Stereotactic body radiotherapy for recurrent and oligometastatic soft tissue sarcoma.

BACKGROUND: Soft tissue sarcoma (STS) is a malignant tumor of highly heterogeneous mesenchymal origin. STS has a biological pattern and clinical transformation with localized invasive growth and is susceptible to hematogenous metastasis. Local therapeutic strategies may treat recurrent and oligometastatic STS, including surgery and radiation therapy. This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for recurrent and oligometastatic STS. METHODS: We retrospectively analyzed 37 recurrent and oligometastatic STS patients with 58 lesions treated with SBRT from 2009 to 2019 at our institution. Oligometastatic is defined as metastatic lesions less than or equal to 3. The primary endpoint was local control (LC); secondary endpoints were survival and toxicity. RESULTS: The median follow-up was 21.0 months (3.0 to 125.0 months). Among 37 patients, 18 were recurrent patients, and 19 were oligometastatic patients. Median LC was 25.0 months (95% CI 20.0-45.0). The 1-, 2-, and 3-year LC rates were 80.2%, 58.3%, and 46.6%, respectively. Median overall survival (OS) was 24.0 months (95% CI 13.0-28.0), and the survival rates after SBRT were 71.5%, 40.0%, and 29.1% at 1, 2, and 3-year, respectively. Median progression-free survival (PFS) was 10.0 months (95% CI 8.0-15.0 months), PFS rate after SBRT was 43.6%, 26.8%, and 18.4% at 1, 2, and 3 years, respectively. Late grade 3 radiation dermatitis was observed in one patient (2.7%). Using univariate and multivariate COX analysis, better OS, PFS, and LC were obtained in the histologic grade 1(G1) group, and tumor size and a number of lesions influenced LC. CONCLUSIONS: SBRT is a safe and effective treatment for patients with recurrent and oligometastatic STS. Histological grade influences local control and survival. SBRT may be a promising treatment option for recurrent and oligometastatic STS.

Interim results of a real-world observational study of eribulin in soft tissue sarcoma including rare subtypes.

BACKGROUND: Although eribulin is used to treat soft tissue sarcomas (STSs), treatment data for rare subtypes are limited. We conducted a post-marketing surveillance study to assess safety and efficacy of eribulin in STS patients stratified by subtype. METHODS: Japanese patients (n = 256) with advanced or metastatic STS receiving eribulin treatment were monitored for treatment status, adverse events, diagnostic imaging, and clinical outcomes at 3 months and 1 year. Interim analysis was performed. Patients will be monitored up to 2 years. RESULTS: Interim analysis included 3-month (n = 255), imaging (n = 226), and 1-year (n = 105) data. STS subtype distribution was normal. Median number of eribulin cycles was 3.0 (range: 1-17 cycles). Among patients with imaging data, best overall tumor response (12 weeks) was partial response, 7.5% (n = 17); stable disease, 34.5% (n = 78); and stable disease ≥11 weeks, 10.2% (n = 23). Overall response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) for all patients were 7.5%, 42.0% and 17.7%, respectively. ORR, DCR, and CBR were 10.3%, 32.0% and 16.5%, respectively, for patients with STS subtypes other than liposarcoma and leiomyosarcoma and included responses from patients with rare STS subtypes. Adverse drug reactions (ADRs) occurred in 211 (82.7%) patients (42 [16.5%] patients had serious ADRs), and none led to death. ADRs leading to drug withdrawal and dose reduction occurred in 27 (10.6%) and 55 (21.6%) patients, respectively. CONCLUSION: Eribulin was generally well tolerated and showed antitumor activity against STSs, including rare subtypes that currently have few treatment options. CLINICAL TRIAL NUMBER: NCT03058406 (ClinicalTrials.gov).

Optimal surgical margin for infiltrative soft tissue sarcomas: Assessing the efficacy of excising beyond the infiltration.

