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1.  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.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-014-3910-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11999-014-3910-5
PMCID: PMC4390948  PMID: 25193692
2.  Prognostic value of SS18–SSX fusion type in synovial sarcoma; systematic review and meta-analysis 
SpringerPlus  2015;4:375.
SS18–SSX (formerly called SYT–SSX) fusion gene has been established clinically as a molecular diagnostic test for synovial sarcoma, but the prognostic value of the fusion gene variant for survival is controversial. The objective of this systematic review is to provide an up-to-date and unprecedented summary of the prognostic impact of SS18–SSX fusion type in synovial sarcoma. Studies evaluating SS18–SSX fusion type as a prognostic marker in synovial sarcoma were systematically searched for in MEDLINE, EMBASE, and Web of Science. Comparative analysis of the pooled hazard ratios (HR) between fusion types was carried out, in order to assess the likelihood of overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and metastasis-free survival (MFS). A total of 10 studies comprising 902 patients with synovial sarcoma were considered for the meta-analysis. The pooled HR for eight eligible studies evaluating for OS or DSS was 1.28 (95% confidence interval: 0.81–2.00), suggesting no significant difference between SS18–SSX1 and SS18–SSX2 (P = 0.29). For seven studies which evaluated for PFS or MFS, the presence of SS18–SSX1 may indicate a lower survival probability than that of SS18–SSX2, although the effect did not reach a level of statistical significance (P = 0.09). There was no significant difference in OS or DSS between SS18–SSX1 and SS18–SSX2, but there were indications of SS18–SSX1 being an unfavorable prognostic factor of PFS or MFS. Further studies including cohorts with a longer follow-up period are needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s40064-015-1168-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s40064-015-1168-3
PMCID: PMC4514732  PMID: 26217552
Meta-analysis; Synovial sarcoma; Fusion gene; SS18–SSX; Survival
3.  Extraosseous Extension Caused by Epidural Hematoma in Gaucher Disease Mimicking Malignant Bone Tumor 
JIMD Reports  2013;14:67-70.
Gaucher disease is an inherited autosomal-recessive disorder caused by the defective hydrolysis of glucocerebroside. The resultant hepatosplenomegaly, hematological changes, and orthopedic complications are the predominant symptoms. However, extraosseous manifestation of Gaucher disease, mimicking malignant bone tumor, is supposed to be rare. No reports of extraosseous manifestation of Gaucher disease caused by epidural hematoma were identified in the English literature. A 64-year-old man visited a nearby clinic for low back pain and was referred to our tumor clinic on suspicion of malignant bone tumor on sacral MRI. MRI revealed a demarcated solid lesion extending into the surrounding soft tissues on both sides of the sacral roots. During preoperative examination, he suffered from pathologic fracture in right mid-femur. We performed internal fixation with intramedullary nailing, simultaneously harvesting tissue specimens. Histopathological analysis showed aggregates of Gaucher cells in the right femur and hematoma in the sacrum. Epidural hematoma in Gaucher disease, usually attributed to thrombocytopenia, is a rare manifestation of skeletal complication, mimicking malignant processes.
doi:10.1007/8904_2013_285
PMCID: PMC4213331  PMID: 24363036
4.  Diversity of angiogenesis among malignant bone tumors 
Molecular and Clinical Oncology  2012;1(1):131-136.
