One-Stage Surgical Resection and Functional Reconstruction for Upper Limb Soft Tissue Sarcoma.

BACKGROUND: Currently, the gold standard of treatment for extremity soft tissue sarcoma (STS) is limb-sparing surgery. When the upper extremity is involved, the functional outcome is frequently poor. A 1-step resection and functional reconstruction would be advisable to obtain a fast recovery. Our study aims at retrospectively analyzing our case series of immediate nerves and tendons reconstructions of the upper limb after STS resection, while combining a review of the literature. METHODS: A retrospective review was conducted on a consecutive series of patients who underwent an immediate functional reconstruction after STS resection of the upper limb between 2015 and 2022 among the IRCCS Foundation "Istituto Nazionale dei Tumori." The Disabilities of the Arm, Shoulder and Hand (DASH) score was considered the primary outcome. The obtained DASH scores were compared through groups that underwent different reconstructive procedures. The literature review was conducted according to the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) criteria among 3 databases (PubMed, EMBASE, and Cochrane) using the search parameters "(((upper extremity) OR (upper limb)) AND (functional reconstruction) AND (soft tissue sarcoma)." RESULTS: Between 2015 and 2022, 52 patients required a functional reconstruction. The mean follow-up time was 49.63 months. The DASH score analysis reported a mean value of 44.1 ± 26.7. A statistically significant difference was found between groups who underwent different reconstruction techniques, whereas no difference was found regarding exposure to neoadjuvant radiation therapy. The literature review reported few articles focusing on immediate functional reconstruction after STS resection, and only 6 articles were included in the review. CONCLUSIONS: Our review aimed at reporting our case series of immediate functional reconstructions after STS of the upper extremity, which is currently the most substantial one reported in literature to set an effective baseline for further studies in the field.

Comprehensive analysis of prognostic and immunological role of basement membrane-related genes in soft tissue sarcoma.

BACKGROUND: Soft tissue sarcoma (STS) represents highly multifarious malignant tumors that often occur in adolescents and have a poor prognosis. The basement membrane, as an ancient cellular matrix, was recently proven to play a vital role in developing abundant tumors. The relationship between basement membrane-related genes and STS remains unknown. METHODS: Consensus clustering was employed to identify subgroups related to differentially expressed basement membrane-related genes. Cox and least absolute shrinkage and selection operator regression analyses were utilized to construct this novel signature. Then, we established a nomogram and calibration curve, including the risk score and available clinical characteristics. Finally, we carried out functional enrichment analysis and immune microenvironment analysis to investigate enriched pathways and the tumor immune microenvironment related to the novel signature. RESULTS: A prognostic predictive signature consisting of eight basement membrane-related genes was established. Kaplan-Meier survival curves demonstrated that the patients in the high-risk group had a poor prognosis. Independent analysis illustrated that this risk model could be an independent prognostic predictor. We validated the accuracy of our signature in the validation data set. In addition, gene set enrichment analysis and immune microenvironment analysis showed that patients with low-risk scores were enriched in some pathways associated with immunity. Finally, in vitro experiments showed significantly differential expression levels of these signature genes in STS cells and PSAT1 could promote the malignant behavior of STS. CONCLUSIONS: The novel signature is a promising prognostic predictor for STS. The present study may improve the prognosis and enhance individualized treatment for STS in the future.

Prognostic factors of cutaneous soft tissue sarcomas in children: a SEER population-based study.

This study aims to analyze the clinicopathological characteristics and survival outcomes of cutaneous soft tissue sarcomas (CSTS) in children. We selected pediatric cases of CSTS diagnosed between 2000 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) database. Survival rates were calculated using Kaplan-Meier methods. We performed univariate analyses with the log-rank test and multivariate survival analyses using Cox proportional-hazards models to determine factors affecting overall survival (OS). Additionally, we constructed a predictive nomogram based on the outcomes of the Cox regression. A total of 148 pediatric patients with CSTS were reviewed. The median age at diagnosis was 13 years (range: 0-18 years). Prognostically, tumors located on the extremities showed better outcomes compared to those on the head, neck, or trunk. Among the histological types, angiosarcoma had the lowest five-year survival rate at 51.3%, which was substantially lower compared to fibrous histiocytoma and leiomyosarcoma. Cox regression analysis highlighted surgical intervention as the only significant independent prognostic factor for OS, with an increased risk of mortality observed in patients not undergoing surgery. Additionally, patients with distant-stage disease exhibited significantly lower survival rates than those with localized conditions. Pediatric CSTS represents a diverse and infrequent group of tumors, predominantly fibrous histiocytoma and leiomyosarcoma. Surgery was identified as the crucial determinant of survival, underscoring its role in effectively managing these patients.

