Search

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2024. The Author(s).)

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.

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., Competing Interests: Declaration of interests C.R.B. received research funding from PreComb Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sarcomas are rare malignancies with over 100 distinct histological subtypes. Their rarity and heterogeneity pose significant challenges to identifying effective therapies, and approved regimens show varied responses. Novel, personalized approaches to therapy are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) model tumor behavior across an array of malignancies. We leverage PDTOs to characterize the landscape of drug resistance and sensitivity in sarcoma, collecting 194 specimens from 126 patients spanning 24 distinct sarcoma subtypes. Our high-throughput organoid screening pipeline tested single agents and combinations, with results available within a week from surgery. Drug sensitivity correlated with clinical features such as tumor subtype, treatment history, and disease trajectory. PDTO screening can facilitate optimal drug selection and mirror patient outcomes in sarcoma. We could identify at least one FDA-approved or NCCN-recommended effective regimen for 59% of the specimens, demonstrating the potential of our pipeline to provide actionable treatment information., Competing Interests: Declaration of interests A.S., J.Y., P.C.B., and N.C.F. are founders and owners of Icona BioDx. A.S. is a founder and owner of MiRiO., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Introduction: For retroperitoneal sarcomas (RPS), aggressive surgical resection offers the only chance for a cure; however, 5-year survival remains below 65%. Therefore, there is a critical need to identify drivers of poor clinical outcomes., Materials and Methods: To identify biomarkers of tumors likely to recur following curative intent resection, we performed genomic and transcriptomic sequencing for 47 and 34 patients, respectively, with non-metastatic RPS at a single, high-volume sarcoma center., Results: At the DNA level, alterations in TERT were associated with poor disease-free survival (DFS) and overall survival (OS). Increased RNA expression of gene sets related to growth signaling and DNA repair were associated with poor DFS and OS. Infiltration of CD8 + T-Cells and activated dendritic cells were associated with poor DFS and OS., Conclusion: These findings may help to better identify and treat non-metastatic, high-risk RPS., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma., Patients and Methods: Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from days 1 to 14 every 3 weeks until disease progression or intolerable adverse events (AE) occurred. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate, and disease control rate (DCR). The safety profile was also evaluated., Results: Forty patients were enrolled from April 2019 to June 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI), 4.17-8.71] and the median OS 27.40 months (95% CI, 16.43-not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for liposarcoma patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%)., Conclusions: The findings suggest a potential benefit in using front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the liposarcoma subgroup of patients were encouraging. See related commentary by Napolitano et al., p. 4257., (©2024 The Authors; Published by the American Association for Cancer Research.)

Sarcomas rarely develop in bones previously compromised by infarcts. These infarct-associated sarcomas often present as undifferentiated pleomorphic sarcomas (UPS), and their genetic characteristics are poorly understood. High-grade UPS of bone are typically treated with a combination of surgery and chemotherapy, similar to osteosarcoma. We conducted a detailed clinicopathologic and genomic analysis of 6 cases of intraosseous sarcomas arising from histologically and radiographically confirmed bone infarcts. We analyzed 523 genes for sequence-level mutations using next-generation sequencing with the TruSight Oncology 500 panel and utilized whole-genome single nucleotide polymorphism Microarray (OncoScan CNV) to detect copy number alterations and loss of heterozygosity (LOH). Genomic instability was assessed through homologous recombination deficiency (HRD) metrics, incorporating LOH, telomeric allelic imbalance, and large-scale state transitions. Fluorescence in situ hybridization and immunohistochemistry validated the findings. The cohort included 3 men and 3 women, with a median age of 70 years, and tumors located in the femur and tibia. Five of the 6 patients developed distant metastases. Treatment involved surgery and chemotherapy or immune checkpoint inhibitors. Genomic analysis revealed significant complexity and high HRD scores, ranging from 32 to 57 (with a cutoff of 32). Chromosome 12 alterations, including segmental amplification or chromothripsis, were observed in 4 cases. Notably, MDM2 amplification, confirmed by fluorescence in situ hybridization, was detected in 2 cases. Homozygous deletion of CDKN2A/B was observed in all six cases. Tumor mutational burden levels ranged from 2.4 to 7.9 mutations per megabase. Notable pathogenic mutations included H3-3A mutations (p.G35R and p.G35W), and mutations in HRAS, DNMT3A, NF2, PIK3CA, POLE, and TP53, each in one case. These results suggest that high-grade infarct-associated sarcomas of bone, whereas sharing high levels of structural variations with osteosarcoma, may exhibit potentially less frequent TP53 mutations and more common CDKN2A/B deletions. This points to the possibility that the mutation spectrum and disrupted pathways could be distinct from conventional osteosarcoma., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

