Pleomorphic Sarcoma Research Articles

A Retrospective Study of 291 Patients With Head and Neck Sarcomas: Treatment, Outcomes, and Prognostic Factors

AimsSarcomas constitute a group of rare malignant neoplasms, commonly subcategorized into soft tissue sarcomas (STS) and bone sarcomas. This study aims to describe the treatment modalities and outcome of head and neck sarcoma (HNS) patients in western Denmark and to identify prognostic factors for overall survival and recurrence in HNS patients. Materials and methodsThe Aarhus sarcoma registry, The National Danish Sarcoma Database, and the Danish National Pathology Registry were used to identify HNS adult patients diagnosed between 1979 and 2022. ResultsAltogether, 291 patients were included in this study. The prevalent histological subtypes were undifferentiated pleomorphic sarcoma (16%; 48/291) and leiomyosarcoma (15%; 44/291) for STS patients (n = 230) and chondrosarcoma (10%; 28/291) and osteosarcoma (7%; 19/291) for bone sarcoma patients (n = 61). Surgery with curative intent was performed in 71% (164/230) and 70% (43/61) of STS and bone sarcoma patients, respectively. Clear resection was achieved in 59% (97/164) of STS patients and 44% (19/43) of bone sarcoma patients. Eighty-nine patients relapsed (STS n = 66, bone sarcoma n = 23) after a median time of 2.7/5.5 years for STS/bone sarcoma patients. The five-year overall survival rates were 45% for STS patients and 66% for bone sarcoma patients.The following factors were significantly, negatively associated with overall survival in STS patients: Age (hazard ratio (HR)) = 1.02, p < 0.001), tumour size ≥5 cm (HR = 1.75, p = 0.003), metastatic disease (HR = 3.17, p < 0.001), high grade tumour (HR = 2.24, p = 0.004), previous cancer (HR = 2.84, p < 0.001), and high Aarhus composite biomarker score (ACBS) (HR = 4.56, p = 0.001). For relapse in STS patients, higher tumour grade (HR = 3.19, p = 0.014), intralesional margins (HR = 2.84, p < 0.001), ≥2 previous cancers (HR = 3.00, p = 0.004), and high ACBS (HR = 3.29, p = 0.047), were negatively associated. For bone sarcomas only higher age (HR = 1.02, p = 0.049) and intralesional margins (HR = 2.91, p = 0.042) were significant negative factors for overall survival. ConclusionMultiple prognostic factors for overall survival and relapse were identified, especially for STS patients.

Best Overall Response-Associated Signature to Doxorubicin in Soft Tissue Sarcomas: A Transcriptomic Analysis from ANNOUNCE.

This exploratory analysis evaluated the tumor samples of the patients treated with doxorubicin (with or without olaratumab) in a negative phase III ANNOUNCE trial to better understand the complexity of advanced soft tissue sarcomas (STS) and to potentially identify its predictive markers. RNA sequencing was performed on pretreatment tumor samples (n = 273) from the ANNOUNCE trial to evaluate response patterns and identify potential predictive treatment markers for doxorubicin. A BOR-associated signature to doxorubicin (REDSARC) was created by evaluating tumors with radiographic response versus progression. An external cohort of doxorubicin-treated patients from the Spanish Group for Research on Sarcomas (GEIS) was used for refinement and validation. A total of 259 samples from the trial were considered for analysis. Comparative analyses by the treatment arm did not explain the negative trial. However, there was an association between the BOR signature and histologic subtype (χ2P = 2.0e-7) and grade (P = 0.002). There were no associations between the BOR signature and gender, age, ethnicity, or stage. Applied to survival outcomes, REDSARC was also predictive for progression-free survival (PFS) and overall survival (OS). Using the GEIS cohort, a refined 25-gene signature was identified and applied to the ANNOUNCE cohort, where it was predictive of PFS and OS in leiomyosarcoma, liposarcoma, and other sarcoma subtypes, but not in undifferentiated pleomorphic sarcoma. The refined REDSARC signature provides a potential tool to direct the application of doxorubicin in sarcomas and other malignancies. Validation and further refinement of the signature in other potentially subtype specific prospective cohorts is recommended.

