Special Issue "Bone and Soft Tissue Tumors"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2020).

Special Issue Editor

Dr. Shinji Miwa
E-Mail Website
Guest Editor
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
Interests: bone and soft tissue tumors; surgery; reconstruction
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Due to the rarity and heterogeneity of bone and soft tissue tumors, investigation into molecular targets and new treatments has been particularly challenging. Although intensive chemotherapy and establishment of surgical procedures have improved the outcomes of patients with bone and soft tissue tumors, the curative rate of recurrent and metastatic sarcomas remains unsatisfactory. Recent basic science research has revealed some of the mechanisms of progression and metastasis of malignancies including proliferation, apoptosis, angiogenesis, tumor microenvironment, migration, invasion, and regulation of antitumor immune systems. Based on these basic studies, new anticancer drugs have been developed and the efficacies and safety of the new drugs have been assessed by clinical trials. This review summarizes new molecular therapeutic targets and advances in the treatment for bone and soft tissue sarcomas.

This Special Issue of Cancers aims to bring together the highest quality original/review articles on basic and clinical research for bone and soft tissue tumors. Molecular biology, microenvironment, mechanisms of metastasis, as well as articles analyzing recent clinical researches of new therapeutic approaches are invited.

Dr. Shinji Miwa
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (20 papers)

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Editorial

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Open AccessEditorial
Bone and Soft Tissue Tumors: New Treatment Approaches
Cancers 2021, 13(8), 1832; https://doi.org/10.3390/cancers13081832 - 12 Apr 2021
Viewed by 195
Abstract
Bone and soft tissue sarcomas require intensive treatments, including chemotherapy, surgical resection with safe margin, and radiotherapy [...] Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)

Research

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Open AccessArticle
Autophagy in Osteosarcoma Cancer Stem Cells Is Critical Process which Can Be Targeted by the Antipsychotic Drug Thioridazine
Cancers 2020, 12(12), 3675; https://doi.org/10.3390/cancers12123675 - 07 Dec 2020
Viewed by 441
Abstract
Cancer stem cells (CSCs) represent a minor population of cancer cells with stem cell-like properties which are able to fuel tumor growth and resist conventional treatments. Autophagy has been described to be upregulated in some CSCs and to play a crucial role by [...] Read more.
Cancer stem cells (CSCs) represent a minor population of cancer cells with stem cell-like properties which are able to fuel tumor growth and resist conventional treatments. Autophagy has been described to be upregulated in some CSCs and to play a crucial role by maintaining stem features and promoting resistance to both hostile microenvironments and treatments. Osteosarcoma (OS) is an aggressive bone cancer which mainly affects children and adolescents and autophagy in OS CSCs has been poorly studied. However, this is a very interesting case because autophagy is often deregulated in this cancer. In the present work, we used two OS cell lines showing different autophagy capacities to isolate CSC-enriched populations and to analyze the autophagy in basal and nutrient-deprived conditions. Our results indicate that autophagy is more efficient in CSCs populations compared to the parental cell lines, suggesting that autophagy is a critical process in OS CSCs. We also showed that the antipsychotic drug thioridazine is able to stimulate, and then impair autophagy in both CSC-enriched populations, leading to autosis, a cell death mediated by the Na+/K+ ATPase pump and triggered by dysregulated accumulation of autophagosomes. Taken together, our results indicate that autophagy is very active in OS CSCs and that targeting this pathway to switch their fate from survival to death could provide a novel strategy to eradicate these cells in osteosarcoma. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis
Cancers 2020, 12(11), 3097; https://doi.org/10.3390/cancers12113097 - 23 Oct 2020
Cited by 2 | Viewed by 491
Abstract
The overall prognosis for sarcoma-based cancer patients has remained largely unchanged over the past 10 years. Because there is no effective anticancer drug for patients with chemoresistant osteosarcoma (OS), novel approaches are needed to improve the prognosis. Here, we investigated whether rapamycin (Rapa) [...] Read more.
