Enhancing radiotherapy response via intratumoral injection of a TLR9 agonist in autochthonous murine sarcomas.

Radiation therapy (RT) is frequently used to treat cancers, including soft-tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to RT in transplanted tumors, but the mechanisms of this enhancement remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft-tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and 2 doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to CpG+RT, we performed bulk RNA-Seq, single-cell RNA-Seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and IFN-γ. CpG+RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG+RT, TCR clonality analysis suggests an increase in clonal T cell dominance. Collectively, these findings demonstrate that CpG+RT significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft-tissue sarcoma.

Structural Variants in the SMC1A Gene Associated With Near-Haploidy in Undifferentiated Pleomorphic Sarcomas.

Near-haploidization, that is, loss of one copy of most chromosomes, is a relatively rare phenomenon in most tumors, but is enriched among certain soft tissue sarcomas, including undifferentiated pleomorphic sarcoma (UPS). Presumably, near-haploidization can arise through many mechanisms. This study aimed to identify gene rearrangements that could cause near-haploidization. We here present two UPS in which near-haploidization was an early event, identified through single nucleotide polymorphism (SNP) array analysis. One of the cases was studied further using whole genome and transcriptome sequencing, as well as cytogenetic and molecular cytogenetic methods. Both tumors had chromosomal rearrangements in the form of copy number shifts/structural variants affecting the SMC1A gene. These findings suggest that cohesin defects could contribute to mitotic errors resulting in massive loss of chromosomes. SMC1A encodes one of the components of the cohesin multiprotein complex, which is critical for proper alignment of the sister chromatids during S-phase and separation to opposite spindle poles. Further studies should explore the role of cohesin defects in near-haploidization in other sarcomas and to clarify its role in tumor development.

Validity of the Musculoskeletal Tumor Society Score for lower extremity in patients with bone sarcoma or giant cell tumour of bone undergoing bone resection and reconstruction surgery in hip and knee.

BACKGROUND: The Musculoskeletal Tumor Society Score (MSTS) is widely used to evaluate functioning following surgery for bone and soft-tissue sarcoma. However, concerns have been raised about its content validity due to the lack of patient involvement during item development. Additionally, literature reports inconsistent results regarding data quality and structural validity. This study aimed to evaluate content, structural and construct validity of the Danish version of the MSTS for lower extremity (MSTS-LE). METHODS: The study included patients from three complete cohorts (n = 87) with bone sarcoma or giant cell tumour of bone who underwent bone resection and reconstruction surgery in hip and knee. Content validity was evaluated by linking MSTS items to frameworks of functioning, core outcome sets and semi-structured interviews. Data quality, internal consistency and factor analysis were used to assess the underlying structure of the MSTS. Construct validity was based on predefined hypotheses of correlation between the MSTS and concurrent measurements. RESULTS: Content validity analysis revealed concerns regarding the MSTS. The MSTS did not sufficiently cover patient-important functions, the item Emotional acceptance could not be linked to the framework of functioning, the items Pain and Emotional acceptance pertained to domains beyond functioning and items' response options did not match items. A two-factor solution emerged, with the items Pain and Emotional acceptance loading highly on a second factor distinct from functioning. Internal consistency and construct validity showed values below accepted levels. CONCLUSION: The Danish MSTS-LE demonstrated inadequate content validity, internal consistency, and construct validity. In addition, our analyses did not support unidimensionality of the MSTS. Consequently, the MSTS-LE is not a simple reflection of the construct of functioning and the interpretation of a sum score is problematic. Clinicians and researcher should exercise caution when relying solely on MSTS scores for assessing lower extremity function. Alternative outcome measurements of functioning should be considered for the evaluation of postoperative function in this patient group.

Progress in histology specific treatments in soft tissue sarcoma.

