Malignant Fibrous Histiocytoma Research Articles

Factors Influencing Long-Term Local Recurrence, Distant Metastasis, and Survival in Patients with Soft Tissue Sarcoma of the Extremities Treated with Radiotherapy

Introduction: The prognostic factors for extremity soft-tissue sarcomas (ESTSs) treated with multimodal surgery and radiotherapy (RT) remain a subject of debate across diverse and heterogeneous studies. Methods: We retrospectively analyzed nonmetastatic ESTS patients treated with RT between 2007 and 2020 in Strasbourg, France. We assessed local control (LC), distant control (DC), overall survival (OS), and complications. Results: A total of 169 patients diagnosed with localized ESTS were included. The median age was 64 years (range 21–94 years). ESTS primarily occurred proximally (74.6%) and in the lower limbs (71%). Most tumors were grade 2–3 (71.1%), deep-seated (86.4%), and had R0 margins (63.9%). Most patients were treated with helical tomotherapy (79.3%). The median biologically effective dose (BED) prescribed was 75 BEDGy4 (range 45.0–109.9). The median follow-up was 5.5 years. The 5- and 10-year LC, DC, and OS rates were 91.7%, 76.8%, and 83.8% and 84.2%, 74.1%, and 77.6%, respectively. According to the univariate analysis, LC was worse for patients who received less than 75 BEDGy4 (p = 0.015). Deep tumors were associated with worse OS (p < 0.05), and grade 2–3 and undifferentiated pleomorphic sarcoma (UPS) were linked to both shorter DC and shorter OS (p < 0.05). IMRT was associated with longer LC than 3DRT (p = 0.018). Multivariate analysis revealed that patients with liposarcoma had better OS (p < 0.05) and that patients with distant relapse had shorter OS (p < 0.0001). Conclusion: RT associated with surgical resection was well tolerated and was associated with excellent long-term rates of LC, DC, and OS. Compared with 3DRT, IMRT improved local control. Liposarcoma was a favorable prognostic factor for OS. Intermediate- and high-grade tumors and deep tumors were associated with lower DC and OS.

Undifferentiated pleomorphic sarcoma of maxilla

Abstract Undifferentiated pleomorphic sarcoma (UPS) formerly known as malignant fibrous histiocytoma is a high-grade aggressive soft-tissue sarcoma. UPS is a soft-tissue sarcoma without a definable line of differentiation. Men between the ages of 50 and 70 are frequently affected by it. In adults, the lower extremity and retroperitoneum are the most affected sites, while the paranasal sinus is affected in younger individuals. A 16-year-old male patient reported with swelling in his left posterior maxilla for 2 months. The swelling began quickly and gradually expanded to its current size. On examination, an ill-defined, deep-seated exophytic, ovoid growth was seen on the left maxillary alveolus. Histopathological findings indicated UPS. UPS is a rare malignancy that typically originates in the body’s soft tissues. The treatment for UPS is determined on the site of the cancer, but it typically includes surgery and radiation.

High-Grade Pleomorphic Sarcomas Treated with Immune Checkpoint Blockade: The MD Anderson Cancer Center Experience.

Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available. The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution. This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded. Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0012, p = 0.0019 and p = 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity. Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors.

Genomic profiling of pleomorphic rhabdomyosarcoma reveals a genomic signature distinct from that of embryonal rhabdomyosarcoma.

Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle-aged adults and showing a variable degree of skeletal muscle differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well-characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA-targeted Next generation sequencing (NGS) panels (MSK-IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31-76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm-level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression-free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable.

