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BackgroundmTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS).MethodsHuman tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media. 13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling.ResultsAsn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth.ConclusionsAsn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS.

ObjectivesFibroblast activation protein alpha (FAP) is highly expressed by cancer-associated fibroblasts in multiple epithelial cancers. The aim of this study was to characterize FAP expression in sarcomas to explore its potential utility as a diagnostic and therapeutic target and prognostic biomarker in sarcomas.MethodsAvailable tissue samples from patients with bone or soft tissue tumors were identified at the University of California, Los Angeles. FAP expression was evaluated via immunohistochemistry (IHC) in tumor samples (n = 63), adjacent normal tissues (n = 30), and positive controls (n = 2) using semiquantitative systems for intensity (0 = negative; 1 = weak; 2 = moderate; and 3 = strong) and density (none, 75%) in stromal and tumor/nonstromal cells and using a qualitative overall score (not detected, low, medium, and high). Additionally, RNA sequencing data in publicly available databases were utilized to compare FAP expression in samples (n = 10,626) from various cancer types and evaluate the association between FAP expression and overall survival (OS) in sarcoma (n = 168).ResultsThe majority of tumor samples had FAP IHC intensity scores ≥2 and density scores ≥25% for stromal cells (77.7%) and tumor cells (50.7%). All desmoid fibromatosis, myxofibrosarcoma, solitary fibrous tumor, and undifferentiated pleomorphic sarcoma samples had medium or high FAP overall scores. Sarcomas were among cancer types with the highest mean FAP expression by RNA sequencing. There was no significant difference in OS in patients with sarcoma with low versus high FAP expression.ConclusionThe majority of the sarcoma samples showed FAP expression by both stromal and tumor/nonstromal cells. Further investigation of FAP as a potential diagnostic and therapeutic target in sarcomas is warranted.

BackgroundAlthough IGF2BP3 has been implicated in tumorigenesis and poor outcomes in multiple cancers, its role in soft-tissue sarcoma (STS) remains unknown. Preliminary data have suggested an association with IGF2BP3 expression among patients with well-differentiated/dedifferentiated liposarcoma (WD/DD LPS), a disease where molecular risk stratification is lacking.MethodsWe examined the survival associations of IGF2BP3 via univariate and multivariate Cox regression in three unique datasets: (1) the Cancer Genome Atlas (TCGA), (2) an in-house gene microarray, and (3) an in-house tissue microarray (TMA). A fourth dataset, representing an independent in-house TMA, was used for validation.ResultsWithin the TCGA dataset, IGF2BP3 expression was a poor prognostic factor uniquely in DD LPS (OS 1.6 vs. 5.0 years, p = 0.009). Within the microarray dataset, IGF2BP3 expression in WD/DD LPS was associated with worse survival (OS 7.7 vs. 21.5 years, p = 0.02). IGF2BP3 protein expression also portended worse survival in WD/DD LPS (OS 3.7 vs. 13.8 years, p < 0.001), which was confirmed in our validation cohort (OS 2.7 vs. 14.9 years, p < 0.001). In the multivariate model, IGF2BP3 was an independent risk factor for OS, (HR 2.55, p = 0.034).ConclusionIGF2BP3 is highly expressed in a subset of WD/DD LPS. Across independent datasets, IGF2BP3 is also a biomarker of disease progression and worse survival.

