Osteoblastic Lesions Research Articles

Comment on "Plant thorn synovitis of elbow in children".

We read with interest the article titled “Plant thorn synovitis of elbow in children”1 and based on our clinical experiences2 would like to share some important aspects of these thorn injuries, which have not been highlighted in this paper. Acacia thorn injuries are common in Northern and Central India, where the Acacia Arabica plants are found in abundance especially in villages and on road side. The sharp thorns of these plants can easily penetrate the exposed parts of the extremities, both upper and lower limbs. These injuries are most commonly seen in foot, as in rural India there is a still a trend towards barefoot walking and/or not wearing strong shoes. The senior author had published already the world's largest series of acacia thorn injuries in 1990,2 in which he described foot to be the most common site (14 out of 22 patients). Incidentally, the present paper has failed to include this important landmark publication in their reference. Acacia Arabica thorns contain severely irritating toxins or alkaloids which trigger severe inflammatory response in the soft tissues and also in the bones.3 The authors would also like to bring to the readers' attention the presence of bony lesions in association with acacia thorn injuries. These lesions may be osteolytic, osteoblastic or mixed lesions and can easily be confused with chronic low grade osteomyelitis or benign neoplasms, if adequate history is not taken.2 Although not noticed in any of the cases in the present series, the radiographs should always be assessed for the presence of any lesions. The authors have described the presence of acacia thorns in the synovium, which were identified macroscopically per operatively. We do not have similar experience, as we had noticed that the acacia thorns if broken and entrapped in the synovium may not be easily visible to the naked eye all the times and hence careful microscopic examination of the total excised tissue should be done to look for the thorns in the specimen. Ultrasonagraphy and MRI can also be useful adjuncts for the diagnosis of thorn injuries. We do agree with the authors that an awareness and high index of suspicion about the possibilities of thorn injuries is crucial in reaching to an early diagnosis and hence a careful history about the foreign body prick, like thorns must be elucidated in all these patients.

A rare case of scapular metastasis from bronchogenic carcinoma with ipsilateral malignant pleural effusion.

A rare case of scapular metastasis from bronchogenic carcinoma with ipsilateral malignant pleural effusion.

Primary Lymphoma of Bone: Imaging Findings to Improve Diagnosis of a Rarely Considered Disease Prior to Biopsy

Objective: Primary lymphoma of bone (PLB) is a rare malignant bone tumor often presenting in the fifth-sixth decades involving appendicular long bones. Published radiological findings indicate that PLB typically presents as a moth-eaten osteolytic lesion with periosteal reaction, while MRI commonly demonstrates marrow infiltration with extraosseous extension. Given rarity and variable appearances, PLB may not be primarily considered prior to biopsy. Our objective was to evaluate preoperative imaging findings in effort to increase awareness and improve a perceived deficiency in preoperative diagnosis. Materials and Methods: Following IRB approval, retrospective review identified 60 patients with newly diagnosed bone lesions proven to represent PLB in accordance with WHO definition. Preoperative radiographs (n = 46), MRI (n = 33) and PET (n = 37) were independently reviewed by two radiologists. At radiography, lesions were classified: purely lytic, mixed, purely sclerotic, or occult; lytic lesions were graded utilizing Lodwick’s classification. At MRI, lesions were defined as focal or infiltrative and the presence or absence of extraosseous disease was recorded. Extraosseous masses were defined as small ( 1 cm) and subjectively correlated with degree of cortical destruction. At PET, lesions were recorded as FDG-avid or not. Primary radiograph reports when available (n = 33) were reviewed and exact wording of differential considerations was recorded. Results: Radiographs demonstrated mixed (n = 22), lytic (n = 15), and sclerotic (n = 8) appearances; one radiographically occult lesion was seen by MRI. Lytic lesions were graded: IB (n = 3), IC (n = 5), II (n = 4), and III (n = 3); none were IA. At MRI, 30 lesions were infiltrative and 3 were focal; 11 were not associated with extraosseous extension, while 22 showed bony disease with small (n = 7) or large (n = 15) soft tissue mass. Of large masses, 13 demonstrated minimal cortical destruction. At PET, 36 demonstrated FDG uptake; one study was technically limited. Review of reports found that only 5 included “lymphoma” as a diagnostic consideration. Conclusion: Contrary to most published data, we suggest that PLB typically demonstrates some degree of osteosclerosis, often a mixed pattern of sclerosis and lucency; purely lytic lesions may be less common. Similar to existing reports, MRI commonly demonstrates marrow infiltration with extraosseous extension of disease, typically a large soft tissue mass with disproportionate (minimal) cortical destruction. Familiarity with these findings should improve preoperative consideration of PLB in the appropriate clinical scenario when a new osteoblastic lesion is identified.

