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Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma

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

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 35811

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Dr. Joanna Szkandera

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Guest Editor

Division of Oncology, Medical University of Graz, 8036 Graz, Austria
Interests: biomarkers; cancer prognosis; tumor microenvironment; soft tissue and bone sarcoma; GIST

Dr. Dimosthenis Andreou

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Guest Editor

Division of Orthopedic Oncology and Sarcoma Surgery, Helios Hospital Bad Saarow, Sarcoma Center Berlin-Brandenburg, 15526 Bad Saarow, Germany
Interests: bone sarcoma; soft tissue sarcoma; surgical treatment; prognostic parameters; megaprostheses; local recurrence

Special Issue Information

Dear Colleagues,

Sarcomas are a group of rare cancers that arise in connective tissues of the body. These tumours exhibit a wide range of differing behaviours and underlying molecular pathologies. The two main types of sarcoma are soft tissue and bone sarcomas, but there are more than 70 different entities within these two categories.

There is limited medical understanding of this type of rare malignancy. The natural history of these aggressive tumours is characterized by a strong tendency toward local recurrence and metastatic spreading. Despite advances in therapeutic approaches over the last several decades, the outcome for metastatic patients remains poor. Therefore, it is important to identify patients who are at high risk for tumour recurrence and dissemination, which has resulted in an increasing interest in the investigation of prognostic biomarkers that help to guide treatment decisions.

Surgical resection is pivotal for the management of locoregional disease. In locally advanced or metastatic disease settings, systemic therapy has an important role in the multidisciplinary management of sarcoma. Cytotoxic therapy has been the mainstay of treatment for many years. However, recent advances in molecular pathogenesis, the investigation of the tumour microenvironment, changes in clinical trial design, and increased international collaboration have led to the development of histology-driven therapy. Furthermore, genomic profiling has highlighted that, while some sarcomas have complex karyotypes, others are driven by translocation, amplification and mutation, representing targets for the development of novel therapies. Checkpoint inhibitors have been used as single agents or in combination in clinical sarcoma trials. This progress will move the therapeutic modality in sarcoma patients from the “one-size-fits-all” approach towards a more personalized therapeutic algorithm and better outcomes in the near future.

In this Special Issue we will present original research and review articles highlighting novel therapeutic approaches in the treatment of sarcoma patients.

Dr. Joanna Szkandera
Dr. Dimosthenis Andreou
Guest Editors

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Keywords

soft tissue sarcoma
bone sarcoma
GIST
biomarkers
prognostic parameters
tumour microenvironment
systemic treatment
surgical treatment

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Research

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13 pages, 2106 KiB

Open AccessArticle

Genomic Landscape of Angiosarcoma: A Targeted and Immunotherapy Biomarker Analysis

by Andrea P. Espejo-Freire, Andrew Elliott, Andrew Rosenberg, Philippos Apolinario Costa, Priscila Barreto-Coelho, Emily Jonczak, Gina D’Amato, Ty Subhawong, Junaid Arshad, Julio A. Diaz-Perez, Wolfgang M. Korn, Matthew J. Oberley, Daniel Magee, Don Dizon, Margaret von Mehren, Moh’d M. Khushman, Atif Mahmoud Hussein, Kirsten Leu and Jonathan C. Trent

Cancers 2021, 13(19), 4816; https://doi.org/10.3390/cancers13194816 - 26 Sep 2021

Cited by 34 | Viewed by 5767

Abstract

We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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10 pages, 468 KiB

Open AccessArticle

Does the Duration of Primary and First Revision Surgery Influence the Probability of First and Subsequent Implant Failures after Extremity Sarcoma Resection and Megaprosthetic Reconstruction?

by Christoph Theil, Kristian Nikolaus Schneider, Georg Gosheger, Ralf Dieckmann, Niklas Deventer, Jendrik Hardes, Tom Schmidt-Braekling and Dimosthenis Andreou

Cancers 2021, 13(11), 2510; https://doi.org/10.3390/cancers13112510 - 21 May 2021