Visceral fat area and subcutaneous fat area as measures of body composition in soft tissue sarcoma.

BACKGROUND AND OBJECTIVES: Soft tissue sarcomas (STS) are a heterogenous group of malignancies of mesenchymal origin. Given recent data linking obesity as well as the pattern of fat distribution with cancer outcomes, we sought to investigate the association of visceral fat area (VFA) and subcutaneous fat area (SFA) with oncologic outcomes in patients with STS undergoing surgery. METHODS: We analyzed data from 88 patients with STS diagnosed from 2008 to 2022. Predictor variables included body mass index (BMI), VFA, and SFA. VFA and SFA were obtained from computed tomography of the abdomen and pelvis. Univariable and multivariable Cox regression analysis was used to analyze associations between predictor variables and overall survival and recurrence-free survival. RESULTS: Although BMI was closely correlated with VFA (r = 0.69, p < 0.0001) and SFA (r = 0.80, p < 0.0001), there was no significant association between high BMI, VFA or SFA, and worse oncologic outcomes. CONCLUSIONS: Although VFA and SFA are strongly correlated with BMI, we did not observe BMI nor imaging metrics of fat composition to be associated with worse oncologic outcomes. Further research is needed to elucidate any links between body fat content and metabolic or immune factors governing oncologic outcomes in STS.

The role of radiotherapy in multimodal treatment of non-rhabdomyosarcoma soft tissue sarcomas in children: A real life report from a tertiary center.

OBJECTIVE: The current treatment of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) is a multimodal risk-based approach. Today, smaller fields and lower doses of radiotherapy (RT) have become standard. In this study, it was aimed to evaluate the treatment outcomes and toxicity profile in children with NRSTS that received RT as a part of multimodal therapy. METHODS: Twenty-nine patients with pediatric NRSTS treated with neoadjuvant or adjuvant RT between 1998 and 2022 were evaluated retrospectively. Kaplan-Meier method was used for survival analyses. RESULTS: Median follow-up was 36 months (range, 6-291 months). The median neoadjuvant and adjuvant RT doses were 50 Gy (range, 45-66 Gy) and 54 Gy (45-66 Gy), respectively. During follow-up, six (21%) patients developed a local recurrence and 10 (35%) had distant metastasis. The 5-year local control, overall survival (OS), local recurrence-free survival, and distant metastasis-free survival rate was 79%, 67%, 59%, and 61%, respectively. In multivariate analysis, a ≤5-cm tumor, gross tumor resection, Children's Oncology Group (COG) low-risk group, and absence of neoadjuvant chemotherapy were independent favorable prognostic factors for OS. Severe (≥ grade 3) late toxicity was observed in 6 (20%) patients. CONCLUSIONS: RT is a crucial component in the multimodal risk-based treatment approach for pediatric NRSTS. However, late toxicity rates are still high and should be improved. Patients with a ≤5-cm tumor, COG low-risk group and treated with gross tumor resection have increased survival rates.

Proof of Concept for Genome Profiling of the Neurofibroma/Sarcoma Sequence in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness.

Cell-cycle phase progression analysis identifies three unique phenotypes in soft tissue sarcoma.