1 BACKGROUND: COVID-19 pandemic had a major impact on the healthcare system globally. This work aims to evaluate COVID-19 impact on local treatment in bone sarcoma treated in a single, high-throughput institution. 2 METHODS: We have analyzed the local outcomes (i.e., possibility of limb sparing surgery) in all bone sarcoma patients treated between January 2016 and November 2022 in the main sarcoma reference center in Poland. Patients treated in the 2016-2019 period were regarded as "pre-pandemic" group, patients treated in 2020-2022 - "pandemic". Mann-Whitney U and Chi-square tests were used in the statistical analysis. No correction for multiple testing was applied. Tests with p < 0.05 were deemed significant. 3 RESULTS: There were 302 eligible patients identified. The group characteristics are presented in table 1. There were no differences in patient-related variables and histological subtypes of tumors between two groups. The tumor size did not differ (p = 0.053), when all tumor grades were considered, but high grade tumors were larger in the "pandemic" group (p = 0.034). This was reflected in the percentage of limb sparing surgeries which dropped from 83.3 % to 68.2 % ("pre-pandemic" vs. "pandemic", p = 0.004). This difference was even more stark in case of high grade tumors - 78 % vs. 54 % respectively (p = 0.001). 4 CONCLUSION: To our knowledge, this is the first report of the long lasting impact of COVID-19 pandemic on oncologic treatment outcomes in patients with malignant bone tumors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Certain undifferentiated round cell sarcomas displaying EWSR1::NFATC2 fusion have recently been reported, mostly in the bones. This report presents clinicopathological features of 3 additional EWSR1::NFATC2 fusion sarcomas of bone and soft tissues. We present 2 soft tissue and 1 bone tumors: A 62-year-old man with pain and a slowly growing, 8-cm-sized soft tissue mass in the anterolateral compartment of his right calf, along with multiple pulmonary metastatic lesions; a 63-year-old man with a 5-cm sized axillary mass of 4 months duration and a cystic renal mass; and a 53-year-old man with a complaint of leg pain was found to have a 2-cm diameter, intramedullary, lytic mass in the diaphysis of his left femur. Microscopic examination of the tumors in all patients revealed round to epithelioid cells arranged in cords and trabeculae in a myxohyaline stroma. Immunohistochemically, the tumor cells were positive for MIC2/CD99 (3/3), EMA (3/3), NKX3.1 (3/3), NKX2.2 (2/2), CD10 (2/2), and aggrecan (1/1), while negative for S100P and GFAP. Various keratins were also negative except focal AE1/AE3 positivity in the third tumor. By fluorescence in-situ hybridization, 2 tumors (#1 and #3) revealed EWSR1 gene rearrangement and amplification. Furthermore, 2 tumors (#1 and #2) displayed EWSR1ex8::NFATC2ex3 fusion with next-generation sequencing (NGS). The first patient was offered chemotherapy. However, he died of pulmonary metastasis. This report highlights the value of combining histopathological features and immunostains such as NXK3.1, NKX2.2, CD10, and aggrecan, along with EWSR1 testing for triaging these tumors for rare gene fusions by NGS that has prognostic implications., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Adolescents (15-19 years) with sarcoma are known to have significantly worse survival than children (0-14 years). One possible reason may be that the adolescent sarcomas exhibit specific biological characteristics resulting in differences in clinical presentation and treatment resistance behaviors. The BIOSCA project aims to further explore these age-related differences in survival accounting for molecular tumor characteristic in children and adolescents with sarcoma., Methods: A retrospective national population-based observational study with documented somatic genetic analyses was conducted between 2011 and 2016 of all patients aged from 0 to 17 years with a diagnosis of sarcoma using the National Registry of Childhood Cancers Database., Results: A total of 1637 children (0-9years: 40%), preadolescents (10-14years: 35%) and adolescents (15-17 years: 25%) with a diagnosis of bone (N = 845) or soft-tissue (N = 792) sarcoma were included. Adolescents had significantly worse outcome for undifferentiated small round cell sarcoma (USRCS), alveolar rhabdomyosarcoma (ARMS), and epithelioid sarcoma. Five-year overall survivals were worse among CIC-rearranged USRCS cases (47% [95%CI:21-69]) as compared to other USRCS, and PAX3::FOXO1 ARMS patients (44% [95%CI:32-55]) as compared to other ARMS. Adjusting for stage and genomic-profiling status, adolescents with USRCS were 1.6-fold more likely to die than children (P = 0.05), while the difference in survival between age of ARMS patients was weaken. Indeed, the prevalence of PAX3::FOXO1 increased significantly with age., Conclusion: Age was an independent prognostic factor of outcome only in patients with USRCS, while the association between age and survival of patients with ARMS could be partly explained by differences in prevalence of PAX3::FOXO1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Retroperitoneal sarcomas (RPSs) present a surgical challenge, with complex anatomic relationships to organs and vascular structures. This pilot study investigated the role of three-dimensional (3D) augmented reality (3DAR) compared with standard imaging in preoperative planning and resection strategies., Methods: For the study, 13 patients who underwent surgical resection of their RPS were selected based on the location of their tumor (right, left, pelvis). From the patients' preoperative computed tomography (CT) scans, 3DAR models were created using a D2P program and projected by an augmented-reality (AR) glass (Hololens). The 3DAR models were evaluated by three experienced sarcoma surgeons and compared with the baseline two-dimensional (2D) contrast-enhanced CT scans., Results: Three members of the surgical team evaluated 13 models of retroperitoneal sarcomas, resulting in a total of 26 responses. When the surgical team was asked to evaluate whether the 3DAR better prepared the surgeon for planned surgical resection, 10 responses favored the 3DAR, 5 favored the 2D CT scans and 11 showed no difference (p = 0.074). According to 15 (57.6 %) of the 26 responses, the 3DAR offered additional value over standard imaging in the preoperative planning (median score of 4; range, 1-5). The median stated likelihood that the surgeons would consult the 3DAR was 5 (range, 2-5) for the preoperative setting and 3 (range, 1-5) for the intraoperative setting., Conclusions: This pilot study suggests that the use of 3DAR may provide additional value over current standard imaging in the preoperative planning for surgical resection of RPS, and the technology merits further study., (© 2024. Society of Surgical Oncology.)

