Utility of intraoperative magnetic resonance imaging for giant cell tumor of bone after denosumab treatment: a pilot study.

BACKGROUND: Giant cell tumor of bone (GCTB) is an intermediate but locally aggressive neoplasm. Current treatment of high-risk GCTB involves administration of denosumab, which inhibits bone destruction and promotes osteosclerosis. However, denosumab monotherapy is not a curative treatment for GCTB and surgical treatment remains required. Denosumab treatment complicates surgery, and the recurrence rate of GCTB is high (20%-30%). PURPOSE: To examine the utility of intraoperative magnetic resonance imaging (iMRI) for detection and reduction of residual tumor after denosumab treatment and to investigate the utility of iMRI, which is not yet widely used. MATERIAL AND METHODS: We enrolled five patients who received denosumab for a median period of eight months (range 6-12 months). Surgery was performed when the degree of osteosclerosis around the articular surface was deemed appropriate. We performed iMRI using a modified operation table to identify residual tumor after initial curettage and evaluated the rate of detection of residual tumor by iMRI, intraoperative and postoperative complications, exposure time of iMRI, and operation time. RESULTS: Suspected residual tumor tissue was identified in all five cases and was confirmed by histopathology after additional curettage. The rate of detection of residual tumor by iMRI was 100%. Residual tumor was located in sites which were difficult to remove due to osteosclerosis. The iMRI was performed safely and without trouble. During the median follow-up period of 10 months (range 6-24 months), no adverse events or recurrences occurred. CONCLUSION: Intraoperative MRI could contribute to the reduction of residual tumor tissue and it may prevent recurrence of GCTB after denosumab therapy.

Osteosarcoma in patients over 50 years of age: Multi-institutional retrospective analysis of 104 patients.

BACKGROUND: Primary osteosarcoma in elderly patients are rare malignant tumors. Its optimal treatment has not yet been determined. METHODS: This retrospective study included 104 patients aged >50 years with resectable, non-metastatic osteosarcoma treated by the members of the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group. The effects of adjuvant chemotherapy were estimated by comparing outcomes in patients who received surgery plus chemotherapy with those who underwent surgery alone. RESULTS: Median age at presentation was 59 years. Neoadjuvant and adjuvant chemotherapy was administered to 83 (79.8%) patients. Patients who underwent surgery plus chemotherapy and those who underwent surgery alone had 5-year overall survival (OS) rates of 68.6% and 71.7%, respectively (p = 0.780), and 5-year relapse free survival (RFS) rates of 48.2% and 43.6%, respectively (p = 0.64). Univariate analysis showed that resection with wide margins was significantly correlated with better prognosis. CONCLUSIONS: The addition of chemotherapy to surgery did not improve OS or RFS in patients aged >50 years with resectable, non-metastatic osteosarcoma. Surgery with wide margins was only significantly prognostic of improved survival. The effect of chemotherapy in elderly osteosarcoma patients was unclear.

Clinical outcome of primary giant cell tumor of bone after curettage with or without perioperative denosumab in Japan: from a questionnaire for JCOG 1610 study.

BACKGROUND: Giant cell tumor of bone (GCTB) is an intermediate tumor known to be locally aggressive, but rarely metastasizing. To plan a prospective study of GCTB, we performed a questionnaire survey for institutions participating in the Bone and Soft Tissue Tumor Study Group (BSTTSG) in the Japan Clinical Oncology Group (JCOG) in 2015. METHODS: We reviewed 158 consecutive patients with primary GCTB treated with curettage without perioperative denosumab from 2008 to 2010 in Japan. We investigated local and distant recurrence rates after definitive curettage. We also investigated the recurrence rate after treatment with preoperative and/or postoperative denosumab with curettage in recent years. There were 40 patients treated with perioperative denosumab, and the factors affecting recurrence in them were investigated. RESULTS: Answers were available from 24 of 30 institutions (80.0%) participating in JCOG BSTTSG. Thirty (19.0%) and 4 (2.5%) of 158 patients developed local and distant recurrence after curettage without perioperative denosumab from 2008 to 2010, respectively. Campanacci grade and embolization before surgery were significantly associated with increasing incidence of local recurrence after curettage (p = 0.034 and p = 0.022, respectively). In patients treated with perioperative desnosumab, 120 mg denosumab was administered subcutaneously for a median 6 (2-41) and 6 (1-14) times in preoperative and postoperative settings, respectively. The recurrence rates were 6 of 21 (28.6%), 2 of 9 (22.2%), and 0 of 10 (0.0%) in the preoperative, postoperative, and both pre- and postoperative denosumab treatment groups, respectively. With all of the preoperative treatments, administration exceeding five times was significantly associated with a decreased incidence of local recurrence after curettage (p < 0.001). CONCLUSION: The recurrence rate of GCTB was still high after curettage, especially in Campanacci grade III, and improvements in the therapeutic strategy are needed in this cohort. There is a possibility that a sufficient dose of preoperative denosumab can reduce recurrence after curettage. Recently, we have started a clinical trial, JCOG1610, to investigate the efficacy of preoperative denosumab in patients who can be treated with curettage in GCTB.