Abstract 5094: Immunotherapy in advanced cutaneous non-melanomatous spindle cell neoplasms

Abstract Background: Non-melanomatous cutaneous spindle cell neoplasms (NMCSpC) are a rare group of malignancies including pleomorphic dermal sarcoma (PDS) and spindle-cell cutaneous squamous cell carcinoma (SpSCC). They present a diagnostic challenge with overlapping morphological features and variable patterns of immunohistochemical (IHC) staining. There is a lack of consensus on how to best manage advanced NMCSpC and limited reports of immunotherapy (IO) responses. This study reviews the efficacy of IO in NMCSpC and performs comprehensive tumor profiling to identify biological rationale for IO use in this rare group of tumors. Methods: We performed a single-center retrospective review of all locally-advanced or metastatic NMCSpCs treated with IO. Blinded histopathology reviews occurred to confirm each diagnosis. Overall response rates (ORR) were collected as per Response Evaluation Criteria in Solid Tumors 1.1 or Positron Emission Tomography Response Criteria 1.0. Comprehensive tumor profiling included whole exome sequencing for tumor mutational burden (TMB) and ultraviolet(UV)-signatures, and IHC for immune-cell infiltration (CD103/CD4/CD3/CD8/CD20) and immune-checkpoint expression (PD-L1/TIGIT/LAG3). Results: 7 patients were identified. Median follow up was 18.1 months (range: 5.3-34.7). ORR 86% (6/7) with five complete responses (CR). One patient who achieved stable disease progressed. Responses were durable with two patients in CR &amp;gt;30 months after IO commencement. Blinded pathological review identified 3 SpSCC, 2 PDS and 2 spindle cell tumors of unclear sub-classification. All patients had high TMB and UV-signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression (Table 1). Conclusion: In advanced NMCSpC, excellent responses to IO with durable disease control was observed. IO is worthy of further exploration in these patients. UV-signatures and high TMB could be used to help select patients for treatment. Immunohistochemistry (IHC)^, tumor mutational burden and ultraviolet signatures Patient T-cell markers B-cell marker Immune-checkpoints Tumor mutational burden (mutations/megabase) Ultraviolet-mutational signature Best response assessment# CD103 CD4 CD3 CD8 CD20 PD-L1 TIGIT LAG3 1 1 20 1 1 0 7 0 0 17.94 Yes Stable metabolic response 2 1 20 30 10 0 100 0 10 35.34 Yes Complete metabolic response 3 1 10 10 5 0 5 0 0 104.87 Yes Complete metabolic response 4 1 0 1 0 0 0 0 0 74.04 Yes Partial metabolic response 5* NA NA NA NA NA NA NA NA 29 Yes Complete metabolic response 6 1 0 0 5 0 0 0 4 12.02 Yes Complete metabolic response 7 1 0 5 1 0 0 0 0 41.17 Yes Complete response ^IHC scores are % of positively stained cells, except for PD-L1 which is combined positive score (CPS). *Insufficient tissue for IHC on Patient 5. #As per PERCIST 1.0 on FDG-PET/CT or RECIST1.1 on CT. Citation Format: Luke S. McLean, Annette M. Lim, Christopher Angel, Richard J. Young, Angela Pizzolla, Stuart Archer, Alesha A. Thai, Benjamin Solomon, Jeremy Lewin, Danny Rischin. Immunotherapy in advanced cutaneous non-melanomatous spindle cell neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5094.

Abstract 1096: Enhancing effector function in T cell adoptive cell therapy in murine models of pediatric sarcomas

Abstract New treatment approaches for high-risk pediatric sarcomas are desperately needed. Immunotherapy advances with adoptive cell therapy in hematologic malignancies have not yet translated to pediatric solid tumors including sarcomas. Hallmarks of the immune microenvironment in pediatric sarcomas include the presence of immunosuppressive cytokines and immune cells and a lack of potent T cell activation. We are seeking ways to overcome these barriers to effective adoptive cell therapy in pediatric sarcoma. We are exploring introduction of a novel synthetic co-receptor, CD8a:MyD88, that can augment tumor-specific T cell effector function and potentially improve outcomes in murine models of sarcoma. Tumor-antigen specific T cells or tumor-infiltrating T cell populations are transduced ex vivo to express the CD8a:MyD88 synthetic co-receptor resulting in MyD88 signaling when T cells encounter their cognate MHC I/epitope complex. We have studied the effects of CD8a:MyD88 expression on cytokine production and lytic activity against murine sarcoma cell lines in vitro. Initial experiments utilized the OT1 T cell model (specific to the model antigen chicken ovalbumin) which we introduced into our murine sarcoma cell lines (KPSarc pleomorphic sarcoma and M3-9M rhabdomyosarcoma). Using GFP as a marker of T cell transduction, the production of effector cytokine interferon gamma was measured following T cell activation compared with GFP-negative non-transduced T cells. CD8a:MyD88 expressing T cells expressed higher levels of interferon gamma at basal levels and following antigen-specific activation when co-cultured with Ova-expressing sarcoma cells. Improved tumor-specific lytic function in CD8a:MyD88 expressing T cells was also observed in co-culture experiments compared to untransduced or control vector- transduced T cells. We further hypothesized that skewing T cell differentiation toward an effector phenotype with the addition of interleukin-12 during T cell expansion would increase the anti-tumor effect of the CD8a:MyD88 expressing T cells. Co-culture with our murine sarcoma cell lines showed increased tumor-lytic function in T cells primed with IL-12. We have ongoing experiments studying the in vivo effects of the CD8a:MyD88 expressing T cells in model antigen-expressing murine sarcoma models. In addition, the ability of the CD8a:MyD88 co-receptor to augment the effector function of polyclonal sarcoma infiltrating T cells is being explored. These results will further define the obstacles and potential solutions to successful adoptive T cell therapy for pediatric sarcomas. Citation Format: Jessica P. Sanchez, Eduardo Davila, Brian H. Ladle. Enhancing effector function in T cell adoptive cell therapy in murine models of pediatric sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1096.

