Treatment Of Soft Tissue Sarcomas Research Articles

Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Preliminary results of a phase II trial of the German Interdisciplinary Sarcoma Group (GISG-15, NitraSarc) for the non-L sarcoma cohort.

11545 Background: Single-agent PD-1 inhibitors have modest activity in the treatment of most STS. Potential strategies to increase efficacy include combination therapies targeting the tumor microenvironment. Considering that apart from direct growth inhibition and death of malignant cells, trabectedin (Tr) also induces macrophage depletion and/or different immunologic effects, suggesting a possible synergistic effect of combined Tr plus anti-PD-1 treatment. We therefore aimed to evaluate the efficacy and safety of combined Tr and nivolumab (Ni) as a second-line treatment in STS. Methods: The prospective, explorative, two group, non-randomized phase II NiTraSarc trial enrolled pretreated patients (pt) with advanced STS (Group A: lipo- or leiomyosarcomas, Group B: non-L-sarcomas). Pt were initially treated with 3 cycles of Tr 1.5 mg/m2, followed by the combination of Tr 1.5 mg/m2 + Ni 240 mg (“late combination cohort” (LCC)) for up to 16 cycles. After positive results of a preplanned interim analysis, pt received the combination therapy starting with cycle 2 (“early combination cohort” (ECC)). 92 pt were recruited to the trial (55 in Group A, 37 in Group B). Primary efficacy endpoint is progression-free survival rate after 6 months (PFSR6) according to RECIST v.1.1. This is a first analysis of the primary efficacy endpoint in Group B based on a modified intention-to-treat (mITT) population of evaluable 36 pt: 23 and 13 pt from the LCC and ECC, respectively. Results: The most common Group B subtypes comprised undifferentiated pleomorphic/not otherwise specified sarcoma (UPS/NOS, 13pt) and fibromyxoid sarcoma (FMS, 6pt). After a median follow-up of 5 months (m) PFSR6 was 13.9% for all pt, 8.7% in LCC and 23.1% in ECC. Median duration of disease stabilization (DoDS) was 4m in all pt, the LCC and the ECC. Two pt had a partial response (PR), 10 had disease stabilization (SD), while 13 pt progressed, and 11 had missing data. By subtype: PR- UPS/NOS=2 (DoDS 12.7m/12.5m). SD: UPS/NOS=3, epithelioid=2, synovial=2, FMS=1, fibrosarcoma=1, other=1. All 36 pt experienced at least one adverse event (AE) reaching a total of 579 AEs, 141 (24.4%) of which were considered to be grade ≥3 treatment-related AEs. The main grade ≥3 AEs were: leukopenia (47.2% of pt), neutropenia (41.7% of pt), thrombocytopenia (33.3% of pt), increased ALT (30.6% of pt), and anemia (27.8% of pt). Conclusions: Tr+Ni was well tolerated and showed activity in at least some patients with non-L-sarcomas (mostly UPS/NOS) especially in the ECC. Analyses of the collected data, including PD-L1 expression profile, with the goal to establish whether Tr+Ni should be further pursued in these patients, are ongoing. ClinicalTrials.gov Identifier: NCT03590210; EudraCT: 2017-001083-38. Clinical trial information: NCT03590210.

Phase II trial of pegylated arginine deiminase in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma.