PURPOSE: Loddo et al. (Br J Cancer 100:959-70, 2009) established the prognostic significance of cell cycle markers and "Cell-Cycle Phenotypes" in breast carcinoma. This study aims to 1) identify prognostic cell-cycle markers in sarcoma, and 2) assess the prognostic potential of specific cell-cycle phenotypes in sarcoma. METHODS: Tissue samples from 128 soft tissue sarcomas were stained for four cell cycle-specific markers: Mcm2, Geminin, Plk1, and H3S10ph. Only primary soft tissue tumors (liposarcoma, leiomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma) were included in the analysis. Any tumor coming from a recurrent or metastatic lesion were excluded from the analysis. Three cell-cycle phenotypes (I, II, III) were derived from marker expression patterns. Prognostic significance was evaluated in a subset of primary soft tissue sarcomas using Cox regression for survival analysis. RESULTS: Compared to phenotype I, the phenotype III tumors had a decreased 5-year overall survival (HR 6.81 [2.36-19.61]; p = < 0.001), 5-year disease-free survival (HR 1.07 (1.02-1.18); p = 0.004), and 5-year metastasis-free survival (HR 4.34 [1.58-11.93]; p = 0.004). High expression of Plk1 was associated with decreased 5-year overall survival (HR: 4.04 CI [1.21-6.67; p = 0.02) and 5-year metastasis-free survival (HR: 2.91 CI [1.15-7.37]; p = 0.03). Geminin was also found to have a decreased 5-year overall survival (HR:2.84 CI [1.21-6.67]; p = 0.02). No statistical difference in prognostication were noted between phenotypes and the AJCC system. CONCLUSIONS: We identified three unique sarcoma cell cycle phenotypes that have prognostic significance. This performs similarly to the AJCC staging system.

[Pediatric soft tissue tumors : Tumors of uncertain origin]. / Kindliche Weichteiltumoren : Tumoren unklaren Ursprungs.

Soft tissue tumors of childhood are an extremely heterogeneous group of tumors that require precise diagnosis for therapy. In this article, selected tumors of uncertain origin that exhibit characteristic histological, immunophenotypical, and molecular features are addressed. Angiomatoid fibrous histiocytoma, alveolar soft part sarcoma, extrarenal rhabdoid tumor, synovial sarcoma, and desmoplastic small round cell tumor differ in their pathology, their clinical behavior, and prognosis.

Establishment and characterization of 18 Sarcoma Cell Lines: Unraveling the Molecular Mechanisms of Doxorubicin Resistance in Sarcoma Cell Lines.

Sarcomas, malignant tumors from mesenchymal tissues, exhibit poor prognosis despite advancements in treatment modalities such as surgery, radiotherapy, and chemotherapy, with doxorubicin being a cornerstone treatment. Resistance to doxorubicin remains a significant hurdle in therapy optimization. This study aims to dissect the molecular bases of doxorubicin resistance in sarcoma cell lines, which could guide the development of tailored therapeutic strategies. Eighteen sarcoma cell lines from 14 patients were established under ethical approvals and classified into seven subtypes. Molecular, genomic, and transcriptomic analyses included whole-exome sequencing, RNA sequencing, drug sensitivity assays, and pathway enrichment studies to elucidate the resistance mechanisms. Variability in doxorubicin sensitivity was linked to specific genetic alterations, including mutations in TP53 and variations in the copy number of genomic loci like 11q24.2. Transcriptomic profiling divided cell lines into clusters by karyotype complexity, influencing drug responses. Additionally, pathway analyses highlighted the role of signaling pathways like WNT/BETA-CATENIN and HEDGEHOG in doxorubicin-resistant lines. Comprehensive molecular profiling of sarcoma cell lines has revealed complex interplays of genetic and transcriptomic factors dictating doxorubicin resistance, underscoring the need for personalized medicine approaches in sarcoma treatment. Further investigations into these resistance mechanisms could facilitate the development of more effective, customized therapy regimens.

Let's get functional: Drug sensitivity profiling to enable precision sarcoma medicine.

Drug sensitivity profiling in patient-derived tumor models offers new hope for improving outcomes in cancers lacking effective therapies. Al Shihabi et al.1 demonstrate that short-term cultures from bone and soft tissue sarcomas enable clinically meaningful screening of multiple drugs and combinations, marking a significant advance in personalized care for these high-risk diseases.

Ciliary body myxoid epithelioid sarcoma in a cat: a case report.

