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Item Anticancer peptides from induced tumor-suppressing cells for inhibiting osteosarcoma cells(e-Century, 2023-09-15) Cui, Chang-Peng; Huo, Qing-Ji; Xiong, Xue; Li, Ke-Xin; Ma, Peng; Qiang, Gui-Fen; Pandya, Pankita H.; Saadatzadeh, Mohammad R.; Vishehsaraei, Khadijeh Bijangi; Kacena, Melissa A.; Aryal, Uma K.; Pollok, Karen E.; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyOsteosarcoma (OS) is the most frequent primary bone cancer, which is mainly suffered by children and young adults. While the current surgical treatment combined with chemotherapy is effective for the early stage of OS, advanced OS preferentially metastasizes to the lung and is difficult to treat. Here, we examined the efficacy of ten anti-OS peptide candidates from a trypsin-digested conditioned medium that was derived from the secretome of induced tumor-suppressing cells (iTSCs). Using OS cell lines, the antitumor capabilities of the peptide candidates were evaluated by assaying the alterations in metabolic activities, proliferation, motility, and invasion of OS cells. Among ten candidates, peptide P05 (ADDGRPFPQVIK), a fragment of aldolase A (ALDOA), presented the most potent OS-suppressing capabilities. Its efficacy was additive with standard-of-care chemotherapeutic agents such as cisplatin and doxorubicin, and it downregulated oncoproteins such as epidermal growth factor receptor (EGFR), Snail, and Src in OS cells. Interestingly, P05 did not present inhibitory effects on non-OS skeletal cells such as mesenchymal stem cells and osteoblast cells. Collectively, this study demonstrated that iTSC-derived secretomes may provide a source for identifying anticancer peptides, and P05 may warrant further evaluations for the treatment of OS.Item Clinical and radiographic presentation of pelvic sarcoma in children(EDP Sciences, 2018) Kadhim, Muayad; Oyoun, Nariman Abol; Womer, Richard B.; Dormans, John P.; Orthopaedic Surgery, School of MedicineINTRODUCTION: Pelvic sarcomas may present with vague symptoms. The aim of this study was to examine the characteristics and clinical presentations of different types of pelvic sarcoma in children. METHODS: This is a retrospective cohort study of patients up to 21 years of age with the diagnosis of pelvic sarcoma between January 2000 and June 2013. Data on demographics, tumor type and location, and clinical presentation were collected from the medical records. RESULTS: A total of 59 patients [37 males (62.7%) and 22 females (37.3%)] were examined in this study. Mean age at presentation was 11.3 ± 5 years (range 0.8-21 years). Thirty-six patients had Ewing sarcoma (61%), 9 osteosarcoma (6.8%), 4 undifferentiated sarcoma (6.8%), 2 (3.4%) rhabdomyosarcoma, 2 synovial cell sarcoma, and one (1.7%) of each fibrosarcoma, dermatofibrosarcoma, fibromyxoid sarcoma, chondrosarcoma, chordoma, and epithelioid sarcoma. Pain at presentation was reported in 41 patients, 13 mass, 8 limping, and 5 neurologic symptoms. Most of the bony tumors were painful (77%), while most of the soft tissue tumors were painless (70%). Nine patients presented with constitutional symptoms. Most patients presented within 4-12 months from symptoms beginning. Twenty-one patients (35.6%) presented with metastases (14 Ewing sarcoma, 6 osteosarcoma, and 1 synovial cell sarcoma). Pelvic radiographs showed lytic lesion in 11 patients, 4 sclerotic lesions, 6 mixed lesion, 6 had only soft tissue mass, 1 radiograph showed osteopenia, and 2 radiographs were reported normal. CONCLUSION: Ewing sarcoma was the most common pelvic sarcoma tumor in children. In most cases, pelvic sarcoma in children presented with pain mimicking other benign conditions. Some patients presented with metastatic disease with no prognostic clinical or radiographical signs or symptoms. Pelvic sarcoma should be considered a differential diagnosis as part of children work up.Item D136. Spare the Limb and Spoil the Outcome: Why do Some Osteosarcoma Patients Pursue Revision Amputation and Does the Amputation Improve The Outcome?