Therapy For Soft Tissue Sarcoma Research Articles

Recombinant Methioninase Increases Eribulin Efficacy 16-fold in Highly Eribulin-resistant HT1080 Fibrosarcoma Cells, Demonstrating Potential to Overcome the Clinical Challenge of Drug-resistant Soft-tissue Sarcoma.

A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro. HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated. The IC50 of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC50 of 0.15 nM on HT1080 cells, a 6-fold increase. The IC50 of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells. The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma.

Recombinant Methioninase Is Selectively Synergistic With Doxorubicin Against Wild-type Fibrosarcoma Cells Compared to Normal Cells and Overcomes Highly-Doxorubicin-resistant Fibrosarcoma.

Doxorubicin is first-line therapy for soft-tissue sarcoma, but patients can develop resistance which is usually fatal. As a novel therapeutic strategy, the present study aimed to determine the synergy of recombinant methioninase (rMETase) and doxorubicin against HT1080 fibrosarcoma cells compared to Hs27 normal fibroblasts, and rMETase efficacy against doxorubicin-resistant HT1080 cells in vitro. The 50% inhibitory concentrations (IC50) of doxorubicin and rMETase, as well as their combination efficacy, against HT1080 human fibrosarcoma cells, Hs27 normal human fibroblasts and doxorubicin-resistant HT1080 (DR-HT1080) cells were determined. Dual-color HT1080 cells which expressed red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nuclei were used to visualize nuclear fragmentation during treatment. Nuclear fragmentation was observed with an IX71 fluorescence microscope. The IC50 for doxorubicin was 3.3 μM for HT1080 cells, 12.4 μM for DR-HT1080 cells, and 7.25 μM for Hs27 cells. The IC50 for rMETase was 0.75 U/ml for HT1080 cells, 0.42 U/ml for DR-HT1080 cells, and 0.93 U/ml for Hs27 cells. The combination of rMETase and doxorubicin was synergistic against fibrosarcoma cells but not against normal fibroblasts. The combination of doxorubicin plus rMETase also caused more fragmented nuclei than either treatment alone in HT1080 cells. rMETase alone was highly effective against the DR-HT1080 cells as well as the parental HT1080 cells. The present results indicate the future clinical potential of rMETase in combination with doxorubicin for fibrosarcoma, including doxorubicin-resistant fibrosarcoma.

Preoperative Ultrahypofractionated Radiation Therapy for Soft Tissue Sarcomas: Low Rate of Wound Complications

Background: Normofractionated pre-operative radiotherapy (nRT) with 50 Gy applied in 25 fractions represents the most widely used radiotherapy (RT) regimen in combined local treatment of soft tissue sarcomas (STS). STS are characterized by a low α/β ratio of 4-5 Gy, which may translate into a higher sensitivity for hypofractionation. Increasing data from cohorts and phase II trials on ultra-hypofractionated RT (uhRT) regimens is available. We prospectively assessed our preoperative uhRT sarcoma patient cohort with a focus on short term wound complications (WC). Methods: This is a prospective registry analysis of a single center patient cohort, treated from 03.2020-10.2023 with uhRT (25 Gy in 5 fractions in 1 week). The same radiation oncologists (GS/CG) and surgeon (BF) performed the treatment (61/61 and 58/60), as well as the same reference pathologist (BB) confirmed all histopathological diagnoses. WC (according to CAN-NCIC-SR2 trial) and intermediate local control (LC) rates were assessed and compared with outcome data of a previously published cohort of 67 extremity/trunk sarcoma patients treated with nRT by the same authors (7% WC, 98% LC at 3 years). Results: After a mean/median follow-up (FU) of 19/19 months (range 0-46), LC at 1.5y was 94%. Surgery was performed at a mean/median of 20/16 days (range 4-60) after uhRT completion. WC were observed in 7/60 operated patients (12%), and in 5/51 (10%) extremity/trunk lesions. Early tolerance was excellent, limited to G0-1, even in 3 patients with prior RT to the same region. Clear resection margins were achieved in 55/60 patients (92%). Pathologic necrosis of ≥95% was reported in 5%, 75% achieved less than <50% necrosis. Conclusion: These results show low rates of WC and high LC for uhRT and are comparable to our previously published nRT data. This study supports the routine use of preoperative uhRT for STS.

