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Introduction: Solitary cutaneous reticulohistiocytosis represents a rare form of benign monocyte/macrophage proliferation. On routine histology, these lesions are typically described as large cells with cytoplasm showing ground glass appearance and giant cells. They grow up to 1 cm in size with rare cases exceeding this size. Case Report: This case report of a 28-year-old male demonstrated a nodule of reticulohistiocytosis measuring 2.2 cm in size. Microscopic features showed a well-demarcated nodule in the dermis with large histiocytes with ground-glass eosinophilic cytoplasm, giant cells, and foamy macrophages in a background of mixed inflammatory cells. Immunohistochemical staining showed positive staining for vimentin, CD68, CD31, with focal and patchy positivity for S100, CD43, and CD45 and negative staining for CD1a, langerin, CD21, CD23, CD30, CD34, ERG, D2-40, AE1/AE3, epithelial membrane antigen (EMA), smooth muscle actin (SMA), myogenin, desmin, SOX10, HMB-45, tyrosinase, and MelanA. Conclusion: The microscopic and immunohistochemical findings are characteristic of this entity but it is important to recognize for proper management and differentiation from other malignant lesions.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumour-like fibro-osseous lesion in the neuraxis including the spine. It is diagnosed by the presence of the following histological features: granular amorphous to chondromyxoid fibrillary cores with calcification/ossification, peripheral palisading of spindle to epithelioid cells, variable fibrous stroma, and foreign body reaction with multinucleated giant cells, as well as positive NF-L immunostaining. Spinal CAPNON is sometimes named as tumoural calcinosis that is tumour-like dystrophic calcification usually in the periarticular tissue and also described in calcified synovial cyst (CSC). We examined clinical, radiological and pathological features of five spinal CAPNONs and 21 spinal CSCs including three recurrent lesions. The results demonstrated some radiological and pathological overlaps between these two entities, as well as distinct features of each entity to be diagnosed. All CAPNONs showed the diagnostic histological features with NF-L positivity mainly in lesion cores and variable CD8+ T-cells. In contrast, CSCs exhibited the synovial lining and variable degenerative/reactive changes with some CAPNON-like features, but mostly no to occasionally limited NF-L positivity and less CD8+ T-cells with statistically significant differences between groups of CAPNONs and CSCs. Four CSCs contained CAPNON-like foci with the CAPNON diagnostic features including prominent NF-L positivity, and some transitional features from CSC to CAPNON. As the pathogenesis of CAPNON is likely reactive/degenerative in association with an inflammatory/immunological process involving NF-L protein deposition, our findings suggest the link between spinal CAPNON and CSC, with possible transition from CSC to CAPNON or CAPNON developing in reaction to CSC.

Background: The role of denosumab in patients with resectable giant cell tumour of bone remains unclear. We asked the following research question: for patients (aged ≥ 12 years) with resectable giant cell tumour of bone, what are the benefits and harms of denosumab compared with no denosumab in terms of (1) facilitation of surgery (operative time, blood loss), (2) disease recurrence, (3) pain control, (4) disease stability, and (5) adverse effects (e.g., malignant transformation, osteonecrosis of jaw, atypical femur fracture)? One previous systematic review addressed only one outcome—disease recurrence. Therefore, we undertook this new systematic review to address the above five outcomes. Methods: MEDLINE, EMBASE, PubMed, and Cochrane Database of Systematic Reviews databases were searched on June 30, 2020. Results: This systematic review included one previous systematic review and five comparative studies. Due to poor quality, non-randomized studies fraught with selection bias, it is difficult to determine if a significant difference exists in the outcomes for surgical giant cell tumour of bone with perioperative denosumab. There were no reported cases of adverse effects from denosumab. Conclusion: To date, there is insufficient evidence to understand the value of denosumab in the perioperative setting in patients with giant cell tumour of bone.

Background:Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like lesion with unknown pathogenesis. It is likely under-reported due to diagnostic challenges including the nonspecific radiographic features, lack of diagnostic markers, and often asymptomatic nature of the lesions.Methods:We performed detailed examination of 11 CAPNON specimens diagnosed by histopathology, with the help of electron microscopy and immunohistochemistry.Results:Electron microscopy revealed the presence of fibrillary materials consistent with neurofilaments. In addition to some entrapped axons at the periphery of CAPNONs, we discovered that all specimens stained positive for neurofilament-light (NF-L) within the granular amorphous cores, but not neurofilament-phosphorylated (NF-p). CAPNONs also showed variable infiltration of CD8+ T-cells and a decreased ratio of CD4/CD8+ T-cells, suggesting an immune-mediated process in the pathogenesis of CAPNON.Conclusion:NF-L and CD4/CD8 immunostains may serve as diagnostic markers for CAPNON and shed light on its pathogenesis.

