Fibrosarcoma Research Articles

The single cell transcriptional landscape of fibrosarcoma.

235 Background: Fibrosarcoma (FS) is a relatively uncommon subtype of soft tissue sarcoma, which predominantly occurs in the extremities and girdles of elderly individuals. FS are famous for its high recurrence and metastasis rate. However, the current treatment regimens have shown poor efficacy in treating these progressive lesions. Therefore, a deep understanding of the tumor microenvironment characteristics of fibrosarcoma is needed to develop more effective drugs.Therefore, a deeper understanding of the tumor microenvironment characteristics of fibrosarcoma is needed for further development of therapeutic drugs. Methods: We performed single-cell transcriptome sequencing for the first time on 6 patients bearing with FS. Bulk-seq data of soft tissue sarcoma was downloaded from public database including TCGA and GEO for prognostic analysis. What' s more, a cohort of 54 FS patients was retrospectively collected for protein detection. Results: The tumor microenvironment landscape was characterized by the presence of malignant fibroblast, diverse macrophages, limited T-cell presence, and high levels of vascular infiltration. The expression of siglec15 was significantly upregulated in the malignant cells. And the prognostic significance of siglec15 was confirmed by the TCGA public database. What’s more, the high expression of siglec15 protein was negatively related to overall survival of fibrosarcoma patients from our institution. We also explored the interactions among different cell subtypes, especially the interactions between malignant cells and endothelial cells, as well as macrophages and endothelial cells, which not only promote tumor progression but also inhibit T-cell infiltration and function. Conclusions: In total, our work has uncovered the low T cell infiltration landscape of FS. The primary reason of insufficient immune infiltration may be due to the blockage of T cell extravasation caused by the interaction between endothelial cells, malignant cells and macrophages.

Morphological and immunohistochemical features can potentially help with the differential diagnosis of rare oral mesenchymal tumors

ObjectiveThe aim of this study was to evaluate the features of rare oral and maxillofacial benign and malignant tumors of fibroblastic, myofibroblastic and fibrohistiocytic origin in an attempt to contribute to the diagnosis of these tumors. MethodsThe sample consisted of 16 cases of benign fibrohistiocytic (BFH) tumor, myofibroma (MF), solitary fibrous tumor (SFT), fibrosarcoma (FS), dermatofibrosarcoma protuberans (DFSP), and myofibroblastic sarcoma (MFS), obtained from a laboratory of oral pathology. They were submitted to morphological, histochemical (Masson’s trichrome), and immunohistochemical (α-SMA, vimentin, desmin, CD34, Bcl-2, S100, CD68, CD99, and Ki-67) analysis. ResultsMorphological analysis revealed variable features in the tumors studied. Masson’s trichrome resulted in blue staining in most cases. Regarding the immunohistochemical features, all cases were positive for vimentin and negative for desmin. The BFH tumors exhibited positive staining for CD68 and S100, while MFs were positive for α-SMA and SFTs were positive for CD34, CD99 and Bcl-2. With respect to malignant tumors, DFSP was positive for CD34 and Bcl-2 and MFS was positive for α-SMA and Bcl-2, while FS was negative for most of the antibodies analyzed. A higher proliferation index (Ki-67) was observed in malignant tumors. ConclusionsConsidering their similarity, the use of auxiliary techniques might help in the differential diagnosis of these tumors.

Identification of common factors among fibrosarcoma, rhabdomyosarcoma, and osteosarcoma by network analysis

Sarcoma cancers are uncommon malignant tumors, and there are many subgroups, including fibrosarcoma (FS), which mainly affects middle-aged and older adults in deep soft tissues. Rhabdomyosarcoma (RMS), on the other hand, is the most common soft-tissue sarcoma in children and is located in the head and neck area. Osteosarcomas (OS) is the predominant form of primary bone cancer among young adults, primarily resulting from sporadically random mutations. This frequently results in the dissemination of cancer cells to the lungs, commonly known as metastasis. Mesodermal cells are the origin of sarcoma cancers. In this study, a rather radical approach has been applied. Instead of comparing homogenous cancer types, we focus on three main subtypes of sarcoma: fibrosarcoma, rhabdomyosarcoma, and osteosarcoma, and compare their gene expression with normal cell groups to identify the differentially expressed genes (DEGs). Next, by applying protein-protein interaction (PPI) network analysis, we determine the hub genes and crucial factors, such as transcription factors (TFs), affected by these types of cancer. Our findings indicate a modification in a range of pathways associated with cell cycle, extracellular matrix, and DNA repair in these three malignancies.Results showed that fibrosarcoma (FS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) had 653, 1270, and 2823 differentially expressed genes (DEGs), respectively. Interestingly, there were 24 DEGs common to all three types. Network analysis showed that the fibrosarcoma network had two sub-networks identified in FS that contributed to the catabolic process of collagen via the G-protein coupled receptor signaling pathway. The rhabdomyosarcoma network included nine sub-networks associated with cell division, extracellular matrix organization, mRNA splicing via spliceosome, and others. The osteosarcoma network has 13 sub-networks, including mRNA splicing, sister chromatid cohesion, DNA repair, etc. In conclusion, the common DEGs identified in this study have been shown to play significant and multiple roles in various other cancers based on the literature review, indicating their significance.