INTRODUCTION: Soft tissue sarcomas (STS) represent a heterogenous group of rare tumors, primarily treated with surgery. Preoperative radiotherapy is often recommended for extremity high-risk STS. Neoadjuvant chemotherapy, typically based on doxorubicin with ifosfamide, has shown efficacy in limbs and trunk wall STS. Second-line chemotherapy, commonly utilized in the metastatic setting, is mostly histology-driven. Molecular targeted agents are used across various histologies, and although the use of immunotherapy in STS is still in its early stages, there is increasing interest in exploring its potential. AREAS COVERED: This article involved an extensive recent search on PubMed. It explored the current treatment landscape for localized and metastatic STS, focusing on the combined use of radiotherapy and chemotherapy for both extremity and retroperitoneal tumors, and with a particular emphasis on the most innovative histopathology driven therapeutic approaches. Additionally, ongoing clinical trials identified via clinicaltrials.gov are included. EXPERT OPINION: Recently there have been advancements in the treatment of STS, largely driven by the outcomes of clinical trials. However further research is imperative to comprehend the effect of chemotherapy, targeted therapy and immunotherapy in various STS, as well as to identify biomarkers able to predict which patients are most likely to benefit from these treatments.

Clinicopathological and genetic characterization of radiotherapy-induced undifferentiated pleomorphic sarcoma following breast cancer: a case series of three tumors and comprehensive literature review.

AIMS: Compared to primary breast sarcoma (BSs), radiotherapy-induced sarcoma (RIS) is a less frequent type of secondary breast sarcoma. Undifferentiated pleomorphic sarcoma (UPS) is an even rarer occurrence within the RIS category. This study aimed to present the clinicopathologic and molecular features of breast radiotherapy-induced UPS. METHODS: A retrospective study was conducted at the Third Affiliated Hospital of Soochow University to analyze three patients with radiation-induced undifferentiated pleomorphic sarcoma (UPS) following breast cancer, spanning from 2006 to 2023. The clinical and pathological variables were extracted from the medical records, while immunohistochemistry was employed to analyze the immunophenotypes of these tumors. Genomic characteristics were assessed through DNA and RNA sequencing techniques. Another 15 cases from the literature were also reviewed to better characterize the tumor. RESULTS: The affected areas encompass the chest wall and breasts, with an incubation period ranging from 6 to 17 years. The tumor cells exhibit pleomorphism and demonstrate a high degree of pathological mitosis. Notably, two cases displayed an accelerated disease progression, characterized by recurrent tumors and metastases occurring within short intervals of 48 and 7 months respectively subsequent to the initial diagnosis. The two prevailing identified genes were TP53 (2/3, 66.7%) and RB1 (1/3, 33.3%). Through analysis of somatic copy number variation (CNV), it was discovered that two oncogenes, MCL1 (1/3, 33.3%) and MYC (1/3, 33.3%), had experienced gains in CNV. The Tumor Mutational Burden (TMB) values for case 1, case 2, and case 3 were 5.9 mut/Mb, 1.0 mut/Mb, and 3.0 mut/Mb, respectively. Moreover, the analysis of RNA-NGS (next-generation sequencing) revealed the presence of a novel gene fusion, named COL3A1-GULP1, in case 2. CONCLUSIONS: Based on our thorough analysis of research findings and previous reports, it is evident that radiotherapy-induced UPS exhibits a highly diverse and frequently severe clinical and biological behavior. Identifying tumor formation using genome sequencing can help understand its biological behavior and determine personalized treatments.

Bone Radiation-Induced Sarcomas: Outcomes Based on Histology and Surgical Treatment: A Systematic Review of the Literature.