The overall prognosis for sarcoma-based cancer patients has remained largely unchanged over the past 10 years. Because there is no effective anticancer drug for patients with chemoresistant osteosarcoma (OS), novel approaches are needed to improve the prognosis. Here, we investigated whether rapamycin (Rapa) could enhance the anti-tumor effects of gemcitabine (Gem) in OS. Gem dose-dependently killed the OS cells, but exhibited much lower cytotoxicity on osteoblasts. Treatment with a combination Gem and Rapa was much more effective than that of either single agent with respect to reducing cell viability, cell invasion, cell migration, and vascular endothelial growth factor production in vitro. Moreover, the combination of these agents suppressed tumor growth, angiogenesis, and lung metastasis in allograft and xenograft murine models of OS with minimal adverse effects. Overall, the combination therapy prolonged the overall survival of tumor-bearing mice. Mechanistically, Gem induced apoptosis and increased the levels of cleaved caspases, while Rapa induced autophagy and microtubule-associated protein light chain 3 (LC3)-I/LC3-II expression both in vitro and in vivo. Our findings suggest that chemotherapy using Gem combined with Rapa may be a novel and promising therapeutic approach for the treatment of OS. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
Molecular Characterisation of Canine Osteosarcoma in High Risk Breeds
Cancers 2020, 12(9), 2405; https://doi.org/10.3390/cancers12092405 - 25 Aug 2020
Cited by 1 | Viewed by 1127
Abstract
Dogs develop osteosarcoma (OSA) and the disease process closely resembles that of human OSA. OSA has a poor prognosis in both species and disease-free intervals and cure rates have not improved in recent years. Gene expression in canine OSAs was compared with non-tumor [...] Read more.
Dogs develop osteosarcoma (OSA) and the disease process closely resembles that of human OSA. OSA has a poor prognosis in both species and disease-free intervals and cure rates have not improved in recent years. Gene expression in canine OSAs was compared with non-tumor tissue utilising RNA sequencing, validated by qRT-PCR and immunohistochemistry (n = 16). Polymorphic polyglutamine (polyQ) tracts in the androgen receptor (AR/NR3C4) and nuclear receptor coactivator 3 (NCOA3) genes were investigated in control and OSA patients using polymerase chain reaction (PCR), Sanger sequencing and fragment analysis (n = 1019 Rottweilers, 379 Irish Wolfhounds). Our analysis identified 1281 significantly differentially expressed genes (>2 fold change, p < 0.05), specifically 839 lower and 442 elevated gene expression in osteosarcoma (n = 3) samples relative to non-malignant (n = 4) bone. Enriched pathways and gene ontologies were identified, which provide insight into the molecular pathways implicated in canine OSA. Expression of a subset of these genes (SLC2A1, DKK3, MMP3, POSTN, RBP4, ASPN) was validated by qRTPCR and immunohistochemistry (MMP3, DKK3, SLC2A1) respectively. While little variation was found in the NCOA3 polyQ tract, greater variation was present in both polyQ tracts in the AR, but no significant associations in length were made with OSA. The data provides novel insights into the molecular mechanisms of OSA in high risk breeds. This knowledge may inform development of new prevention strategies and treatments for OSA in dogs and supports utilising spontaneous OSA in dogs to improve understanding of the disease in people. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
MiR-155-5p and MiR-203a-3p Are Prognostic Factors in Soft Tissue Sarcoma
Cancers 2020, 12(8), 2254; https://doi.org/10.3390/cancers12082254 - 12 Aug 2020
Cited by 1 | Viewed by 492
Abstract
Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with a five-year survival rate of approximately 50%. Reliable molecular markers for risk stratification and subsequent therapy management are still needed. Therefore, we analyzed the prognostic potential of miR-155-5p and miR-203a-3p expression [...] Read more.
Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with a five-year survival rate of approximately 50%. Reliable molecular markers for risk stratification and subsequent therapy management are still needed. Therefore, we analyzed the prognostic potential of miR-155-5p and miR-203a-3p expression in a cohort of 79 STS patients. MiR-155-5p and miR-203a-3p expression was measured from tumor total RNA by qPCR and correlated with the demographic, clinicopathological, and prognostic data of the patients. Elevated miR-155-5p expression was significantly associated with increased tumor stage and hypoxia-associated mRNA/protein expression. High miR-155-5p expression and low miR-203a-3p expression, as well as a combination of high miR-155-5p and low miR-203a-3p expression, were significantly associated with poor disease-specific survival in STS patients in the Kaplan–Meier survival analyses (p = 0.027, p = 0.001 and p = 0.0003, respectively) and in the univariate Cox regression analyses (RR = 1.96; p = 0.031; RR = 2.59; p = 0.002 and RR = 4.76; p = 0.001, respectively), but not in the multivariate Cox regression analyses. In conclusion, the oncomiR miR-155-5p and the tumor suppressor-miR miR-203a-3p exhibit an association with STS patient prognosis and are suggested as candidates for risk assessment. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
The Perceived Impact of Length of the Diagnostic Pathway Is Associated with Health-Related Quality of Life of Sarcoma Survivors: Results from the Dutch Nationwide SURVSARC Study
Cancers 2020, 12(8), 2088; https://doi.org/10.3390/cancers12082088 - 28 Jul 2020
Cited by 1 | Viewed by 527
Abstract
Background: Sarcoma patients often experience a long time to diagnosis, known as the total interval. This interval can be divided into the patient (time from symptoms to doctor consultation) and diagnostic intervals (time from first consultation to diagnosis). In other cancers, a long [...] Read more.
Background: Sarcoma patients often experience a long time to diagnosis, known as the total interval. This interval can be divided into the patient (time from symptoms to doctor consultation) and diagnostic intervals (time from first consultation to diagnosis). In other cancers, a long total interval has been associated with worse outcomes, but its effect on health-related quality of life (HRQoL) has never been investigated among sarcoma patients. This study investigates the association between (1) the actual time to diagnosis and HRQoL; (2) the perceived impact of the diagnostic interval length and HRQoL; (3) the actual length and perceived impact of the length and the HRQoL of sarcoma survivors. Methods: A cross-sectional study was performed among sarcoma patients aged ≥18, diagnosed 2–10 years ago in the Netherlands. The participants completed a questionnaire on HRQoL, the time to diagnosis, the perceived impact of the diagnostic interval on HRQoL, and coping. Results: 1099 participants were included (response rate, 58%). The mean time since diagnosis was 67.4 months. More than half reported a patient (60%) or diagnostic interval (55%) ≥1 month. A third (31%) perceived a negative impact of the diagnostic interval length on HRQoL. Patient or diagnostic interval length was not associated with HRQoL. By contrast, participants perceiving a negative impact (32%) had lower HRQoL scores than those perceiving a positive (11%) or no impact (58%) (p = 0.000). This association remained significant in a multivariable model, in which maladaptive coping strategies and tumour characteristics were also found to be associated with HRQoL. Participants perceiving a negative impact of the length of the diagnostic interval related this to high psychological distress levels, more physical disabilities, and worse prognosis. Conclusion: The perceived impact of the diagnostic interval length was associated with the HRQoL of sarcoma survivors, whereas the actual length was not associated with HRQoL. Maladaptive coping strategies were independently associated with HRQoL. This offers opportunities for early intervention to improve HRQoL. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
Cross-Cultural Validation of the Italian Version of the Bt-DUX: A Subjective Measure of Health-Related Quality of Life in Patients Who Underwent Surgery for Lower Extremity Malignant Bone Tumour
Cancers 2020, 12(8), 2015; https://doi.org/10.3390/cancers12082015 - 23 Jul 2020
Viewed by 496
Abstract
The purpose of this study was to translate the English bone tumour DUX (Bt-DUX-Eng) questionnaire for lower extremity bone tumour patients, a disease-specific quality of life (QoL) instrument, into Italian and then examine the validity of the Italian version of Bt-DUX (Bt-DUX-It). The [...] Read more.