Correlation of IVIM/DKI Parameters with Hypoxia Biomarkers in Fibrosarcoma Murine Models: Direct Control of MRI and Pathological Sections

To investigate whether intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) parameters correlate with hypoxia biomarkers, namely hypoxia inducible factor-1ɑ (HIF-1ɑ), carbonic anhydrase IX (CAIX), and pimonidazole (PIMO), in fibrosarcoma (FS) murine models. A model of 30 FS nude mice was established. All mice underwent magnetic resonance imaging (MRI) scans after which the IVIM (standard apparent diffusion coefficient [standard ADC], pure diffusion coefficient [D], pseudo-diffusion coefficient [D*], and perfusion fraction [f]) and DKI parameters (mean diffusion [MD], mean kurtosis [MK]) were obtained. Based on an MRI-pathology controlled method, correlations between each MRI parameter and hypoxia biomarkers were assessed by Pearson or Spearman tests. An independent sample t-test or Wilcoxon's rank sum test, and receiver operating characteristic curves were used to identify whether MRI parameters could differentiate between high and low expressions of hypoxia biomarkers. The IVIM/DKI parameters showed varying degrees of correlation with HIF-1α, CAIX, and PIMO expression. Among them, the D, f, and MK values could confirm HIF-1α expression, while D, f, and MK values could assess CAIX expression. Finally, standard D and MK values could evaluate PIMO expression levels. IVIM and DKI parameters can be used to reflect hypoxic biomarkers of FS and have the potential to detect tumor hypoxia.

Adaptation of the Tumor Antigen Presentation Machinery to Ionizing Radiation.

Ionizing radiation (IR) can reprogram proteasome structure and function in cells and tissues. In this article, we show that IR can promote immunoproteasome synthesis with important implications for Ag processing and presentation and tumor immunity. Irradiation of a murine fibrosarcoma (FSA) induced dose-dependent de novo biosynthesis of the immunoproteasome subunits LMP7, LMP2, and Mecl-1, in concert with other changes in the Ag-presentation machinery (APM) essential for CD8+ T cell-mediated immunity, including enhanced expression of MHC class I (MHC-I), β2-microglobulin, transporters associated with Ag processing molecules, and their key transcriptional activator NOD-like receptor family CARD domain containing 5. In contrast, in another less immunogenic, murine fibrosarcoma (NFSA), LMP7 transcripts and expression of components of the immunoproteasome and the APM were muted after IR, which affected MHC-I expression and CD8+ T lymphocyte infiltration into NFSA tumors invivo. Introduction of LMP7 into NFSA largely corrected these deficiencies, enhancing MHC-I expression and invivo tumor immunogenicity. The immune adaptation in response to IR mirrored many aspects of the response to IFN-γ in coordinating the transcriptional MHC-I program, albeit with notable differences. Further investigations showed divergent upstream pathways in that, unlike IFN-γ, IR failed to activate STAT-1 in either FSA or NFSA cells while heavily relying on NF-κB activation. The IR-induced shift toward immunoproteasome production within a tumor indicates that proteasomal reprogramming is part of an integrated and dynamic tumor-host response that is specific to the stressor and the tumor and therefore is of clinical relevance for radiation oncology.

Combination of Everolimus and Bortezomib Inhibits the Growth and Metastasis of Bone and Soft Tissue Sarcomas via JNK/p38/ERK MAPK and AKT Pathways.

