. Therefore, a computerized approachmore » is needed. Also for the preclinical research, a reproducible measurement of the lesions is essential. Here, the authors present an automated segmentation method for the measurement of missing bone mass in a preclinical rat model with bone metastases in the hind leg bones based on 3D CT scans. Methods: The affected bone structure is compared to a healthy model. Since in this preclinical rat trial the metastasis only occurs on the right hind legs, which is assured by using vessel clips, the authors use the left body side as a healthy model. The left femur is segmented with a statistical shape model which is initialised using the automatically segmented medullary cavity. The left tibia and fibula are segmented using volume growing starting at the tibia medullary cavity and stopping at the femur boundary. Masked images of both segmentations are mirrored along the median plane and transferred manually to the position of the affected bone by rigid registration. Affected bone and healthy model are compared based on their gray values. If the gray value of a voxel indicates bone mass in the healthy model and no bone in the affected bone, this voxel is considered to be osteolytic. Results: The lesion segmentations complete the missing bone structures in a reasonable way

Denosumab for the management of bone disease in patients with solid tumors.

PubMed

Body, Jean-Jacques

2012-03-01

Many patients with advanced cancer develop bone metastases, which reduces their quality of life. Bone metastases are associated with an increased risk of skeletal-related events, which can lead to increased morbidity and mortality. In patients with bone metastases, tumor cells disrupt the normal process of bone remodeling, leading to increased bone destruction. Denosumab is a fully human monoclonal antibody against receptor activator of NF-κB ligand (RANKL), a key regulatory factor in bone remodeling. By binding to RANKL, denosumab disrupts the cycle of bone destruction. In clinical studies in patients with prostate or breast cancer and bone metastases, denosumab was superior to the current standard of care, zoledronic acid, for delaying skeletal-related events, while in patients with other solid tumors or multiple myeloma, denosumab was noninferior to zoledronic acid. This article examines the pharmacokinetics, efficacy, and safety and tolerability of denosumab for the management of bone events in patients with cancer.

Use of Single- versus Multiple-Fraction Palliative Radiation Therapy for Bone Metastases: Population-Based Analysis of 16,898 Courses in a Canadian Province

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olson, Robert A., E-mail: rolson2@bccancer.bc.ca; University of Northern British Columbia, Prince George, British Columbia; University of British Columbia, Vancouver, British Columbia

2014-08-01

Purpose: There is abundant evidence that a single fraction (SF) of palliative radiation therapy (RT) for bone metastases is equivalent to more protracted and costly multiple fraction courses. Despite this, there is low utilization of SFRT internationally. We sought to determine the utilization of SFRT in a population-based, publicly funded health care system. Methods and Materials: All consecutive patients with bone metastases treated with RT during 2007 to 2011 in British Columbia (BC) were identified. Associations between utilization of SFRT and patient and provider characteristics were investigated. Results: A total of 16,898 courses of RT were delivered to 8601 patients.more » SFRT was prescribed 49% of the time. There were positive relationships among SFRT utilization and primary tumor group (P<.001; most commonly in prostate cancer), worse prognosis (P<.001), increasing physician experience (P<.001), site of metastases (P<.001; least for spine metastases), and area of training (P<.001; most commonly for oncologists trained in the United Kingdom). There was wide variation in the prescription of SFRT across 5 regional cancer centers, ranging from 25.5% to 73.4%, which persisted after controlling for other, potentially confounding factors (P<.001). Conclusions: The large variability in SFRT utilization across BC Cancer Agency (BCCA) cancer centers suggests there is a strong cultural effect, where physicians' use of SFRT is influenced by their colleagues' practice. SFRT use in BC was similar to that in other Canadian and western European reports but strikingly higher than in the United States. Further work is needed to standardize SFRT prescribing practices internationally for this common indication for RT, with the potential for huge health system cost savings and substantial improvements in patients' quality of life.« less

Incidence and sites of distant metastases from head and neck cancer.

PubMed

Ferlito, A; Shaha, A R; Silver, C E; Rinaldo, A; Mondin, V

2001-01-01

The incidence of distant metastases in head and neck squamous cell carcinoma (SCC) is relatively small in comparison to other malignancies. Distant metastases adversely impact survival and may significantly affect treatment planning. The incidence of distant metastases is influenced by location of the primary tumor, initial T and N stage of the neoplasm, and the presence or absence of regional control above the clavicle. Patients with advanced nodal disease have a high incidence of distant metastases, particularly in the presence of jugular vein invasion or extensive soft tissue disease in the neck. Primary tumors of advanced T stages in the hypopharynx, oropharynx and oral cavity are associated with the highest incidence of distant metastases. Pulmonary metastases are the most frequent in SCC, accounting for 66% of distant metastases. It may be difficult to distinguish pulmonary metastasis from a new primary tumor, particularly if solitary. Other metastatic sites include bone (22%), liver (10%), skin, mediastinum and bone marrow. An important question remains as to how intensely pre- and postoperative screening for distant metastases should be performed. Preoperative chest X-ray is warranted in all cases. If the primary tumor and nodal status place the patient at high risk for pulmonary metastasis, then preoperative computed tomography scan of the chest should be done. Screening for distant metastases at other sites is usually not indicated in SCC of the upper aerodigestive tract. Postoperatively, annual X-rays of the chest are usually sufficient, but in high-risk situations a chest X-ray performed every 3-6 months may be beneficial. Certain histologic types of primary tumor have greater or lesser propensity to metastasize distantly, and have a different natural history. Adenoid cystic carcinoma metastasizes frequently, even in the absence of extensive local or regional disease. Basaloid squamous cell carcinoma and neuroendocrine carcinomas also metastasize widely

Factors influencing the distribution of metastases and survival in metastatic breast carcinoma.

PubMed

Barişta, I; Baltali, E; Güllü, I H; Güler, N; Celik, I; Saraçbaşi, O; Tekuzman, G; Kars, A; Ozişik, Y; Ruacan, S; Atahan, I L; Firat, D

1996-12-01

A total of 370 patients with metastatic breast, carcinoma who had been followed at Hacettepe Oncology Department between 1980 and 1991 were retrospectively analyzed for the factors influencing the distribution of metastases and survival. Median age was 47 years. Radical or modified radical mastectomies were performed in 199 (53.8%). Infiltrative ductal carcinoma was the most common pathologic subtype (69.4%). In 191 patients who were evaluated for estrogen receptor (ER) status, 101 (52.9%) were positive and 90 (47.1%) were negative. The distribution of first metastases did not differ between the soft tissue, bone, and visceral sites. The second, third, and fourth metastases were more common in visceral sites (p < 0.05). ER and menopausal status did not affect distribution. Mortality rate was significantly lower in the group having the first metastasis to the bone (p < 0.05). Of interest, first metastases were predominantly found in visceral sites in patients having radical or modified radical mastectomies (p < 0.05). Response to therapy, presence of initial metastases, axillary status, and age were the important factors influencing the overall survival in univariate analysis, whereas response to therapy, ER status, age, and presence of initial metastases were the important factors according to the multivariate analysis.

Race does not predict the development of metastases in men with nonmetastatic castration-resistant prostate cancer.

PubMed

Whitney, Colette A; Howard, Lauren E; Amling, Christopher L; Aronson, William J; Cooperberg, Matthew R; Kane, Christopher J; Terris, Martha K; Freedland, Stephen J

2016-12-15

Although race is associated with prostate cancer progression in early stage disease, once men have advanced disease, it is unclear whether race continues to predict a poor outcome. The authors hypothesized that, in an equal-access setting among patients with castration-resistant prostate cancer (CRPC) and no known metastases (M0/Mx), black men would receive imaging tests at similar rates as nonblack men (ie, there would be an equal opportunity to detect metastases) but would have a higher risk of metastatic disease. In total, 837 men who were diagnosed with M0/Mx CRPC during 2000 through 2014 from 5 Veterans Affairs hospitals in the SEARCH (Shared Equal Access Regional Cancer Hospital) database were analyzed. Data on all imaging tests after CRPC diagnosis were collected, including date, type, and outcome. Multivariable Cox models were used to test associations between race and the time to first metastasis, first bone metastasis, first bone scan, second bone scan among men who had a negative first bone scan, and overall survival. Black men (n = 306) were equally as likely as nonblack men (n = 531) to receive a first and second bone scan after a diagnosis of CRPC. There were no significant differences in the risk of developing any metastases, bone metastases, time to bone scans, or overall survival between black men and nonblack men (all P > .2). The lack of racial differences in the development of metastases and scanning practices observed in this study suggests that, once men have a diagnosis of M0/Mx CRPC, race may not be a prognostic factor. Efforts to understand prostate cancer racial disparities may derive greater benefit by focusing on the risk of developing prostate cancer and on the outcomes of men who have early stage disease. Cancer 2016;122:3848-3855. © 2016 American Cancer Society. © 2016 American Cancer Society.

Molecular insights into melanoma brain metastases.

PubMed

Westphal, Dana; Glitza Oliva, Isabella C; Niessner, Heike

2017-06-01

Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society. © 2017 American Cancer Society.

Gallium, a promising candidate to disrupt the vicious cycle driving osteolytic metastases.

PubMed

Strazic-Geljic, Ivana; Guberovic, Iva; Didak, Blanka; Schmid-Antomarchi, Heidy; Schmid-Alliana, Annie; Boukhechba, Florian; Bouler, Jean-Michel; Scimeca, Jean-Claude; Verron, Elise

2016-09-15

Bone metastases of breast cancer typically lead to a severe osteolysis due to an excessive osteoclastic activity. On the other hand, the semi-metallic element gallium (Ga) displays an inhibitory action on osteoclasts, and therefore on bone resorption, as well as antitumour properties. Thus, we explored in vitro Ga effects on osteoclastogenesis in an aggressive bone metastatic environment based on the culture of pre-osteoclast RAW 264.7 cells with conditioned medium from metastatic breast tumour cells, i.e. the breast tumour cell line model MDA-MB-231 and its bone-seeking clone MDA-231BO. We first observed that Ga dose-dependently inhibited the tumour cells-induced osteoclastic differentiation of RAW 264.7 cells. To mimic a more aggressive environment where pro-tumourigenic factors are released from bone matrix due to osteoclastic resorption, metastatic breast tumour cells were stimulated with TGF-β, a mayor cytokine in bone metastasis vicious cycle. In these conditions, we observed that Ga still inhibited cancer cells-driven osteoclastogenesis. Lastly, we evidenced that Ga affected directly and strongly the proliferation/viability of both cancer cell lines, as well as the expression of major osteolytic factors in MDA-231BO cells. With the exception of two small scale clinical studies from 1980s, this is the first time that antitumour properties of Ga have been specifically studied in the context of bone metastases. Our data strongly suggest that, through its action against the vicious cycle involving bone cells and tumour cells, Ga represents a relevant and promising candidate for the local treatment of bone metastases in patients with breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Presence of bone marrow micro-metastases in stage I-III colon cancer patients is associated with worse disease-free and overall survival.

PubMed

Viehl, Carsten T; Weixler, Benjamin; Guller, Ulrich; Dell-Kuster, Salome; Rosenthal, Rachel; Ramser, Michaela; Banz, Vanessa; Langer, Igor; Terracciano, Luigi; Sauter, Guido; Oertli, Daniel; Zuber, Markus

2017-05-01

The prognostic significance of bone marrow micro-metastases (BMM) in colon cancer patients remains unclear. We conducted a prospective cohort study with long-term follow-up to evaluate the relevance of BMM as a prognostic factor for disease free (DFS) and overall survival (OS) in stage I-III colon cancer patients. In this prospective multicenter cohort study 144 stage I-III colon cancer patients underwent bone marrow aspiration from both iliac crests prior to open oncologic resection. The bone marrow aspirates were stained with the pancytokeratin antibody A45-B/B3 and analyzed for the presence of epithelial tumor cells. DFS and OS were analyzed using a Cox proportional hazard model and robust standard errors to account for clustering in the multicenter setting. Median overall follow-up was 6.2 years with no losses to follow-up, and 7.3 years in patients who survived. BMM were found in 55 (38%) patients. In total, 30 (21%) patients had disease recurrence and 56 (39%) patients died. After adjusting for known prognostic factors, BMM positive patients had a significantly worse DFS (hazard ratio [HR] 1.33; 95% confidence interval [95% CI]: 1.02-1.73; P = 0.037) and OS (HR 1.30; 95% CI: 1.09-1.55; P = 0.003) compared to BMM negative patients. Bone marrow micro-metastases occur in over one third of stage I-III colon cancer patients and are a significant, independent negative prognostic factor for DFS and OS. Future trials should evaluate whether node-negative colon cancer patients with BMM benefit from adjuvant chemotherapy. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases

NASA Astrophysics Data System (ADS)

Denis-Bacelar, Ana M.; Chittenden, Sarah J.; Murray, Iain; Divoli, Antigoni; McCready, V. Ralph; Dearnaley, David P.; O'Sullivan, Joe M.; Johnson, Bernadette; Flux, Glenn D.

2017-04-01

Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83-105 Gy), whilst a median of 183 Gy (interquartile range: 107-247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r  =  0.98, P  <  0.0001). The metastatic burden reduction curves showed a potential large reduction in metastatic burden for a small increase in absorbed dose in 91% of patients. The results indicate the range of absorbed doses required to potentially obtain a significant survival benefit. The metastatic burden reduction method provides a simple tool that could be used in routine clinical practice for patient selection and to indicate the required administered activity to achieve a predicted patient mean absorbed dose and reduction in metastatic tumour burden.

Cervical spine metastases: techniques for anterior reconstruction and stabilization.

PubMed

Sayama, Christina M; Schmidt, Meic H; Bisson, Erica F

2012-10-01

The surgical management of cervical spine metastases continues to evolve and improve. The authors provide an overview of the various techniques for anterior reconstruction and stabilization of the subaxial cervical spine after corpectomy for spinal metastases. Vertebral body reconstruction can be accomplished using a variety of materials such as bone autograft/allograft, polymethylmethacrylate, interbody spacers, and/or cages with or without supplemental anterior cervical plating. In some instances, posterior instrumentation is needed for additional stabilization.

Complete metabolic remission with Gefitinib in a hemodialysis patient with bone metastases from non-small cell lung cancer.

PubMed

Del Conte, Alessandro; Minatel, Emilio; Schinella, Domenico; Baresic, Tanja; Basso, Stefano M M; Lumachi, Franco

2014-01-01

Gefitinib is highly active in patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating mutation of the epidermal growth factor receptor (EGFR) gene. The feasibility and the degree of response to treatment with gefitinib in patients with chronic renal failure (CRF) undergoing hemodialysis has not yet been fully described in literature. We describe the case of a 70-year-old man with CRF undergoing hemodialysis three times-a-week who developed vertebral and rib bone metastasis three years after lobectomy. The bone biopsy confirmed the pulmonary origin and pyrosequencing analysis revealed deletion in E746-E750 of exon 19. We started daily administration of 250 mg gefitinib with no changes in the hemodialysis schedule. Gefitinib was well-tolerated without any adverse event. After three months, the (18)F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) showed complete metabolic remission of bone lesions. The patient is still under treatment and maintains response (30 months to date). To our knowledge, this is the first description of complete metabolic remission in this type of patient. In conclusion, gefitinib has been safely administered to a patient with NSCLC with EGFR-activating mutation undergoing chronic hemodialysis and its use has achieved an excellent and prolonged response on bone metastases.

International field testing of the reliability and validity of the EORTC QLQ-BM22 module to assess health-related quality of life in patients with bone metastases.

PubMed

Chow, Edward; Nguyen, Janet; Zhang, Liying; Tseng, Ling-Ming; Hou, Ming-Feng; Fairchild, Alysa; Vassiliou, Vassilios; Jesus-Garcia, Reynaldo; Alm El-Din, Mohamed A; Kumar, Aswin; Forges, Fabien; Chie, Wei-Chu; Bottomley, Andrew

2012-03-01

The objective of this international field study was to test the reliability, validity, and responsiveness of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BM22 module to assess health-related quality of life (HRQOL) in patients with bone metastases. Patients undergoing a variety of bone metastases-specific treatments were accrued. The QLQ-BM22 was administered with the QLQ-C30 at baseline and at 1 follow-up time point internationally. A debriefing questionnaire was administered to determine patient acceptability and understanding. Large-scale field testing of the QLQ-BM22 in addition to the QLQ-C30 took place in 7 countries: Brazil, Canada, Cyprus, Egypt, France, India, and Taiwan. A total of 400 patients participated. Multitrait scaling analyses confirmed 4 scales in the 22-item module. The scales were able to discriminate between clinically distinct patient groups, such as between those with a poor and those with a better performance status. The QLQ-BM22 was well received in all 7 countries, and the majority of patients did not recommend any significant changes from the module in its current form. The final QLQ-BM22 module contains 22 items and 4 scales assessing Painful Sites, Painful Characteristics, Functional Interference, and Psychosocial Aspects. Results confirmed the validity, reliability, cross-cultural applicability, and sensitivity of the 22-item EORTC QLQ-BM22. It is therefore recommended that the QLQ-BM22 be used in addition to the QLQ-C30 in clinical trials to assess HRQOL in patients with bone metastases. Copyright © 2011 American Cancer Society.

Psoralen inhibits bone metastasis of breast cancer in mice.

PubMed

Wu, Chunyu; Sun, Zhenping; Ye, Yiyi; Han, Xianghui; Song, Xiaoyun; Liu, Sheng

2013-12-01

Breast cancer is the most common female malignancy and it frequently metastasizes to bone. Metastatic breast cancer continues to be the primary cause of death for women in East and Southeast Asia. Psoralen is a furocoumarin that can be isolated from the seeds of Psoralea corylifolia L. Psoralen exhibits a wide range of biological properties and has been demonstrated as an antioxidant, antidepressant, anticancer, antibacterial, and antiviral agent. Additionally, it is involved in the formation and regulation of bone. This study investigated whether psoralen can inhibit metastasis of breast cancer to bone in vivo. Histological, molecular biological, and imaging analyses revealed that psoralen inhibits bone metastases in mice. Psoralen may function to inhibit breast cancer cell growth in the bone microenvironment and regulate the function of osteoblasts and osteoclasts in tumor-bearing mice. The results of this study suggest that psoralen is a bone-modifying agent and a potential therapeutic to treat patients with bone metastases. © 2013.

Magnetic resonance-guided focused ultrasound surgery for treatment of painful osseous metastases

NASA Astrophysics Data System (ADS)

Hurwitz, Mark; Machtinger, Ronit; Fennessy, Fiona

2011-03-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is an emerging technology that can non-invasively heat and ablate targeted tissue utilizing ultrasound energy. Use of MR imaging for treatment guidance provides several key advantages over more widely used ultrasound guidance for focused ultrasound ablation. MR allows for precise targeting, detailed beam path visualization, real time non-invasive temperature measurement, and treatment feedback to ensure therapeutic goals are achieved. In the realm of oncology, management of painful bone metastases is a common and daunting clinical problem. The Insightec ExAblate System has been shown in phase I/II trials for treatment of bone metastases to have an excellent safety profile and high rates of pain response. An international multi-center phase III trial for patients with painful bone metastases or multiple myeloma who are not candidates for radiation therapy is currently open. Patients are randomized 3:1 to MRgFUS or sham treatment with crossover to study treatment allowed for sham failures. The primary study endpoint is assessment of pain control over 3 months following treatment. In addition safety, quality of life, cost effectiveness analysis, and patient perceived clinical benefit are also being assessed. Details of the MRgFUS system, technical and clinical therapeutic parameters, use of real time non-invasive MR thermometry, and examples of patient treatments with use of MRgFUS to treat bone metastases will be discussed. New directions in use of MRgFUS including an update on development of a new mobile applicator and integration of MRgFUS in multimodality oncologic care will also be presented.

An Osteoblast-Derived Proteinase Controls Tumor Cell Survival via TGF-beta Activation in the Bone Microenvironment

PubMed Central

Thiolloy, Sophie; Edwards, James R.; Fingleton, Barbara; Rifkin, Daniel B.; Matrisian, Lynn M.; Lynch, Conor C.

2012-01-01

Background Breast to bone metastases frequently induce a “vicious cycle” in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. Given the role of MMP-2 in extracellular matrix degradation and growth factor/cytokine processing, we tested whether osteoblast derived MMP-2 contributed to the vicious cycle of tumor progression in the bone microenvironment. Methodology/Principal Findings To test our hypothesis, we utilized murine models of the osteolytic tumor-bone microenvironment in immunocompetent wild type and MMP-2 null mice. In longitudinal studies, we found that host MMP-2 significantly contributed to tumor progression in bone by protecting against apoptosis and promoting cancer cell survival (caspase-3; immunohistochemistry). Our data also indicate that host MMP-2 contributes to tumor induced osteolysis (μCT, histomorphometry). Further ex vivo/in vitro experiments with wild type and MMP-2 null osteoclast and osteoblast cultures identified that 1) the absence of MMP-2 did not have a deleterious effect on osteoclast function (cd11B isolation, osteoclast differentiation, transwell migration and dentin resorption assay); and 2) that osteoblast derived MMP-2 promoted tumor survival by regulating the bioavailability of TGFβ, a factor critical for cell-cell communication in the bone (ELISA, immunoblot assay, clonal and soft agar assays). Conclusion/Significance Collectively, these studies identify a novel “mini-vicious cycle” between the osteoblast and metastatic cancer cells that is key for initial tumor survival in the bone microenvironment. In conclusion, the findings of our study suggest that the targeted inhibition of MMP-2 and/or TGFβ would be beneficial for the treatment

Osthole inhibits bone metastasis of breast cancer

PubMed Central

Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

2017-01-01

Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-β/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases. PMID:28938572

Fractionation of Palliative Radiation Therapy for Bone Metastases in Ontario: Do Practice Guidelines Guide Practice?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ashworth, Allison; Cancer Center of Southeastern Ontario, Kingston, Ontario; Kong, Weidong

Purpose: To evaluate the effect of a provincial practice guideline on the fractionation of palliative radiation therapy for bone metastases (PRT.B) in Ontario. Methods and Materials: The present retrospective study used electronic treatment records linked to Ontario's population-based cancer registry. Hierarchical multivariable regression analysis was used to evaluate temporal trends in the use of single fractions (SFs), controlling for patient-related factors associated with the use of SFs. Results: From 1984 to 2012, 43.9% of 161,835 courses of PRT.B were administered as SFs. The percentage of SF courses was greater for older patients (age <50 years, 39.8% vs age >80 years, 52.5%), thosemore » with a shorter life expectancy (survival >12 months, 36.9% vs < 1 month, 53.6%), and those who lived farther from a radiation therapy center (<10 km, 42.1% vs > 50 km, 47.3%). The percentage of SFs to spinal fields was lower than that to other skeletal sites (31.5% vs 57.1%). The percentage of SFs varied among the cancer centers (range, 26.0%-67.8%). These differences were all highly significant in the multivariable analysis (P<.0001). In 2004, Cancer Care Ontario released a practice guideline endorsing the use of SFs for uncomplicated bone metastases. The rate of use of SFs increased from 42.3% in the pre-guideline period (1999-2003) to 52.6% in the immediate post-guideline period (2004-2007). However, it subsequently decreased again to 44.0% (2009-2012). These temporal trends were significant after controlling for patient-related factors in the multivariable analysis (P<.0001). Large intercenter variations in the use of SFs persisted after publication of the guideline. Conclusions: The publication of an Ontario practice guideline endorsing the use of SF PRT.B was associated with only a transient increase in the use of SFs in Ontario and did little to reduce intercenter variations in fractionation.« less

Clinical management and outcomes in patients with hyperfunctioning distant metastases from differentiated thyroid cancer after total thyroidectomy and radioactive iodine therapy.

PubMed

Qiu, Zhong-Ling; Shen, Chen-Tian; Luo, Quan-Yong

2015-02-01

Hyperfunctioning distant metastasis (HFDM) from differentiated thyroid cancer (DTC) is a rare entity. This study aimed to assess the outcomes of DTC patients presenting with HFDM after total thyroidectomy and radioactive iodine therapy. A total of 5367 DTC patients treated with (131)I after total thyroidectomy were analyzed retrospectively from January 1991 to June 2013. Therapeutic efficacy was evaluated based on changes in serum thyroglobulin (Tg) and anatomical imaging changes in metastatic lesions. The relationships between survival time and several variables were assessed by univariate and multivariate analyses using the Kaplan-Meier method and Cox's proportional hazards model respectively. Thirty-eight patients with HFDM from DTC were diagnosed, including four with hyperthyroidism, four with subclinical hyperthyroidism, and three with subclinical hypothyroidism. The remaining 27 were euthyroid. Of 25 patients with lung metastases, 84% (21/25) showed disappearance or shrinkage of lung nodules; of 24 patients with bone metastases, 66.67% (16/24) exhibited no obvious imaging changes in metastatic bone lesions after (131)I therapy. Serum Tg decreased significantly in 81.58% (31/38) and increased in 18.42% (7/38) after (131)I therapy. The 10-year survival rate of DTC patients with HFDM was 65.79% (25/38). Multivariate analyses identified age at occurrence of distant metastases (<45 years), only lung metastases, and papillary thyroid cancer (PTC; p=0.032, NA, and 0.043) as independent predictors of survival. The response of hyperfunctioning lung metastases to (131)I treatment was better than that of non-hyperfunctioning lung metastases in DTC, while hyperfunctioning bone metastases responded similarly compared to non-hyperfunctioning bone metastases. Patients younger than 45 years at occurrence of distant metastases, those with only lung metastases, and patients with PTC had better prognoses.

Neurosurgical treatment of breast cancer metastases to the neurocranium.

PubMed

Stark, Andreas M

2010-12-16

Breast cancer metastases to the neurocranium might involve the bone, the dura, or the brain parenchyma. The latter location is the far most common. The annual incidence of brain metastases in patients with breast cancer is in the range of 4-11 per 100.000 persons per year. Symptoms and findings mainly result from the location of the lesion. The diagnostic method of choice is magnetic resonance imaging before and after administration of contrast material. Breast cancer brain metastases present as solid, cystic, or partially cystic lesions with marked contrast enhancement and perilesional edema. The therapeutic option of choice is microsurgical resection whenever possible. Adjuvant treatment includes radiotherapy, radiosurgery, and/or chemotherapy.

Neurosurgical Treatment of Breast Cancer Metastases to the Neurocranium

PubMed Central

Stark, Andreas M.

2011-01-01

Breast cancer metastases to the neurocranium might involve the bone, the dura, or the brain parenchyma. The latter location is the far most common. The annual incidence of brain metastases in patients with breast cancer is in the range of 4–11 per 100.000 persons per year. Symptoms and findings mainly result from the location of the lesion. The diagnostic method of choice is magnetic resonance imaging before and after administration of contrast material. Breast cancer brain metastases present as solid, cystic, or partially cystic lesions with marked contrast enhancement and perilesional edema. The therapeutic option of choice is microsurgical resection whenever possible. Adjuvant treatment includes radiotherapy, radiosurgery, and/or chemotherapy. PMID:21209717

Bone Metabolism of the Patient with a Malignant Melanoma during the Entry Examination and the Check-up of Whole-body Bone Scintigraphy.

PubMed

Weissensteiner, Jaroslav; Babušíková, Eva

Malignant melanoma is a malignancy located predominantly in the skin and the incidence of melanoma increases. We compared the markers of bone metabolism - osteocalcin (OC), beta-carboxyterminal cross-linked telopeptide of type I collagen (β-CrossLaps, β-CTx) and tumour marker - human epididymis protein 4 (HE4) in the serum with finding during the entry examination and the check-up of whole-body bone scintigraphy of the patient with a malignant melanoma. Serum concentrations of OC, β-CTx, HE4 were determined in 1 patient (female, age 64 years) with malignant melanoma and correlated with the presence of equivocal bone metastases detected by whole-body bone scintigraphy (the entry examination and check-up after 6 months). Concentrations of bone metabolism markers decreased during six months and we observed progress in bone metastases. The change of the markers levels during the entry examination and the check-up of the whole-body bone scintigraphy with equivocal finding of bone metastases could be a sign of a possible initiating progression of malignant melanoma despite a clinically negative finding that does not prove the progression of the disease.

The use of collagen-based scaffolds to simulate prostate cancer bone metastases with potential for evaluating delivery of nanoparticulate gene therapeutics.

PubMed

Fitzgerald, Kathleen A; Guo, Jianfeng; Tierney, Erica G; Curtin, Caroline M; Malhotra, Meenakshi; Darcy, Raphael; O'Brien, Fergal J; O'Driscoll, Caitriona M

2015-10-01

Prostate cancer bone metastases are a leading cause of cancer-related death in men with current treatments offering only marginally improved rates of survival. Advances in the understanding of the genetic basis of prostate cancer provide the opportunity to develop gene-based medicines capable of treating metastatic disease. The aim of this work was to establish a 3D cell culture model of prostate cancer bone metastasis using collagen-based scaffolds, to characterise this model, and to assess the potential of the model to evaluate delivery of gene therapeutics designed to target bone metastases. Two prostate cancer cell lines (PC3 and LNCaP) were cultured in 2D standard culture and compared to 3D cell growth on three different collagen-based scaffolds (collagen and composites of collagen containing either glycosaminoglycan or nanohydroxyapatite). The 3D model was characterised for cell proliferation, viability and for matrix metalloproteinase (MMP) enzyme and Prostate Specific Antigen (PSA) secretion. Chemosensitivity to docetaxel treatment was assessed in 2D in comparison to 3D. Nanoparticles (NPs) containing siRNA formulated using a modified cyclodextrin were delivered to the cells on the scaffolds and gene silencing was quantified. Both prostate cancer cell lines actively infiltrated and proliferated on the scaffolds. Cell culture in 3D resulted in reduced levels of MMP1 and MMP9 secretion in PC3 cells. In contrast, LNCaP cells grown in 3D secreted elevated levels of PSA, particularly on the scaffold composed of collagen and glycosaminoglycans. Both cell lines grown in 3D displayed increased resistance to docetaxel treatment. The cyclodextrin.siRNA nanoparticles achieved cellular uptake and knocked down the endogenous GAPDH gene in the 3D model. In conclusion, development of a novel 3D cell culture model of prostate cancer bone metastasis has been initiated resulting, for the first time, in the successful delivery of gene therapeutics in a 3D in vitro model

[Surgical treatment of pulmonary metastases from colon and rectal cancer].

PubMed

Togashi, Ken-ichi; Aoki, K; Hirahara, H; Sugawara, M; Oguma, F

2004-09-01

We retrospectively studied the surgical treatment for pulmonary metastases from colon and rectal cancer. A total of 24 patients (9 males and 15 females; mean age 61 years) underwent 29 thoracotomies for metastatic colon carcinoma, while 22 patients (16 males and 6 females; mean age 63 years) underwent 29 thoracotomies for metastatic rectal cancer. The median interval between the primary procedure and lung resection for metastases was 26 months in the patients with colon carcinoma and 32 months in the patients with rectal cancer. In the patients with colon carcinoma, 16 underwent wedge resection or segmentectomy (including 4 video-assisted procedures) and 13 (54%) underwent lobectomy or pneumonectomy. In the patients with rectal cancer, 15 underwent wedge or segmentectomy (including 1 video-assisted procedure), 13 (59%) underwent lobectomy or pneumonectomy, and 1 underwent exploratory thoracotomy. All procedures except exploratory thoracotomy were curative operations. There was no mortality. Overall 5-year survival was 56% (n=46). Five-year survival was 65% for patients with colon metastases (n=24) and 45% for patients with rectal metastases (n=22), and there was no significant difference. Recurrent sites were 4 lungs (36%), 4 livers (36%), 1 bone, 1 uterus, and 1 peritoneum in patients with colon carcimoma, and 10 lungs (43%), 5 brains (22%), 3 livers (13%), 1 bone, and 1 vagina in patients with rectal cancer. Pulmonary resection for metastases from colon carcinoma may have better prognosis than that from rectal cancer. However, further investigation may be required to obtain convincing conclusions.

The effect of distant metastases sites on survival in de novo stage-IV breast cancer: A SEER database analysis.

PubMed

Wu, San-Gang; Li, Hui; Tang, Li-Ying; Sun, Jia-Yuan; Zhang, Wen-Wen; Li, Feng-Yan; Chen, Yong-Xiong; He, Zhen-Yu

2017-06-01

To investigate the effect of distant metastases sites on survival in patients with de novo stage-IV breast cancer. From 2010 to 2013, patients with a diagnosis of de novo stage-IV breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on breast cancer-specific survival and overall survival. A total of 7575 patients were identified. The most common metastatic sites were bone, followed by lung, liver, and brain. Patients with hormone receptor+/human epidermal growth factor receptor 2- and hormone receptor+/human epidermal growth factor receptor 2+ status were more prone to bone metastases. Lung and brain metastases were common in hormone receptor-/human epidermal growth factor receptor 2+ and hormone receptor-/human epidermal growth factor receptor 2- subtypes, and patients with hormone receptor+/ human epidermal growth factor receptor 2+ and hormone receptor-/human epidermal growth factor receptor 2+ subtypes were more prone to liver metastases. Patients with liver and brain metastases had unfavorable prognosis for breast cancer-specific survival and overall survival, whereas bone and lung metastases had no effect on patient survival in multivariate analyses. The hormone receptor-/human epidermal growth factor receptor 2- subtype conferred a significantly poorer outcome in terms of breast cancer-specific survival and overall survival. hormone receptor+/human epidermal growth factor receptor 2+ disease was associated with the best prognosis in terms of breast cancer-specific survival and overall survival. Patients with liver and brain metastases were more likely to experience poor prognosis for breast cancer-specific survival and overall survival by various breast cancer subtypes. Distant metastases sites have differential impact on clinical outcomes in stage-IV breast cancer. Follow-up screening for brain and

Skin metastases from lung cancer: a case report.

PubMed

Pajaziti, Laura; Hapçiu, Syzana Rexhepi; Dobruna, Shkendije; Hoxha, Naim; Kurshumliu, Fisnik; Pajaziti, Artina

2015-04-11

Lung cancer is one of the most frequent malignancies, with high mortality rates. It can metastasize in almost all organs, but more often invades hilar nodes, liver, adrenal glands, bones and brain. There are various data on the incidence of lung cancer metastases in the skin. In 1-12% of patients with lung cancer are developed skin metastases. Metastases in the skin may be the first sign of lung cancer. Forty-five years old Albanian male, smoker, was admitted to our department with multiple nodules localized in the skin of the head, neck, back and chest. The nodules measuring 5-15 millimeters in greatest dimension were round and skin-colored, with telangiectasias, firm and tender. They appeared in an eruptive form about two weeks before being admitted at our hospital. In addition, the patient exhibited signs of weight loss, anorexia and fatigue. Excisional biopsy was performed to one of the lesions. Histopathology confirmed metastatic nature of the lesion namely, malignant tumor of neuroendocrine phenotype consistent with small-cell carcinoma. Chest X-ray and computed tomography revealed an expansive process in the 7(th) segment of the left lung, left hilar and mediastinal lymphadenopathy and a suspicious initial secondary deposit in the left adrenal gland. The patient was referred to the department of oncology for further treatment. After the third cycle of chemotherapy, the magnetic resonance imaging revealed brain metastases. The patient passed away four months after the diagnosis of lung cancer first presented with skin metastases. Metastases in skin may be the first sign of lung cancer. Although rare appearing, we should raise suspicion in cases of atypical lesions in the skin not only of the smokers, but also of the non-smokers. Skin metastases from small-cell lung carcinoma are a poor prognostic indicator. The appearance of multiple skin metastases with other internal metastases shorten the survival time.

Liver metastases

MedlinePlus

Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic; Colorectal cancer - liver metastases; Colon cancer - liver metastases; Esophageal cancer - liver metastases; Lung cancer - liver metastases; Melanoma - liver metastases

Contemporary Statewide Practice Pattern Assessment of the Palliative Treatment of Bone Metastasis.