(Wolters Kluwer, 2023-04-26) Polovneff, Alexandra; Seitz, Vienne; Panoch, Janet; Hoben, Gwendolyn; Obstetrics and Gynecology, School of MedicinePURPOSE: There is tremendous emphasis on limb sparing surgery (LSS) in osteosarcoma. However, a substantial number of LSS patients choose to transition to an amputation-type revision, including rotation-plasty and turn-up plasty. The purpose of this study was to determine motivating factors for revision and whether those interventions better address the motivating factors. METHODS: We identified the most popular public Osteosarcoma Facebook group and selected posts from a 12 month period regarding surgical interventions. We used iterative inductive and deductive thematic analysis to collect qualitative data RESULTS: 378 comments from the Osteosarcoma and Ewing’s Sarcoma Support Group were analyzed. Three themes emerged: (1) There is a lack of options presented to patients seeking treatment of osteosarcoma. (2) Many patients were unsatisfied and regretted their decision to undergo LSS because of numerous revisions, physical limitations, and chronic pain. (3) Many patients treated primarily or secondarily (following LSS) with rotation-plasty were satisfied with their lifestyle outcomes and mentioned improved mobility, range of motion, and limited chronic pain. CONCLUSION: LSS can result in significant morbidity and despite sparing the limb, some patients are choosing to pursue amputation. Further work will need to examine amputation interventions to ensure that they can successfully address the problems identified with LSS, including mobility and pain. Prior concerns with amputation, including phantom limb pain, can now be addressed with targeted muscle reinnervation and regenerative peripheral nerve interfaces. Moreover, these options may deserve more discussion in the setting of the primary surgery.Item Do Surgical Margins Affect Local Recurrence and Survival in Extremity, Nonmetastatic, High-grade Osteosarcoma?(Springer, 2016-03) Bertrand, Todd E.; Cruz, Alex; Binitie, Odion; Cheong, David; Letson, G. Douglas; Department of Orthopaedic Surgery, IU School of MedicineBACKGROUND: Long-term survival for all patients with osteosarcoma using current aggressive adjuvant chemotherapy and surgical resection is between 60% and 70%. In patients who present with nonmetastatic, high-grade extremity osteosarcoma of bone, limb salvage surgery is favored, when appropriate, over amputation to preserve the limb, because limb salvage may lead to a superior quality of life compared with amputation. However, concern remains that in the attempt to preserve the limb, close or microscopically positive surgical margins may have an adverse effect on event-free survival. QUESTIONS/PURPOSES: (1) Does a positive or close surgical margin increase the likelihood of a local recurrence? (2) Does a positive or close surgical margin adversely affect the development of metastatic disease? (3) What is the relationship of surgical margin on overall survival? METHODS: With institutional review board approval, we retrospectively evaluated 241 patients treated at our institution between 1999 and 2011. Exclusion criteria included nonextremity locations, metastatic disease at initial presentation, low- or intermediate-grade osteosarcoma, treatment regimens that did not follow National Comprehensive Cancer Network (NCCN) guidelines, incomplete medical records, and any part of treatment performed outside of Moffitt Cancer Center or All Children's Hospital. Fifty-one patients were included in the final analysis, of whom 31 (61%) had followup data at a minimum of 2 years or whose clinical status was known but had died before 2 years of followup. Margin status was defined as (1) microscopically positive; (2) negative ≤ 1 mm; and (3) negative > 1 mm. Margin status, histologic response (tumor percent necrosis), type of osteosarcoma, type of surgery, presence of local recurrence, metastatic disease, and overall survival were recorded for each patient. The mean age was 22 years (range, 12-74 years) and the mean followup was 3 years (range, 0.1-14 