The combination of the mammalian target of rapamycin and proteasome inhibitors is a new treatment strategy for various tumors. Herein, we investigated the synergistic effect of everolimus and bortezomib on tumor growth and metastasis in bone and soft tissue sarcomas. The antitumor effects of everolimus and bortezomib were assessed in a human fibrosarcoma (FS) cell line (HT1080) and mouse osteosarcoma (OS) cell line (LM8) by MTS assays and Western blotting. The effects of everolimus and bortezomib on HT1080 and LM8 tumor growth in xenograft mouse models were evaluated using tumor volume and the number of metastatic nodes of the resected lungs. Immunohistochemistry was used to evaluate cleaved PARP expression. The combination therapy decreased FS and OS cell proliferation compared with either drug alone. This combination induced more intense p-p38, p-JNK, and p-ERK and activated apoptosis signals, such as caspase-3, compared with single-agent treatment. The combination treatment reduced p-AKT and MYC expression, decreased FS and OS tumor volumes, and suppressed lung metastases of OS. The combination therapy inhibited tumor growth in FS and OS and metastatic progression of OS via the JNK/p38/ERK MAPK and AKT pathways. These results could aid in the development of new therapeutic strategies for sarcomas.

Proteomic profiling of canine fibrosarcoma and adjacent peritumoral tissue

Fibrosarcoma (FSA) are rare soft tissue tumors that display aggressive local behavior and invasive growth leading to high rates of tumor recurrence. While the low incidence in humans hampers detailed understanding of the disease, FSA are frequent in dogs and present potential models for the human condition. However, a lack of in-depth molecular characterization of FSA and unaffected peritumoral tissue (PTT) in both species impedes the translational potential of dogs. To address this shortcoming, we characterized canine FSA and matched skeletal muscle, adipose and connective tissue using laser-capture microdissection (LCM) and LC-MS/MS in 30 formalin-fixed paraffin embedded (FFPE) specimens. Principal component analysis of 3’530 different proteins detected across all samples clearly separates the four tissues, with several targets strongly differentiating tumor from all three PTTs. 25 proteins were exclusively found in tumor tissue in ≥80% of cases. Among these, CD68 (a macrophage marker), Optineurin (OPTN), Nuclear receptor coactivator 5 (NCOA5), RAP1GDS1 (Rap1 GTPase-GDP dissociation stimulator 1) and Stromal cell derived factor 2 like 1 (SDF2L1) were present in ≥90% of FSA. Protein expression across all FSA was highly homogeneous and characterized by MYC and TP53 signaling, hyperactive EIF2 and immune-related changes as well as strongly decreased oxidative phosphorylation and oxidative lipid metabolism. Finally, we demonstrate significant molecular homology between canine FSA and human soft-tissue sarcomas, emphasizing the relevance of studying canine FSA as a model for human FSA. In conclusion, we provide the first detailed overview of proteomic changes in FSA and surrounding PTT with relevance for the human disease.

Efficacy and safety of apatinib in advanced refractory soft tissue sarcoma and association with histologic subtypes: a multicenter retrospective study.

BackgroundAntiangiogenic therapy is a potential strategy against advanced refractory soft tissue sarcoma (STS). This retrospective study aimed to assess the efficacy and safety of apatinib in patients with advanced refractory STS and explore its clinical effect on the different histologic subtypes.MethodsPatients with pathologically diagnosed and metastatic STS who had failed at least standard chemotherapy and were naive to angiogenesis inhibitors were enrolled in this multicenter respective study. Apatinib was administered orally at a dosage of 250 to 850 mg/day. The primary endpoints were objective response rate (ORR) and disease control rate (DCR). The secondary endpoints were progression free survival (PFS) and overall survival (OS). Tumor assessment was done after the first 4 weeks and every 8 weeks thereafter.ResultsTwenty-six patients were enrolled from seven centers between December 2015 and December 2020, consisting of 9 leiomyosarcomas (LMS), 4 rhabdomyosarcomas (RMS), 3 undifferentiated pleomorphic cell sarcomas (UPS), 3 fibrosarcomas (FS), 3 alveolar soft part sarcomas (ASPS), 2 angiosarcomas (AS) and 2 synovial sarcomas (SS). The median age was 49.0 [26–77] years, 15 females and 11 males. The ORR was 34.62% [9/26, 95% confidence interval (CI): 19.42–53.78%] and DCR was as high as 84.62% (22/26, 95% CI: 66.47–93.85%). The median progression-free survival and overall survival were 6.0 months (95% CI: 2.42–9.58) and 19.3 months (95% CI: 7.31–31.29) respectively. Furthermore, 181 patients from seven studies as well as this trial were included for pooled analysis of apatinib efficacy dependency on histology. In terms of ORR, RMS (41.7%), ASPS (78.6%), and Ewing sarcoma (40.7%) seemed to benefit more than the other histologic subtypes. Common adverse events (AEs) included hand-foot skin reaction (n=13, 50.0%), hypertension (n=12, 46.15%), proteinuria (n=10, 38.46%). Seven patients (7/26, 26.92%) had grade 3 AEs and no grade 4 AEs occurred. 2 patients (2/26, 7.69%) and 15 patients (15/26, 57.69%) experienced dose withdrawal and dose reduction respectively.ConclusionsApatinib showed promising efficacy and a manageable safety profile in patients with advanced refractory STS. In addition, the response to apatinib in STS seemed to be dependent on histology.