BACKGROUND: Bone radiation-induced sarcomas (B-RIS) are secondary neoplasms with reportedly worse overall survival than de novo bone sarcoma. Treatment strategy for these neoplasms remains uncertain. Our systematic review sought to assess overall survival based on histology and surgical intervention. METHODS: A systemic review was conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines and registered in PROSPERO (438415). Studies describing oncologic outcomes of patients with B-RIS in the appendicular and axial skeleton were included. The Strengthening the Reporting of Observational Studies in Epidemiology checklist was used for quality assessment. Survival analysis by histologic subtype and surgery type was performed in a subset of 234 patients from 11 articles with individualized data. A total of 20 articles with a total of 566 patients were included. The most frequent location was the pelvis (27.7%), and the main histological types were osteosarcoma (69.4%), undifferentiated pleomorphic sarcoma (14.1%), and fibrosarcoma (9.2%). Limb-salvage and amputation were performed in 68.5% and 31.5% of cases, respectively. RESULTS: Local recurrence was 13%, without difference between limb-salvage surgery and amputation (p = 0.51). The metastasis rate was 42.3%. Five-year OS was 43.7% (95% confidence interval [CI], 33.3%-53.5%) for osteosarcoma, 31.5% (95% CI, 11.3%-54.2%) for UPS, and 28.1% (95% CI, 10.6%-48.8%) for fibrosarcoma. Five-year OS was 49.2% (95% CI, 35.3%-61.6%) for limb-salvage and 46.9% (95% CI, 29.1%-62.9%) for amputation. There was no difference in 5-year OS between histologic subtypes (p = 0.18) or treatment type (p = 0.86). CONCLUSION: B-RIS demonstrated poor OS at 5 years after initial management regardless of histology. Limb-salvage surgery was not associated with lower 5-year OS compared with amputation. Future studies should compare both groups while controlling for confounders. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

Importance of encouraging early presentation and referral for soft tissue lesions.

Delays in both the presentation and referral of soft tissue lesions have been extensively recorded in the existing literature. Such delays may result in lesions invading into surrounding tissues including neurovascular structures, increasing the risk of surgical complications and adverse consequences for patients. Delays in initiation of treatment of soft tissue sarcomas have further been associated with increased rates of metastasis. As such, patients' recovery may be limited due to late presentations, and residual morbidity may be more pronounced. This case report presents the predicament of a fungating mass in a female in her 80s in order to emphasise the importance of identifying and referring to such lesions early on. The referral delay of this lesion highlights the impact increasing awareness of this condition among both healthcare professionals and patients could have by allowing for earlier interventions.

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Advances in the multidisciplinary surgical approach to primary spinal sarcomas: insights from a retrospective case series on outcomes and survival.

INTRODUCTION: The management of spinal sarcomas is complex, given their widespread involvement and high recurrence rates. Despite consensus on the need for a multidisciplinary approach with surgery at its core, there is a lack of definitive guidelines for clinical decision-making. This study examines a case series of primary spinal sarcomas, focusing on the surgical strategies, clinical results, and survival data to inform and guide therapeutic practices. METHODS: We conducted a retrospective analysis of patients who underwent surgical resection for primary spinal sarcomas between 2005 and 2022. The study focused on gathering data on patient demographics, surgical details, postoperative complications, overall hospital stay, and mortality within 90 days post-surgery. RESULTS: The study included 14 patients with a primary diagnosis of spinal sarcoma, with an average age of 48.6 ± 12.6 years. Chondrosarcoma emerged as the most common tumor type, representing 57.1% of cases, followed by Ewing sarcoma at 35.7%, and synovial sarcoma at 7.1%. Patients with chondrosarcoma were treated with en-bloc resection, while the patient with synovial sarcoma underwent intra-lesional excision and those with Ewing sarcoma received decompression and tumor debulking. Postoperative assessments revealed significant improvements in neurological conditions. Notably, functional status as measured by the Karnofski Performance Index (KPI), improved substantially post-surgery (from 61.4 to 80.0%) The mean follow-up was 34.9 ± 9.2 months. During this time period one patient experienced fatal bleeding after en-bloc resection complications involving the vena cava. None of the patient needed further surgery. CONCLUSIONS: Our 16-year study offers vital insights into managing primary spinal sarcomas, showcasing the effectiveness of surgical intervention, particularly en-bloc resection. Despite their rarity and complexity, our multidisciplinary treatment approach yields improved outcomes and highlights the potential for refined surgical strategies to become standardized care in this challenging domain.

Setting the international research agenda for sarcomas with patients and carers: results of phase II of the Sarcoma Patient Advocacy Global Network (SPAGN) priority setting partnership.