Chondrosarcomas are a diverse group of malignant cartilaginous matrix-producing neoplasms. Conventional chondrosarcomas are a continuum of disease based on the biologic activity of the tumor. The tumors range from the relatively biologically benign low-grade tumors or intermediate atypical cartilaginous tumors (ACTs), to malignant, aggressive high-grade tumors. The clinical presentation, radiographic and pathologic findings, treatments and outcomes vary significantly based on the histologic grade of the tumor. Chondrosarcomas present a diagnostic dilemma, particularly in the differentiation between high- and intermediate-grade tumors and that of low-grade tumors from benign enchondromas. A multidisciplinary team at a tertiary sarcoma centre allows for optimal care of these patients.

This paper focuses on business continuity management in organizations that use modern e-business technologies: the Internet, mobile computing, e-services, and virtual infrastructure. The aim is to make the shift from traditional Business Continuity Management (BCM) towards ?e-Business Continuity Management? (e-BCM) suitable for modern technological environments. We have defined a comprehensive framework for the implementation of an adaptive e-BCM adjustable to changes in the business environment. The framework consists of practical steps for defining elements of a business continuity management system: business impact analysis, risk assessment, and a business continuity plan. We have implemented and evaluated the framework within three financial organizations. The key finding is that Business Impact Analysis and the continual improvement of the Business Continuity Management System are the driving factors for the effective establishment of an adaptive e-BCM. The proposed framework is general, and can be applied to any organization that uses modern e-business technologies.

Synovial sarcomas (SS) represent a unique subset of soft tissue sarcomas (STS) and account for 5–10% of all STS. Synovial sarcoma differs from other STS by the relatively young age at diagnosis and clinical presentation. Synovial sarcomas have unique genomic characteristics and are driven by a pathognomonic t(X;18) chromosomal translocation and subsequent formation of the SS18:SSX fusion oncogenes. Similar to other STS, diagnosis can be obtained from a combination of history, physical examination, magnetic resonance imaging, biopsy and subsequent pathology, immunohistochemistry and molecular analysis. Increasing size, age and tumor grade have been demonstrated to be negative predictive factors for both local disease recurrence and metastasis. Wide surgical excision remains the standard of care for definitive treatment with adjuvant radiation utilized for larger and deeper lesions. There remains controversy surrounding the role of chemotherapy in the treatment of SS and there appears to be survival benefit in certain populations. As the understanding of the molecular and immunologic characteristics of SS evolve, several potential systematic therapies have been proposed.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like lesion with unclear pathogenesis. Collision lesions of CAPNONs with neoplasms are occasionally reported. In this article, we report the first case of collision lesions between CAPNON and rheumatoid nodules (RNs) in a patient with systemic lupus erythematosus. The patient was a 51-year-old female who presented with lower back pain and subsequently a lower back mass over 2 years. Spinal magnetic resonance imaging demonstrated a heterogeneous, partially calcified mass centered in the L3-4 paravertebral regions. A biopsy of the mass was diagnostic of CAPNON. As the mass grew over the following 5 months, it was resected en bloc. Its pathological examination revealed collision lesions of RNs at different histopathological stages and CAPNON lesions, and transitional lesions exhibiting combined RN and CAPNON features, with immune cell infiltrates. Our findings provide new evidence for an immune-mediated reactive process and insights into the pathogenies of CAPNON.

Anastomosing hemangioma (ah) is a rare subtype of primary vascular tumour that can, clinically and radiologically, present similarly to malignant renal tumours such as renal cell carcinoma (rcc) and angiosarcoma. Rarely seen in the genitourinary system, the ah we report here occurred in a 40-year-old male patient diagnosed initially with rcc based on imaging and successfully treated by laparoscopic left radical nephrectomy, with adrenal sparing and perihilar lymph node dissection. The pathologic diagnosis of ah can be challenging on small biopsy specimens, we therefore opine that it is appropriate to excise these lesions to facilitate diagnosis and definitively exclude common renal cancers. However, in this review, we describe some radiologic and pathologic distinctions between ah and malignant tumours.

A rare case of intra-articular solitary fibrous tumor of the knee in an 84-year-old man is presented. This case report illustrates that solitary fibrous tumor should be included in the extended differential diagnosis of an intra-articular soft tissue mass.