The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis.

Prostate cancer (PCa) is the second leading cause of cancer death in men worldwide. Most PCa deaths are due to osteoblastic bone metastases. What triggers PCa metastasis to the bone and what causes osteoblastic lesions remain unanswered. A major contributor to PCa metastasis is the host microenvironment. Here, we address how the primary tumor microenvironment influences PCa metastasis via integrins, extracellular proteases, and transient epithelia-mesenchymal transition (EMT) to promote PCa progression, invasion, and metastasis. We discuss how the bone-microenvironment influences metastasis; where chemotactic cytokines favor bone homing, adhesion molecules promote colonization, and bone-derived signals induce osteoblastic lesions. Animal models that fully recapitulate human PCa progression from primary tumor to bone metastasis are needed to understand the PCa pathophysiology that leads to bone metastasis. Better delineation of the specific processes involved in PCa bone metastasize is needed to prevent or treat metastatic PCa. Therapeutic regimens that focus on the tumor microenvironment could add to the PCa pharmacopeia.

Paleopathological description and diagnosis of metastatic carcinoma in an Early Bronze Age (4588+34 Cal. BP) forager from the Cis-Baikal region of Eastern Siberia.

Extensive osteolytic and osteoblastic lesions were observed on the skeletal remains of an adult male excavated from an Early Bronze Age cemetery dated to 4556+32 years BP, located in the Cis-Baikal region of Siberia (Russian Federation). Lytic lesions ranged in size from several mm to over 60 mm in diameter and had irregular, moth-eaten borders. Many of these lesions destroyed trabecular bone, though a hollowed shell of cortical bone often remained observable. Radiographic analysis revealed numerous lytic lesions within trabecular bone that had not yet affected the cortex. Blastic lesions were identified as spiculated lines, bands, or nodules of mostly immature (woven) bone formed at irregular intervals. Anatomical elements with the greatest involvement included those of the axial skeleton (skull, vertebrae, sacrum, ribs, and sternum) as well as proximal appendicular elements (ossa coxae, proximal femora, clavicles, scapulae, and proximal humeri). Osteocoalescence of destructive foci was observed on the ilium and frontal bone, with the largest lesion found on the right ilium. Differential diagnoses include metastatic carcinoma, mycotic infections, tuberculosis, Langerhan's cell histiocytosis, and multiple myeloma. Based on lesion appearance and distribution, age and sex of the individual, as well as pathogen endemism, the most likely diagnostic option for this set of lesions is metastatic carcinoma. The age and sex of this individual and appearance of the lesions may reflect carcinoma of the lung or, possibly, prostate. This represents one of the earliest cases of metastatic carcinoma worldwide and the oldest case documented thus far from Northeast Asia.

Prostate cancer cells induce osteoblastic differentiation via semaphorin 3A.

Prostate cancer metastasis to bone is the second most commonly diagnosed malignant disease among men worldwide. Such metastatic disease is characterized by the presence of osteoblastic bone lesions, and is associated with high rates of mortality. However, the various mechanisms involved in prostate cancer-induced osteoblastic differentiation have not been fully explored. Semaphorin 3A (Sema 3A) is a newly identified regulator of bone metabolism which stimulates differentiation of pre-osteoblastic cells under physiological conditions. We investigated in this study whether prostate cancer cells can mediate osteoblastic activity through Sema 3A. We cultured osteoprogenitor MC3T3-E1 cells in prostate cancer-conditioned medium, and analyzed levels of Sema 3A protein in diverse prostate cancer cell lines to identify cell lines in which Sema 3A production showed a positive correlation with osteo-stimulation. C4-2 cells were stably transfected with Sema 3A short hairpin RNA to further determine whether Sema 3A contributes to the ability of C4-2 cells to induce osteoblastic differentiation. Down-regulation of Sema 3A expression decreased indicators of C4-2 CM-induced osteoblastic differentiation, including alkaline phosphatase production and mineralization. Additionally, silencing or neutralizing Sema 3A in C4-2 cells resulted in diminished β-catenin expression in osteogenitor MC3T3-E1 cells. Our results suggest that prostate cancer-induced osteoblastic differentiation is at least partially mediated by Sema 3A, and may be regulated by the β-catenin signalling pathway. Sema 3A may represent a novel target for treatment of prostate cancer-induced osteoblastic lesions.