11508 Background: Soft tissue sarcoma (STS) is dependent on extracellular arginine as it often lacks expression of argininosuccinate synthase 1 (ASS1), the urea cycle enzyme needed to produce intracellular arginine. PEGylated arginine deiminase (ADI-PEG 20) is an extracellular arginine-degrading enzyme that causes ASS1 deficient tumors to enter the starvation state. Preclinical data demonstrated that addition of docetaxel (D) with ADI-PEG20 upregulates expression of the transporter for gemcitabine (G), overcoming transporter level resistance, and causing increased cell death. In vivo modeling demonstrated that the combination of ADI-PEG20 with G+D was superior to G+D alone. Therefore, we performed a phase 2 trial testing the addition of ADI-PEG20 to G+D. Methods: We performed an investigator-initiated, phase 2, multicenter, multi-arm clinical trial of ADI-PEG20 with G (90minute infusion)+D in STS, Ewing’s, osteosarcoma and small cell lung cancer. We are reporting Arm A, the STS arm. Eligible patients had STS that would be standardly treated with G+D that had progressed on at least one prior line of therapy with measurable disease by RECIST1.1 and had adequate organ function Based on a historic median PFS of 6.2 months for G+D, we targeted to enroll N = 75 patients in cohort A to detect a 2.8 month improvement with 80% power at a 5% alpha level. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), clinical benefit rate (CBR), safety, tolerability, cancer related mortality, and correlation with ASS1 expression by IHC. We evaluated PFS by Kaplan-Meier method and estimated overall response rate (ORR). Results: 75 patients were treated and deemed evaluable. The trial underwent two dose reductions by the data safety monitoring board due to prolonged neutropenia and thrombocytopenia preventing the use of day 8 G+D, consistent with preclinical mechanism of action data showing that ADI-PEG 20+D enhanced G uptake. Originally, the G dose was 900mg/m2 reduced first to 750mg/m2 then to 600mg/m2. D was dose reduced at the time of the second dose reduction from 75mg/m2 to 60mg/m2. ADI-PEG20 was given at a fixed intramuscular dose (36 mg/m2) weekly. The need for two dose reductions affected the PFS. The PFS/OS (months) were for the 600mg/m2 group (n = 31) was 6.0/N.D., leiomyosarcoma (LMS) (N = 33) 7.2/22.5, liposarcoma 5.1/17.4, and other (N = 36) 2.8/15.0. Responses were 8% complete (6/75) (3 LMS, 1 synovial and 2 angiosarcoma), 17% partial (13/75), and 43% stable disease (32/75), for an ORR of 25% (19/75) and CBR of 68% (51/75). There was a trend for ASS1 negative tumors to benefit more than ASS1 positive tumors. Conclusions: The combination of ADI-PEG20 with G+D can be safely and effectively given at a dose of 600mg/m2 G and 60mg/m2 D. Future randomized trials of ADI-PEG20 with G+D are planned. Clinical trial information: NCT03449901.

A retrospective study to evaluate the safety and efficacy of anlotinib plus camrelizumab in management of advanced retroperitoneal sarcoma.

e23545 Background: Several studies have demonstrated the antitumor activity of single-agent anlotinib in the treatment of soft tissue sarcoma (STS). However, the most effective results were from cases of alveolar soft part sarcoma (ASPS), which was a rare subtype in retroperitoneal sarcoma (RPS). The therapy of RPS is still dismal. Thus, we evaluated the effectiveness and safety of anlotinib plus camrelizumab for the treatment of RPS. Methods: We retrospectively reviewed the data of 36 patients with advanced/metastatic RPS in Sarcoma Centre of Peking University Cancer Hospital from July 2019 to February 2021. Anlotinib was given 12mg Qd 2 weeks on and 1 week off, and camrelizumab was transfused 200mg at Q3w. Patients that underwent at least 4 cycles of therapy were enrolled in this study. The primary endpoint is objective response rate (ORR) and evaluated according to the irRECIST 1.1 criteria. Results: The pathologic subtypes of enrolled cases include liposarcoma (LP) (n = 16), leiomyosarcoma (LMP) (n = 5), uncertain differentiation sarcoma (n = 7), fibroblastic and myofibroblastic tumours (n = 4), rhabdomyosarcoma (n = 2) and malignant peripheral nerve sheath tumour (MPNST) (n = 2). Two patients (5.6%) achieved CR and 9 patients (25.0%) achieved PR, with an ORR of 30.6%. Eighteen patients (50.0%) achieved SD and 7 patients (19.4%) were evaluated as PD, with the disease control rate (DCR) of 80.6%. The progression-free rate (PFR) at six months was 60.0%. Five patients underwent further radical surgical resection. The two CR cases were diagnosed as dedifferentiated liposarcoma (DDLP) and MDM2 amplified MPNST respectively, and both patients have been under CR status for over 12 months until now. The only grade 3 or higher treatment related adverse event was hypertension (22.2%). Camrelizumab related reactive cutaneous capillary endothelial proliferation (RCCEP) was not observed in this group of patients. Conclusions: The combination of anlotinib and camrelizumab demonstrated encouraging efficacy and safety in the treatment of RPS. A further clinical study with biomarker exploration should be performed in the future.