years). Margin status was positive in 10% (five of 51), negative ≤ 1 mm 26% (13 of 51), and negative > 1 mm 65% (33 of 51). RESULTS: Local recurrence was noted to be 14% (seven of 51) at 3.4 years. After controlling for relevant confounding variables, the presence of a positive margin compared with a negative margin > 1 mm was the only independent predictor of local recurrence (hazard ratio [HR], 8.006; 95% confidence interval [CI], 1.314-48.781; p = 0.0241). At a mean of 3.4 years, 29% (15 of 51) of the patients developed metastatic disease with no difference with the numbers available in the probability of developing metastatic disease among the three margin groups (p = 0.614). Overall survival at 3.8 years was 75% (38 of 51). After controlling for relevant confounding variables, we found that patients with positive margins were more likely to die from disease than those with negative margins (HR, 6.26; 95% CI, 1.50-26.14; p = 0.0119); no other independent predictors of survival were identified. CONCLUSIONS: With the numbers of patients we had, we observed that patients with extremity, nonmetastatic, high-grade osteosarcoma who had positive margins showed a higher probability of local recurrence in comparison to those with negative surgical margins. Given that positive margins appear to be associated with poorer survival in patients with high-grade osteosarcoma of the extremities, surgeons should strive to achieve negative margins, but larger studies are needed to confirm these findings. LEVEL OF EVIDENCE: Level III, therapeutic study.Item Engineering Oncolytic Vaccinia Virus to redirect Macrophages to Tumor Cells(Wiley, 2021) Cao, Felicia; Nguyen, Phuong; Hong, Bangxing; DeRenzo, Christopher; Rainusso, Nino C.; Rodriguez Cruz, Tania; Wu, Meng-Fen; Liu, Hao; Song, Xiao-Tong; Suzuki, Masataka; Wang, Lisa L.; Yustein, Jason T.; Gottschalk, Stephen; Biostatistics and Health Data Science, School of MedicineOncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system. We reasoned that it might also be possible to engineer oncolytic viruses to redirect tumor-associated macrophages to tumor cells for therapeutic benefit. We engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα-Fc-VV). SIRPα-Fc-VV readily replicated in tumor cells and redirected M1 as well as M2 macrophages to tumor cells in vitro. In contrast, control VVs that either encoded YFP (YFP-VV) or SIRPα (SIRPα-VV) did not. In vivo, SIRPα-Fc-VV had greater antitumor activity than YFP-VV and SIRPα-VV in an immune competent osteosarcoma model resulting in a significant survival advantage. Pretreatment with cytoxan further augmented the antitumor activity of SIRPα-Fc-VV. Thus, arming oncolytic viruses with SIRPα-Fc may present a promising strategy to enhance their antitumor activity for the virotherapy of solid tumors.Item Enhancing anti-tumor potential: low-intensity vibration suppresses osteosarcoma progression and augments MSCs' tumor-suppressive abilities(Ivyspring, 2024-01-27) Xiong, Xue; Huo, Qingji; Li, Kexin; Cui, Changpeng; Chang, Chunyi; Park, Charles; Ku, BonHeon; Hong, Chin-Suk; Lim, HeeChang; Pandya, Pankita H.; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Lin, Chien-Chi; Kacena, Melissa A.; Pollok, Karen E.; Chen, Andy; Liu, Jing; Thompson, William R.; Li, Xue-Lian; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyRationale: Osteosarcoma (OS), a common malignant bone tumor, calls for the investigation of novel treatment strategies. Low-intensity vibration (LIV) presents itself as a promising option, given its potential to enhance bone health and decrease cancer susceptibility. This research delves into the effects of LIV on OS cells and mesenchymal stem cells (MSCs), with a primary focus on generating induced tumor-suppressing cells (iTSCs) and tumor-suppressive conditioned medium (CM). Methods: To ascertain the influence of vibration frequency, we employed numerical simulations and conducted experiments to determine the most effective LIV conditions. Subsequently, we generated iTSCs and CM through LIV exposure and assessed the impact of CM