An update on SOC-1882: A phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin for advanced leiomyosarcoma.

e23570 Background: Intratumoral injection of Talimogene Laherparepvec (TVEC) has a local oncolytic effect and evokes a cytotoxic immune response. The combination of Trabectedin (T) and Nivolumab (N) is a safe and effective therapy in soft tissue sarcoma (STS). Here, we report an update on an ongoing Phase 2 study that aims to determine the efficacy and safety of adding TVEC to the combination of T and N in advanced leiomyosarcoma (LMS). Objectives: Primary: To assess progression-free survival (PFS). Secondary: (1) To evaluate the best overall response, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to the resectable tumor, and (5) Incidence of treatment-related adverse events (TRAEs). Patients and Methods: Eligible patients included patients ≥ 18 years of age with locally advanced unresectable or metastatic LMS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg q2 weeks), T (1.2 mg/m2 q3 weeks), and TVEC (1x108 PFU/ml q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x106 PFU/ml) was initially given, followed by a total dose of 1x108 PFU/ml q 2 weeks depending on tumor size) three weeks later. Results: Efficacy: Per protocol, there were 17 evaluable subjects (Modified Intention to Treat [mITT] patients who had completed at least one treatment cycle and had a follow-up CT scan). The median number of prior lines of therapy was 4 (range 1-9). The disease control rate (PR+SD) was 94% with 1 PR, and 15 SD. The median PFS was 8.0 months (95% CI:4.8-11.28) with a 6-month PFS rate of 71%; median OS 19.2 months (95% CI:12.7- 25.7); 6-month OS rate, 82%. Safety: 22 patients (Intention to treat [ITT] who had received at least one-time drug administration) were evaluated for safety analysis. The &gt; Grade 3 TRAEs include anemia (n = 3), thrombocytopenia (n = 3), neutropenia (n = 1), increased ALT (n = 1), increased GGT (n = 1), decreased LVEF (n = 1), dehydration (n = 1), hyponatremia (n = 1). There were no new safety signals noted in this study. Conclusions: Taken together, the data confirms our previous report that (1) the combination regimen using Talimogene laherparepvec, Nivolumab &amp; Trabectedin may be more effective and treatment for previously treated patients with advanced leiomyosarcoma with manageable toxicity, and (2) The best responders are patients with HR+ uterine LMS. Clinical trial information: NCT03886311 .

Trends in the use of immunotherapy to treat soft tissue sarcoma

BackgroundThe role of immune-oncology (IO) therapy in soft tissue sarcoma (STS) is underexplored. This study characterized IO use in STS. MethodsThis is a retrospective analysis of patients with a soft tissue mass in the National Cancer Database, 2011–2021. Patients were categorized by IO receipt status. Groupwise testing and proportional trend tests were performed with Chi-squared tests. Multivariate logistic regression was performed to assess factors associated with IO receipt. ResultsOf the 103,092 patients with STS, 1935 (1.9 ​%) received or were recommended IO therapy. IO use increased 10-fold (0.24 ​%–2.5 ​% from 2011 to 2021; p ​< ​0.0001). Patients had higher odds of receiving IO when having higher grade tumors and metastatic disease, and when treated at an academic research center (all p ​< ​0.001). ConclusionsIO use in STS is low but increasing and primarily used in the metastatic setting. Future studies should identify biomarkers of IO response and facilitators for treatment receipt.

DNA-Binding Agent Trabectedin Combined With Recombinant Methioninase Is Synergistic to Decrease Fibrosarcoma Cell Viability and Induce Nuclear Fragmentation But Not Synergistic on Normal Fibroblasts.