A Novel Prognostic Nomogram and Risk Classification System for Predicting Cancer-Specific Survival of Postoperative Fibrosarcoma Patients: A Large Cohort Retrospective Study.

Background Fibrosarcoma (FS) is a typically invasive sarcoma formed by fibroblasts and collagen fibers. Currently, the standard treatment for FS is the surgical resection, but the high recurrence rate and poor prognosis limit the benefits of postoperative patients. Exploring what factors affect the benefit of postoperative patients is significant for guiding the implementation of surgical resection. Therefore, this study aims to construct a novel nomogram to predict the cancer-specific survival (CSS) of postoperative fibrosarcoma (POFS) patients. Methods The included patients were randomly assigned to the training and validation sets at a ratio of 7 : 3. CSS was indexed as the research endpoint. Firstly, univariate and multivariate Cox regression analyses were used on the training set to determine independent prognostic predictors and build a nomogram for predicting the 1-, 3-, and 5-year CSS of POFS patients. Secondly, the nomogram's discriminative power and prediction accuracy were evaluated by receiver operating characteristic (ROC) and the calibration curve, and a risk classification system for POFS patients was constructed. Finally, the nomogram's clinical utility was evaluated using decision curve analysis (DCA). Results Our study included 346 POFS patients, divided into the training (244) and validation sets (102). Multivariate Cox regression analysis demonstrated that tumor size, SEER stage, and tumor grade were independent prognostic predictors of CSS for POFS patients. They were used to create a nomogram. In the training and validation sets, the ROC curve showed that the 1-, 3-, and 5-year area under the curve (AUC) were higher than 0.700, indicating that the nomogram had good reliability and accuracy. DCA also showed that the nomogram has high application value in clinical practice. Conclusion The larger tumor size, higher tumor grade, and distant metastasis were independently related to the poor prognosis of POFS patients. The nomogram constructed based on the above variables could accurately predict the 1-, 3-, and 5-year CSS of POFS patients. So, the nomogram and risk classification system we built might help make accurate judgments in clinical practice, optimize patient treatment decisions, maximize postoperative benefits, and ultimately improve the prognosis of POFS patients.

Long-term efficacy and safety of anlotinib in advanced sarcomas.

e23564 Background: Treatment of sarcomas has advanced in recent years partly because of the application of multitarget tyrosine kinase inhibitor (TKI) drugs. Anlotinib is an oral TKI with the dual effects of antiproliferation and antiangiogenesis, and it has a therapeutic effect with good tolerance and low side effects. In theory, physicians can gain long-term tumor control with anlotinib in certain advanced sarcomas. Methods: We conducted a retrospective analysis of patients with advanced sarcomas with measurable target lesions who had been treated in our ward since 2018. There were 22 patients who had taken anlotinib regularly for more than 12 months. Their general information, clinical efficacy, and toxicities were statistically analyzed. We used a swimmer plot to observe the efficacy and duration of the drugs and a waterfall plot to express the best treatment effect. Results: There were 14 male and 8 female patients, ranging in age from 14 to 75 (44.77 on average) years. The primary sarcomas were ASPS in five cases; synovial sarcoma (SS) in four cases; LMS in three cases; epithelioid sarcoma (ES) and UPS in two cases each; and clear cell sarcoma, RMS, angiosarcoma (AS), fibrosarcoma (FS), pleomorphic liposarcoma (LS), and osteosarcoma (OS) in one case each. The sites of metastasis were the lung in 15 cases, lymph nodes in 4 cases, and multiple sites in 3 cases. Therapies were as follows: first-line therapy (6 cases), second-line therapy (9 cases), third-line therapy (5 cases), and more than third-line therapy (2 cases). The current therapy protocols were nine cases with oral anlotinib alone, nine cases with combination chemotherapy, and four cases with combination immunotherapy (anti-PD1). The best clinical efficacy of this group was complete response (CR) in four cases (18.18%), partial response (PR) in five cases (22.73%), and stable disease in 13 cases (59.09%), with an overall response rate of 40.91% and the longest lasting time of 26, 16, 38 months in different response groups. The mean of progression-free survival (PFS) was 23.32 months. The main adverse effects included myelosuppression in seven cases (31.82%), hypertension in three cases (13.64%), and hand-foot syndrome and weakness in two cases (9.10%). Severe adverse effects included hypothyroidism with weakness in one case and wound ulceration with pneumothorax formation in another case. Conclusions: Anlotinib monotherapy or combination therapy can be an effective and safe choice for some advanced sarcomas with a longer maintenance time and acceptable side effects. Besides, anlotinib combined with anti-PD1 therapy has better therapeutic efficacy for specific diseases such as ASPS and ES. Anlotinib combined with chemotherapy has therapeutic efficacy for SS, LMS, FS, and RMS. Clinical efficacy such as CR and PR may be a prediction of long-term PFS in some advanced sarcomas.