The photoelectric Factor (PEF) log is a powerful tool for distinguishing between siliciclastic and carbonate lithofacies in well-log analysis and 2D correlations. However, its application in complex reservoirs has some challenges due to well spacing. We present a workflow to extend its capabilities into a 3D environment to characterize the Pennsylvanian Strawn and Canyon reef complex in the Salt Creek field, Kent County, West Texas. The productive zones within this reservoir are composed of porous oolitic grainstones and skeletal packstones. However, there are some porous shale beds within the reef complex that are indistinguishable from the porous limestone zones on the neutron porosity log that have posed major challenges to hydrocarbon production. To address these problems, we used a machine-learning procedure involving multiattribute analysis and probabilistic neural network (PNN) to predict photoelectric factor (PEF) volume to characterize the reservoir and identify the shale beds. By combining neutron porosity, gamma ray, and the predicted PEF logs, we found that (1) these shale beds, hereby referred to as shale-influenced carbonates, are characterized by photoelectric factor values ranging from 4 to 4.26 B/E. (2) Based on the PEF values, the least porous interval is the Canyon System, having 4.78 B/E; while the most porous interval is the Strawn System, composed mostly of zones with porosity ranging from 3% to 28%, characterized by PEF values varying from 4.26 to 4.78 B/E.

Background Cancer is one of the leading causes of death worldwide, and cardiopulmonary comorbidities may further adversely affect cancer prognosis. We recently described lung cancer-associated pulmonary hypertension (PH) as a new form of PH and comorbidity of lung cancer. While patients with lung cancer with PH had significantly reduced overall survival compared with patients without PH, the prevalence and impact of PH in other cancers remain unclear.Methods In this retrospective, observational cohort study, we analysed the prevalence and impact of PH on clinical outcomes in 1184 patients with solid tumours other than lung cancer, that is, colorectal, head and neck, urological, breast or central nervous system tumours, using surrogate markers for PH determined by CT.Results PH prevalence in this cohort was 10.98%. A Cox proportional hazard model revealed a significant reduction in the median survival time of patients with cancer with PH (837 vs 2074 days; p

This article shows that enabling teachers to integrate comparing solution strategies into their teaching fosters student flexibility in algebra. We designed two professional development (PD) programs that either focused exclusively on comparing solution strategies, or additionally introduced the accountable talk approach to guiding productive classroom discussions. The effects of both PD programs were investigated in an experimental field study (N = 39 teachers, 739 students). In both experimental groups, student posttest gains in strategy flexibility and procedural knowledge were greater than in the control group. The accountable talk group also increased conceptual knowledge. Significant effects in strategy flexibility were still observed 2.5 months later. We discuss recommendations for PD programs to foster flexibility in algebra using comparing.

The purpose of this study was to evaluate 18F-FLT PET/CT as an early prognostic imaging biomarker of long-term overall survival and disease-specific survival (DSS) in soft-tissue sarcoma (STS) patients treated with neoadjuvant therapy (NAT) and surgical resection. Methods: This was a 10-y follow-up of a previous single-center, single-arm prospective clinical trial. Patients underwent 18F-FLT PET/CT before treatment (PET1) and after NAT (PET2). Posttreatment pathology specimens were assessed for tumor necrosis or fibrosis and for Ki-67 and thymidine kinase 1 expression. Maximally selected cutoffs for PET and histopathologic factors were applied. Survival was calculated from the date of subject consent to the date of death or last follow-up. Results: The study population consisted of 26 patients who underwent PET1; 16 of the 26 with primary STS underwent PET2. Thirteen deaths occurred during a median follow-up of 104 mo. In the overall cohort, overall survival was longer in patients with a low than a high PET1 tumor SUVmax (dichotomized by an SUVmax of ≥8.5 vs.