The alkylating agent trabectedin, which binds the minor groove of DNA, is second-line therapy for soft-tissue sarcoma but has only moderate efficacy. The aim of the present study was to determine the synergistic efficacy of recombinant methioninase (rMETase) and trabectedin on fibrosarcoma cells in vitro, compared with normal fibroblasts. HT1080 human fibrosarcoma cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm and Hs27 normal human fibroblasts, were used. Each cell line was cultured in vitro and divided into four groups: no-treatment control; trabectedin treated; rMETase treated; and trabectedin plus rMETase treated. The dual-color HT1080 cells were used to quantitate nuclear fragmentation in each treatment group. The combination of rMETase and trabectedin was highly synergistic to decrease HT1080 cell viability. In contrast, there was no synergy on Hs27 cells. Moreover, nuclear fragmentation occurred synergistically with the combination of trabectedin and rMETase on dual-color HT1080 cells. The combination treatment of trabectedin plus rMETase was highly synergistic on fibrosarcoma cells in vitro suggesting that the combination can improve the outcome of trabectedin alone in future clinical studies. The lack of synergy of rMETase and trabectedin on normal fibroblasts suggests the combination is not toxic to normal cells. Synergy of the two drugs may be due to the high rate of nuclear fragmentation on treated HT1080 cells, and the late-S/G2 cell-cycle block of cancer cells by rMETase, which is a target for trabectedin. The results of the present study suggest the future clinical potential of the combination of rMETase and trabectedin for soft-tissue sarcoma.

Recent Advances in the Surgical Management of Radiation-Induced Fractures following Soft Tissue Sarcomas.

Background: Post-radiation fractures are a significant complication of cancer treatment, often being challenging to manage and impacting patients' quality of life. This study systematically reviews the literature on fractures in irradiated bones, focusing on risk factors, treatment modalities, and prevention strategies. Factors increasing fracture risk include exposure to high doses of radiation of at least 50 Gy, female gender, menopausal age, and periosteal stripping. Additionally further risk factors are the size of the original tumor and osteoporosis. Methods: A search of PubMed yielded 541 articles, with 4 were ultimately included in the review. These retrospective studies focused on patients undergoing Combined Limb-Sparing Surgery and Radiation Therapy for soft tissue sarcoma. Results: Results show post-radiation fractures affect approximately 4% of patients, with the femur being the most frequently affected site. Intramedullary nailing emerges as the gold standard treatment, with prosthetic replacement or megaprostheses used in the metaepiphyseal region and as salvage procedures. Non-union and infection remain formidable complications. Conclusions: This study highlights the importance of prophylactic nailing in fracture prevention and the efficacy of free vascularized fibular flaps to achieve bone union during revision surgeries. Limited case availability and patient follow-up hinder comprehensive studies, impacting treatment outcomes.

Superoxide Dismutase Mimetic Avasopasem Manganese Enhances Radiation Therapy Effectiveness in Soft Tissue Sarcomas and Accelerates Wound Healing.

Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.

Genetic, Epigenetic and Transcriptome Alterations in Liposarcoma for Target Therapy Selection.

Liposarcoma (LPS) is one of the most common adult soft-tissue sarcomas (STS), characterized by a high diversity of histopathological features as well as to a lesser extent by a spectrum of molecular abnormalities. Current targeted therapies for STS do not include a wide range of drugs and surgical resection is the mainstay of treatment for localized disease in all subtypes, while many LPS patients initially present with or ultimately progress to advanced disease that is either unresectable, metastatic or both. The understanding of the molecular characteristics of liposarcoma subtypes is becoming an important option for the detection of new potential targets and development novel, biology-driven therapies for this disease. Innovative therapies have been introduced and they are currently part of preclinical and clinical studies. In this review, we provide an analysis of the molecular genetics of liposarcoma followed by a discussion of the specific epigenetic changes in these malignancies. Then, we summarize the peculiarities of the key signaling cascades involved in the pathogenesis of the disease and possible novel therapeutic approaches based on a better understanding of subtype-specific disease biology. Although heterogeneity in liposarcoma genetics and phenotype as well as the associated development of resistance to therapy make difficult the introduction of novel therapeutic targets into the clinic, recently a number of targeted therapy drugs were proposed for LPS treatment. The most promising results were shown for CDK4/6 and MDM2 inhibitors as well as for the multi-kinase inhibitors anlotinib and sunitinib.