In vitro antimicrobial and anti-proliferative activity of crude methanolic extract of pigment from Streptomycetes spp. on HT-1080 fibro sarcoma cell line

The ability to produce secondary metabolites like antibiotics is the characteristic feature of Streptomyces. Besides antibiotics, they are also seen to produce other bioactive compounds of economic importance like pigments which are potentially used in industries with remarkably appealing results. Under this backdrop, extraction of such priceless molecule from microbial source was the aim of this work. Actinomycetes strain isolated from water sample was identified as Streptomycetes with conventional and molecular approach. The metabolite exhibited antibacterial, antioxidant and anticancer activity as evident from the liquid fermentation. The crude ethanolic pigment extract was shown to be antibacterial on gram negative human pathogens. Also it exhibited antioxidant and anticancer activity against two cancer cell lines i.e. HeLa and HT-1080. Pigments from bacteria can be effectively used as natural source of treatment against various human ailments. Our results provide insights into effective role of pigment as potent bioactive metabolites with effective pharmaceutical properties.

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: could the combination with other drugs improve its antitumoral effect?

BackgroundEribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS).MethodsIn this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity.ResultsEribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS.ConclusionsOur results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

Primary Site and Other Prognostic Factors for Fibrosarcoma: An Analysis of the National Cancer Database.

Purpose: Fibrosarcoma (FS) is a rare and malignant tumor that can occur in a variety of anatomic sites. The goal of this study is to use the National Cancer Database (NCDB) to analyze various factors affecting overall survival in FS and to be one of the rare studies to characterize the significance of the primary anatomic sites.Methods: The study cohort included 2,278 patients diagnosed with fibrosarcoma who received surgery from the NCDB. Kaplan-Meier curves, log-rank tests, and a multivariable Cox proportional hazard model were used to analyze the significance of factors affecting overall survival.Results: The head, face, and neck (HR = 1.44; 95% CI: 1.01-2.05; P = 0.046) and thorax anatomical sites (HR = 1.33; 95% CI: 1.02-1.73; P = 0.035) had a higher increased risk of death in comparison to the lower limb and hip. Compared to patients with private insurance, patients without insurance (HR = 1.99; 95% CI: 1.22 to 3.25; P = 0.006) and patients with Medicaid (HR = 1.99; 95% CI: 1.37 to 2.90; P < 0.001) had decreased overall survival. Patients associated with a zip code-level median household income ≥ $63,000 had a decreased risk of mortality when compared to lower income groups.Conclusion: In general, older patients with comorbidities, advanced-stage disease, and larger tumors who did not have private insurance and were from areas associated with lower income levels had poorer overall survival. No significant difference in overall survival was associated with receipt of neoadjuvant chemotherapy or neoadjuvant radiation.

Abstract 2163: Molecular characteristics of CDK4 and/or MDM2 amplification in Chinese soft tissue sarcoma (STS) patients