Several studies have demonstrated that angiogenesis assessed by microvessel density (MVD) correlates with patient prognosis in various types of cancer, whereas data regarding the relevance of angiogenesis and prognosis in malignant bone tumors are scarce and controversial. The aim of this study was to examine MVD in representative malignant bone tumors, such as osteosarcoma, chondrosarcoma and Ewing’s sarcoma, in order to clarify the role of angiogenesis in prognosis. A total of 69 patients with malignant bone tumors, including 44 osteosarcomas, 20 chondrosarcomas and 5 Ewing’s sarcomas, were reviewed retrospectively and treated at our hospital between 1980 and 2007. Biopsy or pre-chemotherapy surgical specimens were immunohistochemically stained with anti-CD34 antibody. The MVD values of osteosarcomas and Ewing’s sarcomas were significantly higher compared to chondrosarcoma. In osteosarcomas with high MVD, American Joint Committee on Cancer stage IIA, good histological response to chemotherapy was significantly correlated with better disease-free survival, while MVD was closely associated with age and chemotherapy response. In chondrosarcomas, the surgical margin (marginal and intralesional), MVD (high), tumor size (≥8) and histological grade (grades 2 and 3) significantly correlated with a shorter disease-free survival, while MVD was closely associated with age and histological grade. These findings showed that osteosarcomas and Ewing’s sarcomas were hypervascular, compared to chondrosarcomas. In osteosarcomas, hypervascularity induced good chemotherapy response, leading to better prognosis, while in chondrosarcomas, high MVD was associated with histological grade and predicted poor prognosis.
doi:10.3892/mco.2012.11
PMCID: PMC3956242  PMID: 24649135
angiogenesis; osteosarcoma; chondrosarcoma; Ewing’s sarcoma; prognosis
5.  Correlation between p38 mitogen-activated protein kinase and human telomerase reverse transcriptase in sarcomas 
Background
One of the major components of telomerase is the human telomerase reverse transcriptase (hTERT) as the catalytic protein. hTERT mRNA expression are reported to be associated with prognosis and tumor progression in several sarcomas. However, there is no clear understanding of the mechanisms of hTERT in human sarcomas. Recent studies have suggested that signals transmitted through p38 mitogen-activated protein kinase (MAPK) can increase or decrease hTERT transcription in human cells. The purpose of this study was to analyse the correlation between p38 MAPK and hTERT in sarcoma samples.
Methods
We investigated 36 soft tissue malignant fibrous histiocytomas (MFH), 24 liposarcomas (LS) and 9 bone MFH samples for hTERT and p38 MAPK expression. Quantitative detection of hTERT and p38 MAPK was performed by RT-PCR.
Results
There was a significant positive correlation between the values of hTERT and p38 MAPK in all samples (r = 0.445, p = 0.0001), soft tissue MFH (r = 0.352, p = 0.0352), LS (r = 0.704, p = 0.0001) and bone MFH samples (r = 0.802, p = 0.0093). Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis than other patients (p = 0.0036).
Conclusions
p38 MAPK may play a role in up-regulation of hTERT, and therefore, p38 MAPK may be a useful marker in the assessment of hTERT and patients' prognosis in sarcomas.
doi:10.1186/1756-9966-31-5
PMCID: PMC3296589  PMID: 22243975
p38 mitogen-activated protein kinase; human telomerase reverse transcriptase; malignant fibrous histiocytoma; liposarcoma
6.  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 anti-cancer 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, 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.
doi:10.1021/ja808285e
PMCID: PMC2753403  PMID: 19309137
7.  Liposarcoma Arising in the Foot: A Case Report 
Case Reports in Medicine  2009;2009:630203.
Liposarcoma is categorized as a soft tissue sarcoma and most commonly appears in the lower extremities and rarely in the foot during adulthood. We present a very rare case report of a primary well-differentiated liposarcoma arising in the foot on a 60-year-old female. Marginal resection of the tumor with metatarsal ray amputation was eventually performed. The patient's postoperative course was uneventful without recurrence 5 years after the original operation. The authors review the literature and also report on the low incidence of this tumor arising in the foot.
doi:10.1155/2009/630203
PMCID: PMC2774536  PMID: 19902014
8.  Immunohistochemical expression of promyelocytic leukemia body in soft tissue sarcomas 
Background
The function of promyelocytic leukemia (PML) bodies is not well known but plays an important role in controlling cell proliferation, apoptosis and senescence. This study was undertaken to analyze the clinical significance of PML body expression in primary tumor samples from malignant fibrous histiocytoma (MFH) and liposarcoma patients.