Introduction. Mazabraud’s Syndrome is a rare condition that is defined by the presence of fibrous dysplasia lesions in the bone and intramuscular myxomas in the soft tissue. Malignant transformation, in the setting of Mazabraud’s Syndrome, of the fibrous dysplasia lesions into a sarcomatous neoplasm occurs in less than 1% of cases—with only six previously reported cases. Case Presentation. Here, we present a 62-year-old Caucasian female who developed an osteosarcoma in a fibrous dysplasia lesion of the proximal femur in the background of Mazabraud’s Syndrome. The patient was treated with wide excision and endoprosthetic reconstruction. She declined adjuvant chemotherapy. She is alive without evidence of disease one-year postoperatively. Conclusion. Patients with Mazabraud’s Syndrome remain at low risk for malignant transformation. However, close monitoring of asymptomatic patients with this condition for radiographic changes in their lesions and/or clinical symptoms is recommended.

Aims To make recommendations on the indications for molecular testing regarding the diagnosis, prediction of prognosis, and treatment selection in adult patients with s oft tissue sarcomas (STS) excluding gastrointestinal stromal tumour. Materials and methods This guideline was developed by the Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) and the Sarcoma Disease Site Group (DSG). The medline, embase, and Cochrane Library databases, main guideline websites, abstracts of relevant annual meetings, and PROSPERO databases were searched (January 2005 to October 2016). Internal and external reviews were conducted, with final approval by the PEBC and the Sarcoma DSG. Results Based on the available evidence, we made three S trong Recommendations, 14 Recommendations, 9 Qualified Statements, and seven No Recommendations. The three Strong Recommendations include: i) MDM2 amplification by fluorescence in situ hybridization (FISH) is recommended as a sensitive and specific test to differentiate patients with atypical lipomatous tumour/well-differentiated liposarcoma, or dedifferentiated liposarcoma from lipoma or other STS in the differential diagnosis; ii) SS18 (SYT) break-apart by FISH or SS18-SSX (SYT-SSX) fusion by reverse transcription-polymerase chain reaction is recommended as a sensitive and specific test to differentiate patients with synovial sarcoma from other sarcomas; iii) CTNNB1 S45F mutation by polymerase chain reaction is recommended as a prognostic factor for poor recurrence-free survival in patients with desmoid tumours. Conclusion This guideline may serve as a framework for the thoughtful implementation of molecular studies at cancer centres and other jurisdictions. Some of the recommendations may need to be updated when new evidence appears in the future.

Breast cancer cells release the signalling molecule glutamate via the system xC− antiporter, which is upregulated to exchange extracellular cystine for intracellular glutamate to protect against oxidative stress. Here, we demonstrate that this antiporter is functionally influenced by the actions of the neurotrophin nerve growth factor on its cognate receptor tyrosine kinase, TrkA, and that inhibiting this complex may reduce cancer-induced bone pain via its downstream actions on xCT, the functional subunit of system xC−. We have characterized the effects of the selective TrkA inhibitor AG879 on system xC− activity in murine 4T1 and human MDA-MB-231 mammary carcinoma cells, as well as its effects on nociception in our validated immunocompetent mouse model of cancer-induced bone pain, in which BALB/c mice are intrafemorally inoculated with 4T1 murine carcinoma cells. AG879 decreased functional system xC− activity, as measured by cystine uptake and glutamate release, and inhibited nociceptive and physiologically relevant responses in tumour-bearing animals. Cumulatively, these data suggest that the activation of TrkA by nerve growth factor may have functional implications on system xC−-mediated cancer pain. System xC−-mediated TrkA activation therefore presents a promising target for therapeutic intervention in cancer pain treatment.

Aim To describe the radiologic and corresponding histopathologic features of calcifying pseudoneoplasms of the neural axis. Methods Two cases of calcifying pseudoneoplasm of the neural axis were retrospectively reviewed. The first case was documented in a 64-year-old woman, who presented with lower back pain with radiation to her left leg. The second case was documented in a 70-year-old man, who presented with headaches. Medical records, radiologic and histologic findings, and related literature were reviewed. Results In the first case, imaging of the lumbar spine revealed a 3.8 × 2.2-cm calcified lesion at the level of vertebrae L5 and S1. A subsequent excision exposed an extradural lesion at L5. Histopathologic examination showed amorphous and granular calcifying material with occasional fibrohistiocytic and giant cell reaction, consistent with calcifying pseudoneoplasm of the neural axis. In the second case, imaging of the head revealed a 2.4 × 2.6-cm well-circumscribed, lobulated, calcified lesion within the basal frontal lobe. Subsequent resection exposed an intradural mass with a nodular arrangement of amorphous and granular calcifying material associated with fibrohistiocytic and giant cell reaction. Both patients had a favorable postoperative course and failed to show any clinical or radiologic sign of recurrence. Conclusion Calcifying pseudoneoplasm of the neural axis is an uncommon condition with an excellent prognosis but is often misdiagnosed due to its nonspecific clinical presentation and varied findings on radiology.