Cited by 3 | Viewed by 1773

Abstract

Complications in megaprosthetic reconstruction following sarcoma resection are quite common. While several risk factors for failure have been explored, there is a scarcity of studies investigating the effect of the duration of surgery. We performed a retrospective study of 568 sarcoma patients that underwent megaprosthetic reconstruction between 1993 and 2015. Differences in the length of surgery and implant survival were assessed with the Kaplan–Meier method, the log-rank test and multivariate Cox regressions using an optimal cut-off value determined by receiver operating curves analysis using Youden’s index. 230 patients developed a first and 112 patients a subsequent prosthetic failure. The median duration of initial surgery was 210 min. Patients who developed a first failure had a longer duration of the initial surgery (225 vs. 205 min, p = 0.0001). There were no differences in the probability of infection between patients with longer and shorter duration of initial surgery (12% vs. 13% at 5 years, p = 0.492); however, the probability of mechanical failure was higher in patients with longer initial surgery (38% vs. 23% at 5 years, p = 0.006). The median length of revision surgery for the first megaprosthetic failure was 101 min. Patients who underwent first revision for infection and did not develop a second failure had a longer median duration of the first revision surgery (150 min vs. 120 min, p = 0.016). A shorter length of the initial surgery appears beneficial, however, the notion that longer operating time increases the risk of deep infection could not be reproduced in our study. In revision surgery for infection, a longer operating time, possibly indicating a more thorough debridement, appears to be associated with a lower risk for subsequent revision. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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13 pages, 8479 KiB

Open AccessArticle

Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues

by Georgia Karpathiou, Maroa Dridi, Lila Krebs-Drouot, François Vassal, Emmanuel Jouanneau, Timothée Jacquesson, Cédric Barrey, Jean Michel Prades, Jean Marc Dumollard, David Meyronet, Jean Boutonnat and Michel Péoc’h

Cancers 2021, 13(9), 2169; https://doi.org/10.3390/cancers13092169 - 30 Apr 2021

Cited by 12 | Viewed by 2346

Abstract

Chordomas are notably resistant to chemotherapy. One of the cytoprotective mechanisms implicated in chemoresistance is autophagy. There are indirect data that autophagy could be implicated in chordomas, but its presence has not been studied in chordoma tissues. Sixty-one (61) chordomas were immunohistochemically studied for autophagic markers and their expression was compared with the expression in notochords, clinicopathological data, as well as the tumor immune microenvironment. All chordomas strongly and diffusely expressed cytoplasmic p62 (sequestosome 1, SQSTM1/p62), whereas 16 (26.2%) tumors also showed nuclear p62 expression. LC3B (Microtubule-associated protein 1A/1B-light chain 3B) tumor cell expression was found in 44 (72.1%) tumors. Autophagy-related 16‑like 1 (ATG16L1) was also expressed by most tumors. All tumors expressed mannose-6-phosphate/insulin-like growth factor 2 receptor (M6PR/IGF2R). LC3B tumor cell expression was negatively associated with tumor size, while no other parameters, such as age, sex, localization, or survival, were associated with the immunohistochemical factors studied. LC3B immune cell expression showed a significant positive association with programmed death-ligand 1 (PD-L1)+ immune cells and with a higher vascular density. ATG16L1 expression was also positively associated with higher vascular density. Notochords (n = 5) showed different immunostaining with a very weak LC3B and M6PR expression, and no p62 expression. In contrast to normal notochords, autophagic factors such as LC3B and ATG16L1 are often present in chordomas, associated with a strong and diffuse expression of p62, suggesting a blocked autophagic flow. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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10 pages, 778 KiB

Open AccessArticle

Relative Sensitivity of Core-Needle Biopsy and Incisional Biopsy in the Diagnosis of Musculoskeletal Sarcomas

by Alexander Klein, Theresa Fell, Christof Birkenmaier, Julian Fromm, Volkmar Jansson, Thomas Knösel and Hans Roland Dürr