Association between Tumor Volume Change on MRI with Surgical Margin Status, Pathological Response, and Local Control Following Pre-Operative Radiation Therapy for Soft Tissue Sarcoma

The clinical significance of radiographic progression during pre-operative radiation therapy (RT) for soft tissue sarcoma (STS) remains unclear. We sought to evaluate associations between radiographic change on T1 post-contrast (T1c) and T2 weighted magnetic resonance imaging (MRI) with percent pathological response (PR%), positive surgical margins (+SM), and local control (LC). We retrospectively identified patients with STS undergoing neoadjuvant RT who had both pre- and post-RT MRI prior to surgical resection. Gross tumor volumes were contoured on pre- and post-RT T1c and T2 MRI sequences and relative change in volume from baseline was calculated. Radiographic classification was defined as response (>30% reduction), progression (>30% increase), or stable (≤30% reduction or ≤30% increase). Chi squared, Fishers Exact, and Kruskal Wallis (KW) tests were used to assess differences between groups. Linear and binary logistic regression models used to assess associations between MRI response and PR% and +SM, respectively. LC was modeled with Kaplan Meier methods and log rank tests. A total of 68 STS patients were identified, with a median follow up of 49 months (range 7-229). With a median age of 60.5 years (25-88) and tumor size of 10.8cm (2.7-25.7), the most common histologies were undifferentiated pleomorphic sarcoma (UPS; 32.4%) and myxoid liposarcoma (ML; 16.2%), and were primarily grade 2-3 disease (89.7%). With a median RT dose of 50 Gy in 25 fractions (44-60Gy), the median radiographic volume change was 2% (-86.4 to 953.6%) and -2.1% (-89.6 to 962.5%) for T1c and T2, respectively. Radiographic classification of response/stable/progression was 25.4%/49.2%/25.4% and 27.9%/52.5%/19.7% for T1c and T2, respectively. Histology (ML vs. UPS) and grade (1 vs. 3) were predictors for radiographic response on both T1c (72.7% vs 18.8%, p = 0.03 and 71.4% vs. 10.4%, p = 0.03) and T2 (71.5% vs. 18.2%, p = 0.02 and 71.4% vs. 14.6%, p = 0.002), respectively. With 6 +SM (8.8%), the rate of +SM for response/stable/progression was 20%/10.3%/0% in T1c (p = 0.2) and 5.9%/12.5%/0% in T2 (p = 0.5). As a continuous variable, neither relative change on T1c (p = 0.2) or T2 (p = 0.4) were associated with +SM. With an overall median PR% of 64% (0-100%), the median PR% was significantly different for response/stable/progression for both T1c (95%/42%/73%, p = 0.02) and T2 (95%/50%/87.5%, p = 0.04). Radiographic change on neither T1c (p = 0.4) or T2 (p = 0.5) were associated with PR% on a continuous basis. With a total of 4 local recurrences, there was no significant difference in LC by radiographic classification on either T1c (p = 0.65) or T2 (p = 0.85). While radiographic response may be correlated with pathological response, radiographic progression on either T1c or T2 following neoadjuvant RT was not associated with a detriment in surgical margins or local control. These findings suggest that STS radiographic "pseudoprogression" is not associated with worse outcome.

Dosimetric Analysis of Major Wound Complications Following Preoperative Ultra-Hypofractionated Radiation Therapy for Soft Tissue Sarcoma

Preoperative radiation therapy (RT) for soft tissue sarcomas (STS), delivered with conventional fractionation, has been shown to reduce long-term toxicity at the expense of increased postoperative major wound complications (MWC). Ultra-hypofractionated RT has emerged as a potential alternative preoperative modality with early but comparable outcomes to conventional regimens. However, limited data are available evaluating dosimetric, patient, and treatment specific factors associated with development of MWC in this setting. This IRB approved review included STS patients treated with preoperative 5 fraction daily RT followed by surgical resection within 7 days. Patients were evaluated for MWCs in association with patient and tumor characteristics, dosimetric parameters, and treatment techniques. MWCs were defined as a return to operating room, readmission for wound care or IV antibiotics, and persistent deep packing for >120 days. Prescription isodose line, PTV mean dose and the PTV volume exposed to 105% and 110% of prescribed dose were recorded. Dose to tissue likely to be involved in wound healing was assessed by creating a 1 cm thick superficial skin strip within 2 cm of the PTV which was then evaluated for volume, mean dose, V15, V21, V27, and V30. Secondary endpoints were locoregional control (LRC), metastasis free survival (MFS), and overall survival (OS). A total of 31 patients with a median age of 66 years (range 28-87) and a median follow up of 21 months (IQR 8-43) were included. All patients received 30 Gy in 5 fractions using IMRT/VMAT. There were 11 upper limb (36%) and 20 lower limb (65%) tumors included. Median time to resection following RT was 1 day (IQR 0-3). Median tumor size was 8 cm (IQR 5-13). MWC occurred in 13 patients (42%) with 10 patients (32%) requiring additional surgery. Dehiscence and infection requiring IV antibiotics occurred in 12 (39%) and 6 patients (19%), respectively. RT plans were predominately prescribed to the PTV mean (87%) with a median prescription isodose of 97% (IQR 96-97) and PTV mean dose of 3110 cGy (IQR 3089-3142). Median PTV volume, mean dose, and volume of PTV receiving 105% and 110% of the prescribed dose were higher in the MWC cohort although none reached significance. Similarly, for the 1 cm skin strip the median volume, mean dose, V30, V27, V21, and V15 were all higher in the MWC cohort without significant difference. Among patient, treatment, and tumor factors: tumor size, location, grade, margin status, type of wound closure, and prior non-oncologic resection were not associated with MWC. LRC, MFS, and OS at 3-years were 96%, 67%, and 76%, respectively. Although not reaching significance, increased plan homogeneity and reduced dose/volume relationships in proximity to the skin trended to reduced MWC in this limited cohort. Multi-institutional collaboration may be warranted to better identify factors associated with MWC in patients treated with preoperative ultra-hypofractionated RT.