The purpose of this study was to translate the English bone tumour DUX (Bt-DUX-Eng) questionnaire for lower extremity bone tumour patients, a disease-specific quality of life (QoL) instrument, into Italian and then examine the validity of the Italian version of Bt-DUX (Bt-DUX-It). The adaptation and translation process included forward translation, back-translation, and a review of the back-translation by an expert committee. The Bt-DUX-It was validated in a sample of adolescents treated for lower extremity osteosarcoma in Italy. Assessments included the Bt-DUX, the Toronto Extremity Salvage Score (TESS), and the European Organization for Research and Treatment Core Quality of Life Questionnaire of Cancer Patients (EORTC QLQ-C30). Fifty-one patients with a median age of 20 years (range: 15–25) completed the questionnaires. The mean Bt-DUX score was 70 (range: 16.30–100). The internal consistency of the overall score and that of the Bt-DUX-It was good: Cronbach’s α was 0.95. Spearman’s correlation coefficient between the Bt-DUX (total and domain scores) and EORTC QLQ C30 and TESS were overall moderate to good, reaching a p-value <0.01 in all cases. The Bt-DUX-It version is a useful tool for measuring QoL in patients with bone tumour and has similar internal consistency, construct validity, and discrimination as those of the Dutch and English versions. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas
Cancers 2020, 12(7), 1873; https://doi.org/10.3390/cancers12071873 - 11 Jul 2020
Cited by 1 | Viewed by 1069
Abstract
Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic [...] Read more.
Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients—72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
Changes in Functional Outcome and Quality of Life in Soft Tissue Sarcoma Patients within the First Year after Surgery: A Prospective Observational Study
Cancers 2020, 12(2), 463; https://doi.org/10.3390/cancers12020463 - 17 Feb 2020
Cited by 2 | Viewed by 742
Abstract
Soft tissue sarcoma (STS) patients undergoing surgery may experience reduced functional outcome (FO) and quality of life (QoL) compared to the general population. The aim of this study was to evaluate the development of FO and QoL in patients with STS in the [...] Read more.
Soft tissue sarcoma (STS) patients undergoing surgery may experience reduced functional outcome (FO) and quality of life (QoL) compared to the general population. The aim of this study was to evaluate the development of FO and QoL in patients with STS in the extremities within the first year after first-time limb-sparing surgery. Twenty-nine out of 40 eligible patients were included in the present study. QoL and FO were evaluated by questionnaires while FO was also evaluated by objective tests. Patients were assessed before surgery and at fixed time points within the first year after surgery. Patients with STS in the extremities had an average strength of 82.34% (95% CI: 68.57–96.11) of the expected strength at one year post surgery. Multivariate, repeated ANOVA showed statistically significant reductions in strength in the disease-affected extremity when compared with the healthy side after surgery. Multivariate, repeated ANOVA showed a statistically significant improvement in FO and QoL within the first year post surgery. Limb-sparing surgery for STS significantly reduced strength in the disease-affected extremity and generally reduced FO and QoL in the first months after surgery. Improvements were observed for FO and QoL at one year after surgery. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
Negative Impact of Wound Complications on Oncologic Outcome of Soft Tissue Sarcomas of the Chest Wall
Cancers 2020, 12(1), 101; https://doi.org/10.3390/cancers12010101 - 31 Dec 2019
Cited by 2 | Viewed by 732
Abstract
A link of complications with worse oncologic prognosis has been established for multiple malignancies, while the limited literature on soft-tissue sarcomas is inconclusive. The aim of this study was to examine risk factors and the oncologic impact of wound complications after curative resection [...] Read more.
A link of complications with worse oncologic prognosis has been established for multiple malignancies, while the limited literature on soft-tissue sarcomas is inconclusive. The aim of this study was to examine risk factors and the oncologic impact of wound complications after curative resection of primary soft-tissue sarcomas of the chest wall. Patients with primary soft tissue sarcomas of the chest wall were identified. Groups with and without wound complications were compared by using univariate and multivariate analysis to identify risk factors. For patients with clear surgical margins (R0), univariate and multivariate analysis of factors associated with 5-year local recurrence free survival (LRFS), metastasis free survival (MFS), and disease specific survival (DSS) were performed. A total of 102 patients were included in the study. Wound complications occurred in 11 patients (10.8%) within 90 days. Cardiovascular morbidity and operation time represented independent risk factors for wound complications. In 94 patients with clear surgical margins, those with wound complications had an estimated 5-year LRFS of 30% versus 72.6% and a 5-year DSS of 58.3% versus 82.1%. Wound complications could be identified as an independent predictor for worse LRFS and DSS. Patients with a high risk of wound complications should be identified and strategies implemented to reduce surgical complications and possibly improve oncologic prognosis. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
Individualizing Follow-Up Strategies in High-Grade Soft Tissue Sarcoma with Flexible Parametric Competing Risk Regression Models
Cancers 2020, 12(1), 47; https://doi.org/10.3390/cancers12010047 - 21 Dec 2019
Cited by 4 | Viewed by 917
Abstract
Currently, patients with extremity soft tissue sarcoma (eSTS) who have undergone curative resection are followed up by a heuristic approach, not covering individual patient risks. The aim of this study was to develop two flexible parametric competing risk regression models (FPCRRMs) for local [...] Read more.