IntroductionData supporting hypofractionated preoperative radiation therapy (RT) for patients with extremity and trunk soft tissue sarcoma (STS) are currently limited to phase II single-institution studies. We sought to understand the type and thresholds of clinical evidence required for experts to adopt hypofractionated RT as a standard-of-care option for patients with STS.MethodsAn electronic survey was distributed to multidisciplinary sarcoma experts. The survey queried whether data from a theoretical, multi-institutional, phase II study of 5-fraction preoperative RT could change practice. Using endpoints from RTOG 0630 as a reference, the survey also queried thresholds for acceptable local control, wound complication, and late toxicity for the study protocol to be accepted as a standard-of-care option. Responses were logged from 8/27/2020 to 9/8/2020 and summarized graphically.ResultsThe survey response rate was 55.3% (47/85). Local control is the most important clinical outcome for sarcoma specialists when evaluating whether an RT regimen should be considered standard of care. 17% (8/47) of providers require randomized phase III evidence to consider hypofractionated preoperative RT as a standard-of-care option, whereas 10.6% (5/47) of providers already view this as a standard-of-care option. Of providers willing to change practice based on phase II data, most (78%, 29/37) would accept local control rates equivalent to or less than those in RTOG 0630, as long as the rate was higher than 85%. However, 51.3% (19/37) would require wound complication rates superior to those reported in RTOG 0630, and 46% (17/37) of respondents would accept late toxicity rates inferior to RTOG 0630.ConclusionConsensus building is needed among clinicians regarding the type and threshold of evidence needed to evaluate hypofractionated RT as a standard-of-care option. A collaborative consortium-based approach may be the most pragmatic means for developing consensus protocols and pooling data to gradually introduce hypofractionated preoperative RT into routine practice.

IntroductionThis is a prospective, single-center trial in pediatric patients with sarcoma aiming to evaluate [18F]FDG PET/CT as a tool for early response assessment to neoadjuvant chemotherapy (neo-CTX).MethodsBone or soft tissue sarcoma patients with (1) baseline [18F]FDG PET/CT within 4 weeks prior to the start of neo-CTX (PET1), (2) early interim [18F]FDG PET/CT (6 weeks after the start of neo-CTX (PET2), (3) evaluation of neo-CTX response by histology or MRI, and (4) definitive therapy after neo-CTX (surgery or radiation) were included. Semiquantitative PET parameters (SUVmax, SUVmean, SUVpeak, MTV and TLG) and their changes from PET1 to PET2 (ΔPET) were obtained. The primary endpoint was to evaluate the predictive value of PET1, PET2 and ΔPET parameters for overall survival (OS) and time to progression (TTP). The secondary outcome was to evaluate if [18F]FDG PET/CT can predict the response to neo-CTX assessed by histopathology or MRI. Primary and secondary outcomes were also evaluated in a subpopulation of patients with bone involvement only.ResultsThirty-four consecutive patients were enrolled (10 females; 24 males; median age 15.1 years). 17/34 patients (50%) had osteosarcoma, 13/34 (38%) Ewing's sarcoma, 2/34 (6%) synovial sarcoma and 2/34 (6%) embryonal liver sarcoma. Median follow-up was 39 months (range 16-84). Eight of 34 patients (24%) died, 9/34 (27%) were alive with disease, and 17/34 (50%) had no evidence of residual/recurrent disease. Fifteen of 34 (44%) and 19/34 (56%) were responders and non-responders, respectively. PET2-parameters were associated with longer TTP (p

The objective of this study was to explore radiomics features from longitudinal diffusion-weighted MRIs (DWIs) for pathologic treatment effect prediction in patients with localized soft tissue sarcoma (STS) undergoing hypofractionated preoperative radiotherapy (RT). Thirty patients with localized STS treated with preoperative hypofractionated RT were recruited to this longitudinal imaging study. DWIs were acquired at three time points using a 0.35 T MRI-guided radiotherapy system. Treatment effect score (TES) was obtained from the post-surgery pathology as a surrogate of treatment outcome. Patients were divided into two groups based on TES. Response prediction was first performed using a support vector machine (SVM) with only mean apparent diffusion coefficient (ADC) or delta ADC to serve as the benchmark. Radiomics features were then extracted from tumor ADC maps at each of the three time points. Logistic regression and SVM were constructed to predict the TES group using features selected by univariate analysis and sequential forward selection. Classification performance using SVM with features from different time points and with or without delta radiomics were evaluated. Prediction performance using only mean ADC or delta ADC was poor (area under the curve (AUC) < 0.7). For the radiomics study using features from all time points and corresponding delta radiomics, SVM significantly outperformed logistic regression (AUC of 0.91 ± 0.05 v.s. 0.85 ± 0.06). Prediction AUC values using single or multiple time points without delta radiomics were all below 0.74. Including delta radiomics of mid- or post-treatment relative to the baseline drastically boosted the prediction. In this work, an SVM model was built to predict the TES using radiomics features from longitudinal DWI. Based on this study, we found that use of mean ADC, delta ADC, or radiomics features alone was not sufficient for response prediction, and including delta radiomics features of mid- or post-treatment relative to the baseline can optimize the prediction of TES, a pathologic and clinical endpoint.

