Perioperative Adriamycin plus ifosfamide vs. gemcitabine plus docetaxel for high-risk soft tissue sarcomas: randomised, phase II/III study JCOG1306.

BACKGROUND: This randomised phase II/III trial aimed to determine whether perioperative chemotherapy with gemcitabine plus docetaxel (GD) is non-inferior to the standard Adriamycin plus ifosfamide (AI) in terms of overall survival (OS) in patients with soft tissue sarcoma (STS). METHODS: Patients with localised high-risk STS in the extremities or trunk were randomised to receive AI or GD. The treatments were repeated for three preoperative and two postoperative courses. The primary endpoint was OS. RESULTS: Among 143 enrolled patients who received AI (70 patients) compared to GD (73 patients), the estimated 3-year OS was 91.4% for AI and 79.2% for GD (hazard ratio 2.55, 95% confidence interval: 0.80-8.14, P = 0.78), exceeding the prespecified non-inferiority margin in the second interim analysis. The estimated 3-year progression-free survival was 79.1% for AI and 59.1% for GD. The most common Grade 3-4 adverse events in the preoperative period were neutropenia (88.4%), anaemia (49.3%), and febrile neutropenia (36.2%) for AI and neutropenia (79.5%) and febrile neutropenia (17.8%) for GD. CONCLUSIONS: Although GD had relatively mild toxicity, the regimen-as administered in this study-should not be considered a standard treatment of perioperative chemotherapy for high-risk STS in the extremities and trunk. CLINICAL TRIAL REGISTRATION: jRCTs031180003.

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.

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.

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.

Inhibition of microRNA-222 expression accelerates bone healing with enhancement of osteogenesis, chondrogenesis, and angiogenesis in a rat refractory fracture model.

BACKGROUND: It is difficult to achieve bone union in case of non-union with non-invasive techniques. MicroRNAs (miRNAs) are short, non-coding RNAs that act as repressors of gene expression at the level of post-transcriptional regulation. This study focuses on microRNA (miR)-222 as it is known to be a negative modulator of angiogenesis, an essential component of fracture healing. The purpose of this study was to analyze the effects of miR-222 on osteogenic and chondrogenic differentiation in human mesenchymal stromal cell (MSC)s in vitro, and to determine whether local administration of miR-222 inhibitor into the fracture site could achieve bone union in vivo. METHOD: miR-222 expression in human bone marrow mesenchymal stem cells (hMSCs), and osteogenic differentiation in hMSCs, were investigated. The gain or loss of miR-222 function was examined, in order to assess the effects of miR-222 on osteogenic and chondrogenic differentiation in hMSCs. A femoral transverse fracture was completed in rats, and the periosteum at the fracture site was cauterized. Then, either an miR-222 inhibitor or an miR-222 mimics, mixed with atelocollagen, was administered into the fracture site. A non-functional inhibitor negative control was administered to the control group. At 2, 4, 6, and 8 weeks, radiographs of the fractured femurs were obtained. Immunohistochemistry was performed at 2 weeks to evaluate the capillary density. At 8 weeks, micro-computed tomography (µCT) imaging analysis and histological evaluations were performed. RESULTS: The expression of miR-222 significantly decreased as osteogenic differentiation of hMSCs proceeded. Inhibition of miR-222 promoted osteogenic differentiation, and over expression of miR-222 inhibited osteogenic differentiation in hMSCs, which was confirmed by measuring expression of Runx2, collagen type 1A1 (COL1A1), and osteocalcin. Inhibition of miR-222 promoted chondrogenic differentiation in hMSCs, which was confirmed by measuring expression of collagen type II (COL2A1), aggrican, and SOX9. Bone union at the fracture site was achieved in only the groups treated with the miR-222 inhibitor, confirmed by radiographic, µCT and histological evaluation at 8 weeks after administration. Immunohistochemistry showed that capillary density in the miR-222 inhibitor group was significantly higher than that in the control group and in the miR-222 mimics group. CONCLUSION: Local administration of miR-222 inhibitor can accelerate bone healing by enhancing osteogenesis, chondrogenesis, and angiogenesis in the rat refractory model.

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.

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.

Myopericytoma of the patella with local recurrence and patellectomy: A case report.

INTRODUCTION AND IMPORTANCE: Myopericytomas are tumors originating from perivascular myoid cells and exhibiting a wide range of histologic growth patterns. They rarely occur in bones, and no case of myopericytoma in the patella has been reported so far. CASE PRESENTATION: A 74-year-old male presented with a chief complaint of pain in the left knee. Magnetic resonance imaging revealed bone tumor and osteolytic lesions of the patella. The patient underwent bone tumor curettage and filling of the cavity with artificial bone. However, as the tumor reoccurred, a patellectomy was performed. The patient regained premorbid functional status after surgery. Additionally, there was no radiological evidence of recurrence of the lesion 3 years after patellectomy. CLINICAL DISCUSSION: Myopericytoma of the patella is very rare. However, it should be considered for the differential diagnosis of lytic lesions of the bone. Although surgery is curative, patellectomy may be necessary for recurrent cases. CONCLUSION: In conclusion, we report the first case of patellar myopericytoma. Although patellar myopericytoma might be rare, it should be considered for the differential diagnosis of lytic lesions of the bone. Surgery is curative; however, patellectomy may be necessary in recurrent cases.