BACKGROUND: Typically, researchers and clinicians determine the agenda in sarcoma research. However, patient involvement can have a meaningful impact on research. Therefore, the Patient-Powered Research Network (PPRN) of the Sarcoma Patient Advocacy Global Network (SPAGN) set up a Priority Setting Partnership (PSP). The primary objective of this partnership is to identify priorities for research and patient advocacy topics. METHODS: In the first phase of this PSP, including 264 sarcoma patients and carers from all over the world, 23 research topics regarding sarcomas and 15 patient advocacy topics were identified using an online survey. In the second phase, participants were asked to fill in a top five and a top three of research and patient advocacy topics, respectively. Additionally, sociodemographic characteristics and sarcoma characteristics were collected. Social media channels, local national patient advocacy groups and the SPAGN website were used to distribute the survey. RESULTS: In total, 671 patients (75%) and carers (25%) participated in this survey. The five highest ranked research topics were related to causes of sarcoma (43%), prognosis and risk of recurrence (40%), specific subtypes of sarcoma (33%), the role of immunotherapy, targeted therapy and combined therapy (30%), and hereditary aspects (30%). The three highest ranked patient advocacy topics were improving the diagnostic process of sarcoma (39%), access to tumor DNA analysis (37%) and establishing an international sarcoma registry (37%). CONCLUSIONS: This sarcoma PSP has identified priorities for research and patient advocacy, offering guidance for researchers, assisting funding agencies with assessing project relevance and empowering patient advocates to represent the needs of patients and carers.

[Chest wall reconstruction with a non-rigid synthetic rib prosthesis: a multicenter study]. / Rekonstruktsiya grudnoi stenki nerigidnym sinteticheskim protezom rebra: mul'titsentrovoe issledovanie.

Chest wall resection is performed for a variety of diseases, for primary rib and soft tissue tumors, metastatic lesions, or locally invasive growth of lung and mediastinal tumors being the most common indications. Following the resection phase, it is essential to determine the method of chest wall reconstruction that will restore the structural function, preserve pulmonary biomechanics, reduce the likelihood of residual pleural space, pulmonary hernia, and protect intrathoracic organs. The main objective of this study is to investigate the outcomes of chest wall resection with reconstruction using Codubix material. MATERIAL AND METHODS: This retrospective multicenter study included 22 patients who underwent chest wall tumor resection with subsequent Codubix rib endoprosthesis reconstruction from 2019 to 2023. Four medical institutions participated in the study: P.A. Herzen Moscow Cancer Research Institute, Sverdlovsk Regional Oncology Hospital, Morozov Children's City Clinical Hospital and Kaluga Regional Oncology Hospital. Inclusion criteria were the presence of chest wall tumors, both primary and secondary, removal of more than 2 ribs, resection of the rib arch and the sternum. RESULTS: The median age was 60 years (48-66), 11 (50%) patients were females and 11 (50%) males. Operations for chest wall sarcoma, metastatic lesions, and lung cancer were performed in 9 (40.9%), 4 (18.2%), and 3 (13.6%) patients, respectively. The median number of removed ribs was 3 (2-4), with a maximum of 7. Sternotomy was performed in 9 (40.9%) patients, and subtotal resection of the body or handle of the sternum was carried out in 77.7%. Combined resections were performed in 14 (63.6%) patients. Radical tumor removal (R0) was achieved in 21 (95.5%) patients. Complications were observed in 9 (40.9%) patients, with intermuscular seroma being the most common in three (33.3%), followed by hydrothorax in 2 (22.2%), bilateral pneumonia, acute respiratory failure, and postoperative delirium in 1 (11.1%) patient each. One patient had the Codubix plate removed due to postoperative wound infection. The median overall and recurrence-free survival was not reached, and the 1-year recurrence-free survival was 63.9%, with an overall survival of 86.8%. CONCLUSION: Reconstruction with Codubix material allows for satisfactory functional and cosmetic results, characterized by a low complication rate and good adaptive properties.

The molecular conversations of sarcomas: exosomal non-coding RNAs in tumor's biology and their translational prospects.

Exosomes mediate cell-to-cell crosstalk involving a variety of biomolecules through an intricate signaling network. In recent years, the pivotal role of exosomes and their non-coding RNAs cargo in the development and progression of several cancer types clearly emerged. In particular, tumor bulk and its microenvironment co-evolve through cellular communications where these nanosized extracellular vesicles are among the most relevant actors. Knowledge about the cellular, and molecular mechanisms involved in these communications will pave the way for novel exosome-based delivery of therapeutic RNAs as well as innovative prognostic/diagnostic tools. Despite the valuable therapeutic potential and clinical relevance of exosomes, their role on sarcoma has been vaguely reported because the rarity and high heterogeneity of this type of cancer. Here, we dissected the scientific literature to unravel the multifaceted role of exosomal non-coding RNAs as mediator of cell-to-cell communications in the sarcoma subtypes.