Background and Objectives: Undifferentiated pleomorphic sarcoma (UPS) is a frequent subtype within the heterogeneous group of soft tissue sarcomas (STS). The use of radiotherapy (RT) has become an important component of a multimodal approach to treating STS. Key studies have demonstrated that the addition of RT improves rates of local control in STS, though the effect on overall survival (OS) is less clear. Furthermore, there is very limited and conflicting evidence regarding effect of RT on overall survival in UPS. The purposes of this investigation were to examine the association between RT and OS in UPS patients undergoing surgical resection and to determine independent prognostic indicators of OS in this patient population., Methods: This was a retrospective review of patients who underwent surgical treatment for primary UPS from 1993 to 2021. Associations between RT and OS were analyzed with Kaplan-Meier curves and log-rank testing. Cox proportional hazards regression analysis was used to determine independent prognostic factors of OS., Results: One hundred and fourteen patients who underwent surgical resection of primary UPS were included in the study. Ninety-six (84.2 %) patients received RT perioperatively. Use of RT was associated with improved OS on log-rank testing (hazard ratio (HR) 0.20; 95 % confidence interval (CI) 0.11-0.36; p < 0.001). On multivariate analysis, RT was an independent predictor of improved OS (HR 0.18; 95 % CI 0.09-0.39; p < 0.001) while metastasis at presentation (HR 4.82; 95 % CI 2.26-10.27; p < 0.001) and older age (HR 1.92; 95 % CI 1.20-3.36; p = 0.02) were predictive of decreased OS. Use of RT was not significantly associated with a lower rate of local recurrence in our cohort (p = 0.49)., Conclusions: Use of RT in combination with surgery was an independent prognostic indicator of improved overall survival in UPS patients. Older age and metastasis at presentation were associated with worse overall survival. Based on this and other available studies, treatment for UPS should involve limb-sparing resection when feasible with RT to ensure optimal survival., Competing Interests: Declaration of competing interest ATB: BMJ Case Reports: Editorial or governing board; Clinical Orthopaedics and Related Research: Editorial or governing board; Exparel/pacira: Stock or stock Options; Journal of Oncology Practice: Editorial or governing board; Journal of Surgical Oncology: ad hoc reviewer; Lancet - Oncology: Editorial or governing board; Musculoskeletal Tumor Society: Board or committee member; Onkos Surgical: Paid consultant; Pediatric Blood and Cancer: Editorial or governing board; Rare Tumors: Editorial or governing board; Rush Orthopedic Journal: Editorial or governing board. MWC: Educational speaking: Stryker Spine; Consulting: Orthofix, Alphatec Spine, HT Medical, Spinal Elements; Royalties: Alphatec Spine, Spinal Elements; Committee or Board Member: MSTS, CSRS, AO Spine; Research/fellowship grants: CSRS, AO Spine., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Sarcoma encompasses a diverse group of cancers that are typically resistant to current therapies, including immune checkpoint blockade (ICB), and underlying mechanisms are poorly understood. The contexture of sarcomas limits generation of high-quality data using cutting-edge molecular profiling methods, such as single-cell RNA-sequencing, thus hampering progress in understanding these understudied cancers., Experimental Design: Here, we demonstrate feasibility of producing multimodal single-cell genomics and whole-genome sequencing data from frozen tissues, profiling 75,716 cell transcriptomes of five undifferentiated pleomorphic sarcoma and three intimal sarcoma samples, including paired specimens from two patients treated with ICB., Results: We find that genomic diversity decreases in patients with response to ICB, and, in unbiased analyses, identify cancer cell programs associated with therapy resistance. Although interactions of tumor-infiltrating T lymphocytes within the tumor ecosystem increase in ICB responders, clonal expansion of CD8+ T cells alone was insufficient to predict drug responses., Conclusions: This study provides a framework for studying rare tumors and identifies salient and treatment-associated cancer cell intrinsic and tumor microenvironmental features in sarcomas., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Localization of non-palpable melanoma, Merkel cell carcinoma (MCC) and soft tissue sarcoma (STS) lesions can be difficult due to size, location, and obesity of patients or fibrosis due to previous treatments. Magnetic seed localization (MSL) is a common method to localize non-palpable breast lesions, but the feasibility of MSL for non-palpable melanoma, MCC and STS lesions has not yet been described., Methods: In this retrospective single center cohort study, all consecutive patients between January 2021 and October 2023 who had a resection of a non-palpable melanoma, MCC or STS lesion guided by Sirius Pintuition, a MSL technique, were included. The primary endpoint was successful lesion localization during surgery and the secondary endpoints were seed migration, negative resection margins, and complications., Results: Seventy-nine seeds were placed for 76 lesions, which were resected during 68 surgeries in 61 patients. All lesions (100 %) were localized and resected. Median time of surgery was 44 min. No seed migration was observed. A negative resection margin was achieved for 60 (78.9 %) lesions. Clavien Dindo grade ≥2 complications occurred in 7.4 %., Conclusion: Magnetic seed localization with Sirius Pintuition is feasible for both non-palpable melanoma, MCC, and STS lesions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: WJ Van Houdt reports financial support was provided by Sirius Medical Systems B.V. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: Sarcomas are rare cancers with many subtypes in soft tissues, bone and cartilage. International survival trends in these cancers are not well known. We present 50-year survival trends for soft tissue sarcoma (STS) and bone sarcoma (BS) in Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE)., Methods: Relative 1-, 5/1 conditional- and 5-year survival data were obtained from the NORDCAN database for years 1971-20. We additionally estimated annual changes in survival rates and determined significant break points., Results: In the last period, 2016-20, 5-year survival in STS was best for NO men (74.6%) and FI women (71.1%). For the rarer BS, survival rates for SE men (72.0%) and DK women (71.1%) were best. Survival in BS was lower than that in STS in 1971-75 and the difference remained in 2016-20 for men, but for women the rates were almost equal. Sex- and country-specific differences in survival in STS were small. The 50-year improvement in 5-year survival in STS was highest in NO men, 34.0 % units and FI women, 30.0 % units. The highest improvements in BS were in SE men 26.2 % units and in FI women 29.2 % units., Conclusions: The steady development in survival over the half century suggests contribution by stepwise improvements in diagnostics, treatment and care. The 10-15% mortality in the first year probably indicates diagnostic delays which could be improved by organizing patient pathways for aggressive rare diseases. Early diagnosis would also reduce metastatic disease and breakthroughs in treatment are a current challenge., Competing Interests: Declaration of Competing Interest A.H. is shareholder in Targovax ASA. A.H. is employee and shareholder in TILT Biotherapeutics Ltd. Other authors declared no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tumors with pathogenic DICER1 mutation are rare and encompass sporadic or hereditary benign, intermediate and malignant tumors. DICER1-associated sarcomas are heterogeneous; however, the prototypical ones in the GYN-tract include embryonal rhabdomyosarcoma, adenosarcoma and moderately to poorly differentiated Sertoli-Leydig tumor. In this report, we present three unique uterine sarcomas with DICER1 mutation and remarkable diffuse round/spindle cell morphology. The tumors occurred in cervix (n = 1), and uterine corpus (n = 2). The patient ages were 30, 37 and 59 years with tumor size of 8.8, 10 and 8.6 cm, respectively. Morphologically all three tumors were characterized by distinct spindle/round cell morphology and various amounts of neuroectodermal differentiation (yolk sac-like tubules, blastomatous areas and rosette formation). Other morphologic features of DICER1-sarcoma reported in the literature including cambium layer, focal or diffuse anaplasia, solid and cystic architecture, and chondroid/osteoid areas were absent. All three sarcomas were positive for SALL4 and had variable neuroendocrine marker expression. Whole genome methylation analysis was performed on one of the uterine sarcomas, which clustered the tumor with embryonal tumor with multilayered rosettes. Follow up information was available on all three cases. Two patients were alive with no evidence of disease 13 and 14 months post operation, while one patient had imaging evidence of local recurrence 4 months post operation. In summary, we describe three unique DICER1-sarcomas and expand the phenotypic spectrum of this emerging entity, particularly with GYN-tract origin., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