PubMed

Spratt, Daniel E; Mancini, Brandon R; Hayman, James A; Boike, Thomas; Pierce, Lori J; Moran, Jean M; Dominello, Michael M; Fireman, Mark; Griffith, Kent; Jolly, Shruti

2018-06-01

Palliative radiation therapy for bone metastases is often viewed as a single entity, despite national guidelines providing input principally only for painful uncomplicated bone metastases. Data surrounding the treatment of bone metastases are often gleaned from questionnaires of what providers would theoretically do in practice or from population-based data lacking critical granular information. We investigated the real-world treatment of bone metastases with radiation therapy. Twenty diverse institutions across the state of Michigan had data extracted for their 10 most recent cases of radiation therapy delivered for the treatment of bone metastases at their institution between January and February 2017. Uni- and multivariable binary logistic regression was used to assess the use of single fraction (8 Gy × 1) radiation therapy. A total of 196 cases were eligible for inclusion. Twenty-eight different fractionation schedules were identified. The most common schedule was 3 Gy × 10 fractions (n = 100; 51.0%), 4 Gy × 5 fractions (n = 32; 16.3%), and 8 Gy × 1 (n = 15; 7.7%). The significant predictors for the use of single fraction radiation therapy were the presence of oligometastatic disease (P = .008), previous overlapping radiation therapy (P = .050), and academic practice type (P = .039). Twenty-nine cases (14.8%) received >10 fractions (median 15, range 11-20). Intensity modulated radiation therapy was used in 14 cases (7.1%), stereotactic body radiation therapy in 11 (5.6%), and image guidance with cone beam computed tomography in 11 (5.6%). Of the cases of simple painful bone metastases (no previous surgery, spinal cord compression, fracture, soft tissue extension, or overlapping previous radiation therapy; n = 70), only 12.9% were treated with 8 Gy × 1. Bone metastases represent a heterogeneous disease, and radiation therapy for bone metastases is similarly diverse. Future work is needed to understand the barriers to single

Engineering a humanized bone organ model in mice to study bone metastases.

PubMed

Martine, Laure C; Holzapfel, Boris M; McGovern, Jacqui A; Wagner, Ferdinand; Quent, Verena M; Hesami, Parisa; Wunner, Felix M; Vaquette, Cedryck; De-Juan-Pardo, Elena M; Brown, Toby D; Nowlan, Bianca; Wu, Dan Jing; Hutmacher, Cosmo Orlando; Moi, Davide; Oussenko, Tatiana; Piccinini, Elia; Zandstra, Peter W; Mazzieri, Roberta; Lévesque, Jean-Pierre; Dalton, Paul D; Taubenberger, Anna V; Hutmacher, Dietmar W

2017-04-01

Current in vivo models for investigating human primary bone tumors and cancer metastasis to the bone rely on the injection of human cancer cells into the mouse skeleton. This approach does not mimic species-specific mechanisms occurring in human diseases and may preclude successful clinical translation. We have developed a protocol to engineer humanized bone within immunodeficient hosts, which can be adapted to study the interactions between human cancer cells and a humanized bone microenvironment in vivo. A researcher trained in the principles of tissue engineering will be able to execute the protocol and yield study results within 4-6 months. Additive biomanufactured scaffolds seeded and cultured with human bone-forming cells are implanted ectopically in combination with osteogenic factors into mice to generate a physiological bone 'organ', which is partially humanized. The model comprises human bone cells and secreted extracellular matrix (ECM); however, other components of the engineered tissue, such as the vasculature, are of murine origin. The model can be further humanized through the engraftment of human hematopoietic stem cells (HSCs) that can lead to human hematopoiesis within the murine host. The humanized organ bone model has been well characterized and validated and allows dissection of some of the mechanisms of the bone metastatic processes in prostate and breast cancer.

Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets

NASA Astrophysics Data System (ADS)

Dant, James T.; Richardson, Richard B.; Nie, Linda H.

2013-05-01

Alpha (α) particles and low-energy beta (β) particles present minimal risk for external exposure. While these particles can induce leukemia and bone cancer due to internal exposure, they can also be beneficial for targeted radiation therapies. In this paper, a trabecular bone model is presented to investigate the radiation dose from bone- and marrow-seeking α and β emitters to different critical compartments (targets) of trabecular bone for different age groups. Two main issues are addressed with Monte Carlo simulations. The first is the absorption fractions (AFs) from bone and marrow to critical targets within the bone for different age groups. The other issue is the application of 223Ra for the radiotherapy treatment of bone metastases. Both a static model and a simulated bone remodeling process are established for trabecular bone. The results show significantly lower AFs from radionuclide sources in the bone volume to the peripheral marrow and the haematopoietic marrow for adults than for newborns and children. The AFs from sources on the bone surface and in the bone marrow to peripheral marrow and haematopoietic marrow also varies for adults and children depending on the energy of the particles. Regarding the use of 223Ra as a radionuclide for the radiotherapy of bone metastases, the simulations show a significantly higher dose from 223Ra and its progeny in forming bone to the target compartment of bone metastases than that from two other more commonly used β-emitting radiopharmaceuticals, 153Sm and 89Sr. There is also a slightly lower dose from 223Ra in forming bone to haematopoietic marrow than that from 153Sm and 89Sr. These results indicate a higher therapy efficiency and lower marrow toxicity from 223Ra and its progeny. In conclusion, age-related changes in bone dimension and cellularity seem to significantly affect the internal dose from α and β emitters in the bone and marrow to critical targets, and 223Ra may be a more efficient

State-of-the-art considerations in small cell lung cancer brain metastases

PubMed Central

Lukas, Rimas V.; Gondi, Vinai; Kamson, David O.; Kumthekar, Priya; Salgia, Ravi

2017-01-01

Background Small cell lung cancer (SCLC) frequently leads to development of brain metastases. These unfortunately continue to be associated with short survival. Substantial advances have been made in our understanding of the underlying biology of disease. This understanding on the background of previously evaluated and currently utilized therapeutic treatments can help guide the next steps in investigations into this disease with the potential to influence future treatments. Design A comprehensive review of the literature covering epidemiology, pathophysiology, imaging characteristics, prognosis, and therapeutic management of SCLC brain metastases was performed. Results SCLC brain metastases continue to have a poor prognosis. Both unique aspects of SCLC brain metastases as well as features seen more universally across other solid tumor brain metastases are discussed. Systemic therapeutic studies and radiotherapeutic approaches are reviewed. Conclusions A clearer understanding of SCLC brain metastases will help lay the framework for studies which will hopefully translate into meaningful therapeutic options for these patients. PMID:29050358

Colorectal cancer: Metastases to a single organ

PubMed Central

Vatandoust, Sina; Price, Timothy J; Karapetis, Christos S

2015-01-01

Colorectal cancer (CRC) is a common malignancy worldwide. In CRC patients, metastases are the main cause of cancer-related mortality. In a group of metastatic CRC patients, the metastases are limited to a single site (solitary organ); the liver and lungs are the most commonly involved sites. When metastatic disease is limited to the liver and/or lungs, the resectability of the metastatic lesions will dictate the management approach and the outcome. Less commonly, the site of solitary organ CRC metastasis is the peritoneum. In these patients, cytoreduction followed by hyperthermic intraperitoneal chemotherapy may improve the outcome. Rarely, CRC involves other organs, such as the brain, bone, adrenals and spleen, as the only site of metastatic disease. There are limited data to guide clinical practice in these cases. Here, we have reviewed the disease characteristics, management approaches and prognosis based on the metastatic disease site in patients with CRC with metastases to a single organ. PMID:26557001

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases

PubMed Central

Himelstein, Andrew L.; Foster, Jared C.; Khatcheressian, James L.; Roberts, John D.; Seisler, Drew K.; Novotny, Paul J.; Qin, Rui; Go, Ronald S.; Grubbs, Stephen S.; O’Connor, Tracey; Velasco, Mario R.; Weckstein, Douglas; O’Mara, Ann; Loprinzi, Charles L.; Shapiro, Charles L.

2017-01-01

IMPORTANCE Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. OBJECTIVE To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. DESIGN, SETTING, PARTICIPANTS Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. INTERVENTIONS; Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. MAIN OUTCOMES AND MEASURES; The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7%as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0–10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0–4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). RESULTS Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiplemyeloma), 795 completed the study at 2 years. A total of 260

Quality of Life After Palliative Radiation Therapy for Patients With Painful Bone Metastases: Results of an International Study Validating the EORTC QLQ-BM22

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeng Liang; Chow, Edward, E-mail: edward.chow@sunnybrook.ca; Bedard, Gillian

2012-11-01

Purpose: Radiation therapy (RT) is an effective method of palliating painful bone metastases and can improve function and reduce analgesic requirements. In advanced cancer patients, quality of life (QOL) is the primary outcome of interest over traditional endpoints such as survival. The purpose of our study was to compare bone metastasis-specific QOL scores among patients who responded differently to palliative RT. Methods and Materials: Patients receiving RT for bone metastases across 6 countries were prospectively enrolled from March 2010-January 2011 in a trial validating the QLQ-BM22 and completed the QLQ-BM22 and the core measure (QLQ-C30) at baseline and after 1more » month. Pain scores and analgesic intake were recorded, and response to RT was determined according to the latest published guidelines. The Kruskal-Wallis nonparametric and Wilcoxon rank sum tests compared changes in QOL among response groups. A Bonferroni-adjusted P<.003 indicated statistical significance. Results: Of 79 patients who received palliative RT, 59 were assessable. Partial response, pain progression, and indeterminate response were observed in 22, 8, and 29 patients, respectively; there were no patients with a complete response. Patients across all groups had similar baseline QOL scores apart from physical functioning (patients who progressed had better initial functioning). One month after RT, patients who responded had significant improvements in 3 of 4 QLQ-BM22 domains (painful site, P<.0001; painful characteristic, P<.0001; and functional interference, P<.0001) and 3 QLQ-C30 domains (physical functioning, P=.0006; role functioning, P=.0026; and pain, P<.0001). Patients with progression in pain had significantly worse functional interference (P=.0007) and pain (P=.0019). Conclusions: Patients who report pain relief after palliative RT also have better QOL with respect to bone metastasis-specific issues. The QLQ-BM22 and QLQ-C30 are able to discriminate among patients with

The Risk of Misdiagnosing the Primary Site Responsible for Bone Metastases in Patients With Chronic Lymphocytic Leukemia and a Second Primary Carcinoma

PubMed Central

Hatoum, Georges; Meshkin, Cyrus; Alkhunaizi, Sufana; Levene, Richard; Formoso-Onofrio, Julie

2015-01-01

Chronic lymphocytic leukemia (CLL) is a common malignancy which may coexist with other primary cancers. CLL is rarely the cause of solitary bone lesions; such lesions in the context of CLL are believed to result from either Richter’s transformation or metastasis from another primary malignancy. Renal cell carcinoma (RCC), on the other hand, is a malignancy which frequently metastasizes to bone and may cause an osteolytic solitary bone lesion. The origin of a solitary bone lesion in a patient with multiple potential primary malignancies has prognostic implications and affects treatment protocol, and as such must be diagnosed accurately. We describe a patient with CLL and a history of RCC who is found to have an incidental solitary bone lesion of the T11 vertebra. After two separate CT-guided biopsies revealed various lymphoid cell predominance and no evidence of RCC, treatment with low dose external beam radiation therapy (EBRT) was employed. Post-therapy MRI showed further propagation of the lesion. Surgical corpectomy was subsequently performed and postoperative pathology of the lesion was consistent with RCC. The patient was treated with bisphosphonates and a higher dose of EBRT. Our case illustrates the importance of surgical excisional biopsy for accurately diagnosing the primary source metastatic to the bone in a patient with CLL and another potential primary cancer. PMID:29147427

Well-Designed Bone-Seeking Radiolabeled Compounds for Diagnosis and Therapy of Bone Metastases

PubMed Central

2015-01-01

Bone-seeking radiopharmaceuticals are frequently used as diagnostic agents in nuclear medicine, because they can detect bone disorders before anatomical changes occur. Furthermore, their effectiveness in the palliation of metastatic bone cancer pain has been demonstrated in the clinical setting. With the aim of developing superior bone-seeking radiopharmaceuticals, many compounds have been designed, prepared, and evaluated. Here, several well-designed bone-seeking compounds used for diagnostic and therapeutic use, having the concept of radiometal complexes conjugated to carrier molecules to bone, are reviewed. PMID:26075256

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

PubMed

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

2015-09-01

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

Assessment of National Practice for Palliative Radiation Therapy for Bone Metastases Suggests Marked Underutilization of Single-Fraction Regimens in the United States

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rutter, Charles E., E-mail: charles.rutter@yale.edu; Yale Cancer Center, New Haven, Connecticut; Yu, James B.

2015-03-01

Purpose: To characterize temporal trends in the application of various bone metastasis fractionations within the United States during the past decade, using the National Cancer Data Base; the primary aim was to determine whether clinical practice in the United States has changed over time to reflect the published randomized evidence and the growing movement for value-based treatment decisions. Patients and Methods: The National Cancer Data Base was used to identify patients treated to osseous metastases from breast, prostate, and lung cancer. Utilization of single-fraction versus multiple-fraction radiation therapy was compared according to demographic, disease-related, and health care system details. Results: Wemore » included 24,992 patients treated during the period 2005-2011 for bone metastases. Among patients treated to non-spinal/vertebral sites (n=9011), 4.7% received 8 Gy in 1 fraction, whereas 95.3% received multiple-fraction treatment. Over time the proportion of patients receiving a single fraction of 8 Gy increased (from 3.4% in 2005 to 7.5% in 2011). Numerous independent predictors of single-fraction treatment were identified, including older age, farther travel distance for treatment, academic treatment facility, and non-private health insurance (P<.05). Conclusions: Single-fraction palliative radiation therapy regimens are significantly underutilized in current practice in the United States. Further efforts are needed to address this issue, such that evidence-based and cost-conscious care becomes more commonplace.« less

Is the assessment of the central skeleton sufficient for osseous staging in breast cancer patients? A retrospective approach using bone scans.

PubMed

Krammer, Julia; Engel, Dorothee; Schnitzer, Andreas; Kaiser, Clemens G; Dinter, Dietmar J; Brade, Joachim; Schoenberg, Stefan O; Wasser, Klaus

2013-06-01

By analyzing bone scans we aimed to determine whether the assessment of the central skeleton is sufficient for osseous staging in breast cancer patients. This might be of interest for future staging modalities, especially positron emission tomography/computed tomography, usually sparing the peripheral extremities, as well as the skull. In this retrospective study, a total of 837 bone scans for initial staging or restaging of breast cancer were included. A total of 291 bone scans in 172 patients were positive for bone metastases. The localization and distribution of the metastases were re-evaluated by two readers in consensus. The extent of the central skeleton involvement was correlated to the incidence of peripheral metastases. In all 172 patients bone metastases were seen in the central skeleton (including the proximal third of humerus and femur). In 34 patients (19.8 %) peripheral metastases of the extremities (distally of the proximal third of humerus and femur) could be detected. Sixty-four patients (37.2 %) showed metastases of the skull. Summarizing the metastases of the distal extremities and skull, 79 patients (45.9 %) had peripheral metastases. None of the patients showed peripheral metastases without any affliction of the central skeleton. The incidence of peripheral metastases significantly correlated with the extent of central skeleton involvement (p<0.001). Regarding bone scans, an isolated metastatic spread to the peripheral skeleton without any manifestation in the central skeleton seems to be the exception. Thus, the assessment of the central skeleton should be sufficient in osseous breast cancer staging and restaging. However, in case of central metastases, additional imaging of the periphery should be considered for staging and restaging.

Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis.

PubMed

Dumont, Bruno; Castronovo, Vincent; Peulen, Olivier; Blétard, Noëlla; Clézardin, Philippe; Delvenne, Philippe; De Pauw, Edwin A; Turtoi, Andrei; Bellahcène, Akeila

2012-04-06

The classical fate of metastasizing breast cancer cells is to seed and form secondary colonies in bones. The molecules closely associated with these processes are predominantly present at the cell surface and in the extracellular space, establishing the first contacts with the target tissue. In this study, we had the rare opportunity to analyze a bone metastatic lesion and its corresponding breast primary tumor obtained simultaneously from the same patient. Using mass spectrometry, we undertook a proteomic study on cell surface and extracellular protein-enriched material. We provide a repertoire of significantly modulated proteins, some with yet unknown roles in the bone metastatic process as well as proteins notably involved in cancer cell invasiveness and in bone metabolism. The comparison of these clinical data with those previously obtained using a human osteotropic breast cancer cell line highlighted an overlapping group of proteins. Certain differentially expressed proteins are validated in the present study using immunohistochemistry on a retrospective collection of breast tumors and matched bone metastases. Our exclusive set of selected proteins supports the setup of further investigations on both clinical samples and experimental bone metastasis models that will help to reveal the finely coordinated expression of proteins that favor the development of metastases in the bone microenvironment.

Bone marrow invasion in multiple myeloma and metastatic disease.

PubMed

Vilanova, J C; Luna, A

2016-04-01

Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Prostate Cancer and Bone: The Elective Affinities

PubMed Central

2014-01-01

The onset of metastases dramatically changes the prognosis of prostate cancer patients, determining increased morbidity and a drastic fall in survival expectancy. Bone is a common site of metastases in few types of cancer, and it represents the most frequent metastatic site in prostate cancer. Of note, the prevalence of tumor relapse to the bone appears to be increasing over the years, likely due to a longer overall survival of prostate cancer patients. Bone tropism represents an intriguing challenge for researchers also because the preference of prostate cancer cells for the bone is the result of a sequential series of targetable molecular events. Many factors have been associated with the peculiar ability of prostate cancer cells to migrate in bone marrow and to determine mixed osteoblastic/osteolytic lesions. As anticipated by the success of current targeted therapy aimed to block bone resorption, a better understanding of molecular affinity between prostate cancer and bone microenvironment will permit us to cure bone metastasis and to improve prognosis of prostate cancer patients. PMID:24971315

Diagnostic test accuracy study of 18F-sodium fluoride PET/CT, 99mTc-labelled diphosphonate SPECT/CT, and planar bone scintigraphy for diagnosis of bone metastases in newly diagnosed, high-risk prostate cancer

PubMed Central

Fonager, Randi F; Zacho, Helle D; Langkilde, Niels C; Fledelius, Joan; Ejlersen, June A; Haarmark, Christian; Hendel, Helle W; Lange, Mine Benedicte; Jochumsen, Mads R; Mortensen, Jesper C; Petersen, Lars J

2017-01-01

The aim of this study was to prospectively compare planar, bone scan (BS) versus SPECT/CT and NaF PET/CT in detecting bone metastases in prostate cancer. Thirty-seven consecutive, newly diagnosed, prostate cancer patients with prostate specific antigen (PSA) levels ≥ 50 ng/mL and who were considered eligible for androgen-deprivation therapy (ADT) were included in this study. BS, SPECT/CT, and NaF PET/CT, were performed prior to treatment and were repeated after six months of ADT. Baseline images from each index test were independently read by two experienced readers. The reference standard was based on a consensus decision made by a multidisciplinary team on the basis of baseline and follow-up images of the index tests, the findings of the baseline index tests by the experienced readers, and any available imaging, biochemical, and clinical data, including the response to ADT. Twenty-seven (73%) of the 37 patients had bone metastases according to the reference standard. The sensitivities for BS, SPECT/CT and NaF PET/CT were 78%, 89%, and 89%, respectively, and the specificities were 90%, 100%, and 90%, respectively. The positive predictive values of BS, SPECT/CT and NaF PET/CT were 96%, 100%, and 96%, respectively, and the negative predictive values were 60%, 77% and 75%, respectively. No statistically significant difference among the three imaging modalities was observed. All three imaging modalities showed high sensitivity and specificity. NaF PET/CT and SPECT/CT showed numerically improved, but not statistically superior, sensitivity compared with BS in this limited and selected patient cohort. PMID:29181269

Bone metastases in castration-resistant prostate cancer: associations between morphologic CT patterns, glycolytic activity, and androgen receptor expression on PET and overall survival.

PubMed

Vargas, Hebert Alberto; Wassberg, Cecilia; Fox, Josef J; Wibmer, Andreas; Goldman, Debra A; Kuk, Deborah; Gonen, Mithat; Larson, Steven M; Morris, Michael J; Scher, Howard I; Hricak, Hedvig

2014-04-01

To compare the features of bone metastases at computed tomography (CT) to tracer uptake at fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and fluorine 18 16β-fluoro-5-dihydrotestosterone (FDHT) PET and to determine associations between these imaging features and overall survival in men with castration-resistant prostate cancer. This is a retrospective study of 38 patients with castration-resistant prostate cancer. Two readers independently evaluated CT, FDG PET, and FDHT PET features of bone metastases. Associations between imaging findings and overall survival were determined by using univariate Cox proportional hazards regression. In 38 patients, reader 1 detected 881 lesions and reader 2 detected 867 lesions. Attenuation coefficients at CT correlated inversely with FDG (reader 1: r = -0.3007; P < .001; reader 2: r = -0.3147; P < .001) and FDHT (reader 1: r = -0.2680; P = .001; reader 2: r = -0.3656; P < .001) uptake. The number of lesions on CT scans was significantly associated with overall survival (reader 1: hazard ratio [HR], 1.025; P = .05; reader 2: HR, 1.021; P = .04). The numbers of lesions on FDG and FDHT PET scans were significantly associated with overall survival for reader 1 (HR, 1.051-1.109; P < .001) and reader 2 (HR, 1.026-1.082; P ≤ .009). Patients with higher FDHT uptake (lesion with the highest maximum standardized uptake value) had significantly shorter overall survival (reader 1: HR, 1.078; P = .02; reader 2: HR, 1.092; P = .02). FDG uptake intensity was not associated with overall survival (reader 1, P = .65; reader 2, P = .38). In patients with castration-resistant prostate cancer, numbers of bone lesions on CT, FDG PET, and FDHT PET scans and the intensity of FDHT uptake are significantly associated with overall survival. RSNA, 2013

Bone Metastases in Castration-Resistant Prostate Cancer: Associations between Morphologic CT Patterns, Glycolytic Activity, and Androgen Receptor Expression on PET and Overall Survival

PubMed Central

Wassberg, Cecilia; Fox, Josef J.; Wibmer, Andreas; Goldman, Debra A.; Kuk, Deborah; Gonen, Mithat; Larson, Steven M.; Morris, Michael J.; Scher, Howard I.; Hricak, Hedvig

2014-01-01

Purpose To compare the features of bone metastases at computed tomography (CT) to tracer uptake at fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and fluorine 18 16β-fluoro-5-dihydrotestosterone (FDHT) PET and to determine associations between these imaging features and overall survival in men with castration-resistant prostate cancer. Materials and Methods This is a retrospective study of 38 patients with castration-resistant prostate cancer. Two readers independently evaluated CT, FDG PET, and FDHT PET features of bone metastases. Associations between imaging findings and overall survival were determined by using univariate Cox proportional hazards regression. Results In 38 patients, reader 1 detected 881 lesions and reader 2 detected 867 lesions. Attenuation coefficients at CT correlated inversely with FDG (reader 1: r = −0.3007; P < .001; reader 2: r = −0.3147; P < .001) and FDHT (reader 1: r = −0.2680; P = .001; reader 2: r = −0.3656; P < .001) uptake. The number of lesions on CT scans was significantly associated with overall survival (reader 1: hazard ratio [HR], 1.025; P = .05; reader 2: HR, 1.021; P = .04). The numbers of lesions on FDG and FDHT PET scans were significantly associated with overall survival for reader 1 (HR, 1.051–1.109; P < .001) and reader 2 (HR, 1.026–1.082; P ≤ .009). Patients with higher FDHT uptake (lesion with the highest maximum standardized uptake value) had significantly shorter overall survival (reader 1: HR, 1.078; P = .02; reader 2: HR, 1.092; P = .02). FDG uptake intensity was not associated with overall survival (reader 1, P = .65; reader 2, P = .38). Conclusion In patients with castration-resistant prostate cancer, numbers of bone lesions on CT, FDG PET, and FDHT PET scans and the intensity of FDHT uptake are significantly associated with overall survival. © RSNA, 2013 PMID:24475817

Cost per patient and potential budget implications of denosumab compared with zoledronic acid in adults with bone metastases from solid tumours who are at risk of skeletal-related events: an analysis for Austria, Sweden and Switzerland

PubMed Central

Lothgren, Mickael; Ribnicsek, Erna; Schmidt, Louise; Habacher, Wolfgang; Lundkvist, Jonas; Pfeil, Alena M; Biteeva, Irina; Vrouchou, Polina; Bracco, Andrea

2013-01-01

Objectives To assess cost implications per patient, per year, and to predict the potential annual budget impact when patients with bone metastases secondary to solid tumours at risk of skeletal-related events (SREs) transition from zoledronic acid (ZA; 4 mg every 3–4 weeks) to denosumab (120 mg every 4 weeks) in Austria, Sweden and Switzerland. Methods Country specific costs for medication and administration, patient management and SREs (defined as pathologic fracture, radiation to bone, surgery to bone and spinal cord compression) were assessed over a 1-year time horizon. Drug administration and patient management costs were taken from available public sources. SRE costs were based on local unit costs applied to country specific healthcare resources obtained from a multinational retrospective chart review study. Due to lack of real world data for the included countries, SRE rates were derived from phase III clinical trials in patients with advanced cancer and bone metastases. These trials demonstrated that denosumab was superior to ZA in the reduction of SREs. Results Estimated total annual cost savings for each patient transitioned from ZA to denosumab varied by country and cancer type, ranging from €1583 to €2375 in Austria, from €1980 to €2319 in Sweden (9.1 SEK/€) and from €3408 to €3857 in Switzerland (1.2 CHF/€). Cost savings were mainly driven by the lower SRE related costs and lower administration costs of denosumab compared with ZA. Conclusions Denosumab offers superior efficacy compared with ZA in patients with solid tumours and bone metastases. Cost savings are predicted in the Austrian, Swedish and Swiss healthcare systems following treatment transition from ZA to denosumab. PMID:23888248

A comparison of bone-related biomarkers and CA27.29 to assess response to treatment of osseous metastatic breast cancer.

PubMed

Lüfter, D; Richter, A; Günther, S; Flath, B; Akrivakis, C; Geppert, R; Wernecke, K D; Possinger, K

2000-01-01

The assessment of bone metastases by clinical examination or imaging techniques is still considered unreliable. We compared a specific marker of bone resorption, urinary deoxypyridinoline (DPD)-crosslinks, with serum calcium (Ca), alkaline phosphatase (AP) and CA27.29, to evaluate the status of bone metastases in patients with breast cancer. Second morning voided urine was collected from 2 groups of patient (pts), those without evidence of disease (n = 118), and those with bone metastases (n = 85) under specific therapy plus pamidronate. DPD and CA27.29 were measured on the automated ACS180 system (Bayer Diagnostics, Tarrytown, NY, USA). Receiver operating characteristics (ROC) curves were established for each of the 4 biomarkers to determine whether they could distinguish the 2 subsets of pts with clinically sufficient validity, and to establish the corresponding cut-off values. Neither Ca nor AP was useful in discriminating the 2 subgroups. At a DPD cut-off of 13 nmol/mmol, we found a specificity of 69% and a sensitivity of 53% for diagnosing bone metastases. Best results, however, were seen for CA27.29. A cut-off value of 30 U/ml resulted in a specificity of 62% and a sensitivity of 81%. CA27.29 was the best parameter for the discrimination of stage IV breast cancer with bone metastases. The primary advantage of DPD lies in the monitoring of bone metastases under specific therapy.

Autocrine inhibition of the c-fms proto-oncogene reduces breast cancer bone metastasis assessed with in vivo dual-modality imaging.

PubMed

Jeffery, Justin J; Lux, Katie; Vogel, John S; Herrera, Wynetta D; Greco, Stephen; Woo, Ho-Hyung; AbuShahin, Nisreen; Pagel, Mark D; Chambers, Setsuko K

2014-04-01

Breast cancer cells preferentially home to the bone microenvironment, which provides a unique niche with a network of multiple bidirectional communications between host and tumor, promoting survival and growth of bone metastases. In the bone microenvironment, the c-fms proto-oncogene that encodes for the CSF-1 receptor, along with CSF-1, serves as one critical cytokine/receptor pair, functioning in paracrine and autocrine fashion. Previous studies concentrated on the effect of inhibition of host (mouse) c-fms on bone metastasis, with resulting decrease in osteolysis and bone metastases as a paracrine effect. In this report, we assessed the role of c-fms inhibition within the tumor cells (autocrine effect) in the early establishment of breast cancer cells in bone and the effects of this early c-fms inhibition on subsequent bone metastases and destruction. This study exploited a multidisciplinary approach by employing two non-invasive, in vivo imaging methods to assess the progression of bone metastases and bone destruction, in addition to ex vivo analyses using RT-PCR and histopathology. Using a mouse model of bone homing human breast cancer cells, we showed that an early one-time application of anti-human c-fms antibody delayed growth of bone metastases and bone destruction for at least 31 days as quantitatively measured by bioluminescence imaging and computed tomography, compared to controls. Thus, neutralizing human c-fms in the breast cancer cell alone decreases extent of subsequent bone metastasis formation and osteolysis. Furthermore, we are the first to show that anti-c-fms antibodies can impact early establishment of breast cancer cells in bone.

Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis

PubMed Central

Goldstein, Robert H; Reagan, Michaela R; Anderson, Kristen; Kaplan, David L; Rosenblatt, Michael

2010-01-01

American women have a nearly 25% lifetime risk of developing breast cancer, with 20–40% of these patients developing life-threatening metastases. Over 70% of patients presenting with metastases have skeletal involvement, which signals progression to an incurable stage. Tumor-stroma cell interactions are only superficially understood, specifically regarding the ability of stromal cells to affect metastasis. In vivo models show that exogenously supplied hBMSCs (human bone-marrow derived stem cells) migrate to breast cancer tumors, but no reports have shown endogenous hBMSC migration from the bone to primary tumors. Here we present a model of in vivo hBMSC migration from a physiologic human bone environment to human breast tumors. Further, hBMSCs alter tumor growth and bone metastasis frequency. hBMSCs may home to certain breast tumors based on tumor-derived TGF-β1. Moreover, at the primary tumor IL-17B/IL-17BR signaling may mediate interactions between hBMSCs and breast cancer cells (BCCs). PMID:21159629

Urothelial bladder cancer with cavitary lung metastases

PubMed Central

Kurian, Anil; Lee, Jason; Born, Abraham

2011-01-01

Transitional cell carcinoma (TCC) of the bladder tends to remain superficial; however, in 5% to 20% of cases, it progresses to muscle invasion and, more rarely, can metastasize. TCC of the bladder primarily spreads via regional lymphatics. The most common sites of distant metastases of TCC are the liver, lung, mediastinum and bone. Long-term survival of patients with metastatic bladder cancer is rare. Patterns of pulmonary metastasis include multiple nodules, a solitary mass or interstitial micronodule. When multiple nodules are present, they are round and well-circumscribed, without calcification or cavitation. An unusual case of rapidly metastatic TCC to the lung causing large cavitary masses and nodules is presented. Imaging performed after the patient began chemotherapy revealed widespread necrosis of the metastatic cavitary masses causing moderate volume hemoptysis. PMID:21766082

Murine models of breast cancer bone metastasis

PubMed Central

Wright, Laura E; Ottewell, Penelope D; Rucci, Nadia; Peyruchaud, Olivier; Pagnotti, Gabriel M; Chiechi, Antonella; Buijs, Jeroen T; Sterling, Julie A

2016-01-01

Bone metastases cause significant morbidity and mortality in late-stage breast cancer patients and are currently considered incurable. Investigators rely on translational models to better understand the pathogenesis of skeletal complications of malignancy in order to identify therapeutic targets that may ultimately prevent and treat solid tumor metastasis to bone. Many experimental models of breast cancer bone metastases are in use today, each with its own caveats. In this methods review, we characterize the bone phenotype of commonly utilized human- and murine-derived breast cell lines that elicit osteoblastic and/or osteolytic destruction of bone in mice and report methods for optimizing tumor-take in murine models of bone metastasis. We then provide protocols for four of the most common xenograft and syngeneic inoculation routes for modeling breast cancer metastasis to the skeleton in mice, including the intra-cardiac, intra-arterial, orthotopic and intra-tibial methods of tumor cell injection. Recommendations for in vivo and ex vivo assessment of tumor progression and bone destruction are provided, followed by discussion of the strengths and limitations of the available tools and translational models that aid investigators in the study of breast cancer metastasis to bone. PMID:27867497

Genetically fluorescent melanoma bone and organ metastasis models.

PubMed

Yang, M; Jiang, P; An, Z; Baranov, E; Li, L; Hasegawa, S; Al-Tuwaijri, M; Chishima, T; Shimada, H; Moossa, A R; Hoffman, R M

1999-11-01

We report here the establishment and metastatic properties of bright, highly stable, green fluorescent protein (GFP) expression transductants of the B16 mouse malignant melanoma cell line and the LOX human melanoma line. The highly fluorescent malignant melanoma cell lines allowed the visualization of skeletal and multiorgan metastases after i.v. injection of B16 cells in C57BL/6 mice and intradermal injection of LOX cells in nude mice. The melanoma cell lines were transduced with the pLEIN expression retroviral vector containing the GFP and neomycin resistance genes. Stable B16F0 and LOX clones expressing high levels of GFP were selected stepwise in vitro in levels of G418 of up to 800 microg/ml. Extensive bone and bone marrow metastases of B16F0 were visualized by GFP expression when the animals were sacrificed 3 weeks after cell implantation. Metastases for both cell lines were visualized in many organs, including the brain, lung, pleural membrane, liver, kidney, adrenal gland, lymph nodes, skeleton, muscle, and skin by GFP fluorescence. This is the first observation of experimental skeletal metastases of melanoma, which was made possible by GFP expression. These models should facilitate future studies of the mechanism and therapy of bone and multiorgan metastasis of melanoma.

Future directions in treatment of brain metastases

PubMed Central

Barani, Igor J.; Larson, David A.; Berger, Mitchel S.

2013-01-01

Background: Brain metastases affect up to 30% of patients with cancer. Management of brain metastases continues to evolve with ever increasing focus on cognitive preservation and quality of life. This manuscript reviews current state of brain metastases management and discusses various treatment controversies with focus on future clinical trials. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) are discussed in context of multiple (4+ brain metastases) as well as new approaches combining radiation and targeted agents. A brief discussion of modified WBRT approaches, including hippocampal-avoidance WBRT (HA-WBRT) is included as well as a section on recently presented results of Radiation Therapy Oncology Group (RTOG) 0614, a randomized, double-blind, placebo-controlled trial of menantine for prevention of neurocognitive injury after WBRT. Methods: A search of selected studies relevant to management of brain metastases was performed in PubMed as well as in various published meeting abstracts. This data was collated and analyzed in context of contemporary management and future clinical trial plans. This data is presented in tabular form and discussed extensively in the text. Results: The published data demonstrate continued evolution of clinical trials and management strategies designed to minimize and/or prevent cognitive decline following radiation therapy management of brain metastases. Hippocampal avoidance whole-brain radiation therapy (HA-WBRT) and radiosurgery treatments for multiple brain metastases are discussed along with preliminary results of RTOG 0614, a trial of memantine therapy to prevent cognitive decline following WBRT. Trial results appear to support the use of memantine for prevention of cognitive decline. Conclusions: Different management strategies for multiple brain metastases (>4 brain metastases) are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following WBRT. PMID

P14.21 Can vascular risk factors influence number of brain metastases?

PubMed Central

Berk, B.; Nagel, S.; Kortmann, R.; Hoffmann, K.; Gaudino, C.; Seidel, C.