Background The molecular pathogenesis of many forms of soft tissue sarcomas (STS) have been rigorously characterized in the medical literature, which may be particularly important for the diagnosis and prediction of prognosis in STS. Methods Electronic databases (2005 to October 2016) were searched. Gastrointestinal stromal tumor and pediatric sarcomas were excluded. The eligible individual study’s risk of bias and the quality of aggregate evidence were assessed. Meta-analyses were performed. Results Of 6674 identified articles, 70 were eligible and analyzed, covering 13 types of STS. Meta-analyses showed that the test of detecting MDM2 amplification by fluorescence in situ hybridization was accurate in differentiating atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcoma from benign tumors (N = 971; sensitivity = 95%, 95% confidence interval [CI] 89–98; specificity = 100%, CI 89–100) or from other STS (N = 347; sensitivity = 99%, CI 72–100; specificity = 90%, CI 78–95); that the test of detecting SS18-SSX fusion by reverse transcription polymerase chain reaction (PCR) was accurate in differentiating synovial sarcoma from other STS (N = 532; sensitivity = 93%, CI 85–96; specificity = 99%, CI 96–100). The presence of a CTNNB1 S45F mutation detected by PCR was a risk factor for decreased recurrence-free survival in desmoid tumors (N = 418; hazard ratio from 3.50 [CI 1.51–8.14] to 6.20 [CI 2.24–17.15]). Conclusions Sarcomas are rare cancers whose molecular pathogenesis is becoming increasingly understood. The current evidence demonstrates that molecular analyses are useful in the diagnosis and prediction of prognosis in some STS.

Extraskeletal para-articular osteochondromas of the infrapatellar fat pad are unique soft-tissue tumors whose etiology and clinical history remain poorly understood. We report three cases and a systematic review of the literature. Three females, aged 47, 54, and 70 years, presented with pain and a parapatellar knee mass. All three underwent marginal excision with no complications and no recurrence. In the literature, 32 reports describing 42 cases were identified. Mean age at presentation was 51.1 years (range: 12-75). There were 25 females and 20 males. Seven patients (15.6%) had a history of antecedent trauma. Mean duration of presenting symptoms was 63.9 months (range: 2-300). All patients except for one underwent open excision. Mean follow-up was 14.9 months (range: 3-96). There were no reports of recurrence or malignant transformation. Para-articular extraskeletal osteochondromas of the infrapatellar fat pad have a benign clinical history regardless of whether they are managed by arthroscopic or open marginal excision.

The incidence of renal cell carcinoma (RCC) is steadily rising in Western societies. In the United States, an estimated 58 240 new cases and 13 040 (22.4%) deaths occurred in 2010 (Jemal et al, 2010), whereas worldwide these numbers are estimated at 289 000 new cases and 102 000 (35.3%) deaths per year (Rini et al, 2009). There are several histological forms of RCC, but the vast majority, ∼75%, are clear cell RCC (ccRCC) (Pantuck et al, 2001). Accumulating evidence suggests that dysregulation of energy-sensing pathways, a common feature of several hamartoma syndromes, is also critical in the pathogenesis of RCC (Linehan et al, 2010). The metabolic regulation coordinating the cancer cell's energy demands with its energy-consuming malignant phenotype is largely controlled by the 5′-AMP activated protein kinase (AMPK) via the regulation of the mammalian target of rapamycin (mTOR). The AMPK system acts as an ‘energy checkpoint' (ratio of cellular AMP/ATP) that determines whether cellular energy status is sufficient before the cell commits to a programme of cell growth triggered by the mTOR pathway. There are also indications that AMPK activation in response to low energy status inhibits cell division by affecting DNA replication and mitosis. Specifically, the catalytic α-subunit of AMPK is activated by phosphorylation of Thr172 by one of three upstream kinases: liver kinase B1 (LKB1 or serine/threonine kinase 11 (STK11)), calmodulin-dependent protein kinase kinase-β, or TGF-β-activated-kinase 1 (Viollet et al, 2010). The LKB1 tissue-specific knockout mice revealed that LKB1 mediates AMPK activation in the majority of tissues (Shackelford et al, 2009). Although the major downstream target of LKB1 tumour suppressor is AMPK, LKB1 has at least 12 other substrates, which include members of the AMPK-related protein kinase subfamily, such as MARK1-4 (Lizcano et al, 2004). Activated AMPK turns on catabolic pathways that generate ATP, while inhibiting ATP-consuming processes, such as gluconeogenesis and cell growth. One of the downstream targets of AMPK is the tumour-suppressor protein TSC2 that inhibits mTOR. This has particular significance in RCC (Robb et al, 2007) in which the mTOR pathway is constitutively active. Overall, LKB1-mediated activation of AMPK induces tumour suppression primarily by inhibiting mTOR via activation of TSC2. The implications of attenuated AMPK activation for tumourigenesis have been demonstrated in other RCC subtypes, including hereditary leiomyomatosis RCC, as a result of inactivation of fumarate hydratase (Tong et al, 2011), in type I papillary RCC through altered HGF/Met signalling, and in patients with Birt–Hogg–Dube syndrome who are predisposed to develop chromophobe RCC, as a result of underexpression of folliculin (Linehan et al, 2010). In this study, we hypothesise that attenuated AMPK activation also occurs in ccRCC, the most common form of RCC. We focussed our investigation on LKB1, the key activator of AMPK (Viollet et al, 2010).