CIC-rearranged sarcoma (CRS) is a group of high-grade undifferentiated small round cell sarcomas examined as a separate entity in the current WHO classification; since it shows more aggressive clinical behavior and distinct morphological and molecular features compared to Ewing sarcoma (ES). As CCNE1 expression is associated with tumor growth in CIC::DUX4 sarcomas, we aimed to demonstrate the value of cyclin E1 expression in CRS. Cyclin E1 immunohistochemistry and break-apart FISH for EWSR1 and CIC gene rearrangements were performed on 3-mm tissue microarrays composed of 40 small round cell tumors. Five cases were classified as CRS, whereas 22 were ES and 13 were unclassified (EWSR1-/CIC-). Among all three diagnostic groups, we found cyclin E1 expression level to be higher in CRS (80 %) and unclassified groups (61.5 %) compared to ES (4.5 %, p < 0.001). In addition, high cyclin E1 expression levels were associated with higher mean age at diagnosis, presence of atypical histology and myxoid stroma, low CD99 expression, and presence of metastasis at diagnosis. The sensitivity and specificity of high cyclin E1 expression in detecting non-ES cases were 95.5 % and 66.7 %, respectively. However, the correlation between cyclin E1 expression level and survival was not statistically significant. This is the first study that shows cyclin E1 immunohistochemical expression in EWSR1-negative undifferentiated small cell sarcomas, particularly CRS., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Recently, DNA methylation clocks have been proven to be precise age predictors, and the application of these clocks in cancer tissue has revealed a global age acceleration in a majority of cancer subtypes when compared to normal tissue from the same individual. The polycomb repressor complex 2 plays a pivotal role in the aging process, and its targets have been shown to be enriched in CpG sites that gain methylation with age. This complex is further regulated by the chromatin remodeling complex SWItch/Sucrose Non-Fermentable and its core subunit, notably the tumor suppressor gene SMARCB1, which under physiological conditions inhibits the activity of the polycomb repressor complex 2. Hence, the loss of function of core members of the SWItch/sucrose non-fermentable complex, such as the tumor suppressor gene SMARCB1, results in increased activity of polycomb repressor complex 2 and interferes with the aging process. SMARCB1-deficient neoplasms represent a family of rare tumors, including amongst others malignant rhabdoid tumors, atypical teratoid and rhabdoid tumors, and epithelioid sarcomas. As aging pathways have recently been proposed as therapeutic targets for various cancer types, these tumors represent candidates for testing such treatments. Here, by deriving epigenetic age scores from more than 1000 tumor samples, we identified epigenetic age acceleration as a hallmark feature of epithelioid sarcoma. This observation highlights the potential of targeting aging pathways as an innovative treatment approach for patients with epithelioid sarcoma., (© 2024. The Author(s).)

In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient-derived ex vivo models of NTRK fusion-positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents. © 2024 The Pathological Society of Great Britain and Ireland., (© 2024 The Pathological Society of Great Britain and Ireland.)