on OS cells. We also explored the underlying mechanisms of the tumor-suppressive effects of LIV-treated MSC CM, with a specific focus on vinculin (VCL). We employed cytokine array, RNA sequencing, and Western blot techniques to investigate alterations in cytokine profiles, transcriptomes, and tumor suppressor proteins. Results: Numerical simulations validated LIV frequencies within the 10-100 Hz range. LIV induced notable morphological changes in OS cells and MSCs, confirming its dual role in inhibiting OS cell progression and promoting MSC conversion into iTSCs. Upregulated VCL expression enhanced MSC responsiveness to LIV, significantly bolstering CM's efficacy. Notably, we identified tumor suppressor proteins in LIV-treated CM, including procollagen C endopeptidase enhancer (PCOLCE), histone H4 (H4), peptidylprolyl isomerase B (PPIB), and aldolase A (ALDOA). Consistently, cytokine levels decreased significantly in LIV-treated mouse femurs, and oncogenic transcript levels were downregulated in LIV-treated OS cells. Moreover, our study demonstrated that combining LIV-treated MSC CM with chemotherapy drugs yielded additive anti-tumor effects. Conclusions: LIV effectively impeded the progression of OS cells and facilitated the transformation of MSCs into iTSCs. Notably, iTSC-derived CM demonstrated robust anti-tumor properties and the augmentation of MSC responsiveness to LIV via VCL. Furthermore, the enrichment of tumor suppressor proteins within LIV-treated MSC CM and the reduction of cytokines within LIV-treated isolated bone underscore the pivotal tumor-suppressive role of LIV within the bone tumor microenvironment.Item Intracardiac extension of chondroblastic osteosarcoma(Oxford University Press, 2021) Madison, Mackenzie K.; Matthews, Caleb R.; Lee, Lawrence S.; Surgery, School of MedicineIntravascular tumour extension invading the intracardiac space is rarely seen with osteosarcoma. We present a patient with a history of previously resected pelvic osteosarcoma who was later found to have a local recurrence with continuous intravascular extension from the right femoral vein to the right atrium. Preoperative imaging studies initially described extensive thrombus burden, and a multidisciplinary approach involving open and percutaneous thrombectomy was planned. Intraoperative inspection and pathological analysis revealed unresectable malignant solid tumour rather than thrombus. Though exceedingly rare, the possibility of metastatic tumour must be considered when planning treatment strategies for these patients.Item Limb-salvage surgery offers better five-year survival rate than amputation in patients with limb osteosarcoma treated with neoadjuvant chemotherapy. A systematic review and meta-analysis(Elsevier, 2020-09-15) Papakonstantinou, Evgenia; Stamatopoulos, Alexandros; I Athanasiadis, Dimitrios; Kenanidis, Efstathios; Potoupnis, Michael; Haidich, Anna-Bettina; Tsiridis, Eleftherios; Medicine, School of MedicineBackground Osteosarcoma is the most common primary bone sarcoma. Currently, the main treatment option for high-grade osteosarcomas is neoadjuvant chemotherapy, followed by surgical resection of the lesion and adjuvant chemotherapy. Limb salvage surgery (LSS) and amputation are the main surgical techniques; however, controversy still exists concerning the best surgical method. Our meta-analysis compared the effectiveness of LSS and amputation combined with neoadjuvant chemotherapy in patients with limb osteosarcoma, in terms of 5-year overall survival (OS), 5-year disease-free survival (DFS) and local recurrence rate. Methods Following the established methodology of PRISMA guidelines, a literature search was conducted in PubMed, Cochrane, Google Scholar from 1975 until January 2020. Two independent reviewers evaluated the study quality based on the Newcastle-Ottawa scale. Odds ratio and 95% confidence interval of the OS, DFS and local recurrence rate were calculated. Results Thirteen studies were finally included with a total of 2884 patients; 1986 patients undergone LSS and 898 amputations. Five-year overall