Abstract 4340: Profiling the evolutionary history of giant cancer cells in sarcomas: Hopeful monsters or an evolutionary dead end

Abstract Background: As tumors evolve, they accumulate somatic mutations that serve as an archeological record of their evolutionary past. Undifferentiated pleomorphic sarcomas (USARCs) are malignant soft tissue tumors that often contain scattered giant cancer cells, or potential ‘hopeful monster cells’, histologically. As USARCs frequently undergo whole genome doubling (WGD) and chromothripsis (Steele et al, 2019), both mutational events are likely to contribute to the formation of giant cancer cells, which frequently display atypical nuclear features such as polyploidy, micronuclei and extrachromosomal DNA. Giant cancer cells are also a common histological finding in other sarcoma types, such as dedifferentiated liposarcomas. Aims: This study aims to leverage single cell sequencing approaches to determine the evolutionary history and genomic landscape of giant cancer cells in sarcomas. Methods: 112 giant cancer cells identified in 8 USARCs, 1 dedifferentiated liposarcoma (DDLPS) and 1 myxofibrosarcoma by histology (i.e. nuclear size and shape, as well as multi-nucleation) were isolated via laser capture microdissection thereby retaining important spatial and morphological information. Once isolated, single cell DNA was extracted and amplified using the Ampli1 whole genome amplification (WGA) kit and underwent WGS. DNA was also estimated at a single cell level in one USARC using FACS. Once sorted into different ploidy populations, single nuclei also underwent WGS. Allele specific copy number aberrations (CNAs) were inferred in all single cells. Bulk tumour and normal WGS was also performed. Results: LCM isolated giant cancer cells exhibited extreme sub-clonal heterogeneity with some demonstrating de novo chromothripsis events that was not present in bulk WGS. FACS analysis and copy number inference of single cancer cells in one USARC also revealed the presence of three ploidy populations, including a haploid, a near diploid and a WGD population. Single cell WGS and copy number profiling demonstrated that following near genome scale haploidisation, multiple haploid cells underwent successive rounds of WGD. Conclusions: Chromothripsis and WGD emerges as major contributors to intra-tumor heterogeneity in sarcoma giant cancer cells. Single cell LCM and WGS revealed that some giant cancer cells contained de novo chromothripsis events that were not observed in bulk WGS. Multiple sub-clonal WGD events also permitted one USARC to continue to explore its fitness landscape contributing to ongoing tumor heterogeneity and lethality. Citation Format: Amy Bowes, Tom Lesluyes, Sara Waise, Annelien Verfaillie, Adrienne Flanagan, Jonas Demeulemeester, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo. Profiling the evolutionary history of giant cancer cells in sarcomas: Hopeful monsters or an evolutionary dead end [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4340.

Abstract 3858: Peripheral CD38+ effector memory (EM) T cells are dynamic biomarkers of response to neoadjuvant immune checkpoint blockade (NeoICB) in patients (pts) with resectable dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS)

