tbuckley/cabot-search huggingface dataset:
Intimal sarcomas (ISarc) of the cardiac chambers (CC) of the heart and great vessels (GV): A comprehensive genomic profiling (CGP) study.
Authors: Maroun Bou Zerdan, Dean Pavlick, Jeffrey S. Ross, Stephen L. Graziano, Alina Basnet
Journal: Journal of Clinical Oncology (2024)

11575 Background: ISarc of the CC and GV are extremely rare primary tumors of the cardiac chambers (CC), aortic root (AO) and pulmonary artery (PA). These tumors are rarely resectable and are associated with rapid progression and poor clinical outcome. We queried whether CGP could uncover new routes to targeted therapies for this aggressive form of malignancy. Methods: 27 cases of ISarc were centrally reviewed and required direct association with the intimal surfaces of the CC and GV with supporting routine histologic features and immunohistochemical staining patterns. DNA and RNA extracted from the ISarc cases were both sequenced using a hybrid-capture based CGP to study all classes of genomic alterations (GA) and determine MSI status, TMB level, HRD score, genomic ancestry, cosmic trinucleotide signature (Signature) and germline status. PD-L1 expression was measured by IHC (Dako 22C3 and TPS scoring). Results: The 27 ISarc cases included 15 CC and 12 GV (11 pulmonary artery ISarc and 1 aortic root Isarc). There were 24 (88.9%) histologic grade 3 and 3 (11.1%) grade 2 tumors. Median ages for all ISarc ranged from 45 to 46 years and were similar in both groups. The CC ISarc pts tended to be female when compared with the GV pts (73% vs 50%; P=.26). GA potentially impacting targeted therapy selection in clinical trials for rare tumors included amplifications of MDM2 in 66.7% of CC ISarc and 50% of GV ISarc, PDGFRA in 53.3% CC and 41.7% of GV; homozygous deletions in CDKN2A in 26.7% in CC vs 66.7% of GV was near significant (p=0.055) and significantly more frequent point mutations in PIK3CAin CC at 20% vs 0% in GV (p=.007) and ERBB3 in 13.3% of CV and 8.3% of GV which was not significant. EUR ancestry was present in slightly more than 50% of ISarc cases and similar in both sub-groups. Median TMB was similar and ranged from 4.3 to 4.7 mutations/Mb with 1 (6.7%) CC ISarc having a TMB of &gt; 10 mut/Mb. 1/5 (20%) tested ISarc cases stained for low level PD-L1 expression. Conclusions: CGP of ISarc cases reveals that these tumors do feature a modest number of GA potentially associated with benefit for targeted therapies but low and absent biomarkers predictive of immunotherapy benefit. Further study of ISarc in a setting of rare tumor clinical trials appears warranted. [Table: see text]
Integrated multi-omics analysis reveals immune landscape of tertiary lymphoid structure in retroperitoneal liposarcoma.
Authors: Ping Tao, Zhenyu Wang, Jiongyuan Wang, Jun Chen, Liang Hong, Lijie Ma, Yong Zhang, Hanxing Tong
Journal: Journal of Clinical Oncology (2024)