Iliacus-piriformis abscess and septic arthritis from Theban Tomb (TT) 65

The incomplete skeletonized remains of Person 3/3a, from Shaft Tomb 3 of Theban Tomb (TT) 65, show mixed osteolytic and osteoblastic lesions in the left os coxa, sacrum, and distal right radius, with less pronounced osteoblastic, possibly related lesions elsewhere. Iliacus-piriformis abscess and septic arthritis are deemed primarily responsible while other considered etiological entities are less likely.

Stereotactic radiation therapy in painful bone metastases.

74 Background: Disease local control and therefore pain relief is the main objective in patients with painful bone metastases. The introduction of Stereotactic Body Radiation Therapy in combination with image guided radiotherapy offers the opportunity to safely apply hypofractionated schemes. Methods: From May 2009 to May 2014, 104 patients with total 158 single or multiple bone metastases from several primary tumors were treated with Stereotactic Body Radiation Therapy with palliative intent. Concrete osteolytic or painful osteoblastic lesions of maximum length 3cm where treated with two hypofractionated schemes: 24Gy in 6 fractions or 21Gy in 3 fractions depending on lesion size and location. All patients were provided with MDStation software installed on a tablet that analyzes their behavioral change based on evaluation questionnaires on their clinical status and pain intensity. Results: All patients completed the treatment plan with no major toxicity. Follow up was scheduled at the end of the treatment, three and six months after. Total pain relief was achieved in 130 lesions (82%), while in the rest 28 sites (18%) pain was significantly less and patients decreased medication. Conclusions: Stereotactic Body Radiation Therapy for bone metastases is a very effective technique for pain management. Palliation is achieved quite promptly with minimal toxicity.

Differences of osteoblastic bone metastases and osteolytic bone metastases in clinical features and molecular characteristics.

Several cancers tend to metastasize to bone, leading to osteolytic or osteoblastic bone lesions. The respective phenotypes of bone destruction and bone formation vary in clinical features, including incidence, prognosis, skeletal-related events and bone biomarkers. In addition, different molecular mechanisms explain the difference in phenotype. For example, molecules involved in osteolytic bone metastases (represented with breast cancer) include parathyroid hormone-related protein, transforming growth factor-β, while in osteoblastic lesions (represented with prostate cancer), endothelin-1 and morphogenetic proteins, etc. play a more important role in bone formation. It is important for us to understand the differences of bone metastases between two phenotypes to help clinicians to understand the underlying mechanisms, behaviors and therapies in development and currently available for bone metastases.

RGD peptide conjugated liposomal drug delivery system for enhance therapeutic efficacy in treating bone metastasis from prostate cancer

Targeting αvβ3 integrin is particularly promising for the treatment of bone metastases by targeting integrin-rich tumor cells and by inhibiting integrin-involved bone metastases. In this work, a liposomal drug delivery system conjugated with cyclic arginine-glycine-aspartic acid-tyrosine-lysine peptide (cRGDyk) as αvβ3 integrin ligand was thus developed to improve therapeutic efficacy in a mice model of bone metastasis from prostate cancer. The resultant liposomes were characterized in terms of size, morphology, zeta potential, stability, drug encapsulation percentage and loading efficiency, and drug release. Compared with free cisplatin and cRGDyk-free liposomes, cRGDyk conjugated liposomes showed significantly higher cellular uptake and higher cytotoxicity of loaded cisplatin, as evidenced by in vitro cell experiments. In vivo results revealed that free cisplatin and free cRGDyk could relieve tumor-induced pain but had no contributions to tumor regression and overall survival improvement. cRGDyk-free liposomal drug system with prolonged blood circulation time could accumulated in the tumor sites in the bone through enhanced permeability and retention (EPR) effects and however, did not exhibit desirable therapeutic efficacy superior to free cisplatin and free cRGDyk. This strongly suggested that ERP effects were not effective in treating metastases. By taking advantages of targeted drug delivery and synergistic antitumor activity of cRGDyk and loaded cisplatin, cRGDyk conjugated liposomal drug system could inhibit osteoclastic and osteoblastic bone lesions, relieve pain, and improve overall survival. Inspired by their enhanced therapeutic efficacy and low organ toxicity, cRGDyk conjugated liposomes could serve as an effective drug system for targeted and synergistic therapy of bone metastases.

Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer.

BackgroundCastration resistant prostate cancer (CRPC) is a leading cause of cancer-related deaths in men. The primary cause of mortality and morbidity in patients is bone metastases and remodeling resulting in osteoblastic and osteolytic lesions. Recently, cabozantinib, a multi-kinase inhibitor (VEGFR2 and c-MET inhibitor), was shown to have efficacy on bone lesions in patients. In this study we tested multi-kinase inhibitors: axitinib (VEGFR inhibitor) and crizotinib (c-MET inhibitor) in a combination trial in mice models.MethodsVCaP-Luc cells were grown as subcutaneous implants in intact and castrated NOD-SCID-gamma (NSG) mice to confirm the androgen dependency. For bone metastasis model two cohorts of NSG mice (castrated and intact) received orthotopic injection of VCaP-Luc cells into the bone marrow cavity of left tibia. Mice were monitored weekly for tumor growth using bioluminescence imaging. Animals were randomized into 4 groups based on the tumor bioluminescence signal: vehicle, crizotinib alone, axitinib alone, crizotinib and axitinib in combination. Animals were imaged weekly by in vivo 2-D X-ray imaging to monitor bone remodeling. At the end of the study animals were euthanized and both tibias were extracted for ex vivo high-resolution 3-D micro-computed tomography (μCT) imaging.ResultsSubcutaneous model showed that androgen stimulation may be helpful but not essential for the growth of VCaP-Luc cells. VCaP-Luc cells grown intra-tibially in intact animals caused extensive remodeling of bone with mixed osteoblastic (bone formation) and osteolytic (bone matrix dissolution) lesions. The osteoblastic lesions were predominant and at times extended beyond the tibial shaft into the surrounding tissue. In contrast, only osteolytic lesions were prominent throughout the study in castrated animals. Treatment with crizotinib alone reduced the osteolytic lesions in castrated animals. Axitinib alone reduced the osteoblastic lesions in the intact animals. Combination therapy with axitinib and crizotinib remarkably inhibited the tibial remodeling by VCaP-Luc cells which resulted in a significant reduction of both osteoblastic and osteolytic lesions.ConclusionOur data show that combined inhibition of c-MET and VEGFR can be beneficial for treatment of metastatic bone disease in CRPC and that the drugs act on two different stages of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-742) contains supplementary material, which is available to authorized users.

Abstract 1: Interaction of prostate cancer cells with tumor microenvironment promotes EMT and DTCs activation

Abstract Metastasis causes high mortality in malignancies, which includes prostate cancer (PCa), breast cancer, lung cancer and other cancer types. PCa cells, for example, frequently metastasize to bone resulting in a mixture of osteoblastic and osteolytic lesions. There are currently no effective treatments proven to cure PCa skeletal metastases. Accumulating data has suggested that cancer cells undergo epithelial-to-mesenchymal transition (EMT) to initiate tumor progression. Recent evidence has addressed a link between EMT and activation of disseminated tumor cells (DTCs) that are located in bone marrow and called “sleeping cells” when they are inactive state. However, there is lack of studies regarding direct evidence of localized PCa cells occurring EMT and DTCs activation when tumor cells interact with microenvironment. In this study, we first generated luciferase labeled PCa cells (PC3-luc and C4-2B-luc), and implanted the cells subcutaneously into nude mice. Tumor growth was monitored by in vivo bioluminescense imaging and tumor volume was measured twice a week. We found that tumor volumes were at heterogeneous levels. Then, the tumors were removed, exercised, and digested ex vivo to generate single cell suspension (we named the cells as PC3-lucsc and C4-2B-lucsc), and the cells were subcutaneously re-injected into nude mice. We observed those cells grew faster than that of parental cells and enhanced neo-vessel formation. We compared the differences of gene and protein expressions between PC3-lucand PC3-lucsc cells and found that hallmarkers of EMT, for example vimentin, slug and ZEB2 were expressed at higher levels in PC3-lucsc compared to PC3-luccells. Accordingly, production of E-cadherin and β-catenin was significantly decreased in PC3-lucsc cells. Angiogenesis markers, including VEGFR2, VEGFR3, MCP-3, MCP-4, I-TAC, I309, uPAR, GCP-2 and GROα, were also increased in PC3-lucsc cells using antibody array. Interestingly, CCL2 was significantly increased in PC3-lucsc cells comparing to the parental cells. We finally flushed out bone marrow and we were able to detect DTCs by RT-PCR and successfully isolated DTCs by Magnetic Activated Cell Sorting (MACS), in addition to confirmation of DTCs by immunohistochemical staining. This is the first report showing that interaction of PCa cells with tumor microenvironment promotes EMT and DTCs activation. The current study may provide potential therapeutic targets and diagnostic markers in PCa progression. Supported by NSF projects 81171993 and 81272415; NSF key project 81130046. Citation Format: Junlin Shi, Yudui Xia, Qiong Song, Xiaolin Zhou, Atsushi Mizokami, Evan Keller, Jian Zhang, Yi Lu. Interaction of prostate cancer cells with tumor microenvironment promotes EMT and DTCs activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1. doi:10.1158/1538-7445.AM2014-1