Abstract Introduction: NeoICB is a promising approach for pts with DDLPS and UPS. However, biomarkers to identify which pts benefit from this treatment and understanding the mechanisms of response and resistance to ICB remains a challenge. Methods: We conducted a randomized phase 2 trial of neoICB (anti-PD1 +/- CTLA4) in pts with resectable DDLPS (n=17) and UPS (n=10). Pts with UPS received concurrent neoICB and radiation. The primary endpoint of the trial was pathological response; 3 DDLPS and 9 UPS pts were responders (R) and 14 DDLPS and 1 UPS pts were non-responders (NR). Peripheral blood mononuclear cells (PBMCs) were collected at baseline, prior to cycle 2 of neoICB (C2D1), and at the time of surgery (SURG). We performed mass cytometry (CyTOF) to identify immune cells associated with response and their dynamic changes with neoICB. We designed a custom 41-parameter panel using CD45 live cell barcoding with 31 markers for immune profiling, of which 23 were selected to detect key cell lineage and 8 to detect signaling markers. Batch correction and high dimensional data analyses were performed using CyCombine and CyTOF workflow R packages. Longitudinal comparisons between immune cell populations were conducted using Mann-Whitney U Test. Results: Of 79 available PBMC samples from 27 pts, 63 passed quality control after thawing (≥30% viability) and data clean-up (at least 10,000 events). Data was down-sampled to 5000 events for analysis. Of 19 immune cell types identified, monocytes were the most common followed by CD4+ and CD8+ T cells. There was an early increase in CD38+ effector/effector memory (EM) T cells at C2D1 in pts with DDLPS (CD8+ p=0.005, CD4+ p&amp;lt;0.001) and a similar increase observed in pts with UPS (CD8+ C2D1 p=NS, SURG p=0.034; CD4+ C2D1 p=0.024, SURG p=0.06) and these cells had higher Ki67 expression than CD38- T cells (p&amp;lt;0.005). At baseline, R pts with DDLPS had higher fractions of CD38+ EM CD8+ T cells than NR pts (p=0.044). Analysis in the UPS cohort was limited by the low number of NR pts. Higher expression of TIGIT was observed on CD38+ EM CD8+ T cells compared to CD38- counterparts at all time points. Conclusion: Peripheral CD38+ EM CD8+ T cells are associated with response to neoICB in pts with DDLPS. Longitudinal peripheral immune profiling reveals an increase in CD38+ EM CD8+ and CD4+ T cells with neoICB in pts with DDLPS and UPS. These cells are proliferative and express higher levels of TIGIT, which could be a future target for therapeutic exploration. Importantly, changes in the peripheral immune populations may precede changes in the tumor microenvironment (TME) as preliminary analyses of the TME did not identify early (C2D1) changes. TME imaging mass cytometry analyses are currently underway to associate peripheral and intratumor changes in immune populations. Citation Format: Elise F. Nassif, Hsinyi Lu, Michael Stanford, Karen Millerchip, Diana Romero, Jared Malke, Brenna Matejka, Jeffrey E. Gershenwald, Susmita Kumari, Duncan H. Mak, Angelique J. Lin, Jared K. Burks, Wei-Lien Wang, Alexander J. Lazar, Neeta Somaiah, Cara Haymaker, Christina L. Roland, Emily Z. Keung. Peripheral CD38+ effector memory (EM) T cells are dynamic biomarkers of response to neoadjuvant immune checkpoint blockade (NeoICB) in patients (pts) with resectable dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3858.

Abstract 6456: The utility of clinical sequencing in the diagnosis and treatment of soft tissue sarcomas; Real world data based on nation-wide database

Abstract Purpose: Soft tissue sarcomas (STS) are rare and heterogeneous tumors arising from mesenchymal connective tissue, accounting for approximately 1%-2% of all malignancies. Due to their rarity and heterogeneity, it is challenging for accurate diagnosis, prognosis, and treatment of sarcoma. Recently, next-generation sequencing (NGS)-based comprehensive cancer genome profiling (CGP) has increasingly become a routine practice for patients with solid cancers worldwide. To collect genomic information and clinical characteristics of patients who underwent CGP, the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has also been established since 2018 in Japan. Almost all the clinical and genomic data of patients who received CGP tests the had been collected in C-CAT. Here, we examined the utility of CGP test in the diagnosis and treatment of STS using this nation-wide database. Patients and Methods: We retrospectively evaluated the records of patients with STS who received F1CDx between 2019 and 2022 and registered in C-CAT. This assay carries 324 genes and determines nucleotide substitutions, insertions/deletions, and copy number (CN) alterations of 309 genes, fusions of 36 genes, tumor mutation burden (TMB) and microsatellite instability (MSI). High TMB (TMB-H) was defined as a TMB value &amp;gt;10 muts/Mb. Ranges of the MSI score were assigned MSI-High (MSI-H) or microsatellite stable (MSS). Results: From 2019 to 2022, 1387 patients with STS were registered in C-CAT. The histological types included leiomyosarcoma in 357 patients, dedifferentiated liposarcoma in 178 patients, and undifferentiated pleomorphic sarcoma in 82 patients, and the others. The most commonly altered genes included TP53, CDKN2A, Rb1, and CDKN2B. Among the 1387 cases, we observed 110 fusion events in 108 cases (7.7%), and 2 cases showed 2 types of fusion transcripts. Fifteen (2.8%) patients were re-classified based on the detection of highly histology-specific translocations. Among them, an initial diagnosis of sarcoma NOS was classified as Ewing Sarcoma (EWSR1-FLI1 in 2 patients), NTRK-rearranged spindle cell neoplasm (NTRK fusion in 3 patients), CIC-rearranged sarcoma (CIC-DUX4 in 3 patients), and sarcoma with BCOR genetic alterations (BCOR-ZC3H7B in 1 patient) as these gene fusions were identified. Druggable gene alterations was detected in 347 patients (25%) and 55 patients (4%) who received genotype-matched therapy. In 38 patients for whom the effect of treatment could be evaluated, complete response and partial response were achieved in 2 (5%) and 10 (26%) patients, respectively. Discussion: In conclusion, the comprehensive genomic profiling test appears to be an important tool in the diagnosis and treatment of sarcomas. Citation Format: Eiji Nakada, Tomohiro Fujiwara, Toshi Kunisada, Shota Takihira, Daisuke Ennishi, Hideki Yamamoto, Kiichiro Ninomiya, Shuta Tomida, Mashu Futagawa, Akira Hirasawa, Shinichi Toyooka, Toshifumi Ozaki. The utility of clinical sequencing in the diagnosis and treatment of soft tissue sarcomas; Real world data based on nation-wide database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6456.