Abstract Background: Cyclin-dependent kinase 4 (CDK4) and mouse double minute 2 homolog (MDM2) amplification occur at high frequency in well-differentiated liposarcoma and dedifferentiated liposarcoma, which are generally considered to be diagnostic criteria for these tumors. Studies have also reported that CDK4 and/or MDM2 amplification can emerge in STS subtypes, such as Ewing's sarcoma (ES) and fibrosarcoma (FS). However, the clinical pathological and molecular characteristics of CDK4 and/or MDM2 amplification in STS are still unclear. We systematically depicted the clinical characteristics of MDM2 and CDK4 gene amplification in Chinese STS patients (pts), aiming to assist the precise diagnosis and treatment of STS. Methods: Totally 184 Chinese pts with different STS subtypes were included in this study. In terms of subtypes distribution, the cohort contained multiple STS subtypes including myofibroblastic sarcoma (MFS, n = 23), liposarcoma (LPS, n = 21), FS (n = 20), rhabdomyosarcoma (RMS, n = 19), liomyosarcoma (LMS, n = 12), undifferentiated pleomorphic sarcoma (n = 11), clear cell sarcoma (n = 10), synovial sarcoma (n = 8), ES (n = 7), hemangiosarcoma (n=7), other rare subtypes (n = 37) and unknown types (n = 9). The amplification status of CDK4 and MDM2 in the tumor tissues of these pts was reviewed by the DNA and RNA next generation sequencing method. Results: Totally 16.8% (31/184) of the Chinese STS pts harbored CDK4 and/or MDM2 amplification. Among the 31 pts, 17 were with co-amplification of CDK4 and MDM2, including 12 LPSs, two RMSs, one MFS, one LMS and one FS. Fourteen pts were with single amplification of MDM2 or CDK4, including LPS (n = 4), RMS (n = 3), MFS (n = 3), FS (n = 2), ES (n = 1), and malignant peripheral nerve sheath tumor (n = 1). In LPS, the ratios of co-amplification and single amplification of CDK4/MDM2 were 57.1% (12/21) and 19.0% (4/21) respectively. Other STS subtypes with high frequency of CDK4 and/or MDM2 amplification included RMS (26.3%, 5/19) and MFS (19.4%, 4/23). Meanwhile, our study revealed that co-amplification of CDK4 and MDM2 appeared to be a strong driver event in STS, which mutated exclusively with other driver genes, such as TP53, MYOD1, ATRX and PTEN. Pts with co-amplification of CDK4 and MDM2 were likely to benefit from the treatment of CDK4 and/or MDM2 inhibitors. However, more than half of the pts with single amplification of CDK4 or MDM2 were accompanied by mutations in other driven genes, such as FLI1-EWSR1 fusion, PAX3-FOXO1 fusion, MYOD1 p.L122R, TP53 p.R273S, and NRAS p.G13C. In these pts, single amplification of CDK4 or MDM2 may not be the main driver event, who may be less likely to benefit from CDK4 or MDM2 inhibitor monotherapy. Conclusion: Our study revealed the clinicopathologic and molecular features of CDK4 and/or MDM2 amplification in Chinese STS pts, which can guide the selection of personalized treatment strategies in STS pts. Citation Format: Gu Jin, Chunyang Wang, Xiaojuan Wang, Qifan He, Tonghui Ma. Molecular characteristics of CDK4 and/or MDM2 amplification in Chinese soft tissue sarcoma (STS) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2163.

The incidence of unplanned excision in patients with soft tissue sarcoma: Reports from the Bone and Soft Tissue Tumor registry in Japan

BackgroundDue to their rarity, soft tissue sarcomas (STS)s are often treated surgically as unplanned excisions (UE)s before referral to specialists. The Bone and Soft Tissue Tumor (BSTT) registry is a nationwide, organ-specific cancer registry for bone and soft-tissue tumors in Japan. The aim of this study was to elucidate the incidence and risk factors for UEs using data from the BSTT registry. MethodsOur study comprised 8761 patients with STS including 4826 males and 3935 females, with a mean age of 59 years (range, 0–105 years). Patients were classified into primary STS and UE groups. ResultsSuperficial and deep tumors were found in 2533 and 6120 patients, respectively. The mean STS size was 8.6 cm (range, 0.2–49 cm). We identified 6610 patients with high-grade, and 1758 patients with low-grade STS. Of the total 8761 patients, 7770 patients had primary STSs, whereas 991 patients were referred after undergoing UE. The UE mean incidence rate over 11 years was 11.3%. The UE incidence rates for leiomyosarcoma (LMS) (odds ratio [OR] = 1.75, p < 0.0001), fibrosarcoma (FS) (OR = 2.28, p < 0.0001), and epithelioid sarcoma (OR = 1.82, p = 0.01) were higher than the mean UE incidence rate (11.3%). Of 757 patients who underwent UE, 354 (47%) patients had superficial (≤5 cm) STSs, whereas 156 (20.6%) of patients had deep STSs (>5 cm) (p < 0.0001). Logistic regression analysis revealed that UE was frequently associated with males and small, superficial, and trunk STSs. ConclusionsIn the present study, the mean UE incidence rate (11.3%) was significantly different from the individual UE incidence rates of histological diagnoses suggesting that surgeons should consider STS, even with small tumors. Continuous education during training for medical students and surgeons is essential to ensure awareness and correct diagnostic procedures for STS.