174 Neutrophil-To-Lymphocyte Ratio Post-Hypofractionated Radiation Therapy in Soft Tissue Sarcomas is a Prognostic Biomarker for Recurrence and Metastases

174 Neutrophil-To-Lymphocyte Ratio Post-Hypofractionated Radiation Therapy in Soft Tissue Sarcomas is a Prognostic Biomarker for Recurrence and Metastases

Pseudoprogression in patients with uterine leiomyosarcoma treated with first-line single-agent doxorubicin

AimTo evaluate the incidence of pseudoprogression in patients with metastatic or inoperable uterine leiomyosarcoma (LMS) treated with first-line single-agent doxorubicin. MethodsThe Royal Marsden NHS Foundation Trust Sarcoma Unit database was searched to identify all patients with metastatic or inoperable LMS treated with first-line doxorubicin from January 2006 to January 2022. Patients with available computed tomography scans performed at baseline and during doxorubicin therapy were included. Response evaluation criteria in solid tumours v1.1 and Choi criteria were applied. Any increase in the sum of the longest diameter that decreased on the subsequent scan was labelled as pseudoprogression. ResultsThe total number of patients evaluated was 52. In total, 19% (n = 10) of patients treated with doxorubicin showed pseudoprogression. However, pseudoprogression at the time of the second scan was not associated with time to doxorubicin failure. Choi criteria identified 30% (n = 3) of pseudoprogressors as responding. ConclusionDespite the use of doxorubicin as first-line therapy for soft-tissue sarcomas for over 40 years, pseudoprogression has not been described. This retrospective study shows that pseudoprogression occurs in 19% of patients with metastatic/inoperable uterine LMS treated with first-line doxorubicin. Choi criteria were not consistently able to differentiate pseudoprogression from true progression. It is imperative that oncologists and radiologists are aware of this as symptomatically stable/improving patients may benefit from continued treatment despite initial radiological growth in tumour size.

The Correlation Between Lymphocyte Nadir and Radiation Therapy for Soft Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance

The objectives of this study were to identify key dosimetric parameters associated with postradiation therapy lymphopenia and uncover any effect on clinical outcomes. This was a retrospective review of 69 patients (between April 2010 and January 2023) who underwent radiation therapy (RT) as a part of curative intent for soft tissue sarcoma (STS) at a single academic institution. All patients with treatment plans available to review and measurable absolute lymphocyte count (ALC) nadir within a year after completion of RT were included. Median follow-up was 22 months after the start of RT. A decrease in lymphocyte count was noted as early as during treatment and persisted at least 3 months after the completion of RT. On multivariable linear regression, the strongest correlations with ALC nadir were mean body dose, body V10 Gy, mean bone dose, bone V10 Gy, and bone V20 Gy. Five-year overall survival was 60% and 5-year disease-free survival was 44%. Advanced T-stage, chemotherapy use, use of intensity-modulated RT, lower ALC nadir, and the development of grade ≥2 lymphopenia at nadir were associated with worse overall survival and disease-free survival. Post-RT lymphopenia was associated with worse outcomes in STS. There were associations between higher body V10 Gy and bone V10 Gy and lower post-RT ALC nadir, despite the varying sites of STS presentation, which aligns with the well-known radiosensitivity of lymphocyte cell lines. These findings support efforts to reduce treatment-related hematopoietic toxicity as a way to improve oncologic outcomes. Additionally, this study supports the idea that the effect of radiation on lymphocyte progenitors in the bone marrow is more significant than that on circulating lymphocytes in treatments with limited involvement of the heart and lung.

