Thymic Epithelial Tumors (TETs) represent a rare tumor family, originating from the epithelial component of the thymus gland. Clinicopathologically, they are segregated into six major subtypes, associated with distinct histological features and clinical outcomes. Their emergence and evolution are accompanied by the generation of a complex tumor microenvironment (TME), dominated by phenotypically and functionally divergent immune cellular subsets, in different maturation states and in analogies that vary significantly among different subtypes. These heterogenous leukocyte populations exert either immune-permissive and tumor-suppressive functions or vice versa, and the dynamic equilibrium established among them either dictates the tumor immune milieu towards an immune-tolerance state or enables the development of a productive spontaneous tumoricidal response. The immunologically “hot” microenvironment, defining a significant proportion of TETs, makes them a promising candidate for the implementation of immune checkpoint inhibitors (ICIs). A number of phase I and II clinical trials have already demonstrated significant, type-specific clinical efficacy of PD-L1 inhibitors, even though substantial limitations in their utilization derive from their immune-mediated adverse effects. Moreover, the completed clinical studies involved relatively restricted patient samples and an expansion in the enrolled cohorts is required, so that more trustworthy conclusions regarding the benefit from ICIs in TETs can be extracted.

Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary breast malignancies, limiting most reports to small retrospective case series. They constitute a heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype. Other sarcoma histotypes, such as undifferentiated pleomorphic sarcoma and leiomyosarcoma, can also be identified. Radiation-induced breast angiosarcoma (RIBA) has an incidence of approximately 0.1% after breast-conserving therapy and arises mainly from the dermis of the irradiated breast. MYC gene amplification is highly indicative of secondary breast angiosarcomas. Their clinical presentation often mimics benign port-radiation lesions, leading to a delay in diagnosis and a lost window of opportunity for cure. Surgery with negative margins is the mainstay of treatment of localized RIBS. In the case of angiosarcoma, technical difficulties, including multifocality, infiltrative margins, and difficulty in assessing tumor margins, render surgical treatment quite challenging. A limited number of studies showed that adjuvant radiation therapy reduces local recurrences; therefore, it is proposed by many groups for large, high-grade tumors. Chemotherapy has been evaluated retrospectively in a small subset of patients, with some evidence supporting its use in angiosarcoma patients. Approximately half of patients with RIBA will show local recurrence. In the advanced setting, different therapeutic options are discussed in the review, including chemotherapy, antiangiogenic therapy, and immunotherapy, whereas the need for further research on molecular therapeutic targets is pointed out.

Advanced osteosarcomas (OSs) and Ewing sarcomas (ESs) tend to have poor prognosis with limited therapeutic options beyond first-line therapy. Aberrant angiogenesis and MET signaling play an important role in preclinical models. The anti-angiogenic drug cabozantinib was tested in a phase 2 trial of advanced OS and ES and was associated with clinical benefits. We retrospectively analyzed the off-label use of cabozantinib in adult patients with advanced OS and ES/primitive neuroectodermal tumors (PNETs) in three centers of the Hellenic Group of Sarcoma and Rare Cancers (HGSRC). Between April 2019 and January 2022, 16 patients started taking 60 mg of cabozantinib for advanced bone sarcoma or PNET. Median age at cabozantinib initiation was 31 years (17–83). All patients had received peri-operative chemotherapy for primary sarcoma and between 0 and 4 lines of treatment (median; 2.5) for advanced disease. The most common adverse effects included fatigue, anorexia, hypertransaminasemia, weight loss, and diarrhea. One toxic death was noted (cerebral hemorrhage). Dose reduction to 40 mg was required in 31.3% of the patients. No objective response was noted, and 9/16 patients exhibited stable disease outcomes. Progression-free survival varied from 1 to 8 (median; 5) months. Our study demonstrates that cabozantinib has antitumor activity in this population. In the real-life setting, we observed similar adverse events as in the CABONE study and in other neoplasms.

Musculoskeletal sarcomas represent rare heterogenous malignancies of mesenchymal origin that can be divided in two distinct subtypes, bone and soft tissue sarcomas. Current treatment options combine the surgical excision of local tumors and multidrug chemotherapy to prevent metastatic widespread disease. Due to the grim prognosis that usually accompanies such tumors, researchers have attempted to shed light on the molecular pathways implicated in their pathogenesis in order to develop novel, innovative, personalized therapeutic strategies. Erythropoietin-producing human hepatocellular receptors (EPHs) are tyrosine-kinase transmembrane receptors that, along with their ligands, ephrins, participate in both tumor-suppressive or tumor-promoting signaling pathways in bone and soft tissue sarcomas. The EPH/ephrin axis orchestrates cancerous processes such as cell–cell and cell–substrate adhesion and enhances the remodeling of the intracellular cytoskeleton to stimulate the motility and invasiveness of sarcoma cells. The purpose of our study was to review published PubMed literature to extract results from in vitro, in vivo and clinical trials indicative of the role of EPH/ephrin signaling in bone and soft tissue sarcomas. Based on these reports, significant interactions between the EPH/ephrin signaling pathway and a plethora of normal and abnormal cascades contribute to molecular mechanisms enhancing malignancy during sarcoma progression. In addition, EPHs and ephrins are prospective candidates for diagnostic, monitoring and therapeutic purposes in the clinical setting against bone and soft tissue sarcomas.

Genomic profiling has improved our understanding of the pathogenesis of different cancers and led to the development of several targeted therapies, especially in epithelial tumors. In this review, we focus on the clinical utility of next-generation sequencing (NGS) to inform therapeutics in soft tissue sarcoma (STS). The role of NGS is still controversial in patients with sarcoma, given the low mutational burden and the lack of recurrent targetable alterations in most of the sarcoma histotypes. The clinical impact of genomic profiling in STS has not been investigated prospectively. A limited number of retrospective, mainly single-institution, studies have addressed this issue using various NGS technologies and platforms and a variety of criteria to define a genomic alteration as actionable. Despite the detailed reports on the different gene mutations, fusions, or amplifications that were detected, data on the use and efficacy of targeted treatment are very scarce at present. With the exception of gastrointestinal stromal tumors (GISTs), these targeted therapies are administered either through off-label prescription of an approved drug or enrollment in a matched clinical trial. Based mainly on anecdotal reports, the outcome of targeted therapies in the different STS histotypes is discussed. Prospective studies are warranted to assess whether genomic profiling improves the management of STS patients.

Uterine sarcomas are rare gynecological tumors arising from the myometrium or the connective tissue of the endometrium with a relatively poor prognosis. MicroRNAs (miRNAs) represent small, single-stranded, non-coding RNA molecules that can function as oncogenes or tumor suppressors under certain conditions. The current review aims at studying the role of miRNAs in uterine sarcoma diagnosis and treatment. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms “microRNA” and “uterine sarcoma” were employed, and we were able to identify 24 studies published between 2008 and 2022. The current manuscript represents the first comprehensive review of the literature focusing on the particular role of miRNAs as biomarkers for uterine sarcomas. miRNAs were found to exhibit differential expression in uterine sarcoma cell lines and interact with certain genes correlating with tumorigenesis and cancer progression, whereas selected miRNA isoforms seem to be either over- or under-expressed in uterine sarcoma samples compared to normal uteri or benign tumors. Furthermore, miRNA levels correlate with various clinical prognostic parameters in uterine sarcoma patients, whereas each uterine sarcoma subtype is characterized by a unique miRNA profile. In summary, miRNAs seemingly represent novel trustworthy biomarkers for the diagnosis and treatment of uterine sarcoma.