Fibroblastic sarcomas of the mediastinum.

Primary mediastinal fibroblastic sarcomas constitute a rare, heterogeneous group of neoplasms, mainly including solitary fibrous tumor (SFT) (benign and malignant), low grade fibromyxoid sarcoma (LGFMS), adult fibrosarcoma (FS), myxofibrosarcoma, sclerosing epithelioid FS, etc. Although morphologically diverse, they frequently have similar clinical and radiological features. Overlapping of histological features among these neoplasms can make it challenging for pathologists to come to an accurate diagnosis. In addition, other mesenchymal neoplasms and spindle cell neoplasms of the epithelial cell origin can occur in the mediastinum. Immunostaining and molecular testing are important ancillary studies to confirm or rule out primary mediastinal fibroblastic neoplasms. SFT and LGFMS occur more often than adult FS in the mediastinum and both have reliable immunostaining markers STAT6 and MUC4, respectively, and unique molecular changes. The incidence of adult FS has decreased dramatically due to recognition of morphologically and genetically distinctive subtypes of fibroblastic sarcoma and better understanding of mesenchymal and non-mesenchymal mimickers. Adult FS is extremely rare and a diagnosis of exclusion. Adult FS can be rendered only after careful histological examination and thorough ancillary studies have ruled out all its mimickers. This article is focused on reviewing clinicopathological features, immunostaining, molecular changes, prognosis and differential diagnosis of SFT, LGFMS, and adult FS. Correct diagnosis is crucial for oncologists to make appropriate clinical management plans.

Abstract 2773: Increased tumor control boosting hypoxic regions identified with EPR pO2 imaging in 2 tumor types

Abstract Introduction: It has been known for over a century that all living systems develop radiation resistance under hypoxic conditions - low pO2. But giving extra radiation - dose painting - or boosting hypoxic tumors regions has not shown enhanced control in mammalian tumors. Pulse EPR quantitative pO2 values can be tomographically imaged as a magnetic resonance measurement with fixed stepped gradients. If there are distinct hypoxic regions, their images can then be extra radiation dose boosts. An isocentric animal irradiation system allowed conformal boosts to tiny resistant tumor subvolumes with 3D printed tungsten loaded plastic blocks. A randomized trial compared radiation boosts to hypoxic tumor vs well oxygenated tumor to determine hypoxic boost control advantage. Methods: Carcinomas (MCa4) and fibrosarcomas (FSa) in mouse legs with mean volume of 350 μl were treated with an XRAD225Cx animal irradiator to a dose that controlled 15% of tumors (TCD15), determined in separate experiments. Pulse electron paramagnetic resonance (EPR) using Spin Lattice Relaxation (SLR) and a soluble trityl spin probe has been shown to quantitatively image solution and tumor pO2. This and boost treatments were given after EPR pO2 imaging, reconstruction, registration with tumor defining T2 MRI, determination of all tumor hypoxic regions (pO2 ≤10 torr) and 3D printed tungsten loaded plastic aperture fabrication to radiate either well oxygenated or hypoxic tumor regions. Mice were followed for either 180 days (MCa4) or 90 days (FSa) sufficient for 99% of local failures to occur. Treatment of 3D hypoxic volumes was also analyzed for control dependence on surface to volume ratio (SVR). Results: Tumor control was doubled by radiating hypoxic tumor relative to well oxygenated tumor in 48 MCa4 tumors (p=0.013) and 54 FSa tumors (p=0.04). This was the first demonstration in mammalian tumors of an advantage to targeting hypoxic regions in tumors. It provides the first evidence of image based dose painting within the volume of the tumor. For MCa4 tumors, SVR values below median had significant increased survival (p=0.003) while for FSa tumors below median SVR tumors trended to increased survival (p=0.3). Clinical Relevance: Modern radiation delivery used intensity modulated radiation therapy (IMRT) for dose gradients outside the tumor volume to reduce doses to critical structures. Dose within the tumor have strict inhomogeneity limits. Allowance of higher dose variation within the tumor volume allows “hot spots” to resistant tumor volumes, sharper gradients outside the volume to protect critical structures. This will enhance the therapeutic ratio. Citation Format: Howard Halpern, Matthew Maggio, Eugene Barth, Darwin Bodero, Richard C. Miller, Charles A. Pelizzari, Martyna Krzykawska-Serda, Subramanian V. Sundramoorthy, Bulent Aydogan, Ralph R. Weichselbaum, Victor M. Tormyshev, Inna Gertsenshteyn, Boris Epel. Increased tumor control boosting hypoxic regions identified with EPR pO2 imaging in 2 tumor types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2773.

