Taisuke Furuta

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model

Paracrine signaling by bone‐marrow‐derived mesenchymal stem cells (MSCs) plays a major role in tissue repair. Although the production of regulatory cytokines by MSC transplantation is a critical modulator of tissue regeneration, we focused on exosomes, which are extracellular vesicles that contain proteins and nucleic acids, as a novel additional modulator of cell‐to‐cell communication and tissue regeneration. To address this, we used radiologic imaging, histological examination, and immunohistochemical analysis to evaluate the role of exosomes isolated from MSC‐conditioned medium (CM) in the healing process in a femur fracture model of CD9−/− mice, a strain that is known to produce reduced levels of exosomes. We found that the bone union rate in CD9−/− mice was significantly lower than wild‐type mice because of the retardation of callus formation. The retardation of fracture healing in CD9−/− mice was rescued by the injection of exosomes, but this was not the case after the injection of exosomes‐free conditioned medium (CM‐Exo). The levels of the bone repair‐related cytokines, monocyte chemotactic protein‐1 (MCP‐1), MCP‐3, and stromal cell‐derived factor‐1 in exosomes were low compared with levels in CM and CM‐Exo, suggesting that bone repair may be in part mediated by other exosome components, such as microRNAs. These results suggest that exosomes in CM facilitate the acceleration of fracture healing, and we conclude that exosomes are a novel factor of MSC paracrine signaling with an important role in the tissue repair process.

Prognostic significance of 18F-FDG PET at diagnosis in patients with soft tissue sarcoma and bone sarcoma; systematic review and meta-analysis

PURPOSE The usefulness of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) for the survival prognosis in soft tissue sarcoma (STS) and bone sarcoma (BS) is controversial. The objective of this systematic review was to provide an up-to-date and unprecedented summary of the prognostic value of (18)F-FDG PET at diagnosis in STS and BS. METHODS Studies evaluating pre-treatment (18)F-FDG PET for overall survival of STS and BS were systematically searched for in MEDLINE, EMBASE, and Web of Science. Comparative analyses of the pooled hazard ratios (HR) of overall survival were performed between patients with high and low maximum standardised uptake value (SUVmax). The quality of study designs was evaluated using the Newcastle-Ottawa scale (NOS) for quality assessment of cohort studies. P < 0.05 was defined as statistically significant. RESULTS A total of six studies comprising 514 patients with STS and BS were considered for the meta-analysis. The pooled HR for overall survival was 1.22 (95% confidence interval: 1.03-1.46), suggesting that high SUVmax predicts a significantly shorter overall survival period than low SUVmax (P = 0.03). Additional subgroup analyses using patients with STS alone showed that high SUVmax might predict poorer overall survival than low SUVmax (P = 0.004), although only two studies consisting of 96 patients were included. The overall quality of the included studies evaluated by the NOS assessment was adequate. CONCLUSION (18)F-FDG PET at diagnosis provides a very useful predictive tool for patients with STS and BS.

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.

Prognostic value of PAX3/7–FOXO1 fusion status in alveolar rhabdomyosarcoma: Systematic review and meta-analysis

PURPOSE The objective of this systematic review is to provide an unprecedented summary of the prognostic impact of PAX3/7-FOXO1 fusion status in alveolar rhabdomyosarcoma. METHODS Studies evaluating PAX3/7-FOXO1 fusion gene or its variants as a prognostic marker were systematically searched and comparative meta-analysis of overall survival was carried out. RESULTS A total of 7 studies comprising 993 patients with rhabdomyosarcoma were included. Three eligible studies showed no significant difference of survival between fusion positive and negative alveolar rhabdomyosarcoma. Four eligible studies showed that PAX3-FOXO1 fusion variant may indicate a lower survival probability than PAX7-FOXO1, although the effect did not reach a level of statistical significance (pooled hazard ratios, 1.66; 95% CI, 0.95-2.89; p=0.07). CONCLUSIONS There was no significant difference in the overall survival between patients with the positive and negative fusion gene, but there were indications of PAX3-FOXO1 being an unfavorable prognostic factor.

Quantitative 201thallium scintigraphy for prediction of histological response to neoadjuvant chemotherapy in osteosarcoma; systematic review and meta-analysis

PURPOSE The histological assessment of tumor necrosis of the excised lesion after neoadjuvant chemotherapy is the most important prognostic factor for patients with osteosarcoma, but more early prognostic factors are needed for the adjustment of adjuvant treatment regimen. The objective of this systematic review is to provide an up-to-date and unprecedented summary of the value of (201)thallium ((201)Tl) scintigraphy for the preoperative evaluation of the chemotherapy response of osteosarcoma. METHODS Studies evaluating (201)Tl scintigraphy for the preoperative evaluation of the chemotherapy response of osteosarcoma were systematically searched for in MEDLINE, EMBASE, and Web of Science. 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 139 patients who fulfilled all of the inclusion criteria were considered for the meta-analysis. The pooled sensitivity and specificity were 0.93 (95% CI, 0.83-0.98) and 0.63 (95% CI, 0.52-0.74), 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 0.840, indicating excellent diagnostic accuracy. There was no statistically significant heterogeneity among the six studies. CONCLUSIONS The alteration ratio derived from (201)Tl scintigraphy was useful for evaluating the histological response of patients to neoadjuvant chemotherapy in osteosarcoma.

Value of diffusion‑weighted imaging for evaluating chemotherapy response in osteosarcoma: A meta‑analysis

The histological examination of the tumor necrosis upon surgery remains the most reliable prognostic factor for osteosarcoma. However, the detection of more early prognostic factors is desirable in order to increase the survival rates and decrease the risk rates for iatrogenic toxicity. The purpose of the current systematic review and meta-analysis was to provide an up-to-date summary of the role of diffusion-weighted imaging (DWI) for the preoperative assessment of the chemotherapy response in osteosarcoma. Articles evaluating DWI for the preoperative assessment of the chemotherapy response of osteosarcoma were systematically searched for in four electronic literature databases. The mean difference in apparent diffusion coefficient (ADC) following neoadjuvant chemotherapy between good and poor histological responders was assessed in 5 studies. The mean difference in the ADC ratio (the percentage change in ADC between post-neoadjuvant and pre-neoadjuvant chemotherapy) reported in 3 studies was also assessed. Five articles with 106 patients fulfilled all of the inclusion criteria for the meta-analysis. Significant mean differences were found between good and poor responders in the ADC in the 5 studies (P=0.03) and the ADC ratio in the 3 studies (P<0.00001). The good responders demonstrated a higher ADC and a higher ADC ratio than the poor responders. DWI performed with ADC values was useful for predicting the chemotherapeutic response of osteosarcoma. This method may have promising potential as a preoperative non-invasive modality.

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

Long-term survival after sporadic and delayed metastases of conventional osteosarcoma: A case report

Abstract Histologically conventional osteosarcoma, once metastasized to the lung, generally causes a rapid and fatal outcome. Osteosarcoma metastasis to the gastrointestinal tract is extremely rare. We report herein a case of osteoblastic osteosarcoma with exceptionally unique features: sporadic lung metastases and delayed metastases to the stomach and the jejunum with long-term survival. She received multiple operations and chemotherapies, but consequently died of peritoneal dissemination. A review of the literature on osteosarcoma metastasis to the gastrointestinal tract is presented. This patient was very unusual in terms of a long-term survival and metastatic sites, suggesting the importance of vigilance and thorough follow-up for patients with conventional osteosarcoma.

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.