11563 Background: Retroperitoneal liposarcoma (RPLS) is a rare type of mesenchymal tumor characterized by difficult surgical management, immune desert, poor response to immunotherapy and high local recurrence rate. However, how tertiary lymphoid structures (TLS) dictates complex biological processes such as antitumor immunity remains unknown. Thus, we aimed to investigate the spatio-temporal heterogeneity of TLS formation, maturation, and functional involvement in TIME, and the clinical value of TLS in multiple retrospective RPLS clinical cohorts. Methods: 330 patients were retrospectively enrolled into five independent cohorts from the two largest retroperitoneal tumor research centers in China and the TCGA database. Single-cell RNA sequencing (sc-RNA seq) (n=4) and spatial transcriptome seq (n=2) were performed for the estimation of TIME based on treatment-naive RPLS. Transcriptomic profiles of 309 cases in five cohorts were obtained from the ZSFD, GEO, and TCGA databases. TLS was quantified in three different anatomic subregions (intra-tumor, invasion margin and peri-tumor) and correlated with overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis. Multiplex immunohistochemistry (mIHC) was performed to characterize and validate the spatial composition of TLS in another treatment-naive RPLS cohort (n=16), neoadjuvant chemotherapy (n=12) and neoadjuvant radiotherapy (n=20) RPLS cohorts. Results: The joint scoring system of T and P scores stratified RPLS into four immune classes with different TLS distribution patterns and prognoses (p&lt;0.001). The immune class C-index was significantly higher than the TNM staging system (0.798 vs. 0.62, p=0.005). Importantly, mIHC revealed that regulatory T cells (Tregs) and M2 phenotype tumor-associated macrophages (TAMs) were significantly increased in intra-tumoral TLS in DDLPS compared to WDLPS, showing an immunosuppressive pattern. Strikingly, neoadjuvant chemotherapy and radiotherapy could block this status of immunosuppressive, induced TLS formation and restore the antitumor immune balance with significantly more CD38+IgG+ plasma cells (PCs) in responsive RPLS, whereas non-responsive RPLS deteriorated into a more suppressive one. Sc-RNA Seq and ST analysis further revealed significant intra- and inter-tumoral TIME heterogeneity and identified the underlying transcriptomic programs driving each phenotype. Conclusions: Our study provides a high-resolution map of TIME in treatment-naive and neoadjuvant chemotherapy/radiotherapy RPLS. Effective neoadjuvant chemotherapy and radiotherapy can induce TLS formation and restore the antitumor immune balance in RPLS.
Prognostic significance of plasma circulating tumor DNA fraction in patients with advanced sarcoma: A French Sarcoma Group study.
Authors: Sofiane Taleb, Maxime Brunet, Laila Belcaid, Rastislav Bahleda, Benjamin Verret, Axel Le Cesne, Florent Peyraud, Mariella spalato-Ceruso, Maud Toulmonde, Antoine Italiano
Journal: Journal of Clinical Oncology (2024)

11574 Background: The integration of liquid biopsies into clinical guidelines is revolutionizing the management of late-stage cancer. A notable advancement is the use of broad genomic analysis of circulating tumor DNA (ctDNA) for quantifying tumor fraction (TF). While TF's prognostic relevance in carcinomas has been explored, its significance in sarcomas remains unclear. Methods: This study involved patients with advanced sarcomas from two precision medicine studies (BIP, Institut Bergonié, Bordeaux, France; STING, Gustave Roussy, Villejuif, France) across two French Sarcoma Group sites. All participating patients underwent comprehensive genomic profiling with the FDA approved FoundationOne Liquid CDx assay. TF was measured using single-nucleotide polymorphism-based aneuploidy analysis as previously described (Reichert et al. 2023). Progression-free survival (PFS) and overall survival (OS) were assessed from treatment commencement (PFS) or the date of ctDNA profiling (OS) to disease progression, death, or last patient contact. Univariate analysis examined variables such as age, gender, tumor grade, metastatic sites, performance status (PS), and prior treatment lines. Results: 195 patients (103 males, 92 females) entered the study. The three most frequent histological subtypes were leiomyosarcomas, dedifferentiated liposarcomas, and undifferentiated pleiomorphic sarcomas. Median age was 56 (range 18-91). Thirty patients (15.4%) had high TF (≥ 10%). Among the 189 patients who underwent systemic treatment post-ctDNA profiling, elevated TF correlated with significantly poorer PFS (2.6 vs 4.3 months, p=0.018) and OS (6.7 vs 14.1 months, p=0.005). Multivariate analysis identified TF and ECOG performance status as independent predictors of OS. Conclusions: Plasma ctDNA TF is a practical and independent prognostic biomarker in advanced sarcoma patients. Its integration into treatment paradigms can facilitate precision therapeutic strategies tailored to individual tumor biology.
Active surveillance in patients with extra-abdominal desmoid-type fibromatosis: A combined analysis of three prospective observational studies.
Authors: Chiara Colombo, Stefanie Hakkesteegt, Axel Le Cesne, Francesco Barretta, Jean-Yves Blay, Dirk J. Grunhagen, Nicolas Penel, Laurent Lam, Marco Fiore, Elena Palassini, Giovanni Grignani, Francesco Tolomeo, Paola Collini, Alessandra Merlini, Federica Perrone, Silvia Stacchiotti, Cornelis Verhoef, Sylvie Bonvalot, Alessandro Gronchi
Journal: Journal of Clinical Oncology (2024)