Grafting of CdTe quantum dots on thiol functionalized MCM-41 mesoporous silica for 68Ga radiolabeling: introducing a novel PET agent

Radiolabeled fluorescent nanocomposite, 68Ga@CdTeQDs@SH-Propyl@MCM-41, was prepared. The prepared material was characterized using X-ray diffraction, thermal analysis, radio-thin layer chromatography, field Emission scanning electron microscopy, transmission electron microscopy and N2 adsorption and desorption measurements. In vivo biodistribution and tumor avidity of the nanoconposite was investigated among the organs of rats bearing fibro sarcoma tumor. The results showed that the mesoporous structure of MCM-41 after functionalization and grafting of quantum dots remains intact and the nanosilica can be labeled with 68Ga radionuclide very fast. The results showed a rapid and high tumor uptake for 68Ga@CdTeQDs@SH-Propyl@MCM-41 which revealed that the tumor uptake is modulated by size and character of the host.

Glucagon-like peptide-1 and gastrin synergistically promote the differentiation of insulin-producing cells

Objective Glucagon-like peptide-1(GLP-1) and gastrin synergistically promote the differentiation of insulin-producing cells which differentiated from rat bone marrow mesenchymal stem cells (BMSCs). Methods (1)Prepare IPCs model: pancreatic duodenal homeobox 1 (Pdx-1), neurogenin 3 (Ngn3) combined with V-type tendon fibrosarcoma oncogene homolog A (MafA) co-transfected BMSCs differentiation into IPCs; (2)IPCs were divided into 4 groups: Group A(uninduced group), group B(GLP-1 induction group), group C(gastrin induction group), and group D(GLP-1 combined with gastrin induction group). Cultured in high glucose medium for 7 days, the expression levels of insulin2, Pdx-1, GK, nestin, and glucagon mRNA were detected by RT-PCR. The insulin secretion of each group was detected by ELISA. Results After cultured for 7 days under high glucose conditions, the morphology of IPCs in each induction group changed significantly, gradually aggregated and formed scattered cell masses, and the combined induction group formed large cell masses. The staining of disulfide brown was reddish brown; The levels of insulin secretion increased gradually on the 0, 3rd, 5th, 7th, and 9th day after induction, and the increase was the most significant in the combined induction group (P<0.05). Compared with group A, the expression of insulin2 and GK in group B and D was significantly up-regulated, the expression of glucagon was down-regulated in group D, the expression of Pdx-1 was down-regulated in group C, and the expression of glucagon was up-regulated (P<0.05). Compared with group B, The expression of insulin2 was down-regulated in group C, and the expression level of glucagon was up-regulated. The expression levels of Pdx-1 and Insulin2 were significantly up-regulated in group D, and the expression level of glucagon was down-regulated (P<0.05). Compared with group C, the expression level of Pdx-1, insulin2 and GK was significantly up-regulated in group D, and the expression level of glucagon was down-regulated (P<0.05). Conclusion GLP-1 and gastrin synergistically promote the differentiation of IPCs into islet β cells by up-regulating GK and insulin2 and down-regulating glucagon. Key words: Glucagon-like peptide 1; Gastrin; Pancreatic duodenal homeobox 1; Neurogenin 3; V-type tendon fibrosarcoma oncogene homologous gene A; Insulin-producing cells

A Case of Rapidly Growing Hepatic Fibrosarcoma

原発性肝肉腫は原発性肝悪性腫瘍の約0.2％といわれ，その多くは血管内皮腫や悪性間葉腫であり，肝線維肉腫は稀である．症例は62歳，女性．発熱を主訴に受診し，入院時に施行した造影CTで，肝後区域に92mmの周囲より遷延性に造影される内部不均一な腫瘍を認めた．MRIではT1で低信号，T2で高信号を示し内部に出血を認めた．入院19日目に施行したCTで腫瘍径は102mmと急速な増大傾向を認めたため，25日目に肝拡大後区域切除術を施行した．病理所見では結合織性の被膜を有する結節状の腫瘍を認め，中央に出血と壊死を伴っていた．組織学的に紡錘形腫瘍細胞の特徴的配列である魚骨様形態，herringbone patternを認め，肝線維肉腫と診断した．術後2年経過した現在，無再発生存中である．肝線維肉腫は，本症例のように急速に増大することもあるが，積極的な切除により長期予後も期待できる可能性が示唆された．