BACKGROUND: The majority of primary, intraocular tumors in cats originate from the uvea and include feline diffuse iris melanoma, lymphoma, and iridociliary epithelial adenoma or adenocarcinoma. In this case report, we describe for the first time the clinical, histological, and immunohistochemical findings of a rare myxoid intraocular neoplasm arising from the ciliary body in a cat. CASE PRESENTATION: A 14-year-old, female, spayed domestic shorthaired cat was presented for evaluation of discolouration of the right eye. Upon examination, a clear to light whitish-tan, bubble-shaped intraocular mass adherent to the inferior ciliary body and extending into the anterior chamber was noted. Within five weeks, the tumor was significantly larger and the eye had developed secondary glaucoma so was enucleated. Light microscopic examination of the globe revealed a multinodular, hypocellular neoplasm arising from the ciliary body composed of interwoven spindle cells embedded in abundant amounts of a lightly basophilic myxoid matrix. Neoplastic cells exhibited strong immunoreactivity for cytokeratin while also showing moderate to strong immunoreactivity to vimentin. A diagnosis was therefore made of an unusual intraocular myxoid epithelioid sarcoma arising from the ciliary body. CONCLUSIONS: Although apparently exceedingly rare, epithelioid myxosarcoma should be included as a differential diagnosis for intraocular tumors in cats and they represent a clinical, histologic, and immunohistochemical diagnostic challenge. Early surgical intervention should be considered to prevent local invasion and ascension to the brain.

The utility of MRI for the preoperative differential diagnosis of uterine sarcoma and leiomyoma: a single-center study.

Although uterine sarcoma is a rare disease, its prognosis is extremely poor;thus, it is important to differentiate it from uterine leiomyoma.　In this retrospective study, we examined the association between preoperative MRI findings and postoperative pathology results in 170 patients with uterine tumors who underwent preoperative MRI examination at Fukushima Red Cross Hospital.　In 4 cases of sarcoma / smooth muscle tumor of unknown malignant potential (STUMP), abnormal findings were found at a high frequency with T1-weighted imaging (T1WI) (75%), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast enhancement (CE) (100%).　In cases of ordinary leiomyoma, on the other hand, abnormal findings were less frequent.　The rates of high DWI signal intensity for degenerated and cellular leiomyoma were 31% and 64%, respectively, and the CE-positive rates were 31% and 57%, respectively.　Apparent Diffusion Coefficient (ADC) values appeared to be useful in differentiating degenerated leiomyoma from sarcoma.　The relatively characteristic findings of uterine sarcoma on MRI images may overlap with those of degenerated leiomyoma and cellular leiomyoma, making it difficult to diagnose sarcoma on imaging alone.　However, findings that distinguish sarcoma from ordinary, degenerated, and cellular leiomyoma cases are worthy of attention, to avoid overlooking sarcoma.

A Simple Eco-Friendly HPLC-PDA Method for the Simultaneous Determination of Paclitaxel and Seliciclib in Plasma Samples for Assessing Their Pharmacodynamics and Pharmacokinetics in Combination Therapy for Uterine Sarcoma.

Background/Objectives: Uterine sarcoma, a rare cancer originating in the smooth muscle of the uterus, exhibits high rates of recurrence and metastasis. It represents one of the most challenging types of cancer due to its chemorefractory nature, showing little response to conventional chemotherapy methods and displaying a relative survival rate of 30-40%. A potentially promising approach for treating uterine sarcoma involves combination therapy with paclitaxel (PAC), a microtubule-targeting agent, and seliciclib (SEL), a cyclin-dependent kinase inhibitor. SEL has been identified as a drug that can enhance the effectiveness of PAC through synergistic effects. To further refine this treatment strategy, an efficient analytical tool capable of simultaneously measuring the concentrations of PAC and SEL in blood plasma is needed. This tool would make it easier to study the pharmacokinetic interactions of potential drugs and assist in monitoring therapy when administering this combination treatment. Regrettably, a method meeting these specific requirements has not been documented in the existing literature. Methods: This article introduces the first HPLC technique employing a PDA detector to concurrently measure PAC and SEL levels in plasma. The methodology underwent validation in accordance with the ICH standards for validating bioanalytical methods. Results: The method exhibited linearity in the concentrations ranging from 0.8 to 100 µg mL-1 for both PAC and SEL. The limits of quantification were determined and found to be 1.34 and 1.25 µg mL-1 for PAC and SEL, respectively. All the other validation criteria conformed to the ICH validation standards. The HPLC-PDA method was successfully employed to quantify both PAC and SEL in plasma samples with a high level of reliability (in terms of accuracy and precision). The eco-friendliness of the approach was verified using three thorough assessments. This technique serves as a valuable asset in establishing the correct dosage and administration schedule for the combined treatment involving PAC and SEL, ensuring the desired therapeutic effects and safety in managing uterine sarcoma. Conclusions: The proposed HPLC-PDA method is the first reliable and eco-friendly method developed to simultaneously determine PAC and SEL in high-throughput plasma samples in clinical laboratories.