The use of upfront chemotherapy for primary localized soft tissue sarcoma (STS) of the extremity and trunk is debated. It remains unclear if chemotherapy adds clinical benefit, which patients are likely to benefit, and whether the timing of therapy affects outcomes. We used the National Cancer Database (NCDB) to examine the association between overall survival (OS) and chemotherapy in 5436 patients with the five most common subtypes of STS with primary disease localized to the extremity or trunk, mirroring the patient population of a modern phase 3 clinical trial of neoadjuvant chemotherapy. We then examined associations between timing of multi-agent chemotherapy (neoadjuvant or adjuvant) and OS. We used a Cox proportional hazards model and propensity score matching (PSM) to account for covariates including demographic, patient, clinical, treatment, and facility factors. In the overall cohort, we observed no association between multi-agent chemotherapy or its timing and improved OS. Multi-agent chemotherapy was associated with improved OS in several subgroups, including patients with larger tumors (>5 cm), those treated at high-volume centers, or those who received radiation. We also identified an OS benefit to multi-agent chemotherapy among the elderly (>70 years) and African American patients. Multi-agent chemotherapy was associated with improved survival for patients with tumors >5 cm, who receive radiation, or who receive care at high-volume centers. Neither younger age nor chemotherapy timing was associated with better outcomes. These 'real-world' findings align with recent randomized trial data supporting the use of multi-agent chemotherapy in high-risk patients with localized STS.

PurposeIn a single-institution phase II study, we evaluated the safety of a 5-day dose-equivalent neoadjuvant radiotherapy (RT) regimen for high-risk primary soft tissue sarcoma.Patients and methodsPatients received neoadjuvant RT alone (30 Gy in five fractions) to the primary tumor with standard margins. The primary endpoint was grade ≥2 late-radiation toxicity. Major wound complications, local recurrences, and distant metastases were also examined. In exploratory analysis, we evaluated germline biomarkers for wound toxicity and the effects of the study on treatment utilization.ResultsOver 2 years, 52 patients were enrolled with median follow-up of 29 months. Seven of 44 evaluable patients (16%) developed grade ≥2 late toxicity. Major wound complications occurred in 16 of 50 patients (32%); a signature defined by 19 germline SNPs in miRNA-binding sites of immune and DNA damage response genes, in addition to lower extremity tumor location, demonstrated strong predictive performance for major wound complications. Compared with the preceding 2-year period, the number of patients treated with neoadjuvant RT alone at our institution increased 3-fold, with a concomitant increase in the catchment area.ConclusionsA shorter 5-day neoadjuvant RT regimen results in favorable rates of wound complications and grade ≥2 toxicity after 2-year follow-up. Five-day RT significantly increased utilization of neoadjuvant RT at our high-volume sarcoma center. With further validation, a putative germline biomarker for wound complications may guide safer RT utilization.