Neutrophil-to-lymphocyte ratio for the prediction of soft tissue sarcomas response to pre-operative radiation therapy

Purpose/ObjectiveThis study aims to assess the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in soft tissue sarcomas (STS) treated with pre-operative hypofractionated radiotherapy (HFRT). Materials/MethodsThis retrospective analysis included patients treated with pre-operative HFRT of 30 Gy in 5 fractions between 2016 and 2023. Clinical, demographic, and complete blood count (CBC) data were collected. NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Only patients with CBCs conducted within 6 months after radiotherapy were included. Cox proportional-hazard regression models were used to assess the impact of NLR and different variables on outcomes. Kaplan Meier were used to illustrate survival curves. A p-value < 0.05 was considered significant, and 95 % confidence intervals (CI) were employed. ResultsA total of 40 patients received HFRT and had CBCs within 6 months after radiotherapy. There were 17 (42.5 %) females and 23 (57.5 %) males with a mean age of 66 years. The mean largest tumor size dimension was 7.1 cm, and the mean NLR post-RT was 5.3. The most frequent histological subtypes were myxofibrosarcoma (17.5 %), pleomorphic spindle cell sarcoma (10 %), leiomyosarcoma (7.5 %), and myxoid liposarcoma (5 %). The median follow-up period was 15.4 months. From all patients, 14 patients had disease progression, 12 metastatic disease and 3 died of disease. Multivariable Cox proportional-hazards regression analysis displayed that a higher post-RT NLR was associated with worse disease-free survival (DFS) (HR: 1.303 [1.098–1.548], p = 0.003), and distant metastasis-free survival (DMFS) (HR: 1.38 [1.115–1.710], p = 0.003). Moreover, post-NLR ≥ 4 as a single variable was associated with worse DFS, DMFS, but not worse local recurrence or overall survival. ConclusionThis study is the first to evaluate NLR as a prognostic biomarker in STS patients treated with pre-operative radiotherapy. A higher NLR after pre-operative radiotherapy was associated with increased disease progression.

Progression of Atypical Fibroxanthoma to Metastatic Pleomorphic Dermal Sarcoma in a Lung Transplant Recipient

Introduction: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare cutaneous malignancies often seen in elderly patients with photodamaged skin. Although solid organ transplant recipients (SOTRs) with AFX/PDS appear to have worse outcomes than the general population, the risk of progression from AFX to PDS in this group is not well studied. We present the case of a lung transplant patient with AFX recurring as PDS. Case Presentation: A 68-year-old male lung transplant patient with an extensive history of skin cancer presented with a 9-millimeter erythematous papule on the right vertex scalp. Biopsy revealed AFX, and the tumor cleared with 1 stage of MMS. Seven months later, the patient developed a rapidly growing, hemorrhagic nodule at the site, which was diagnosed as PDS. Despite initial treatment with doxorubicin, pazopanib, and radiation to the lung, liver, and bone lesions, the patient’s disease progressed. The patient was started on pembrolizumab with prednisone to mitigate the risk of organ rejection but succumbed to pneumonia with septic shock and respiratory failure. Discussion: Transplant patients have an increased risk of poor outcomes related to PDS. ICIs may be considered in advanced cases in which other treatment options have been exhausted. In conclusion, SOTRs with AFX/PDS should be aggressively treated and monitored as their risk of unfavorable outcomes appears to be increased.

Hydrochlorothiazide and increased risk of atypical fibroxanthoma and pleomorphic dermal sarcoma.

