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13 pages, 1793 KiB

Open AccessArticle

Radiotherapy in the Management of Pediatric and Adult Osteosarcomas: A Multi-Institutional Cohort Analysis

by Mateusz Jacek Spałek, Jan Poleszczuk, Anna Małgorzata Czarnecka, Monika Dudzisz-Śledź, Aleksandra Napieralska, Jacek Matysiakiewicz, Marzanna Chojnacka, Anna Raciborska, Aleksandra Sztuder, Adam Maciejczyk, Agata Szulc, Tomasz Skóra, Bożena Cybulska-Stopa, Tomasz Winiecki, Joanna Kaźmierska, Bartłomiej Tomasik, Jacek Fijuth and Piotr Rutkowski

Cells 2021, 10(2), 366; https://doi.org/10.3390/cells10020366 - 10 Feb 2021

Cited by 8 | Viewed by 3183

Abstract

Background: Due to the rarity of osteosarcoma and limited indications for radiotherapy (RT), data on RT for this tumor are scarce. This study aimed to investigate the utilization of RT for osteosarcomas in the recent 20 years and to identify factors related to [...] Read more.

Background: Due to the rarity of osteosarcoma and limited indications for radiotherapy (RT), data on RT for this tumor are scarce. This study aimed to investigate the utilization of RT for osteosarcomas in the recent 20 years and to identify factors related to patients’ response to radiation. Methods: We performed a retrospective analysis of patients irradiated for osteosarcoma treatment. We planned to assess differences in the utilization of RT between the periods of 2000–2010 and 2011–2020, identify the risk factors associated with local progression (LP), determine whether RT-related parameters are associated with LP, and calculate patients’ survival. Results: A total of 126 patients with osteosarcoma who received 181 RT treatments were identified. We found a difference in RT techniques between RT performed in the years 2000–2010 and that performed in the years 2011–2020. LP was observed after 37 (20.4%) RT treatments. Intent of RT, distant metastases, and concomitant systemic treatment affected the risk of LP. Five-year overall survival was 33% (95% confidence interval (26%–43%)). Conclusions: RT for osteosarcoma treatment has evolved from simple two-dimensional palliative irradiation into more conformal RT applied for new indications including oligometastatic and oligoprogressive disease. RT may be a valuable treatment modality for selected patients with osteosarcoma. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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12 pages, 655 KiB

Open AccessFeature PaperArticle

High Dose Ifosfamide in Relapsed and Unresectable High-Grade Osteosarcoma Patients: A Retrospective Series

by Emanuela Palmerini, Elisabetta Setola, Giovanni Grignani, Lorenzo D’Ambrosio, Alessandro Comandone, Alberto Righi, Alessandra Longhi, Marilena Cesari, Anna Paioli, Rossella Hakim, Michela Pierini, Emanuela Marchesi, Daniel Vanel, Ymera Pignochino, Davide Maria Donati, Piero Picci and Stefano Ferrari

Cells 2020, 9(11), 2389; https://doi.org/10.3390/cells9112389 - 31 Oct 2020

Cited by 25 | Viewed by 4061

Abstract

Background: The evidence on high-dose ifosfamide (HD-IFO) use in patients with relapsed osteosarcoma is limited. We performed a retrospective study to analyze HD-IFO activity. Methods: Patients with osteosarcoma relapsed after standard treatment [methotrexate, doxorubicin, cisplatin +/− ifosfamide (MAP+/−I)] with measurable disease [...] Read more.

Background: The evidence on high-dose ifosfamide (HD-IFO) use in patients with relapsed osteosarcoma is limited. We performed a retrospective study to analyze HD-IFO activity. Methods: Patients with osteosarcoma relapsed after standard treatment [methotrexate, doxorubicin, cisplatin +/− ifosfamide (MAP+/−I)] with measurable disease according to RECIST1.1 were eligible to ifosfamide (3 g/m²/day) continuous infusion (c.i.) days 1–5 q21d. RECIST1.1 overall response rate (ORR) (complete response (CR) + partial response (PR)), progression-free survival at 6-month (6m-PFS), duration of response (DOR), and 2-year overall survival (2y-OS) were assessed. PARP1 expression and gene mutations were tested by immunohistochemistry and next-generation sequencing. Results: 51 patients were included. ORR was 20% (1 CR + 9 PR). Median DOR was 5 months (95%CI 2–7). Median PFS, 6m-PFS, OS, and 2y-OS were 6 months (95%CI 4–9), 51%, 15 months (10–19), and 30%, respectively. A second surgical complete remission (CR2) was achieved in 26 (51%) patients. After multivariate analysis, previous use of ifosfamide (HR 2.007, p = 0.034) and CR2 (HR 0.126, p < 0.001) showed a significant correlation with PFS and OS, respectively. No significant correlation was found between outcomes and PARP1 or gene mutations. Conclusions: HD-IFO should be considered as the standard first-line treatment option in relapsed osteosarcoma and control arm of future trial in this setting. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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Review

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15 pages, 820 KiB

Open AccessFeature PaperReview

Targeting the VEGF Pathway in Osteosarcoma

by Tarek Assi, Sarah Watson, Bachar Samra, Elie Rassy, Axel Le Cesne, Antoine Italiano and Olivier Mir

Cells 2021, 10(5), 1240; https://doi.org/10.3390/cells10051240 - 18 May 2021

Cited by 40 | Viewed by 4570

Abstract

Osteosarcoma is the most common primary tumor of the bones affecting mainly young adults. Despite the advances in the field of systemic anticancer therapy, the prognosis of relapsed of metastatic osteosarcoma patients remain dismal with very short survival. However, the better understanding of [...] Read more.