Efficacy and safety of anlotinib combined with liposomal doxorubicin in first-line treatment of advanced soft-tissue sarcoma.

e23530 Background: Anthracycline-based chemotherapy is the main first-line treatment option for advanced soft-tissue sarcoma (STS). Anlotinib has been approved for the treatment of STS by the Chinese agency. This study was performed to evaluate the efficacy and safety of Anlotinib combined with liposomal doxorubicin in first-line treatment of patients with advanced STS. Methods: This is a single-center, retrospective study. Eligible patients were those ≥14 years old, ECOG performance state of 0-1, with histologically confirmed locally advanced, unresectable or metastatic STS, previously untreated, with measurable disease by RECIST v1.1. All patients received Anlotinib (12mg once daily, 2 weeks on and 1 week off) and liposomal doxorubicin (40-50 mg/m2, IV, D1, every 3 weeks) until disease progression or unacceptable adverse events. The primary endpoint was progression-free survival (PFS). Disease control rate (DCR), objective response rate (ORR), and side effects were also calculated. Results: Between April 2019 and December 2020, 8 patients were evaluated, including 2 undifferentiated pleomorphic sarcoma, 1 liposarcoma, 4 fibrosarcomas, and 1 synovial sarcoma. The median age was 42 years. 2 patients (25%) achieved a confirmed partial response (PR) and 3(37.5%) had stable disease (SD). The ORR and DCR were 25% and 62.5% respectively. The median PFS was 11.3 months, and the PFS rate at 4 months was 50%. Treatment-related adverse events included hand-foot syndrome (3/8, 37.5%), pneumothorax (1/8, 12.5%), oral mucositis (2/8, 25%), epistaxis (2/8, 25%), hypertension (2/8, 25%), arrhythmias (1/8, 12.5%), and pharyngeal pain (1/8, 12.5%). Three patients experienced grade 3 or 4 adverse events, 2 hand-foot syndrome (2/8, 25%) and 1 pneumothorax (1/8, 12.5%). Conclusions: This study suggested that the combination of Anlotinib and liposomal doxorubicin might have anti-tumor activity and acceptable toxicity in first-line treatment of patients with advanced STS.

A randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib (2ND-STEP, JCOG1802).

TPS11580 Background: Soft tissue sarcomas (STS) are a rare type of malignancy, which comprises of a variety of histologies. Chemotherapy is the standard treatment for patients with advanced STS. Doxorubicin alone or in combination with ifosfamide is widely accepted as the first-line chemotherapy for advanced STS. While a combination with gemcitabine and docetaxel is regarded as a standard regimen of the second-line chemotherapy after failure of doxorubicin-based first-line regimen, the efficacy is not sufficient. Trabectedin, eribulin, and pazopanib are the candidates of the second-line chemotherapy for advanced STS, although there is no clear evidence showing which is better among those agents. The purpose of this clinical trial conducted by Bone and Soft Tissue Tumor Study Group of Japan Clinical Oncology Group (JCOG) is to determine the most promising regimen among trabectedin, eribulin and pazopanib as the test arm regimen in the future phase III trial of the second-line treatment for patients with advanced STS. Methods: The study, JCOG1802, is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 IV, every 3 weeks), eribulin (1.4 mg/m2 IV, days 1 and 8, every 3 weeks) and pazopanib (800 mg PO, everyday) for patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. Eligibility criteria include 16 year-old or older, unresectable and/or metastatic STS, an exacerbation within 6 months prior to registration, histological diagnosis of STS other than Ewing sarcoma, well-differentiated liposarcoma and myxoid liposarcoma, a history of chemotherapy for STS other than doxorubicin-based regimen, ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2, and sufficient organ function. Primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. To select the most promising regimen in median PFS (3 months in the worst regimen and 4 months in the best regimen) with a probability of at least 80%, a total of 120 patients will be enrolled from 37 institutions in Japan. After JCOG1802, a subsequent phase III trial comparing the winner of this study and a combination of gemcitabine and docetaxel will be planned. The study was activated at December 5, 2019 and 22 of planned 120 patients have been enrolled as of February 15, 2021. Clinical trial information: jRCTs031190152.

Results of the phase 1b soft-tissue sarcoma (STS) portion of the global randomized, double-blind, placebo-controlled study of tazemetostat (TAZ) plus doxorubicin (DOX) as frontline therapy for advanced epithelioid sarcoma (ES).