Previous work has demonstrated that hydrochlorothiazide (HCTZ) is a risk factor for squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) due to pro-photocarcinogenic effects. Atypical fibroxanthoma (AFX) and pleomorphic sarcoma (PDS), both ultraviolet-induced cancers, display a rare but rising cutaneous tumor entity. This study aimed to evaluate if the use of HCTZ is higher in patients with AFX/PDS than in patients with SCC/BCC and subsequently may be a risk factor for AFX/PDS-development. In a retrospective study of four German skin cancer centers, AFX/PDS cases and SCC/BCC controls were sex and age matched (1:3) over a time-period of 7years (2013-2019) to evaluate the use of HCTZ, immunosuppressive medication, second malignancies, and presence of diabetes mellitus. Overall, 146 AFX/PDS and 438 controls (SCC/BCC) were included in the study. The use of HCTZ was significantly higher in patients with AFX/PDS (44.5%) compared to patients with SCC/BCC (25.3%). Additionally, the presence of diabetes mellitus was significantly higher in AFX/PDS patients. This study demonstrates a significantly higher use of HCTZ in patients with AFX/PDS compared to SCC/BCC. This result suggests that HCTZ may be a risk factor for AFX/PDS. Additionally, diabetes mellitus or its comorbidities may be associated with an increased risk for AFX/PDS.

ATRX guards against aberrant differentiation in mesenchymal progenitor cells.

Alterations in the tumor suppressor ATRX are recurrently observed in mesenchymal neoplasms. ATRX has multiple epigenetic functions including heterochromatin formation and maintenance and regulation of transcription through modulation of chromatin accessibility. Here, we show in murine mesenchymal progenitor cells (MPCs) that Atrx deficiency aberrantly activated mesenchymal differentiation programs. This includes adipogenic pathways where ATRX loss induced expression of adipogenic transcription factors and enhanced adipogenic differentiation in response to differentiation stimuli. These changes are linked to loss of heterochromatin near mesenchymal lineage genes together with increased chromatin accessibility and gains of active chromatin marks. We additionally observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Finally, we demonstrated that loss of ATRX in a mesenchymal malignancy, undifferentiated pleomorphic sarcoma, results in similar epigenetic disruption and de-repression of transposable elements. Together, our results reveal a role for ATRX in maintaining epigenetic states and transcriptional repression in mesenchymal progenitors and tumor cells and inpreventing aberrant differentiation in the progenitor context.

Atypical Fibroxanthoma Treated with a Topical Combination of Imiquimod, Tazarotene, and 5-Fluorouracil.

This case report describes an 80-year-old man who presented with a growing erythematous nodule with erosion, measuring 0.6cm × 0.6cm, on his right temple. This lesion was later diagnosed as atypical fibroxanthoma (AFX). Instead of undergoing Mohs surgery, the gold standard treatment, the patient opted to pursue a topical treatment regimen because of financial costs associated with surgical removal and repair. This topical regimen consisted of tazarotene cream, imiquimod cream, and 5-fluorouracil solution, applied for 30days. The patient was directed to use this combination 5days per week for 6weeks. The specified dosage for each medication was a fifth of a packet of imiquimod 5% cream, an equivalent amount of tazarotene 0.1% cream, and a single drop of 5-fluorouracil 2% solution. These were combined on a bandage and placed on the lesion overnight. Following the treatment, a 3-week post-application examination revealed an erosion, 1.0cm × 0.9cm, amidst erythema. A subsequent incisional biopsy with histopathology and stains for CD10 and CD99, 3weeks after treatment, and three punch biopsies with histopathology and stains for CD10 and CD99, 1-year post-treatment, confirmed the absence of AFX. AFX is a superficial variant of pleomorphic dermal sarcoma (PDS), which shares histologic similarities, yet the exact relationship between AFX/PDS and undifferentiated pleomorphic sarcoma is still not well understood. Previous studies have indicated a genomic similarity between AFX/PDS and cutaneous squamous cell carcinoma (cSCC), which suggests the potential efficacy of cSCC-targeted treatments for AFX/PDS. This case marks the first recorded instance of successful topical medical treatment of AFX, offering an alternative for patients who may opt out of surgical intervention. Continued research to assess the broader efficacy of this approach is encouraged.

Detection of MDM2 gene amplification by fluorescence in situ hybridization and its diagnostic value in low-grade osteosarcoma