ObjectivesPeripheral nerve sheath tumors (PNSTs) are clinically heterogenous, comprising benign (BPNST) and malignant (MPNST) variants. BPNSTs can be managed with nerve-sparing excision or observation. MPNSTs require radical resection and multidisciplinary oncologic management (1, 15). Image-guided core-needle biopsy (IGCNBx) is the well-established standard to obtain preoperative tissue diagnosis of soft tissue tumors. However, there has been resistance to performing IGCNBx of PNSTs because of the presumed risk of nerve injury and unknown accuracy in determining malignancy. We sought to define the accuracy and safety of IGCNBx in PNSTs.Materials and methodsAll patients that underwent both IGCNBx and surgical resection of a PNST at our institution between 2002 and 2016 were analyzed. The accuracy of IGCNBx in determining malignancy was calculated, including subgroup analyses by histologic subtype and neurofibromatosis 1 status. Complication data were collected and analyzed.ResultsAmong the 78 PNSTs with IGCNBx and postresection surgical pathology, 76% (n=59) had BPNST and 24% (n=19) had MPNST on postresection surgical pathology. IGCNBx accurately determined malignancy in 94% of cases. IGCNBx demonstrating schwannoma or MPNST were 100% accurate in determining malignancy. IGCNBx demonstrating neurofibroma or indeterminate results were 33% and 57% malignant on postresection surgical pathology, respectively. There were no long-term complications, including sensory or motor deficits, from IGCNBx.ConclusionsPercutaneous IGCNBx demonstrates 94% accuracy in differentiating benign from malignant PNSTs. IGCNBx demonstrating neurofibroma or indeterminate pathology should be interpreted with caution because of risk of malignant reclassification on surgical pathology. Our results reaffirm the safety of IGCNBx, as no patients experienced long-term complications.

Denosumab has been used successfully to treat disease-associated osteoclast overactivity, including giant cell tumor of bone. Given its mechanism of action, denosumab is a potent potential treatment of other osteoclast bone dysplasias including central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC), and cherubism. Relatively little is known about the safety and efficacy of denosumab in patients with these conditions, especially in children. We report on 3 pediatric patients treated with denosumab over a 3-year period at UCLA Medical Center (Los Angeles and Santa Monica, CA, USA): a 12-year-old with recurrent ABC of the pelvis, a 14-year-old with CGCG of the mandible, and a 12-year-old with cherubism. All were started on a 1-year course of 15 doses 120 mg s.c., given monthly with two loading doses on day 8 and 15. All patients demonstrated rapid and pronounced clinical improvement while on denosumab, including a significant reduction in pain and sclerosis of lytic lesions on radiographs. Within 1 month of initiating therapy, 2 patients experienced hypocalcemia (Common Terminology Criteria for Adverse Events [CTCAE] grade 2) and hypophosphatemia, with 1 patient experiencing symptoms. One patient went on to experience symptomatic rebound hypercalcemia (CTCAE grade 4) 5 months after completing therapy, requiring bisphosphonates and calcitonin. For the second patient, we developed a schedule to wean denosumab involving the progressive lengthening of time between doses from 1 to 4 months in 1-month increments before cessation. We found that denosumab therapy results in significant clinical and radiographic improvement for pediatric patients with nonresectable ABC, CGCG, and cherubism. Problems with serum calcium may be more common in younger patients, with symptomatic and protracted rebound hypercalcemia after cessation of therapy the most significant. We present a potential solution to this problem with progressive spacing of doses. Potential serious adverse events from alterations in calcium homeostasis should be explored in prospective clinical trials. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

BACKGROUND:Malignant peripheral nerve sheath tumors (MPNSTs) comprise a rare, aggressive subtype of soft tissue sarcoma. While surgery is the mainstay of therapy for this disease, the role of neoadjuvant therapy remains undefined. METHODS:This study reviewed patients 16 years of age and older who underwent surgical treatment for MPNST between 1974 and 2012 at the authors' institution. Univariate and multivariate analyses were performed of clinicopathologic and treatment variables predictive of disease-specific survival (DSS) and disease-free survival. RESULTS:Eighty-eight patients with primary localized MPNST underwent surgical treatment between 1974 and 2012 at our institution. Of these, 38 (43%) underwent neoadjuvant chemotherapy and had tissue available for analysis. Neoadjuvant radiation was given to 25 patients (68%). The median follow-up time for survivors was 12.5 years (range, 4 to 27 y). Nine patients (23%) had underlying MPNST. With a cutoff of ≥90% pathologic necrosis and/or fibrosis defining response, we identified 14 responders (36%). On univariate analysis, patient age, tumor size, and pathologic response were significantly associated with DSS (P=0.015, 0.011, and 0.030, respectively). CONCLUSIONS:Although the impact of neoadjuvant chemotherapy on the outcome of primary localized MPNST patients continues to be debated, this study shows that a pathologic response to therapy is associated with a significant improvement in DSS. The challenge moving forward is to determine upfront which patients will be "responders" to standard systemic therapy and which patients should be considered for newer investigational agents as part of a clinical trial.