Anticancer Activity of Polyoxometalate-Bisphosphonate Complexes: Synthesis, Characterization, In Vitro and In Vivo Results.

We synthesized a series of polyoxometalate-bisphosphonate complexes containing MoVIO6 octahedra, zoledronate, or an N-alkyl (n-C6 or n-C8) zoledronate analogue, and in two cases, Mn as a heterometal. Mo6L2 (L = Zol, ZolC6, ZolC8) and Mo4L2Mn (L = Zol, ZolC8) were characterized by using single-crystal X-ray crystallography and/or IR spectroscopy, elemental and energy dispersive X-ray analysis and 31P NMR. We found promising activity against human nonsmall cell lung cancer (NCI-H460) cells with IC50 values for growth inhibition of ∼5 µM per bisphosphonate ligand. The effects of bisphosphonate complexation on IC50 decreased with increasing bisphosphonate chain length: C0 ≈ 6.1×, C6 ≈ 3.4×, and C8 ≈ 1.1×. We then determined the activity of one of the most potent compounds in the series, Mo4Zol2Mn(III), against SK-ES-1 sarcoma cells in a mouse xenograft system finding a ∼5× decrease in tumor volume than found with the parent compound zoledronate at the same compound dosing (5 µg/mouse). Overall, the results are of interest since we show for the first time that heteropolyoxomolybdate-bisphosphonate hybrids kill tumor cells in vitro and significantly decrease tumor growth, in vivo, opening up new possibilities for targeting both Ras as well as epidermal growth factor receptor driven cancers.

Novel sluggish speed signs on ultrasound is indicative of hemangiomas.

Background Hemangiomas are sometimes difficult to diagnose with current techniques. Sluggish speed signs (SSS) are a phenomenon that: (i) cannot be depicted as Doppler flow on Doppler ultrasound; (ii) can be observed as fluid movements on Doppler ultrasound; and (iii) cannot be depicted as waveforms on pulse Doppler mode. We hypothesized that SSS could be diagnostic indicators for hemangiomas. Purpose To evaluate whether ultrasound findings, in particular those relating to SSS, are a reliable tool for detecting hemangiomas compared to magnetic resonance imaging (MRI) and the gold standard for hemangioma diagnosis: pathological examination by biopsy or after surgical resection. Material and Methods Totally, 105 patients (mean age, 44.9 years) with soft-tissue tumors underwent MRI and ultrasound examination before biopsy or tumor resection. Ultrasound findings were compared with MRI as well as pathological findings, which were used as reference. Results Hemangiomas were identified in 16 (6.25%) of the 105 patients. On MRI, flow voids showed sensitivity and specificity values of 81.3% and 96.6%, respectively. On ultrasound examination, SSS was the only finding to show equally high sensitivity (93.8%) and specificity (96.6%) for diagnosing hemangiomas. There was no significant difference in the diagnostic capabilities between these two parameters ( P = 0.479). Conclusion SSS showed a high sensitivity and specificity for diagnosing hemangiomas and therefore are useful diagnostic tools to supplement MRI.