Cancers 2021, 13(6), 1393; https://doi.org/10.3390/cancers13061393 - 19 Mar 2021

Cited by 13 | Viewed by 2456

Abstract

Background: There is no evidence as to the diagnostic value of the two most frequently used methods of biopsies in sarcomas: Incisional or core needle biopsy. The aim of our study was to evaluate the diagnostic sensitivity of the incisional and the core needle biopsy techniques in the diagnosis of bone and soft tissue sarcomas. Methods: We included 417 patients with a definitive diagnosis of bone or soft tissue sarcoma in whom a total of 472 biopsies had been performed. We correlated the results of the biopsies with the result of the definitive histopathological examination of the resected tumor. Dignity, entity, and grading (whenever possible) of the tissue samples were evaluated. Results: A total of 258 biopsies (55%) were performed in order to diagnose a soft tissue tumor and 351 biopsies (74.4%) were core needle biopsies. The number of repeat core needle biopsies, necessitated because of inconclusive histopathological results, was significantly higher (50 vs. 5; p = 0.003). We observed no significant difference regarding dignity, entity, and grading between the 2 different types of biopsies. Only with regards to the determination of dignity and entity of chondroid tumors, incisional biopsy was superior with statistical significance (p = 0.024). Conclusions: This study represents the largest study on biopsies for bone and soft tissue sarcomas. Based only on our results, we are unable to favor one method of biopsy and found high accuracy with both methods. Considering the potential complications, the added oncological risks of incisional biopsies and the ready availability of core needle biopsies, the latter, in our assessment, represents a valid and favourable method for bone and soft tissue sarcomas. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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13 pages, 30556 KiB

Open AccessArticle

The Feasibility Study of Hypofractionated Radiotherapy with Regional Hyperthermia in Soft Tissue Sarcomas

by Mateusz Jacek Spałek, Aneta Maria Borkowska, Maria Telejko, Michał Wągrodzki, Daria Niebyłowska, Aldona Uzar, Magdalena Białobrzeska and Piotr Rutkowski

Cancers 2021, 13(6), 1332; https://doi.org/10.3390/cancers13061332 - 16 Mar 2021

Cited by 12 | Viewed by 2741

Abstract

Introduction: Management of marginally resectable or unresectable soft tissue sarcomas (STS) in patients who are not candidates for neoadjuvant chemotherapy due to chemoresistant pathology or contraindications remains a challenge. Therefore, in these indications, we aimed to investigate a feasibility of 10x 3.25 Gy radiotherapy combined with regional hyperthermia (HT) that could be followed by surgery or 4x 4 Gy radiotherapy with HT. Materials and methods: We recruited patients with locally advanced marginally resectable or unresectable STS who (1) presented chemoresistant STS subtype, or (2) progressed after neoadjuvant chemotherapy, or (3) were unfit for chemotherapy. The primary endpoint was the feasibility of the proposed regimen. Results: Thirty patients were enrolled. All patients received the first part of the treatment, namely radiotherapy with HT. Among them, 14 received the second part of radiotherapy with HT whereas 13 patients underwent surgery. Three patients did not complete the treatment protocol. The feasibility criteria were fulfilled in 90% of patients. Two patients developed distant metastases. One patient died due to distant progression. One patient developed rapid local recurrence after surgery. Conclusions: Hypofractionated radiotherapy with HT is a feasible treatment for marginally resectable or unresectable STS in patients who are not candidates for chemotherapy. Results of this clinical trial support the further validation of RT and HT combinations in STS. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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10 pages, 457 KiB

Open AccessFeature PaperArticle

Treatment of Angiosarcoma with Pazopanib and Paclitaxel: Results of the EVA (Evaluation of Votrient^® in Angiosarcoma) Phase II Trial of the German Interdisciplinary Sarcoma Group (GISG-06)

by Daniel Pink, Dimosthenis Andreou, Sebastian Bauer, Thomas Brodowicz, Bernd Kasper, Peter Reichardt, Stephan Richter, Lars H. Lindner, Joanna Szkandera, Viktor Grünwald, Maxim Kebenko, Marietta Kirchner and Peter Hohenberger