Abstract 3198: Extract from Scutellaria baicalensis Georgi inhibits prostate cancer growth in bone

Abstract Prostate cancer (PCa) frequently metastasizes to bone forming predominantly osteoblastic lesions with underlined osteolytic components. Because current therapies are generally ineffective in PCa skeletal metastases, patients seek alternative medicines such as herbal medicines, which have been used for many centuries in Asian countries. The purpose of this study was to identify Chinese herbal medicines that may be effective in PCa skeletal metastasis. We first screened 130 Chinese herbs (ethanol extracts) for anti-proliferation effects by non-radioactive cell proliferation assay in LNCaP and C4-2B PCa cells. We found five extracts with anti-proliferation activity including extract from Scutellaria baicalensis Georgi (Huang Qin, HQ), which had the strongest effect. We next evaluated HQ's ability to induce apoptosis of LNCaP and C4-2B cells. HQ, in a dose-dependent manner, induced apoptosis of both cell lines based on TUNEL assay. In addition, HQ induced apotosis-related gene caspase-3 and suppressed bcl-2 expressions in both cell lines. Therefore, we tested if HQ (1mg per mouse three times a week for 8 weeks intraperitoneally) could diminish establishment of skeletal metastases in mice. We injected C4-2B cells into tibia of SCID mice. The animals were randomized into two groups to receive either HQ or vehicle only (n=8/group). At 8 weeks post-tumor injection, mice were sacrificed and tumor establishment in the skeleton was determined using radiography, dual energy x-ray absorptiometry and histology. Radiographic and histological lesions were present in 7/8 vehicle-treated mice and in 6/8 HQ-treated mice. However, the radiographically- and histologically-determined areas of the tumors in the HQ-treated mice were approximately 47% that of the vehicle-treated animals. We conclude that HQ has efficacy for inducing PCa cells apoptosis in vitro and has the ability to diminish growth of PCa in murine bone. Supported by NSF key project 81130046, NSF projects 81171993 and 81272415. Citation Format: Chaoqian Li, Hongwei Guo, Yi Lu, Jinlu Dai, Evan Keller, Jian Zhang. Extract from Scutellaria baicalensis Georgi inhibits prostate cancer growth in bone. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3198. doi:10.1158/1538-7445.AM2014-3198

Abstract 3595: Mesenchymal stem cells play crucial roles in the generation of osteogenic prostate to bone metastases