Real-world efficacy, safety data and predictive clinical parameters for treatment outcomes in advanced soft tissue sarcoma treated with combined immunotherapy and antiangiogenic therapy.

BACKGROUND: The combination of immunotherapy and antiangiogenic therapy has shown potential in the treatment of numerous malignant tumors, but limited evidence was available for soft tissue sarcomas (STS). Therefore, the aim of the present study is to assess the efficacy and safety of immunotherapy in conjunction with antiangiogenic therapy in patients diagnosed with advanced STS (aSTS). METHODS: The study enrolled patients with aSTS from January 2014 to October 2022. Eligible participants had previously received anthracycline-based chemotherapy, presented with an anthracycline-resistant sarcoma subtype, or were ineligible for anthracycline treatment due to medical conditions. Following enrollment, these patients received a combination of immunotherapy and antiangiogenic therapy. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS), while the secondary endpoints included the disease control rate (DCR), overall survival (OS), and the incidence of adverse events. RESULTS: Fifty-one patients were included in this cohort study. The median duration of follow-up was 15.8 months. The ORR and DCR were 17.6%, and 76.5%, respectively. The median PFS (mPFS) was 5.8 months (95% CI: 4.8-6.8) for all patients, and the median OS had not been reached as of the date cutoff. Multivariate analysis indicated that Eastern Cooperative Oncology Group performance status of 0-1 and ≤ second-line treatment were positive predictors for both PFS and OS. Patients with alveolar soft part sarcoma or clear cell sarcoma had longer mPFS (16.2 months, 95% CI: 7.8-25.6) when compared to those with other subtypes of STS (4.4 months, 95% CI: 1.4-7.5, P < 0.001). Among the observed adverse events, hypertension (23.5%), diarrhea (17.6%), and proteinuria (17.6%) were the most common, with no treatment-related deaths reported. CONCLUSION: The combination of immunotherapy and antiangiogenic agents showed promising efficacy and acceptable toxicity in patients with aSTS, especially those with alveolar soft part sarcoma or clear cell sarcoma.

Laryngeal rare benign non-epithelial tumors and sarcomas emphasizing on chondrosarcomas: A literature review and a case presentation.

Laryngeal rare tumors include benign and malignant tumors of epithelial, non-epithelial, or mesenchymal origin. Chondrosarcomas are the most common mesenchymal malignant tumors of the larynx. We performed a literature review (Pubmed/Medline; PRISMA 2020) to detect the frequency of published studies from 2021 to April 2024 regarding benign and malignant epithelial, non-epithelial, or mesenchymal rare tumors of the larynx, emphasizing laryngeal chondrosarcoma (LC) cases. Articles including cases discussed before 2021 were excluded and articles without available English translations. We included 154 articles investigating rare tumors of the larynx, the majority of them discussed non-epithelial or mesenchymal entities (75 %). Specifically, a high proportion of studies examined benign non-epithelial or mesenchymal tumors (79.5 %) or mesenchymal rare malignancies (72 %) of the larynx concerning epithelial tumors in the last three years. Sarcomas were discussed in 74 % of mesenchymal laryngeal malignancies and more than 50 % of rare laryngeal tumor studies, and LC was discussed in ∼50 % of laryngeal sarcoma studies. LC studies reported 174 cases, 21 % of them of high-grade LC (II), including a new case of LC presented here in the supraglottic (grade II), which showed intense staining for the S100 marker. Our study highlights the awareness of rare laryngeal tumors emphasizing non-epithelial benign tumors and laryngeal sarcomas, including chondrosarcomas, as pathologic entities of the larynx. Although the majority of LC included low-grade neoplasms, a markedness proportion of LC cases was evaluated as high-grade. Future research approaches, including a range of low and high-grade tumors, would reveal prognostic markers or therapeutic targets for LC and other rare laryngeal malignancies of non-epithelial or mesenchymal origin.

Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) using dose-volume constraints development: a study protocol.

INTRODUCTION: Radiotherapy improves local tumour control in patients with soft tissue sarcoma of the extremities (STSE) but it also increases the probability of long-term toxicities such as tissue fibrosis, joint stiffness and lymphoedema. The use of radiation dose and volume thresholds, called dose constraints, may potentially reduce the development of toxicities in STSE. The aim of this study is to determine predictors of radiotherapy-related side effects for STSE. METHODS AND ANALYSIS: Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) is a multicentre observational study comprising two cohorts (PredicT A and B). PredicT A, a retrospective analysis of the UK VorteX (NCT00423618) and IMRiS clinical trials (NCT02520128), is aimed at deriving a statistical model for development of dose-volume constraints. This model will use receiving operator characteristics and multivariate analysis to predict radiotherapy side effects and patient-reported outcomes. PredicT B, a prospective cohort study of 150 patients with STSE, is aimed at testing the validity of those dose-volume constraints. PredicT B is open and planned to complete recruitment by September 2024. ETHICS AND DISSEMINATION: PredicT B has received ethical approval from North West - Liverpool Central Research Ethics Committee (20/NW/0267). Participants gave informed consent to participate in the study before taking part. We will disseminate our findings via publications, presentations, national and international conference meetings and engage with local charities. TRIAL REGISTRATION NUMBER: NCT05978024.

Soft tissue sarcomas of the head and neck region: clinical and histopathological study of 39 patients.

<b>Introduction:</b> Soft tissue sarcomas (STS) constitute about 1-2% of all malignant tumors, with approximately 10% of them located in the head and neck region.<b>Aim:</b> The aim of this study was the assessment of treatment efficiency in head and neck STS of adult patients of the ENT Department of Medical University of Silesia, treated surgically in the period 1980-2023.<b>Materials and methods:</b> Retrospective analysis of 39 patients with the diagnosis of head and neck STS.<b>Results:</b> Histopathological examination showed 21 different types of STS located most commonly in: paranasal sinuses (13 cases), orbital cavity (6 cases), nasal cavity (3 cases), and larynx (3 cases). Other locations: parapharyngeal space, parotid gland, nasal septum, bridge of the nose, soft and hard palate, mandibular mucosa, tongue, auricle, palatine tonsil, and cheek. All those patients underwent chemoradiation as postoperative treatment. Radical surgical procedure was achieved in 32 patients (82%). However, in 11 patients (28%), microscopic examination did not confirm radical resection (R1 - PSM - positive surgical margin). In 7 patients (18%), the surgical procedure turned out to be not radical on macroscopic examination (R2). Dissemination of neoplasms (distant metastases) was found in 7 patients (18%). Five-year survival time without local recurrence was achieved in 25 patients (64%). The most frequent reason for unsuccessful interventions was local recurrence noted in 18 patients (46%), while distant metastases occurred in 9 patients (23%).<b>Conclusions:</b> The basic procedure in the treatment of STS is radical surgery combined with preoperative or postoperative radiotherapy and/or chemotherapy and, in case of a metastasis, surgical removal thereof. Despite the fact that sarcomas are rare tumors, they remain a challenge for head and neck surgery. Recurrence rates and mortality remain high due to the high degree of malignancy.

Improving Diagnosis and Care for Patients With Sarcoma: Do Real-World General Practitioners Data and Prospective Data Collections Have a Place Next to Clinical Trials?