Feasibility and efficacy of gemcitabine and docetaxel combination chemotherapy for bone and soft tissue sarcomas: multi-institutional retrospective analysis of 134 patients.

BACKGROUND: Bone and soft tissue sarcomas (BSTS) are rare malignant tumors. Recently, the combination of gemcitabine and docetaxel (GD) was shown to have activity as second-line setting in BSTS. However, the efficacy as first-line and adjuvant settings and precise profiles of adverse events in Japanese patients are not known yet. In the present study, the feasibility and efficacy of GD in patients with BSTS were investigated. METHODS: Patients with BSTS treated with GD in our institutions were retrospectively analyzed. Information regarding clinical features, adverse events, and outcome was collected and statistically studied. Factors related to survival were analyzed using log-rank test and Cox proportional hazard regression method. RESULTS: A total of 134 patients were analyzed. GD was carried out as adjuvant setting in 9, first-line in 23, second-line in 56, and third-or-greater line in 46 patients. The response rate (RR) for all patients was 9.7%. RR for the patients treated as adjuvant or first-line setting was 18.8%, whereas that as second-or-greater line was 6.9%. The median progression-free survival (PFS) and overall survival (OS) of all patients were 4.8 (95% CI 3.5-6.1) and 16.4 (95% CI 9.8-22.9) months, respectively. Survival tended to be better in the patients treated as first-line than in those treated as second-or-greater line. Multivariate analysis demonstrated that history of prior chemotherapy (p = 0.046) and response to GD (p = 0.009) was significantly associated with PFS and OS, respectively. The leucopenia and neutropenia were the most frequent adverse events, and grade 3 or 4 leucopenia and neutropenia were observed in 69.4 and 72.4% of the patients. Grade 2 or 3 pneumonitis was observed in one (0.7%) and four (3.0%) patients, respectively. All the patients with pneumonitis had experienced prior chemotherapy and/or radiotherapy. CONCLUSIONS: GD used as both first- and second/later line is effective chemotherapy for a proportion of patients with advanced BSTS. Higher response rate and better outcome was achieved in chemotherapy-naïve patients. This regimen is associated with high incidence of severe hematological toxicity, as well as the risk of severe pneumonitis, especially in pre-treated patients. GD is promising for further analysis by phase III study for the patients with BSTS.

Percent slope analysis of dynamic magnetic resonance imaging for assessment of chemotherapy response of osteosarcoma or Ewing sarcoma: systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review is to provide an up-to-date and unprecedented summary of percent slope analysis of dynamic magnetic resonance imaging (MRI) for the preoperative evaluation of the chemotherapy response of osteosarcoma or Ewing sarcoma. MATERIALS AND METHOD: Studies evaluating dynamic MRI for the preoperative evaluation of the chemotherapy response of osteosarcoma or Ewing sarcoma were systematically searched for in MEDLINE, EMBASE, and Web of Science. More than 60 % reduction of the slope of the time intensity curve derived from dynamic MRI was defined as a positive response. Pooled sensitivity and specificity for each study were calculated into 2 × 2 contingency tables. The DerSimonian-Laird random-effects method was used for determining the pooled diagnostic odds ratio and the area under curve (AUC) of the summary receiver operating characteristic (SROC) curve. RESULTS: A total of six studies with 66 patients who fulfilled all of the inclusion criteria were considered for the meta-analysis. The pooled sensitivity and specificity were 0.73 (95 % CI, 0.54-0.88) and 0.83 (95 % CI, 0.67-0.94), respectively. A significant difference was found between the good and poor responders in the diagnostic odds ratio. The SROC curve showed that the AUC was 0.839, indicating diagnostic accuracy in estimating good therapy response. CONCLUSION: The slope of the time intensity curve derived from dynamic MRI was useful for evaluating the histological response of patients to neoadjuvant chemotherapy in osteosarcoma or Ewing sarcoma.

Polyoxomolybdate Bisphosphonate Heterometallic Complexes: Synthesis, Structure, and Activity on a Breast Cancer Cell Line.