Abstract The skeleton is a common target for prostate metastases. In bone, prostate cancer cells induce extensive bone formation/osteogenesis by promoting osteoblast differentiation. This results in painful bony lesions that are incurable. The precise mechanisms through which prostate cancer cells induce bone formation are not well understood. Analysis of human and mouse specimens of prostate to bone metastasis demonstrate the presence of MSCs (smooth muscle actin positive). Given that MSCs are precursors of osteoblasts, we hypothesizes that MSC recruitment to the bone microenvironment would contribute to the formation of osteoblastic lesions and enhance tumor progression. Methodology: Using in-vitro and in-vivo studies we aim to elucidate the effects of MSC's on prostate tumor progression in bone. To determine the effect of the MSCs on the growth of the prostate cancer cells, mouse MSCs were directly co-cultured at various ratios with luciferase expressing PAIII prostate cancer cells for 24-96 hours. In-vivo, mice were intratibially inoculated with either PAIIIs, PAIIIs/MSCs (1:1), or MSCs (n=8/group, 104 total cells in 20µl). Tumor growth was measured over 15 days using luminescence imaging. Subsequently the tibias were collected for x-ray, micro CT, and histological analysis. Results: In-vitro MSCs inhibited the growth of the PAIII cells from 24 to 96 hours. At a 1:1 ratio, MSCs inhibited PAIII growth by up to 55% at 96 hours (p<0.05). A cleaved caspase 3 western blot of the lysates of PAIIIs treated with MSC CM provides evidence that soluble factors from the MSCs are inducing caspase dependent apoptosis. Consistent with our in vitro observations, we observed in vivo that at day 11, the average tumor size in the PaIII/MSC (1:1 ratio) group was 57.7% significantly smaller than the PAIII group alone (p<0.05). However by day 15 the tumors were growing at comparable rates. Tumor bearing tibias were X-rayed and an overall decrease in tumor-induced osteolysis was observed between the PAIII/MSC and PAIII groups. μCT scans of tumor bearing bones show an increase in bone volume in bones injected with MSCs alone and PaIII/MSCs when compared to PAIIIs, a finding that was consistent with X-ray and hisotmorphometrical data. Conclusions: In conclusion we have found that in-vitro and in-vivo MSCs have an early inhibitory effect on the growth of prostate tumor cells. This impact on growth is coupled to an apparent decrease in tumor-induced osteolysis and increase in osteogenesis. Currently, we are examining 1) the impact of the MSCs on tumor-induced osteogenesis and 2) identifying the MSC derived factors that are inhibiting prostate cancer growth. Understanding the role of MSCs in the prostate tumor-bone microenvironment will lead to the identification of new therapeutic targets to treat the disease. Citation Format: Jeremy Jonathan Mcguire, Gemma Shay, Leah Cook, Jeremy Frieling, Conor Lynch. Mesenchymal stem cells play crucial roles in the generation of osteogenic prostate to bone metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3595. doi:10.1158/1538-7445.AM2014-3595

Femur chondrosarcoma misdiagnosed as acute knee arthritis and osteomyelitis—Further developing a hitherto unreported complication of tumor embolic ischemic ileal perforation after arthroscopic lavage

The differentiation between osteomyelitis and bone tumor may be difficult due to their overlapping clinical and radiological features. A 25-year-old lady presented with left knee pain and joint effusion associated with redness and hotness. A sub-optimally taken plain radiograph showed mixed osteolytic and osteoblastic lesion in the left lower femur with surrounding soft tissue swelling. Since the clinical diagnosis was acute osteomyelitis and arthritis, arthroscopic lavage was performed as a diagnostic and therapeutic procedure. The removed loose bodies and fibrinous tissue showed pathological features suspicious of chondrosarcoma. Subsequent MRI revealed an infiltrative tumor eroding through the cortex and joint cartilage. En bloc excision of the left lower femur, upper tibia including the knee joint and patella was performed, and the final diagnosis was grade 2 chondrosarcoma. The patient developed bilateral pulmonary metastasis 33 months after operation. Five months later, she suffered from a hitherto undescribed complication of ischemic perforation of the terminal ileum secondary to tumor embolic arterial obstruction with no macroscopic intestinal or peritoneal tumor deposit. The patient developed multiple brain metastases and died 43 months after initial presentation.Our case illustrates that malignant bone tumor as a differential diagnosis of acute osteomyelitis and arthritis merits recognition and exclusion before arthroscopic lavage, which may enhance tumor dissemination and in our patient results in embolic ischemic ileal perforation.

Runx2-Smad signaling impacts the progression of tumor-induced bone disease.