Methods
We studied MFH and liposarcoma samples from 55 patients for PML bodies. Fluorescent immunostaining of PML bodies was performed in the paraffin-embedded tumor sections.
Results
PML body immunostaining was identified in 63.9% of MFH and 63.2% of liposarcoma samples. PML body expression rates of all sarcoma cells were 1.5 ± 1.8% (range: 0–7.0) in MFH and 1.3 ± 1.4% (0–5.2) in liposarcoma samples. PML body expression (p = 0.0053) and a high rate of PML body expression (p = 0.0012) were significantly greater prognostic risk factors for death than the other clinical factors in MFH patients. All liposarcoma patients without expression of PML were disease free at the end of the study.
Conclusion
Our study suggests that the presence of PML bodies may indicate a poor prognosis for MFH and liposarcoma patients.
doi:10.1186/1756-9966-27-73
PMCID: PMC2611968  PMID: 19025608
9.  Nerve tolerance to high-dose-rate brachytherapy in patients with soft tissue sarcoma: a retrospective study 
BMC Cancer  2005;5:79.
Background
Brachytherapy, interstitial tumor bed irradiation, following conservative surgery has been shown to provide excellent local control and limb preservation in patients with soft tissue sarcomas (STS), whereas little is known about the tolerance of peripheral nerves to brachytherapy. In particular, nerve tolerance to high-dose-rate (HDR) brachytherapy has never been properly evaluated. In this study, we examined the efficacy and radiation neurotoxicity of HDR brachytherapy in patients with STS in contact with neurovascular structures.
Methods
Between 1995 and 2000, seven patients with STS involving the neurovascular bundle were treated in our institute with limb-preserving surgery, followed by fractionated HDR brachytherapy. Pathological examination demonstrated that 6 patients had high-grade lesions with five cases of negative margins and one case with positive margins, and one patient had a low-grade lesion with a negative margin. Afterloading catheters placed within the tumor bed directly upon the preserved neurovascular structures were postoperatively loaded with Iridium-192 with a total dose of 50 Gy in 6 patients. One patient received 30 Gy of HDR brachytherapy combined with 20 Gy of adjuvant external beam radiation.
Results
With a median follow-up of 4 years, the 5-year actuarial overall survival, disease-free survival, and local control rates were 83.3, 68.6, and 83.3%, respectively. None of the 7 patients developed HDR brachytherapy-induced peripheral neuropathy. Of 5 survivors, 3 evaluable patients had values of motor nerve conduction velocity of the preserved peripheral nerve in the normal range.
Conclusion
In this study, there were no practical and electrophysiological findings of neurotoxicity of HDR brachytherapy. Despite the small number of patients, our encouraging results are valuable for limb-preserving surgery of unmanageable STS involving critical neurovascular structures.
doi:10.1186/1471-2407-5-79
PMCID: PMC1181808  PMID: 16026629
10.  Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma 
Background
We have developed magnetite cationic liposomes (MCLs) and applied them to local hyperthermia as a mediator. MCLs have a positive charge and generate heat under an alternating magnetic field (AMF) by hysteresis loss. In this study, the effect of hyperthermia using MCLs was examined in an in vivo study of hamster osteosarcoma.
Method
MCLs were injected into the osteosarcoma and then subjected to an AMF.
Results
The tumor was heated at over 42°C, but other normal tissues were not heated as much. Complete regression was observed in 100% of the treated group hamsters, whereas no regression was observed in the control group hamsters. At day 12, the average tumor volume of the treated hamsters was about 1/1000 of that of the control hamsters. In the treated hamsters, no regrowth of osteosarcomas was observed over a period of 3 months after the complete regression.
Conclusion
These results suggest that this treatment is effective for osteosarcoma.
doi:10.1186/1477-044X-2-3
PMCID: PMC400754  PMID: 15040804

Results 1-10 (10)