P133 Anti-synthetase syndrome: an experience from a tertiary referral center

Abstract Background/Aims Anti-synthetase syndrome (ASS) is a subset of Idiopathic inflammatory myositis (IIMs). It is a syndromic diagnosis classified by Connors et al. and Solomon et al. criteria. Raynaud’s phenomenon (RP), fever, arthritis, mechanics hands, ILD and myositis constitute this syndrome along with the classical Anti-aminoacyl tRNA synthetase antibodies (ARS). About 25% of IIMs patients are classified as ASS. This study was planned to evaluate the prevalence of ASS; their phenotype, antibody subtypes, treatment responsiveness and outcomes. Methods All consecutive ASS patients were enrolled in the study fulfilling Connors et al. criteria during January, 2016 to August2023. Their demographic details, clinical features, laboratory and imaging features, treatment were analyzed. ARS were considered positive on a Line Immunoassay with cutoff &amp;gt;6U/ML using BlueDriverQuantrix-ANA25 Screen IgG kit (includes Jo1, Pl-7, Pl-12) from D-tek, Belgium including three ASS antibodies (Jo-1, PL-12, PL-7). Anti EJ, OJ antibodies were not present in the kit. Descriptive analysis were used to describe disease characteristics. Results Among 139 total IIM patients, 21(15%) patients were diagnosed with ASS. All patients fulfilled Connors et al. criteria while 66.6% patients fulfilled stricter criteria by Solomon et al. Mean(±SD) age group was 43(±16.4) years. 71.4% were Females. Anti Jo-1 was the predominant antibody seen in 66.6% while Anti PL-12 and Anti Pl-7 antibodies were present in 19% and 14.3% respectively. 66.6% had ANA positivity and MAA antibodies were seen in 52.3%. Rash was seen in 61.9%, mechanics hands in 38%, RP in 52.3% fever in 38% ,arthritis in 57%, myositis 62% and ILD in 80.9%. NSIP (66.6%) was the predominant type, followed by OP (9.5%) and UIP (4.7%). Median (IQR) CPK level was 736 (210-4556)U/L. Anti Jo-1 patients had higher prevalence of mechanics hands and rash whereas ILD was observed in all cases of Anti PL-7 and Anti PL-12 antibodies. Malignancy was seen in two patients (Malignant fibrous histiocytoma, Metastatic Pancreatic carcinoma). Mean (SD) MMT8 score was 62.8(±22.2) at presentation . Treatment is with steroids in all cases followed by maintenance with azathioprine in 57.1%, Methotrexate in 14.2%. Rituximab was used in 14.2%, cyclophosphamide in 9.5% and mycophenolate mofetil in 23.8%. Mortality was seen in one patient with respiratory failure. Lung involvement was severe in patients with both MSA and MAA positivity. 62% patients were in remission. Conclusion ILD and Arthritis were the main presenting complaints in our cohort. Myositis is relatively less prevalent in ASS. NSIP was the predominant ILD subtype. Non Jo-1 group had high MAA positivity. Jo-1 was associated with mechanic’s hands and rash. Malignancy was less prevalent in ASS. All patients with PL-7 and PL-12 antibodies had lung involvement. Biologics were required in few refractory cases. Disclosure P. Khatri: None. J.R. Yadavalli: None. S. Dhuria: None. N. Negalur: None. K. Shivam: None. R. Gupta: None.

Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment.

CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.

The use of vascularized fibula flap with allograft in post-oncologic microsurgical bone reconstruction of lower limbs in pediatric patients.