11573 Background: Three observational studies on active surveillance (AS) in patients with extra-abdominal desmoid-type fibromatosis (DTF) provided prospective evidence supporting AS as frontline approach. Identification of prognostic factors for failure of AS will help determine the appropriate treatment strategy. The aim of this study was to confirm previous findings and investigate the prognostic impact of clinical and molecular variables on a larger series. Methods: Data available on January 31st 2024 from 3 prospective observational studies in Italy, the Netherlands and France in which DTF patients were followed for ≥3 years during an initial AS approach were merged. Patients ≥18 years, with primary extra-abdominal sporadic DTF (abdominal wall, extremity, head &amp; neck, trunk) and with CTNNB1 mutation (T41A, S45F, S45P, WT, “other”) available were eligible for the analyses. The primary study endpoint was treatment-free survival (TFS). Secondary endpoints included incidence of RECIST progression, spontaneous RECIST regression and regression post-RECIST progression. Results: Two hundred and eighty-two patients (n= 282) with median follow up of 53 months (IQ, 39-63) were included. Three-year and five-year TFS and crude cumulative incidences (CCI) of RECIST progression, RECIST regression and regression post-RECIST progression were 69% (64-75%) and 66% (61-73), 34% (95% CI 28-40) and 35% (30-41), 26% (95% CI 21-32) and 34% (29-41), and 35% (95% CI 26-47) and 40% (30-52), respectively. Larger initial tumour size (P=0.031), CTNNB1 mutation (S45F and “other” mutation P=0.049), and head/neck and extremity tumour locations (P=0.032) were associated with worse TFS at multivariable analysis (Table 1). Consistently smaller size and abdominal wall were associated with higher probability of initial spontaneous RECIST regression and a specular trend for mutation was also seen (Table). Conclusions: This study confirms that spontaneous regression occurs in a significant proportion of patients and two third are treatment free at 5 years. Initial size, CTNNB1 mutation and location should be factored in the initial decision-making process. [Table: see text]
GD2 target antigen and CAR T cells: does it take more than 2 to tango?
Authors: Franco Locatelli, Concetta Quintarelli
Journal: Clinical Cancer Research (2024)

Over the past decade, chimeric antigen receptor T cells have emerged as a breakthrough cancer therapy in selected hematologic malignancies. Translating the success of this therapy to solid tumors is challenging. In this issue, we discuss strategies potentially useful to increase the chimeric antigen receptor T-cell efficacy in this clinical indication. See related article by Fischer-Riepe et al., p. 3564.
Immune infiltrate analysis to reveal distinct immune classes for leiomyosarcomas.
Authors: Alicia Gingrich, Hannah Beird, Rossana Lazcano Segura, Ryan Denu, Michael Nakazawa, Ravin Ratan, J. Andrew Livingston, Maria Alejandra Zarzour, Anthony Paul Conley, Neeta Somaiah, Dejka M. Araujo, S Shreyaskumar Patel, Christina Lynn Roland, Andrew Futreal, Alexander J. Lazar, Emily Zhi-Yun Keung, Elise F Nassif Haddad
Journal: Journal of Clinical Oncology (2024)

11546 Background: Leiomyosarcomas (LMS) are aggressive malignancies of smooth-muscle origin. Few targeted molecular options exist and immunotherapy (IO) agents against T cells have been disappointing. In this study, we examine the immune infiltrate of LMS tumors by immunohistochemistry (IHC) and gene expression. Our objective was to identify actionable targets for immunotherapy in patients with LMS. Methods: Tumor samples from a series of LMS patients were prospectively collected and banked for DNA and RNA sequencing as part of the MD Anderson Patient Mosaic. Associated clinical data for the patients were collected and maintained. IHC was performed on available separate tissue microarrays. Differential gene expression (DGE) analysis was done using the DESeq2 package for R and the Benjamini-Hochberg procedure used to control for false discovery rate. Immune cell fractions were estimated using the MCPcounter package. All gene expression analyses were repeated on The Cancer Genome Atlas (TCGA) dataset as an independent dataset. Results: A total of 104 TCGA samples and 72 samples from Mosaic from 53 patients with uterine or soft tissue LMS were included in the analysis. Tumors in the TCGA group were treatment naive. Of the samples in the Mosaic group, 61 (85%) had been previously treated with chemotherapy, 8 (11%) had been radiated, and 5 (7.5%) had been previously treated with immunotherapy. Thirty-one (43%) tumors were metastatic. Fifty-one (70%) were soft tissue LMS and 21 (30%) were uterine LMS. Four distinct immune classes were seen in both the TGCA and Mosaic: a predominantly B-cell group, a monocyte/macrophage group, a mixed infiltrate group and a group with a neutrophil signature. DGE performed between the subgroups revealed a unique gene expression pattern for tumors in the B cell and monocyte/macrophage subgroups. Interrogation of specific immune-associated genes revealed low levels of expression in the neutrophil group, suggesting this may be the most immunologically “cold” subset. Some of these results were reproduced by IHC using a TMA: the presence of a cluster of samples with B-cells and higher expression of immune checkpoints, a macrophage driven cluster, and an immunologically cold cluster. Conclusions: Analyses of LMS samples across two large datasets demonstrate the existence of 4 distinct immune classes of tumors that persist despite variation in clinical and treatment conditions: B cell, monocytic/macrophage, mixed-infiltrate and neutrophil rich. The B cell and monocytic groups have increased expression of immune markers which may be amenable to targeted therapies.
Apatinib combined with ifosfamide and etoposide versus ifosfamide and etoposide in relapsed or refractory osteosarcoma (OAIE/PKUPH-sarcoma 11): A multicenter, randomized controlled trial.
Authors: Lu Xie, Jie Xu, Xin Sun, Xin Liang, Kuisheng Liu, Kunkun Sun, Yuan Li, Rong Liu, Du Wang, Shurong Shao, Peiyu Li, Zheng Pang, Guangxin Zhou, Sujia Wu, Yingqi Hua, Haiyan Hu, Yi Yang, Tao Ji, Wei Guo, Xiaodong Tang
Journal: Journal of Clinical Oncology (2024)