Currently, patients with extremity soft tissue sarcoma (eSTS) who have undergone curative resection are followed up by a heuristic approach, not covering individual patient risks. The aim of this study was to develop two flexible parametric competing risk regression models (FPCRRMs) for local recurrence (LR) and distant metastasis (DM), aiming at providing guidance on how to individually follow-up patients. Three thousand sixteen patients (1931 test, 1085 validation cohort) with high-grade eSTS were included in this retrospective, multicenter study. Histology (9 categories), grading (time-varying covariate), gender, age, tumor size, margins, (neo)adjuvant radiotherapy (RTX), and neoadjuvant chemotherapy (CTX) were used in the FPCRRMs and performance tested with Harrell-C-index. Median follow-up was 50 months (interquartile range: 23.3–95 months). Two hundred forty-two (12.5%) and 603 (31.2%) of test cohort patients developed LR and DM. Factors significantly associated with LR were gender, size, histology, neo- and adjuvant RTX, and margins. Parameters associated with DM were margins, grading, gender, size, histology, and neoadjuvant RTX. C-statistics was computed for internal (C-index for LR: 0.705, for DM: 0.723) and external cohort (C-index for LR: 0.683, for DM: 0.772). Depending on clinical, pathological, and patient-related parameters, LR- and DM-risks vary. With the present model, implemented in the updated Personalised Sarcoma Care (PERSARC)-app, more individualized prediction of LR/DM-risks is made possible. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
Tumor Suppressor Function of miR-127-3p and miR-376a-3p in Osteosarcoma Cells
Cancers 2019, 11(12), 2019; https://doi.org/10.3390/cancers11122019 - 14 Dec 2019
Cited by 10 | Viewed by 983
Abstract
Since the introduction of high-dose chemotherapy about 35 years ago, survival rates of osteosarcoma patients have not been significantly improved. New therapeutic strategies replacing or complementing conventional chemotherapy are therefore urgently required. MicroRNAs represent promising targets for such new therapies, as they are [...] Read more.
Since the introduction of high-dose chemotherapy about 35 years ago, survival rates of osteosarcoma patients have not been significantly improved. New therapeutic strategies replacing or complementing conventional chemotherapy are therefore urgently required. MicroRNAs represent promising targets for such new therapies, as they are involved in the pathology of multiple types of cancer, and aberrant expression of several miRNAs has already been shown in osteosarcoma. In this study, we identified silencing of miR-127-3p and miR-376a-3p in osteosarcoma cell lines and tissues and investigated their role as potential tumor suppressors in vitro and in vivo. Transfection of osteosarcoma cells (n = 6) with miR-127-3p and miR-376a-3p mimics significantly inhibited proliferation and reduced the colony formation capacity of these cells. In contrast, we could not detect any influence of miRNA restoration on cell cycle and apoptosis induction. The effects of candidate miRNA restoration on tumor engraftment and growth in vivo were analyzed using a chicken chorioallantoic membrane (CAM) assay. Cells transfected with mir-127-3p and miR-376a-3p showed reduced tumor take rates and tumor volumes and a significant decrease of the cumulative tumor volumes to 41% and 54% compared to wildtype cells. The observed tumor suppressor function of both analyzed miRNAs indicates these miRNAs as potentially valuable targets for the development of new therapeutic strategies for the treatment of osteosarcoma. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessArticle
Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status
Cancers 2019, 11(12), 1918; https://doi.org/10.3390/cancers11121918 - 02 Dec 2019
Cited by 4 | Viewed by 1307
Abstract
Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. [...] Read more.
Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose–response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Review

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Open AccessReview
Molecular Biology of Osteosarcoma
Cancers 2020, 12(8), 2130; https://doi.org/10.3390/cancers12082130 - 31 Jul 2020
Cited by 16 | Viewed by 1970
Abstract
Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or [...] Read more.
Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond–Blackfan anemia. TP53 is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK–ERK pathways. Several genomic studies showed frequent alterations in the RB gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessReview
Epithelioid Sarcoma—From Genetics to Clinical Practice
Cancers 2020, 12(8), 2112; https://doi.org/10.3390/cancers12082112 - 29 Jul 2020
Cited by 1 | Viewed by 1127
Abstract
Epithelioid sarcoma is a mesenchymal soft tissue sarcoma often arising in the extremities, usually in young adults with a pick of incidence at 35 years of age. Epithelioid sarcoma (ES) is characterized by the loss of SMARCB1/INI1 (integrase interactor 1) or other proteins of [...] Read more.
Epithelioid sarcoma is a mesenchymal soft tissue sarcoma often arising in the extremities, usually in young adults with a pick of incidence at 35 years of age. Epithelioid sarcoma (ES) is characterized by the loss of SMARCB1/INI1 (integrase interactor 1) or other proteins of the SWI/SNF complex. Two distinct types, proximal and distal, with varying biology and treatment outcomes, are distinguished. ES is known for aggressive behavior, including a high recurrence rate and regional lymph node metastases. An optimal long-term management strategy is still to be defined. The best treatment of localized ES is wide surgical resection. Neo-adjuvant or adjuvant radiotherapy may be recommended, as it reduces the local recurrence rate. Sentinel lymph node biopsy should be considered in ES patients. Patients with metastatic ES have a poor prognosis with an expected median overall survival of about a year. Doxorubicin-based regimens are recommended for advanced ES. Tazemetostat, an EZH2 methyltransferase, has shown promising results in ES patients. Novel therapies, including immunotherapy, are still needed. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessReview
Neoadjuvant Treatment Options in Soft Tissue Sarcomas
Cancers 2020, 12(8), 2061; https://doi.org/10.3390/cancers12082061 - 26 Jul 2020
Cited by 2 | Viewed by 1172
Abstract
Due to the heterogeneity of soft tissue sarcomas (STS), the choice of the proper perioperative treatment regimen is challenging. Neoadjuvant therapy has attracted increasing attention due to several advantages, particularly in patients with locally advanced disease. The number of available neoadjuvant modalities is [...] Read more.
Due to the heterogeneity of soft tissue sarcomas (STS), the choice of the proper perioperative treatment regimen is challenging. Neoadjuvant therapy has attracted increasing attention due to several advantages, particularly in patients with locally advanced disease. The number of available neoadjuvant modalities is growing continuously. We may consider radiotherapy, chemotherapy, targeted therapy, radiosensitizers, hyperthermia, and their combinations. This review discusses possible neoadjuvant treatment options in STS with an emphasis on available evidence, indications for each treatment type, and related risks. Finally, we summarize current recommendations of the STS neoadjuvant therapy response assessment. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
Open AccessReview
Non-Conventional Treatments for Conventional Chondrosarcoma
Cancers 2020, 12(7), 1962; https://doi.org/10.3390/cancers12071962 - 19 Jul 2020
Viewed by 830
Abstract
Chondrosarcomas are the most common malignant tumors of the cartilage, are seen predominantly in adults, and have varied clinical behavior. The majority of them affect the medullary canal of long bones and pelvic bones. The prognosis of chondrosarcoma is closely related to histological [...] Read more.
Chondrosarcomas are the most common malignant tumors of the cartilage, are seen predominantly in adults, and have varied clinical behavior. The majority of them affect the medullary canal of long bones and pelvic bones. The prognosis of chondrosarcoma is closely related to histological grading; however, the grading is subject to interobserver variability. Conventional chondrosarcomas are overall considered to be chemotherapy- and radiation-resistant, resulting in limited treatment options. The majority of advanced conventional chondrosarcomas are treated with chemotherapy without any survival benefit. Recent studies have evaluated molecular genetic findings which have improved the understanding of chondrosarcoma biology. Newer therapeutic targets are desperately needed. In this review article, we explore ongoing clinical trials evaluating novel ways of treating advanced conventional chondrosarcoma. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
Open AccessReview
Recent Advances and Challenges in the Treatment of Rhabdomyosarcoma
Cancers 2020, 12(7), 1758; https://doi.org/10.3390/cancers12071758 - 02 Jul 2020
Cited by 1 | Viewed by 926
Abstract
Rhabdomyosarcoma, the most common soft tissue sarcoma noted in childhood, requires multimodality treatment, including chemotherapy, surgical resection, and/or radiation therapy. The majority of the patients with localized rhabdomyosarcoma can be cured; however, the long-term outcomes in patients with metastatic rhabdomyosarcoma remain poor. The [...] Read more.