Post-oncologic surgical reconstruction of lower limbs in pediatrics remains a challenging topic. Microsurgical techniques allow reconstructions of large bony defects. The use of vascularized fibular flap with allograft has proven to be an ideal biologic construct. We aim to assess the success rate of this operation, including flap survival, bony union, weight-bearing ambulation, and complications in a long-term follow-up in our case series compared to the literature. Our case-series includes 18 femoral resections (9 osteosarcomas, 8 Ewing sarcoma, and 1 desmoid tumor) and 15 tibial resections (10 osteosarcoma, 4 Ewing sarcoma, and 1 Malignant Fibrous Histiocytoma). We collected patients' demographics, type of tumor, type of resection, defect size, fibula-flap length, method of fixation, anastomosis site, follow-up data, complications, and their management. All survivals were examined by X-ray and CT-scan to evaluate the morphological changes of the vascularized fibula and follow-up. The functional evaluation was performed by the 30-point Musculoskeletal Tumor Society Rating Score (MSTS) for the lower limb (Enneking et al., Clinical Orthopaedics and Related Research 1993(286):241-246). The mean age of the femur resection patients' group was 11.2 years with a mean defect size of 14 cm and a mean length of the fibular flap of 18 cm; for the tibia the mean age was 12 years with a mean defect size of 14 cm and a mean length of the fibular flap of 16.6 cm. The overall survival of the reconstructions at 5 years follow-up was 17 out 18 cases for the femur and 13 out of 15 cases for the tibia. MSTS score was 28.2 for the femur and 23.7 for the tibia. The average time of union of the fibula was seen after 5 months, while allograft consolidation was observed around 19.7 months. The mean time of follow-up was 144.5 months for the femur and 139.2 months for the tibia. The complication rate observed was 7 out of 18 for the femur and 7 out of 15 for the tibia reconstructions. The viability of the fibula is a cornerstone in the success of reconstruction as well as the successful management of complications in intercalary defects after tumor resection in pediatrics to restore good functionality. Our results are in line with those reported in the literature in terms of overall complication rates. The high primary union of allograft, the high MSTS score obtained, and the low rate of severe complications reflect the mechanical role of this reconstructive technique over a long follow-up.

Abstract CT188: A Phase I trial of AVA6000, a Fibroblast Activation Protein (FAP)-released and tumor microenvironment (TME)-targeted doxorubicin peptide drug conjugate in patients with FAP-positive solid tumors

Abstract Background: AVA6000 is a peptide drug conjugate, consisting of a peptide moiety that is specifically cleaved by FAP in the TME that is bound to doxorubicin. FAP is selectively overexpressed in many solid tumors. The peptide moiety linker (pre|CISIONTM) prevents cellular entry of doxorubicin unless cleaved by FAP, thus enabling targeted delivery of doxorubicin to tumors. Design: The safety, PK and preliminary efficacy of AVA6000 was studied in a first-in-man, multicenter dose escalation phase I trial. AVA6000 was administered intravenously q3w using a standard 3+3 design in patients with locally advanced or metastatic solid tumors reported to be FAP-positive. PK (AUC) based dosing was implemented to calculate maximum cycles of AVA6000 with the cumulative limit of 550 mg/m2. Results: Forty patients (median age 65 years, range 30-79), with median 3 prior lines of therapy (range, 0-7) received escalating AVA6000 doses from 80mg/m2 (51 mg/m2 doxorubicin; molar equivalent, 0.675) to 385 mg/m2 (260 mg/m2 doxorubicin equivalent). Tumor types included soft tissue sarcoma (30%), colorectal cancer (27.5%), pancreatic cancer (20%), cancers of the biliary tract (7.5%). The safety profile was favorable, the most frequent adverse events (any grade) being fatigue (50%), alopecia (42.5%), and nausea (32.5%), with rare grade 3-4 hematologic toxicities of neutropenia (7.5%), anemia, thrombocytopenia, and WBC decreased (5% each). Grade 3 non-hematologic toxicities included mucositis, fatigue and hematemesis (n=1 each). No grade 4 non-hematologic toxicities were reported. Two DLTs were observed of grade 2 cardiac failure (120 mg/m2; LVEF decrease 61 to 39%) and grade 4 neutropenia/thrombocytopenia (200 mg/m2). AVA6000 distributes rapidly with a t1/2 of 45 min. The Cmax of released doxorubicin was reduced as compared to standard dose doxorubicin (range 78-93% reduction) across dose cohorts. Tumor biopsy data demonstrate concentration of doxorubicin in the TME of mean 860 ng/gm (range 76-2310 ng/gm, n=9). In contrast, blood samples taken with the biopsy demonstrate a circulating free doxorubicin of 8.3 ng/ml (range 2.4-15.9), indicating concentration of doxorubicin in the tumor relative to plasma. Using RECISTv.1.1, one PR (-65%) with duration of 6 months was observed in a patient with undifferentiated pleomorphic sarcoma at 160 mg/m2, and a mixed response in a patient with angiosarcoma (SLD -22%) at 200 mg/m2. The disease control rate was 50%, at 12 wks. In each case, SD &amp;gt; 4 months or PR was associated with high FAP enzyme activity in the on-study tumor biopsy compared to observed disease progression as best response (n=6). Conclusions: AVA6000 delivers high concentration of doxorubicin to the TME relative to plasma which results in antitumor activity in tumors with high FAP activity. A q2w dose escalation arm is ongoing. Citation Format: Udai Banerji, Natalie Cook, Alan Anthoney, Ruth Plummer, William D. Tap, Jeffry T. Evans, Lee D. Cranmer, Christopher Plummer, Paul Loadman, Gezim Lahu, Huw S. Jones, Nelson Kinnersley, Fiona McLaughlin, Chris Twelves. A Phase I trial of AVA6000, a Fibroblast Activation Protein (FAP)-released and tumor microenvironment (TME)-targeted doxorubicin peptide drug conjugate in patients with FAP-positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT188.

Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative.

Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS. From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at sevenacademic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR),time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed. Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLRrecurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation. For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

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.

Malignant primary tumors of scalp with cranial extension: multidisciplinary surgical strategies and outcomes.

Malignant cancers arising in the scalp may exhibit calvarial invasion, dural extension, and rarely cerebral involvement. Typically, such lesions require a multidisciplinary approach involving both neurosurgery and plastic surgery for optimal resection and reconstruction. The authors present a retrospective analysis of patients with scalp malignancies who underwent resection and reconstruction. Patients presenting with scalp malignancies (1993-2021, n = 84) who required neurosurgical assistance for tumor resection were prospectively entered into a database. These data were retrospectively reviewed for this case series. The extent of neurosurgical resection was classified into four levels of involvement: scalp (level I), calvarial (level II), dural (level III), or intraparenchymal (level IV). Complications and evidence of local, locoregional, or regional recurrence were documented. Patients underwent level I (n = 2), level II (n = 61), level III (n = 13), and level IV (n = 8) resections. Pathologies consisted of primarily squamous cell carcinoma (n = 50, 59.5%), basal cell carcinoma (n = 11, 13.1%), and melanoma (n = 9, 10.7%), with infrequent lesions including sarcoma, atypical fibroxanthoma, and malignant fibrous histiocytoma. For cases requiring a cranioplasty, 92.2% were done using titanium mesh and 7.8% with methylmethacrylate. At a mean follow-up of 35.5 ± 45.9 months, the overall survival was 48.8% (n = 41) and recurrence-free survival was 31.0% (n = 43). Scalp-based reconstruction involving plastic surgery was performed in 75 (89.3%) patients. The most commonly used free flap was a latissimus dorsi muscle flap (n = 46, 61.3%). One or more postoperative complications occurred in 21.4% of all patients, the most common being wound dehiscence or delayed wound healing in 13% (n = 11). A multidisciplinary approach with aggressive neurosurgical resection is associated with good outcomes in patients with primary malignant scalp tumors, despite invasive disease on presentation. This analysis suggests that aggressive resection (level II and higher) is effective at reducing locoregional recurrence and is not associated with a higher risk of complications relative to resection without craniectomy. As most patients require scalp reconstruction to close the postresection defect, usually with vascularized free tissue transfer, involving a plastic surgeon in the surgical planning and execution is essential.

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 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 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 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.