Six polyoxometalates containing Mn(II) , Mn(III) , or Fe(III) as the heteroelement were synthesized in water by treating Mo(VI) precursors with biologically active bisphosphonates (alendronate (Ale), zoledronate (Zol), an n-alkyl bisphosphonate (BPC9 ), an aminoalkyl bisphosphonate (BPC8 NH2 )) in the presence of additional metal ions. The Pt complex was synthesized from a polyoxomolybdate bisphosphonate precursor with Mo(VI) ions linked by the 2-pyridyl analogue of alendronate (AlePy). The complexes Mo4 Ale2 Mn, Mo4 Zol2 Mn, Mo4 Ale2 Fe, Mo4 Zol2 Fe, Mo4 (BPC8 NH2 )2 Fe, and Mo4 (BPC9 )2 Fe contain two dinuclear Mo(VI) cores bound to a central heterometallic ion. The oxidation state of manganese was determined by magnetic measurements. Complexes Mo12 (AlePy)4 and Mo12 (AlePy)4 Pt4 were studied by solid-state NMR spectroscopy and the photochromic properties were investigated in the solid state; both methods confirmed the complexation of Pt. Activity against the human breast adenocarcinoma cell line MCF-7 was determined and the most potent compound was Mn(III) -containing Mo4 Zol2 Mn (IC50 ≈1.3 µM). Unlike results obtained with vanadium-containing polyoxometalate bisphosphonates, cell growth inhibition was rescued by the addition of geranylgeraniol, which reverses the effects of bisphosphonates on isoprenoid biosynthesis/protein prenylation. The results indicate an important role for both the heterometallic element and the bisphosphonate ligand in the mechanism of action of the most active compounds.

Does expression of glucose transporter protein-1 relate to prognosis and angiogenesis in osteosarcoma?

BACKGROUND: The survival of patients who present with nonmetastatic extremity osteosarcoma has dramatically improved, but there are some patients who do not respond to chemotherapy. The ability to identify patients with a poorer prognosis might allow us to target different therapy for these patients. Glucose transporter protein-1 (Glut-1), one of the key factors in glucose metabolism, has been reported to be an independent prognostic factor in various tumors. However, little is known about the role of the Glut-1 pathway in osteosarcoma. QUESTIONS/PURPOSES: We asked (1) if Glut-1 expression is a prognostic marker for survival in patients with osteosarcoma, and (2) if there is a relationship between Glut-1 expression and tumor angiogenesis. PATIENTS AND METHODS: Thirty-seven patients with resectable high-grade osteosarcomas treated between 1982 and 2007 were reviewed retrospectively. Patients were excluded if representative biopsy material and followup data were not available. The expression of Glut-1 and the number of CD34-positive microvessels for angiogenic activity were measured immunohistochemically. The median followup was 6 years 6 months (range, 11-211 months). Survival analyses were evaluated using the Kaplan-Meier method and the Cox proportional hazards model. The association between Glut-1 expression and microvessel density was analyzed using Student's t-test and chi-square test. For 12 (32.4%) of 37 patients with osteosarcoma, the expression of Glut-1 was positive, with four patients (10.8%) showing strong expression of Glut-1 protein. RESULTS: The expression of Glut-1 correlated with a shorter disease-free survival period (relative risk, 20.13; 95% CI, 1.77-229.3; p=0.0016). The microvessel density mean value of positive Glut-1 expression (mean±SD, 26.5±19.4) was lower than that of negative expression (mean±SD, 46.4±35.3; Student's t-test, p=0.038). When more than 50 was defined as a high microvessel density, positive expression of Glut-1 was significantly associated with low microvessel density (chi-square test, p=0.049). CONCLUSIONS: These findings indicate that Glut-1 is a potential predictor of survival in patients with osteosarcoma and that glucose metabolism may be negatively associated with angiogenesis. If substantiated in larger numbers of patients, these findings might stimulate the development of novel treatments for patients with a poorer prognosis. LEVEL OF EVIDENCE: Level III, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration.