Cancers 2021, 13(6), 1223; https://doi.org/10.3390/cancers13061223 - 11 Mar 2021

Cited by 19 | Viewed by 3093

Abstract

We aimed to evaluate the efficacy and toxicity of paclitaxel combined with pazopanib in advanced angiosarcoma (AS). The primary end point was progression-free survival (PFS) rate at six months (PFSR6). Planned accrual was 44 patients in order to detect a PFSR6 of >55%, with an interim futility analysis of the first 14 patients. The study did not meet its predetermined interim target of 6/14 patients progression-free at 6 months. At the time of this finding, 26 patients had been enrolled between July 2014 and April 2016, resulting in an overrunning of 12 patients. After a median follow-up of 9.5 (IQR 7.7–15.4) months, PFSR6 amounted to 46%. Two patients had a complete and seven patients a partial response. Patients with superficial AS had a significantly higher PFSR6 (61% vs. 13%, p = 0.0247) and PFS (11.3 vs. 2.7 months, p < 0.0001) compared to patients with visceral AS. The median overall survival in the entire cohort was 21.6 months. A total of 10 drug-related serious adverse effects were reported in 5 patients, including a fatal hepatic failure. Although our study did not meet its primary endpoint, the median PFS of 11.6 months in patients with superficial AS appears to be promising. Taking recent reports into consideration, future studies should evaluate the safety and efficacy of VEGFR and immune checkpoint inhibitors with or without paclitaxel in a randomized, multiarm setting. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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13 pages, 2542 KiB

Open AccessArticle

Survival Analysis of 3 Different Age Groups and Prognostic Factors among 402 Patients with Skeletal High-Grade Osteosarcoma. Real World Data from a Single Tertiary Sarcoma Center

by Richard E. Evenhuis, Ibtissam Acem, Anja J. Rueten-Budde, Diederik S. A. Karis, Marta Fiocco, Desiree M. J. Dorleijn, Frank M. Speetjens, Jakob Anninga, Hans Gelderblom and Michiel A. J. van de Sande

Cancers 2021, 13(3), 486; https://doi.org/10.3390/cancers13030486 - 27 Jan 2021

Cited by 14 | Viewed by 3205

Abstract

Age is a known prognostic factor for many sarcoma subtypes, however in the literature there are limited data on the different risk profiles of different age groups for osteosarcoma survival. This study aims to provide an overview of survival in patients with high-grade osteosarcoma in different age groups and prognostic variables for survival and local control among the entire cohort. In this single center retrospective cohort study, 402 patients with skeletal high-grade osteosarcoma were diagnosed and treated with curative intent between 1978 and 2017 at the Leiden University Medical Center (LUMC). Prognostic factors for survival were analyzed using a Cox proportional hazard model. In this study poor overall survival (OS) and event-free survival (EFS) were associated with increasing age. Age groups, tumor size, poor histopathological response, distant metastasis (DM) at presentation and local recurrence (LR) were important independent prognostic factors influencing OS and EFS. Differences in outcome among different age groups can be partially explained by patient and treatment characteristics. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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Review

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21 pages, 1536 KiB

Open AccessReview

Tumor and Peripheral Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy

by Luana Madalena Sousa, Jani Sofia Almeida, Tânia Fortes-Andrade, Manuel Santos-Rosa, Paulo Freitas-Tavares, José Manuel Casanova and Paulo Rodrigues-Santos

Cancers 2021, 13(15), 3885; https://doi.org/10.3390/cancers13153885 - 1 Aug 2021

Cited by 17 | Viewed by 4469

Abstract

Soft Tissue Sarcomas (STS) are a heterogeneous and rare group of tumors. Immune cells, soluble factors, and immune checkpoints are key elements of the complex tumor microenvironment. Monitoring these elements could be used to predict the outcome of the disease, the response to therapy, and lead to the development of new immunotherapeutic approaches. Tumor-infiltrating B cells, Natural Killer (NK) cells, tumor-associated neutrophils (TANs), and dendritic cells (DCs) were associated with a better outcome. On the contrary, tumor-associated macrophages (TAMs) were correlated with a poor outcome. The evaluation of peripheral blood immunological status in STS could also be important and is still underexplored. The increased lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR), higher levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and Tim-3 positive CD8 T cells appear to be negative prognostic markers. Meanwhile, NKG2D-positive CD8 T cells were correlated with a better outcome. Some soluble factors, such as cytokines, chemokines, growth factors, and immune checkpoints were associated with the prognosis. Similarly, the expression of immune-related genes in STS was also reviewed. Despite these efforts, only very little is known, and much research is still needed to clarify the role of the immune system in STS. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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21 pages, 741 KiB