Objective: To investigate the diagnostic value of detecting MDM2 gene amplification by fluorescence in situ hybridization (FISH) in low-grade osteosarcoma (LGOS). Methods: Thirty cases of parosteal osteosarcoma (POS) and 14 cases of low-grade central osteosarcoma (LGCOS) from April 2009 to August 2022 at Beijing Jishuitan Hospital, Capital Medical University were analyzed for the presence of MDM2 gene amplification by FISH. Fifty-eight additional cases were used as negative controls (including 28 cases of fibrous dysplasia, 5 cases of giant cell tumor, 4 cases of conventional osteosarcoma, 2 cases each of periosteal osteosarcoma, reparative changes after fracture, pleomorphic undifferentiated sarcoma, low grade myofibroblastic sarcoma, fibrous dysplasia with malignant transformation, one case each of leiomyosarcoma, sclerosing epithelioid fibrosarcoma, malignant peripheral nerve sheath tumor, desmoplastic fibroma of bone, solitary fibrous tumor, aneurysmal bone cyst, clear cell chondrosarcoma, osteofibrous dysplasia, and 3 cases of unclassified spindle cell tumor). Results: Among the 30 patients with POS, 15 were male and 15 were female, ranging in age from 10 to 59 years (mean 35 years, median 30.5 years). Among the 14 patients with LGCOS, four were male and 10 were female, ranging in age from 15 to 56 years (mean 37 years, median 36 years). All except one case were successfully detected by FISH. MDM2 gene amplification was detected in 27 cases of POS (27/29,91.3%) and 8 cases of LGCOS (8/14). All the negative controls were negative for MDM2 gene amplification. The positive rate of MDM2 gene amplification was significantly different between the case group and the control group (P<0.05). The sensitivity and specificity of MDM2 gene amplification in diagnosing POS and LGCOS were 91.3% and 100.0%; and 57.1% and 100.0%, respectively. The sensitivity and specificity of MDM2 gene amplification in diagnosing LGOS (including POS and LGCOS) were 81.3% and 100.0%, respectively. In cases where MDM2 gene was amplified, the MDM2 amplified signal was clustered. Nine cases showed increased CEP12 signal different from polyploidy which was displayed as small and weak signal points or cloud flocculent and cluster signals. Conclusions: Detection of MDM2 gene amplification by FISH is a highly sensitive and specific marker for LGOS. The interpretation criteria for FISH detection of MDM2 amplification are currently not unified. The signal characteristics need more attention when interpreting.

Single-cell landscape of undifferentiated pleomorphic sarcoma.

Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive malignant soft tissue tumor with a poor prognosis; however, the identity and heterogeneity of tumor populations remain elusive. Here, eight major cell clusters were identified through the RNA sequencing of 79,569 individual cells of UPS. UPS originates from mesenchymal stem cells (MSCs) and features undifferentiated subclusters. UPS subclusters were predicted to exist in two bulk RNA datasets, and had a prognostic value in The Cancer Genome Atlas (TCGA) dataset. The functional heterogeneity of malignant UPS cells and the immune microenvironment were characterized. Additionally, the fused cells were innovatively detected by expressing both monocyte/macrophage markers and other subcluster-associated genes. Based on the ligand-receptor interaction analysis, cellular interactions with epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) were abundant. Furthermore, 73% of patients with UPS (48/66) showed positive EGFR expression, which was associated with a poor prognosis. EGFR blockade with cetuximab inhibited tumor growth in a patient-derived xenograft model. Our transcriptomic studies delineate the landscape of UPS intratumor heterogeneity and serve as a foundational resource for further discovery and therapeutic exploration.

Pancreatic metastasis from undifferentiated pleomorphic sarcoma. An extremely rare entity

Undifferentiated pleomorphic sarcoma (UPS) is a very aggressive malignant tumor that originates in bone or soft tissues, being its most frequent location in the extremities. We present the case of a 71-year-old man who, two years of follow-up after a lower right limb UPS excision surgery, presented a single metastasis of sarcomatoid origin in the pancreas that was treated by cephalic pancreaticoduodenectomy. Sarcomatoid metastases to the pancreas are extremely rare. Resection of the metastasis is the only therapeutic alternative that has reported benefit in terms of the survival of these patients.

Undifferentiated Pleomorphic Sarcoma

Undifferentiated Pleomorphic Sarcoma

Multidisciplinary management of pleomorphic dermal sarcoma of the scalp: A single institution study

BackgroundPleomorphic dermal sarcoma (PDS) of the scalp is a rare cutaneous malignancy, the location of which creates unique technical and cosmetic obstacles. Optimal management is not defined. We reviewed our institution’s approach and outcomes for this entity. Materials & methodsBetween 2000–2020, 15 patients with scalp PDS were evaluated and treated at our multidisciplinary sarcoma center. Patient characteristics, treatment approach, and outcomes were analyzed. ResultsThirteen patients (87%) presented with primary disease alone, one (7%) presented with recurrent disease after initial resection, and one (7%) presented with synchronous primary and metastatic disease. Radiation therapy (RT) was recommended in 10 patients (67%) and completed in 8 (53%) (3 preoperative, 5 postoperative). Eight patients (53%) underwent staged plastic surgery complex wound closure. Thirteen patients were alive without disease, one was alive with disease, and one was deceased with known recurrent disease at time of last follow-up. ConclusionLimited data are available to guide management of scalp PDS. Due to possible need for staged plastic surgery closure to ensure negative margins and optimize wound healing, initiation of postoperative RT may be delayed. Future multi-institutional study is required to further define the extent of surgery and role and timing of RT.