MicroRNAs (miRNAs) have emerged as potential anticancer agents, but their clinical application is limited by the lack of an effective delivery system to tumors. Exosomes are small vesicles that play important roles in intercellular communication. Here, we show that synthetic miR-143 introduced into cells is released enveloped in exosomes and that the secreted exosome-formed miR-143 is transferred to osteosarcoma cells. The delivery of exosome-formed miR-143 significantly reduced the migration of osteosarcoma cells. The delivery efficiency of exosome-formed miR-143 was less than that achieved with lipofection, but the migratory potential of osteosarcoma cells was similarly inhibited after both strategies. Our results suggest that exosomes can deliver synthetic miR-143 and are a potentially efficient and functional delivery system.

Therapeutic effect and risk factors for complications of excision in 76 patients with schwannoma.

BACKGROUND: Benign schwannoma is the most common tumor of peripheral nerves. However, the clinical course of excision and risk factors associated with postoperative neurological deficits are not well known. We evaluated the incidence of preoperative symptoms, the incidence of postoperative neurological deficits, and the risk factors of neurological deficits. METHODS: We retrospectively reviewed data of 76 patients with schwannomas treated at our institution. We reviewed the clinical characteristics, and postoperative results, and determined the possible risk factors influencing the development of complications. RESULTS: Excision of schwannoma improved the Tinel-like signs in 47 of 51 patients and spontaneous pain in 14 of 15. Eleven of 17 patients with sensory deficits showed complete recovery, but six continued to show deficits with or without improvement. Motor deficits that were observed in four patients persisted in one. New neurological deficits developed in 21 patients and persisted until final follow-up in 8. Tinel-like signs was the risk factor of surgery-related neurological deficits (p = 0.009). CONCLUSIONS: New deficits developed predominantly in patients with preoperative Tinel-like signs. Attention should be given to patients with the factor.

A novel assessment method of serum alkaline phosphatase for the diagnosis of osteosarcoma in children and adolescents.

BACKGROUND: A high serum alkaline phosphatase (ALP) level is valuable for the diagnosis of osteosarcoma in adults, but its use in teenagers is problematic because ALP levels are affected by age, gender, and pubertal stage. Because serum acid phosphatase (ACP) shows the same tetraphasic pattern as serum ALP in children and adolescents, we presumed that serum levels of ALP and ACP would have a strong correlation and that the ratio of ALP to ACP (ALP/ACP) would show little variation and would be useful for the diagnosis of osteosarcoma in teenagers. The purpose of this study was to evaluate the correlation between the serum levels of ALP and ACP and to investigate the validity of ALP/ACP in the differential diagnosis of osteosarcoma in children and adolescents. METHODS: We retrospectively examined 538 patients aged 1-18 years, including 24 with osteosarcomas, 8 with other malignant bone tumors, 56 with benign bone tumors, and with 450 non-tumor lesions (controls). We evaluated the serum levels of ALP and ACP, both obtained by preoperative examination. RESULTS: There were significant correlations between the serum ALP and ACP levels in the controls (r = 0.805 in males and r = 0.860 in females). The ratios of ALP to ACP in the controls showed little variation with age. In ROC curve analysis, to discriminate between the osteosarcomas and the controls, the cutoff levels of serum ALP and ALP/ACP were 956 (U/l) and 50.9 in males and 748 (U/l) and 43.3 in females, respectively. The sensitivity and specificity of serum ALP and ALP/ACP in the differential diagnosis of osteosarcoma were 50.0 and 89.0%, and 60.0 and 94.1%, respectively in males, and 61.5 and 72.7%, and 69.2 and 84.2%, respectively, in females. CONCLUSIONS: The results suggest that ALP/ACP is more useful than the serum ALP level in diagnosing osteosarcoma because it is little affected by the age.

Oncolytic Effect of a Recombinant Vesicular Stomatitis Virus Encoding a Tumor-suppressor MicroRNA in an Osteosarcoma Mouse Model.