Osteosarcoma is the most common primary tumor of the bones affecting mainly young adults. Despite the advances in the field of systemic anticancer therapy, the prognosis of relapsed of metastatic osteosarcoma patients remain dismal with very short survival. However, the better understanding of the pathophysiology of this subtype of sarcoma has led to the identification of new targeted agents with significant activity. In fact, increased angiogenesis plays a major role in the tumor growth and survival of osteosarcoma patients. Several targeted agents have demonstrated a significant anti-tumor activity including multi-kinase inhibitors. In this review, we will discuss the pathophysiology, rationale, and role of targeting angiogenesis via the VEGF pathway in patients with osteosarcoma with emphasis on the published clinical trials and future directions. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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10 pages, 1470 KiB

Open AccessReview

Radiologic Assessment of Osteosarcoma Lung Metastases: State of the Art and Recent Advances

by Anna Maria Chiesa, Paolo Spinnato, Marco Miceli and Giancarlo Facchini

Cells 2021, 10(3), 553; https://doi.org/10.3390/cells10030553 - 4 Mar 2021

Cited by 18 | Viewed by 4554

Abstract

The lung is the most frequent site of osteosarcoma (OS) metastases, which are a critical point in defining a patient’s prognosis. Chest computed tomography (CT) represents the gold standard for the detection of lung metastases even if its sensitivity widely ranges in the [...] Read more.

The lung is the most frequent site of osteosarcoma (OS) metastases, which are a critical point in defining a patient’s prognosis. Chest computed tomography (CT) represents the gold standard for the detection of lung metastases even if its sensitivity widely ranges in the literature since lung localizations are often atypical. ESMO guidelines represent one of the major references for the follow-up program of OS patients. The development of new reconstruction techniques, such as the iterative method and the deep learning-based image reconstruction (DLIR), has led to a significant reduction of the radiation dose with the low-dose CT. The improvement of these techniques has great importance considering the young-onset of the disease and the strict chest surveillance during follow-up programs. The use of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is still controversial, while volume doubling time (VDT) and computer-aided diagnosis (CAD) systems are recent diagnostic tools that could support radiologists for lung nodules evaluation. Their use, well-established for other malignancies, needs to be further evaluated, focusing on OS patients. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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9 pages, 635 KiB

Open AccessReview

MiRNAs in Canine and Human Osteosarcoma: A Highlight Review on Comparative Biomolecular Aspects

by Leonardo Leonardi, Katia Scotlandi, Ilaria Pettinari, Maria Serena Benassi, Ilaria Porcellato and Laura Pazzaglia

Cells 2021, 10(2), 428; https://doi.org/10.3390/cells10020428 - 18 Feb 2021

Cited by 14 | Viewed by 3671

Abstract

Osteosarcoma (OS) is the most frequent primary malignant tumor of bone in humans and animals. Comparative oncology is a field of study that examines the cancer risk and tumor progression across the species. The canine model is ideally suited for translational cancer research. [...] Read more.

Osteosarcoma (OS) is the most frequent primary malignant tumor of bone in humans and animals. Comparative oncology is a field of study that examines the cancer risk and tumor progression across the species. The canine model is ideally suited for translational cancer research. The biological and clinical characteristics of human and canine OS are common to hypothesize as that several living and environmental common conditions shared between the two species can influence some etiopathogenetic mechanisms, for which the canine species represents an important model of comparison with the human species. In the canine and human species, osteosarcoma is the tumor of bone with the highest frequency, with a value of about 80–85% (in respect to all other bone tumors), a high degree of invasiveness, and a high rate of metastasis and malignancy. Humans and dogs have many genetic and biomolecular similarities such as alterations in the expression of p53 and in some types of microRNAs that our working group has already described previously in several separate works. In this paper, we report and collect new comparative biomolecular features of osteosarcoma in dogs and humans, which may represent an innovative update on the biomolecular profile of this tumor. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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18 pages, 1431 KiB

Open AccessReview

Patient Derived Xenografts for Genome-Driven Therapy of Osteosarcoma

by Lorena Landuzzi, Maria Cristina Manara, Pier-Luigi Lollini and Katia Scotlandi

Cells 2021, 10(2), 416; https://doi.org/10.3390/cells10020416 - 17 Feb 2021

Cited by 22 | Viewed by 5151

Abstract

Osteosarcoma (OS) is a rare malignant primary tumor of mesenchymal origin affecting bone. It is characterized by a complex genotype, mainly due to the high frequency of chromothripsis, which leads to multiple somatic copy number alterations and structural rearrangements. Any effort to design [...] Read more.