Runx2, a master regulator of osteogenesis, is abnormally expressed in advanced prostate cancer. Here, we addressed Runx2 contribution to formation of prostate cancer-related osteolytic and osteoblastic bone lesions by mediating TGFβ/BMP signaling through direct interaction with Smads. Further, we examined involvement of the Runx2-Smad complex in mediating tumor growth and distal metastasis. To identify Runx2-Smad-specific mechanisms of prostate tumor activity in bone, we generated PC3 prostate cancer cell lines expressing Runx2-WT or one of two mutant proteins (Runx2-HTY and Runx2-ΔC) that each disrupt the Runx2-Smad interaction, either directly through a point mutation or by deletion of the functional C-terminus, respectively. Intratibial tumors generated from these cells revealed that Runx2-WT-expressing cells resulted in predominantly osteolytic disease, whereas cells expressing mutant proteins exhibited tumors with mixed osteolytic/osteoblastic lesions. Extent of bone loss and woven bone formation was assessed by radiography and micro-computed tomography. Bioluminescent imaging showed the presence of labeled prostate cancer cells in the lung at the latest time point examined, with Runx2-WT group exhibiting increased incidence of tumor cells in lung. Notably, disruption of the Runx2-Smad interaction significantly reduced incidence and size of lung tumors. Altered expression of Runx2 target genes involved in invasion, growth, adhesion and metastasis supported our findings. Thus, our studies demonstrate that Runx2 in prostate cancer cells plays a significant role in intratibial prostate cancer-related tumor growth and bone loss through mechanisms mediated by the Runx2-Smad signaling pathway. This work expands upon the potential importance of Runx2 as a therapeutic target in cancer.

Comparison of combined 18 F-FDG and 18 F-NaF PET/CT vs. 18 F-FDG PET/CT imaging in initial metastatic workup in cases of locally advanced breast cancer (LABC)

Background: The addition of 18F-FDG PET to the standard work-up of patients with LABC may lead to the detection of unexpected distant metastases of which skeleton is the most common site. 18F-FDG has limitations in detecting osteoblastic malignant skeletal lesions. Bone scintigraphy (with 99mTc-MDP of 18F-NaF) is the routine imaging modality for the diagnosis of osteoblastic skeletal metastases. We combined both the 18F-FDG and 18F-NaF PET/CT into a single study to examine its role in detecting skeletal metastases.

A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease

Radium-223 dichloride (radium-223) mimics calcium and emits high-energy, short-range alpha-particles resulting in an antitumor effect on bone metastases. This open-label, phase IIa nonrandomized study investigated safety and short-term efficacy of radium-223 in breast cancer patients with bone-dominant disease. Twenty-three advanced breast cancer patients with progressive bone-dominant disease, and no longer candidates for further endocrine therapy, were to receive radium-223 (50 kBq/kg IV) every 4 weeks for 4 cycles. The coprimary end points were change in urinary N-telopeptide of type 1 (uNTX-1) and serum bone alkaline phosphatase (bALP) after 16 weeks of treatment. Exploratory end points included sequential 18F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) to assess metabolic changes in osteoblastic bone metastases. Safety data were collected for all patients. Radium-223 significantly reduced uNTX-1 and bALP from baseline to end of treatment. Median uNTX-1 change was −10.1 nmol bone collagen equivalents/mmol creatinine (−32.8 %; P = 0.0124); median bALP change was −16.7 ng/mL (−42.0 %; P = 0.0045). Twenty of twenty-three patients had FDG PET/CT identifying 155 hypermetabolic osteoblastic bone lesions at baseline: 50 lesions showed metabolic decrease (≥25 % reduction of maximum standardized uptake value from baseline) after 2 radium-223 injections [32.3 % metabolic response rate (mRR) at week 9], persisting after the treatment period (41.5 % mRR at week 17). Radium-223 was safe and well tolerated. Radium-223 targets areas of increased bone metabolism and shows biological activity in advanced breast cancer patients with bone-dominant disease.

MP31-10 THE MOLECULAR SIGNATURE OF THE STROMA RESPONSE IN OSTEOBLASTIC BONE METASTASIS REVEALS ENRICHMENT IN HAEMATOPOIETIC STEM CELL NICHE COMPONENTS