survival was almost 2-fold in patients treated with LSS than those treated with amputation (OR: 1.99; 95% CI: 1.35–2.93; I2 = 74%, p < 0.001). No difference was found in 5-year DFS between LSS patients and amputees (OR: 1.24; 95% CI: 0.55–2.79; I2 = 67%, p = 0.01). The odds of local recurrence was numerically higher in LSS compared to amputation but not statistically significant (OR: 2.29; 95% CI: 0.95–5.53; I2 = 47%, p = 0.05). However, the included studies did not clearly define differences in the stages of patients of the two groups. Conclusion Our study demonstrated that in patients with limb osteosarcoma treated with neoadjuvant chemotherapy, LSS is associated with a higher 5-year overall survival and the odds of local recurrence may be increased but these results should be interpreted with caution due to high heterogeneity.Item MiR-20a-5p represses multi-drug resistance in osteosarcoma by targeting the KIF26B gene(BioMed Central, 2016-08-05) Pu, Youguang; Zhao, Fangfang; Wang, Haiyan; Cai, Wenjing; Cai, Shanbao; Fi, Qiyi; Department of Medicine, IU School of MedicineBACKGROUND: Chemoresistance hinders curative cancer chemotherapy in osteosarcoma (OS), resulting in only an approximately 20 % survival rate in patients with metastatic disease at diagnosis. Identifying the mechanisms responsible for regulating chemotherapy resistance is crucial for improving OS treatment. METHODS: This study was performed in two human OS cell lines (the multi-chemosensitive OS cell line G-292 and the multi-chemoresistant OS cell line SJSA-1). The levels of miR-20a-5p and KIF26B mRNA expression were determined by quantitative real-time PCR. KIF26B protein levels were determined by western blot analysis. Cell viability was assessed by MTT assay. Apoptosis was evaluated by flow cytometry. RESULTS: We found that miR-20a-5p was more highly expressed in G-292 cells than in SJSA-1 cells. Forced expression of miR-20a-5p counteracted OS cell chemoresistance in both cell culture and tumor xenografts in nude mice. One of miR-20a-5p's targets, kinesin family member 26B (KIF26B), was found to mediate the miR-20a-5p-induced reduction in OS chemoresistance by modulating the activities of the MAPK/ERK and cAMP/PKA signaling pathways. CONCLUSIONS: In addition to providing mechanistic insights, our study revealed that miR-20a-5p and KIF26B contribute to OS chemoresistance and determined the roles of these genes in this process, which may be critical for characterizing drug responsiveness and overcoming chemoresistance in OS patients.Item The New Treatment of Osteosarcoma by Biologic Response Modifiers(Office of the Vice Chancellor for Research, 2016-04-08) Chen, Xiaoping; Zhao, Huadong; Cheng, LiangOsteosarcoma is a kind of bone cancer mainly affecting children and young adults and is lethal in about a third of cases. The treatment of osteosarcoma has evolved greatly during the last 40 years, however, the great progress that was seen in the 1970s and early 1980s has since stalled. The main challenge now is that advanced combination treatment can’t continue prolong the survival. Based on the micro-metastatic disease related to shorter survival, biologic response modifiers become a new treatment which can stimulate the immune system to eradicate minimal residual disease post-surgery, chemotherapy and radiotherapy. This kind immune treatment may improve the disease-free and long-term survival rates of patients. Mifamurtide is a novel biologic response modifier which is indicated for the treatment of highgrade, non-metastasizing, resectable osteosarcoma following complete surgical removal in children, adolescents, and young adults. In our study, we searched for non-phase l Mifamurtide clinical studies on osteosarcoma through Medline, Google Scholar, and Clinical Trial Government Database. Among six clinical studies we found, two phase ll trials, one phase lll trial, one patient-access study, one decision study, and one cohort study. We systematically analyzed these studies and further evaluated the efficacy, side effects and safety of Mifamurtide on osteosarcoma.