Interim results of a phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin for advanced leiomyosarcoma.

11556 Background: Intratumoral injection of Talimogene Laherparepvec (TVEC) has a local oncolytic effect and evokes a cytotoxic immune response. The combination of Trabectedin (T) and Nivolumab (N) is a safe and effective therapy in soft tissue sarcoma (STS). This study aims to determine the safety and efficacy of adding TVEC to the combination of T and N in advanced leiomyosarcoma (LMS). Methods: Objectives: Primary: To assess progression-free survival (PFS). Secondary: (1) To evaluate the best overall response, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to the resectable tumor, and (5) Incidence of treatment-related adverse events (TRAEs). Patients and Methods: Eligible patients included patients ≥ 18 years of age with locally advanced unresectable or metastatic LMS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg q2 weeks), T (1.2 mg/m2 q3 weeks), and TVEC (1x10e8 PFU/ml q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x10e6 PFU/ml) was initially given, followed by a total dose of 1x10e8 PFU/ml q 2 weeks depending on tumor size) three weeks later. Results: Efficacy: Per protocol, there were 11 evaluable subjects (Modified Intention to Treat [mITT] patients who had completed at least one treatment cycle and had a follow-up CT scan). The median number of prior lines of therapy was 4 (range 1-8). Confirmed Best Overall Response (BOR)by RECIST v1.1 = 2 PR, 9 SD (BOR Rate 18.2%). The disease control rate (PR+SD) at week 6 was 100%. The median PFS was 7 months (range: 3- 18); 6-month PFS rate, 55%; median OS 18.2 months (range: 4- 32); 6-month OS rate, 91%. There was no conversion from unresectable to resectable tumor. Response was not related to PD-L1 positivity but both patients with PR were ER+/PR+ and had uterine LMS. There were 15 evaluable subjects for OS analysis under the Intention-to-Treat (ITT) population who received at least one dose of study drug. The median OS was 12 (range 0-32) months; 6-month OS rate, 60%. Safety: Eight of 15 (53.3%) patients experienced at least one &gt; Grade 3 treatment-related adverse event (TRAE). Grade 3 TRAEs include anemia (n=3), thrombocytopenia (n=2), neutropenia (n=1), increased ALT (n=1), increased GGT (n=1), decreased LVEF (n=1), myalgia (n=1) . Grade 4 TRAE include thrombocytopenia (n=1). The TRAEs were related to Trabectedin use. No new safety signals noted in this study. Conclusions: These results suggest that (1) By indirect comparison, the combination regimen using Talimogene laherparepvec, Nivolumab &amp; Trabectedin may be more effective as second/third-line/fourth therapy for advanced leiomyosarcoma with manageable toxicity (Trabectedin alone for LMS= 4.3 mos; Dacarbazine alone = 1.6 mos; Demetri 2015), and (2) The best responders are patients with HR+ uterine LMS. Clinical trial information: NCT03886311 .

Multimodal treatment of localized high-grade soft tissue sarcomas of the extremities : Summary and discussion of the current S3 guidelines on adult soft tissue sarcomas and the ESMO guidelines on soft tissue and visceral sarcomas

Soft tissue sarcomas are rare, heterogeneous tumors that are frequently in the extremities. Treatment includes surgical resection, combination chemotherapy and/or radiotherapy, as well as supplementary procedures such as isolated limb perfusion and regional deep hyperthermia. The prognosis depends on the tumor stage and the approximately 70 histological subtypes, with specific treatment approaches existing only for some subtypes. This review summarizes the recommendations of the German S3 guideline "Adult Soft Tissue Sarcomas" and the European Society for Medical Oncology (ESMO) guideline "Soft tissue and visceral sarcomas" regarding the diagnostic workup and therapy of soft tissue sarcomas of the extremities.