2017-01-01

Abstract BACKGROUND: Up to 30-40% of patients with solid tumors develop cerebral metastases. Number of cerebral metastases is relevant for treatment and prognosis. However, factors that determine number of metastases are not well defined. Distribution of metastases is influenced by blood vessels and cerebral small vessel disease can reduce number of metastases. Aim of this pilot study was to analyze the influence of vascular risk factors (arterial hypertension, diabetes mellitus, smoking, hypercholesterolemia) and of peripheral arterial occlusive disease (PAOD) on number of brain metastases. METHODS: 200 patients with pre-therapeutic 3D-brain MRI and available clinical data were analyzed retrospectively. Number of metastases (NoM) was compared between patients with/without vascular risk factors (vasRF). Results: Patients with PAOD had significant less brain metastases than patients without PAOD (NoM=4.43 vs. 6.02, p=0.043), no other single vasRF conferred a significant effect on NoM. NoM differed significantly between different tumor entities. CONCLUSION: Presence of PAOD showed some effect on number of brain metastases implying that tumor-independent vascular factors can influence brain metastasation.

Esophageal Cancer Metastases to Unexpected Sites: A Systematic Review

PubMed Central

2017-01-01

The most common pattern of esophageal cancer metastases (ECM) is to the lymph nodes, lung, liver, bones, adrenal glands, and brain. On the other hand, unexpected metastasis (UM) spread to uncommon sites has increasingly reported and consequently affected the pathway of diagnosis, staging, and management. Using the PubMed database, a systematic search of the following headings “Esophageal” and “Metastasis” or “Metastases” was performed, 10049 articles were identified, and the articles were included if they demonstrated unexpected ECM. 84% of cases were men with an average age of 60.7 years. EC was located in the lower third in 65%. Two-thirds of the UM originated from the lower esophagus, and the two major histological types were adenocarcinoma 40% and squamous cell carcinoma 60%. Metastases were disseminated toward five main anatomical sites: the head and neck (42%), thoracic (17%), abdomen and pelvis (25%), extremities (9%), and multiple skin and muscle metastases (7%). The EC metastases were found to be synchronous 42% and metachronous 58%, isolated in 53.5% and multiple in 46.5%. The overall survival rate was 10.2 months. Since distant metastases are responsible for most EC-related deaths, understanding of ECM dissemination patterns needs more extensive studies. These critical data are the cornerstone of optimal cancer approach and treatment. PMID:28659974

Iodine-131-labeled diphosphonates for palliative treatment of bone metastases: II. Preliminary clinical results with iodine-131 BDP3.

PubMed

Eisenhut, M; Berberich, R; Kimmig, B; Oberhausen, E

1986-08-01

The kinetics, dosimetry, and response of iodine-131 alpha-amino-(4-hydroxybenzylidene)-diphosphonate ([131I]BDP3) treatment were investigated with patients who had pain symptoms from bone metastases of various primary carcinoma. The blood clearance of [131I]BDP3 was rapid. More than 90% disappeared from the blood pool at 2 hr after injection. The excretion of the activity occurred solely through the kidneys and mean total-body retention at 48 hr was 48.6%. The urinary activity showed a metabolite which must be formed by an in vivo cleavage reaction of a phosphorus-carbon bond. The uptake of in vivo cleaved [131I]iodide in the unblocked thyroid was approximately 0.5%. The effective half-life of [131I]BDP3 in metastatic bone (median 182 hr; range 177-205 hr) proved to be longer than in unaffected areas (145 hr; 140-165 hr). Palliative therapies were performed with 18 patients. They received doses ranging between 6 and 48 mCi [131I]BDP3. The response was 44% complete pain relief, 6% substantial pain relief, 22% minimal improvement, and 28% no change. The duration of response ranged between 1 and 8 wk.

The role of bone marrow evaluation in the staging of patients with otherwise localized, low-risk neuroblastoma.

PubMed

Russell, Heidi V; Golding, Laurie A; Suell, Mary Nell; Nuchtern, Jed G; Strother, Douglas R

2005-12-01

Bone marrow aspirations and biopsies are standard staging procedures for neuroblastoma because the tumor frequently metastasizes to the bone marrow. The presence of bone marrow metastases indicates stage 4 or 4S neuroblastoma by International Neuroblastoma Staging System (INSS) criteria; these stages are also associated with other metastatic sites of disease. We questioned whether bone marrow studies changed the staging or treatment of children with localized, completely resected tumors if there was no other evidence of metastatic spread. If stage of disease rarely changed with bone marrow results, it might be possible to avoid this procedure in a subset of patients with neuroblastoma. The staging studies of patients with INSS stage 1 (n = 29), 4 (n = 60), and 4S (n = 13) neuroblastoma from two institutions were reviewed. There were no patients upstaged from stage 1 to 4 or 4S by bone marrow metastases alone. Fifty-nine of 60 stage 4 patients had other sites of metastases on imaging studies, the remaining patient had an unresectable primary tumor and marrow disease. All subjects with stage 4S disease had liver metastases. Bone marrow studies did not contribute data that changed the stage of patients who had surgically resectable tumors and no evidence of metastatic spread on imaging studies. When present, metastatic spread to the marrow was associated with advanced local tumors or other sites of metastatic disease. Given the relatively small size of our study population, further studies are warranted that investigate the utility of bone marrow studies for patients who otherwise have INSS stage 1 neuroblastoma. 2005 Wiley-Liss, Inc.

An Interesting Case of Retropharyngeal Lymph Nodal Metastases in a Case of Iodine-Refractory Thyroid Cancer.

PubMed

Harisankar, Chidambaram Natrajan Balasubramanian; Vijayabhaskar, Ramakrishnan

2018-01-01

Metastases to cervical lymph node are fairly common in differentiated thyroid cancer. In iodine-refractory disease, the disease may persist in the thyroid bed, cervical lymph nodes, lungs, or the bones commonly. Retropharyngeal lymph nodal involvement in thyroid cancer is unusual and may even be the presenting complaint. We represent a case of iodine-refractory thyroid cancer with retropharyngeal lymph nodal involvement in addition to lung metastases.

Macrophage Efferocytosis and Prostate Cancer Bone Metastasis

DTIC Science & Technology

2015-10-01

prostate cancer bone metastasis through the phagocytosis of apoptotic tumor cells (efferocytosis). Specific Aims: 1. To identify the phagocytic ...2: To identify the phagocytic /efferocytic macrophage population in the tumor microenvironment of prostate bone metastases and determine its ability...preparation for Cancer Research. We obtained an array of prostate cancer tissue including bone metastasis (N=72) and stained the tissue for the phagocytic

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

DTIC Science & Technology

2013-06-01

and in vivo bone imaging [months 6-10]. b. Determine apoptosis of bone cells (OT, OB & OC) by quantifying TUNEL staining [months 6-10]. Animal...Zoledronic acid will be used as positive control for inhibition of apoptosis and also inhibition of resorption [month 10]. c. Perform in vivo bone imaging ...described and presented in Task 3. Task 5: Image calvarial osteocytes in real-time after single dose exposure of 2 Gy [months 6-12] A single dose of

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hayeon, E-mail: kimh2@upmc.edu; Rajagopalan, Malolan S.; Beriwal, Sushil

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)more » 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 �

Occipital condyle syndrome secondary to bone metastases from rectal cancer.

PubMed

Marruecos, J; Conill, C; Valduvieco, I; Vargas, M; Berenguer, J; Maurel, J

2008-01-01

Skull-base metastases are very unfrequent. Occipital condyle syndrome (OCS) is usually underdiagnosed. Until now few cases have been reported in the literature. We present a 71-year-old woman with metastatic rectum adenocarcinoma, with right occipital headache and ipsilateral hypoglossal palsy, diagnosed by computed tomography and magnetic resonance imaging of OCS due to a skull-base metastasis and treated with radiation therapy.

An in vitro 3D bone metastasis model by using a human bone tissue culture and human sex-related cancer cells.

PubMed

Salamanna, Francesca; Borsari, Veronica; Brogini, Silvia; Giavaresi, Gianluca; Parrilli, Annapaola; Cepollaro, Simona; Cadossi, Matteo; Martini, Lucia; Mazzotti, Antonio; Fini, Milena

2016-11-22

One of the main limitations, when studying cancer-bone metastasis, is the complex nature of the native bone environment and the lack of reliable, simple, inexpensive models that closely mimic the biological processes occurring in patients and allowing the correct translation of results. To enhance the understanding of the mechanisms underlying human bone metastases and in order to find new therapies, we developed an in vitro three-dimensional (3D) cancer-bone metastasis model by culturing human breast or prostate cancer cells with human bone tissue isolated from female and male patients, respectively. Bone tissue discarded from total hip replacement surgery was cultured in a rolling apparatus system in a normoxic or hypoxic environment. Gene expression profile, protein levels, histological, immunohistochemical and four-dimensional (4D) micro-CT analyses showed a noticeable specificity of breast and prostate cancer cells for bone colonization and ingrowth, thus highlighting the species-specific and sex-specific osteotropism and the need to widen the current knowledge on cancer-bone metastasis spread in human bone tissues. The results of this study support the application of this model in preclinical studies on bone metastases and also follow the 3R principles, the guiding principles, aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes.

An in vitro 3D bone metastasis model by using a human bone tissue culture and human sex-related cancer cells

PubMed Central

Salamanna, Francesca; Borsari, Veronica; Brogini, Silvia; Giavaresi, Gianluca; Parrilli, Annapaola; Cepollaro, Simona; Cadossi, Matteo; Martini, Lucia; Mazzotti, Antonio; Fini, Milena

2016-01-01

One of the main limitations, when studying cancer-bone metastasis, is the complex nature of the native bone environment and the lack of reliable, simple, inexpensive models that closely mimic the biological processes occurring in patients and allowing the correct translation of results. To enhance the understanding of the mechanisms underlying human bone metastases and in order to find new therapies, we developed an in vitro three-dimensional (3D) cancer-bone metastasis model by culturing human breast or prostate cancer cells with human bone tissue isolated from female and male patients, respectively. Bone tissue discarded from total hip replacement surgery was cultured in a rolling apparatus system in a normoxic or hypoxic environment. Gene expression profile, protein levels, histological, immunohistochemical and four-dimensional (4D) micro-CT analyses showed a noticeable specificity of breast and prostate cancer cells for bone colonization and ingrowth, thus highlighting the species-specific and sex-specific osteotropism and the need to widen the current knowledge on cancer-bone metastasis spread in human bone tissues. The results of this study support the application of this model in preclinical studies on bone metastases and also follow the 3R principles, the guiding principles, aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes. PMID:27765913

Is there any significance of lung cancer histology to compare the diagnostic accuracies of (18)F-FDG-PET/CT and (99m)Tc-MDP BS for the detection of bone metastases in advanced NSCLC?

PubMed

Inal, Ali; Kaplan, Muhammed Ali; Kucukoner, Mehmet; Urakcı, Zuhat; Dostbil, Zeki; Komek, Hail; Onder, Hakan; Tasdemir, Bekir; Isıkdogan, Abdurrahman

2014-01-01

Bone scintigraphy (BS) and fluorine-18 deoxyglucose positron emission tomography computed tomography ((18)F-FDG-PET/CT) are widely used for the detection of bone involvement. The optimal imaging modality for the detection of bone metastases in histological subgroups of non-small cell lung cancer (NSCLC) remains ambiguous. The aim of this study was to compare the efficacy of (18)F-FDG-PET/C and 99mTc-methylene diphosphonate ((99m)Tc-MDP) BS in the detection of bone metastases of patients in NSCLC. Specifically, we compared the diagnostic accuracies of these imaging techniques evaluating bone metastasis in histological subgroups of NSCLC. Fifty-three patients with advanced NSCLC, who had undergone both (18)F-FDG-PET/CT and BS and were eventually diagnosed as having bone metastasis, were enrolled in this retrospective study. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of (18)F-FDG-PET/CT and BS were 90.4%, 99.4%, 98.1%, 96.6%, 97.0% and 84.6%, 93.1%, 82.5%, 93.2, 90.8%, respectively. The κ statistics were calculated for (18)F-FDG-PET/CT and BS. The κ-value was 0.67 between (18)F-FDG-PET/CT and BS in all patients. On the other hand, the κ-value was 0.65 in adenocarcinoma, and 0.61 in squamous cell carcinoma between (18)F-FDG-PET/CT and BS. The κ-values suggested excellent agreement between all patients and histological subgroups of NSCLC. (18)F-FDG-PET/CT was more favorable than BS in the screening of metastatic bone lesions, but the trend did not reach statistical significance in all patients and histological subgroups of NSCLC. Our results need to be validated in prospective and larger study clinical trials to further clarify this topic.

A 5-year retrospective longitudinal study on the incidence and the risk factors of osteonecrosis of the jaws in patients treated with zoledronic acid for bone metastases from solid tumors.

PubMed

Manfredi, M; Mergoni, G; Goldoni, M; Salvagni, S; Merigo, E; Meleti, M; Vescovi, P

2017-05-01

The aim of this study was to evaluate the incidence and the risk factors of osteonecrosis of the jaw (ONJ) in a group of patients treated with zoledronic acid (ZA) for bone metastases from solid tumors and enrolled in a preventive dental program. This 5-year retrospective longitudinal study included all consecutive oncological patients who underwent at least one infusion with ZA between 2004 and 2011 for bone metastases due to solid neoplasms. Of the 156 patients enrolled in the study, 17 developed ONJ (10.89%). At the multivariate analysis, severe periodontal disease (P=0.025), tooth extraction (P<0.0001) and starting the preventive dental program after the beginning of ZA therapy (P=0.02) were the only factors which showed a significant association with the occurrence of ONJ. This study demonstrated the importance of beginning dental prevention before zoledronic acid exposure in reducing ONJ occurrence, especially in the long term. The results of this research show that control of periodontal disease and an increase in the time between tooth extraction and the first ZA administration are recommended in order to reduce the risk of ONJ development.

[Radionuclide bone scan in patients with newly diagnosed prostate cancer. Clinical aspects and cost analysis].

PubMed

Klatte, T; Klatte, D; Böhm, M; Allhoff, E P

2006-10-01

The indication for a radionuclide bone scan in patients with newly diagnosed, untreated prostate cancer remains controversial. In this retrospective study we examined 406 patients who had received a staging bone scan irrespective of their PSA serum level and histology. We evaluated different guidelines and recommendations with respect to their usefulness. The costs were calculated according to EBM and GOA. We evaluated the classification systems of bone metastases according to Soloway, Crawford, and Rigaud. The bone scan was positive in 41 (10%) of 406 patients. The EAU guidelines turned out to be useful with respect to both clinical value and cost efficiency. The Rigaud classification of bone metastases predicted outcome better than the Soloway or Crawford classification. The EAU guidelines from 2005 are a useful tool to decide whether to perform a bone scan in patients with newly diagnosed, untreated prostate cancer. A bone scan should be performed if PSA levels exceed 20 ng/ml in patients with a G1/G2 histology, and in patients with G3 histology and locally advanced disease irrespective of PSA level. Bone scan metastases should be classified according to Rigaud.

Treatment of painful bone metastases in prostate and breast cancer patients with the therapeutic radiopharmaceutical rhenium-188-HEDP. Clinical benefit in a real-world study.

PubMed

Lange, Rogier; Overbeek, Floor; de Klerk, John M H; Pasker-de Jong, Pieternel C M; van den Berk, Alexandra M; Ter Heine, Rob; Rodenburg, Cees J; Kooistra, Anko; Hendrikse, N Harry; Bloemendal, Haiko J

2016-09-26

Rhenium-188-HEDP ((188)Re-HEDP) is an effective radiopharmaceutical for the palliative treatment of osteoblastic bone metastases. However, only limited data on its routine use are available and its effect on quality of life (QoL) has not been studied. Therefore, we evaluated the clinical benefit of (188)Re-HEDP in routine clinical care. Prostate or breast cancer patients with painful bone metastases receiving (188)Re-HEDP as a routine clinical procedure were eligible for evaluation. Clinical benefit was assessed in terms of efficacy and toxicity. Pain palliation and QoL were monitored using the visual analogue scale (VAS), corrected for opioid intake, and the EORTC QLQ-C30 Global health status/QoL-scale. Thrombocyte and leukocyte nadirs were used to assess haematological toxicity. 45 and 47 patients were evaluable for pain palliation and QoL, respectively. After a single injection of (188)Re-HEDP, the overall pain response rate was 69% and mean VAS-scores decreased relevantly and significantly (p < 0.05). Repeated treatment resulted in similar pain response. The overall QoL response rate was 68% and mean Global health status/QoL-scores increased relevantly and significantly. Haematological side effects were mild and transient. The clinically relevant response on pain and quality of life and the limited adverse events prove clinical benefit of treatment with (188)Re-HEDP and support its use in routine clinical care. Its effectiveness appears comparable to that of external beam radiotherapy.

A case report of apatinib in treating osteosarcoma with pulmonary metastases.

PubMed

Zhou, Yong; Zhang, Wengeng; Tang, Fan; Luo, Yi; Min, Li; Zhang, Wenli; Shi, Rui; Duan, Hong; Tu, Chongqi

2017-04-01

Osteosarcoma is the most common malignant bone tumor in children and adolescents. Pulmonary metastases lead to a significantly increased risk of death. Apatinib, a new potent oral small-molecule tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), shows survival benefits in treating advanced or metastatic gastric adenocarcinoma, non-squamous non-small cell lung cancer and metastatic breast cancer. However, its efficacy in metastatic osteosarcoma has not been reported yet. Herein, we presented a 50-year-old man patient who visited hospital due to local bone pain in the left leg. He was initially diagnosed with osteoblastic osteosarcoma. The patient suffered repeated resection surgeries but developed multiple lung metastases. Positive staining for CD31, CD34, and VEGFR-2 were detected in the tumor section. As he refused to receive chemotherapy due to concerns regarding the chemotherapy toxicities and sorafenib due to high cost, apatinib was given at a dose of 500 mg daily. Eleven months following apatinib administration, the patient achieved a partial response according to the RECIST 1.1 standard. No severe toxicity or drug-related side effect was observed during the treatment. Therefore, apatinib could be a new option for the treatment of metastatic osteosarcoma. Clinical trials are required to further confirm the efficacy and safety of apatinib in treating pulmonary metastases from osteosarcoma.

Vertebral metastases from neuroendocrine tumours: How to avoid false positives on 68Ga-DOTA-TOC PET using CT pattern analysis?

PubMed

Gauthé, Mathieu; Testart Dardel, Nathalie; Ruiz Santiago, Fernando; Ohnona, Jessica; Nataf, Valérie; Montravers, Françoise; Talbot, Jean-Noël

2018-03-12

To develop criteria to improve discrimination between vertebral metastases from neuroendocrine tumours (NETs) and benign bone lesions on PET combined with CT using DOTA-D-Phe 1 -Tyr 3 -octreotide labelled with gallium-68 ( 68 Ga-DOTA-TOC). In 535 NET patients, 68 Ga-DOTA-TOC PET/CT examinations were reviewed retrospectively for vertebral CT lesions and/or PET foci. For each vertebral PET abnormality, appearance on CT, biological volume (BV), standardized uptake value (SUV max ) and ratios to those of reference organs were determined. All vertebral abnormalities were characterized as a metastasis, a typical vertebral haemangioma (VH) or other benign lesion. In 79 patients (14.8 %), we found 107 metastases, 34 VHs and 31 other benign lesions in the spine. The optimal cut-off values to differentiate metastases from benign lesions were BV ≥0.72 cm 3 , SUVmax ≥2, SUVmax ratio to a reference vertebra ≥2.1, to liver ≥0.28 and to spleen ≥0.14. They corresponded to lesion-based 68 Ga-DOTA-TOC PET/CT sensitivity of 87 %, 98 %, 97 %, 99 % and 94 %, and specificity of 55 %, 100 %, 90 %, 97 %, 100 %, respectively. The high sensitivity of 68 Ga-DOTA-TOC-PET/CT in detecting NET vertebral metastases was confirmed; this study showed that specificity could be improved by combining CT features and quantifying 68 Ga-DOTA-TOC uptake. • Bone metastases in neuroendocrine tumours correlate with prognosis. • Benign bone lesions may mimic metastases on 68 Ga-DOTA-TOC PET/CT imaging. • The specific polka-dot CT pattern may be missing in some vertebral haemangiomas. • Lesion atypical for haemangiomas can be better characterized by quantifying 68 Ga-DOTA-TOC uptake.

Strontium 89 in the treatment of pain due to diffuse osseous metastases: a university hospital experience.

PubMed Central

Ashayeri, Ebrahim; Omogbehin, Adedamola; Sridhar, Rajagopalan; Shankar, Ravi A.

2002-01-01

More than two-thirds of the patients with osseous metastases experience debilitating bone pain, requiring some form of pain relief. Analgesics are limited in their efficacy. Palliative application of hemi-body external beam radiation therapy in the treatment of multiple osseous metastases also is limited due to toxicity associated with large treatment ports. Intravenous injections of bone seeking radioisotopes are effective in the palliation of pain with fewer side effects. Forty-one patients with multiple osseous metastases due to prostate and breast cancer were treated with strontium chloride 89 (89Sr) at the department of radiation oncology, in a university hospital. A retrospective analysis of these patients indicated that all subjects had severe pain that diminished their quality of life. Most of these patients had multiple co-morbid factors. Many were on opioids leading to adverse effects such as nausea, constipation, and drowsiness that required additional medication. Objective findings and evaluation of the responses were not always available for all patients. Following treatmentwith 89Sr, over two-thirds of the patients responded favorably and required lower doses of opioids. PMID:12152927

Denosumab for bone diseases: translating bone biology into targeted therapy.

PubMed

Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C

2011-12-01

Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.

An elevated serum alkaline phosphatase level in hepatic metastases of grade 1 and 2 gastrointestinal neuroendocrine tumors is unusual and of prognostic value

PubMed Central

Andriantsoa, Maeva; Hoibian, Solene; Autret, Aurelie; Gilabert, Marine; Sarran, Anthony; Niccoli, Patricia

2017-01-01

Background In our clinical practice we have observed that despite a high hepatic metastatic tumor burden, serum alkaline phosphatase (AP) levels are frequently normal in cases of metastatic neuroendocrine tumor (NET). Patients and methods We retrospectively reviewed the records of patients with grade 1 and 2 NETs with liver metastases but without bone metastases seen at our institution in 2013. In total, 49 patients were included (22 female), with a median age of 60 years (range: 28 to 84 years). The primary tumors were located in the duodenum/pancreas (n = 29), small bowel (n = 17) or colon/rectum (n = 3); 10 cases were grade 1 and 39 grade 2. Hepatic involvement was bulky, with more than 10 lesions in 23 patients and a tumor burden above 10% of the liver volume in 26 patients. Results Serum AP levels were elevated (≥ upper limit of normal (ULN)) in 16 patients. In multiparametric analysis, elevated serum AP levels were not associated with the primary site, grade, or number or volume of metastases. In multiparametric analysis, progression-free survival was only correlated with grade (p = 0.010) and AP level (p = 0.017). Conclusions Serum AP levels are frequently normal in liver metastases from NET, even in the event of a major tumor burden, and the serum AP level can be of prognostic value. PMID:28562682

Is there a role of whole-body bone scan in patients with esophageal squamous cell carcinoma

PubMed Central

2012-01-01

Background Correct detection of bone metastases in patients with esophageal squamous cell carcinoma is pivotal for prognosis and selection of an appropriate treatment regimen. Whole-body bone scan for staging is not routinely recommended in patients with esophageal squamous cell carcinoma. The aim of this study was to investigate the role of bone scan in detecting bone metastases in patients with esophageal squamous cell carcinoma. Methods We retrospectively evaluated the radiographic and scintigraphic images of 360 esophageal squamous cell carcinoma patients between 1999 and 2008. Of these 360 patients, 288 patients received bone scan during pretreatment staging, and sensitivity, specificity, positive predictive value, and negative predictive value of bone scan were determined. Of these 360 patients, surgery was performed in 161 patients including 119 patients with preoperative bone scan and 42 patients without preoperative bone scan. Among these 161 patients receiving surgery, 133 patients had stages II + III disease, including 99 patients with preoperative bone scan and 34 patients without preoperative bone scan. Bone recurrence-free survival and overall survival were compared in all 161 patients and 133 stages II + III patients, respectively. Results The diagnostic performance for bone metastasis was as follows: sensitivity, 80%; specificity, 90.1%; positive predictive value, 43.5%; and negative predictive value, 97.9%. In all 161 patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.009, univariately). In multivariate comparison, absence of preoperative bone scan (P = 0.012, odds ratio: 5.053) represented the independent adverse prognosticator for bone recurrence-free survival. In 133 stages II + III patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0

The effect of void creation prior to vertebroplasty on intravertebral pressure and cement distribution in cadaveric spines with simulated metastases.

PubMed

Li, Ka; Yan, Jun; Yang, Qiang; Li, Zhenfeng; Li, Jianmin

2015-01-28

For osteoporosis or spinal metastases, percutaneous vertebroplasty is effective in pain relief and improvement of mobility. However, the complication rate (cement extravasation and fat embolisms) is relatively higher in the treatment of spinal metastases. The presence of tumor tissue plays a significant role in intravertebral pressure and cement distribution and thereby affects the occurrence of complications. We investigated the effect of void creation prior to vertebroplasty on intravertebral pressure and cement distribution in spinal metastases. Eighteen vertebrae (T8-L4) from five cadaveric spines were randomly allocated for two groups (group with and without void) of nine vertebrae each. Defect was created by removing a central core of cancellous bone in the vertebral body and then filling it with 30% or 100% fresh muscle paste by volume to simulate void creation or no void creation, respectively. Then, 20% bone cement by volume of the vertebral body was injected into each specimen through a unipedicular approach at a rate of 3 mL/min. The gender of the donor, vertebral body size, bone density, cement volume, and intravertebral pressure were recorded. Then, computed tomography scans and cross sections were taken to evaluate the cement distribution in vertebral bodies. No significant difference was found between the two groups in terms of the gender of the donor, vertebral body size, bone density, or bone cement volume. The average maximum intravertebral pressure in the group with void creation was significantly lower than that in the group without void creation (1.20 versus 5.09 kPa, P = 0.001). Especially during the filling of void, the difference was more pronounced. Void creation prior to vertebroplasty allowed the bone cement to infiltrate into the lytic defect. In vertebroplasty for spinal metastases, void creation produced lower intravertebral pressure and facilitated cement filling. To reduce the occurrence of complication, it may be an alternative

A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer.

PubMed

Parker, Christopher C; Pascoe, Sarah; Chodacki, Aleš; O'Sullivan, Joe M; Germá, Josep R; O'Bryan-Tear, Charles Gillies; Haider, Trond; Hoskin, Peter

2013-02-01

Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile. To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases. In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n=41), 50 kBq/kg (n=39), or 80 kBq/kg (n=42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥ 50% in baseline prostate-specific antigen (PSA) levels. Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups. The study met its primary end point with a statistically significant dose-response relationship in confirmed ≥ 50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p=0.0297). A ≥ 50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p<0.0001). The most common treatment-related AEs (≥ 10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline. Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223

Electrochemotherapy of Spinal Metastases Using Transpedicular Approach—A Numerical Feasibility Study

PubMed Central

Cindrič, Helena; Tedesco, Giuseppe; Cadossi, Matteo; Gasbarrini, Alessandro; Miklavčič, Damijan

2018-01-01

Vertebral column is the most frequent site for bone metastases. It has been demonstrated in previous studies that bone metastases can be efficiently treated by electrochemotherapy. We developed a novel approach to treat spinal metastases, that is, transpedicular approach that combines electrochemotherapy with already established technologies for insertion of fixation screws in spinal surgery. In the transpedicular approach, needle electrodes are inserted into the vertebral body through pedicles and placed around the tumor. The main goal of our study was to numerically investigate the feasibility of the proposed treatment approach. Three clinical cases were used in this study—1 with a tumor completely contained within the vertebral body and 2 with tumors spread also to the pedicles and spinal canal. Anatomically accurate numerical models were built for all 3 cases, and numerical computations of electric field distribution in tumor and surrounding tissue were performed to determine the treatment outcome. Complete coverage of tumor volume with sufficiently high electric field is a prerequisite for successful electrochemotherapy. Close to 100% tumor coverage was obtained in all 3 cases studied. Two cases exhibited tumor coverage of >99%, while the coverage in the third case was 98.88%. Tumor tissue that remained untreated was positioned on the margin of the tumor volume. We also evaluated hypothetical damage to spinal cord and nerves. Only 1 case, which featured a tumor grown into the spinal canal, exhibited potential risk of neural damage. Our study shows that the proposed transpedicular approach to treat spinal metastases is feasible and safe if the majority of tumor volume is contained within the vertebral body. In cases where the spinal cord and nerves are contained within the margin of the tumor volume, a successful and safe treatment is still possible, but special attention needs to be given to evaluation of potential neural damage. PMID:29759043

A case of rectal carcinoma with skin and bone marrow metastasis with concurrent extensive visceral involvement; unusual and dismal co-incidence.

PubMed

Arslan, Cagatay; Sen, Cenk Ahmet; Ortac, Ragip

2015-06-01

Novel systemic therapies and modern surgical and ablative approaches have improved the survival rates for the patients with metastatic colorectal cancer. However, there are still patients with poor prognosis and underlying mechanisms that could not be defined clearly. Metastatic colorectal cancer patients with skin metastasis have a poor prognosis. A 45-year-old man, who presented with large bowel obstruction, was diagnosed with metastatic rectal adenocarcinoma. Unresectable liver metastases were found at diagnosis. FOLFOX plus bevacizumab treatment was started, but the patient developed bowel obstruction after the third cycle. Therefore, ileostomy was performed. Multiple skin, lung, liver and bone metastases appeared during that time. Bone marrow biopsy demonstrated diffuse infiltration by adenocarcinoma cells. Even though partial remission was achieved after 4 cycles of FOLFIRI-cetuximab, the disease progressed after the 8th cycle. The patient lost his life due to disease progression 8 months after the diagnosis. Bone marrow and skin are unusual sites of metastasis for colorectal carcinoma. Metastases in bone marrow and skin develop at later stages of metastatic disease. This patient lived only 4 months after the development of skin and bone marrow metastases. Skin and bone marrow metastases may be the harbingers of short survival. Biopsy of metastatic sites is crucial for diagnosis and detailed molecular analysis. Molecular pathway alterations underlying worse disease course may be found, and hence probable targets for drug improvement may be indicated.

Primary hemangiosarcoma of the spleen with angioscintigraphic demonstration of metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hermann, G.G.; Fogh, J.; Graem, N.

1984-04-15

A case of primary hemangiosarcoma of the spleen in a 48-year-old woman is presented. Twenty-eight months after splenectomy the patient developed a severe anemia of the microangiopathic type, thrombocytopenia, and a leukoerythroblastic peripheral blood picture. In contrast to x-ray and conventional /sup 99m/Tc-methylene-diphosphonate (MDP) bone scintigraphy, which showed only a few minor focal changes in the spine and ribs, angioscintigraphy with in vitro labeled /sup 99m/Tc-erythrocytes revealed extensive pathologic accumulations throughout the spine, femurs, and the liver, indicating the presence of extremely vascular metastases. Autopsy 15 months later confirmed the scintigraphic findings. Angiography with /sup 99m/Tc-labeled erythrocytes seems to bemore » useful for monitoring metastases from hemangiosarcomas.« less

A case report of apatinib in treating osteosarcoma with pulmonary metastases

PubMed Central

Zhou, Yong; Zhang, Wengeng; Tang, Fan; Luo, Yi; Min, Li; Zhang, Wenli; Shi, Rui; Duan, Hong; Tu, Chongqi

2017-01-01

Abstract Rationale: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Pulmonary metastases lead to a significantly increased risk of death. Apatinib, a new potent oral small-molecule tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), shows survival benefits in treating advanced or metastatic gastric adenocarcinoma, non-squamous non-small cell lung cancer and metastatic breast cancer. However, its efficacy in metastatic osteosarcoma has not been reported yet. Patient concerns: Herein, we presented a 50-year-old man patient who visited hospital due to local bone pain in the left leg. Diagnoses: He was initially diagnosed with osteoblastic osteosarcoma. Interventions: The patient suffered repeated resection surgeries but developed multiple lung metastases. Positive staining for CD31, CD34, and VEGFR-2 were detected in the tumor section. As he refused to receive chemotherapy due to concerns regarding the chemotherapy toxicities and sorafenib due to high cost, apatinib was given at a dose of 500 mg daily. Outcomes: Eleven months following apatinib administration, the patient achieved a partial response according to the RECIST 1.1 standard. No severe toxicity or drug-related side effect was observed during the treatment. Lessons: Therefore, apatinib could be a new option for the treatment of metastatic osteosarcoma. Clinical trials are required to further confirm the efficacy and safety of apatinib in treating pulmonary metastases from osteosarcoma. PMID:28403086

[Evaluation and classification of drug therapy for breast cancer with bone-only metastasis].

PubMed

Meng, X Y; Song, S T

2017-03-23

Skeleton is one of the most common metastatic organs for breast cancer, which has a better prognosis than visceral metastases. Bone-only metastasis was defined"non-measurable" in the RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and was excluded by clinical trials. However, patients with bone-only metastasis are also in need of effective treatment to prolong survival. Endocrine therapy is the most important treatment for bone metastatic patients. Tumor response of bone metastases can be determined objectively by bone-window CT. Effective treatment should be continued if the symptoms are relieved or osteogenesis is observed. Osteoblastic change in bone-window CT is a sign of improvement after treatment. Endocrine therapy is proper for ER-positive patients. The patients with initial osteoblastic metastasis should not be treated with salvage chemotherapy or anti-HER2 treatment, only if osteolytic metastasis or visceral metastasis is observed. Bishosphonates are just auxiliary drugs in bone metastasis, which should not be abused.

The Application of Lean Thinking to the Care of Patients With Bone and Brain Metastasis With Radiation Therapy

PubMed Central

Kim, Christopher S.; Hayman, James A.; Billi, John E.; Lash, Kathy; Lawrence, Theodore S.

2007-01-01

Purpose Patients with bone and brain metastases are among the most symptomatic nonemergency patients treated by radiation oncologists. Treatment should begin as soon as possible after the request is generated. We tested the hypothesis that the operational improvement method based on lean thinking could help streamline the treatment of our patients referred for bone and brain metastases. Methods University of Michigan Health System has adopted lean thinking as a consistent approach to quality and process improvement. We applied the principles and tools of lean thinking, especially value as defined by the customer, value stream mapping processes, and one piece flow, to improve the process of delivering care to patients referred for bone or brain metastases. Results and Conclusion The initial evaluation of the process revealed that it was rather chaotic and highly variable. Implementation of the lean thinking principles permitted us to improve the process by cutting the number of individual steps to begin treatment from 27 to 16 and minimize variability by applying standardization. After an initial learning period, the percentage of new patients with brain or bone metastases receiving consultation, simulation, and treatment within the same day rose from 43% to nearly 95%. By implementing the ideas of lean thinking, we improved the delivery of clinical care for our patients with bone or brain metastases. We believe these principles can be applied to much of the care administered throughout our and other health care delivery areas. PMID:20859409

The application of lean thinking to the care of patients with bone and brain metastasis with radiation therapy.

PubMed

Kim, Christopher S; Hayman, James A; Billi, John E; Lash, Kathy; Lawrence, Theodore S

2007-07-01

Patients with bone and brain metastases are among the most symptomatic nonemergency patients treated by radiation oncologists. Treatment should begin as soon as possible after the request is generated. We tested the hypothesis that the operational improvement method based on lean thinking could help streamline the treatment of our patients referred for bone and brain metastases. University of Michigan Health System has adopted lean thinking as a consistent approach to quality and process improvement. We applied the principles and tools of lean thinking, especially value as defined by the customer, value stream mapping processes, and one piece flow, to improve the process of delivering care to patients referred for bone or brain metastases. The initial evaluation of the process revealed that it was rather chaotic and highly variable. Implementation of the lean thinking principles permitted us to improve the process by cutting the number of individual steps to begin treatment from 27 to 16 and minimize variability by applying standardization. After an initial learning period, the percentage of new patients with brain or bone metastases receiving consultation, simulation, and treatment within the same day rose from 43% to nearly 95%. By implementing the ideas of lean thinking, we improved the delivery of clinical care for our patients with bone or brain metastases. We believe these principles can be applied to much of the care administered throughout our and other health care delivery areas.