Synergistic VSV Virotherapy and Carbon Nanotube Photothermal Therapy for Osteosarcoma in Murine Models.

BACKGROUND/AIM: Wide resection is usually performed for malignant bone and soft tissue tumors, but there is often functional impairment of the affected limb. In this study, we performed virotherapy with the vesicular stomatitis virus (VSV) and photothermal therapy using carbon nanotubes (CNTs) in combination for osteosarcoma, followed by marginal excision. The possibility of local treatment of the primary tumor was then assessed. MATERIALS AND METHODS: LM-8 cells (1×107) were subcutaneously implanted into 5-week-old mice to generate an in vivo osteosarcoma mouse model. Marginectomy was performed. Four groups with six mice each were created: VSV+SWCNTs group, VSV group, SWCNTs group, and an untreated group. Tumor margin resection was performed 2 weeks after tumor cell transplantation. The primary tumor volume, local recurrence, distant metastasis, and survival rate were evaluated. RESULTS: The combination of VSV virotherapy and CNTs photothermal therapy resulted in shrinkage of the primary tumor and reduced local recurrence after marginectomy. There was no significant difference in distant metastasis or survival rate for all groups. CONCLUSION: Combining virotherapy with VSV and CNTs photothermal therapy is useful for local treatment of osteosarcoma in murine models, possibly allowing for smaller tumor resection margins.

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.

Giant cell tumor of the cervical spine treated by carbon ion radiotherapy: A case report.

INTRODUCTION: Giant cell tumor (GCT) of the bone is a benign-malignant intermediate tumor with locally destructive growth and a relatively high local recurrence rate. Neurological symptoms may develop in patients with GCT of the spine, and surgical treatment is prioritized in cases where resection is possible. However, the local recurrence rate of GCT of the bone is higher than that of GCT at other sites owing to the associated surgical challenges, and treatment is often difficult. No study to date has reported long-term remission of recurrent tumors for more than 5 years by treatment with carbon ion beam radiotherapy after resection of GCT of the cervical spine. PATIENT CONCERNS: A 14-year-old boy who experienced recurrence after surgery for GCT of the cervical spine. DIAGNOSIS: The patient presented with cervical pain, and computed tomography revealed a mass of the C2 vertebral body. He underwent surgery for tumor resection and autologous bone grafting, and the final pathological diagnosis was GCT. The transplanted bone exhibited gradual progression of resorption, and recurrent tumors were observed on computed tomography and magnetic resonance imaging 1 year and 4 months after surgery. INTERVENTIONS: The patient was started on denosumab at 15 years of age and received carbon ion beam therapy with 70.4 Gy administered in 32 sessions over 7 weeks. OUTCOMES: No progressive tumor growth was observed, there were no neurological symptoms such as paralysis or pain were noted, and the patient was in remission for 5 years after irradiation. CONCLUSION: These findings suggest that carbon ion radiotherapy is a safe and effective therapeutic option for patients with recurrent GCT of the cervical spine.

Extraskeletal Ewing sarcoma attached to the ulnar nerve: A case report.

INTRODUCTION: Extraskeletal Ewing sarcoma (EES) of the extremity is uncommon, and only a small number of reported cases have been devoted to the upper-extremity. PRESENTATION OF CASE: A 65-year-old woman presented with a recurrent EES, a highly malignant tumor, involving the ulnar nerve at the right elbow region which was initially suspected as a benign soft tissue tumor, schwannoma, thus marginal excision had been performed. Due to its malignant behaviour, we treated the recurrent lesion with wide excision and reconstruction combined with chemotherapy. Histological evaluation revealed a monotonous small round cells appearance. DISCUSSION: EES of the extremity involving the ulnar nerve is fairly uncommon. The tumor was often smaller in the adult than in the child population which was consistent with the present case, thus may mimic a benign tumor. Because of the overlapping histopathological features of EES with other tumors, other investigations such as immunohistochemistry and cytogenetic studies must be performed to allow definitive diagnosis. The result of our study was negative for the EWSR1-FLI-1 and CIC-DUX4 fusion gene, however, other less frequent translocations could be found in this case which does not exclude the diagnosis of Ewing sarcoma family. CONCLUSION: Few cases of EES involving the ulnar nerve have been previously reported. The correct diagnosis of EES involving the ulnar nerve has become particularly important in order to enable the initiation of comprehensive management that have the potential to reduce disease progression and the avoidance of improper and potentially harmful surgical therapy.

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.

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.

Conventional 99mTc-(hydroxy) methylene diphosphate remains useful to predict osteosarcoma response to neoadjuvant chemotherapy: Individual patient data and aggregate data meta-analyses.