There has been growing interest in the use of real-world data (RWD) to address clinically and policy-relevant (research) questions that cannot be answered with data from randomized controlled trials (RCTs) alone. This is, for example, the case in rare malignancies such as sarcomas as limited patient numbers pose challenges in conducting RCTs within feasible timeliness, a manageable number of collaborators, and statistical power. This narrative review explores the potential of RWD to generate real-world evidence (RWE) in sarcoma research, elucidating its application across different phases of the patient journey, from prediagnosis to the follow-up/survivorship phase. For instance, examining electronic health records (EHRs) from general practitioners (GPs) enables the exploration of consultation frequency and presenting symptoms in primary care before a sarcoma diagnosis. In addition, alternative study designs that integrate RWD with well-designed observational RCTs may offer relevant information on the effectiveness of clinical treatments. As, especially in cases of ultrarare sarcomas, it can be an extreme challenge to perform well-powered randomized prospective studies. Therefore, it is crucial to support the adaptation of novel study designs. Regarding the follow-up/survivorship phase, examining EHR from primary and secondary care can provide valuable insights into identifying the short- and long-term effects of treatment over an extended follow-up period. The utilization of RWD also comes with several challenges, including issues related to data quality and privacy, as described in this study. Notwithstanding these challenges, this study underscores the potential of RWD to bridge, at least partially, gaps between evidence and practice and holds promise in contributing to the improvement of sarcoma care.

Müllerian adenosarcoma with sarcomatous overgrowth and heterologous elements: A case report and literature review.

Uterine mullerian adenosarcoma (MA) is a rare biphasic tumour that accounts for less than 0.5% of uterine neoplasms. The age range of presentation is wide, with the median age in the 5th decade of life. It usually has a good prognosis; however, it worsens when it presents with sarcomatous overgrowth, heterologous elements or infiltrates the myometrium. We report the case of a 63-year-old woman presenting with abnormal vaginal bleeding and a sensation of solid material coming out of the cervical canal who was diagnosed with mullerian adenosarcoma with sarcomatous overgrowth (MASO) and presence of heterologous elements after performing a mass biopsy and subsequent hysterectomy. We reviewed the literature, focusing especially on the differential diagnoses to be evaluated, as well as the differences in prognosis and treatment according to whether or not they present histologic features of poor prognosis.

Uncommon adrenal rest tumors and massive adrenal enlargement in adult with congenital adrenal hyperplasia mimicking metastasis from pleomorphic sarcoma.

BACKGROUND: Congenital adrenal hyperplasia (CAH) encompassed a bunch of autosomal recessive disorders characterized by impaired cortisol levels due to an enzymatic deficiency in steroid synthesis. In adult male patients with CAH, a frequent complication related to poor disease control is the development of ectopic adrenocortical tissue in the testes, named testicular adrenal rest tumors (TART). Conversely, ovarian adrenal rest tumors (OART) in females are extremely rare and adrenal rests in sites other than gonads are so uncommon to have been described only few times in literature. CASE PRESENTATION: We report a case of a male patient with untreated CAH and oncologic history of pleomorphic sarcoma who presented with massive bilateral adrenal enlargement and adrenal rest tumors in peri-lumbar and peri-cecal sites, which mimicked metastasis from sarcoma. CONCLUSIONS: The development of massive adrenal enlargement and ectopic adrenal rest tumors in sites other than gonads, even if very uncommon, should be suspected in patients with CAH and prolonged periods of undertreatment.

Clinical and translational implications of immunotherapy in sarcomas.

Immunotherapy has emerged as promising treatment in sarcomas, but the high variability in terms of histology, clinical behavior and response to treatments determines a particular challenge for its role in these neoplasms. Tumor immune microenvironment (TiME) of sarcomas reflects the heterogeneity of these tumors originating from mesenchymal cells and encompassing more than 100 histologies. Advances in the understanding of the complexity of TiME have led to an improvement of the immunotherapeutic responsiveness in sarcomas, that at first showed disappointing results. The proposed immune-classification of sarcomas based on the interaction between immune cell populations and tumor cells showed to have a prognostic and potential predictive role for immunotherapies. Several studies have explored the clinical impact of immune therapies in the management of these histotypes leading to controversial results. The presence of Tumor Infiltrating Lymphocytes (TIL) seems to correlate with an improvement in the survival of patients and with a higher responsiveness to immunotherapy. In this context, it is important to consider that also immune-related genes (IRGs) have been demonstrated to have a key role in tumorigenesis and in the building of tumor immune microenvironment. The IRGs landscape in soft tissue and bone sarcomas is characterized by the connection between several tumor-related genes that can assume a potential prognostic and predictive therapeutic role. In this paper, we reviewed the state of art of the principal immune strategies in the management of sarcomas including their clinical and translational relevance.