11563 Background: ES is a rare, aggressive subtype of STS for which cytotoxic chemotherapy has limited effectiveness. TAZ, an FDA-approved EZH2 inhibitor, has shown single-agent clinical activity and a favorable safety profile in patients with metastatic or locally advanced ES. In preclinical studies, TAZ has shown synergistic antitumor activity with DOX, which is often used as frontline treatment for STS. Here, we present results of the phase 1b study (NCT04204941), designed to assess the recommended phase 3 dose (RP3D), safety, and efficacy of TAZ + DOX in patients with advanced STS. Methods: The open-label, phase 1b portion of this study enrolled adult patients with previously untreated advanced STS. A standard 3 + 3 design was used to assess TAZ 400 mg, 600 mg, and 800 mg orally twice daily in combination with DOX (75 mg/m2 intravenously on day 1 of each cycle, for up to 6 cycles) as frontline therapy. Dose-limiting toxicities (DLTs) were predefined in the protocol. The RP3D of TAZ was determined by Scientific Review Committee review of the safety and pharmacokinetic data from the phase 1b trial, with a target DLT rate of < 33%. Results: As of February 1, 2021, 16 patients are enrolled, including 2 with ES; 10 are still receiving TAZ + DOX and 6 have discontinued (5 due to disease progression, 1 due to patient withdrawal). The median age was 49.5 years (range, 29–82) and all had unresectable STS. Median (range) time on treatment was 13 (0.1–51.1+) weeks across all dose levels evaluated. Two DLTs, both of febrile neutropenia, were observed, one in the TAZ 600 mg + DOX cohort (n = 1/6, 17%), and one in the TAZ 800 mg + DOX cohort (n = 1/3, 33%). When used in combination with DOX, the RP3D of TAZ was 800 mg. Grade 3 or 4 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 13/16 (81.3%) patients. The most common (≥ 20%) TR-TEAEs were neutropenia (n = 11, 69%), anemia (n = 10, 63%), fatigue (n = 10, 63%), stomatitis (n = 9, 56%), nausea (n = 8, 50%), febrile neutropenia (n = 7, 44%), constipation (n = 6, 38%), vomiting (n = 6, 38%), and decreased appetite (n = 5, 31%). TR-TEAEs were defined as attributable to either study agent. Conclusions: The combination of TAZ + DOX was generally well tolerated in this dose finding study in patients with advanced STS. The RP3D to be tested in the phase 3 randomized, double blind, placebo controlled study is TAZ 800 mg twice daily + DOX. The safety profile of this combination is consistent with the respective safety information for TAZ and for DOX. The TR-TEAEs include known toxicities of DOX or TAZ. Further comparison with DOX + placebo in the phase 3 trial will aid in assessing efficacy and safety of the combination of TAZ + DOX. The global phase 3 confirmatory trial will enroll patients with ES who have unresectable disease and have had no prior systemic therapy. Clinical trial information: NCT04204941.

Efficacy and safety of toripalimab combined with doxorubicin as first-line treatment for metastatic soft tissue sarcomas: an observational study.

Programmed cell death protein 1 (PD-1) inhibitors have demonstrated promising activity among patients with advanced soft tissue sarcomas (STS) in phase II trials. The purpose of this study was to assess the efficacy and safety of toripalimab (a novel PD-1 inhibitor) combined with doxorubicin as first-line treatment in patients with metastatic STS between December 2018 and September 2019. A total of 30 patients with metastatic STS were included and followed up retrospectively. One patient had complete response (CR), 10 patients obtained partial response, and 13 patients achieved stable disease. The objective response rate was 36.7% and the disease control rate was 80%. The median progression-free survival (PFS) was 8 months (95% CI: 6.30–10.64). The most frequent any grade adverse events were nausea (66.7%), fatigue (60%), and vomiting (40%). Neutropenia (20%) was the most common grade 3/4 adverse events, followed by leucopenia (13.3%) and febrile neutropenia (6.7%). No death related to treatment was observed during the drugs administration. Toripalimab combined with doxorubicin is effective in patients with metastatic STS as first-line treatment with manageable adverse events.

Impact of Smoking History on Pulmonary Metastasis-free Survival in Patients With Soft-tissue Sarcoma.

Although smoking history is predictive of poor pulmonary metastasis-free survival (PMFS) in patients with epithelial tumors, the impact of smoking history on PMFS in those with soft-tissue sarcoma (STS) is not known. Patients undergoing treatment for STS at our institutes between 2008 and 2017 were enrolled. Patients were excluded if they had metastatic lesion, or had a histopathological classification demonstrating small round-cell sarcoma. The impact of smoking history on PMFS and overall survival was examined with multivariate analysis using a Cox proportional hazards model. A total of 250 patients were retrospectively reviewed. Patients with smoking history had worse PMFS on multivariate analysis (hazard ratio=2.00, 95% confidence interval=1.12-3.60). On the other hand, smoking history did not significantly affect overall survival (hazard ratio=1.26, 95% confidence interval=0.61-2.58). Patients with STS need to be followed-up by frequent clinical assessments if they have a smoking history.