Immune thrombocytopenia (ITP) is a common autoimmune disorder characterized by low platelet counts that can lead to bleeding (1). ITP patients typically have no other physical or laboratory findings to confirm the diagnosis; thus, ITP remains a diagnosis of exclusion. Measurements of platelet turnover and antiplatelet antibodies have been examined in ITP patients; however, platelet turnover studies are not easily applied in practice and current platelet autoantibody testing is insensitive (2, 3). The recent introduction of thrombopoietin (TPO) receptor agonists as an effective treatment for ITP has reaffirmed that ITP may be caused by an impairment in platelet production and has refocused attention on abnormalities of bone marrow megakaryocytes (4). Bone marrow examinations in ITP have been investigated in studies dating back several decades. Some investigators have found megakaryocyte numbers to be increased (5–7), while others have found them to be normal (8). Similarly, abnormal megakaryocyte morphology including diminished granularity and decreased nuclear ploidy among other findings were observed by some investigators (9, 10) but not others (11, 12). These discrepancies may have arisen because early studies lacked appropriate methodological tools or as a reflection of the subjective nature of bone marrow reporting. Overall, investigators have reached differing conclusions as to whether bone marrow morphology displays unique features in ITP, and the value of bone marrow examinations in ITP in general. Recent guidelines recommend against bone marrow examinations in typical ITP patients (13); however, the evidence in support of this recommendation was weak. To definitively address the usefulness of bone marrow examinations in patients with ITP, we determined the inter-rater reliability and accuracy of this test based on blinded, independent review of bone marrow specimens by three experienced hematopathologists. The objectives were to determine the agreement between raters and to describe morphological features unique to ITP patients. This study has implications for clinical practice and may shed light on ITP pathogenesis.

Chondrosarcoma is a unique type of bone cancer in that it does not respond to chemotherapy or radiation therapy, and therefore many affected patients die from metastatic disease. Metastasis has been correlated with the upregulation of the matrix metalloproteinase (MMP) family of proteases, which can degrade extracellular components. ETV5 is a transcription factor which has shown to be overexpressed in various types of invasive tumors. We hypothesized that ETV5 regulates MMP2 in human chondrosarcoma with the protease acting as a downstream effector. Gene knock-down of ETV5 in human chondrosarcoma cells reduces MMP2 mRNA expression as well as decreased protein production and significantly decreased MMP2 activity. With plasmid transfected ETV5 upregulation, MMP2 expression is similarly upregulated at the gene expression and protein levels. Data from our bone resorption studies revealed that when a matrix metalloproteinase-2 inhibitor is added to the growth media of chondrosarcoma cells, collagen released from bone chips incubated with the cells decreased by 27%. This data suggests that ETV5 has a significant role in regulating MMP2 expression and therefore matrix resorption in human chondrosarcoma, and thus may be a targetable upstream effector of the metastatic cascade in this cancer.

Giant cell tumor of bone (GCT) is an aggressively osteolytic primary bone tumor that is characterized by the presence of abundant multinucleated osteoclast-like giant cells, hematopoietic monocytes, and a distinct mesenchymal stromal cell component. Previous work in our laboratory has shown that matrix metalloproteinase (MMP)-13 is the principal proteinase expressed by the stromal cells of GCT. The release of cytokines, particularly interleukin-1beta, by the giant cells of GCT acts on stromal cells to stimulate a surge in MMP-13 secretion. The purpose of this study was to determine the bone resorption capabilities of the cellular elements of GCT and the significance of the MMP-13 expression involved in GCT bone resorption. We present a 3-dimensional histomorphometric technique developed to analyze resorption pit depth and yield an accurate measurement of bone resorption with a direct physical view of lacunae on bone slices. In this study, we demonstrate that the mesenchymal stromal cells and the multinucleated giant cells of GCT are independently capable of bone resorption. However, coculture of these 2 cell fractions shows a synergistic increase in bone resorption. In addition, inhibition of MMP-13 reduces resorptive activity of the cells indicating that MMP-13 likely plays an important role in this tumor. This cell-cell cooperation involves giant cell-derived cytokine up-regulation of MMP-13 in the stromal cells, which in turn assists the giant cells in bone resorption. Future research will involve elucidation of the role of cell-cell/matrix communication pathways in bone resorption and tumorigenesis in GCT.