BACKGROUND: The current standard of chemotherapy response evaluation holds the most important prognostic factor to be the histological assessment of the tumor necrosis of the excised lesion, but the major challenge is to find an early prognostic factor that will allow the adjuvant treatment regimen to be adjusted. The objective of this systematic review is to provide an up-to-date and unprecedented summary of the value of Technetium-methylene diphosphate or -hydroxymethylene diphosphate (Tc-MDP/HMDP) scintigraphy for the preoperative evaluation of osteosarcoma response to chemotherapy. METHODS: Studies evaluating the alteration ratio (percentage change of the Tc-99m -MDP/HMDP uptake between before and after neoadjuvant chemotherapy) to predict the histological response of osteosarcoma to chemotherapy were searched for in MEDLINE, EMBASE, and Web of Science. A meta-analysis of individual patient data (IPD) was performed to determine the optimal cut-off point from the receiver operating characteristic (ROC) curve. Additionally, aggregate data (AD) meta-analysis was performed to compare the value of Tc-MDP/HMDP scintigraphy with that of other quantitative modalities, such as dynamic magnetic resonance imaging (MRI), Tl scintigraphy, and F-FDG PET-CT. RESULTS: Seven studies with 154 patients were included for the IPD meta-analysis. The optimal cut-off point of the alteration ratio was 31.0%. Five studies with 123 patients were considered for the AD meta-analysis. The pooled sensitivity and specificity were 0.76 (95% CI, 0.63-0.86) and 0.89 (95% CI, 0.79-0.95), respectively. There was a significant difference between the good and poor responders in terms of the diagnostic odds ratio. The summary ROC curve demonstrated that the area under curve (AUC) was 0.892, indicating excellent diagnostic accuracy. CONCLUSION: Our findings have suggested that conventional Tc-MDP/HMDP scintigraphy remains as useful as recent quantitative modalities to predict the histological response of osteosarcoma to neoadjuvant chemotherapy.

A meta-analysis supports core needle biopsy by radiologists for better histological diagnosis in soft tissue and bone sarcomas.

BACKGROUND: Although surgical biopsy has historically been considered to be the standard diagnostic biopsy for soft tissue and bone sarcomas, recent literature suggests that percutaneous core needle biopsy yields similar results. Therefore, an evaluation of the exact diagnostic accuracy and associated influential variables of core needle biopsy that is based on a large data set would be useful. METHODS: We searched MEDLINE, Web of Science, and EMBASE to identify core needle biopsy studies for predicting final histological subtypes of musculoskeletal lesions. The diagnostic accuracies of core needle biopsy and of surgical biopsy were assessed and compared by using random-effect meta-analyses. The factors relevant to diagnostic accuracy were evaluated by meta-regression and subgroup analyses. RESULTS: We selected 32 studies comprising 7209 musculoskeletal lesions. The pooled proportion estimate for the diagnostic accuracy of core needle biopsy was 0.84 (95% confidential interval, CI: 0.81-0.87), which indicated an approximate 84% concordance between core needle biopsy results and final histological diagnoses. The findings of meta-regression and subgroup analyses suggested that radiologists were better core needle biopsy operators than surgeons. An additional meta-analysis for direct comparison between core needle biopsy and surgical biopsy demonstrated that diagnostic accuracy was significantly lower for core needle biopsy than for surgical (pooled odds ratio: 0.39, 95% CI: 0.20-0.76). CONCLUSION: Our results suggested that core needle biopsy should be performed by expert radiologists and that surgical biopsy should be performed if diagnosis following core needle biopsy does not match the clinical presentation and radiographic findings.

Metastatic tumor cells detection and anti-metastatic potential with vesicular stomatitis virus in immunocompetent murine model of osteosarcoma.

Sarcomas are associated with a high incidence of lung metastasis, which leads to a high-risk of cancer death. This study was performed to explore the pre-clinical theranostic potential of a novel fully functional recombinant vesicular stomatitis virus carrying imaging gene Katushka (rVSV-K), as virotherapy and circulating tumor cells (CTCs) detection in the syngeneic mouse model of osteosarcoma with spontaneous pulmonary metastases. Recombinant VSV-K was generated and evaluated in vitro on human and murine osteosarcoma cells. Spontaneous osteosarcoma metastases were established in immune-competent mice by implanting subcutaneously syngeneic osteosarcoma LM8 cells. The vector was injected into the tumor-bearing mice via jugular vein either once or repeatedly. To assess effectiveness, primary tumor growth and development of lung metastasis as well as survival were evaluated. We found that rVSV-K efficiently replicated in and killed all osteosarcoma cell lines in time-dependent manners. Both single or repeated systemic injections of the virus did not inhibit the growth of the primary tumor, but the repeated administration could effectively suppress the development of lung metastases and was likely responsible for the observed increase in survival. Furthermore, we demonstrated, for the first time, that CTCs in blood samples from syngeneic osteosarcoma-bearing mice were successfully detected by utilizing rVSV-K ex vivo. Our results show that repeated systemic injections of rVSV-K are an effective anti-metastatic agent against osteosarcoma in immune-competent mice and this virus to be a useful tool for detection of osteosarcoma CTCs, suggesting that further development of future viral-based theranostic approach in patients with osteosarcoma is warranted. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2562-2569, 2018.