Assessment of a Structurally Modified Alternanthera Mosaic Plant Virus as a Delivery System for Sarcoma Cells.

The virions of plant viruses and their structurally modified particles (SP) represent valuable platforms for recombinant vaccine epitopes and antitumor agents. The possibility of modifying their surface with biological compounds makes them a tool for developing medical biotechnology applications. Here, we applied a new type of SP derived from virions and virus-like particles (VLP) of Alternanthera mosaic virus (AltMV) and well-studied SP from Tobacco mosaic virus (TMV). We have tested the ability of SP from AltMV (AltMV SPV) and TMV virions also as AltMV VLP to bind to and penetrate Ewing sarcoma cells. The adsorption properties of AltMV SPV and TMV SP are greater than those of the SP from AltMV VLP. Compared to normal cells, AltMV SPV adsorbed more effectively on patient-derived sarcoma cells, whereas TMV SP were more effective on the established sarcoma cells. The AltMV SPV and TMV SP were captured by all sarcoma cell lines. In the established Ewing sarcoma cell line, the effectiveness of AltMV SPV penetration was greater than that of TMV SP. The usage of structurally modified plant virus particles as a platform for drugs and delivery systems has significant potential in the development of anticancer agents.

Spindle Cell Neoplasm With a Novel MN1::TAF3 Fusion: A Rare Case in a Toddler.

Spindle cell tumors in the pediatric population are uncommonly reported. This case discusses an 18-month-old who presented initially with unilateral ptosis and was found to have an orbital spindle cell tumor. Pathology evaluation of the tissue was extensive with nonspecific morphologic and immunohistochemical features. Molecular testing demonstrated an MN1::TAF3 fusion on RNA sequencing, which has not been previously described in the literature in association with spindle cell neoplasms. This case highlights the challenging nature of classifying and treating a tumor with a novel fusion.

Predictive value of tumor microenvironment on pathologic response to neoadjuvant chemotherapy in patients with undifferentiated pleomorphic sarcomas.

Undifferentiated pleomorphic sarcomas (UPS) represent a prevalent and aggressive subtype of soft tissue sarcomas (STS) in adults. Despite advancements in loco regional treatments, many patients with high grade STS, including UPS, develop metastatic disease. Neoadjuvant chemotherapy is a standard approach to mitigate this risk, but response variability necessitates refined patient selection strategies. This study investigated the correlation between UPS microenvironment and neoadjuvant chemotherapy response in resectable UPS. The NEOSARCOMICS study (NCT02789384) enrolled patients with resectable STS from six sarcoma centers in France. Patients received anthracycline based chemotherapy, followed by surgery. Histological response, gene expression profiling, and multiplex immunohistofluorescence were performed on baseline and post treatment tumor samples. Plasma proteomics was analyzed to identify biomarkers. Good responders to neoadjuvant chemotherapy showed enrichment in genes related to stemness and cell cycle regulation, while poor responders exhibited immune related gene enrichment. Proteomic profiling revealed immune pathway activation and downregulation of cell cycle pathways in non responders. Despite being associated with a good prognosis, high immune infiltration, particularly of CD8 + T cells and CD20 + B cells, predicts a poor response to neoadjuvant chemotherapy in UPS, suggesting the need for alternative therapeutic strategies for patients with inflamed UPS.Ongoing clinical trials are exploring the efficacy of combining chemotherapy with immune checkpoint inhibitors to improve outcomes.

B7-H3 is widely expressed in soft tissue sarcomas.

PURPOSE: Targeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS. PATIENTS AND METHODS: This retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature. RESULTS: Specimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93-0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61-0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1. CONCLUSION: These data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.