BACKGROUND/AIM: Attempts have been made to enhance treatment with vesicular stomatitis virus (VSV) for osteosarcoma. We have previously shown that VSV incorporated with miRNA143 enhanced the antitumor effect at some doses; however, the range of the doses was narrow. This has not been evaluated in vivo, and the synergistic effect of this antitumor effect in animals is unknown. The purpose of the study was to evaluate the oncolytic effect of VSV-miRNA on osteosarcoma cells in vivo. MATERIALS AND METHODS: A novel oncolytic VSV was developed by incorporating the tumor-suppressor microRNA143 (rVSV-miR143). In order to compare the antitumor effects of administration methods (intravenous and intratumoral administration) of rVSV-miR143 with those of VSV, a comparative analysis of primary tumor volume, metastatic lesions and survival rate was performed in mouse models of osteosarcoma. RESULTS: Following intratumoral injection, rVSV-miR143 showed a significant reduction in primary tumor volume, but no significant difference was observed in metastatic lesions and survival rate compared to VSV. Following intravenous injection, rVSV-miR143 revealed no significant difference in primary tumor volume, metastatic lesion and survival rate compared to VSV. CONCLUSION: VSV incorporating tumor-suppressor miRNA143 demonstrated a slightly synergistic antitumor effect on osteosarcoma in vivo.

Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.

We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.

Rapidly growing Fibro-osseous pseudotumor of the digit: A case report.

INTRODUCTION: Fibro-osseous pseudotumor of the digit is a rare benign lesion of subcutaneous tissue that typically arises in the parabone site of the proximal phalanx in young adult females. The lesion is histopathologically characterized by fibroblastic proliferation and osteoid formation. Good prognosis following complete surgical excision of the tumor has been reported, with a very low recurrence rate and no reports of malignant transformation. Despite its benign clinical behavior, the lesion can be mistaken for a malignant neoplasm, such as an extraskeletal or parosteal osteosarcoma, in case of rapid growth, thereby rendering the diagnosis challenging. PATIENT CONCERNS: We report the case of a 30-year-old right-handed male who presented to our hospital with a rapidly growing mass on the dorsal aspect of the right little finger. DIAGNOSIS: The patient was suspected to have soft tissue tumor of the little finger. The lesion could be considered a malignant tumor on the basis of clinical findings. INTERVENTIONS: The patient underwent surgery for exploration and excision of the mass. OUTCOMES: The excised mass was diagnosed to be fibro-osseous pseudotumor of the digit upon histological assessment. Postoperatively, the wound healed without complications. At postoperative 6 months, there were no signs or symptoms of recurrence, and the patient returned to his premorbid functional status. CONCLUSION: Following the detection of a soft tissue mass with clinicopathological features of pseudomalignancy in the digit, clinicians should consider fibro-osseous pseudotumor of the digit as a possible diagnosis, thereby avoiding unnecessary aggressive surgery.

Development of an Oncolytic Recombinant Vesicular Stomatitis Virus Encoding a Tumor-suppressor MicroRNA.

BACKGROUND: Attempts have been made to enhance systemic therapy for osteosarcoma. In our previous study, the systemic administration of a vesicular stomatitis virus (VSV) improved the survival rates of mice with osteosarcoma but did not improve the long-term survival of the animals. MATERIALS AND METHODS: In the present study, we developed a novel oncolytic VSV by incorporating tumor-suppressor microRNA143 (rVSV-miR143) to compare the antitumor effects of various doses (10×10-4, 5×10-4, and 1×10-4 multiplicity of infection) of rVSV-miR143 with those of VSV in vitro. RESULTS: The cytotoxicity and migration-inhibitory effects of rVSV-miR143 on the osteosarcoma cells were significantly higher than those of VSV alone at a dose of 5×10-4 multiplicity of infection, indicating that rVSV-miRNA143 enhances the antitumor effect at certain doses. CONCLUSION: VSV incorporating tumor-suppressor miRNA143 demonstrated a synergistic antitumor effect on osteosarcoma cells in vitro.

Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.

Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

Coexistence of giant cell tumor of tendon sheath and enchondroma in the middle phalanx of the little finger mimicking a malignant tumor: A case report.