High incidence of hypocalcemia and serum creatinine increase in patients with bone metastases treated with zoledronic acid.

PubMed

Zuradelli, Monica; Masci, Giovanna; Biancofiore, Giuseppe; Gullo, Giuseppe; Scorsetti, Marta; Navarria, Pierina; Tancioni, Flavio; Berlusconi, Marco; Giordano, Laura; Santoro, Armando

2009-05-01

Zoledronic acid belongs to the new generation of bisphosphonates with demonstrated clinical benefit for the treatment of bone metastases from different kinds of neoplasms. Hypocalcemia and serum creatinine elevation are expected adverse events during this therapy. The monitoring of serum calcium and creatinine is therefore recommended. The primary aim of this study was to establish the actual incidence of hypocalcemia and serum creatinine elevation during treatment with zoledronic acid. Skeletal-related events and side effects were also assessed. Serum creatinine and calcium levels were evaluated in 240 consecutive patients (83 males, 157 females; mean age, 62 years) with metastatic bone lesions from different solid tumors treated with zoledronic acid. Overall, 93 of 240 patients (38.8%) developed hypocalcemia, which was grade (G)1 in 45 patients (48.4%), G2 in 37 patients (39.8%), G3 in 10 patients (10.8%), and G4 in one patient (1.1%). The median time to occurrence of hypocalcemia (any grade) was 2.3 months after the beginning of the treatment (range, 0-34.9 months). Increased serum creatinine was observed in 33 of 240 patients (13.7%), of whom 19 had G1 (57.6%), 11 had G2 (33.3%), and three had G3 (9.1%). The median time to serum creatinine increase (for any grade) was 4.7 months (range, 0-29.2 months). Our analysis shows a high incidence of hypocalcemia and increased serum creatinine level during treatment with zoledronic acid. These results strongly support the need for accurate monitoring of plasma calcium and creatinine levels.

Bone metastases as initial presentation of hepatocellular carcinoma.

PubMed

Monteserin, Luzdivina; Mesa, Alicia; Fernandez-Garcia, Maria Soledad; Gadanon-Garcia, Arantza; Rodriguez, Manuel; Varela, María

2017-10-18

Extra-hepatic spread is present in 5% to 15% of patients with hepatocellular carcinoma (HCC) at the time of diagnosis. The most frequent sites are lung and regional lymph nodes. Here, we report 3 cases of unsuspected HCC with symptoms due to bone lesions as initial presentation. Morphological characteristics and immunohistochemistry from the examined bone were the key data for diagnosis. None of the patients had an already known chronic liver disease. Differential diagnoses with HCC upon ectopic liver disease or hepatoid adenocarcinoma were shown. Therapy with the orally active multikinase inhibitor sorafenib plus symptomatic treatment was indicated.

Awareness, concern, and communication between physicians and patients on bone health in cancer.

PubMed

Tripathy, Debu; Durie, Brian G M; Mautner, Beatrice; Ferenz, Krag S; Moul, Judd W

2014-06-01

This study aims to explore physician-patient communications about bone metastases and cancer treatment-induced bone loss (CTIBL). The study utilizes online survey of patients with breast cancer, prostate cancer, and multiple myeloma, and the physicians who treat them. Even though 69 and 48 % of patients with nonmetastatic breast and prostate cancer aware of treatment-induced bone loss, only 39 and 23 %, respectively, were concerned about bone loss. Yet, 62 and 71 % of oncologists treating breast and prostate cancer felt that their patients were concerned. Among patients with metastatic breast and prostate cancer, two thirds had not discussed treatment for bone metastases with their doctor; when discussed, 88 and 91 % of discussions were initiated by the doctor, usually prior to initiating treatment. Most myeloma patients (77 %) had discussed treatment options with their physicians; 99 % of hematologists reported discussing treatment of bone disease with patients. Physicians are primary sources of information to patients regarding bone health. There is a gap between what physicians assume their patients know about bone health and the patients' perceptions, presenting a need for systematic awareness and education.

Novel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases.

PubMed

Zhao, Hong; Jin, Guangxu; Cui, Kemi; Ren, Ding; Liu, Timothy; Chen, Peikai; Wong, Solomon; Li, Fuhai; Fan, Yubo; Rodriguez, Angel; Chang, Jenny; Wong, Stephen T C

2013-10-15

A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease. ©2013 AACR.

Osteoprotegerin in bone metastases: mathematical solution to the puzzle.

PubMed

Ryser, Marc D; Qu, Yiding; Komarova, Svetlana V

2012-01-01

Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

CT-guided percutaneous screw fixation plus cementoplasty in the treatment of painful bone metastases with fractures or a high risk of pathological fracture.

PubMed

Pusceddu, Claudio; Fancellu, Alessandro; Ballicu, Nicola; Fele, Rosa Maria; Sotgia, Barbara; Melis, Luca

2017-04-01

To evaluate the feasibility and effectiveness of computed tomography (CT)-guided percutaneous screw fixation plus cementoplasty (PSFPC), for either treatment of painful metastatic fractures or prevention of pathological fractures, in patients who are not candidates for surgical stabilization. Twenty-seven patients with 34 metastatic bone lesions underwent CT-guided PSFPC. Bone metastases were located in the vertebral column, femur, and pelvis. The primary end point was the evaluation of feasibility and complications of the procedure, in addition to the length of hospital stay. Pain severity was estimated before treatment and 1 and 6 months after the procedure using the visual analog scale (VAS). Functional outcome was assessed by improved patient walking ability. All sessions were completed and well tolerated. There were no complications related to either incorrect positioning of the screws during bone fixation or leakage of cement. All patients were able to walk within 6 h after the procedure and the average length of hospital stay was 2 days. The mean VAS score decreased from 7.1 (range, 4-9) before treatment to 1.6 (range, 0-6), 1 month after treatment, and to 1.4 (range 0-6) 6 months after treatment. Neither loosening of the screws nor additional bone fractures occurred during a median follow-up of 6 months. Our results suggest that PSFPC might be a safe and effective procedure that allows the stabilization of the fracture and the prevention of pathological fractures with significant pain relief and good recovery of walking ability, although further studies are required to confirm this preliminary experience.

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

PubMed Central

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

2013-01-01

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

Hypocalcaemia in patients with metastatic bone disease treated with denosumab.

PubMed

Body, Jean-Jacques; Bone, Henry G; de Boer, Richard H; Stopeck, Alison; Van Poznak, Catherine; Damião, Ronaldo; Fizazi, Karim; Henry, David H; Ibrahim, Toni; Lipton, Allan; Saad, Fred; Shore, Neal; Takano, Toshimi; Shaywitz, Adam J; Wang, Huei; Bracco, Oswaldo L; Braun, Ada; Kostenuik, Paul J

2015-09-01

This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab. Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836). The overall incidence of laboratory events of hypocalcaemia grade ⩾ 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus ⩽ 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 μg/L [median] versus ⩽ 20.77 μg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with ⩽ 2 bone metastases at baseline. Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab's greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Tumor-targeting Salmonella typhimurium A1-R inhibits human prostate cancer experimental bone metastasis in mouse models.

PubMed

Toneri, Makoto; Miwa, Shinji; Zhang, Yong; Hu, Cameron; Yano, Shuya; Matsumoto, Yasunori; Bouvet, Michael; Nakanishi, Hayao; Hoffman, Robert M; Zhao, Ming

2015-10-13

Bone metastasis is a frequent occurrence in prostate cancer patients and often is lethal. Zoledronic acid (ZOL) is often used for bone metastasis with limited efficacy. More effective models and treatment methods are required to improve the outcome of prostate cancer patients. In the present study, the effects of tumor-targeting Salmonella typhimurium A1-R were analyzed in vitro and in vivo on prostate cancer cells and experimental bone metastasis. Both ZOL and S. typhimurium A1-R inhibited the growth of PC-3 cells expressing red fluorescent protien in vitro. To investigate the efficacy of S. typhimurium A1-R on prostate cancer experimental bone metastasis, we established models of both early and advanced stage bone metastasis. The mice were treated with ZOL, S. typhimurium A1-R, and combination therapy of both ZOL and S. typhimurium A1-R. ZOL and S. typhimurium A1-R inhibited the growth of solitary bone metastases. S. typhimurium A1-R treatment significantly decreased bone metastasis and delayed the appearance of PC-3 bone metastases of multiple mouse models. Additionally, S. typhimurium A1-R treatment significantly improved the overall survival of the mice with multiple bone metastases. The results of the present study indicate that S. typhimurium A1-R is useful to prevent and inhibit prostate cancer bone metastasis and has potential for future clinical use in the adjuvant setting.

Lung metastases

MedlinePlus

Metastases to the lung; Metastatic cancer to the lung; Lung cancer - metastases ... Metastatic tumors in the lungs are cancers that developed at other places in the body (or other parts of the lungs). They then spread through the bloodstream or lymphatic ...

[Percutaneous ablation of metastases: where are we and new techniques].

PubMed

Palussière, Jean; Buy, Xavier; Fonck, Mariane

2013-04-01

When a metastatic disease is localized and slowly evolving either spontaneously or after a general treatment, a local treatment may be proposed. For about 15 years, image-guided percutaneous ablation has been developed which allows to treat tumors with temperature modifications. These mini-invasive techniques may be repeated in patients whose disease may be chronic. Ablation techniques are also used in a more palliative manner on bone metastases to obtain pain relief.

TARGETING POLYMER THERAPEUTICS TO BONE

PubMed Central

Low, Stewart; Kopeček, Jindřich

2012-01-01

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides an unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems. PMID:22316530

Pulsed Radiofrequency Application for the Treatment of Pain Secondary to Sacroiliac Joint Metastases.

PubMed

Yi, Yu Ri; Lee, Na Rea; Kwon, Young Suk; Jang, Ji Su; Lim, So Young

2016-01-01

Sacroiliac (SI) joint pain can result from degeneration, infection, malignancy, and trauma. Patients with metastatic bone pain who do not respond to conventional treatment may need more aggressive neuroinvasive approaches. Recently, pulsed radiofrequency (PRF) neuromodulation has emerged as a promising treatment alternative for refractory cases of SI joint pain. Nevertheless, there is no report on the treatment of pain arising from SI joint metastases with PRF. We are reporting about a 63-year-old woman suffering from buttock pain due to breast cancer metastases in the SI joint. We treated this patient with PRF neuromodulation of the L4-S3 primary dorsal rami and lateral branches using a rotating curved needle technique. The patient tolerated the procedures well, without any complications. She experienced about 70% reduction in pain, and pain relief was sustained for 10 months. This result suggests that PRF neuromodulation is a safe, effective treatment for pain from SI joint metastases.

The Usefulness of Bone Biomarkers for Monitoring Treatment Disease: A Comparative Study in Osteolytic and Osteosclerotic Bone Metastasis Models.

PubMed

Martín-Fernández, Marta; Valencia, Karmele; Zandueta, Carolina; Ormazábal, Cristina; Martínez-Canarias, Susana; Lecanda, Fernando; de la Piedra, Concepción

2017-04-01

The skeleton is the most common site of colonization by metastatic cancers. Zoledronic acid (ZA) has been shown to be effective for the treatment of bone metastases regardless of whether the bone lesions are osteolytic or osteoblastic. Biochemical markers of bone turnover may be useful tools to quantify the degree of bone remodeling in the presence of bone metastases. The aim of this work was to establish the correlation between tumor dispersion (bioluminescence) and biochemical markers of bone turnover in two osteolytic and osteoblastic metastasis models in mice. The A549M1 cell line that produces osteolytic metastases and the LADOB cell line extracted from a patient with a lung carcinoma and osteoblastic metastases cells were retrovirally transduced with a luciferase reporter gene for in vivo image analysis. Forty-four-week-old mice were inoculated in the left cardiac ventricle with A549M1 or LADOB cells. Twenty mouse of each group were treated with a single dose of ZA (70 μg/kg) 5 days after i.c. Ten animals of each group were sacrificed at 21 and 28 days postinoculation in A549M1 and 60 and 75 days in the LADOB assay. Bioluminescence analysis was quantified 7, 14, 21 ,and 28 days postinoculation in A549M1 mice and 33, 45, 60, and 75 days after inoculation in LADOB mice. Osteocalcin (BGP), aminoterminal propeptide of procollagen I (PINP), carboxiterminal telopeptide of type I collagen (CTX), and 5b isoenzyme of tartrate-resistant acid phosphatase were measured by ELISA (IDS, UK). Bioluminescence imaging revealed a significant increase of tumor burden on time in both osteolytic and osteoblastic mice models. ZA administration resulted in a significant decrease in tumor burden at 21 and 28 days in the A549M1 animals and 60 and 70 days postinoculation in the LADOB line. Biomarkers levels were significantly increased in the untreated group at every point in the osteolytic model. In the osteoblastic model, 2 months after inoculation, all biomarkers were significantly

Giant Cell Tumor of Bone - An Overview

PubMed Central

Sobti, Anshul; Agrawal, Pranshu; Agarwala, Sanjay; Agarwal, Manish

2016-01-01

Giant Cell tumors (GCT) are benign tumors with potential for aggressive behavior and capacity to metastasize. Although rarely lethal, benign bone tumors may be associated with a substantial disturbance of the local bony architecture that can be particularly troublesome in peri-articular locations. Its histogenesis remains unclear. It is characterized by a proliferation of mononuclear stromal cells and the presence of many multi- nucleated giant cells with homogenous distribution. There is no widely held consensus regarding the ideal treatment method selection. There are advocates of varying surgical techniques ranging from intra-lesional curettage to wide resection. As most giant cell tumors are benign and are located near a joint in young adults, several authors favor an intralesional approach that preserves anatomy of bone in lieu of resection. Although GCT is classified as a benign lesion, few patients develop progressive lung metastases with poor outcomes. Treatment is mainly surgical. Options of chemotherapy and radiotherapy are reserved for selected cases. Recent advances in the understanding of pathogenesis are essential to develop new treatments for this locally destructive primary bone tumor. PMID:26894211

Painful bone metastasis in elderly treated with radiation therapy: Single- or multiple-fraction regimen? A multicentre retrospective observational analysis.

PubMed

Falivene, S; Pezzulla, D; Di Franco, R; Giugliano, F M; Esposito, E; Scoglio, C; Amato, B; Borzillo, V; D'Aiuto, M; Muto, P

2017-02-01

Bone metastases are a frequent complication of advanced oncologic disease. Pain associated to bone metastasis is a major cause of morbidity in cancer patients, especially in elderly. The aim of this multicentric retrospective observational study is to evaluate the efficacy of different schedules of radiation therapy in elderly patients in terms of pain relief. 206 patients over the age of 60 were enrolled in 1 year time for a multicentre retrospective observational study. Patients were treated with palliative purposes for painful bone metastases. Pain intensity difference (PID) was found in 72% of patients. Reported PID was statistically significant for p < 0.01. Pain intensity measured by a point numeric rating scale was statistically significant reduced for p < 0.05 by one-fraction regimen compared to other two regimens. In recent years, numerous studies have evaluated the most appropriate regimen of fractionation in individual cases, despite this, a consensus about the best schedule is still debated. On our analysis, single-fractionation scheme (8 Gy) confirmed to be statistical significant effective in providing pain reduction due to bone metastases. Radiation therapy provides significant pain relief of symptomatic bone metastases, but appropriate radiotherapy scheduled is needed in order to get significant response to treatment. Multidisciplinary approach is warranted to value the balance between the therapeutic objectives and the patient quality of life.

Calvarial and skull base metastases: expanding the clinical utility of Gamma Knife surgery.

PubMed

Kotecha, Rupesh; Angelov, Lilyana; Barnett, Gene H; Reddy, Chandana A; Suh, John H; Murphy, Erin S; Neyman, Gennady; Chao, Samuel T

2014-12-01

Traditionally, the treatment of choice for patients with metastases to the calvaria or skull base has been conventional radiation therapy. Because patients with systemic malignancies are also at risk for intracranial metastases, the utility of Gamma Knife surgery (GKS) for these patients has been explored to reduce excess radiation exposure to the perilesional brain parenchyma. The purpose of this study was to report the efficacy of GKS for the treatment of calvarial metastases and skull base lesions. The authors performed a retrospective chart review of 21 patients with at least 1 calvarial or skull base metastatic lesion treated with GKS during 2001-2013. For 7 calvarial lesions, a novel technique, in which a bolus was placed over the treatment site, was used. For determination of local control or disease progression, radiation therapy data were examined and posttreatment MR images and oncology records were reviewed. Survival times from the date of procedure were estimated by using Kaplan-Meier analyses. The median patient age at treatment was 57 years (range 29-84 years). A total of 19 (90%) patients received treatment for single lesions, 1 patient received treatment for 3 lesions, and 1 patient received treatment for 4 lesions. The most common primary tumor was breast cancer (24% of patients). Per lesion, the median clinical and radiographic follow-up times were 10.3 months (range 0-71.9 months) and 7.1 months (range 0-61.3 months), respectively. Of the 26 lesions analyzed, 14 (54%) were located in calvarial bones and 12 (46%) were located in the skull base. The median lesion volume was 5.3 cm(3) (range 0.3-55.6 cm(3)), and the median prescription margin dose was 15 Gy (range 13-24 Gy). The median overall survival time for all patients was 35.9 months, and the 1-year local control rate was 88.9% (95% CI 74.4%-100%). Local control rates did not differ between lesions treated with the bolus technique and those treated with traditional methods or between calvarial

Predictive value of seven preoperative prognostic scoring systems for spinal metastases.

PubMed

Leithner, Andreas; Radl, Roman; Gruber, Gerald; Hochegger, Markus; Leithner, Katharina; Welkerling, Heike; Rehak, Peter; Windhager, Reinhard

2008-11-01

Predicting prognosis is the key factor in selecting the proper treatment modality for patients with spinal metastases. Therefore, various assessment systems have been designed in order to provide a basis for deciding the course of treatment. Such systems have been proposed by Tokuhashi, Sioutos, Tomita, Van der Linden, and Bauer. The scores differ greatly in the kind of parameters assessed. The aim of this study was to evaluate the prognostic value of each score. Eight parameters were assessed for 69 patients (37 male, 32 female): location, general condition, number of extraspinal bone metastases, number of spinal metastases, visceral metastases, primary tumour, severity of spinal cord palsy, and pathological fracture. Scores according to Tokuhashi (original and revised), Sioutos, Tomita, Van der Linden, and Bauer were assessed as well as a modified Bauer score without scoring for pathologic fracture. Nineteen patients were still alive as of September 2006 with a minimum follow-up of 12 months. All other patients died after a mean period of 17 months after operation. The mean overall survival period was only 3 months for lung cancer, followed by prostate (7 months), kidney (23 months), breast (35 months), and multiple myeloma (51 months). At univariate survival analysis, primary tumour and visceral metastases were significant parameters, while Karnofsky score was only significant in the group including myeloma patients. In multivariate analysis of all seven parameters assessed, primary tumour and visceral metastases were the only significant parameters. Of all seven scoring systems, the original Bauer score and a Bauer score without scoring for pathologic fracture had the best association with survival (P < 0.001). The data of the present study emphasize that the original Bauer score and a modified Bauer score without scoring for pathologic fracture seem to be practicable and highly predictive preoperative scoring systems for patients with spinal metastases

Predictive value of seven preoperative prognostic scoring systems for spinal metastases

PubMed Central

Leithner, Andreas; Radl, Roman; Gruber, Gerald; Hochegger, Markus; Leithner, Katharina; Welkerling, Heike; Rehak, Peter

2008-01-01

Predicting prognosis is the key factor in selecting the proper treatment modality for patients with spinal metastases. Therefore, various assessment systems have been designed in order to provide a basis for deciding the course of treatment. Such systems have been proposed by Tokuhashi, Sioutos, Tomita, Van der Linden, and Bauer. The scores differ greatly in the kind of parameters assessed. The aim of this study was to evaluate the prognostic value of each score. Eight parameters were assessed for 69 patients (37 male, 32 female): location, general condition, number of extraspinal bone metastases, number of spinal metastases, visceral metastases, primary tumour, severity of spinal cord palsy, and pathological fracture. Scores according to Tokuhashi (original and revised), Sioutos, Tomita, Van der Linden, and Bauer were assessed as well as a modified Bauer score without scoring for pathologic fracture. Nineteen patients were still alive as of September 2006 with a minimum follow-up of 12 months. All other patients died after a mean period of 17 months after operation. The mean overall survival period was only 3 months for lung cancer, followed by prostate (7 months), kidney (23 months), breast (35 months), and multiple myeloma (51 months). At univariate survival analysis, primary tumour and visceral metastases were significant parameters, while Karnofsky score was only significant in the group including myeloma patients. In multivariate analysis of all seven parameters assessed, primary tumour and visceral metastases were the only significant parameters. Of all seven scoring systems, the original Bauer score and a Bauer score without scoring for pathologic fracture had the best association with survival (P < 0.001). The data of the present study emphasize that the original Bauer score and a modified Bauer score without scoring for pathologic fracture seem to be practicable and highly predictive preoperative scoring systems for patients with spinal

Successful high-resolution animal positron emission tomography of human Ewing tumours and their metastases in a murine xenograft model.

PubMed

Franzius, Christiane; Hotfilder, Marc; Poremba, Christopher; Hermann, Sven; Schäfers, Klaus; Gabbert, Helmut Erich; Jürgens, Heribert; Schober, Otmar; Schäfers, Michael; Vormoor, Josef

2006-12-01

As primary osseous metastasis is the main adverse prognostic factor in patients with Ewing tumours, a NOD/scid mouse model for human Ewing tumour metastases has been established to examine the mechanisms of metastasis. The aim of this study was to evaluate the feasibility of diagnostic molecular imaging by small animal PET in this mouse model. Human Ewing tumour cells were transplanted into immune-deficient NOD/scid mice via s.c injection (n=17) or i.v. injection (n=17). The animals (mean weight 23.2 g) were studied 2-7 weeks after transplantation using a submillimetre resolution animal PET scanner. To assess glucose utilisation and bone metabolism, mice were scanned after intravenous injection of 9.6 MBq (mean) 2-[(18)F]fluoro-2-deoxy-D: -glucose (FDG) or 9.4 MBq (mean) [(18)F]fluoride. Whole-body PET images were analysed visually and semi-quantitatively [%ID/g, tumour to non-tumour ratio (T/NT)]. Foci of pathological uptake were identified with respect to the physiological organ uptake in corresponding regions. Subcutaneously transplanted Ewing tumours demonstrated a moderately increased glucose uptake (median %ID/g 2.5; median T/NT 2.2). After i.v. transplantation, the pattern of metastasis was similar to that in patients with metastases in lung, bone and soft tissue. These metastases showed an increased FDG uptake (median %ID/g 3.6; median T/NT 2.7). Osseous metastases were additionally visible on [(18)F]fluoride PET by virtue of decreased [(18)F]fluoride uptake (osteolysis; median %ID/g 8.4; median T/NT 0.59). Metastases were confirmed immunohistologically. Diagnostic molecular imaging of Ewing tumours and their small metastases in an in vivo NOD/scid mouse model is feasible using a submillimetre resolution PET scanner.

Combination of icotinib, surgery, and internal-radiotherapy of a patient with lung cancer severely metastasized to the vertebrae bones with EGFR mutation: a case report.

PubMed

Qu, Li-Li; Qin, Hai-Feng; Gao, Hong-Jun; Liu, Xiao-Qing

2015-01-01

A 48-year-old Chinese female was referred to us regarding EGFR-mutated advanced non-small cell lung cancer, and metastasis to left scapula and vertebrae bones which caused pathological fracture at T8 and T10 thoracic vertebrae. An aggressive combined therapy with icotinib, vertebrae operation, and radioactive particle implantation and immunotherapy was proposed to prevent paraplegia, relieve pain, and control the overall and local tumor lesions. No postoperative symptoms were seen after surgery, and the pain was significantly relieved. Icotinib merited a 31-month partial response with grade 1 diarrhea as its drug-related adverse event. High dose of icotinib was administered after pelvis lesion progression for 3 months with good tolerance. Combination therapy of icotinib, surgery, and internal radiation for metastases of the vertebrae bones from non-small cell lung cancer seems to be a very promising technique both for sufficient pain relief and for local control of the tumor, vertebrae operation can be an encouraging option for patients with EFGR positive mutation and good prognosis indicator.

INCIDENCE OF PULMONARY AND SKIN METASTASES IN WOMEN WITH BREAST CANCER WHO RECEIVED POSTOPERATIVE IRRADIATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dao, T.L.; Kovaric, J.

1962-07-01

The effect of x-ray treatment (total dose of 4500 r over a 3-week period) was evaluated in 354 patients, some of whom had previously undergone mastectomy. In clinically and pathologically comparable cases, ipsilateral pulmonary iaetastases and skin metastases in patients who had radical mastectomy were 14 and 34%, respectively, whereas in patients who received irradiation after mastectomy, incidences of metastases at those 2 sites were 37 and 52%. A similar change of patterns of metastases in lungs and skin was also observed in patients who have had simple mastectomy and irradiation. The increase in the incidence of ipsilateral skin andmore » pulmonary metastases is ascribed to the effect of irradiation, and the observations strongly support the postulate that irradiation favors development of metastases in the lungs. The fact that metastases developed in the skin within the portals of irradiation, and in the ipsilateral lung in the same patients, is evidence that the lymphatic and vascular obstructions due to fibrosis contribute to the development of the metastases in these tissues. The different patterns of skin and lung metastases in nonirradiated patients render additional support to the theory. The incidence of these injuries in 50 irradiated patients was: 18 had permanent disability of the upper extremities; 14 had necrosis of the bones with fractures of the clavicle and ribs; 25 had initial pneumonitis and subsequently pulmonary fibrosis; and 40 had skin changes, ranging from desquamation to ulceration. No significant difference was demonstrated in the survival of patients with cancer of the breast who received radical irradiation in addition to mastectomy. Furthermore, irradiation may favor the development of metastases in the lungs and skin, and cause disabling injuries. (TCO)« less

Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers.

PubMed

Kruger, Thomas E; Miller, Andrew H; Godwin, Andrew K; Wang, Jinxi

2014-02-01

The mechanisms underlying malignant cell metastasis to secondary sites such as bone are complex and no doubt multifactorial. Members of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs) family, particularly bone sialoprotein (BSP) and osteopontin (OPN), exhibit multiple activities known to promote malignant cell proliferation, detachment, invasion, and metastasis of several osteotropic cancers. The expression level of BSP and OPN is elevated in a variety of human cancers, particularly those that metastasize preferentially to the skeleton. Recent studies suggest that the "osteomimicry" of malignant cells is not only conferred by transmembrane receptors bound by BSP and OPN, but includes the "switch" in gene expression repertoire typically expressed in cells of skeletal lineage. Understanding the role of BSP and OPN in tumor progression, altered pathophysiology of bone microenvironment, and tumor metastasis to bone will likely result in development of better diagnostic approaches and therapeutic regimens for osteotropic malignant diseases. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Prevalence and Survival Patterns of Patients with Bone Metastasis from Common Cancers in Thailand.

PubMed

Phanphaisarn, Areerak; Patumanond, Jayantorn; Settakorn, Jongkolnee; Chaiyawat, Parunya; Klangjorhor, Jeerawan; Pruksakorn, Dumnoensun

2016-01-01

Bone metastasis is a single condition but presents with various patterns and severities. Skeletal- related events (SREs) deteriorate overall performance status and reduce quality of life. However, guidelines for early detection and management are limited. This study includes a survey of the prevalence of bone metastasis in cases with common cancers in Thailand as well as a focus on survival patterns and SREs. A retrospective cohort analysis was conducted using a database of the Chiang Mai Cancer Registry and the Musculoskeletal Tumor Registry of the OLARN Center, Chiang Mai University. The prevalence of bone metastasis from each type of primary cancer was noted and time-to-event analysis was performed to estimate cancer survival rates after bone metastasis. There were 29,447 cases of the ten most common cancers in Thailand, accounting for 82.2% of the entire cancer registry entries during the study period. Among those cases, there were 2,263 with bone metastases, accounting for 7.68% of entries. Bone metastasis from lung, liver, breast, cervix and prostate are common in the Thai population, accounting for 83.4% of all positive cases. The median survival time of all was 6 months. Of the bone metastases, 48.9% required therapeutic intervention, including treatment of spinal cord and nerve root compression, pathological fractures, and bone pain. The frequency of the top five types of bone metastasis in Thailand were different from the frequencies in other countries, but corresponded to the relative prevalence of the cancers in Thailand and osteophilic properties of each cancer. The results of this study support the establishment of country specific guidelines for primary cancer identification with skeletal lesions of unknown origin. In addition, further clinical studies of the top five bone metastases should be performed to develop guidelines for optimal patient management during palliative care.

Missing metastases as a model to challenge current therapeutic algorithms in colorectal liver metastases.

PubMed

Lucidi, Valerio; Hendlisz, Alain; Van Laethem, Jean-Luc; Donckier, Vincent

2016-04-21

In oncosurgical approach to colorectal liver metastases, surgery remains considered as the only potentially curative option, while chemotherapy alone represents a strictly palliative treatment. However, missing metastases, defined as metastases disappearing after chemotherapy, represent a unique model to evaluate the curative potential of chemotherapy and to challenge current therapeutic algorithms. We reviewed recent series on missing colorectal liver metastases to evaluate incidence of this phenomenon, predictive factors and rates of cure defined by complete pathologic response in resected missing metastases and sustained clinical response when they were left unresected. According to the progresses in the efficacy of chemotherapeutic regimen, the incidence of missing liver metastases regularly increases these last years. Main predictive factors are small tumor size, low marker level, duration of chemotherapy, and use of intra-arterial chemotherapy. Initial series showed low rates of complete pathologic response in resected missing metastases and high recurrence rates when unresected. However, recent reports describe complete pathologic responses and sustained clinical responses reaching 50%, suggesting that chemotherapy could be curative in some cases. Accordingly, in case of missing colorectal liver metastases, the classical recommendation to resect initial tumor sites might have become partially obsolete. Furthermore, the curative effect of chemotherapy in selected cases could lead to a change of paradigm in patients with unresectable liver-only metastases, using intensive first-line chemotherapy to intentionally induce missing metastases, followed by adjuvant surgery on remnant chemoresistant tumors and close surveillance of initial sites that have been left unresected.

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

NASA Astrophysics Data System (ADS)

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

2015-10-01

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

Umbilical metastases: current viewpoint

PubMed Central

Gabriele, Raimondo; Conte, Marco; Egidi, Federico; Borghese, Mario

2005-01-01

Background Umbilical metastases from a malignant neoplasm, also termed Sister Mary Joseph's nodule, are not commonly reported in the English literature, and they have usually been considered as a sign of a poor prognosis for the patient. The present article reports on the current view point on umbilical metastasis besides discussing the epidemiology, clinical presentation, pathophysiology and treatment. Method A search of Pubmed was carried out using the term 'umblic*' and 'metastases' or metastasis' revealed no references. Another search was made using the term "Sister Joseph's nodule" or sister Joseph nodule" that revealed 99 references. Of these there were 14 review articles, however when the search was limited to English language it yielded only 20 articles. Articles selected from these form the basis of this report along with cross references. Results The primary lesions usually arise from gastrointestinal or genitourinary tract malignancies and may be the presenting symptom or sign of a primary tumour in an unknown site. Conclusion A careful evaluation of all umbilical lesions, including an early biopsy if appropriate, is recommended. Recent studies suggest an aggressive surgical approach combined with chemotherapy for such patients may improve survival. PMID:15723695

[Oligometastatic bone disease. Can limited metastatic bone disease be cured? Is there room for local ablative treatments?].

PubMed

Thariat, J; Leysalle, A; Vignot, S; Marcy, P-Y; Lacout, A; Bera, G; Lagrange, J-L; Clezardin, P; Chiras, J

2012-09-01

Solitary metastases have been reported in up to 30% of cases in imaging series. Local treatment aims at consolidating the injured bone and to prevent neurologic complications. Since the prognosis of bony metastatic disease is about 30 months and includes some long survivors, the multisdisciplinary committee in charge of the patient should ask the question and decide on the type of radical/ablative intervention in case of oligometastases. A literature search was performed using MESH terms (bone, metastases, radiotherapy, radiology, cement, radiofrequency ablation, chemoembolisation). Local ablative treatments can yield symptomatic relief and local control rates of about 90%. Stereotactic hypofractionated irradiation and cementoplasty are increasingly used. In conclusion, local ablative treatment of bony oligometastases is an efficient treatment. Its potential impact on survival remains to be demonstrated prospectively in clinical trials. Copyright © 2012 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Progress in the research on the mechanism of bone metastasis in lung cancer

PubMed Central

Luo, Qinqin; Xu, Zhenye; Wang, Lifang; Ruan, Mingyu; Jin, Guiyu

2016-01-01

Lung cancer is still the predominant cause of cancer-associated mortality worldwide. The bone metastasis of lung cancer brings great suffering to the patient. Previous advances have provided insights into the mechanism of bone metastasis. Previous research has investigated lung cancer stem cells and three steps were determined for the lung cancer cells to metastasize to the bone: i) Escaping from the primary tumor; ii) moving in the circulation; iii) colonizing in the bone. Key molecules are involved in each of these process. Although there is a close association and similarity, dynamic microenvironments affect these processes. The receptor activator of nuclear factor-κB (RANK)/RANKL axis serves a vital role in the regulation of the generation and activation of osteoclasts during the osteolytic lesion. However, the specific molecules for the lung cancer cells to metastasize to the bone require further research and exploration. The present study aimed to investigate the relative molecular mechanisms of bone metastasis in lung cancer in recent years, providing a general understanding about the features of lung cancer preferences to bone, and discussing other things that require investigation. PMID:27446555

A brief instrument to measure health-related quality of life in patients with bone metastasis: validation of the German version of Bone Metastases Quality-of-Life-10 (BOMET-QoL-10).

PubMed

Marschner, Norbert; Wilke, Jochen; Reschke, Daniel; Kaiser, Florian; Schmoor, Claudia; Grugel, Renate; Boller, Emil

2018-06-06

This prospective, epidemiologic study was designed to translate the original Spanish Bone Metastases Quality-of-Life-10 (BOMET-QoL-10) questionnaire and undertake a validation of the translated German version of BOMET-QoL-10 in Germany to assess health-related quality of life (HRQoL) in patients with bone metastases (BM). The translation process included forward and backward translations, and a linguistic validation. Patients aged ≥18 years with histological confirmation of cancer, diagnosed with BM, life expectancy ≥6 months, and fluency in German were eligible for this study (enrolled consecutively in 33 outpatient centers in Germany). Patients were given the German version of BOMET-QoL-10 together with European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 and EORTC QLQ-BM22 questionnaires at inclusion, 6 weeks, 3 months, and 6 months after inclusion. A debriefing questionnaire was administered at inclusion to determine patient acceptability and understanding. Data include 364 patients with BM (median age: 68 years; female sex: 71.7%). The BOMET-QoL-10 is brief and clear (median completion time: 5 minutes; >90% of patients completed the questionnaire without assistance). The BOMET-QoL-10 forms only one overall scale. All 10 items showed a substantial correlation with the first factor (factor loading, range: 0.58 - 0.86). BOMET-QoL-10 exhibits high internal consistency and reproducibility (Cronbach's alpha: 0.91; intra-class correlation coefficient: 0.76). BOMET-QoL-10 showed significant correlations (range: 0.69 - 0.79) both with EORTC QLQ-C30 and EORTC QLQ-BM22 within the functioning (physical, social, interference) and symptom (fatigue, pain) scales, displayed significant sensitivity to change in EORTC QLQ-BM22 scores, and proved potential ability to detect change in HRQoL in patients with different disease status. There was a high proportion of females in our study which might represent a limitation. The

Circulating Bone-related Markers and YKL-40 Versus HER2 and TOPO2a in Bone Metastatic and Nonmetastatic Breast Cancer: Diagnostic Implications.