The photoelectric Factor (PEF) log is a powerful tool for distinguishing between siliciclastic and carbonate lithofacies in well-log analysis and 2D correlations. However, its application in complex reservoirs has some challenges due to well spacing. We present a workflow to extend its capabilities into a 3D environment to characterize the Pennsylvanian Strawn and Canyon reef complex in the Salt Creek field, Kent County, West Texas. The productive zones within this reservoir are composed of porous oolitic grainstones and skeletal packstones. However, there are some porous shale beds within the reef complex that are indistinguishable from the porous limestone zones on the neutron porosity log that have posed major challenges to hydrocarbon production. To address these problems, we used a machine-learning procedure involving multiattribute analysis and probabilistic neural network (PNN) to predict photoelectric factor (PEF) volume to characterize the reservoir and identify the shale beds. By combining neutron porosity, gamma ray, and the predicted PEF logs, we found that (1) these shale beds, hereby referred to as shale-influenced carbonates, are characterized by photoelectric factor values ranging from 4 to 4.26 B/E. (2) Based on the PEF values, the least porous interval is the Canyon System, having <1% porosity and characterized by PEF values of >4.78 B/E; while the most porous interval is the Strawn System, composed mostly of zones with porosity ranging from 3% to 28%, characterized by PEF values varying from 4.26 to 4.78 B/E. [ABSTRACT FROM AUTHOR]

ObjectivesThe objective of this study was to analyze outcomes for patients with soft tissue sarcoma of the extremities using neoadjuvant ifosfamide-based chemotherapy and hypofractionated reduced dose radiotherapy, followed by limb-sparing surgery.Materials and methodsAn Institutional Review Board (IRB)-approved retrospective review of patients treated at a single institution between 1990 and 2013 was performed. In total, 116 patients were identified who received neoadjuvant ifosfamide-based chemotherapy and 28 Gy in 8 fractions of preoperative radiation (equivalent dose in 2 Gray fractions, 31.5 Gy [α/β 10] 36.4 Gy [α/β 3]) followed by limb-sparing surgery. Local recurrence (LR), distant failure (DF), and overall survival (OS) were calculated. Univariate and multivariate analysis for LR, DF, and OS were performed using Cox analysis. Statistical significance was set at a P

BackgroundPleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS.MethodsWe used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight.ResultsThe PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p

Pleomorphic liposarcoma (PLPS) is a recalcitrant soft-tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient-derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)-treated; and treated with Salmonella typhimurium A1-R (S. typhimurium A1-R) expressing green fluorescent protein (GFP). Tumor volume and body weight were monitored during the treatment period. The PLPS PDOX was resistant to DOX. In contrast, the PLPS PDOX was highly sensitive to S. typhimurium A1-R. There was no significant body-weight loss among these 3 groups. Fluorescence imaging demonstrated that S. typhimurium A1-R-GFP was very effective to target the PLPS PDOX tumor. The current study demonstrates that a PLPS PDOX, resistant to first-line therapy DOX, was highly sensitive to tumor targeting S. typhimurium A1-R.