Rhabdomyosarcoma, the most common soft tissue sarcoma noted in childhood, requires multimodality treatment, including chemotherapy, surgical resection, and/or radiation therapy. The majority of the patients with localized rhabdomyosarcoma can be cured; however, the long-term outcomes in patients with metastatic rhabdomyosarcoma remain poor. The standard chemotherapy regimen for patients with rhabdomyosarcoma is the combination of vincristine, actinomycin, and cyclophosphamide/ifosfamide. In recent clinical trials, modifications of the standard chemotherapy protocol have shown improvements in the outcomes in patients with rhabdomyosarcoma. In various type of malignancies, new treatments, such as molecular targeted drugs and immunotherapies, have shown superior clinical outcomes compared to those of standard treatments. Therefore, it is necessary to assess the benefits of these treatments in patients with rhabdomyosarcoma. Moreover, recent basic and clinical studies on rhabdomyosarcoma have reported promising therapeutic targets and novel therapeutic approaches. This article reviews the recent challenges and advances in the management of rhabdomyosarcoma. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
Open AccessReview
Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers?
Cancers 2020, 12(3), 645; https://doi.org/10.3390/cancers12030645 - 10 Mar 2020
Cited by 6 | Viewed by 1099
Abstract
Osteosarcoma and Ewing sarcoma are the most prevalent bone pediatric tumors. Despite intensive basic and medical research studies to discover new therapeutics and to improve current treatments, almost 40% of osteosarcoma and Ewing sarcoma patients succumb to the disease. Patients with poor prognosis [...] Read more.
Osteosarcoma and Ewing sarcoma are the most prevalent bone pediatric tumors. Despite intensive basic and medical research studies to discover new therapeutics and to improve current treatments, almost 40% of osteosarcoma and Ewing sarcoma patients succumb to the disease. Patients with poor prognosis are related to either the presence of metastases at diagnosis or resistance to chemotherapy. Over the past ten years, considerable interest for the Hippo/YAP signaling pathway has taken place within the cancer research community. This signaling pathway operates at different steps of tumor progression: Primary tumor growth, angiogenesis, epithelial to mesenchymal transition, and metastatic dissemination. This review discusses the current knowledge about the involvement of the Hippo signaling pathway in cancer and specifically in paediatric bone sarcoma progression. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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Open AccessReview
Precision Medicine in Soft Tissue Sarcoma Treatment
Cancers 2020, 12(1), 221; https://doi.org/10.3390/cancers12010221 - 16 Jan 2020
Cited by 7 | Viewed by 1297
Abstract
Soft tissue sarcoma (STS) is a rare component of malignant diseases. STS includes various histological subtypes, and there are some important differences among the different histological subtypes regarding the mutation profile and sensitivity to antitumor agents. Many clinical trials of STS incorporating many [...] Read more.
Soft tissue sarcoma (STS) is a rare component of malignant diseases. STS includes various histological subtypes, and there are some important differences among the different histological subtypes regarding the mutation profile and sensitivity to antitumor agents. Many clinical trials of STS incorporating many different histological subtypes in various populations have been conducted; it is difficult to compare the findings and make conclusions about clinical efficacy. Targeted therapies focusing on specific histological subtypes and precision therapy focusing on the specific genetic mutation(s) of each STS patient are being investigated. Since STS patients are a small population, new clinical trial designs are required to evaluate and establish new targeted therapies for each histological subtype that has a limited number of patients, and preclinical investigations are needed to detect targetable mutations. Now that cancer genome profiling is used in clinical practice, it is urgently necessary to connect the genome profiling data obtained in clinical settings to the optimal clinical treatment strategies. Herein we review the development and challenges of precision therapy in the management of STS patients. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
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