PubMed

Shaker, Olfat Gamil; Helmy, Hebatullah Samy

2018-06-01

The bone represents one of the most common sites of metastases in breast cancer. The aim of the current study was to evaluate the diagnostic potential of several circulating markers to detect metastasis to bones in patients with breast cancer. Receptor activator of Nuclear Factor-kappa β (NF-Kβ) ligand (RANKL), osteoprotegrin (OPG), vitamin D (VIT D), Chitinase-3-like protein 1; also known as YKL-40, topoisomerase IIα (TOPO2a), and human epidermal growth factor receptor 2 (HER2) were measured in blood samples obtained from 122 patients with breast cancer and 25 healthy controls. All biomarkers were significantly elevated in patients with breast cancer with bone metastasis compared with nonmetastatic patients except YKL-40. RANKL had the highest diagnostic performance for bone metastasis detection with an area under the curve of 97.3, a sensitivity of 85%, and a specificity of 98.6%. Furthermore, logistic regression analysis resulted in a model of RANKL combined with HER2 that had even higher discriminatory power of metastasis to bones than that of RANKL alone. Overall correct classification of the model was 98.9%. We recommend that measuring RANKL together with HER2 can be routinely applied to allow early detection of bone metastases in patients with breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Historical background of bone conduction hearing devices and bone conduction hearing aids.

PubMed

Mudry, Albert; Tjellström, Anders

2011-01-01

During the last 20 years, bone-anchored hearing aids (Baha(®)) became a familiar solution in the treatment of some types of hearing loss. The aim of this chapter is to present the different historical steps which have permitted the production of this new bone conduction hearing device. The recognition of bone conduction hearing is old and was known at least in Antiquity. During the Renaissance, Girolamo Cardano demonstrated a method by which sound may be transmitted to the ear by means of a rod or the shaft of a spear held between one's teeth: this was the beginning of teeth stimulators to improve hearing, firstly in connection with a musical instrument and then, in the second part of the 19th century, with the speaker. The development of the carbon microphone at the beginning of the 20th century allowed the construction of the bone conduction vibrator placed on the mastoid area, notably supported by eyeglasses since the 1950s. Confronted by various problems, and notably the loss of part of sound in the soft tissue of the external mastoid, the idea to implant the vibrator into the mastoid bone was developed in Göteborg, and the first Baha was implanted in 1977 by Anders Tjellström. From that date, various improvements allowed the development of the actual Baha. These different steps are presented in this study, supported by original documentation. Copyright © 2011 S. Karger AG, Basel.

Use of Animal Models in Understanding Cancer-induced Bone Pain

PubMed Central

Slosky, Lauren M; Largent-Milnes, Tally M; Vanderah, Todd W

2015-01-01

Many common cancers have a propensity to metastasize to bone. Although malignancies often go undetected in their native tissues, bone metastases produce excruciating pain that severely compromises patient quality of life. Cancer-induced bone pain (CIBP) is poorly managed with existing medications, and its multifaceted etiology remains to be fully elucidated. Novel analgesic targets arise as more is learned about this complex and distinct pain state. Over the past two decades, multiple animal models have been developed to study CIBP’s unique pathology and identify therapeutic targets. Here, we review animal models of CIBP and the mechanistic insights gained as these models evolve. Findings from immunocompromised and immunocompetent host systems are discussed separately to highlight the effect of model choice on outcome. Gaining an understanding of the unique neuromolecular profile of cancer pain through the use of appropriate animal models will aid in the development of more effective therapeutics for CIBP. PMID:26339191

Cost-effectiveness of zoledronic acid in the prevention of skeletal-related events in patients with bone metastases secondary to advanced renal cell carcinoma: application to France, Germany, and the United Kingdom.

PubMed

Botteman, M F; Meijboom, M; Foley, I; Stephens, J M; Chen, Y M; Kaura, S

2011-12-01

The use of zoledronic acid (ZOL) has recently been shown to significantly reduce the risk of new skeletal-related events (SREs) in renal cell carcinoma (RCC) patients with bone metastases. The present exploratory study assessed the cost-effectiveness of ZOL in this population, adopting a French, German, and United Kingdom (UK) government payer perspective. This cost-effectiveness model was based on a post hoc retrospective analysis of a subset of patients with RCC who were included in a larger randomized clinical trial of patients with bone metastases secondary to a variety of cancers. In the trial, patients were randomized to receive ZOL (n = 27) or placebo (n = 19) with concomitant antineoplastic therapy every 3 weeks for 9 months (core study) plus 12 months during a study extension. Since the trial did not collect costs or data on the quality-adjusted life years (QALYs) of the patients, these outcomes had to be assumed via modeling exercises. The costs of SREs were estimated using hospital DRG tariffs. These estimates were supplemented with literature-based costs where possible. Drug, administration, and supply costs were obtained from published and internet sources. Consistent with similar economic analyses, patients were assumed to experience quality of life decrements lasting 1 month for each SRE. Uncertainty surrounding outcomes was addressed via multivariate sensitivity analyses. Patients receiving ZOL experienced 1.07 fewer SREs than patients on placebo. Patients on ZOL experienced a gain in discounted QALYs of approximately 0.1563 in France and Germany and 0.1575 in the UK. Discounted SRE-related costs were substantially lower among ZOL than placebo patients (-€ 4,196 in France, - € 3,880 in Germany, and -€ 3,355 in the UK). After taking into consideration the drug therapy costs, ZOL saved € 1,358, € 1,223, and € 719 in France, Germany, and the UK, respectively. In the multivariate sensitivity analyses, therapy with ZOL saved costs in 67

An osteoblast-derived proteinase controls tumor cell survival via TGF-beta activation in the bone microenvironment.

PubMed

Thiolloy, Sophie; Edwards, James R; Fingleton, Barbara; Rifkin, Daniel B; Matrisian, Lynn M; Lynch, Conor C

2012-01-01

Breast to bone metastases frequently induce a "vicious cycle" in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. Given the role of MMP-2 in extracellular matrix degradation and growth factor/cytokine processing, we tested whether osteoblast derived MMP-2 contributed to the vicious cycle of tumor progression in the bone microenvironment. To test our hypothesis, we utilized murine models of the osteolytic tumor-bone microenvironment in immunocompetent wild type and MMP-2 null mice. In longitudinal studies, we found that host MMP-2 significantly contributed to tumor progression in bone by protecting against apoptosis and promoting cancer cell survival (caspase-3; immunohistochemistry). Our data also indicate that host MMP-2 contributes to tumor induced osteolysis (μCT, histomorphometry). Further ex vivo/in vitro experiments with wild type and MMP-2 null osteoclast and osteoblast cultures identified that 1) the absence of MMP-2 did not have a deleterious effect on osteoclast function (cd11B isolation, osteoclast differentiation, transwell migration and dentin resorption assay); and 2) that osteoblast derived MMP-2 promoted tumor survival by regulating the bioavailability of TGFβ, a factor critical for cell-cell communication in the bone (ELISA, immunoblot assay, clonal and soft agar assays). Collectively, these studies identify a novel "mini-vicious cycle" between the osteoblast and metastatic cancer cells that is key for initial tumor survival in the bone microenvironment. In conclusion, the findings of our study suggest that the targeted inhibition of MMP-2 and/or TGFβ would be beneficial for the treatment of bone metastases.

Sequential surgical resection of hepatic and pulmonary metastases from colorectal cancer

PubMed Central

Oevermann, Elisabeth; Killaitis, Claudia; Kujath, Peter; Hoffmann, Martin; Bruch, Hans-Peter

2010-01-01

Background Resection of isolated hepatic or pulmonary metastases from colorectal cancer is widely accepted and associated with a 5-year survival rate of 25–40%. The value of aggressive surgical management in patients with both hepatic and pulmonary metastases still remains a controversial area. Materials and methods A retrospective review of 1,497 patients with colorectal carcinoma (CRC) was analysed. Of 73 patients identified with resection of CRC and, at some point in time, both liver and lung metastases, 17 patients underwent metastasectomy (resection group). The remaining 56 patients comprised the non-resection group. Primary tumour, hepatic and pulmonary metastases of all patients were surgically treated in our department of surgery, and the results are that of a single institution. Results The resection group had a 3-year survival of 77%, a 5-year survival of 55% and a 10-year survival of 18%; median survival was 98 months. The longest overall survival was 136 months; six patients are still alive. In the resection group, overall survival was significantly higher than in the non-resection group (p < 0.01). Independent from the chronology of metastasectomy, 5-year survival was 55% with respect to the primary resection, 28% with respect to the first metastasectomy and 14% with respect to the second metastasectomy. A disease-free interval (>18 months), stage III (UICC) and age (<70 years) were found to be significant prognostic factors for overall survival. Conclusion Our report strongly supports aggressive surgical therapy in patients with both hepatic and pulmonary metastases from CRC. Overall survival for surgically treated selected patients with both hepatic and pulmonary metastases from CRC is comparable to hepatic or pulmonary metastasectomy. Simultaneous metastases tend to have a poorer outcome than metachronous metastases. PMID:20165954

Increased risk of SSEs in bone-only metastatic breast cancer patients treated with zoledronic acid.

PubMed

Yanae, Masashi; Fujimoto, Shinichiro; Tane, Kaori; Tanioka, Maki; Fujiwara, Kimiko; Tsubaki, Masanobu; Yamazoe, Yuzuru; Morishima, Yoshiyuki; Chiba, Yasutaka; Takao, Shintaro; Komoike, Yoshifumi; Tsurutani, Junji; Nakagawa, Kazuhiko; Nishida, Shozo

2017-09-01

Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.

Prognostic value of site-specific metastases in pancreatic adenocarcinoma: A Surveillance Epidemiology and End Results database analysis.

PubMed

Oweira, Hani; Petrausch, Ulf; Helbling, Daniel; Schmidt, Jan; Mannhart, Meinrad; Mehrabi, Arianeb; Schöb, Othmar; Giryes, Anwar; Decker, Michael; Abdel-Rahman, Omar

2017-03-14

To evaluate the prognostic value of site-specific metastases among patients with metastatic pancreatic carcinoma registered within the Surveillance, Epidemiology and End Results (SEER) database. SEER database (2010-2013) has been queried through SEER*Stat program to determine the presentation, treatment outcomes and prognostic outcomes of metastatic pancreatic adenocarcinoma according to the site of metastasis. In this study, metastatic pancreatic adenocarcinoma patients were classified according to the site of metastases (liver, lung, bone, brain and distant lymph nodes). We utilized chi-square test to compare the clinicopathological characteristics among different sites of metastases. We used Kaplan-Meier analysis and log-rank testing for survival comparisons. We employed Cox proportional model to perform multivariate analyses of the patient population; and accordingly hazard ratios with corresponding 95%CI were generated. Statistical significance was considered if a two-tailed P value < 0.05 was achieved. A total of 13233 patients with stage IV pancreatic cancer and known sites of distant metastases were identified in the period from 2010-2013 and they were included into the current analysis. Patients with isolated distant nodal involvement or lung metastases have better overall and pancreatic cancer-specific survival compared to patients with isolated liver metastases (for overall survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001) (for pancreatic cancer-specific survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001). Multivariate analysis revealed that age < 65 years, white race, being married, female gender; surgery to the primary tumor and surgery to the metastatic disease were associated with better overall survival and pancreatic cancer-specific survival. Pancreatic adenocarcinoma patients with isolated liver metastases have worse outcomes compared to patients with isolated

Racial disparities in the development of breast cancer metastases among older women: a multilevel study.

PubMed

Schootman, Mario; Jeffe, Donna B; Gillanders, William E; Aft, Rebecca

2009-02-15

Distant metastases are the most common and lethal type of breast cancer relapse. The authors examined whether older African American breast cancer survivors were more likely to develop metastases compared with older white women. They also examined the extent to which 6 pathways explained racial disparities in the development of metastases. The authors used 1992-1999 Surveillance, Epidemiology, and End Results (SEER) data with 1991-1999 Medicare data. They used Medicare's International Classification of Diseases, Ninth Revision, Clinical Modification codes to identify metastases of respiratory and digestive systems, brain, bone, or other unspecified sites. The 6 pathways consisted of patient characteristics, tumor characteristics, type of treatment received, access to medical care, surveillance mammography use, and area-level characteristics (poverty rate and percentage African American) and were obtained from the SEER or Medicare data. Of the 35,937 women, 10.5% developed metastases. In univariate analysis, African American women were 1.61 times (95% confidence interval [CI], 1.54-1.83) more likely to develop metastasis than white women. In multivariate analysis, tumor grade, stage at diagnosis, and census-tract percentage African American explained why African American women were more likely to develop metastases than white women (hazard ratio, 0.84; 95% CI, 0.68-1.03). Interventions to reduce late-stage breast cancer among African Americans also may reduce racial disparities in subsequent increased risk of developing metastasis. African Americans diagnosed with high-grade breast cancer could be targeted to reduce their risk of metastasis. Future studies should identify specific reasons why the racial distribution in census tracts was associated with racial disparities in the risk of breast cancer metastases. (c) 2009 American Cancer Society.

Are metastases from metastases clinical relevant? Computer modelling of cancer spread in a case of hepatocellular carcinoma.

PubMed

Bethge, Anja; Schumacher, Udo; Wree, Andreas; Wedemann, Gero

2012-01-01

Metastasis formation remains an enigmatic process and one of the main questions recently asked is whether metastases are able to generate further metastases. Different models have been proposed to answer this question; however, their clinical significance remains unclear. Therefore a computer model was developed that permits comparison of the different models quantitatively with clinical data and that additionally predicts the outcome of treatment interventions. The computer model is based on discrete events simulation approach. On the basis of a case from an untreated patient with hepatocellular carcinoma and its multiple metastases in the liver, it was evaluated whether metastases are able to metastasise and in particular if late disseminated tumour cells are still capable to form metastases. Additionally, the resection of the primary tumour was simulated. The simulation results were compared with clinical data. The simulation results reveal that the number of metastases varies significantly between scenarios where metastases metastasise and scenarios where they do not. In contrast, the total tumour mass is nearly unaffected by the two different modes of metastasis formation. Furthermore, the results provide evidence that metastasis formation is an early event and that late disseminated tumour cells are still capable of forming metastases. Simulations also allow estimating how the resection of the primary tumour delays the patient's death. The simulation results indicate that for this particular case of a hepatocellular carcinoma late metastases, i.e., metastases from metastases, are irrelevant in terms of total tumour mass. Hence metastases seeded from metastases are clinically irrelevant in our model system. Only the first metastases seeded from the primary tumour contribute significantly to the tumour burden and thus cause the patient's death.

[Breast cancer metastases to the stomach and colon: two case reports].

PubMed

Pulanić, Roland; Jelavić, Marko; Premuzić, Marina; Opacić, Milorad; Jakic-Razumović, Jasminka; Padovan-Stern, Ranka; Vrbanec, Damir

2012-01-01

Summary. Breast cancer has a high potential for metastasis, usually to the lungs, bones, liver and lymph nodes. Metastases in the holow organs of the digestive system are rare and mainly affectes the stomach and colon. They are characterized by very different clinical and radiological manifestations. We have warned that the initial unrecognized breast cancer can appear as a primary tumor of the stomach and colon, and onlya histopathological analysis reveales that it is a metastatic breast cancer. Metastases to the stomach or intestine involve deep layer of the mucosa and pathohistological findings of standard biopsy sample can be falsely negative, despite positive imaging technique (abdominal ultrasound and MSCT, endoscopic ultrasound) that indicate the tumor process. That's,why we emphasize the importance of endoscopic mucosal resection in the detection of malignant process of deeper layers of the gastric mucosa and deep intestinal mucosal biopsies with postoperative analysis of its walls.

Video-Assisted Laser Resection of Lung Metastases-Feasibility of a New Surgical Technique.

PubMed

Meyer, Christian; Bartsch, Detlef; Mirow, Nikolas; Kirschbaum, Andreas

2017-08-01

Background  Our pilot study describes our initial experience to do a laser resection of lung metastases under video-assisted thoracoscopic control via a minithoracotomy. With this approach, if needed, mediastinal lymphadenectomy is also possible. Methods  In this study, 15 patients (11 men and 4 women, mean age: 60 years) with resectable lung metastases of different solid primary tumors (colorectal cancer in seven patients, melanoma in three patients, renal cell carcinoma in two patients, and one each with oropharyngeal cancer, breast cancer, and seminoma) were included. An anterior minithoracotomy incision (approximately 5-7 cm length) was created in the fifth intercostal space and a soft tissue retractor (Alexis Protector; Applied Medical) was positioned. Two additional working ports were inserted. The entire lung was palpated via the minithoracotomy. All detected lung metastases were removed under thoracoscopic control. Nonanatomic resections were performed using a diode-pumped neodymium-doped yttrium aluminium garnet laser (LIMAX120; KLS Martin GmbH & Co KG) with a laser power of 80 W in a noncontact modus. Deeper parenchymal lesions were sutured. Results  A total of 29 lung metastases up to 30 mm in size were resected and all metastases diagnosed on preoperative imaging were detected. All diagnosed lung metastases were completely resected (R0). The median operation time was 102 (range: 85-120) minutes. Median blood loss was 47.6 mL and no postoperative complications occurred. Neither local recurrences nor new lung metastases were observed within 6 months after the procedures. Conclusion  Video-assisted laser resection of lung metastases is safe, effective, and fulfills the requirements of modern lung metastases surgery. Georg Thieme Verlag KG Stuttgart · New York.

Skeletal muscle metastases on magnetic resonance imaging: analysis of 31 cases.

PubMed

Li, Qi; Wang, Lei; Pan, Shinong; Shu, Hong; Ma, Ying; Lu, Zaiming; Fu, Xihu; Jiang, Bo; Guo, Qiyong

2016-01-01

To investigate the magnetic resonance imaging (MRI) features of skeletal muscle metastases (SMM). The records of 31 patients with proven SMM were retrospectively reviewed. Clinical history, type of primary malignancy, location of metastases, and MRI features of SMM were evaluated. Based on MRI findings, SMM were divided into three MRI types. The correlation between MRI types with ages and pathology category, between MRI types of SMM and ages, as well as MRI types of SMM and pathology category were analysed with Spearman's rho. The most common primary tumour was genital tumour (25.8%) and bronchial carcinoma (19.4%), and the most common cell type was adenocarcinoma (58.1%). SMM were located in the iliopsoas muscle (26.3%), paravertebral muscles (21.1%), and upper extremity muscles (18.4%). MRI features: (1) Type-I localised lesions (12.90%), round-like mass limited to local regions with heterogeneous iso-signal intensity in T1WI and heterogeneous hyper-intensity in T2WI; (2) Type-II diffuse lesions without bone destruction (35.48%), abnormal diffuse swelling of the muscle with irregular boundaries and slightly hypo- to iso-intensity in T1WI and hyper-intensity in T2WI; and (3) Type-III diffuse lesions with bone destruction (51.61%), distinct irregular lump with iso-intensity in T1WI and heterogeneous hyper-intensity in T2WI with adjacent bone invasion. There was positive correlation between MRI types and ages (r = 0.431, p < 0.05). There were no significant differences of MRI types with pathology category (p > 0.05). SMM features on MRI can be broadly used to classify lesions, which is beneficial for SMM diagnosis.

Lung Cancer Brain Metastases.

PubMed

Goldberg, Sarah B; Contessa, Joseph N; Omay, Sacit B; Chiang, Veronica

2015-01-01

Brain metastases are common among patients with lung cancer and have been associated with significant morbidity and limited survival. However, the treatment of brain metastases has evolved as the field has advanced in terms of central nervous system imaging, surgical technique, and radiotherapy technology. This has allowed patients to receive improved treatment with less toxicity and more durable benefit. In addition, there have been significant advances in systemic therapy for lung cancer in recent years, and several treatments including chemotherapy, targeted therapy, and immunotherapy exhibit activity in the central nervous system. Utilizing systemic therapy for treating brain metastases can avoid or delay local therapy and often allows patients to receive effective treatment for both intracranial and extracranial disease. Determining the appropriate treatment for patients with lung cancer brain metastases therefore requires a clear understanding of intracranial disease burden, tumor histology, molecular characteristics, and overall cancer prognosis. This review provides updates on the current state of surgery and radiotherapy for the treatment of brain metastases, as well as an overview of systemic therapy options that may be effective in select patients with intracranial metastases from lung cancer.

Disseminated gestational choriocarcinoma presenting with hepatic and uveal metastases, hook effect, and choriocarcinoma syndrome.

PubMed

Aswani, Yashant; Thakkar, Hemangini; Hira, Priya

2016-01-01

Choriocarcinoma is a human chorionic gonadotrophin (HCG)-secreting tumor that comprises vascular channels. It has a tendency for widespread metastasis, common sites for which include the lung, vagina, brain, liver, bone, intestine, and kidney. We describe a 30-year-old female who presented with hepatitis-like features and bilateral diminution of vision, and subsequently developed hemothorax and hemoperitoneum-all rare and seemingly unrelated manifestations which were finally attributable to metastases from gestational choriocarcinoma. To further complicate the clinical scenario, the serum HCG of the patient was mildly raised (due to a phenomenon called hook effect). Subsequently, the patient developed disseminated intravascular coagulation and succumbed to her illness. In this report, we discuss the imaging findings of choriocarcinoma, its potential sites of metastases, and the hook effect.

Osteoimmunology: Influence of the Immune System on Bone Regeneration and Consumption.

PubMed

Limmer, Andreas; Wirtz, Dieter C

2017-06-01

Background Stimulating bone regeneration is a central aim in orthopaedic and trauma surgery. Although the replacement of bone with artificial materials like cement or apatite helps to keep up bone stability, new bone often cannot be regenerated. Increasing research efforts have led to the clinical application of growth factors stimulating bone growth (e.g. bone morphogenic protein, BMP) and inhibitors preventing bone consumption (e.g. RANKL blocking antibodies). These factors mostly concentrate on stimulating osteoblast or preventing osteoclast activity. Current Situation It is widely accepted that osteoblasts and osteoclasts are central players in bone regeneration. This concept assumes that osteoblasts are responsible for bone growth while osteoclasts cause bone consumption by secreting matrix-degrading enzymes such as cathepsin K and matrix metalloproteinases (MMP). However, according to new research results, bone growth or consumption are not regulated by single cell types. It is rather the interaction of various cell types that regulates bone metabolism. While factors secreted by osteoblasts are essential for osteoclast differentiation and activation, factors secreted by activated osteoclasts are essential for osteoblast activity. In addition, recent research results imply that the influence of the immune system on bone metabolism has long been neglected. Factors secreted by macrophages or T cells strongly influence bone growth or degradation, depending on the bone microenvironment. Infections, sterile inflammation or tumour metastases not only affect bone cells directly, but also influence immune cells such as T cells indirectly. Furthermore, immune cells and bone are mechanistically regulated by similar factors such as cytokines, chemokines and transcription factors, suggesting that the definition of bone and immune cells has to be thought over. Outlook Bone and the immune system are regulated by similar mechanisms. These newly identified similarities

Characterisation of the triple negative breast cancer phenotype associated with the development of central nervous system metastases.

PubMed

Laimito, Katerin Rojas; Gámez-Pozo, Angelo; Sepúlveda, Juan; Manso, Luis; López-Vacas, Rocío; Pascual, Tomás; Fresno Vara, Juan A; Ciruelos, Eva

2016-01-01

Breast cancer (BC) is the most frequent tumour in women, representing 20-30% of all malignancies, and continues to be the leading cause of cancer deaths among European women. Triple-negative (TN) BC biological aggressiveness is associated with a higher dissemination rate, with central nervous system (CNS) metastases common. This study aims to elucidate the association between gene expression profiles of PTGS2, HBEGF and ST6GALNAC5 and the development of CNS metastases in TNBC. This is a case-controlled retrospective study comparing patients (pts) with CNS metastases versus patients without them after adjuvant treatment. The selection of the samples was performed including 30 samples in both case and control groups. Formalin-fixed, paraffin-embedded samples were retrieved from the Hospital 12 de Octubre Biobank. Five 10 µm sections from each FFPE sample were deparaffinised with xylene and washed with ethanol, and the RNA was then extracted with the RecoverAll Kit (Ambion). Gene expression was assessed using TaqMan assays. A total of 53 patients were included in the study. The average age was 55 years (range 25-85). About 47 patients (88.67%) had ductal histology and presented high grade (III) tumours (40 patients; 75.47%). Eight women in the case group presented first distant recurrence in the CNS (34.80%), local recurrence (three patients, 13.04%), lungs (two patients; 8.7%), bone (one patient; 4.34%) and other locations (seven patients; 30.38%). In the control group, first distant recurrence occurred locally (six patients; 46.1%), in bone (two patients; 15.4%), lungs (one patient; 7.7%) and other sites (four patients; 23.1%). RNA was successfully obtained from 53 out of 60 samples. PTGS2, HBEGF, and ST6GALNAC5 expression values were not related to metastasis location. TN tumours frequently metastasise to the visceral organs, particularly lungs and brain, and are less common in bone. The literature suggests that expression of the three genes of interest (PTGS2

Characterisation of the triple negative breast cancer phenotype associated with the development of central nervous system metastases

PubMed Central

Laimito, Katerin Rojas; Gámez-Pozo, Angelo; Sepúlveda, Juan; Manso, Luis; López-Vacas, Rocío; Pascual, Tomás; Fresno Vara, Juan A; Ciruelos, Eva

2016-01-01

Aims Breast cancer (BC) is the most frequent tumour in women, representing 20–30% of all malignancies, and continues to be the leading cause of cancer deaths among European women. Triple-negative (TN) BC biological aggressiveness is associated with a higher dissemination rate, with central nervous system (CNS) metastases common. This study aims to elucidate the association between gene expression profiles of PTGS2, HBEGF and ST6GALNAC5 and the development of CNS metastases in TNBC. Methods This is a case-controlled retrospective study comparing patients (pts) with CNS metastases versus patients without them after adjuvant treatment. The selection of the samples was performed including 30 samples in both case and control groups. Formalin-fixed, paraffin-embedded samples were retrieved from the Hospital 12 de Octubre Biobank. Five 10 µm sections from each FFPE sample were deparaffinised with xylene and washed with ethanol, and the RNA was then extracted with the RecoverAll Kit (Ambion). Gene expression was assessed using TaqMan assays. Results A total of 53 patients were included in the study. The average age was 55 years (range 25–85). About 47 patients (88.67%) had ductal histology and presented high grade (III) tumours (40 patients; 75.47%). Eight women in the case group presented first distant recurrence in the CNS (34.80%), local recurrence (three patients, 13.04%), lungs (two patients; 8.7%), bone (one patient; 4.34%) and other locations (seven patients; 30.38%). In the control group, first distant recurrence occurred locally (six patients; 46.1%), in bone (two patients; 15.4%), lungs (one patient; 7.7%) and other sites (four patients; 23.1%). RNA was successfully obtained from 53 out of 60 samples. PTGS2, HBEGF, and ST6GALNAC5 expression values were not related to metastasis location. Conclusion TN tumours frequently metastasise to the visceral organs, particularly lungs and brain, and are less common in bone. The literature suggests that expression of

Follow-up bone scan in breast cancer patients: what is the appropriate interpretation of purely rib uptake?

PubMed

Seo, Minjung; Ko, Byung Kyun; Tae, Soon Young; Koh, Su-Jin; Noh, Young Ju; Choi, Hye-Jeong; Bae, Kyungkyg; Bang, Minseo; Jun, Sungmin; Park, Seol Hoon

2016-12-01

Although rib uptake is frequently detected in follow-up bone scans of breast cancer patients, few studies have assessed its clinical significance. Among 1208 breast cancer patients who underwent a bone scan between 2011 and 2014, 157 patients presented with newly detected rib uptake at follow-up. Patients who had underlying bone metastases (n=8) or had simultaneous new uptake in sites other than the rib (n=13) were excluded. The patients enrolled finally were those who had purely rib uptakes. The location, intensity, and final diagnosis of the uptake were evaluated by nuclear medicine physicians. A total of 275 new instances of rib uptake were detected in follow-up bone scans of 136 patients. These were more frequently located on the ipsilateral side of the breast cancer (61.1%) and the anterior arc (65.1%), and they presented as moderate to intense (93.1%) uptakes. Among these, 265 lesions in 130 patients turned out to be benign fractures (96.4%), whereas only 10 lesions in six patients were metastases. The proportion of metastases was significantly higher if the uptake was linear or if the patient had recurrence. It was marginally higher if the uptake was located in the posterior arc. The proportion of metastases within the radiation field was significantly lower in patients with a history of irradiation. Newly detected purely rib uptake on a follow-up bone scan in patients who have been treated for breast cancer is mostly because of fractures and rarely signals metastasis. However, if the patient has disease recurrence, metastasis should strongly be suspected, particularly when uptake is linear or located in the posterior arc.

Hepatic resection for colorectal metastases - a national perspective.

PubMed Central

Heriot, A. G.; Reynolds, J.; Marks, C. G.; Karanjia, N.

2004-01-01

BACKGROUND: Many consultant surgeons are uncertain about peri-operative assessment and postoperative follow-up of patients for colorectal liver metastases, and indications for referral for hepatic resection. The aim of this study was to assess the views the consultant surgeons who manage these patients. METHODS: A postal questionnaire was sent to all consultant members of the Association of Coloproctology of Great Britain and Ireland and of the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland. The questionnaire assessed current practice for preoperative assessment and follow-up of patients with colorectal malignancy and timing of and criteria for hepatic resection of metastases. Number of referrals/resections were also assessed. RESULTS: The response rate was 47%. Half of the consultants held joint clinics with an oncologist and 89% assessed the liver for secondaries prior to colorectal resection. Ultrasound was used by 75%. Whilst 99% would consider referring a patient with a solitary liver metastasis for resection, only 62% would consider resection for more than 3 unilobar metastases. The majority (83%) thought resections should be performed within the 6 months following colorectal resection. During follow-up, 52% requested blood CEA levels and 72% liver ultrasound. Half would consider chemotherapy prior to liver resection and 76% performed at least one hepatic resection per year with a median number of 2 resections each year. CONCLUSIONS: A substantial proportion of patients are assessed for colorectal liver metastases preoperatively and during follow-up though there is spectrum of frequency of assessment and modality for imaging. Virtually all patients with solitary hepatic metastases are considered for liver resection. Patients with more than one metastasis are likely to be not considered for resection. Many surgeons are carrying out less than 3 resections each year. PMID:15527578

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

PubMed Central

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

2016-01-01

Bone metastases occur in up to 70% of advanced breast cancer. For most patients with breast cancer, bone metastases are predominantly osteolytic. Interactions between tumor cells and stromal cells in the bone microenvironment drive osteolytic bone metastasis, a process that requires the activation of osteoclasts, cells that break down bone. Here, we report that ABL kinases promoted metastasis of breast cancer cells to bone by regulating the crosstalk between tumor and the bone microenvironment. ABL kinases protected tumor cells from apoptosis induced by TRAIL (TNF-related apoptosis-inducing ligand), activated the transcription factor STAT5, and promoted osteolysis through the STAT5-dependent expression of genes encoding the osteoclast activating factors interleukin 6 (IL6) and matrix metalloproteinase-1 (MMP1). Furthermore, ABL kinases increased the abundance of the Hippo pathway mediator TAZ and the expression of TAZ-dependent target genes that promote bone metastasis. Knockdown of ABL kinases or treatment with ABL-specific allosteric inhibitor impaired osteolytic metastasis of breast cancer cells in mice. These findings revealed a role for ABL kinases in regulating tumor-bone interactions and provide a rationale for targeting both tumor and the bone microenvironment with ABL-specific inhibitors. PMID:26838548

Skeletal muscle metastases on magnetic resonance imaging: analysis of 31 cases

PubMed Central

Li, Qi; Wang, Lei; Shu, Hong; Ma, Ying; Lu, Zaiming; Fu, Xihu; Jiang, Bo; Guo, Qiyong

2016-01-01

Aim of the study To investigate the magnetic resonance imaging (MRI) features of skeletal muscle metastases (SMM). Material and methods The records of 31 patients with proven SMM were retrospectively reviewed. Clinical history, type of primary malignancy, location of metastases, and MRI features of SMM were evaluated. Based on MRI findings, SMM were divided into three MRI types. The correlation between MRI types with ages and pathology category, between MRI types of SMM and ages, as well as MRI types of SMM and pathology category were analysed with Spearman's rho. Results The most common primary tumour was genital tumour (25.8%) and bronchial carcinoma (19.4%), and the most common cell type was adenocarcinoma (58.1%). SMM were located in the iliopsoas muscle (26.3%), paravertebral muscles (21.1%), and upper extremity muscles (18.4%). MRI features: (1) Type-I localised lesions (12.90%), round-like mass limited to local regions with heterogeneous iso-signal intensity in T1WI and heterogeneous hyper-intensity in T2WI; (2) Type-II diffuse lesions without bone destruction (35.48%), abnormal diffuse swelling of the muscle with irregular boundaries and slightly hypo- to iso-intensity in T1WI and hyper-intensity in T2WI; and (3) Type-III diffuse lesions with bone destruction (51.61%), distinct irregular lump with iso-intensity in T1WI and heterogeneous hyper-intensity in T2WI with adjacent bone invasion. There was positive correlation between MRI types and ages (r = 0.431, p < 0.05). There were no significant differences of MRI types with pathology category (p > 0.05). Conclusions SMM features on MRI can be broadly used to classify lesions, which is beneficial for SMM diagnosis. PMID:27647989

A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone

PubMed Central

Thibaudeau, Laure; Taubenberger, Anna V.; Holzapfel, Boris M.; Quent, Verena M.; Fuehrmann, Tobias; Hesami, Parisa; Brown, Toby D.; Dalton, Paul D.; Power, Carl A.; Hollier, Brett G.; Hutmacher, Dietmar W.

2014-01-01

ABSTRACT The skeleton is a preferred homing site for breast cancer metastasis. To date, treatment options for patients with bone metastases are mostly palliative and the disease is still incurable. Indeed, key mechanisms involved in breast cancer osteotropism are still only partially understood due to the lack of suitable animal models to mimic metastasis of human tumor cells to a human bone microenvironment. In the presented study, we investigate the use of a human tissue-engineered bone construct to develop a humanized xenograft model of breast cancer-induced bone metastasis in a murine host. Primary human osteoblastic cell-seeded melt electrospun scaffolds in combination with recombinant human bone morphogenetic protein 7 were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. The tissue-engineered constructs led to the formation of a morphologically intact ‘organ’ bone incorporating a high amount of mineralized tissue, live osteocytes and bone marrow spaces. The newly formed bone was largely humanized, as indicated by the incorporation of human bone cells and human-derived matrix proteins. After intracardiac injection, the dissemination of luciferase-expressing human breast cancer cell lines to the humanized bone ossicles was detected by bioluminescent imaging. Histological analysis revealed the presence of metastases with clear osteolysis in the newly formed bone. Thus, human tissue-engineered bone constructs can be applied efficiently as a target tissue for human breast cancer cells injected into the blood circulation and replicate the osteolytic phenotype associated with breast cancer-induced bone lesions. In conclusion, we have developed an appropriate model for investigation of species-specific mechanisms of human breast cancer-related bone metastasis in vivo. PMID:24713276

Beta 2-Microglobulin: A Novel Therapeutic Target for the Treatment of Human Prostate Cancer Bone Metastasis

DTIC Science & Technology

2009-03-14

H, Sodek J, Zhau HE, Chung LW. Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: role of cAMP-dependent...with mesenchymal phenotype b2-m b2-Microglobulin BSP Bone sialoprotein C4-2 Lineage derivative cells from LNCaP C4-2B C4-2 cells metastasized to bone...OPN) and bone sialoprotein (BSP), and RANKL, collectively allow- ing cancer cells to survive and thrive in the bone microenvironment [7–9]. Previous

Lymph node metastases near the celiac trunk should be considered separately from other nodal metastases in patients with cancer of the esophagus or gastroesophageal junction after neoadjuvant treatment and surgery

PubMed Central

Lagarde, Sjoerd M.; Anderegg, Martinus C. J.; Gisbertz, Suzanne S.; Meijer, Sybren L.; Hulshof, Maarten C. C. M.; Bergman, Jacques J. G. H. M.; van Laarhoven, Hanneke W. M.