Giant Cell Tumor of bone (GCT) is an aggressively osteolytic and cytokine-rich bone tumor. Previous work in our lab has shown that matrix metalloproteinase-13 (MMP-13) is the principal proteinase expressed by the mesenchymal stromal cells of GCT. The Runx2 transcription factor is known to have a binding site in the MMP-13 promoter region, and we have previously found this transcription factor to be constitutively expressed in GCT stromal cells. The purpose of this study was to determine the role of Runx2 in MMP-13 regulation in GCT stromal cells. Following in vitro stimulation of GCT stromal cells with incremental concentrations of cytokine IL-1beta or TNF-alpha, the level of MMP-13 mRNA expression increased dramatically over 100-fold with a concomitant increase in MMP-13 protein expression. Inhibition of the ERK and JNK signaling pathways inhibited the upregulation of MMP-13 in these cells. Runx2 siRNA knockdown resulted in MMP-13 knockdown, and this effect was amplified following cytokine stimulation. Our study provides the first evidence that Runx2 may play a crucial role in cytokine-mediated MMP-13 expression in GCT stromal cells.

When cancers are present in bone, a number of complex changes occur that can alter the physiology and structure of the skeleton. To properly understand these oncodynamic processes—how the bone changes in response to cancer cell invasion—it is necessary to define the types of cells that are present in normal bone, to explore the main physiological functions of these cells and of the bone itself, and to describe the types of cancers that often grow in bone. To properly characterize the functional and anatomical responses of bone cells, a broader definition of what cell types are present in bone is required. Using a more comprehensive and inclusive definition of bone cells, adaptations that result from cancer cell invasion can be categorized on the basis of the signalled functional and structural changes that occur between all involved cells in the bone environment. These pathological responses will be integrated with what is known about the chemical mediators that may be involved. This analysis of the normal signalling environment in bone and the potential interactions between cell types will help to better characterize the complex oncodynamic processes that can occur when cancer invades bone and disrupts this carefully balanced microenvironment.

Angiosarcoma is a rare high-grade malignant neoplasm with poor clinical outcome and survival rates, occurring most commonly in the skin and soft tissue. It is composed of neoplastic cells that demonstrate endothelial differentiation. The diagnosis of angiosarcoma can be difficult due to its pathohistologic presentation as a poorly differentiated neoplasm with associated secondary changes. We report a case of angiosarcoma of the adrenal gland with concurrent contralateral renal cell carcinoma (RCC) and renal vein thrombus. The presumptive clinical diagnosis was metastatic renal cell carcinoma to the contralateral adrenal gland. Pathohistologic evaluation demonstrated massive hematoma associated with intravascular papillary endothelial hyperplasia (IPEH)-like features. We discuss the pathohistological features used to ascertain a diagnosis of angiosarcoma in the presence of IPEH-like changes and differentiate it from reactive vascular proliferation seen in IPEH (Masson’s tumour).

Breast cancer cells release the signalling molecule glutamate via the system xC- antiporter, which is upregulated to exchange extracellular cystine for intracellular glutamate to protect against oxidative stress. Here, we demonstrate that this antiporter is functionally influenced by the actions of the neurotrophin nerve growth factor on its cognate receptor tyrosine kinase, TrkA, and that inhibiting this complex may reduce cancer-induced bone pain via its downstream actions on xCT, the functional subunit of system xC-. We have characterized the effects of the selective TrkA inhibitor AG879 on system xC- activity in murine 4T1 and human MDA-MB-231 mammary carcinoma cells, as well as its effects on nociception in our validated immunocompetent mouse model of cancer-induced bone pain, in which BALB/c mice are intrafemorally inoculated with 4T1 murine carcinoma cells. AG879 decreased functional system xC- activity, as measured by cystine uptake and glutamate release, and inhibited nociceptive and physiologically relevant responses in tumour-bearing animals. Cumulatively, these data suggest that the activation of TrkA by nerve growth factor may have functional implications on system xC--mediated cancer pain. System xC--mediated TrkA activation therefore presents a promising target for therapeutic intervention in cancer pain treatment.