Backrgound: Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine carcinoma, frequently associated with clonal Merkel cell polyomavirus integration. MCC can pose significant diagnostic challenges due to its diverse clinical presentation and its broad histological differential diagnosis. Histologically, MCC presents as a small-round-blue cell neoplasm, where the differential diagnosis includes basal cell carcinoma, melanoma, hematologic malignancies, round cell sarcoma and metastatic small cell carcinoma of any site. We here report strong aberrant immunoreactivity for BCOR in MCC, a marker commonly used to identify round cell sarcomas and other neoplasms with BCOR alterations., Methods: Based on strong BCOR expression in three index cases of MCC, clinically mistaken as sarcoma, a retrospective analysis of three patient cohorts, comprising 31 MCC, 19 small cell lung carcinoma (SCLC) and 5 cases of neoplasms with molecularly confirmed BCOR alteration was conducted. Immunohistochemical staining intensity and localization for BCOR was semi-quantitatively analyzed., Results: Three cases, clinically and radiologically mimicking a sarcoma were analyzed in our soft tissue and bone pathology service. Histologically, the cases showed sheets of a small round blue cell neoplasm. A broad panel of immunohistochemistry was used for lineage classification. Positivity for synaptophysin, CK20 and Merkel cell polyoma virus large T-antigen lead to the diagnosis of a MCC. Interestingly, all cases showed strong positive nuclear staining for BCOR, which was included for the initial work-up with the clinical differential of a round cell sarcoma. We analyzed a larger retrospective MCC cohort and found aberrant weak to strong BCOR positivity (nuclear and/or cytoplasmic) in up to 90% of the cases. As a positive control, we compared the expression to a small group of BCOR-altered neoplasms. Furthermore, we investigated a cohort of SCLC as another neuroendocrine neoplasm and found in all cases a diffuse moderate to strong BCOR positivity., Conclusions: This study demonstrates that neuroendocrine neoplasms, such as MCC and SCLC can express strong aberrant BCOR. This might represent a diagnostic challenge or pitfall, in particular when MCC is clinically mistaken as a soft tissue or a bone sarcoma., (© 2024. The Author(s).)

Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft tissue sarcomas. This study determined the value of perfusion-weighted imaging with dynamic-contrast-enhancement (PWI/DCE) morphologic, qualitative, and semiquantitative features for predicting UPS pathology-assessed treatment effect (PATE). This retrospective study included 33 surgically excised extremity UPS patients with pre-surgical MRI. Volumetric tumor segmentation from PWI/DCE was obtained at Baseline (BL), Post-Chemotherapy (PC), and Post-Radiation Therapy (PRT). The surgical specimens' PATE separated cases into Responders (R) (≥ 90%, 16 patients), Partial-Responders (PR) (89 - 31%, 10 patients), and Non-Responders (NR) (≤ 30%, seven patients). Seven semiquantitative kinetic parameters and maps were extracted from time-intensity curves (TICs), and 107 radiomic features were derived. Statistical analyses compared R vs. PR/NR. At PRT, 79% of R displayed a "Capsular" morphology (P = 1.49 × 10 -7 ), and 100% demonstrated a TIC-type II (P = 8.32 × 10 -7 ). 80% of PR showed "Unipolar" morphology (P = 1.03 × 10 -5 ), and 60% expressed a TIC-type V (P = 0.06). Semiquantitative wash-in rate (WiR) was able to separate R vs. PR/NR (P = 0.0078). The WiR radiomics displayed significant differences in the first&#95;order&#95;10 percentile (P = 0.0178) comparing R vs. PR/NR at PRT. The PWI/DCE TIC-type II curve, low WiR, and "Capsular" enhancement represent PRT patterns typically observed in successfully treated UPS and demonstrate potential for UPS treatment response assessment., (© 2024. The Author(s).)

Objectives: To investigate the clinicopathological characteristics and prognosis of patients with uterine sarcoma treated following surgery for presumed benign disease., Methods: We identified all patients with uterine sarcoma found incidentally after primary surgery for presumed benign disease who presented to our institution and received re-exploration for completion surgery from January 1, 2004 to January 1, 2021. We analyzed the clinicopathological characteristics and prognosis., Results: Overall, 95 patients were included in our study. For the initial surgery, myomectomy was performed in 50 (52.6%, 50/95) patients, hysterectomy was performed in 45 (47.4%, 45/95) patients. All patients were re-explored to complete the staging operation. The median time to the staging surgery was 40 days (range 15-90 days). There were 29 patients (30.5%, 29/95) had remnant sarcomas, with 17 patients (17/95, 17.9%) on the remaining uterus, 9 patients (9/95, 9.5%) had disseminated diseases, and 4 patients (4/95, 4.2%) had positive lymph nodes. About 40 patients (42.1%) received adjuvant chemotherapy, 55.2% (16/29) and 36.4% (24/66) patients with/without remnant diseases received adjuvant chemotherapy, respectively (P = 0.087). The median follow-up duration was 76.7 months (IQR: 34.8-118.1 months). And 17 patients (17.9%) had recurrence following re-exploration surgery. 5-year progression-free survival (PFS) and 5-year overall survival (OS) for the entire cohort was 81.7% and 92.1%, respectively. Patients with remnant sarcomas had a tendency towards a worse 5-year PFS and 5-year OS, compared with those without (5-year PFS: 75.6% vs. 84.5%, P = 0.224; 5-year OS: 85.5% vs. 95.1%, P = 0.217). Patients with disseminated diseases had a worse 5-year OS (62.5% vs. 95.1%, P = 0.007) and non-significantly worse 5-year PFS (64.8% vs. 83.4%, P = 0.153) compared with those without., Conclusions: Patients with uterine sarcoma treated following surgery for presumed benign disease have a favorable survival. Patients with disseminated diseases had a worse 5-year OS compared with those without. Surgical re-exploration may be valuable for removing remnant sarcomas and disseminated diseases., (© 2024. The Author(s).)

