Treatment-induced pathologic necrosis is an independent predictor of both local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcomas. A complete pathologic response (> or = 95% pathologic necrosis) correlated with a significantly lower rate of local recurrence and improved overall survival.
Synovial sarcoma accounts about 9% of soft tissue sarcomas, most commonly develops in the extremity of young adults, is considered high grade and contains a characteristic translocation (X;18;p11;q11). While surgery and radiation therapy have achieved excellent local control, distant metastasis remains the principal problem limiting survival. Although ifosfamide based chemotherapy has been associated with an improved survival in patients with synovial sarcoma, the search for less toxic and more targeted systemic therapies is ongoing.
Ifosfamide-based chemotherapy was associated with an improved DSS in adult patients with high-risk, primary, extremity, synovial sarcoma and should be considered in the treatment of such patients.
A patient with high grade undifferentiated pleomorphic soft-tissue sarcoma from a striated muscle was grown orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. Twenty PDOX mice were divided into 4 groups: G1, control without treatment; G2, Salmonella typhimurium (S. typhimurium)A1-R administered by intratumoral (i.t.) injection once a week for 4 weeks; G3, doxorubicin (DOX) administered by intraperitoneal (i.p.) injection once a week for 4 weeks; G4, S. typhimurium A1-R (i.t.) administered once a week for 2 weeks followed by i.p. doxorubicin once a week for 2 weeks. On day 25 from the initiation of treatment, tumor volume in G2, G3, and G4 was significantly lower than G1. Mice found without gross tumor included one mouse (20%) in G2; one mouse (20%) in G3; and 3 mice (60%) in G4. Body weight loss did not significantly differ between the 3 treated groups or from the untreated control. Histological examination revealed eradication of tumor only in G4 where mice were treated with S. typhimurium A1-R followed by DOX. Our present study indicates future clinical potential of combining S. typhimurium A1-R with chemotherapy such as DOX for soft tissue sarcoma patients.
BACKGROUND
Correct pretreatment classification is critical for optimizing diagnosis and treatment of patients with peripheral nerve sheath tumors (PNSTs). The aim of this study was to evaluate whether F18-fluorodeoxyglucose positron emission tomography (FDG PET) can differentiate malignant (MPNST) from benign PNSTs.
METHODS
Thirty-four adult patients presenting with PNST who underwent a presurgical FDG PET/computed tomography (CT) scan between February 2005 and November 2008 were included in the study. Tumors were characterized histologically, by FDG maximum standardized uptake value (SUVmax [g/mL]), and by CT size (tumor maximal diameter [cm]). The accuracy of FDG PET for differentiating MPNSTs from benign PNSTs (neurofibroma and schwannoma) was evaluated by receiver operating characteristic (ROC) curve analysis.
RESULTS
SUVmax was measured in 34 patients with 40 tumors (MPNSTs: n = 17; neurofibromas: n = 9; schwannomas: n = 14). SUVmax was significantly higher in MPNST compared with benign PNST (12.0 ± 7.1 vs 3.4 ± 1.8; P < .001). An SUVmax cutoff point of ≥6.1 separated MPNSTs from BPSNTs with a sensitivity of 94% and a specificity of 91% (P < .001). By ROC curve analysis, SUVmax reliably differentiated between benign and malignant PNSTs (area under the ROC curve of 0.97). Interestingly, the difference between MPNSTs and schwannomas was less prominent than that between MPNSTs and neurofibromas.
CONCLUSIONS
Quantitative FDG PET imaging distinguished between MPNSTs and neurofibromas with high accuracy. In contrast, MPNSTs and schwannomas were less reliably distinguished. Given the difficulties in clinically evaluating PNST and in distinguishing benign PNST from MPNST, FDG PET imaging should be used for diagnostic intervention planning and for optimizing treatment strategies.
Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.
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