2018-01-01

Background The aim of the present study is to identify the incidence and prognostic significance of lymph node metastases near the celiac trunk in patients who underwent neoadjuvant chemo(radio)therapy followed by esophagectomy. Methods Between March 1994 and September 2013 a total of 462 consecutive patients with cancer of the esophagus or gastroesophageal junction (GEJ) who underwent potentially curative esophageal resection after neoadjuvant chemotherapy (N=88; 19.0%) or neoadjuvant chemoradiotherapy (CRT) (N=374; 81.0%) were included. Results Seventy one (15.4%) patients had truncal node metastases in the resection specimen. Metastases to these nodes occurred more frequently in male patients with adenocarcinoma and in tumors at the gastro-esophageal junction. A lower response to neoadjuvant treatment, higher ypT and ypN stages and a poorer grade of differentiation were significantly related with truncal node metastases. Patients with tumor positive truncal nodes had a worse median overall survival (17 vs. 55 months). In multivariate analysis, truncal node metastases were independently associated with a worse survival. Only 22 (31.0%) of the 71 patients with tumor positive truncal nodes were identified preoperatively with EUS or CT. In contrast, 37 patients had suspicious truncal nodes on EUS or CT, but metastases in the pathology specimen were absent. Conclusions In the present study, it is demonstrated that positive truncal nodes in the resection specimen after neoadjuvant therapy, are associated with advanced tumor stages and are an independent factor for inferior survival. PMID:29707301

Liposarcoma of bone with osteosarcomatous foci: Case report and review of the literature

DOE Office of Scientific and Technical Information (OSTI.GOV)

Downey, E.F. Jr.; Worsham, G.F.; Brower, A.C.

1982-03-01

A case of liposarcoma arising in bone with rare foci osteosarcoma is reported. In this case, the tumor metastasized to the lungs as osteosarcoma. This is the third documented case and the fourth known case in the literature. Its rarity is somewhat surprising considering the innumerable possibilities of differentiation of the mesenchyme elements present in the bone marrow.

Quantification of osteolytic bone lesions in a preclinical rat trial

NASA Astrophysics Data System (ADS)

Fränzle, Andrea; Bretschi, Maren; Bäuerle, Tobias; Giske, Kristina; Hillengass, Jens; Bendl, Rolf

2013-10-01

In breast cancer, most of the patients who died, have developed bone metastasis as disease progression. Bone metastases in case of breast cancer are mainly bone destructive (osteolytic). To understand pathogenesis and to analyse response to different treatments, animal models, in our case rats, are examined. For assessment of treatment response to bone remodelling therapies exact segmentations of osteolytic lesions are needed. Manual segmentations are not only time-consuming but lack in reproducibility. Computerized segmentation tools are essential. In this paper we present an approach for the computerized quantification of osteolytic lesion volumes using a comparison to a healthy reference model. The presented qualitative and quantitative evaluation of the reconstructed bone volumes show, that the automatically segmented lesion volumes complete missing bone in a reasonable way.

Three-Dimensional Characterization of the Vascular Bed in Bone Metastasis of the Rat by Microcomputed Tomography (MicroCT)

PubMed Central

Nyangoga, Hervé; Mercier, Philippe; Libouban, Hélène; Baslé, Michel Félix; Chappard, Daniel

2011-01-01

Background Angiogenesis contributes to proliferation and metastatic dissemination of cancer cells. Anatomy of blood vessels in tumors has been characterized with 2D techniques (histology or angiography). They are not fully representative of the trajectories of vessels throughout the tissues and are not adapted to analyze changes occurring inside the bone marrow cavities. Methodology/Principal Findings We have characterized the vasculature of bone metastases in 3D at different times of evolution of the disease. Metastases were induced in the femur of Wistar rats by a local injection of Walker 256/B cells. Microfil®, (a silicone-based polymer) was injected at euthanasia in the aorta 12, 19 and 26 days after injection of tumor cells. Undecalcified bones (containing the radio opaque vascular casts) were analyzed by microCT, and a first 3D model was reconstructed. Bones were then decalcified and reanalyzed by microCT; a second model (comprising only the vessels) was obtained and overimposed on the former, thus providing a clear visualization of vessel trajectories in the invaded metaphysic allowing quantitative evaluation of the vascular volume and vessel diameter. Histological analysis of the marrow was possible on the decalcified specimens. Walker 256/B cells induced a marked osteolysis with cortical perforations. The metaphysis of invaded bones became progressively hypervascular. New vessels replaced the major central medullar artery coming from the diaphyseal shaft. They sprouted from the periosteum and extended into the metastatic area. The newly formed vessels were irregular in diameter, tortuous with a disorganized architecture. A quantitative analysis of vascular volume indicated that neoangiogenesis increased with the development of the tumor with the appearance of vessels with a larger diameter. Conclusion This new method evidenced the tumor angiogenesis in 3D at different development times of the metastasis growth. Bone and the vascular bed can be identified

Outcomes of uterine cervical cancer patients with pelvic lymph node metastases after radiotherapy without boost irradiation of metastases.

PubMed

Yoshizawa, Eriko; Koiwai, Keiichiro; Ina, Hironobu; Fukazawa, Ayumu; Sakai, Katsuya; Ozawa, Takesumi; Matsushita, Hirohide; Kadoya, Masumi

2017-04-01

The aim of this study was to evaluate the outcomes of uterine cervical cancer patients with pelvic lymph node (PLN) metastases after radiotherapy without boost irradiation of the metastases and to clarify the necessity of the boost irradiation of metastatic lesions. Thirty-two patients with uterine cervical cancer metastasizing only to the PLN were treated with definitive radiotherapy without boost irradiation of the metastases between 2008 and 2012 at our institution and were selected for this study. The pattern of progression, overall survival, and progression-free survival were analyzed. Ninety percent of the PLN metastases were controlled by radiotherapy. Twenty-two of 32 patients (69%) experienced progression. Distant metastases as initial progression were observed in 21 of these 22 patients (95%). Only two patients experienced failures in pre-treatment metastatic PLN as initial progression, along with other failures. Severe late lower gastrointestinal toxicities were not observed in any patients. Two-year cumulative overall survival and progression-free survival were 74% and 31%, respectively. Boost irradiation of PLN metastases is not necessarily indispensable. Further studies to examine the necessity of boost irradiation of PLN metastases in radiotherapy for uterine cervical cancer patients with metastases are required. © 2017 Japan Society of Obstetrics and Gynecology.

Systemic candidiasis and mesenteric mast cell tumor with multiple metastases in a dog.

PubMed

Matsuda, Kazuya; Sakaguchi, Kanako; Kobayashi, Shintaro; Tominaga, Makiko; Hirayama, Kazuko; Kadosawa, Tsuyoshi; Taniyama, Hiroyuki

2009-02-01

A 5-year-old female miniature dachshund presenting with persistent vomiting and diarrhea had two concurrent rare pathological conditions: systemic candidiasis and mesenteric mast cell tumor with multiorgan metastases. Neoplastic mast cells formed mass in the mesentery of the cecal-colonic region and were also found in the liver, spleen, kidneys, lungs, adrenal grands, ovaries, bone marrow and other tissues. The cells had intracytoplasmic granules with metachromasia and were immunohistochemically positive for c-kit and histamine. Granulomatous lesions with fungal organisms were present in the heart, lungs, kidneys, pancreas, subserosal and surrounding adipose tissue of the duodenum, thyroid glands and mesenteric mass, and phagocytosed organisms were detected in the liver and bone marrow. Bacteriologically and immunohistochemically, the fungi were consistent with Candida albicans.

Optimal Treatment Decision for Brain Metastases of Unknown Primary Origin: The Role and Timing of Radiosurgery

PubMed Central

Han, Hyun Jin; Chang, Won Seok; Jung, Hyun Ho; Park, Yong Gou

2016-01-01

Background Up to 15% of all patients with brain metastases have no clearly detected primary site despite intensive evaluation, and this incidence has decreased with the use of improved imaging technology. Radiosurgery has been evaluated as one of the treatment modality for patients with limited brain metastases. In this study, we evaluated the effectiveness of radiosurgery for brain metastases from unknown primary tumors. Methods We retrospectively evaluated 540 patients who underwent gamma knife radiosurgery (GKRS) for brain metastases radiologically diagnosed between August 1992 and September 2007 in our institution. First, the brain metastases were grouped into metachronous, synchronous, and precocious presentations according to the timing of diagnosis of the brain metastases. Then, synchronous and precocious brain metastases were further grouped into 1) unknown primary; 2) delayed known primary; and 3) synchronous metastases according to the timing of diagnosis of the primary origin. We analyzed the survival time and time to new brain metastasis in each group. Results Of the 540 patients, 29 (5.4%) presented precocious or synchronous metastases (34 GKRS procedures for 174 lesions). The primary tumor was not found even after intensive and repeated systemic evaluation in 10 patients (unknown primary, 34.5%); found after 8 months in 3 patients (delayed known primary, 1.2%); and diagnosed at the same time as the brain metastases in 16 patients (synchronous metastasis, 55.2%). No statistically significant differences in survival time and time to new brain metastasis were found among the three groups. Conclusion Identification of a primary tumor before GKRS did not affect the patient outcomes. If other possible differential diagnoses were completely excluded, early GKRS can be an effective treatment option for brain metastases from unknown primary tumor. PMID:27867920

A Systematic Analysis of 2 Monoisocentric Techniques for the Treatment of Multiple Brain Metastases

PubMed Central

Stathakis, Sotirios; Gutierrez, Alonso N.; Pappas, Evangelos; Crownover, Richard; Floyd, John R.; Papanikolaou, Niko

2016-01-01

Background: In this treatment planning study, we compare the plan quality and delivery parameters for the treatment of multiple brain metastases using 2 monoisocentric techniques: the Multiple Metastases Element from Brainlab and the RapidArc volumetric-modulated arc therapy from Varian Medical Systems. Methods: Eight patients who were treated in our institution for multiple metastases (3-7 lesions) were replanned with Multiple Metastases Element using noncoplanar dynamic conformal arcs. The same patients were replanned with the RapidArc technique in Eclipse using 4 noncoplanar arcs. Both techniques were designed using a single isocenter. Plan quality metrics (conformity index, homogeneity index, gradient index, and R50%), monitor unit, and the planning time were recorded. Comparison of the Multiple Metastases Element and RapidArc plans was performed using Shapiro-Wilk test, paired Student t test, and Wilcoxon signed rank test. Results: A paired Wilcoxon signed rank test between Multiple Metastases Element and RapidArc showed comparable plan quality metrics and dose to brain. Mean ± standard deviation values of conformity index were 1.8 ± 0.7 and 1.7 ± 0.6, homogeneity index were 1.3 ± 0.1 and 1.3 ± 0.1, gradient index were 5.0 ± 1.8 and 5.1 ± 1.9, and R50% were 4.9 ± 1.8 and 5.0 ± 1.9 for Multiple Metastases Element and RapidArc plans, respectively. Mean brain dose was 2.3 and 2.7 Gy for Multiple Metastases Element and RapidArc plans, respectively. The mean value of monitor units in Multiple Metastases Element plan was 7286 ± 1065, which is significantly lower than the RapidArc monitor units of 9966 ± 1533 (P < .05). Conclusion: For the planning of multiple brain lesions to be treated with stereotactic radiosurgery, Multiple Metastases Element planning software produced equivalent conformity, homogeneity, dose falloff, and brain V12 Gy but required significantly lower monitor units, when compared to RapidArc plans. PMID:27612917

[Muscular metastases from renal cell carcinoma].

PubMed

Montagnac, Richard; Champion, Justine; Pradel, Jean; Takin, Romulus; Eychenne, Dominique; Schendel, Adeline

2016-12-01

Renal cell carcinoma can metastasize to several locations but rarely in muscles. However, this possibility must never be overlooked because muscle metastases may occur a very long time after the initial nephrectomy. So the post-operative follow-up, according to the recommendations, with thoraco-abdomino-pelvic imaging (computed tomography or nuclear magnetic resonance) allowing to detect metastases, including muscle metastases in the trunk, does not have to neglect the metastases located in the members. This search is based upon a thorough clinical examination, completed by targeted imaging in case of symptoms and/or palpable mass. Copyright © 2016 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

The Osteogenic Niche Promotes Early-Stage Bone Colonization of Disseminated Breast Cancer Cells

PubMed Central

Wang, Hai; Yu, Cuijuan; Gao, Xia; Welte, Thomas; Muscarella, Aaron M.; Tian, Lin; Zhao, Hong; Zhao, Zhen; Du, Shiyu; Tao, Jianning; Lee, Brendan; Westbrook, Thomas F.; Wong, Stephen T. C.; Jin, Xin; Rosen, Jeffrey M.; Osborne, C. Kent; Zhang, Xiang H.-F.

2014-01-01

Summary Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. Significance In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases. PMID:25600338

Effect of Occult Metastases on Survival in Node-Negative Breast Cancer

PubMed Central

Weaver, Donald L.; Ashikaga, Takamaru; Krag, David N.; Skelly, Joan M.; Anderson, Stewart J.; Harlow, Seth P.; Julian, Thomas B.; Mamounas, Eleftherios P.; Wolmark, Norman

2011-01-01

BACKGROUND Retrospective and observational analyses suggest that occult lymph-node metastases are an important prognostic factor for disease recurrence or survival among patients with breast cancer. Prospective data on clinical outcomes from randomized trials according to sentinel-node involvement have been lacking. METHODS We randomly assigned women with breast cancer to sentinel-lymph-node biopsy plus axillary dissection or sentinel-lymph-node biopsy alone. Paraffin-embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. Both routine staining and immunohistochemical staining for cytokeratin were used at two widely spaced additional tissue levels. Treating physicians were unaware of the findings, which were not used for clinical treatment decisions. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in the greatest dimension. RESULTS Occult metastases were detected in 15.9% (95% confidence interval [CI], 14.7 to 17.1) of 3887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P = 0.03), disease-free survival (P = 0.02), and distant-disease–free interval (P = 0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95% CI, 1.05 to 1.86), 1.31 (95% CI, 1.07 to 1.60), and 1.30 (95% CI, 1.02 to 1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively. CONCLUSIONS Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in

Novel (188)Re multi-functional bone-seeking compounds: Synthesis, biological and radiotoxic effects in metastatic breast cancer cells.

PubMed

Fernandes, Célia; Monteiro, Sofia; Belchior, Ana; Marques, Fernanda; Gano, Lurdes; Correia, João D G; Santos, Isabel

2016-02-01

Radiolabeled bisphosphonates (BPs) have been used for bone imaging and delivery of β(-) emitting radionuclides for bone pain palliation. As a β(-) emitter, (188)Re has been considered particularly promising for bone metastases therapy. Aimed at finding innovative bone-seeking agents for systemic radiotherapy of bone metastases, we describe herein novel organometallic compounds of the type fac-[(188)Re(CO)3(k(3)-L)], (L=BP-containing chelator), their in vitro and in vivo stability, and their cellular damage in MDAMB231 cells, a metastatic breast cancer cell line. After synthesis and characterization of the novel organometallic compounds of the type fac-[(188)Re(CO)3(k(3)-L)] their radiochemical purity and in vitro stability was assessed by HPLC. In vivo stability and pharmacokinetic profile were evaluated in mice and the radiocytotoxic activity and DNA damage were assessed by MTT assay and by the cytokinesis-block micronucleus (CBMN) assay, respectively. Among all complexes, (188)Re3 was obtained with high radiochemical purity (>95%) and high specific activity and presented high in vitro and in vivo stability. Biodistribution studies of (188)Re3 in Balb/c mice showed fast blood clearance, high bone uptake (16.1 ± 3.3% IA/g organ, 1h p.i.) and high bone-to-blood and bone-to-muscle radioactivity ratios, indicating that it is able to deliver radiation to bone in a very selective way. The radiocytotoxic effect elicited by (188)Re3 in the MDAMB231 cells was dependent on its concentration, and was higher than that induced by identical concentrations of [(188)ReO4](-). Additionally, (188)Re3 elicited morphological changes in the cells and induced DNA damage by the increased number of MN observed. Altogether, our results demonstrate that (188)Re3 could be considered an attractive candidate for further preclinical evaluation for systemic radionuclide therapy of bone metastases considering its ability to deliver radiation to bone in a very selective way and to induce

Effect of COX-2 (PGE2) and IL-6 on Prostate Cancer Bone Metastases

DTIC Science & Technology

2008-02-02

to stimulate both bone targeting and bone reaction (4). Several factors, such as basic fibroblast growth factor (4), osteocalcin, bone sialoprotein (8...Proc Natl Acad Sci U S A 1990;87:75–9. 8. Huang WC, Xie Z, Konaka H, Sodek J, Zhau HE, Chung LWK. Human osteocalcin and bone sialoprotein medi- ating

Ca2+ Receptor, Prostate Cancer, and Bone Metastases

DTIC Science & Technology

2005-03-01

calcium receptor cDNAs. J Biol Chem 270: 12919-12925, 1995. 3. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor 0, Sun A, Hediger MA, Lytton J...Hrol FA , Vassilev PhL, Quinn s, and le.bert SC, G- TOE-p as a result of decreased bone resorption. protein-coupiad. extracelluar Ca zrksensing receptor...bmne cells, several EDTA. FBS was obtainod from Gemini Bio -Produets (Cab nephron segments other than thf distal tubule, and many abasas, CA), and

Cutaneous metastases of internal tumors.

PubMed

Fernández-Antón Martínez, M C; Parra-Blanco, V; Avilés Izquierdo, J A; Suárez Fernández, R M

2013-12-01

Cutaneous metastases are relatively rare in clinical practice and their diagnosis requires a high index of suspicion because clinical findings can be subtle. These metastases reveal the presence of disseminated malignant disease and can lead to the diagnosis of unsuspected internal tumors or the spread or recurrence of an already diagnosed tumor. Early recognition of cutaneous metastases can facilitate prompt and accurate diagnosis resulting in early treatment; however, they are generally indicative of a poor prognosis. Some tumors have a predilection to metastasize to specific areas. Recognition of these patterns provides essential information that can guide the search for the underlying tumor. Copyright © 2011 Elsevier España, S.L. y AEDV. All rights reserved.

A Spontaneous 3D Bone-On-a-Chip for Bone Metastasis Study of Breast Cancer Cells.

PubMed

Hao, Sijie; Ha, Laura; Cheng, Gong; Wan, Yuan; Xia, Yiqiu; Sosnoski, Donna M; Mastro, Andrea M; Zheng, Si-Yang

2018-03-01

Bone metastasis occurs at ≈70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone-on-a-chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co-culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone-on-a-chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms.

PubMed

Herroon, Mackenzie K; Rajagurubandara, Erandi; Hardaway, Aimalie L; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-11-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

PubMed Central

Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-01-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease. PMID:24240026

Metastasizing leiomyoma to heart.

PubMed

Consamus, Erin N; Reardon, Michael J; Ayala, Alberto G; Schwartz, Mary R; Ro, Jae Y

2014-01-01

Cardiac smooth muscle tumors are rare. Three different clinical settings for these tumors have been reported, including benign metastasizing leiomyoma from the uterus, primary cardiac leiomyoma and leiomyosarcoma, and intravenous cardiac extension of pelvic leiomyoma, which is the most common. We present a case of a 55-year-old woman with a benign metastasizing leiomyoma to the heart 17 years after hysterectomy and 16 years after metastasis to the lung. Immunohistochemical stains for smooth muscle actin, desmin, and estrogen and progesterone receptors were positive, indicating a smooth muscle tumor of uterine origin. To our knowledge, this is only the fourth reported case of benign metastasizing leiomyoma to the heart and the first case of long-delayed cardiac metastasis after successful treatment of pulmonary metastasis. It illustrates that benign metastasizing leiomyoma should be included in the differential diagnosis of cardiac tumors in patients with a history of uterine leiomyoma, especially when associated with pulmonary metastasis.

FROM ANEURYSMAL BONE CYST TO TELANGIECTATIC OSTEOSARCOMA WITH METASTASIS IN INGUINAL LYMPH NODES - CASE REPORT.

PubMed

Janevska, Vesna; Spasevska, Liljana; Samardziski, Milan; Nikodinovskai, Violeta; Zhivadinovik, Julija; Trajkovskai, Elizabeta

2015-01-01

Aneurysmal bone cyst is a benign bone lesion composed of blood filled cystic cavities lined by fibrous septa. Its malignant transformation of is a rare event. We report a case of a lesion in the second metatarsal bone in a 29-year-old male, presented as a slight swelling of the right foot. After the curettage had been done, the diagnosis of aneurysmal bone cyst was made but the recurrence occurred 4 years later. The biopsy of the recurrent tumor showed compact neoplastic tissue consistent with diagnosis of giant cell tumor with malignancy. The malignant component was recognized as a high grade sarcoma with osteoid production. A tumor mass with the whole II metatarsal bone was extirpated and a resected part of fibula was transplanted. A year later, another recurrence occurred, an amputation was performed and a teleangiectatic osteosarcoma with ingvinal lymph nodes metastases was diagnosed. No other tumor mass was confirmed, either clinically or by imaging techniques at the time of his third operation. He died 4 months later with multiple pulmonary metastases. We emphasize the importance of team work in order to achieve the accurate diagnosis, highlighting careful radiological examinations, good sampling and awareness of unusual cases in bone tumor pathology.

Radionuclide bone imaging: an illustrative review.

PubMed

Love, Charito; Din, Anabella S; Tomas, Maria B; Kalapparambath, Tomy P; Palestro, Christopher J

2003-01-01

Bone scintigraphy with technetium-99m-labeled diphosphonates is one of the most frequently performed of all radionuclide procedures. Radionuclide bone imaging is not specific, but its excellent sensitivity makes it useful in screening for many pathologic conditions. Moreover, some conditions that are not clearly depicted on anatomic images can be diagnosed with bone scintigraphy. Bone metastases usually appear as multiple foci of increased activity, although they occasionally manifest as areas of decreased uptake. Traumatic processes can often be detected, even when radiographic findings are negative. Most fractures are scintigraphically detectable within 24 hours, although in elderly patients with osteopenia, further imaging at a later time is sometimes indicated. Athletic individuals are prone to musculoskeletal trauma, and radionuclide bone imaging is useful for identifying pathologic conditions such as plantar fasciitis, stress fractures, "shin splints," and spondylolysis, for which radiographs may be nondiagnostic. A combination of focal hyperperfusion, focal hyperemia, and focally increased bone uptake is virtually diagnostic for osteomyelitis in patients with nonviolated bone. Bone scintigraphy is also useful for evaluating disease extent in Paget disease and for localizing avascular necrosis in patients with negative radiographs. Radionuclide bone imaging will likely remain a popular and important imaging modality for years to come. Copyright RSNA, 2003

Profiles of Brain Metastases: Prioritization of Therapeutic Targets.

PubMed

Ferguson, Sherise D; Zheng, Siyuan; Xiu, Joanne; Zhou, Shouhao; Khasraw, Mustafa; Brastianos, Priscilla K; Kesari, Santosh; Hu, Jethro; Rudnick, Jeremy; Salacz, Michael E; Piccioni, David; Huang, Suyun; Davies, Michael A; Glitza, Isabella C; Heymach, John V; Zhang, Jianjun; Ibrahim, Nuhad K; DeGroot, John F; McCarty, Joseph; O'Brien, Barbara J; Sawaya, Raymond; Verhaak, Roeland G W; Reddy, Sandeep K; Priebe, Waldemar; Gatalica, Zoran; Spetzler, David; Heimberger, Amy B

2018-06-19

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of non-small cell lung cancer, breast cancer, and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry), and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification, and mutations among brain metastases, extracranial metastases, and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8178 non-small cell lung cancers (5098 primaries; 2787 systemic metastases; 293 brain metastases), 7064 breast cancers (3496 primaries; 3469 systemic metastases; 99 brain metastases), and 1757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1, and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication, and/or repair. This article is protected by copyright. All rights reserved. © 2018 UICC.

Enhancing MRI of liver metastases with a zwitterionized biodegradable dendritic contrast agent.

PubMed

Zhou, Xiaoxuan; Ye, Mingzhou; Han, Yuxin; Tang, Jianbin; Qian, Yue; Hu, Hongjie; Shen, Youqing

2017-07-25

Metastasis is the main reason for cancer-associated mortality, and accurate diagnostic imaging of metastases is critical for the clinical administration and tailoring personalized treatments for metastatic tumors. However, magnetic resonance imaging of metastases in the liver is impeded by its low sensitivity because the currently used contrast agents accumulate in hepatocytes and Kupffer cells instead of cancer cells. Herein, a 4 th generation zwitterionized biodegradable dendritic contrast agent (DCA) with a size of ca. 9 nm and a longitudinal relaxivity of 15.7 mM -1 s -1 in terms of Gd was synthesized and used to enhance the MRI of liver metastasis. The DCA could remarkably enhance the MRI of metastasized tumors in the liver, because it could simultaneously reduce the background signal in the liver by avoiding uptake by hepatocytes and Kupffer cells through the zwitterionization and increase the signal in tumors through the enhanced permeability and retention effect. Moreover, in contrast to non-biodegradable DCA, this DCA showed minimal long-term Gd 3+ retention in all organs and tissues because it could be degraded into small fragments. The significant capability of enhancing the MRI of metastases in the liver plus its excellent biodegradability made this DCA a promising CA for metastatic tumor imaging.

Radionuclide bone scanning of osteosarcoma: falsely extended uptake patterns.

PubMed

Chew, F S; Hudson, T M

1982-07-01

The pathologic specimens of 18 osteosarcomas of long bones were examined to correlate histologic abnormalities with abnormalities seen on preoperative 99mTc pyrophosphate or methylene diphosphonate bone scans. Seven scans accurately represented the extent of the tumor. Eleven scans disclosed increased activity extending beyond the radiographic abnormalities. In eight of these, there was no occult tumor extension and in the other three, the scan activity did not accurately portray the skip metastases that were present. Therefore, these 11 scans demonstrated the falsely extended pattern of uptake beyond the true limits of the tumors. Pathologic slides were available for 10 of the 11 areas of bone that exhibited extended uptake. In two instances, there was no pathologic abnormality. In the other eight cases we found marrow hyperemia, medullary reactive bone, or periosteal new bone. This is the first description of these histologic abnormalities of medullary bone in areas of extended uptake on radionuclide bone scans.

Hepatic Resection for Colorectal Liver Metastases: A Cost-Effectiveness Analysis

PubMed Central

Beard, Stephen M.; Holmes, Michael; Price, Charles; Majeed, Ali W.

2000-01-01

Objective To analyze the cost-effectiveness of resection for liver metastases compared with standard nonsurgical cytotoxic treatment. Summary Background Data The efficacy of hepatic resection for metastases from colorectal cancer has been debated, despite reported 5-year survival rates of 20% to 40%. Resection is confined to specialized centers and is not widely available, perhaps because of lack of appropriate expertise, resources, or awareness of its efficacy. The cost-effectiveness of resection is important from the perspective of managed care in the United States and for the commissioning of health services in the United Kingdom. Methods A simple decision-based model was developed to evaluate the marginal costs and health benefits of hepatic resection. Estimates of resectability for liver metastases were taken from UK-reported case series data. The results of 100 hepatic resections conducted in Sheffield from 1997 to 1999 were used for the cost calculation of liver resection. Survival data from published series of resections were compiled to estimate the incremental cost per life-year gained (LYG) because of the short period of follow-up in the Sheffield series. Results Hepatic resection for colorectal liver metastases provides an estimated marginal benefit of 1.6 life-years (undiscounted) at a marginal cost of £6,742. If 17% of patients have only palliative resections, the overall cost per LYG is approximately £5,236 (£5,985 with discounted benefits). If potential benefits are extended to include 20-year survival rates, these figures fall to approximately £1,821 (£2,793 with discounted benefits). Further univariate sensitivity analysis of key model parameters showed the cost per LYG to be consistently less than £15,000. Conclusion In this model, hepatic resection appears highly cost-effective compared with nonsurgical treatments for colorectal-related liver metastases. PMID:11088071

Steps in Prostate Cancer Progression that lead to Bone Metastasis

PubMed Central

Jin, Jung-Kang; Dayyani, Farshid; Gallick, Gary E.

2011-01-01

Prostate cancer is a complex disease in which metastasis to the bone is the main cause of death. Initial stages of metastasis are generally similar to those for most solid tumors; however, the mechanisms that underlie the homing of prostate tumor cells to the bone remain incompletely understood. Prostate cancer bone metastasis is also a microenvironment-driven disease, involving bi-directional interactions between the tumor and the bone microenvironment. In this review, we discuss the current understanding of the biologic processes and regulatory factors involved in the metastasis of prostate cancer cells, and their specific properties that promote growth in bone. Although many of these processes still need to be fully elucidated, a better understanding of the complex tumor/microenvironment interplay is slowly leading to more effective therapies for patients with prostate cancer bone metastases. PMID:21365645

Quality of life in responders after palliative radiation therapy for painful bone metastases using EORTC QLQ-C30 and EORTC QLQ-BM22: results of a Brazilian cohort.

PubMed

Mendez, Lucas C; Raman, Srinivas; Wan, Bo Angela; da Silva, José Luiz Padilha; Moraes, Fábio Y; Lima, Kennya M L B; Silva, Maurício F; Diz, Maria Del Pilar Estevez; Chow, Edward; Marta, Gustavo Nader

2017-08-01

Bone metastases cause pain, suffering and impaired quality of life (QoL). Palliative radiotherapy (RT) and/or chemotherapy are effective methods in controlling pain, reducing analgesics use and improving QoL. This study goal was to investigate the changes in QoL scores among patients who responded to palliative treatment. A prospective study evaluating the role of radiation therapy in a public academic hospital in São Paulo-Brazil recorded patients' opioid use, pain score, Portuguese version of QLQ-BM22 and QLQ-C30 before and 2 months after radiotherapy. Analgesic use and pain score were used to calculate international pain response category. Overall response was defined as the sum of complete response (CR) and partial response (PR). CR was defined as pain score of 0 with no increase in analgesic intake whereas PR was defined as pain reduction ≥2 without analgesic increase or analgesic reduction in ≥25% without increase in pain at the treated site. From September 2014 to October 2015, 25 patients with bone metastases responded to RT or chemotherapy (1 CR, 24 PR). There were 8 male and 17 female patients. The median age of the 25 patients was 59 (range, 22 to 80) years old. Patient's primary cancer site was breast [11], prostate [5], lung [2], others [7]. For QLQ-BM 22, the mean scores of 4 categories at baseline were: pain site (PS) 39, pain characteristics (PC) 61, function interference (FI) 49 and psycho-social aspects (PA) 57. At 2 month follow up, the scores were PS 27, PC 37, FI 70 and PA 59. Statistical significant improvement (P<0.05) was seen in PS, PC, FI but not PA. In the QLQ-C30, the scores were not statistically different for all categories, except for pain that demonstrated a 33 point decrease in the median pain score domain (66 to 33). Responders to RT at 2 months presented improvement in BM22 and C30 pain domains, and also improvement in functional interference domain of the BM22 questionnaire.

Genetic background of osteoporosis.

PubMed

Obermayer-Pietsch, B; Chararas, C; Kotschan, S; Walter, D; Leb, G

2000-01-01

Osteoporosis is a systemic disorder of decreased skeletal mass as measured by bone mineral density (BMD), and disturbed skeletal architecture and function which results in an increased risk for bone fractures with consecutively increased morbidity and mortality. Twin and family studies have shown an important genetic component of BMD of about 40-60%. This exceeds other well known factors influencing BMD such as environmental factors like dietary calcium, physical activity or several drugs and diseases. Therefore, interest increased in the genetic background of bone mineral density. Polymorphisms of the Vitamin D receptor gene were the first to be published in this area. Studies on other loci or candidate genes such as the estrogen receptor gene or the collagen type I alpha1 gene also showed associations with bone mineral density that could explain at least a part of the genetic background of osteoporosis. Recently published data suggest that these genetic markers of bone metabolism are important in interaction with each other or in certain bone-affecting diseases. In the future, genetic studies on osteoporosis will have to screen further relevant genes and markers for bone metabolism as well as to evaluate the complex interactions of genetic influences, so that it would be possible to calculate a patient's individual risk for osteoporosis in the context of environmental influences.

Long-term outcomes of ultrasonic scalpel treatment in giant cell tumor of long bones

PubMed Central

SUN, SHENG; ZHANG, QIANG; ZHAO, CHANG-SONG; CAI, JUAN

2014-01-01

Giant cell tumors (GCTs) are generally benign, locally aggressive lesions with the potential to metastasize and a tendency of local recurrence. The present study aimed to investigate the advantages and long-term outcomes of application of ultrasonic scalpel in the treatment of GCT of long bones. This study retrospectively analyzed 32 cases of GCT of long bones, including 24 males and eight females. The age range was from 8 to 34 years old (mean age, 23.5 years old). The 32 cases were randomly divided into an observation group (n=10) and a control group (n=22). Patients in the observation group received curettage by ultrasonic scalpel combined with local methotrexate gelfoam adjuvant treatment, and then the cavity was filled with allograft and/or homograft bone. Patients in the control group eceived curettage by local methotrexate gelfoam adjuvant treatment and bone grafting. No local recurrence or pulmonary metastases were observed among patients in the observation group, however, six patients in the control group exhibited recurrence following surgery, although none of the patients demonstrated distant metastasis (P<0.05). Additionally, all 10 patients showed good bone knitting and rehabilitation without deformity and functional issues. The segmental bone graft was perfectly incorporated without obvious immune rejection, collapse and fracture. Curettage by ultrasonic scalpel with local methotrexate gelfoam adjuvant treatment and filling the site by allograft and/or homograft bone showed satisfactory results. PMID:24959235

Stage IV breast cancer: clinical course and survival of patients with osseous versus extraosseous metastases at initial diagnosis. The GOCS (Grupo Oncológico Cooperativo del Sur) experience.

PubMed

Leone, B A; Romero, A; Rabinovich, M G; Vallejo, C T; Bianco, A; Perez, J E; Machiavelli, M; Rodriguez, R; Alvarez, L A

1988-12-01

The medical records of 414 patients with metastatic breast carcinoma treated between 1978 and 1986 were reviewed and 44 women were identified as having stage IV disease when the primary breast lesion was detected. Of these 44 women, 25 had metastatic disease limited to the skeleton while 19 had extraosseous lesions only. The clinical features, response to therapy, and survival were analyzed and compared for both groups. The median survival of those patients with bone-only metastases was 52 months as compared with 13 months for those with extraskeletal lesions (p = 0.0025). The response rate to first-line systemic therapy was similar for both groups (47% for bone metastases and 44% for extraosseous metastases). The median duration of response was 14 months (range, 3-55 months) for patients with bone disease and 8 months (range, 4-43 months) for those with extraskeletal lesions. We conclude that patients with metastatic breast cancer confined to the skeleton at initial diagnosis tend to follow an indolent, chronic course with prolonged survival. Therefore the increase in response rate with aggressive chemotherapy should be balanced against its higher morbidity. Further studies are needed to confirm whether the better prognosis of these patients is determined by the anatomical confinement of the disease to the skeleton or merely reflects the influence of other prognostic factors.

Diagnosis of metastases from postoperative differentiated thyroid cancer: comparison between FDG and FLT PET/CT studies.