Bone sarcomas are malignant tumors of mesenchymal origin. Complete surgical resection is the cornerstone of multidisciplinary treatment. However, advanced, unresectable forms remain incurable. A crucial step towards addressing this challenge involves comprehending the molecular mechanisms underpinning tumor progression and metastasis, laying the groundwork for innovative precision medicine-based interventions. We previously showed that tyrosine kinase receptor Ephrin Type-A Receptor 2 (EphA2) is overexpressed in bone sarcomas. EphA2 is a key oncofetal protein implicated in metastasis, self-renewal, and chemoresistance. Molecular, genetic, biochemical, and pharmacological approaches have been developed to target EphA2 and its signaling pathway aiming to interfere with its tumor-promoting effects or as a carrier for drug delivery. This review synthesizes the main functions of EphA2 and their relevance in bone sarcomas, providing strategies devised to leverage this receptor for diagnostic and therapeutic purposes, with a focus on its applicability in the three most common bone sarcoma histotypes: osteosarcoma, chondrosarcoma, and Ewing sarcoma., (© 2024. The Author(s).)

Background: The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients., Methods: We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used., Results: All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit β2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS., Conclusion: Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit β2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches., (© 2024. The Author(s).)

Case: This case report describes a patient who presented with clinical and radiographic features of a soft tissue sarcoma of the shoulder. Despite having a painless and relatively large mass, a biopsy and resection revealed nodular fasciitis (NF)., Conclusion: This is an unusual case of a painless 10 cm mass that histopathologically was diagnosed as NF in the upper extremity with proximity to the axillary nerve and posterior humeral circumflex vessels. The USP6 rearrangement was helpful in confirming the diagnosis. Careful clinical, radiographic, and pathologic correlation is necessary in diagnosing these relatively rare tumors. In cases where there are discordant findings, molecular markers can be very helpful., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C430)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Purpose: To investigate the value of multi-parametric MRI-based radiomics for preoperative prediction of lung metastases from soft tissue sarcoma (STS)., Methods: In total, 122 patients with clinicopathologically confirmed STS who underwent pretreatment T1-weighted contrast-enhanced (T1-CE) and T2-weighted fat-suppressed (T2FS) MRI scans were enrolled between Jul. 2017 and Mar. 2021. Radiomics signatures were established by calculating and selecting radiomics features from the two sequences. Clinical independent predictors were evaluated by statistical analysis. The radiomics nomogram was constructed from margin and radiomics features by multivariable logistic regression. Finally, the study used receiver operating characteristic (ROC) and calibration curves to evaluate performance of radiomics models. Decision curve analyses (DCA) were performed to evaluate clinical usefulness of the models., Results: The margin was considered as an independent predictor (p < 0.05). A total of 4 MRI features were selected and used to develop the radiomics signature. By incorporating the margin and radiomics signature, the developed nomogram showed the best prediction performance in the training (AUCs, margin vs. radiomics signature vs. nomogram, 0.609 vs. 0.909 vs. 0.910) and validation (AUCs, margin vs. radiomics signature vs. nomogram, 0.666 vs. 0.841 vs. 0.894) cohorts. DCA indicated potential usefulness of the nomogram model., Conclusions: This feasibility study evaluated predictive values of multi-parametric MRI for the prediction of lung metastasis, and proposed a nomogram model to potentially facilitate the individualized treatment decision-making for STSs., (© 2024. The Author(s).)

Importance: Improved prognostic tools are needed for patients with locally recurrent extremity or truncal soft tissue sarcoma (STS)., Objective: To examine the association between average local recurrence (LR) growth rate and outcomes following resection of locally recurrent extremity or truncal STS., Design, Setting, and Participants: This retrospective cohort study used a prospectively maintained database from a single high-volume tertiary sarcoma referral center in the US to identify patients 16 years of age or older who underwent repeat resection of a locally recurrent extremity or truncal STS between July 1, 1982, and December 31, 2021. Patients with atypical lipomatous tumors, desmoid tumors, dermatofibrosarcoma protuberans, angiosarcomas, and prior or synchronous distant recurrence were excluded. Data were analyzed from November 1, 2022, to June 17, 2024., Exposure: Average LR growth rate, defined as the sum of recurrent tumor maximal diameters divided by the disease-free interval after index operation., Main Outcomes and Measures: The primary outcomes were cumulative incidences of disease-specific death (DSD), with death from other causes as a competing risk, and second LR, with death from any cause as a competing risk., Results: The study cohort included 253 patients (median [IQR] age, 64 [51-73] years; 140 [55.3%] male). The 5-year cumulative incidence of DSD after repeat resection was 29%. Multivariable analysis indicated that LR growth rate (hazard ratio [HR], 1.12 [95% CI, 1.08-1.18]; P < .001), younger age (HR, 0.98 [95% CI, 0.97-0.99]; P = .002), R1 or R2 margins (HR, 1.71 [95% CI, 1.03-2.84]; P = .04), high LR grade (HR, 2.90 [95% CI, 1.17-7.20]; P = .02), and multifocality (HR, 2.92 [95% CI, 1.70-5.00]; P < .001) were independently associated with higher incidence of DSD. Using the minimum P value method, the optimal cutoff for growth rate was found to be 0.68 cm/mo. Patients with values above this cutoff had higher 5-year incidences of DSD following repeat resection (63% vs 19%; permutation test P < .001) and higher amputation rates (19% vs 7%; P = .008). Only R1 margins were independently associated with higher incidence of second LR (HR, 1.81 [95% CI, 1.19-2.78]; P = .006)., Conclusions and Relevance: In this cohort study of patients undergoing resection of a locally recurrent extremity or truncal STS, LR growth rate was independently associated with DSD. These findings suggest that patients with growth rates higher than 0.68 cm/mo who undergo LR resection may have high disease-specific mortality and amputation rates and should be considered for perioperative systemic therapy.

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., (© 2024 Wiley Periodicals LLC.)