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2014MP31-10 THE MOLECULAR SIGNATURE OF THE STROMA RESPONSE IN OSTEOBLASTIC BONE METASTASIS REVEALS ENRICHMENT IN HAEMATOPOIETIC STEM CELL NICHE COMPONENTS Janine Hensel, Berna Özdemir, Chiara Secondini, Antoinette Wetterwald, Ruth Schwaninger, Achim Fleischmann, Wolfgang Raffelsberger, Olivier Poch, Mauro Delorenzi, Ramzi Temanni, Gabri van der Pluijm, Marco G. Cecchini, and George N. Thalmann Janine HenselJanine Hensel More articles by this author , Berna ÖzdemirBerna Özdemir More articles by this author , Chiara SecondiniChiara Secondini More articles by this author , Antoinette WetterwaldAntoinette Wetterwald More articles by this author , Ruth SchwaningerRuth Schwaninger More articles by this author , Achim FleischmannAchim Fleischmann More articles by this author , Wolfgang RaffelsbergerWolfgang Raffelsberger More articles by this author , Olivier PochOlivier Poch More articles by this author , Mauro DelorenziMauro Delorenzi More articles by this author , Ramzi TemanniRamzi Temanni More articles by this author , Gabri van der PluijmGabri van der Pluijm More articles by this author , Marco G. CecchiniMarco G. Cecchini More articles by this author , and George N. ThalmannGeorge N. Thalmann More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.919AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In both primary and metastatic tumors cancer cell survival and growth strongly depend on stromal support. Prostate cancer (PCa) is highly osteotropic and preferentially induces osteoblastic lesions. The molecular cues responsible for survival/growth of osteoinductive cancer cells by the bone stroma are not fully characterized. METHODS We analyzed the stroma transcriptome in response to human osteoinductive PCa cells (VCaP and C4-2B) xenografted in immunocompromised mice. Species-specific cDNA-microarrays (Affymetrix) could successfully dissect the stroma (mouse) from the cancer cell (human) transcriptome. This consisted of 914 stromal genes differentially regulated in VCaP and/or C4-2B xenografts and referred as the osteoblastic bone metastasis-associated stroma transcriptome (ObBMST). Most likely this contains a universal, tissue- and cancer type-independent, response. Therefore, to define the bone-specific fraction of this signature, we subtracted publicly available gene sets representing stroma genes differentially regulated in inflammation/wound healing and in primary, non-osteotropic cancers (esophageal, gastric, pancreatic and colon cancer). The remaining list still shared genes differentially expressed in publicly available stroma signatures derived from primary breast and prostate cancer and these were also subtracted. RESULTS The functional categorization of the top 86 genes in the remaining signature (“Core ObBMST”) revealed that 13 (15%) were encoding components of the haematopoietic stem cell- (HSC-) niche. RT-qPCR validation with mouse specific probes confirmed the differential expression of three representative HSC-niche genes (Ptn, Epha3 and Slit3) in experimental, osteoblastic bone metastasis. CONCLUSIONS This investigation reports for the first time stimulated gene expression of HSC-nice components as a relevant part of the stromal response in osteoblastic bone metastasis. The HSC-niche components revealed by this study are candidate to be also essential constituents of bone/bone marrow metastatic niche specifically supporting survival and growth of osteoinductive PCa cells. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e326 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Janine Hensel More articles by this author Berna Özdemir More articles by this author Chiara Secondini More articles by this author Antoinette Wetterwald More articles by this author Ruth Schwaninger More articles by this author Achim Fleischmann More articles by this author Wolfgang Raffelsberger More articles by this author Olivier Poch More articles by this author Mauro Delorenzi More articles by this author Ramzi Temanni More articles by this author Gabri van der Pluijm More articles by this author Marco G. Cecchini More articles by this author George N. Thalmann More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Fully automated shape model positioning for bone segmentation in whole-body CT scans

Analysing osteolytic and osteoblastic bone lesions in systematically affected skeletons, e.g. in multiple myeloma or bone metastasis, is a complex task. Quantification of the degree of bone destruction needs segmentation of all lesions but cannot be managed manually. Automatic bone lesion detection is necessary. Our future objective is comparing modified bones with healthy shape models. For applying model based strategies successfully, identification and position information of single bones is necessary. A solution to these requirements based on bone medullary cavities is presented in this paper.Medullary cavities are useful for shape model positioning since they have similar position and orientation as the bone itself but can be separated more easily. Skeleton segmentation is done by simple thresholding. Inside the skeleton medullary cavities are segmented by a flood filling algorithm. The filled regions are considered as medullary cavity objects. To provide automatic shape model selection, medullary cavity objects are assigned to bone structures with pattern recognition. To get a good starting position for shape models, principal component analysis of medullary cavities is performed. Bone identification was tested on 14 whole-body low-dose CT scans of multiple myeloma patients.Random forest classification assigns medullary cavities of long bones to the corresponding bone (overall accuracy 90%). Centroid and first principal component of medullary cavity are sufficiently similar to those of bone (mean centroid difference 21.7 mm, mean difference angle 1.54° for all long bones of one example patient) and therefore suitable for shape model initialization.This method enables locating long bone structures in whole-body CT scans and provides useful information for a reasonable shape model initialization.