Giant cell tumor of the tendon sheath is a type of slow-growing benign soft tissue tumor that typically arises from the synovium of the tendon sheath. Enchondroma is a benign bone tumor comprising of mature hyaline cartilage that centrally develops within the tubular bone. While giant cell tumor of the tendon sheath or enchondroma are common benign soft tissue and bone tumors, respectively the simultaneous occurrence of these tumors in the same region of the hand is exceedingly rare, and it can mimic a malignant tumor, thereby making the diagnosis more challenging. Herein, we report an unusual imaging presentation of the coexistence of these tumors in the middle phalanx of the little finger, which to the best of our knowledge has not been previously reported, and this initially present as a single intrinsic osseous lesion mimicking malignancy. The coexistence of these tumor types must be considered in the differential diagnosis of an intramedullary lytic lesion with a poor margin associated with a soft tissue mass of the fingers, and a meticulous preoperative magnetic resonance imaging investigation was required.

Novel Near-Infrared Fluorescence-Guided Surgery With Vesicular Stomatitis Virus for Complete Surgical Resection of Osteosarcomas in Mice.

Attempts have been made to visualize tumor cells intraoperatively with fluorescence guidance. However, the clear demarcation and complete tumor resection have always been a challenging task. To address this, we have developed a novel fluorescence bioimaging system with vesicular stomatitis virus (VSV) incorporating Katushka, near-infrared fluorescent protein. VSV is tumor-specific owing to the deficiency of antiviral interferon signaling pathways in tumor cells. We aimed to evaluate the tumor specificity of the recombinant VSV-Katushka (rVSV-K) in osteosarcoma cells and to assess the feasibility of complete tumor resection by the rVSV-K fluorescence guidance. In in vitro experiments, mouse and human osteosarcoma cell lines and normal human mesenchymal stem cells were infected with rVSV-K and observed by fluorescence microscopy. Near-infrared fluorescence was observed only in osteosarcoma cells, even at a low-concentration of virus infections. In in vivo experiments, mouse osteosarcoma (LM8) cells were transplanted subcutaneously into the back of immune-competent mice to produce an osteosarcoma, which was then injected with rVSV-K. The areas emitting fluorescence were resected using a bioimaging system. The distance between the surgical and tumor margins of the fluorescence-guided resection with rVSV-K group was significantly larger than that of the non-guided resection groups. The local recurrence rate was significantly lower in the fluorescence-guided resection with rVSV-K group than in the non-guided resection groups. The distant metastasis rate and average survival rate were not significantly different between all groups. These results suggest that the rVSV-K is specific to osteosarcoma cells and enables complete tumor resection of osteosarcomas in mice. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Osteoprogenitor differentiation is not affected by immunomodulatory thalidomide analogs but is promoted by low bortezomib concentration, while both agents suppress osteoclast differentiation.

We investigated the effects of bortezomib (PS-341) and immunomodulatory thalidomide analogs (immunomodulatory compounds; CC-4047, CC-6032, and CC-5013, or lenalidomide) on osteoblast and osteoclast differentiation in vitro using human mesenchymal stem cells (hMSC) to commit to osteoprogenitor cells and peripheral blood mononuclear cells (PBMCs) isolated from healthy donors, respectively. First, the concentration of bortezomib for an anti-myeloma effect was more than 1.0 nM in myeloma cells of multiple myeloma (MM) patients and more than 2.5 nM in myeloma cell lines. In contrast, anti-myeloma effects of immunomodulatory compounds on myeloma cells differed among myeloma cells and these compounds themselves. Subsequently, these agents (bortezomib; 0.5-5.0 nM, immunomodulatory compounds; 10 microM) were added to the osteoprogenitor cell culture media or the media for osteoclast differentiation. Low bortezomib concentrations (0.5 and 1.0 nM) increased ALP activity, and the delayed addition of bortezomib further increased ALP activity. Mineralized nodular formation with <2.5 nM bortezomib was not impaired. BMP2 expression on osteoprogenitor cells was found to increase in a time-dependent manner irrespective of treatment with bortezomib. On the other hand, the anti-osteoclast effect with low bortezomib concentration (< or =2.5 nM) depended on MM patients. In contrast, immunomodulatory compounds at 10 microM showed an anti-osteoclast effect without cytotoxicity to osteoblast differentiation, at which dose myeloma cells underwent apoptosis. These findings might improve the treatment strategy for MM patients without damaging BM stromal cells by combining bortezomib with immunomodulatory compounds.