Malignant melanoma, a cancer type with a high mortality rate and increasing incidence worldwide, primarily affects the skin but can also occur in various other organs and tissues, including the respiratory tract. Although primary lung malignant melanomas are rare, they are often diagnosed at advanced stages due to their asymptomatic nature, and their atypical presentations may lead to misdiagnosis as other malignancies. In this case report, a mass lesion almost completely filling the right lung initially led to the consideration of small cell lung carcinoma, but a definitive pathological diagnosis could not be obtained in subsequent studies. The diagnosis was confirmed by soft tissue biopsy taken from the anterior thoracic wall. Considering clinical, pathological, and radiological evaluations, possible diagnoses included sarcoma, small-cell lung cancer, and melanoma. The patient, diagnosed through multiple tissue sampling and detailed dermatological examination, presents an interesting atypical case. This case highlights that rare variants of melanoma can be mistaken for other cancer types, such as lung cancer, sarcoma, or lymphoma. Patients may not always present with a noticeable skin lesion; therefore, a meticulous skin examination is crucial in such cases. Malignant melanoma is a noteworthy disease, considering its increasing incidence and early diagnosis holds vital importance for appropriate treatment and management.

Fibrous dysplasia (FD) is a skeletal disorder characterized by the replacement of normal bone by fibrous tissue. Malignant transformation of FD is extremely rare and has been reported in both monostotic and polyostotic forms of FD. The most frequently reported malignant transformation is osteosarcoma. Among malignant bone tumors, spindle cell sarcomas are uncommon and difficult to diagnose. This report presents the case of a 30-year-old woman with an unusual presentation of a malignant undifferentiated spindle cell neoplasm secondary to fibrous dysplasia. The clinical features, radiological findings and management are discussed., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background/aim: A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro., Materials and Methods: HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated., Results: The IC 50 of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC 50 of 0.15 nM on HT1080 cells, a 6-fold increase. The IC 50 of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells., Conclusion: The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Drug resistance has been a recalcitrant problem for sarcoma patients for many decades. Trabectedin is a second-line chemotherapy for soft-tissue sarcoma that often leads to resistance and death of the patients. The objective of the present study was to address the issue of trabectedin-chemoresistance in HT1080 fibrosarcoma cells by combining recombinant methioninase (rMETase) with trabectedin and examining their efficacy on trabectedin-resistant fibrosarcoma cells in vitro., Materials and Methods: Trabectedin-resistant HT1080 (TR-HT1080) cells were generated by subjecting HT1080 human fibrosarcoma cells to increasing trabectedin concentrations (3.3-8 nM). IC 50 values for trabectedin and rMETase were compared for HT1080 and TR-HT1080 cells. TR-HT 1080 cells were placed into four groups to determine synergy of rMETase and trabectedin on TR-HT1080 cells: a control group with no treatment; a group treated with trabectedin (3.3 nM); a group treated with rMETase (0.75 U/ml); and a group treated with both trabectedin (3.3 nM) and rMETase (0.75 U/ml)., Results: The IC 50 value of trabectedin- on TR-HT1080 cells was 42.9 nM, whereas the IC 50 value of trabectedin on the parental HT1080 cells was 3.3 nM, indicating a 13-fold increase. The combination of rMETase (0.75 U/ml) and trabectedin (3.3 nM) was synergistic on TR-HT1080 cells resulting in an inhibition of 64.2% compared to trabectedin alone (5.7%) or rMETase alone (50.5%) (p<0.05). rMETase increased the efficacy of trabectedin 11-fold on trabectedin-resistant fibrosarcoma cells., Conclusion: The combined administration of trabectedin and rMETase was synergistic on the viability of TR-HT1080 cells in vitro. The combination of rMETase and trabectedin has promising clinical potential for overcoming chemo-resistance of soft-tissue sarcoma., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Trabectedin, approved for the treatment of soft tissue sarcoma (STS), interferes with cell division and genetic transcription processes. Due to its strong anti-tumor activity in only certain histotypes, several studies on trabectedin combinations are currently ongoing to improve its efficacy. In this study, we aimed to investigate novel potential therapeutic strategies to enhance the anti-tumor effect of trabectedin using integrated in silico, in vitro, and in vivo approaches. For in silico analysis, we screened two public datasets, GSEA M5190 and TCGA SARC. Fibrosarcoma, leiomyosarcoma, dedifferentiated, and myxoid liposarcoma cell lines were used for in vitro studies. For in vivo experiments, fibrosarcoma orthotopic murine model was developed. In silico analysis identified Glo1 as the only druggable target upregulated after trabectedin treatment and correlated with poor prognosis. The specific Glo1 inhibitor, S-p-bromobenzylglutathione cyclopentyl diester (BBGC), increased trabectedin cytotoxicity in STS cells, and restored drug sensitivity in myxoid liposarcoma cells resistant to trabectedin. Moreover, the combined treatment with BBGC and trabectedin had a synergistic antitumor effect in vivo without any additional toxicity to mice. Based on these results, we believe that BBGC warrants further investigation to evaluate its potential clinical use in combination with trabectedin., (© 2024. The Author(s).)

Background: Sarcomas are diverse neoplasms with highly variable histological appearances in which diagnosis is often challenging and management options for metastatic/unresectable disease limited. Many sarcomas have distinctive molecular alterations, but the range of alterations is large, variable in type and rapidly increasing, meaning that testing by limited panels is unable to capture the broad spectrum of clinically pertinent genomic drivers required. Paired whole genome sequencing (WGS) in contrast allows comprehensive assessment of small variants, copy number and structural variants along with mutational signature analysis and germline testing., Methods: Introduction of WGS as a diagnostic standard for all eligible patients with known or suspected soft tissue sarcoma over a 2-year period at a soft tissue sarcoma treatment centre., Results: WGS resulted in a refinement in the diagnosis in 37% of cases, identification of a target for personalised therapy in 33% of cases, and a germline alteration in 4% of cases., Conclusion: Introduction of WGS poses logistical and training challenges, but offers significant benefits to this group of patients., (© 2024. Crown.)