Osteosarcoma (OS) is a rare malignant primary tumor of mesenchymal origin affecting bone. It is characterized by a complex genotype, mainly due to the high frequency of chromothripsis, which leads to multiple somatic copy number alterations and structural rearrangements. Any effort to design genome-driven therapies must therefore consider such high inter- and intra-tumor heterogeneity. Therefore, many laboratories and international networks are developing and sharing OS patient-derived xenografts (OS PDX) to broaden the availability of models that reproduce OS complex clinical heterogeneity. OS PDXs, and new cell lines derived from PDXs, faithfully preserve tumor heterogeneity, genetic, and epigenetic features and are thus valuable tools for predicting drug responses. Here, we review recent achievements concerning OS PDXs, summarizing the methods used to obtain ectopic and orthotopic xenografts and to fully characterize these models. The availability of OS PDXs across the many international PDX platforms and their possible use in PDX clinical trials are also described. We recommend the coupling of next-generation sequencing (NGS) data analysis with functional studies in OS PDXs, as well as the setup of OS PDX clinical trials and co-clinical trials, to enhance the predictive power of experimental evidence and to accelerate the clinical translation of effective genome-guided therapies for this aggressive disease. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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10 pages, 275 KiB

Open AccessReview

Precision Medicine in Osteosarcoma: MATCH Trial and Beyond

by Elisa Tirtei, Anna Campello, Sebastian D. Asaftei, Katia Mareschi, Matteo Cereda and Franca Fagioli

Cells 2021, 10(2), 281; https://doi.org/10.3390/cells10020281 - 31 Jan 2021

Cited by 8 | Viewed by 2964

Abstract

Osteosarcoma (OS) is a rare bone malignant tumour with a poor prognosis in the case of recurrence. So far, there is no agreement on the best systemic therapy for relapsed OS. The availability of next generation sequencing techniques has recently revolutionized clinical research. [...] Read more.

Osteosarcoma (OS) is a rare bone malignant tumour with a poor prognosis in the case of recurrence. So far, there is no agreement on the best systemic therapy for relapsed OS. The availability of next generation sequencing techniques has recently revolutionized clinical research. The sequencing of the tumour and its matched normal counterpart has the potential to reveal a wide landscape of genetic alterations with significant implications for clinical practice. The knowledge that the genomic profile of a patient’s tumour can be precisely mapped and matched to a targeted therapy in real time has improved the development of precision medicine trials (PMTs). PMTs aiming at determining the effectiveness of targeted therapies could be advantageous for patients with a tumour refractory to standard therapies. Development of PMTs for relapsed OS is largely encouraging and is in its initial phase. Assessing OS features, such as its rarity, its age distribution, the technical issues related to the bone tissue origin, and its complex genomic landscape, represents a real challenge for PMTs development. In this light, a multidisciplinary approach is required to fully exploit the potential of precision medicine for OS patients. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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15 pages, 11597 KiB

Open AccessReview

Computer Navigation and 3D Printing in the Surgical Management of Bone Sarcoma

by Robert Allan McCulloch, Tommaso Frisoni, Vineet Kurunskal, Davide Maria Donati and Lee Jeys

Cells 2021, 10(2), 195; https://doi.org/10.3390/cells10020195 - 20 Jan 2021

Cited by 21 | Viewed by 3840

Abstract

The long-term outcomes of osteosarcoma have improved; however, patients with metastases, recurrence or axial disease continue to have a poor prognosis. Computer navigation in surgery is becoming ever more commonplace, and the proposed advantages, including precision during surgery, is particularly applicable to the [...] Read more.

The long-term outcomes of osteosarcoma have improved; however, patients with metastases, recurrence or axial disease continue to have a poor prognosis. Computer navigation in surgery is becoming ever more commonplace, and the proposed advantages, including precision during surgery, is particularly applicable to the field of orthopaedic oncology and challenging areas such as the axial skeleton. Within this article, we provide an overview of the field of computer navigation and computer-assisted tumour surgery (CATS), in particular its relevance to the surgical management of osteosarcoma. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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11 pages, 300 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Future Directions in the Treatment of Osteosarcoma

by Alannah Smrke, Peter M. Anderson, Ashish Gulia, Spyridon Gennatas, Paul H. Huang and Robin L. Jones

Cells 2021, 10(1), 172; https://doi.org/10.3390/cells10010172 - 15 Jan 2021

Cited by 131 | Viewed by 10168

Abstract

Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd–3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin (MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly [...] Read more.

Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd–3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin (MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly changed for over thirty years. There is a need for more effective treatment for patients with high risk features but also reduced treatment-related toxicity for all patients. Predictive biomarkers are needed to help inform clinicians to de-escalate or add therapy, including immune therapies, and to contribute to future clinical trial designs. Here, we review a variety of approaches to improve outcomes and quality of life for patients with osteosarcoma with a focus on incorporating toxicity reduction, immune therapy and molecular analysis to provide the most effective and least toxic osteosarcoma therapy. Full article

(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)

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