PO49: Quality Evaluation and Curative Effect Observation of Individualized 3D Printing Template Combined with CT Guided 125I Seed Implantation in the Treatment of Inoperable Limb Soft Tissue Sarcoma

Purpose: To evaluate the dosimetric parameters of 3D printing individualized template combined with CT guided 125I seed implantation, and to explore the efficacy and safety of radioactive 125I seed interstitial implantation in the treatment of unresectable soft tissue sarcoma.

Miscellaneous PO49: Quality Evaluation and Curative Effect Observation of Individualized 3D Printing Template Combined with CT Guided 125I Seed Implantation in the Treatment of Inoperable Limb Soft Tissue Sarcoma

Miscellaneous PO49: Quality Evaluation and Curative Effect Observation of Individualized 3D Printing Template Combined with CT Guided 125I Seed Implantation in the Treatment of Inoperable Limb Soft Tissue Sarcoma

The Lymph-Sparing Quotient: A Retrospective Risk Analysis on Extremity Radiation for Soft Tissue Sarcoma Treatment.

Simple SummarySoft tissue sarcomas, a heterogenous group of tumors with a mesenchymal origin, are mostly located in the extremities and are commonly treated with surgery and radiotherapy. Using opportunities of reducing long-term therapy-related side effects in soft tissue sarcoma treatment is an important task for all physicians involved in soft tissue sarcoma treatment. The extent of lymph-sparing volume in adjuvant radiation therapy of extremity soft tissue sarcoma as a risk factor for lymphedema was analyzed in this study. Patients with a low lymph-sparing volume showed an increased risk of lymphedema in this retrospective study. Maximizing the potential oncologically justifiable lymph-sparing volume should be considered to reduce the risk of high-grade lymphedema when applying RT to extremities.Radiation therapy (RT) for extremity soft tissue sarcoma is associated with lymphedema risk. In this study, we analyzed the influence of lymph-sparing volume on the lymphedema occurrence in patients who received adjuvant extremity RT. The lymph-sparing quotient (LSQ) was calculated by dividing the lymph-sparing volume by the total extremity volume with double weightingfor the narrowest lymph-sparing region. A total of 34 patients were enrolled in this analysis. The median applied total radiation dose was 66.3 Gy in 36 fractions. Acute lymphedema appeared in 12 patients (35%). Most of them (n = 8) were lymphedema grade 1 and five patients had grade 2 to 3 lymphedema. Chronic lymphedema appeared in 22 patients (65%). 17 of these patients had at least a grade 2 lymphedema. In 13 of 14 patients with an LSQ ≤ 0.2 and 11 of 20 patients with an LSQ > 0.2, an acute or chronic lymphedema ≥ grade 2 was observed. A Kaplan–Meier Analysis of the two groups with the endpoint of a two-year lymph edema-free survival (=2-YLEFS) was estimated with an univariate, significant result (2-YLEFS LSQ ≤ 0.2 vs. LSQ > 0.2: 0% vs. 39%; p = 0.006; hazard ratio LSQ ≤ 0.2 vs. > 0.2 2-YLEFS 2.822 (p = 0.013); 95% confidence interval (CI): 1.24–6.42). Maximizing the potential oncologically-justifiable lymph-sparing volume should be considered to reduce the risk of high-grade lymphedema when applying RT to extremities.

Cross-cultural adaption, translation and validation of the Toronto extremity salvage score (TESS) for patients in German-speaking countries.