Gastrointestinal stromal tumor (GIST) is a refractory disease in need of novel efficacious therapy. The aim of our study was to evaluate the effectiveness of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) using on a patient derived orthotopic xenograft (PDOX) model of imatinib-resistant GIST. The GIST was obtained from a patient with regional recurrence, and implanted in the anterior gastric wall of nude mice. The GIST PDOX mice were randomized into 3 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group; G2, imatinib group (oral administration [p.o.], daily, for 3 weeks); G3, S. typhimurium A1-R group (intravenous [i.v.] injection, weekly, for 3 weeks). All mice from each group were sacrificed on day 22. Relative tumor volume was estimated by laparotomy on day 0 and day 22. Body weight of the mouse was evaluated 2 times per week. We found that S. typhimurium A1-R significantly reduced tumor growth in contrast to the untreated group (P = 0.001). In addition, we found that S. typhimurium A1-R was more effective compared to imatinib (P = 0.013). Furthermore, Imatinib was not significantly effective compared to the control group (P = 0.462). These results indicate that S. typhimurium A1-R may be new effective therapy for imatinib-resistant GIST and therefore a good candidate for clinical development of this disease.

Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p < 0.001) and rMETase alone (p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease.

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.

In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. typhimurium A1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G2, and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586; rMETase: p = 0.002; S. typhimurium A1-R: p = 0.002; S. typhimurium A1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.

Doxorubicin (DOX) is often first-line treatment of undifferentiated/unclassified soft tissue sarcoma (USTS). However, the DOX response rate for USTS patients is low. Individualized precision-medicine technology that could identify DOX responders as well as non-responders would be of high value to cancer patients. In the present study, we established 5 patient-derived orthotopic xenograft (PDOX) nude mouse models from 5 USTS patients and evaluated the efficacy of DOX in each PDOX model. USTS's were grown orthotopically in the right thigh of nude mice to establish the PDOX models. Two weeks after implantation, the mouse models were randomized into two groups of 8 mice each: untreated control; and DOX (3 mg/kg, i.p., once a week for 2 weeks). DOX showed significant growth inhibition in only 2 USTS PDOX models out of 5 (p = 0.0054, p = 0.0055, respectively) on day 14 after initiation. DOX was ineffective in the other 3 PDOX models. However, even in the DOX-sensitive cases, DOX could not regress the PDOX tumors responding to treatment. The present study has important implications since this is the first in vivo study to compare the DOX sensitivity for USTS on multiple patient tumors. We showed that only two of five USTS were responsive to DOX, despite DOX being first line chemotherapy for USTS. The 3 resistant cases should not be treated with DOX clinically, in order to spare the patients' unnecessary toxicity. This PDOX model is useful for precise individualized drug sensitivity testing, especially for rare heterogeneous recalcitrant sarcomas such as USTS.

Background and objectiveCemented endoprosthetic reconstruction after resection of primary bone sarcomas has been a standard-of-care option for decades. With increased patient survival, the incidence of failed endoprostheses requiring revision surgery has increased. Revision of cemented endoprotheses by cementing into the existing cement mantle (CiC) is technically demanding.MethodsThis is a retrospective review of our endoprosthesis database of 512 consecutive cemented endoprosthetic reconstructions performed for oncologic diagnoses between 1980 and 2014. A total of 54 implants (mean patient age 32 years, range 13-81) were revised with a CiC technique. Outcomes evaluated were prosthesis survival, revision surgery categorized according to the Henderson Failure Mode Classification, complications, and functional scores.ResultsFifteen-year Kaplan-Meier survival rate was 34% for initial revision and 39% for subsequent revision implants. Mean revised Musculoskeletal Tumor Society (MSTS) Score was 27 at latest follow-up. Infection rate was 2%, 9%, and 13% for primary endoprostheses, initial revisions, and subsequent revisions, respectively. Limb salvage rate was 87%.ConclusionsAt long-term follow up, endoprostheses revised with the CiC technique showed consistent 15-year survival from initial (34%) to subsequent (39%) revision. Despite a relatively high failure rate, these results are encouraging and demonstrate that this is a conservative, repeatable technique.