Background: Giant cell tumor of bone is a primary bone tumor that is treated surgically and is associated with high morbidity in many cases. This tumor consists of giant cells expressing RANK (receptor activator of nuclear factor-κB) and mesenchymal spindle-like stromal cells expressing RANKL (RANK ligand); the interaction of these cells leads to bone resorption. Denosumab is a monoclonal antibody that binds RANKL and directly inhibits osteoclastogenesis. Clinical studies have suggested clinical and histological improvement when denosumab was administered to patients with a giant cell tumor. However, no studies have yet examined the viability and functional characteristics of tumor cells following denosumab treatment. Methods: Specimens were obtained from six patients with a histologically confirmed giant cell tumor. Two of the patients had been treated with denosumab for six months. Primary cultures of stromal cells from fresh tumor tissue were established. Cell proliferation was measured over a two-day time course. The expression of RANKL and osteoprotegerin was analyzed with use of real-time PCR (polymerase chain reaction). Results: Histological specimens from both patients who had completed denosumab treatment showed the absence of giant cells but persistence of stromal cells. Cell proliferation studies indicated that proliferation of stromal cells cultured from clinical specimens following denosumab treatment was approximately 50% slower than that of specimens from untreated patients. The expression of RANKL in the specimens from the treated patients was almost completely eliminated. Conclusions: Once the giant cell tumor tissue was no longer exposed to denosumab, the stromal cells continued to proliferate in vitro, albeit to a lesser degree. However, they also showed almost complete loss of RANKL expression. Clinical Relevance: It is clear that treatment with denosumab only partially addresses the therapeutic need of patients with a giant cell tumor by wiping out the osteoclasts but leaving the neoplastic stromal cells proliferative.

OBJECTIVE: The aim of our study was to evaluate the relationship between the elevated TSH and fracture risk in postmenopausal women with subclinical hypothyroidism for evaluation of individuals with a high risk for osteoporotic fractures. DESIGN: FRAX score calculation (10-year estimated risk for bone fracture) and measurement of bone markers (osteocalcin and beta cross-laps) were performed in 82 postmenopausal women with newly discovered subclinical hypothyroidism (mean age 59.17 +/- 7.07, mean BMI 27.89 +/- 3.46kg/m(2), menopause onset in 48.05 +/- 4.09 years of age) and 51 matched controls (mean age 59.69 +/- 5.72, mean BMI 27.68 +/- 4.66kg/m(2), menopause onset in 48.53 +/- 4.58 years of age) with normal thyroid function. RESULTS: The main FRAX score was significantly higher in the group with subclinical hypothyroidism than in the controls (6.50 +/- 4.58 vs. 4.35 +/- 1.56; p=0.001). Hip FRAX score was significantly higher in the group with subclinical hypothyroidism (1.11 +/- 1.94 vs. 0.50 +/- 0.46; p=0.030). There was no significant difference in bone markers: osteocalcin (23.99 +/- 12.63 vs. 21.79 +/- 5.34 ng/mL; p=0.484) and beta cross-laps (365.76 +/- 184.84 vs. 306.88 +/- 110.73 pg/mL; p=0.21) between the two groups. CONCLUSIONS: Postmenopausal patients with subclinical hypothyroidism, in particular of autoimmune origin, have higher FRAX scores and a thus greater risk for low-trauma hip fracture than euthyroid postmenopausal women. Our results point to the need to monitor postmenopausal patients with subclinical hypothyroidism for avoidance of fractures.

Introduction: Angiosarcoma is a rare, aggressive malignancy that accounts for less than 1% of all sarcomas, characterized by a dismal 5 year survival of 20-30% at best. In striking contrast, atypical vascular lesion (AVL), which typically occurs secondary to radiation, follows for the most part, a benign course. However, debate rages over the true nature of AVL with reports describing both benign and malignant behavior. Further compounding the issue is the fact that overlapping histological features make the important differentiation between AVL and angiosarcoma difficult, especially on limited biopsy specimens. There have been a number of recent studies of c-MYC expression in vascular tumors in relation to this question, yielding varied results. Objectives: This pilot study aimed to investigate c-MYC expression in atypical vascular lesions and angiosarcomas (primary and secondary) to evaluate the clinical utility of c-MYC testing as an adjunct to the histological diagnosis. Methods: A retrospective search for biopsy, resection specimens and internal consult cases with diagnosis of angiosarcoma and/or atypical vascular lesion from January 2008- February 2014 was performed. A total of 32 cases (including controls) obtained after review were stained by dual colour c-MYC copy number probe set. The expression of c-MYC was read by two independent evaluators and final data was collated along with histology findings, follow-up and survival data. Results: c-MYC amplification was found to be a major differentiating factor (p value: 0.00002, 68% sensitivity, 96% specificity) between AVL and angiosarcoma(median c-MYC expression 1.0 vs. 12.14, 95% confidence interval: 0.8-1.9 vs. 9.2-22.3 respectively). The amplification levels of primary (median c-MYC expression:10.9, 95% confidence interval: 3.8-16.6) and secondary angiosarcoma (median c-MYC expression:13.2, 95% confidence interval: 9.0-25.5) were statistically not found to be significantly different (p = 0.07). Although no correlation was found between level of c-MYC amplification and outcome, the study was underpowered to accurately evaluate this relation. Conclusion: Amplification of c-MYC can be used as a reliable ancillary test to differentiate between diagnostically challenging cases of angiosarcoma and AVL. Citation Format: Ipshita Kak, Bekim Sadikovic, Guillaume Pare, Tom Corbett, Snezana Popovic. c-MYC as a differentiating marker between angiosarcoma and atypical vascular lesion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 521.