Pleomorphic dermal sarcoma: a case report

A pleomorphic dermal sarcoma (PDS) is considered a rare and poorly understood neoplasm of the skin.1 This has features similar to atypical fibroxanthoma (AFX).1 As well as the baseline similar characteristics to an AFX, a PDS also exhibits features of an infiltrative growth pattern which allows invasion of the subcutis, tumour necrosis and the possibility of lymphovascular invasion.2 These are more aggressive features than the more extensively reported AFX. There is a degree of metastatic potential associated with a PDS and hence early diagnosis and management with the appropriate multi-disciplinary team (MDT) is important to optimise the clinical prognosis. This case report will discuss a relatively rare diagnosis of a patient presenting with a PDS on the scalp and his management within the Oral and Maxillofacial Surgical (OMFS) Department, including consideration of his overall palliative care. Here, we will discuss the social, medical and physical implications of this diagnosis as well as considering the overall determinants of his quality of life (QoL).

Cancer Radiomic and Perfusion Imaging Automated Framework: Validation on Musculoskeletal Tumors.

Limitations from commercial software applications prevent the implementation of a robust and cost-efficient high-throughput cancer imaging radiomic feature extraction and perfusion analysis workflow. This study aimed to develop and validate a cancer research computational solution using open-source software for vendor- and sequence-neutral high-throughput image processing and feature extraction. The Cancer Radiomic and Perfusion Imaging (CARPI) automated framework is a Python-based software application that is vendor- and sequence-neutral. CARPI uses contour files generated using an application of the user's choice and performs automated radiomic feature extraction and perfusion analysis. This workflow solution was validated using two clinical data sets, one consisted of 40 pelvic chondrosarcomas and 42 sacral chordomas with a total of 82 patients, and a second data set consisted of 26 patients with undifferentiated pleomorphic sarcoma (UPS) imaged at multiple points during presurgical treatment. Three hundred sixteen volumetric contour files were processed using CARPI. The application automatically extracted 107 radiomic features from multiple magnetic resonance imaging sequences and seven semiquantitative perfusion parameters from time-intensity curves. Statistically significant differences (P < .00047) were found in 18 of 107 radiomic features in chordoma versus chondrosarcoma, including six first-order and 12 high-order features. In UPS postradiation, the apparent diffusion coefficient mean increased 41% in good responders (P = .0017), while firstorder_10Percentile (P = .0312) was statistically significant between good and partial/nonresponders. The CARPI processing of two clinical validation data sets confirmed the software application's ability to differentiate between different types of tumors and help predict patient response to treatment on the basis of radiomic features. Benchmark comparison with five similar open-source solutions demonstrated the advantages of CARPI in the automated perfusion feature extraction, relational database generation, and graphic report export features, although lacking a user-friendly graphical user interface and predictive model building.

Case report of high-grade pleomorphic sarcoma (rhabdomyosarcoma): a missed diagnosis in the non-healing post-traumatic wound of the elderly

Rhabdomyosarcoma (RMS) is known to be common childhood soft tissue sarcoma (STS). RMS is infrequent in adults. STS constitute &lt;1% of all adult solid malignant sarcomas and RMS accounts for 3% of all STS. The tumor is divided into three main subtypes-embryonal, alveolar, and pleomorphic (most common in adults). The most common primary sites are extremities. It’s an aggressive lesion with a high rate of metastasis. The patient presented with a non-healing wound over a posterior-medial aspect of the right leg with features suggestive of cellulitis. The patient gave a history of fall 5 months ago for which he took treatment at a local doctor, he continued to have severe pain for which an orthopedic opinion was taken and advised conservative management for an un-displaced fracture of the fibula. He later developed swelling over the lower-middle part of his right leg 3 months ago for which an ultrasound was done suggestive of a large amount of fluid suspicious of hematoma secondary to A-V malformation, an attempt for drainage of fluid was made leading to an evacuation of blood clots further procedure was abandoned and the patient transferred to our center. CT-angio demonstrated it as a heterogeneously attenuating solid cystic lesion. After appropriate consents-wound exploration was done with the evacuation of soft gelatinous material with pus discharge and blood clots. HPE-suggestive of high-grade pleomorphic rhabdomyosarcoma. The patient was advised amputation but denied any further treatment. Post-operative recovery was uneventful with no recurrence for the first 6 months after which the patient did not follow up. Post-traumatic mass at extremities should be evaluated with a high index of suspicion of STS. In case of doubt, either a preoperative biopsy or an intraoperative frozen section is a safe practice.