Immunotherapy for Soft Tissue Sarcomas: Anti-PD1/PDL1 and Beyond.

Sarcomas gather a heterogeneous group of mesenchymal malignant tumors including more than 150 different subtypes. Most of them represent aggressive tumors with poor prognosis at the advanced stage, despite the better molecular characterization of these tumors and the development of molecular-driven therapeutic strategies. During the last decade, immunotherapy has been developed to treat advanced cancers, mainly thanks to immune checkpoint inhibitors (ICI) such as anti-PD1/PDL1 and later to adoptive immune cell therapies. In this review, we aim to summarize the state of the art of immunotherapy in soft tissue sarcomas (STS). Overall, the clinical trials of ICI that included a wide diversity of STS subtypes reported limited efficacy with some outlying responders. Both emerging biomarkers are of interest in selecting good candidates and in the development of combination therapies. Finally, the recent breakthroughs of innovative adoptive therapies in STS seem highly promising.

Neoadjuvant pazopanib in nonrhabdomyosarcoma soft tissue sarcomas (ARST1321): A report of major wound complications from the Children's Oncology Group and NRG Oncology.

The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma. Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy. Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites. The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

Asymmetric Mesoporous Nanoformulation for Combination Treatment of Soft Tissue Sarcoma

Soft tissue sarcoma (STS) is a kind of tumor that is difficult to treat by chemotherapy alone. In recent years, various studies have been conducted on the use of multifunctional nanoparticles with core@shell or indiscriminate coassembly to improve therapeutic efficacy. However, in these multifunctional nanoformulations, the functional subunits are located in the relevant space, in which the different functions are difficult to perform independently during the combination therapy. Herein, the enwinding-structured asymmetric mesoporous Fe3O4&mSiO2–SRF nanoformulation (SRF = Sorafenib) is constructed for the combination therapy of STS, in which the one-dimensional mSiO2 nanorods are enwound on the surface of magnetic Fe3O4 nanoparticles. In this enwinding-structured asymmetric nanoformulation, a Fe3O4 nanosphere subunit is used for the chemodynamic therapy (CDT), and a mesoporous SiO2 (mSiO2) subunit with high surface area is used for the loading of SRF chemotherapy drugs (mSiO2–SRF). Taking advantage of the spatial isolation of mSiO2–SRF and Fe3O4 subunits, the direct exposure of the Fe3O4 subunit can not only enhance the Fenton reaction on the nanoparticles surface but also accelerate the release of Fe2+/Fe3+ in the acidic microenvironment of the tumor, which further induced the upgrade of the cell oxidation level through GSH consumption and CDT. In addition, the SRF loaded mSiO2 functional unit can inhibit the synthesis of GSH, and synergistically work with the Fe3O4 functional unit to enhance the ferroptosis of cancer cells. Compared with traditional core@shell structured nanoformulation, the cancer cell killing efficiency of the asymmetric mesoporous nanoformulation is greatly increased by 41.33%, thus realizing improved tumor restrain efficiency in STS treatment.

Interdisciplinary Surgical Therapy of Extremity Soft-Tissue Sarcomas: A Personalized Resection and Reconstruction Algorithm.

Soft-tissue sarcomas (STS) are rare, but potentially life-threatening malignancies. STS can occur anywhere in the human body with the limbs being the most common site. Referral to a specialized sarcoma center is crucial to guarantee prompt and appropriate treatment. STS treatment strategies should be discussed in an interdisciplinary tumor board to involve expertise from all available resources, including an experienced reconstructive surgeon for an optimal outcome. In many cases, extensive resection is needed to achieve R0 resection, resulting in large defects after surgery. Hence, an evaluation of whether plastic reconstruction might be required is mandatory to avoid complications due to insufficient primary wound closure. In this retrospective observational study, we present data of patients with extremity STS treated at the Sarcoma Center, University Hospital Erlangen, in 2021. We found that complications were more frequent in patients who received secondary flap reconstruction after insufficient primary wound closure compared to patients who received primary flap reconstruction. Additionally, we propose an algorithm for an interdisciplinary surgical therapy of soft-tissue sarcomas regarding resection and reconstruction and present two problematic cases to emphasize the complexity of surgical sarcoma therapy.