Chondrosarcoma is a unique type of bone cancer in that it does not respond to chemotherapy or radiation therapy, and therefore many affected patients die from metastatic disease. Metastasis has been correlated with the upregulation of the matrix metalloproteinase (MMP) family of proteases, which can degrade extracellular components. ETV5 is a transcription factor which has shown to be overexpressed in various types of invasive tumors. We hypothesized that ETV5 regulates MMP2 in human chondrosarcoma with the protease acting as a downstream effector. Gene knock-down of ETV5 in human chondrosarcoma cells reduces MMP2 mRNA expression as well as decreased protein production and significantly decreased MMP2 activity. With plasmid transfected ETV5 upregulation, MMP2 expression is similarly upregulated at the gene expression and protein levels. Data from our bone resorption studies revealed that when a matrix metalloproteinase-2 inhibitor is added to the growth media of chondrosarcoma cells, collagen released from bone chips incubated with the cells decreased by 27%. This data suggests that ETV5 has a significant role in regulating MMP2 expression and therefore matrix resorption in human chondrosarcoma, and thus may be a targetable upstream effector of the metastatic cascade in this cancer.

Matrix-metalloproteinase-13 (MMP-13) has been shown to be an important protease in inflammatory and neoplastic conditions of the skeletal system. In particular, the stromal cells of giant cell tumor of bone (GCT) express very high levels of MMP-13 in response to the cytokine-rich environment of the tumor. We have previously shown that MMP-13 expression in these cells is regulated, at least in part, by the RUNX2 transcription factor. In the current study, we identify the expression of the c-Fos and c-Jun elements of the AP-1 transcription factor in these cells by protein screening assays and real-time PCR. We then used siRNA gene knockdown to determine that these elements, in particular c-Jun, are upstream regulators of MMP-13 expression and activity in GCT stromal cells. We conclude that there was no synergy found between RUNX2 and AP-1 in the regulation of the MMP13 expression and that these transcription factors may be independently regulated in these cells.

The benefits of bisphosphonates (BPs) in reducing skeletal-related events (SREs) in patients with bone metastases has mainly been attributed to their potent osteoclast inhibiting effect. However, despite the use of modern systemic anticancer therapy including potent BPs, many patients with bone metastases continue to have SREs. An improved understanding of the fundamental mechanisms of bone destruction allows for further development of appropriate targeted treatments. In this study, archival paraffin-embedded bone metastases specimens from patients with metastatic breast cancer were examined for the presence of osteoclasts, expression of the receptor activator of nuclear factor kappaB (RANK), RANK Ligand (RANKL), osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF). Histological specimens were available for primary breast cancer, lymph node metastases, normal breast and normal bone tissues for comparison. Bone metastasis specimens were available for 20 BP naïve patients and two BP-treated patients. Osteoclasts were significantly increased in the bone metastases of the BP naïve group compared to normal bone. No osteoclasts were detected in the BP-treated group. RANKL was predominantly expressed in osteoblasts and in the stromal elements of metastatic tissue. Conversely, RANK was present in osteoclasts of bone metastases and normal bone, as well as in tumor cells of metastatic lymph nodes and bone metastases. VEGF was strongly expressed in the control bone and bone metastases regardless of BP treatment. In summary, osteoclasts may not be the singular obligatory factor for osteolysis in bone metastases. An increased expression of RANKL in stromal tissue surrounding bone metastases, RANK in osteoclasts and VEGF may serve as future targeted therapies possibly in conjunction with bisphosphonates. The mechanisms for osteoclast expression and the expression of RANKL, RANK, OPG and VEGF merit further prospective analysis, particularly in the context of BP treatment and progressive bone metastases.