Abstract 3587: Evidence that membrane progesterone receptors (mPR) play a key role in cancer metastases in most cases of metastatic cancer

Abstract An immunomodulatory protein called the progesterone induced blocking factor (PIBF) is essential for the fetal semi-allograft to escape immune surveillance. Many cancer cell lines make both mPRs for PIBF and the protein itself. The progesterone receptor (PR) antagonist mifepristone added to cancer cell line cultures down-regulated mRNA for PIBF and the PIBF protein. This IRB approved study (that required a compassionate use IND from the FDA) evaluated oral mifepristone 200mg per day (majority) or 300mg in patients with very advanced cancers with no more treatment options available. Patients would remain under the care of their primary oncologists (FDA requirement). Because the nuclear (n) PR may be protective against cancer spread, only patients with cancers negative for the nPR were treated. Patients with the following types of cancers received mifepristone: non-small cell lung cancer (NSCLC) (n=9), small cell lung cancer (SCLC) (n=2), colon (n=3), pancreatic (n=2), thymic epithelial cell (n=1), transitional cell carcinoma of the renal pelvis (n=1), malignant fibrous histiocytoma (n=1), glioblastoma multiforme stage IV (n=1), leiomyosarcoma (n=1). All 21 patients showed significant palliative benefits, especially but not limited to, marked reduction in pain and marked improvement in energy, decreased dyspnea on exertion, and return of mental clarity. For those who had repeat CT evaluation no one failed to show shrinkage and decrease in malignant lesions and 2 (leiomyosarcoma and SCLC) showed complete remission after a few months on mifepristone. Five patients (3 females, 2 males) with SCLC (1), NSCL (n=3) and fibrous osteosarcoma (n=1) survived at least 5 years with 2 dying from cancer unrelated causes (SCLC and NSCLC). Two are still alive (NSCLC with EGFR mutation and brain metastases). The male with fibrous osteosarcoma died after stopping mifepristone in favor of a new drug recommended by his oncologist. Two patients lived over 2 years. Most would have lived longer had they not stopped mifepristone. Other observations: significant palliative benefits are seen within 3 weeks of taking mifepristone before any evidence of significant tumor regression. After a period of time, some lesions (especially in the primary location) may start growing slowly, but this is not a sign of loss of drug efficacy and long good quality life is still probable if one remains on the drug. The cancer spreads rapidly if one stops the mifepristone. The usual reason for stopping the drug was intervention by the primary oncologist suggesting a new clinical trial because there has not been complete remission of the cancer or some tumor growth (usually slow) or finances. Not one patient had a side effect. Hopefully this study will generate interest in treating patients with advanced cancer with mifepristone, especially those devoid of the nPR. These data support the role of mPRs in cancer proliferation. Citation Format: Jerome H. Check, Diane Check, Brooke Neumann, Carrie Wilson. Evidence that membrane progesterone receptors (mPR) play a key role in cancer metastases in most cases of metastatic cancer [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 3587.

Intercalary Resection of the Tibia for Primary Bone Tumors: Are Vascularized Fibula Autografts With or Without Allografts a Durable Reconstruction?

Intercalary Resection of the Tibia for Primary Bone Tumors: Are Vascularized Fibula Autografts With or Without Allografts a Durable Reconstruction?

A huge left buttock mass in an old female

IntroductionMyxofibrosarcoma also known as myxoid malignant fibrous histiocytoma is a rare soft tissue sarcoma that has a predilection for the elderly (beyond the 6th decade) Clinical observationWe report a case of a 64 years old patient that presented gradual appearance of huge tumor on her left buttock. Radiologic examination (MRI) concluded to MFS. There was no evidence of systemic involvement. The patient was directed in an oncology center, where the diagnostis of MFS was confirmed through surgical biopsy. DiscussionMFS is one of the most frequent sarcoma of soft tissue that occurs in elderly patients. This is an infiltrant tumor that is extending through muscular fascia. MRI is the gold standard in characterisation; it makes the positive diagnosis of MFS thanks to the myxoid signal, triple signal and the tail sign that is corresponding to the extension of the tumor into the muscular fascia and peri nervous spaces. ConclusionCross-sectionnal imaging in particular MRI plays a key role in the positive diagnosis of soft tissue tumors. It makes possible to approach with great precision the exact nature of the tumor thanks to specific radiological semiology without however claiming to replace histology.

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.