Open AccessReview

Acid Microenvironment in Bone Sarcomas

by Gemma Di Pompo, Margherita Cortini, Nicola Baldini and Sofia Avnet

Cancers 2021, 13(15), 3848; https://doi.org/10.3390/cancers13153848 - 30 Jul 2021

Cited by 22 | Viewed by 3310

Abstract

In bone sarcomas, extracellular proton accumulation is an intrinsic driver of malignancy. Extracellular acidosis increases stemness, invasion, angiogenesis, metastasis, and resistance to therapy of cancer cells. It reprograms tumour-associated stroma into a protumour phenotype through the release of inflammatory cytokines. It affects bone homeostasis, as extracellular proton accumulation is perceived by acid-sensing ion channels located at the cell membrane of normal bone cells. In bone, acidosis results from the altered glycolytic metabolism of bone cancer cells and the resorption activity of tumour-induced osteoclasts that share the same ecosystem. Proton extrusion activity is mediated by extruders and transporters located at the cell membrane of normal and transformed cells, including vacuolar ATPase and carbonic anhydrase IX, or by the release of highly acidic lysosomes by exocytosis. To date, a number of investigations have focused on the effects of acidosis and its inhibition in bone sarcomas, including studies evaluating the use of photodynamic therapy. In this review, we will discuss the current status of all findings on extracellular acidosis in bone sarcomas, with a specific focus on the characteristics of the bone microenvironment and the acid-targeting therapeutic approaches that are currently being evaluated. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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27 pages, 908 KiB

Open AccessSystematic Review

Candidate Biomarkers for Specific Intraoperative Near-Infrared Imaging of Soft Tissue Sarcomas: A Systematic Review

by Zeger Rijs, A. Naweed Shifai, Sarah E. Bosma, Peter J. K. Kuppen, Alexander L. Vahrmeijer, Stijn Keereweer, Judith V. M. G. Bovée, Michiel A. J. van de Sande, Cornelis F. M. Sier and Pieter B. A. A. van Driel

Cancers 2021, 13(3), 557; https://doi.org/10.3390/cancers13030557 - 1 Feb 2021

Cited by 10 | Viewed by 4425

Abstract

Surgery is the mainstay of treatment for localized soft tissue sarcomas (STS). The curative treatment highly depends on complete tumor resection, as positive margins are associated with local recurrence (LR) and prognosis. However, determining the tumor margin during surgery is challenging. Real-time tumor-specific imaging can facilitate complete resection by visualizing tumor tissue during surgery. Unfortunately, STS specific tracers are presently not clinically available. In this review, STS-associated cell surface-expressed biomarkers, which are currently already clinically targeted with monoclonal antibodies for therapeutic purposes, are evaluated for their use in near-infrared fluorescence (NIRF) imaging of STS. Clinically targeted biomarkers in STS were extracted from clinical trial registers and a PubMed search was performed. Data on biomarker characteristics, sample size, percentage of biomarker-positive STS samples, pattern of biomarker expression, biomarker internalization features, and previous applications of the biomarker in imaging were extracted. The biomarkers were ranked utilizing a previously described scoring system. Eleven cell surface-expressed biomarkers were identified from which 7 were selected as potential biomarkers for NIRF imaging: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. Promising biomarkers in common and aggressive STS subtypes are TEM1 for myxofibrosarcoma, TEM1, and PDGFRα for undifferentiated soft tissue sarcoma and EGFR for synovial sarcoma. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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