Purpose: Soft tissue sarcomas (STSs) of the head and neck (H&N) are rare malignancies that are challenging to manage. We sought to describe the outcomes of patients treated with curative intent using combined surgery and radiation therapy (RT) for H&N STS., Methods and Materials: We performed a single-institution retrospective review of patients with nonmetastatic STS of the H&N who were treated from 1968 to 2020. The Kaplan-Meier method was used to estimate disease-specific survival (DSS) and local control (LC). Multivariable analyses (MVAs) were conducted using Cox proportional hazards model., Results: One hundred ninety-two patients had a median follow-up of 82 months. Tumors arose in the neck (n = 50, 26%), paranasal sinuses (n = 36, 19%), or face (n = 23, 12%). Most patients were treated with postoperative RT (n = 134, 70%). Postoperative RT doses were higher (median, 60 Gy; preoperative dose, 50 Gy; P < .001). Treatment sequence was not associated with LC (preoperative RT, 78% [63%-88%]; postoperative RT, 75% [66%-82%]; P = .48). On MVA, positive/uncertain margin was the only variable associated with LC (hazard ratio [HR], 2.54; 95% CI, 1.34-4.82; P = .004). LC was significant on MVA (HR, 4.48; 95% CI, 2.62-7.67; P < .001) for DSS. Patients who received postoperative RT were less likely to experience a major wound complication (7.5% vs 22.4%; HR, 0.28; 95% CI, 0.11-0.68; P = .005). There was no difference in the rate of late toxicities between patients who received preoperative or postoperative RT., Conclusions: H&N STS continues to have relatively poorer LC than STS of the trunk or extremities. We found LC to be associated with DSS. Timing of RT did not impact oncologic or long-term toxicity outcomes; however, preoperative RT did increase the chance of developing a major wound complication., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

A 7-year-old female spayed Bernese Mountain dog was presented for evaluation of hematuria. Incidentally, a right stifle sarcoma was diagnosed via cytology, which raised concern for histiocytic sarcoma (given the patient's signalment) versus another joint-associated sarcoma. Histopathology and immunohistochemistry revealed a CD18-negative, non-histiocytic origin cell population. Findings were consistent with a joint-associated grade II soft tissue sarcoma (STS). The patient's hematuria was progressive over 5 months, and urinary bladder transitional cell carcinoma (TCC) was diagnosed via cystoscopy and histopathology. An enlarged right medial iliac lymph node was identified on routine restaging via abdominal ultrasound 3 months later. Cytology of the lymph node revealed a markedly pleomorphic cell population, again raising concern for histiocytic sarcoma (HS). Other differentials included an anaplastic metastatic population from the joint-associated STS or the TCC. Immunocytochemistry revealed a cytokeratin-positive, CD18-, CD204-, and vimentin-negative cell population, consistent with a carcinoma. DNA was extracted from cytology slides to sequence cells for BRAF mutation status. Sequencing revealed a homozygous V596E (transcript ENSCAFT00845055173.1) BRAF mutation, consistent with the known biology of TCC. In neither case was HS truly present in this patient, but immunocytochemistry provided information that helped to optimize the patient's chemotherapy recommendations., (© 2024 The Authors. Veterinary Clinical Pathology published by Wiley Periodicals LLC on behalf of American Society for Veterinary Clinical Pathology.)

Purpose: The purpose of this study was to provide updated data on oncologic outcomes following definitive surgical treatment of soft tissue sarcoma of the hand in a cohort of 109 patients, as well as to characterize risk factors for poor oncologic and functional outcomes., Methods: We analyzed data from 109 consecutive patients who had definitive surgical treatment for soft tissue sarcoma of the hand performed between 1996 and 2019 by a single surgeon at a sarcoma center. Primary outcomes included functional outcome (assessed by Musculoskeletal Tumor Society scores), disease-free survival (DFS), and overall survival (OS). We compiled descriptive data and used a multivariable linear model to identify factors associated with functional outcomes. Kaplan-Meier methods were used to estimate 5- and 10-year DFS and OS., Results: Patients had a median age of 36 years at presentation. Median follow-up was 6.1 years among patients alive at the end of follow-up. The median Musculoskeletal Tumor Society score was 29; functional outcome was worse among patients with high-grade tumors or complications. Among the 107 patients who became disease-free, there were four local recurrences (one with metastasis), six distant recurrences, and one death without recurrence. All local recurrences were deep tumors (two myxofibrosarcoma and two myxoinflammatory fibrosarcoma). Estimated 5- and 10-year DFS rates were 89% (95% confidence interval [CI]: 83% to 96%) and 88% (95% CI: 80% to 95%). There were seven deaths, and the estimated 5- and 10-year OS rates were 95% (95% CI: 90% to 100%) and 92% (95% CI: 84% to 100%). Larger tumor size and higher stage at diagnosis were associated with shorter DFS and OS in univariable analyses; low event rates precluded multivariable analysis of survival., Conclusions: Aggressive disease-specific surgical and multidisciplinary treatment can yield long DFS and OS, and good functional outcomes. However, complications and high-grade tumors are associated with worse functional scores., Type of Study/level of Evidence: Prognostic II., Competing Interests: Conflicts of Interest Drs Chapman, Nolan, and Athanasian have nothing to disclose. Ms Lavery reports salary support, unrelated to the submitted work, that was paid to her institution by the American Association of Cancer Research Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)