SummaryObjectiveThe preferred treatment for malignant bone and soft tissue tumors is limb salvage surgery; the Toronto extremity salvage score (TESS) is commonly used to measure physical functioning of the affected extremity. The aims of this study were to translate and culturally adapt the German version of the TESS, as well as to explore its convergent reliability, validity and re-test reliability.Study designPatients (n = 50) 32 lower extremity (LE) and 18 upper extremity (UE) were asked to fill out the German TESS two times (t1: clinical visit, t2: regular email) and the SF-36 once.MethodsThe TESS questionnaires were translated from English into German, back translated into English, and culturally adapted. The reliability was assessed with Cronbach’s alpha (α). The validity was measured with the SF-36 physical component score and TESS using the Spearman rank correlation coefficient (r). Furthermore, the test-retest reliability was calculated with the intraclass correlation coefficient (ICC).ResultsInternal consistency for both questionnaires was excellent (LE t1: α = 0.924, t2: α = 0.952; UE t1: α = 0.957, t2: α = 0.898). A statistically significant correlation was found between the SF-36 physical component scale and the German TESS (LE r = 0.741, UE r = 0.713). The ICC between baseline (t1) and re-test (t2) was 0.952 and 0.871 for the lower and upper extremities, respectively.ConclusionInitial evidence demonstrated that the German TESS is a valid and reliable instrument for use with patients after surgical treatment of malignant bone or soft tissue sarcoma.Supplementary InformationThe online version of this article (10.1007/s00508-021-01865-4) contains supplementary material, which is available to authorized users.

Efficacy and Cost-Benefit Analysis of Magnetic Resonance Imaging in the Follow-Up of Soft Tissue Sarcomas of the Extremities and Trunk.

There is no consensus regarding follow-up after soft tissue sarcoma (STS) treatment. This study examines the efficacy and the cost-benefit of MRI imaging for discovering recurrence. A retrospective analysis was performed, collecting data on patient demography, tumor characteristics, treatment, and follow-up. Imaging was correlated to the clinical course, and sensitivity, specificity, and predictive values were calculated. The number needed to screen and costs of finding recurrence are reported. Amongst 216 sarcomas, 73 (35%) exhibited local recurrence during a follow-up of 5.3 ± 3.5 years. 173 entities had complete MRI follow-up with 58 (34%) local recurrences. Thirty-three (57%) were discovered by MRI, 8 (14%) by clinical presentation, and 17 (29%) simultaneously. There was a sensitivity of 100.00%, a specificity of 89%, a positive predictive value of 32%, and a negative predictive value of 100% for detecting local recurrence with MRI. Our data confirm the modalities and intervals proposed by the German guidelines for sarcoma care. The recommended MRI intervals should not be extended. MRI is more cost-effective than clinical examination; still, both modalities should be performed together to discover the maximum number of recurrences.

Traveling to Receive Treatment for Extremity Soft Tissue Sarcomas: Is it worth the drive?

Regionalization of sarcoma care may improve outcomes. Concerns exist regarding the burdens of travel and its effects on care. We evaluate the presence of a "distance bias". Retrospective cohort study of patients with extremity soft tissue sarcoma (stage I-III)within theNCDB. Travel distance (TD) and hospital volume (VOL) were categorized into quartiles. Alternating statistical models were used for analysis. 1,035 hospitals contributed 11,979 cases. Median and maximum VOL were 5 and 45 cases/year. VOL quartiles were "low-volume" (LV) (892 hospitals, < 3 cases/yr.), "intermediate low-volume" (ILV) (89, 3-5 cases/yr.), "intermediate high-volume" (IHV) (39, 6-12 cases/yr.), and "high-volume" (HV) (15, > 12 cases/yr.). TD quartiles: "short-travel" (ST) (< 8 mi), "intermediate-short travel" (IST) (8-17), "intermediate long-travel" (ILT) (18-49), and "long-travel" (LT) (> 50). VOL but not TD is associated with improved survival [HR 0.65 (CI 0.52-0.83)] and rate of R0 resection [1.87 (CI 1.4-2.5)] but has no effect on amputation rates. Matched analyses demonstrate similar results. Hospital volume but not distance traveled to treatment facility is associated with improved survival and R0 resections for extremity soft tissue sarcomas. Despite the inconveniences of travel, patients may benefit from treatment at high volume centers.

Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression.

Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.

Biomolecular interaction mechanism of an anticancer drug, pazopanib with human serum albumin: a multi-spectroscopic and computational approach