11527 Background: Retrospective studies have suggested the potential of apatinib, an anti-angiogenesis tyrosine kinase inhibitor, plus ifosfamide and etoposide (IE) over IE in advanced osteosarcoma. This trial aimed to further compared apatinib plus IE versus IE alone in patients with advanced osteosarcomas post first-line chemotherapy failure. Methods: In this multicenter, randomized controlled trial, patients with histologically confirmed osteosarcoma, progressing after at least one prior line of chemotherapy, were randomized (2:1) to either apatinib plus IE or IE alone. The apatinib plus IE group received oral apatinib 500mg daily plus ifosfamide (1.8 g/m 2 /d) and etoposide (100 mg/m 2 /d) on days 1-3, every 3 weeks. The IE group received IE on days 1-5, every 3 weeks. Apatinib was continued until disease progression or for a maximum of one year, and IE was administered for up to 10 cycles. The primary endpoint was progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1. Results: A total of 81 patients were enrolled, with 53 receiving apatinib and IE, while 28 using IE alone. The median follow-up period was 9.5 (interquartile range, 7.1 to 13.0) months. The apatinib plus IE group showed a median PFS of 5.5 months (95% confidence interval [CI], 3.9 to 6.7), compared to 3.4 months (95% CI, 1.4 to 4.6) in the IE group, yielding a hazard ratio of 0.41 (95% CI, 0.24 to 0.71), P=0.0010. Objective response rates were 32.1% (95% CI, 19.9 to 46.3) for the apatinib plus IE group and 25.0% (95% CI, 10.7 to 44.9) for the IE group. Disease control rates were numerically higher in the apatinib plus IE group at 90.6% (95% CI, 79.3 to 96.9), compared to 60.7% (95% CI, 40.6 to 78.5) in the IE group. The median time to response was 1.4 months (95% CI, 1.2 to 2.6) for the apatinib plus IE group and 1.5 months (95% CI, 1.3 to 2.0) for the IE group. Duration of response also favored the apatinib plus IE group, with a median of 6.1 months (95% CI, 1.9 to 8.0) compared to 4.1 months (95% CI, 1.7 to not estimated [NE]) in the IE group. The median overall survival has not yet been reached in either group. Grade 3-4 treatment-related adverse events occurred in 69.8% of patients in the apatinib plus IE group and 64.3% in the IE group, with the most common events being white blood cell count decreased and neutrophil count decreased. Conclusions: Apatinib plus IE demonstrated a significant improvement in PFS in patients with advanced osteosarcomas, with an acceptable safety. Clinical trial information: NCT05277480 . [Table: see text]
Use of histologic and immunologic factors in sarcoma to predict response rates to immunotherapy.
Authors: Alex Qiang Lee, Clara Hao, Minggui Pan, Kristen N. Ganjoo, Nam Bui
Journal: Journal of Clinical Oncology (2024)