PubMed

Nakajo, Masatoyo; Nakajo, Masayuki; Jinguji, Megumi; Tani, Atsushi; Kajiya, Yoriko; Tanabe, Hiroaki; Fukukura, Yoshihiko; Nakabeppu, Yoshiaki; Koriyama, Chihaya

2013-06-01

To compare positron emission tomography (PET)/computed tomography (CT) studies performed with the glucose analog fluorine 18 ((18)F) fluorodeoxyglucose (FDG) and the cell proliferation tracer (18)F fluorothymidine (FLT) in the diagnosis of metastases from postoperative differentiated thyroid cancer. The institutional ethics review board approved this prospective study. From March 2010 to February 2012, 20 patients (mean age, 53 years; age range, 22-79 years) with postoperative differentiated thyroid cancer underwent both FDG and FLT PET/CT as a staging work-up before radioiodine therapy. In each patient, 28 anatomic areas were set and analyzed for lymph node and distant metastases. The McNemar exact or χ(2) test was used to examine differences in diagnostic indexes in the detection of lymph node and distant metastases between both tracer PET/CT studies. There were 34 lymph node metastases and/or 73 distant metastases (70 metastases in lung and one each in bone, nasopharynx, and brain) in 13 patients. At patient-based analysis, the sensitivity, specificity, and accuracy were 92% (12 of 13 patients), 86% (six of seven patients), and 90% (18 of 20 patients), respectively, for FDG PET/CT and 69% (nine of 13 patients), 29% (two of seven patients), and 55% (11 of 20 patients) for FLT PET/CT. The accuracy of FDG PET/CT was significantly better than that of FLT PET/CT (P = .023). At lesion-based analysis, the sensitivity, specificity, and accuracy for diagnosing lymph node metastases were 85% (29 of 34 lesions), 99.6% (245 of 246 lesions), and 97.9% (274 of 280 lesions), respectively, for FDG PET/CT and 50% (17 of 34 lesions), 90.7% (223 of 246 lesions), and 85.7% (240 of 280 lesions) for FLT PET/CT. The sensitivity, specificity, and accuracy for diagnosing distant metastases were 45% (33 of 73 lesions), 100% (207 of 207 lesions), and 85.7% (240 of 280 lesions), respectively, for FDG PET/CT and 6.8% (five of 73 lesions), 100% (207 of 207 lesions), and 75.7% (212 of 280

Bisphosphonates enhance EGFR-TKIs efficacy in advanced NSCLC patients with EGFR activating mutation: A retrospective study

PubMed Central

Cai, Xiao-Hong; Yao, Wen-Xiu; Xu, Yong; Liu, Xiao-Ke; Zhu, Wen-Jiang; Wang, Yan; Zhou, Jin; Lu, You; Wang, Yong-Sheng

2016-01-01

Background Bisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations. Methods Between January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed. Results Among the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798). Conclusions Concomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases. PMID:26624882

Surgical treatment of solitary brain metastases.

PubMed

Gates, Marilyn; Alsaidi, Mohammed; Kalkanis, Steven

2012-01-01

Brain metastases are the most common form of brain tumors and are diagnosed in about 40% of all patients with systemic malignancies. Although the percentage of solitary brain metastases has dropped in recent estimates from about 50-30% of all patients with brain metastases, this percentage still represents a significant number of patients, and the overall incidence of brain metastases is still on the rise. Historically, brain metastases carried a grim prognosis with a median survival of only a few weeks. The utilization of whole-brain radiation therapy (WBRT) and steroids improved the prognosis to few months. However, it was not until the advent of advanced surgical techniques in conjunction with other treatment modalities such as WBRT and stereotactic radiosurgery that patients became less likely to succumb to neurological complications. In the last few decades, surgical resection has evolved from a mere emergent palliative treatment to a standard treatment modality that has led to improved clinical outcomes in carefully selected patients with brain metastases. This positive contribution has been made possible by randomized clinical trials, advancement of surgical techniques and tools, imaging modalities, and better understanding of the pathophysiology and perioperative care. Copyright © 2012 S. Karger AG, Basel.

Co-registration of multi-modality imaging allows for comprehensive analysis of tumor-induced bone disease

PubMed Central

Seeley, Erin H.; Wilson, Kevin J.; Yankeelov, Thomas E.; Johnson, Rachelle W.; Gore, John C.; Caprioli, Richard M.; Matrisian, Lynn M.; Sterling, Julie A.

2014-01-01

Bone metastases are a clinically significant problem that arises in approximately 70% of metastatic breast cancer patients. Once established in bone, tumor cells induce changes in the bone microenvironment that lead to bone destruction, pain, and significant morbidity. While much is known about the later stages of bone disease, less is known about the earlier stages or the changes in protein expression in the tumor micro-environment. Due to promising results of combining magnetic resonance imaging (MRI) and Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry (MALDI IMS) ion images in the brain, we developed methods for applying these modalities to models of tumor-induced bone disease in order to better understand the changes in protein expression that occur within the tumor-bone microenvironment. Specifically, we integrated three dimensional-volume reconstructions of spatially resolved MALDI IMS with high-resolution anatomical and diffusion weighted MRI data and histology in an intratibial model of breast tumor-induced bone disease. This approach enables us to analyze proteomic profiles from MALDI IMS data with corresponding in vivo imaging and ex vivo histology data. To the best of our knowledge, this is the first time these three modalities have been rigorously registered in the bone. The MALDI mass-to-charge ratio peaks indicate differential expression of calcyclin, ubiquitin, and other proteins within the tumor cells, while peaks corresponding to hemoglobin A and calgranulin A provided molecular information that aided in the identification of areas rich in red and white blood cells, respectively. This multimodality approach will allow us to comprehensively understand the bone-tumor microenvironment and thus may allow us to better develop and test approaches for inhibiting bone metastases. PMID:24487126

How Effective Are Percutaneous Liver-Directed Therapies in Patients with Non-Colorectal Liver Metastases?

PubMed Central

Vogl, Thomas J.; Emam, Ahmed; Naguib, Nagy N.; Eichler, Katrin; Zangos, Stefan

2015-01-01

Summary Background The purpose of this review is to demonstrate the clinical indications, technical developments, and outcome of liver-directed therapies in interventional oncology of non-colorectal liver metastases. Methods Liver-directed therapies are classified into vascular transarterial techniques such as chemoperfusion (TACP), chemoembolization (TACE), radioembolization (selective internal radiation therapy (SIRT)), and chemosaturation, as well as thermal ablation techniques like microwave ablation (MWA), radiofrequency ablation (RFA), laser-induced thermotherapy (LITT), cryotherapy, and irreversible electroporation (IRE). The authors searched the database PubMed using the following terms: ‘image-guided tumor ablation’, ‘thermal ablation therapies’, ‘liver metastases of uveal melanoma’, ‘neuroendocrine carcinoma’, ‘breast cancer’, and ‘non-colorectal liver metastases’. Results Various combinations of the above-mentioned therapy protocols are possible. In neuroendocrine carcinomas, oligonodular liver metastases are treated successfully via thermal ablation like RFA, LITT, or MWA, and diffuse involvement via TACE or SIRT. Although liver involvement in breast cancer is a systemic disease, non-responding nodular metastases can be controlled via RFA or LITT. In ocular or cutaneous melanoma, thermal ablation is rarely considered as an interventional treatment option, as opposed to TACE, SIRT, or chemosaturation. Rarely liver-directed therapies are used in pancreatic cancer, most likely due to problems such as biliary digestive communications after surgery and the risk of infections. Rare indications for thermal ablation are liver metastases of other primary cancers like non-small cell lung, gastric, and ovarian cancer. Conclusion Interventional oncological techniques play a role in patients with liver-dominant metastases. PMID:26889144

Management of Brain Metastases.

PubMed

Jeyapalan, Suriya A.; Batchelor, Tracy

2004-07-01

Advances in neurosurgery and the development of stereotactic radiosurgery have expanded treatment options available for patients with brain metastases. However, despite several randomized clinical trials and multiple uncontrolled studies, there is not a uniform consensus on the best treatment strategy for all patients with brain metastases. The heterogeneity of this patient population in terms of functional status, types of underlying cancers, status of systemic disease control, and number and location of brain metastases make such consensus difficult. Nevertheless, in certain situations, there is Class I evidence that supports one approach or another. The primary objectives in the management of this patient population include improved duration and quality of survival. Very few patients achieve long-term survival after the diagnosis of a brain metastasis.

Detection and quantification of 223Ra uptake in bone metastases of patients with castration resistant prostate carcinoma, with the aim of determining the absorbed dose in the metastases.

PubMed

Mínguez, P; Gómez de Iturriaga, A; Fernández, I L; Rodeño, E

To obtain the necessary acquisition and calibration parameters in order to evaluate the possibility of detecting and quantifying 223 Ra uptake in bone metastases of patients treated for castration resistant prostate carcinoma. Furthermore, in the cases in which the activity can be quantified, to determine the absorbed dose. Acquisitions from a Petri dish filled with 223 Ra were performed in the gamma camera. Monte Carlo simulations were also performed to study the partial volume effect. Formulae to obtain the detection and quantification limits of 223 Ra uptake were applied to planar images of two patients 7 days post-administration of 55kBq/kg of 223 Ra. In order to locate the lesions in advance, whole-body scans and SPECT/CT images were acquired after injecting 99m Tc-HDP. The optimal energy window was found to be at 82keV with a medium-energy collimator MEGP. Of the lesions found in the patients, only those that had been detected in both the AP and PA projections could be quantified. These lesions were those which had shown a higher 99m Tc-HDP uptake. The estimated values of absorbed doses ranged between 0.7Gy and 7.8Gy. Of the lesions that can be detected, it is not possible to quantify the activity uptake in some of them, which means that the absorbed dose cannot be determined either. This does not mean that the absorbed dose in these lesions can be regarded as negligible. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

Mechanisms of Radiation-Induced Bone Loss and Effect on Prostate Cancer Bone Metastases

DTIC Science & Technology

2012-06-01

Develop intravital multiphoton fluorescence microscopy (IVFM) for real-time imaging of osteocytes in calvariae of transgenic mice using i) GFP to...OT, OB counting) and in vivo bone imaging (months 6-10) 8 20 week old female C57Bl/6 mice (n=30) were used in this experiment. The mice were...divided into 2 groups. One group (group A, n=15) was imaged twice by microCT during the experiment that included a baseline microCT that was given 2 days

Choroidal metastasis from primary bone leiomyosarcoma.

PubMed

Cristina, Nieto Gómez; Francisco, Escudero Domínguez; Vanesa, Rivero Gutiérrez; Fernando, Cruz González; Luis, Cacharro Moras; Emiliano, Hernández Galilea

2015-10-01

Choroidal metastases, the most common form of intraocular malignancies, are principally caused by primary tumors from breast, lung, and gastrointestinal tract. These lesions are mostly symptomatic and rarely detected incidentally in the extension study of a previously diagnosed tumor. Leiomyosarcoma is a neoplasm of mesenchymal cells with smooth muscle differentiation and represents the most prevalent soft-tissue sarcoma. Leiomyosarcoma is a notably rare tumor in ophthalmic region. We report a case of primary bone leiomyosarcoma metastatic to the choroid that was treated with chemotherapy and surgery. Although three cases of choroidal metastasis from leiomyosarcomas have been already reported, to our knowledge this is the first case of choroidal metastasis from primary bone leiomyosarcoma.

The rapid access palliative radiotherapy program: blueprint for initiation of a one-stop multidisciplinary bone metastases clinic.

PubMed

Fairchild, A; Pituskin, E; Rose, B; Ghosh, S; Dutka, J; Driga, A; Tachynski, P; Borschneck, J; Gagnon, L; Macdonnell, S; Middleton, J; Thavone, K; Carstairs, S; Brent, D; Severin, D

2009-02-01

Radiotherapy (RT) for palliation of pain due to bone metastases (BM) is effective but underutilized likely due to the traditional practice of separate clinic visits for consultation, treatment planning, and RT delivery. However, recent evidence proves one RT treatment is as effective as multiple for analgesia, enabling investigation of an alternative model of RT delivery, the rapid access palliative radiotherapy program (RAPRP). Prior to the start of the program, needs assessment was performed to determine the composition of the optimal team. Screening tools were implemented to streamline holistic, multidisciplinary assessment. An advertising strategy, treatment and research protocols, and mechanisms for patient feedback were established. After RAPRP implementation, patient outcomes such as symptom relief were tracked. Eighty-six patients with painful BM were referred over the 25-week pilot. Median age was 69.9 years; 64% had prostate cancer, and median performance status was 70. Patient-rated pain was on average 6.1/10 at baseline, improving to 2.6/10 by week 4 post-RT. On average, 6.2 symptoms were reported (baseline) compared to 5.2 (week 4). Team members assessed 10-100% of patients and were successful in stabilizing or improving all symptoms in >75% contacted at week 4. One hundred percent of patients surveyed were satisfied with their experience. Early needs assessment was advantageous in determining the optimal team and methods of assessment for our 'one-stop' BM clinic. This approach was successful in improving pain and other symptoms, and the convenience of seeing multiple providers on 1 day was appreciated by the patients.

Novel therapies in benign and malignant bone diseases.

PubMed

Rachner, Tilman D; Hadji, Peyman; Hofbauer, Lorenz C

2012-06-01

With an ageing population and improving cancer therapies, the two most common benign and malignant bone diseases, osteoporosis and bone metastases, will continue to affect an increasing number of patients. Our expanding knowledge of the molecular processes underlying these conditions has resulted in novel bone targets that are currently being explored in clinical trials. Clearly, the approval of denosumab, a monoclonal antibody directed against RANKL, has just marked the beginning of a new era for bone therapy with several additional new therapies lining up for clinical approval in the coming years. Potential agents targeting the osteoclast include cathepsin K, currently in phase 3 trials, and src inhibitors. Amongst anabolic agents, inhibitors of the Wnt-inhibitor sclerostin and dickkopf-1 are promising in clinical trials. Here, we will provide a comprehensive overview of the most promising agents currently explored for the treatment of bone diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

Changes in the renin angiotensin system during the development of colorectal cancer liver metastases

PubMed Central

2010-01-01

Background Blockade of the renin angiotensin system (RAS) via angiotensin I converting enzyme (ACE) inhibition reduces growth of colorectal cancer (CRC) liver metastases in a mouse model. In this work we defined the expression of the various components of the RAS in both tumor and liver during the progression of this disease. Methods Immunohistochemistry and quantitative RT-PCR was used to examine RAS expression in a mouse CRC liver metastases model. CRC metastases and liver tissue was assessed separately at key stages of CRC liver metastases development in untreated (control) mice and in mice treated with the ACE inhibitor captopril (750 mg/kg/day). Non-tumor induced (sham) mice indicated the effect of tumors on normal liver RAS. The statistical significance of multiple comparisons was determined using one-way analysis of variance followed by Bonferroni adjustment with SAS/STAT software. Results Reduced volume of CRC liver metastases with captopril treatment was evident. Local RAS of CRC metastases differed from the surrounding liver, with lower angiotensin II type 1 receptor (AT1R) expression but increased ANG-(1-7) receptor (MasR) compared to the liver. The AT1R localised to cancer and stromal infiltrating cells, while other RAS receptors were detected in cancer cells only. Tumor induction led to an initial increase in AT1R and ACE expression while captopril treatment significantly increased ACE expression in the final stages of tumor growth. Conversely, captopril treatment decreased expression of AT1R and angiotensinogen. Conclusions These results demonstrate significant changes in RAS expression in the tumor-bearing captopril treated liver and in CRC metastases. The data suggests the existence of a tumor-specific RAS that can be independently targeted by RAS blockade. PMID:20380732

THE EFFECT OF BACKGROUND SIGNAL AND ITS REPRESENTATION IN DECONVOLUTION OF EPR SPECTRA ON ACCURACY OF EPR DOSIMETRY IN BONE.

PubMed

Ciesielski, Bartlomiej; Marciniak, Agnieszka; Zientek, Agnieszka; Krefft, Karolina; Cieszyński, Mateusz; Boguś, Piotr; Prawdzik-Dampc, Anita

2016-12-01

This study is about the accuracy of EPR dosimetry in bones based on deconvolution of the experimental spectra into the background (BG) and the radiation-induced signal (RIS) components. The model RIS's were represented by EPR spectra from irradiated enamel or bone powder; the model BG signals by EPR spectra of unirradiated bone samples or by simulated spectra. Samples of compact and trabecular bones were irradiated in the 30-270 Gy range and the intensities of their RIS's were calculated using various combinations of those benchmark spectra. The relationships between the dose and the RIS were linear (R 2  > 0.995), with practically no difference between results obtained when using signals from irradiated enamel or bone as the model RIS. Use of different experimental spectra for the model BG resulted in variations in intercepts of the dose-RIS calibration lines, leading to systematic errors in reconstructed doses, in particular for high- BG samples of trabecular bone. These errors were reduced when simulated spectra instead of the experimental ones were used as the benchmark BG signal in the applied deconvolution procedures. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Imaging of brain metastases.

PubMed

Fink, Kathleen R; Fink, James R

2013-01-01

Imaging plays a key role in the diagnosis of central nervous system (CNS) metastasis. Imaging is used to detect metastases in patients with known malignancies and new neurological signs or symptoms, as well as to screen for CNS involvement in patients with known cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) are the key imaging modalities used in the diagnosis of brain metastases. In difficult cases, such as newly diagnosed solitary enhancing brain lesions in patients without known malignancy, advanced imaging techniques including proton magnetic resonance spectroscopy (MRS), contrast enhanced magnetic resonance perfusion (MRP), diffusion weighted imaging (DWI), and diffusion tensor imaging (DTI) may aid in arriving at the correct diagnosis. This image-rich review discusses the imaging evaluation of patients with suspected intracranial involvement and malignancy, describes typical imaging findings of parenchymal brain metastasis on CT and MRI, and provides clues to specific histological diagnoses such as the presence of hemorrhage. Additionally, the role of advanced imaging techniques is reviewed, specifically in the context of differentiating metastasis from high-grade glioma and other solitary enhancing brain lesions. Extra-axial CNS involvement by metastases, including pachymeningeal and leptomeningeal metastases is also briefly reviewed.

Targeting G-Protein Signaling for the Therapeutics of Prostate Tumor Bone Metastases and the Associated Chronic Bone Pain

DTIC Science & Technology

2015-09-01

results in increased activity/expression of key pain-sensing receptor channels, such as TRPV1 , such that the channels are constitutively activated...Keywords: Prostate Cancer Bone Metastasis, Bone Cancer Pain, Heterotrimeric G protein betagamma subunits, G protein coupled receptors (GPCRs), TRPV1 ...vitro, as well as mediating GPCR-regulated TRPV1 channel function in cultured mouse sensory neurons (Aim 1) Major Goal/Objective 1: Determine the

Targeting G-Protein Signaling for the Therapeutics of Prostate Tumor Bone Metastases and the Associated Chronic Bone Pain

DTIC Science & Technology

2013-07-01

results in increased activity/expression of key pain-sensing receptor channels, such as TRPV1 , such that the channels are constitutively activated...Keywords: Prostate Cancer Bone Metastasis, Bone Cancer Pain, Heterotrimeric G protein betagamma subunits, G protein coupled receptors (GPCRs), TRPV1 ...cell growth, migration and invasion in vitro, as well as mediating GPCR-regulated TRPV1 channel function in cultured mouse sensory neurons (Aim 1

Painful cutaneous metastases from esophageal carcinoma.

PubMed

Stein, Ronnit Hamuy; Spencer, James M

2002-10-01

Cutaneous metastases, which are not included among the painful dermal tumors, are primarily asymptomatic and of variable clinical appearance. Although, to our knowledge, this case report of painful cutaneous metastases is only the fifth in the literature, physicians who discover a painful tumor perhaps now should consider cutaneous metastasis. In this report, we describe painful nodular scalp lesions related to esophageal adenocarcinoma, which rarely metastasizes to the skin.

Complementary roles of tumour specific PET tracer ¹⁸F-FAMT to ¹⁸F-FDG PET/CT for the assessment of bone metastasis.

PubMed

Morita, Motoho; Higuchi, Tetsuya; Achmad, Arifudin; Tokue, Azusa; Arisaka, Yukiko; Tsushima, Yoshito

2013-10-01

The usefulness of (18)F-FDG PET/CT for bone metastasis evaluation has already been established. The amino acid PET tracer [(18)F]-3-fluoro-alpha-methyl tyrosine ((18)F-FAMT) has been reported to be highly specific for malignancy. We evaluated the additional value of (18)F-FAMT PET/CT to complement (18)F-FDG PET/CT in the evaluation of bone metastasis. This retrospective study included 21 patients with bone metastases of various cancers who had undergone both (18)F-FDG and (18)F-FAMT PET/CT within 1 month of each other. (18)F-FDG-avid bone lesions suspicious for malignancy were carefully selected based on the cut-off value for malignancy, and the SUVmax of the (18)F-FAMT in the corresponding lesions were evaluated. A total of 72 (18)F-FDG-positive bone lesions suspected to be metastases in the 21 patients were used as the reference standard. (18)F-FAMT uptake was found in 87.5 % of the lesions. In the lesions of lung cancer origin, the uptake of the two tracers showed a good correlation (40 lesions, r = 0.68, P < 0.01). Bone metastatic lesions of oesophageal cancer showed the highest average of (18)F-FAMT uptake. Bone metastatic lesions of squamous cell carcinoma showed higher (18)F-FAMT uptake than those of adenocarcinoma. No significant difference in (18)F-FAMT uptake was seen between osteoblastic and osteolytic bone metastatic lesions. The usefulness of (18)F-FAMT PET/CT for bone metastasis detection regardless of the lesion phenotype was demonstrated. The fact that (18)F-FAMT uptake was confirmed by (18)F-FDG uptake suggests that (18)F-FAMT PET/CT has the potential to complement (18)F-FDG PET/CT for the detection of bone metastases.

How Effective Are Clinical Pathways With and Without Online Peer-Review? An Analysis of Bone Metastases Pathway in a Large, Integrated National Cancer Institute-Designated Comprehensive Cancer Center Network

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beriwal, Sushil, E-mail: beriwals@upmc.edu; Rajagopalan, Malolan S.; Flickinger, John C.

2012-07-15

Purpose: Clinical pathways are an important tool used to manage the quality in health care by standardizing processes. This study evaluated the impact of the implementation of a peer-reviewed clinical pathway in a large, integrated National Cancer Institute-Designated Comprehensive Cancer Center Network. Methods: In 2003, we implemented a clinical pathway for the management of bone metastases with palliative radiation therapy. In 2009, we required the entry of management decisions into an online tool that records pathway choices. The pathway specified 1 or 5 fractions for symptomatic bone metastases with the option of 10-14 fractions for certain clinical situations. The datamore » were obtained from 13 integrated sites (3 central academic, 10 community locations) from 2003 through 2010. Results: In this study, 7905 sites were treated with 64% of courses delivered in community practice and 36% in academic locations. Academic practices were more likely than community practices to treat with 1-5 fractions (63% vs. 23%; p < 0.0001). The number of delivered fractions decreased gradually from 2003 to 2010 for both academic and community practices (p < 0.0001); however, greater numbers of fractions were selected more often in community practices (p < 0.0001). Using multivariate logistic regression, we found that a significantly greater selection of 1-5 fractions developed after implementation online pathway monitoring (2009) with an odds ratio of 1.2 (confidence interval, 1.1-1.4) for community and 1.3 (confidence interval, 1.1-1.6) for academic practices. The mean number of fractions also decreased after online peer review from 6.3 to 6.0 for academic (p = 0.07) and 9.4 to 9.0 for community practices (p < 0.0001). Conclusion: This is one of the first studies to examine the efficacy of a clinical pathway for radiation oncology in an integrated cancer network. Clinical pathway implementation appears to be effective in changing patterns of care, particularly with online

Quantitative MRI and spectroscopy of bone marrow

PubMed Central

Ruschke, Stefan; Dieckmeyer, Michael; Diefenbach, Maximilian; Franz, Daniela; Gersing, Alexandra S.; Krug, Roland; Baum, Thomas

2017-01-01

Bone marrow is one of the largest organs in the human body, enclosing adipocytes, hematopoietic stem cells, which are responsible for blood cell production, and mesenchymal stem cells, which are responsible for the production of adipocytes and bone cells. Magnetic resonance imaging (MRI) is the ideal imaging modality to monitor bone marrow changes in healthy and pathological states, thanks to its inherent rich soft‐tissue contrast. Quantitative bone marrow MRI and magnetic resonance spectroscopy (MRS) techniques have been also developed in order to quantify changes in bone marrow water–fat composition, cellularity and perfusion in different pathologies, and to assist in understanding the role of bone marrow in the pathophysiology of systemic diseases (e.g. osteoporosis). The present review summarizes a large selection of studies published until March 2017 in proton‐based quantitative MRI and MRS of bone marrow. Some basic knowledge about bone marrow anatomy and physiology is first reviewed. The most important technical aspects of quantitative MR methods measuring bone marrow water–fat composition, fatty acid composition, perfusion, and diffusion are then described. Finally, previous MR studies are reviewed on the application of quantitative MR techniques in both healthy aging and diseased bone marrow affected by osteoporosis, fractures, metabolic diseases, multiple myeloma, and bone metastases. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:332–353. PMID:28570033

Venting during prophylactic nailing for femoral metastases: current orthopedic practice.

PubMed

Dalgorf, Dustin; Borkhoff, Cornelia M; Stephen, David J G; Finkelstein, Joel; Kreder, Hans J

2003-12-01

Reamed intramedullary nailing, recommended for impending fracture of a femur weakened by bone metastases, causes a rise in intramedullary pressure and increases the risk of a fat embolism syndrome. The pressure can be equalized by the technique of venting--drilling a hole into the distal cortex of the femur. Our objective was to study the current practice of orthopedic surgeons in Ontario with respect to venting during prophylactic intramedullary nailing for an impending femoral fracture due to bone metastases. We mailed a questionnaire to all orthopedic surgeons from the Province of Ontario listed in the 1999 Canadian Medical Directory or on the Canadian Orthopaedic Association membership list, asking if they vent when prophylactically nailing an impending pathologic femoral fracture. The responses were modelled as a function of surgeon volume and year of graduation. Of the 415 surveys mailed, 223 (54%) surgeons responded. Of these, 81% reported having prophylactically treated a femoral metastatic lesion during the previous year; 67% treated 1 to 3 metastatic lesions and 14% treated more than 3; 19% did not treat a metastatic femoral lesion prophylactically. Over two-thirds of surgeons had never considered venting, whereas one-third always or sometimes vented the femoral canal. More recent graduates were 3 times more likely to vent than earlier (before 1980) graduates (odds ratio [OR] = 3.2, 95% confidence interval [CI] 1.6-6.5) as were those who treat a greater number of impending fractures (OR = 1.4, 95% CI 1.1-1.7). Although there is a theoretical rationale for routine venting, there is disagreement among Ontario orthopedic surgeons regarding the use of this technique during prophylactic nailing for femoral metastatic lesions. Prospective evidence will be required to warrant a change in the standard of care.

Future directions in treatment of brain metastases.

PubMed

Barani, Igor J; Larson, David A; Berger, Mitchel S

2013-01-01

Brain metastases affect up to 30% of patients with cancer. Management of brain metastases continues to evolve with ever increasing focus on cognitive preservation and quality of life. This manuscript reviews current state of brain metastases management and discusses various treatment controversies with focus on future clinical trials. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) are discussed in context of multiple (4+ brain metastases) as well as new approaches combining radiation and targeted agents. A brief discussion of modified WBRT approaches, including hippocampal-avoidance WBRT (HA-WBRT) is included as well as a section on recently presented results of Radiation Therapy Oncology Group (RTOG) 0614, a randomized, double-blind, placebo-controlled trial of menantine for prevention of neurocognitive injury after WBRT. A search of selected studies relevant to management of brain metastases was performed in PubMed as well as in various published meeting abstracts. This data was collated and analyzed in context of contemporary management and future clinical trial plans. This data is presented in tabular form and discussed extensively in the text. The published data demonstrate continued evolution of clinical trials and management strategies designed to minimize and/or prevent cognitive decline following radiation therapy management of brain metastases. Hippocampal avoidance whole-brain radiation therapy (HA-WBRT) and radiosurgery treatments for multiple brain metastases are discussed along with preliminary results of RTOG 0614, a trial of memantine therapy to prevent cognitive decline following WBRT. Trial results appear to support the use of memantine for prevention of cognitive decline. Different management strategies for multiple brain metastases (>4 brain metastases) are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following WBRT.

Radium-223 in the treatment of bone metastasis in patients with castration-resistant prostate cancer. Review and procedure.

PubMed

Orcajo-Rincon, J; Caresia-Aróztegui, A P; Del Puig Cózar-Santiago, M; García-Garzón, J R; de Arcocha-Torres, M; Delgado-Bolton, R C; García-Velloso, M J; Alvarez-Ruiz, S; García-Vicente, A M

2018-04-13

Bone metastatic disease is the main cause of morbidity / mortality in patients with prostate cancer, presenting frequently as bone pain, pathological fractures or spinal cord compression, which requires early and timely therapy. Although, for the moment, the therapeutic window for its use has not been definitively established, radium-223 ( 223 Ra), an alpha particle emitter, has proved to be an effective therapeutic tool, pre or post-chemotherapy, in patients with castration-resistant prostate cancer with symptomatic bone metastases and absence of visceral metastases, significantly modifying the prognosis of the disease. It is therefore imperative to define the ideal scenarios and the correct protocol for the use of this therapy and thus offer the greatest possible clinical benefit to the patient. Copyright © 2018 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.

[Conversion Therapy Using Etoposide and Cisplatin Chemotherapy for Liver Metastases from Advanced Gastric Mixed Adenoneuroendocrine Carcinoma - A Case Report].

PubMed

Inaba, Yoko; Fujita, Maiko; Ninomiya, Riki; Hashimoto, Daijo

2017-11-01

Gastric mixed adenoneuroendocrine carcinoma(MANEC)with multiple liver metastases is a rare condition with most data being derived from case reports. We present a case with liver metastases from gastric MANEC that respond remarkably to chemotherapy. Sixty-one-year-old male with severe anemia referred to surgical consultation due to advanced gastric cancer with multiple liver metastases. To relieve uncontrollable tumor bleeding, simple distal gastrectomy for symptom palliation was performed. Based on the tentative diagnosis with gastric poorly differentiated adenocarcinoma, a course of TS-1 and oxaliplatin therapy was administrated. Thereafter final diagnosis with neuroendocrine carcinoma with tubular adenocarcinoma was made, and the chemotherapy was switched to etoposide and cisplatin. Follow up abdominal CT scan after the third course of the therapy showed remarkable tumor shrinkages(PR). In anticipation of the chemotherapy effects in the adjuvant setting, we performed liver metastasectomy for curative intent. Two of 6 resected liver specimens showed no viable cancer cells at all (pCR). However, immediately after the surgery, multiple liver metastases developed, and the recurrent masses had kept growing up rapidly. The third line carboplatin and etoposide chemotherapy was given once but was withdrawn because of bone marrow suppression. At the present, the patient is alive with recurrent diseases for 18 months after initial diagnosis.

Multicenter Prospective Clinical Series Evaluating Radiofrequency Ablation in the Treatment of Painful Spine Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bagla, Sandeep, E-mail: sandeep.bagla@gmail.com; Sayed, Dawood; Smirniotopoulos, John

BackgroundRadiofrequency ablation (RFA) of vertebral body metastases (VBM) has been reported as safe and effective in retrospective studies. This single-arm prospective multicenter clinical study evaluates RFA in the treatment of painful VBM.MethodsFifty patients with VBM were prospectively enrolled during a 13-month period at eight US centers under an IRB-approved study. Percutaneous RFA was performed under imaging guidance with cement augmentation at the discretion of the operator. Pain, disability and quality of life were evaluated at baseline, prior to discharge, days 3, 7, 30 and 90 using the Numerical Pain Rating Scale, Oswestry Disability Index (ODI), the Functional Assessment of Cancermore » Therapy-General 7 (FACT-G7) and Functional Assessment of Cancer Therapy Quality-of-Life Measurement in Patients with Bone Pain (FACT-BP). Adverse events were monitored throughout this time interval.ResultsTwenty-six male and 24 female patients (mean age 61.0) underwent 69 treatments (30 thoracic and 39 lumbar). Cement augmentation was performed in 96 % of reported levels. Significant improvement in mean scores for pain, disability and cancer-specific health-related quality of life from baseline to all time intervals was seen. NRPS improved from 5.9 to 2.1 (p < 0.0001). ODI improved from 52.9 to 37.0 (p < 0.08). FACT-G7 improved form 10.9 to 16.2 (p = 0.0001). FACT-BP improved from 22.6 to 38.9 (p < 0.001). No complications related to the procedure were reported.ConclusionRFA with cement augmentation safely and effectively reduces pain and disability rapidly, while increasing quality of life in patients suffering from vertebral body metastases.« less

Brain metastasization of breast cancer.

PubMed

Custódio-Santos, Tânia; Videira, Mafalda; Brito, Maria Alexandra

2017-08-01

Central nervous system metastases have been reported in 15-25% of breast cancer patients, and the incidence is increasing. Moreover, the survival of these patients is generally poor, with reports of a 1-year survival rate of 20%. Therefore, a better knowledge about the determinants of brain metastasization is essential for the improvement of the clinical outcomes. Here, we summarize the current data about the metastatic cascade, ranging from the output of cancer cells from the primary tumour to their colonization in the brain, which involves the epithelial-mesenchymal transition, invasion of mammary tissue, intravasation into circulation, and homing into and extravasation towards the brain. The phenotypic change in malignant cells, and the importance of the microenvironment in the formation of brain metastases are also inspected. Finally, the importance of genetic and epigenetic changes, and the recently disclosed effects of microRNAs in brain metastasization of breast cancer are highlighted. Copyright © 2017 Elsevier B.V. All rights reserved.

Bone-induced c-kit expression in prostate cancer: a driver of intraosseous tumor growth

PubMed Central

Mainetti, Leandro E.; Zhe, Xiaoning; Diedrich, Jonathan; Saliganan, Allen D.; Cho, Won Jin; Cher, Michael L.; Heath, Elisabeth; Fridman, Rafael; Kim, Hyeong-Reh Choi; Bonfil, R. Daniel

2014-01-01

Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c-kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c-kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c-kit expression promotes migration and invasion of PCa cells. Alongside, we found that c-kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c-kit-transfected PCa cells resulted in reduction of c-kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c-kit. The inverse association between c-kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone-induced c-kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone-induced c-kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis. PMID:24798488

Three-dimensional virtual bone bank system for selecting massive bone allograft in orthopaedic oncology.

PubMed

Wu, Zhigang; Fu, Jun; Wang, Zhen; Li, Xiangdong; Li, Jing; Pei, Yanjun; Pei, Guoxian; Li, Dan; Guo, Zheng; Fan, Hongbin

2015-06-01

Although structural bone allografts have been used for years to treat large defects caused by tumour or trauma, selecting the most appropriate allograft is still challenging. The objectives of this study were to: (1) describe the establishment of a visual bone bank system and workflow of allograft selection, and (2) show mid-term follow-up results of patients after allograft implantation. Allografts were scanned and stored in Digital Imaging and Communications in Medicine (DICOM) files. Then, image segmentation was conducted and 3D model reconstructed to establish a visual bone bank system. Based on the volume registration method, allografts were selected after a careful matching process. From November 2010 to June 2013, with the help of the Computer-assisted Orthopaedic Surgery (CAOS) navigation system, the allografts were implanted in 14 patients to fill defects after tumour resection. By combining the virtual bone bank and CAOS, selection time was reduced and matching accuracy was increased. After 27.5 months of follow-up, the mean Musculoskeletal Tumor Society (MSTS) 93 functional score was 25.7 ± 1.1 points. Except for two patients with pulmonary metastases, 12 patents were alive without evidence of disease at the time this report was written. The virtual bone bank system was helpful for allograft selection, tumour excision and bone reconstruction, thereby improving the safety and effectiveness of limb-salvage surgery.