Pazopanib (PZP) is a multi-targeting tyrosine kinase inhibitor and is currently approved by FDA for the treatment of soft tissue sarcoma and renal cancer. Molecular interaction mechanism of PZP with human serum albumin (HSA) was explored under simulated physiological conditions (pH = 7.4), using fluorescence and UV absorption spectroscopy along with computational methods. Based on the inverse correlation between the Stern-Volmer constant (Ksv ) and temperature, it was concluded that PZP quenched the protein fluorescence through static quenching mechanism. This was also confirmed from the UV-vis absorption spectral results. Moderate binding affinity between PZP and HSA was evident from the Ka values (5.51 − 1.05 × 105 M−1) while PZP-HSA complex formation was driven by hydrophobic and van der Waals interactions as well as hydrogen bonds, as revealed by positive entropy change (ΔS = +98.37 J mol−1 K−1) and negative enthalpy change (ΔH = −60.31 kJ mol−1). Three-dimensional fluorescence spectral results disclosed microenvironmental perturbations around Trp and Tyr residues of the protein upon PZP binding. Interestingly, the addition of PZP to HSA significantly protected the protein against thermal stress. Competitive drug displacement results obtained with warfarin, phenylbutazone and diazepam elucidated Sudlow's Site I, positioned in subdomain IIA of HSA, as the preferred binding site of PZP which was well supported by molecular docking analysis, while molecular dynamics simulation results suggested the stability of the PZP-HSA complex. Communicated by Vsevolod Makeev

Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas.

Soft tissue sarcoma (STS) constitutes a rare group of heterogeneous malignancies. Effective treatment options for most subtypes of STS are still limited. As a result, especially in metastatic disease, prognosis is still dismal. The ligands for the activating immunoreceptor NKG2D (NKG2DL) are commonly expressed in STS, but generally absent in healthy tissues. This provides the rationale for utilization of NKG2DL as targets for immunotherapeutic approaches. We here report on the preclinical characterization of bispecific fusion proteins (BFP) consisting of the extracellular domain of the NKG2D receptor fused to Fab-fragments directed against CD3 (NKG2D-CD3) or CD16 (NKG2D-CD16) for treatment of STS. After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNγ as well as granule associated proteins, resulting in potent target cell lysis. In addition, the stimulatory capacity of the constructs to induce T and NK cell activation was analyzed in heavily pretreated STS patients and found to be comparable to healthy donors. Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.

LncRNA HAR1B has potential to be a predictive marker for pazopanib therapy in patients with sarcoma.

Bone and soft-tissue sarcomas are rare and are highly heterogeneous mesenchymal malignancies. It is therefore challenging to acquire the clinical data of patients with specific histological subtypes of sarcoma using large clinical trials, and there is a need to further establish the diagnosis and treatment of sarcomas. The results of the current study revealed that long non-coding RNA (lncRNA) highly accelerated region 1B (HAR1B) may serve as a predictive biomarker for pazopanib treatment in bone and soft-tissue sarcomas. Using multiplex reverse transcription-quantitative PCR and microarray analyses, the results demonstrated that HAR1B and HOX transcript antisense RNA (HOTAIR) were differentially expressed in pazopanib-sensitive cells and responders. It was further revealed that small interfering RNA-knockdown of HAR1B led to an increased resistance to pazopanib in sarcoma cell lines. Gene expression profiles associated with pazopanib sensitivity included cellular molecular pathways, such as genes involved in von-Willebrand factor-related signaling. The current study demonstrated that lncRNA HAR1B expression in sarcoma cell lines affected cellular sensitivity to pazopanib in patients with sarcoma.

Imaging response evaluation after neoadjuvant treatment in soft tissue sarcomas: Where do we stand?

Soft tissue sarcomas (STS) represent a broad family of rare tumours for which surgery with radiotherapy represents first-line treatment. Recently, neoadjuvant chemo-radiotherapy has been increasingly used in high-risk patients in an effort to reduce surgical morbidity and improve clinical outcomes. An adequate understanding of the efficacy of neoadjuvant therapies would optimise patient care, allowing a tailored approach. Although response evaluation criteria in solid tumours (RECIST) is the most common imaging method to assess tumour response, Choi criteria and functional and molecular imaging (DWI, DCE-MRI and 18F-FDG-PET) seem to outperform it in the discrimination between responders and non-responders. Moreover, the radiologic-pathology correlation of treatment-related changes remains poorly understood. In this review, we provide an overview of the imaging assessment of tumour response in STS undergoing neoadjuvant treatment, including conventional imaging (CT, MRI, PET) and advanced imaging analysis. Future directions will be presented to shed light on potential advances in pre-surgical imaging assessments that have clinical implications for sarcoma patients.

PD-L1 tumour expression is predictive of pazopanib response in soft tissue sarcoma

BackgroundPazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy.MethodsTumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%.ResultsAmong the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8–5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1–9% (n = 3, 4.5%), 10–49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45–5.56, P = 0.006).ConclusionWe identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.