11569 Background: Sarcomas are rare mesenchymal neoplasms with substantial histologic and tumor microenvironment heterogeneity, leading to varied treatment responses, particularly to immunotherapy. Because of the heterogeneity of response rates and high risk of disease progression, further determinations of which patients are most likely to benefit from immunotherapy are crucial. In this study, we aim to characterize factors associated with response to immune checkpoint inhibitors (ICIs). Methods: 216 patients with advanced sarcoma treated with ICIs between 2016-2023 at Stanford Health Care were analyzed. Overall survival (OS), progression free survival (PFS), objective response rates per RECIST criteria (ORR), and reason for ICI discontinuation were analyzed across histologic subtype, ICI regimen, tumor mutational burden (TMB), and PD-L1. Results: The most common histologic subtypes analyzed were leiomyosarcoma (LMS, n=48), liposarcoma (LPS, n=27), and undifferentiated pleomorphic sarcoma (UPS, n=18). Immunotherapy regimens primarily consisted of ipilimumab and nivolumab (77.8%), pembrolizumab (14.8%), and nivolumab monotherapy (6.0%). Median OS for all patients was 12.8 months. Response rates across all sarcomas were complete response (CR) 3.2%, partial response (PR) 13.4%, stable disease (SD) 30%, and progression of disease (PD) 53.2%. The ORR was higher in patients treated with pembrolizumab (21.9%) than with ipilimumab and nivolumab (14.3%). The histologic subtypes with the highest ORR were Kaposi sarcoma (KS, 66.7%), alveolar soft part sarcoma (ASPS, 50%), angiosarcoma (AS, 33.3%), myxofibrosarcoma (MFS, 28.6%), and UPS (27.8%). The subtypes with the lowest ORR were osteosarcoma (OS, 0%), synovial sarcoma (SS, 0%), and LPS (3.7%). The subtypes with the highest median PFS were KS (median not reached, NR), ASPS (NR), MFS (27.3 mo), and UPS (11.3 mo). Overall TMB (n=118) was low with a median of 2 mut/MB. Only 4 patients (3.3%) had a TMB ≥10, with a corresponding ORR of 25%. Overall PD-L1 expression (n=93 with TPS or CPS) was also low with a median of 0%. However, positive PD-L1 (n=36/93, &gt; 1%) was associated with better ORR (27.8%, 10/36). 16.2% of patients discontinued immunotherapy due to autoimmune adverse effects; the most common were pneumonitis (18.4%), colitis (15.8%), arthritis (13.2%), and hepatitis (13.2%). Conclusions: Response and PFS were highly variable across sarcoma histologic subtype. In this large analysis, KS, ASPS, AS, MFS, and UPS demonstrated the best ORR and longest PFS while OS, SS, and LPS were the lowest. TMB ≥10 and PD-L1 expression also correlated with increased ORR. Our findings provide further insight into understanding the sarcoma histologic and immunologic factors that correspond with response to ICIs. [Table: see text]
Gain-of-function human <i>UNC93B1</i> variants cause systemic lupus erythematosus and chilblain lupus
Authors: Clémence David, Carlos A. Arango-Franco, Mihaly Badonyi, Julien Fouchet, Gillian I. Rice, Blaise Didry-Barca, Lucie Maisonneuve, Luis Seabra, Robin Kechiche, Cécile Masson, Aurélie Cobat, Laurent Abel, Estelle Talouarn, Vivien Béziat, Caroline Deswarte, Katie Livingstone, Carle Paul, Gulshan Malik, Alison Ross, Jane Adam, Jo Walsh, Sathish Kumar, Damien Bonnet, Christine Bodemer, Brigitte Bader-Meunier, Joseph A. Marsh, Jean-Laurent Casanova, Yanick J. Crow, Bénédicte Manoury, Marie-Louise Frémond, Jonathan Bohlen, Alice Lepelley
Journal: The Journal of Experimental Medicine (2024)

UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in UNC93B1 causing systemic lupus erythematosus (SLE) or chilblain lupus (CBL) as either autosomal dominant or autosomal recessive traits. As for a D34A mutation causing murine lupus, we recorded a gain of TLR7 and, to a lesser extent, TLR8 activity with the I317M (in vitro) and G325C (in vitro and ex vivo) variants in the context of SLE. Contrastingly, in three families segregating CBL, the L330R, R466S, and R525P variants were isomorphic with respect to TLR7 activity in vitro and, for R525P, ex vivo. Rather, these variants demonstrated a gain of TLR8 activity. We observed enhanced interaction of the G325C, L330R, and R466S variants with TLR8, but not the R525P substitution, indicating different disease mechanisms. Overall, these observations suggest that UNC93B1 mutations cause monogenic SLE or CBL due to differentially enhanced TLR7 and TLR8 signaling.