Resection of Concomitant Hepatic and Extrahepatic Metastases from Colorectal Cancer - A Worthwhile Operation?

PubMed

Diaconescu, Andrei; Alexandrescu, Sorin; Ionel, Zenaida; Zlate, Cristian; Grigorie, Razvan; Brasoveanu, Vladislav; Hrehoret, Doina; Ciurea, Silviu; Botea, Florin; Tomescu, Dana; Droc, Gabriela; Croitoru, Adina; Herlea, Vlad; Boros, Mirela; Grasu, Mugur; Dumitru, Radu; Toma, Mihai; Ionescu, Mihnea; Vasilescu, Catalin; Popescu, Irinel

2017-01-01

Background: The benefit of hepatic resection in case of concomitant colorectal hepatic and extrahepatic metastases (CHEHMs) is still debatable. The purpose of this study is to assess the results of resection of hepatic and extrahepatic metastases in patients with CHEHMs in a high-volume center for both hepatobiliary and colorectal surgery and to identify prognostic factors that correlate with longer survival in these patients. It was performed a retrospective analysis of 678 consecutive patients with liver resection for colorectal cancer metastases operated in a single Centre between April 1996 and March 2016. Among these, 73 patients presented CHEHMs. Univariate analysis was performed to identify the risk factors for overall survival (OS) in these patients. Results: There were 20 CHMs located at the lymphatic node level, 20 at the peritoneal level, 12 at the ovary and lung level, 12 presenting as local relapses and 9 other sites. 53 curative resections (R0) were performed. The difference in overall survival between the CHEHMs group and the CHMs group is statistically significant for the entire groups (p 0.0001), as well as in patients who underwent R0 resection (p 0.0001). In CHEHMs group, the OS was statistically significant higher in patients who underwent R0 resection vs. those with R1/R2 resection (p=0.004). Three variables were identified as prognostic factors for poor OS following univariate analysis: 4 or more hepatic metastases, major hepatectomy and the performance of operation during first period of the study (1996 - 2004). There was a tendency toward better OS in patients with ovarian or pulmonary location of extrahepatic disease, although the difference was not statistically significant. In patients with concomitant hepatic and extrahepatic metastases, complete resection of metastatic burden significantly prolong survival. The patients with up to 4 liver metastases, resectable by minor hepatectomy benefit the most from this aggressive onco

Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid.

PubMed

Meckel, M; Bergmann, R; Miederer, M; Roesch, F

2017-01-01

Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68 Ga-labelled analogues, endoradiotheraphy with 177 Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTA PAM and DOTA ZOL (MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68 Ga and the β - emitting nuclide 177 Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [ 18 F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats. The new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68 Ga and >98 % with 177 Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [ 68 Ga]DOTA ZOL (SUV Femur  = 5.4 ± 0.6) followed by [ 18 F]NaF (SUV Femur  = 4.8 ± 0.2), [ 68 Ga]DOTA PAM (SUV Femur  = 4.5 ± 0.2) and [ 68 Ga]BPAPD (SUV Femur  = 3.2 ± 0.3). [ 177 Lu]DOTA ZOL showed a similar distribution as the diagnostic 68 Ga complex. The 68 Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [ 68 Ga]DOTA ZOL , which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177 Lu. The therapeutic compound [ 177 Lu]DOTA ZOL showed a high target-to-background ratio. SPECT experiments showed concordance

The surgical manegement of metastases to humerus-clinical evaluation.

PubMed

Chrobok, Adam; Spindel, Jerzy; Miszczyk, Leszek; Koczy, Bogdan; Pilecki, Bogdan; Jarosz, Adam; Mrozek, Tomasz

2003-06-30

Background. The humerus is a common localisation of cancer metastases. The restoration of anatomical order and tumor resection within humerus is important for patients quality of everyday life and for their pain relief. The surgical treatment is one of the most important part of the whole oncological ways of tratment.
The study objective was a clinical assesment of tumor resection and reconstruction within humerus according to matastasis localisation and the choice of surgical technique.
Material and methods. In the years 1999-2002 19 patients underwent surgery due to pathological fracture or/and cancer metastasis within humerus. The shaft localisation of the tumor was found in 8 cases and in 11 patients the metastatic foci were found in proximnal diaphysis. In patients with proximal diaphysis localisation of the tumor the partial resection with subsequent joint exchange procedure was made. The humeral shaft metastatic cancer changes were treated by the segmental resection with subsequent surgical cement filling or auto/allogenical bone grafting combined with intramedullary nail or AO/ASIF plate stabilisation. The average follow-up period was 8,5 months.
Results. In patients after resection with shoulder joint alloplasty according to the Enneking test a very good result was found in 7 and very good in 4 cases.
In patients with femoral shaft metastatic tumor locaslisation, 6 good and 2 fair results were found. In 1 patient after 2 months rehabilitation a reoperation was needed due to the mechanical destabilisation. The best results were found in patients after intramedullary nailing.An acute soft tissue inflamation requiering surgical treatment was found in 1 patient after shoulder joint replacement.
Conclusions. After clinical analysis of the material we highly recomend the partial humeral bone resection with subsequent shoulder alloplasty in patients with proximal humeral diaphysis metastatic localisation. In cases with shaft

Stereotactic radiosurgery for multiple brain metastases

NASA Astrophysics Data System (ADS)

Lee, Anna; (Josh Yamada, Yoshiya

2017-01-01

Whole brain radiation therapy has been the traditional treatment of choice for patients with multiple brain metastases. Although stereotactic radiosurgery is widely accepted for the management to up to 4 brain metastases, its use is still controversial in cases of 5 or more brain metastases. Randomized trials have suggested that stereotactic radiosurgery alone is appropriate in up to 4 metastases without concomitant whole brain radiation. Level 1 evidence also suggests that withholding whole brain radiation may also reduce the impact of radiation on neurocognitive function and also may even offer a survival advantage. A recent analysis of a large multicentre prospective database has suggested that there are no differences in outcomes such as the likelihood of new metastasis or leptomeningeal disease in cases of 2-10 brain metastases, nor in overall survival. Hence in the era of prolonged survival with stage IV cancer, stereotactic radiosurgery is a reasonable alternative to whole brain radiation in order to minimize the impact of treatment upon quality of life without sacrificing overall survival.

Diagnostic value of apparent diffusion coefficients to differentiate benign from malignant vertebral bone marrow lesions.

PubMed

Balliu, E; Vilanova, J C; Peláez, I; Puig, J; Remollo, S; Barceló, C; Barceló, J; Pedraza, S

2009-03-01

The aim of this study is to evaluate the value of the apparent diffusion coefficient (ADC) obtained in diffusion-weighted (DW) MR sequences for the differentiation between malignant and benign bone marrow lesions. Forty-five patients with altered signal intensity vertebral bodies on conventional MR sequences were included. The cause of altered signal intensity was benign osteoporotic collapse in 16, acute neoplastic infiltration in 15, and infectious processes in 14; based on plain-film, CT, bone scintigraphy, conventional MR studies, biopsy or follow-up. All patients underwent isotropic DW MR images (multi-shot EPI, b values of 0 and 500 s/mm(2)). Signal intensity at DW MR images was evaluated and ADC values were calculated and compared between malignancy, benign edema and infectious spondylitis. Acute malignant fractures were hyperintense compared to normal vertebral bodies on the diffusion-weighted sequence, except in one patient with sclerotic metastases. Mean ADC value from benign edema (1.9+/-0.39 x 10(-3) mm(2)/s) was significantly (p<0.0001) higher than untreated metastasic lesions (0.9+/-1.3 x 10(-3)mm (2)/s). Mean ADC value of infectious spondilytis (0.96+/-0.49 x 10(-3) mm(2)/s) was not statistically (p>0.05) different from untreated metastasic lesions. ADC value was low (0.75 x 10(-3) mm(2)/s) in one case of subacute benign fracture. ADC values are a useful complementary tool to characterize bone marrow lesions, in order to distinguish acute benign fractures from malignant or infectious bone lesions. However, ADC values are not valuable in order to differentiate malignancy from infection.

Stereotactic radiosurgery of brain metastases.

PubMed

Specht, Hanno M; Combs, Stephanie E

2016-09-01

Brain metastases are a common problem in solid malignancies and still represent a major cause of morbidity and mortality. With the ongoing improvement in systemic therapies, the expectations on the efficacy of brain metastases directed treatment options are growing. As local therapies against brain metastases continue to evolve, treatment patterns have shifted from a palliative "one-treatment-fits-all" towards an individualized, patient adapted approach. In this article we review the evidence for stereotactic radiation treatment based on the current literature. Stereotactic radiosurgery (SRS) as a local high precision approach for the primary treatment of asymptomatic brain metastases has gained wide acceptance. It leads to lasting tumor control with only minor side effects compared to whole brain radiotherapy, since there is only little dose delivered to the healthy brain. The same holds true for hypofractionated stereotactic radiotherapy (HFSRT) for large metastases or for lesions close to organs at risk (e.g. the brainstem). New treatment indications such as neoadjuvant SRS followed by surgical resection or postoperative local therapy to the resection cavity show promising data and are also highlighted in this manuscript. With the evolution of local treatment options, optimal patient selection becomes more and more crucial. This article aims to aid decision making by outlining prognostic factors, treatment techniques and indications and common dose prescriptions.

Photodynamic therapy and fluorescence diagnostics of breast cancer metastases with photosense and alasense

NASA Astrophysics Data System (ADS)

Vakoulovskaya, Elena G.; Shental, Victor V.; Letyagin, Victor P.; Brjezovsky, Vitaly J.; Oumnova, L. V.; Vorozhtsov, Georgy N.; Philinov, V.; Stranadko, Eugeny P.

2002-06-01

Photodynamic Therapy (PDT) and fluorescent diagnostics (FD) using photosensitizers Photosense (Aluminium Phtalocyanine, (NIOPIC, Russia)(PS) and Alasense have been provided in 101 patients with breast cancer as a multicenter study. All patients had recurrences of breast cancer (skin metastases) after combined treatment, chemotherapy and radiotherapy. FD of tumor with detecting of subclinical sites, accumulation of PS in tumor, adjacent tissue, skin before and during PDT was fulfilled. Multiple surface irradiations were carried on with interval 24-72 hours (semiconductive laser - (lambda) =672+2nm) in light does 100J/cm2 and total light does 300-900 J/cm2. 2 months after PDT we had overall response rate of 86,87% with complete response (CR) in 51,48% and partial response in 35,39%. During year after PDT in 52 patients with CR we had CR in 36,6% local recurrences in 23,1%, progression (distant (lung or bone) metastasis) in 40,4% of cases. Our experience show pronounced efficacy of PDT for skin metastases of breast cancer.

Syntheses and evaluation of 68 Ga- and 153 Sm-labeled DOTA-conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases.

PubMed

Chakraborty, Sudipta; Goswami, Dibakar; Chakravarty, Rubel; Mohammed, Sahiralam Khan; Sarma, Haladhar Deb; Dash, Ashutosh

2018-05-05

This article reports the syntheses and evaluation of 68 Ga- and 153 Sm-complexes of a new DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-conjugated geminal bisphosphonate, DOTA-Bn-SCN-BP, for their potential uses in the early detection of skeletal metastases by imaging and palliation of pain arising from skeletal metastases, respectively. The conjugate was synthesized in high purity following an easily adaptable three-step reaction scheme. Gallium-68- and 153 Sm-complexes were prepared in high yield (>98%) and showed excellent in vitro stability in phosphate-buffered saline (PBS) and human serum. Both the complexes showed high affinity for hydroxyapatite particles in in vitro binding study. In biodistribution studies carried out in normal Wistar rats, both the complexes exhibited rapid skeletal accumulation with almost no retention in any other major organ. The newly synthesized molecule DOTA-Bn-SCN-BP would therefore be a promising targeting ligand for the development of radiopharmaceuticals for both imaging skeletal metastases and palliation of pain arising out of it in patients with cancer when radiolabeled with 68 Ga and 153 Sm, respectively. A systematic comparative evaluation, however, showed that there was no significant improvement of skeletal accumulation of the 153 Sm-DOTA-Bn-SCN-BP complex over 153 Sm-DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid) as the later itself demonstrated optimal properties required for an agent for bone pain palliation. © 2018 John Wiley & Sons A/S.

Protocadherin-7 induces bone metastasis of breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ai-Min; Tian, Ai-Xian; Zhang, Rui-Xue

2013-07-05

Highlights: •PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. •PCDH7 is up-regulation in bone metastatic breast cancer tissues. •Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. •PCDH7 induces breast cancer bone metastasis in vivo. -- Abstract: Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bonemore » metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer.« less

Immune Humanization of Immunodeficient Mice Using Diagnostic Bone Marrow Aspirates from Carcinoma Patients

PubMed Central

Werner-Klein, Melanie; Proske, Judith; Werno, Christian; Schneider, Katharina; Hofmann, Hans-Stefan; Rack, Brigitte; Buchholz, Stefan; Ganzer, Roman; Blana, Andreas; Seelbach-Göbel, Birgit; Nitsche, Ulrich

2014-01-01

Tumor xenografts in immunodeficient mice, while routinely used in cancer research, preclude studying interactions of immune and cancer cells or, if humanized by allogeneic immune cells, are of limited use for tumor-immunological questions. Here, we explore a novel way to generate cancer models with an autologous humanized immune system. We demonstrate that hematopoietic stem and progenitor cells (HSPCs) from bone marrow aspirates of non-metastasized carcinoma patients, which are taken at specialized centers for diagnostic purposes, can be used to generate a human immune system in NOD-scid IL2rγ(null) (NSG) and HLA-I expressing NSG mice (NSG-HLA-A2/HHD) comprising both, lymphoid and myeloid cell lineages. Using NSG-HLA-A2/HHD mice, we show that responsive and self-tolerant human T cells develop and human antigen presenting cells can activate human T cells. As critical factors we identified the low potential of bone marrow HSPCs to engraft, generally low HSPC numbers in patient-derived bone marrow samples, cryopreservation and routes of cell administration. We provide here an optimized protocol that uses a minimum number of HSPCs, preselects high-quality bone marrow samples defined by the number of initially isolated leukocytes and intra-femoral or intra-venous injection. In conclusion, the use of diagnostic bone marrow aspirates from non-metastasized carcinoma patients for the immunological humanization of immunodeficient mice is feasible and opens the chance for individualized analyses of anti-tumoral T cell responses. PMID:24830425

Feasibility and performance of novel software to quantify metabolically active volumes and 3D partial volume corrected SUV and metabolic volumetric products of spinal bone marrow metastases on 18F-FDG-PET/CT.

PubMed

Torigian, Drew A; Lopez, Rosa Fernandez; Alapati, Sridevi; Bodapati, Geetha; Hofheinz, Frank; van den Hoff, Joerg; Saboury, Babak; Alavi, Abass

2011-01-01

Our aim was to assess feasibility and performance of novel semi-automated image analysis software called ROVER to quantify metabolically active volume (MAV), maximum standardized uptake value-maximum (SUV(max)), 3D partial volume corrected mean SUV (cSUV(mean)), and 3D partial volume corrected mean MVP (cMVP(mean)) of spinal bone marrow metastases on fluorine-18 fluorodeoxyglucose-positron emission tomography/computerized tomography ((18)F-FDG-PET/CT). We retrospectively studied 16 subjects with 31 spinal metastases on FDG-PET/CT and MRI. Manual and ROVER determinations of lesional MAV and SUV(max), and repeated ROVER measurements of MAV, SUV(max), cSUV(mean) and cMVP(mean) were made. Bland-Altman and correlation analyses were performed to assess reproducibility and agreement. Our results showed that analyses of repeated ROVER measurements revealed MAV mean difference (D)=-0.03±0.53cc (95% CI(-0.22, 0.16)), lower limit of agreement (LLOA)=-1.07cc, and upper limit of agreement (ULOA)=1.01cc; SUV(max) D=0.00±0.00 with LOAs=0.00; cSUV(mean) D=-0.01±0.39 (95% CI(-0.15, 0.13)), LLOA=-0.76, and ULOA=0.75; cMVP(mean) D=-0.52±4.78cc (95% CI(-2.23, 1.23)), LLOA=-9.89cc, and ULOA=8.86cc. Comparisons between ROVER and manual measurements revealed volume D= -0.39±1.37cc (95% CI (-0.89, 0.11)), LLOA=-3.08cc, and ULOA=2.30cc; SUV(max) D=0.00±0.00 with LOAs=0.00. Mean percent increase in lesional SUV(mean) and MVP(mean) following partial volume correction using ROVER was 84.25±36.00% and 84.45±35.94% , respectively. In conclusion, it is feasible to estimate MAV, SUV(max), cSUV(mean), and cMVP(mean) of spinal bone marrow metastases from (18)F-FDG-PET/CT quickly and easily with good reproducibility via ROVER software. Partial volume correction is imperative, as uncorrected SUV(mean) and MVP(mean) are significantly underestimated, even for large lesions. This novel approach has great potential for practical, accurate, and precise combined structural-functional PET

SU-E-T-588: Optimization of Imaging Following 223Ra Administration in Targeted Alpha-Emitting Radionuclide Therapy of Bone Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benabdallah, N; Bernardini, M; Desbree, A

Purpose: With a growing demand of alpha-emitting radiopharmaceuticals, especially Xofigo ({sup 223}RaCl{sub 2}) which is used in the treatment of metastatic bone disease, the optimization of dosimetry becomes necessary. Indeed, in Europe, as stated on the council directive 2013/59/euratom, exposures of target volumes for radiotherapeutic purposes shall be individually planned taking into account that doses to non-target volumes and tissues shall be as low as reasonably achievable. To that aim, the possibility of imaging {sup 223}Ra was first investigated. Methods: The experiments were conducted at the Hopital Europeen Georges Pompidou with an Infinia Hawkeye 4 gamma camera, equipped with amore » medium-energy collimator. Imaging parameters, such as sensibility, spatial resolution and energy spectrum, were determined using several physical phantoms with a source of 6 MBq of {sup 223}Ra. Bone metastases were modeled with a NEMA Body Phantom to investigate image degradation based on the concentration of {sup 223}Ra. Results: The acquired energy spectrum allowed to visualize several photon peaks: at 85, 154 and 270 keV. Camera sensitivity measured from the phantom study was 102.3 cps/MBq for the 85 keV ± 20 %, 89.9 cps/MBq for the 154 ± 20 % window and 65.4 cps/MBq for the 270 ± 10 % window. The spatial resolution (full-width at half-maximum) was respectively 1.7, 1.9 and 1.8 cm for the three energy windows. SPECT/CT images of NEMA Body Phantom without and with attenuation have permitted to determine the best reconstruction parameters. Conclusion: This study has demonstrated that it is possible to obtain clinically relevant information from images of {sup 223}Ra. All these results will be valuable to analyze biodistribution imaging of the radiopharmaceutical in the patient body and go further in the reconstruction of patient images in order to personalize the dosimetry.« less

Nurse exposure doses resulted from bone scintigraphy patient

NASA Astrophysics Data System (ADS)

Tunçman, Duygu; Kovan, Bilal; Poyraz, Leyla; ćapali, Veli; Demir, Bayram; Türkmen, Cüneyt

2016-03-01

Bone scintigraphy is used for displaying the radiologic undiagnosed bone lesions in nuclear medicine. It's general indications are researching bone metastases, detection of radiographically occult fractures, staging and follow-up in primary bone tumors, diagnosis of paget's disease, investigation of loosening and infection in orthopedic implants. It is applied with using 99mTc labeled radiopharmaceuticals (e.g 99m Tc MDP,99mTc HEDP and 99mTc HMDP). 20 -25 mCi IV radiotracer was injected into vein and radiotracer emits gamma radiation. Patient waits in isolated room for about 3 hours then a gamma camera scans radiation area and creates an image. When some patient's situation is not good, patients are hospitalized until the scanning because of patients' close contact care need. In this study, measurements were taken from ten patients using Geiger Muller counter. After these measurements, we calculated nurse's exposure radiations from patient's routine treatment, examination and emergency station.

Musculoskeletal Complications and Bone Metastases in Breast Cancer Patients Undergoing Estrogen Deprivation Therapy

DTIC Science & Technology

2016-10-01

are that any treatment or environmental factor that leads to bone loss (e.g., glucocorticoids, GnRH inhibitors, radiation, fracture , osteoporosis...recurrence and mortality. Previous cell culture and clinical studies have demonstrated that peripheral adipose ( fat ) tissue promotes cancer growth, yet the...contribution of increased MAT on metastatic tumor growth in bone is currently unknown. MAT, which is a historically understudied fat depot, accounts

Intracranial Epidural Metastases of Adrenal Pheochromocytoma: A Rare Entity.

PubMed

Boettcher, Lillian B; Abou-Al-Shaar, Hussam; Ravindra, Vijay M; Horn, Jeffrey; Palmer, Cheryl Ann; Menacho, Sarah T

2018-06-01

Pheochromocytomas are uncommon neuroendocrine tumors of the adrenal medulla. Malignant behavior is seen in approximately 10% of these lesions, evidenced by distant metastasis to sites without chromaffin tissue. Here we report a rare case of intracranial epidural metastases of an adrenal pheochromocytoma in a 24-year-old man. The patient originally presented at age 10 years with adrenal pheochromocytoma and subsequently developed extensive metastatic bone and lung disease. He was monitored in the intervening years until recent imaging demonstrated an enlarging right parietal mass. On surgical resection of the parietal lesion, the tumor was highly vascularized and confined to the epidural space. To the best of our knowledge, this is the first reported case of metastatic epidural spread of pheochromocytoma without concomitant subdural or intraparenchymal extension. Copyright © 2018 Elsevier Inc. All rights reserved.

Metastases of breast cancer to a uterine leiomyoma.

PubMed

Ludovisi, Manuela; Moruzzi, Maria Cristina; Ferrandina, Gabriella; Scambia, Giovanni; Testa, Antonia Carla

2017-09-19

Metastases to the uterus occur very rarely, accounting for less than 10% of all cases of metastases involving the female genital tract; mammary and gastrointestinal carcinomas are the most frequent extragenital primary neoplasms metastasizing to the uterine corpus 1 . Very little data is available in the literature including 24 cases of breast cancer metastasized to a uterine leiomyoma 2 , as assessed at surgery (N = 16), and autoptic evaluation (n = 8). This article is protected by copyright. All rights reserved.

Unusual Metastases in Renal Cell Carcinoma: A Single Institution Experience and Review of Literature

PubMed Central

Villarreal-Garza, Cynthia; Perez-Alvarez, Sandra I.; Gonzalez-Espinoza, Ivan R.; Leon-Rodriguez, Eucario

2010-01-01

Background To report location and management of atypical metastases from renal cell carcinoma (RCC) in the Instituto Nacional de Ciencias Medicas e Investigacion Salvador Zubiran (INCMNSZ) in Mexico City. Methods Between 1987 to 2009, 545 patients with RCC were retrospectively identified at the INCMNSZ. Patients with unusual metastases confirmed by histopathology were analyzed. Epidemiological, clinical, diagnosis, treatment and outcome data were reviewed. Results Sixty patients developed 98 unusual metastases secondary to RCC. The group was comprised of 35 men (58.3%), with a median age of 60 years at diagnosis. Metachronous unusual metastases with primary renal cancer were observed in 37 individuals (61.7%). Median time from primary RCC diagnosis to the first unusual metastasis was 16.5 months. Median survival from diagnosis of the first unusual metastasis to death was 5.0 months (CI 95%: 2.8-7.2 months). Patients with an initial solitary metastatic lesion in an unusual site (28.3%) had a better survival compared to patients who primarily presented with multiple metastases, 17.0 (CI 95%: 6.1-27.9) Vs 3.0 months (CI 95%: 0.9-5.1), p = 0.001. Unusual metastasis resection (21 patients) improved survival, 25.0 (CI 95%: 5.1-44.9) Vs 3.0 months (CI 95%: 0.8-5.2), p < 0.0001. No survival difference was observed between localization of unsual metastases (p = 0.72). Conclusions In patients with advanced RCC we suggest an individual diagnostic and surgical approach to achieve complete resection with disease-free margins, even in the presence of unusual metastatic sites, multifocality, or history of metastasectomy. These strategy might provide not only palliation for symptoms, but an opportunity for meaningful disease free and overall survival. PMID:29147198

The Role of Hedgehog Signaling in Tumor Induced Bone Disease

PubMed Central

Cannonier, Shellese A.; Sterling, Julie A.

2015-01-01

Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors. PMID:26343726

Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice.

PubMed

Campbell, J Preston; Karolak, Matthew R; Ma, Yun; Perrien, Daniel S; Masood-Campbell, S Kathryn; Penner, Niki L; Munoz, Steve A; Zijlstra, Andries; Yang, Xiangli; Sterling, Julie A; Elefteriou, Florent

2012-07-01

Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells.

A taxonomy of epithelial human cancer and their metastases

PubMed Central

2009-01-01

Background Microarray technology has allowed to molecularly characterize many different cancer sites. This technology has the potential to individualize therapy and to discover new drug targets. However, due to technological differences and issues in standardized sample collection no study has evaluated the molecular profile of epithelial human cancer in a large number of samples and tissues. Additionally, it has not yet been extensively investigated whether metastases resemble their tissue of origin or tissue of destination. Methods We studied the expression profiles of a series of 1566 primary and 178 metastases by unsupervised hierarchical clustering. The clustering profile was subsequently investigated and correlated with clinico-pathological data. Statistical enrichment of clinico-pathological annotations of groups of samples was investigated using Fisher exact test. Gene set enrichment analysis (GSEA) and DAVID functional enrichment analysis were used to investigate the molecular pathways. Kaplan-Meier survival analysis and log-rank tests were used to investigate prognostic significance of gene signatures. Results Large clusters corresponding to breast, gastrointestinal, ovarian and kidney primary tissues emerged from the data. Chromophobe renal cell carcinoma clustered together with follicular differentiated thyroid carcinoma, which supports recent morphological descriptions of thyroid follicular carcinoma-like tumors in the kidney and suggests that they represent a subtype of chromophobe carcinoma. We also found an expression signature identifying primary tumors of squamous cell histology in multiple tissues. Next, a subset of ovarian tumors enriched with endometrioid histology clustered together with endometrium tumors, confirming that they share their etiopathogenesis, which strongly differs from serous ovarian tumors. In addition, the clustering of colon and breast tumors correlated with clinico-pathological characteristics. Moreover, a signature was

The role of whole brain radiation therapy in the management of melanoma brain metastases

PubMed Central

2014-01-01

Background Brain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as “radioresistant,” the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT). Methods We reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results WBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years (hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases (HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) ≤ 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08). Conclusions Multiple brain metastases and omission of up-front WBRT (particularly in combination) are

Unusual Bone Superscan, MIBG Superscan, and 68Ga DOTATATE PET/CT in Metastatic Pheochromocytoma.

PubMed

Tan, Teik Hin; Wong, Teck Huat; Hassan, Siti Zarina Amir; Lee, Boon Nang

2015-11-01

A 17-year-old adolescent boy with biochemically raised 2-hour urinary metanephrine and normetanephrine as well as CT findings of retroperitoneal soft tissue mass and bony metastases was referred for further assessment. Apart from Ga DOTATATE PET/CT evaluation, pretargeted systemic radionuclide therapy assessment with I-MIBG scintigraphy showed unusual phenomenon of MIBG superscan. Postsurgically, restaging Tc-MDP bone scintigraphy showed typical bone superscan features. The MIBG superscan was better delineated on post-I-MIBG therapy images.

Osteolytic and mixed cancer metastasis modulates collagen and mineral parameters within rat vertebral bone matrix.

PubMed

Burke, Mikhail V; Atkins, Ayelet; Akens, Margarete; Willett, Thomas L; Whyne, Cari M

2016-12-01

Metastatic involvement in vertebral bone diminishes the mechanical integrity of the spine; however minimal data exist on the potential impact of metastases on the intrinsic material characteristics of the bone matrix. Thirty-four (34) female athymic rats were inoculated with HeLa (N = 17) or Ace-1 (N = 17) cancer cells lines producing osteolytic or mixed (osteolytic and osteoblastic) metastases, respectively. A maximum of 21 days was allowed between inoculation and rat sacrifice for vertebrae extraction. High performance liquid chromatography (HPLC) was utilized to determine modifications in collagen-I parameters such as proline hydroxylation and the formation of specific enzymatic and non-enzymatic (pentosidine) cross-links. Raman spectroscopy was used to determine relative changes in mineral crystallinity, mineral carbonation, mineral/collagen matrix ratio, collagen quality ratio, and proline hydroxylation. HPLC results showed significant increase in the formation of pentosidine and decrease in the formation of the enzymatic cross-link deoxy-pryridinoline within osteolytic bone compared to mixed bone. Raman results showed decreased crystallinity, increased carbonation, and collagen quality (aka 1660/1690 sub-band) ratio with osteolytic bone compared to mixed bone and healthy controls along with an observed increase in proline hydroxylation with metastatic involvement. The mineral/matrix ratio decreased in both osteolytic and mixed bone compared to healthy controls. Quantifying modifications within the intrinsic characteristics of bone tissue will provide a foundation to assess the impact of current therapies on the material behavior of bone tissue in the metastatic spine and highlight targets for the development of new therapeutics and approaches for treatment. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2126-2136, 2016. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Liver resection for colorectal cancer metastases

PubMed Central

Gallinger, S.; Biagi, J.J.; Fletcher, G.G.; Nhan, C.; Ruo, L.; McLeod, R.S.

2013-01-01

Questions Should surgery be considered for colorectal cancer (crc) patients who have liver metastases plus (a) pulmonary metastases, (b) portal nodal disease, or (c) other extrahepatic metastases (ehms)? What is the role of chemotherapy in the surgical management of crc with liver metastases in (a) patients with resectable disease in the liver, or (b) patients with initially unresectable disease in the liver that is downsized with chemotherapy (“conversion”)? What is the role of liver resection when one or more crc liver metastases have radiographic complete response (rcr) after chemotherapy? Perspectives Advances in chemotherapy have improved survival in crc patients with liver metastases. The 5-year survival with chemotherapy alone is typically less than 1%, although two recent studies with folfox or folfoxiri (or both) reported rates of 5%–10%. However, liver resection is the treatment that is most effective in achieving long-term survival and offering the possibility of a cure in stage iv crc patients with liver metastases. This guideline deals with the role of chemotherapy with surgery, and the role of surgery when there are liver metastases plus ehms. Because only a proportion of patients with crc metastatic disease are considered for liver resection, and because management of this patient population is complex, multidisciplinary management is required. Methodology Recommendations in the present guideline were formulated based on a prepublication version of a recent systematic review on this topic. The draft methodology experts, and external review by clinical practitioners. Feedback was incorporated into the final version of the guideline. Practice Guideline These recommendations apply to patients with liver metastases from crc who have had or will have a complete (R0) resection of the primary cancer and who are being considered for resection of the liver, or liver plus specific and limited ehms, with curative intent. 1(a). Patients with liver and lung

Role of surgery in brain metastases.

PubMed

Laghari, Altaf Ali; Ahmed, Syed Ijlal; Shamim, Muhammad Shahzad

2017-08-01

Brain metastases remain the commonest type of brain tumour, being four times more common than primary brain tumours. Although surgical intervention may be recommended for one of various reasons in the management of these tumours, including but not limited to conformation of diagnosis, relief of mass effect, improvement of neurological status and prolongation of survival, the guidelines for management of brain metastases remain largely subjective and therefore controversial. Herein the authors have attempted to review some of the existing evidence on role of surgery in the management of brain metastases and have presented their selected guidelines for the readers.

Near infrared photoimmunotherapy for lung metastases

PubMed Central

Sato, Kazuhide; Nagaya, Tadanobu; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka

2015-01-01

Lung metastases are a leading cause of cancer related deaths; nonetheless current treatments are limited. Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies that target tumors with the toxicity induced by photosensitizers activated by NIR-light. Herein, we demonstrate the efficacy of NIR-PIT in a mouse model of lung metastases. Experiments were conducted with a HER2, luciferase and GFP expressing cell line (3T3/HER2-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. With 3D culture, repeated NIR-PIT could eradicate entire spheroids. In vivo anti-tumor effects of NIR-PIT included significant reductions in both tumor volume (p = 0.0141 vs. APC) and bioluminescence image (BLI) (p = 0.0086 vs. APC) in the flank model, and prolonged survival (p < 0.0001). BLI demonstrated a significant reduction in lung metastases volume (p = 0.0117 vs. APC). Multiple NIR-PIT doses significantly prolonged survival in the lung metastases model (p < 0.0001). These results suggested that NIR-PIT is a potential new therapy for the local control of lung metastases. PMID:26021765

Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases

PubMed Central

Jeong, Han-Sin; Jones, Dennis; Liao, Shan; Wattson, Daniel A.; Cui, Cheryl H.; Duda, Dan G.; Willett, Christopher G.; Jain, Rakesh K.

2015-01-01

Background: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported. Methods: Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9–12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided. Results: Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance P = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm2, 95% CI = 149 to 365 vessels/mm2; bevacizumab group mean = 327 vessels/mm2, 95% CI = 140 to 514 vessels/mm2, P = .78). Conclusion: We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The

Fluorine-18-fluorocholine PET/CT parameters predictive for hematological toxicity to radium-223 therapy in castrate-resistant prostate cancer patients with bone metastases: a pilot study.

PubMed

Vija Racaru, Lavinia; Sinigaglia, Mathieu; Kanoun, Salim; Ben Bouallègue, Fayçal; Tal, Ilan; Brillouet, Sévérine; Bauriaud-Mallet, Mathilde; Zerdoud, Slimane; Dierickx, Lawrence; Vallot, Delphine; Caselles, Olivier; Gabiache, Erwan; Pascal, Pierre; Courbon, Frederic

2018-05-21

This study aims to predict hematological toxicity induced by Ra therapy. We investigated the value of metabolically active bone tumor volume (MBTV) and total bone lesion activity (TLA) calculated on pretreatment fluorine-18-fluorocholine (F-FCH) PET/CT in castrate-resistant prostate cancer (CRPC) patients with bone metastases treated with Ra radionuclide therapy. F-FCH PET/CT imaging was performed in 15 patients with CRPC before treatment with Ra. Bone metastatic disease was quantified on the basis of the maximum standardized uptake value (SUV), total lesion activity (TLA=MBTV×SUVmean), or MBTV/height (MBTV/H) and TLA/H. F-FCH PET/CT bone tumor burden and activity were analyzed to identify which parameters could predict hematological toxicity [on hemoglobin (Hb), platelets (PLTs), and lymphocytes] while on Ra therapy. Pearson's correlation was used to identify the correlations between age, prostate-specific antigen, and F-FCH PET parameters. MBTV ranged from 75 to 1259 cm (median: 392 cm). TLA ranged from 342 to 7198 cm (median: 1853 cm). Patients benefited from two to six cycles of Ra (n=56 cycles in total). At the end of Ra therapy, five of the 15 (33%) patients presented grade 2/3 toxicity on Hb and lymphocytes, whereas three of the 15 (20%) patients presented grade 2/3 PLT toxicity.Age was correlated negatively with both MBTV (r=-0.612, P=0.015) and TLA (r=-0.596, P=0.018). TLA, TLA/H, and MBTV/H predicted hematological toxicity on Hb, whereas TLA/H and MBTV/H predicted toxicity on PLTs at the end of Ra cycles. Receiver operating characteristic curve analysis allowed to define the cutoffs for MBTV (915 cm) and TLA (4198 cm) predictive for PLT toxicity, with an accuracy of 0.92 and 0.99. Tumor bone burden calculation is feasible with F-FCH PET/CT with freely available open-source software. In this pilot study, baseline F-FCH PET/CT markers (TLA, MBTV) have shown abilities to predict Hb and PLT toxicity after Ra therapy and could be explored for

Macrophages: Their Emerging Roles in Bone