BACKGROUND: Tumor infiltration in soft tissue sarcoma (STS) is known to correlate with an inadequate surgical margin and poor local control. This study aims to determine whether the radiological infiltration (R-inf) in STS cor relates with histological infiltration (H-inf) and to devise methods to determine a resection margin for infiltrative STS. METHODS: We reviewed the medical records of 145 patients with high-grade STS. We measured the R-inf on short-T1 inversion recovery or gadolinium-enhanced fat-suppressed (GdFS) magnetic resonance imaging. In addition, we assessed H-inf as the infiltrative growth of atypical tumor cells. The local control rate (LCR) was assessed using the Kaplan-Meier method. RESULTS: A statistically significant positive correlation was found between H-inf and R-inf (P < 0.0001). The R-inf obtained from the GdFS images exhibited a stronger correlation with H-inf than that obtained from the short-T1 inversion recovery images. Univariate and multivariate analyses revealed that a positive H-inf significantly correlated with a poor LCR. Moreover, the contaminated margins, which included intrainfiltration margins, significantly correlated with a poor LCR compared with the wide margins. CONCLUSIONS: R-inf as assessed by the GdFS images significantly correlates with H-inf, suggesting that we should exercise the infiltrative STS beyond their R-infs detected by the GdFS images.

Systematic Review of the Gonadotoxicity and Risk of Infertility of Soft Tissue Sarcoma Chemotherapies in Pre- and Postpubertal Females and Males.

Increasing awareness of gonadotoxicity in cancer treatments and infertility risk is essential for counseling young cancer patients. While fertility preservation options are available in many countries, limited data on gonadotoxicity hinder recommendations, especially for soft tissue cancers. This review, part of the FertiTOX project (www.fertitox.com), organized by FertiPROTEKT (www.fertiprotekt.com), aims to address this knowledge gap to improve fertility preservation guidance. We performed a systematic literature search on gonadotoxicity in soft tissue sarcoma (STS) cancer treatments. Only patients without metastases or recurrent disease were considered. "Suspected infertility" was defined based on low ovarian reserve parameters, low inhibin B levels, high gonadotropin concentration, gonadal dysfunction, amenorrhea, oligomenorrhea, azoospermia, or oligozoospermia due to limited infertility data. The study quality was assessed using the Newcastle-Ottawa Scale. The search yielded 3309 abstracts, with 138 undergoing full-text analysis. Eight studies on STS were included. Suspected infertility was observed in 20 of 28 females (71.4%, range 0-100%) and 38 of 63 males (60.3%, range 34.8-100%) with STS. Six of the eight studies received high-quality scores on the NOS, while two received a fair score. Our data suggest a high risk of infertility from chemotherapy in pre- and postpubertal STS survivors. This underscores the importance of considering fertility preservation measures when counseling these patients.

A Review on Canine and Human Soft Tissue Sarcomas: New Insights on Prognosis Factors and Treatment Measures.

Soft tissue sarcomas (STSs) represent a diverse group of tumors arising from mesenchymal cells, affecting both humans and animals, including dogs. Although STSs represent a class of rare tumors, especially in humans, they pose significant clinical challenges due to their potential for local recurrence and distant metastasis. Dogs, as a model for human STSs, offer several advantages, including exposure to similar environmental risk factors, genetic diversity among breeds, and the spontaneous development of tumors. Furthermore, canine tumors closely mimic the heterogeneity and complexity of human tumors, making them valuable for research into disease progression and treatment effectiveness. Current treatment approaches for STSs in both dogs and humans primarily involve surgery, radiation therapy, and chemotherapy, with treatment decisions based on tumor characteristics and patient factors. However, the development of novel therapeutic strategies is essential, given the high failure rate of new drugs in clinical trials. To better design new tailored treatments, comprehension of the tumor microenvironment (TME) is fundamental, since it plays a crucial role in STS initiation and progression by modulating tumor behavior, promoting angiogenesis, and suppressing immune responses. Notably, TME features include cancer-associated fibroblasts (CAFs), extracellular matrix (ECM) alterations, and tumor-associated macrophages (TAMs) that, depending on their polarization state, can affect immune responses and thus the patient's prognosis. In this review, new therapeutical approaches based on immunotherapy will be deeply explored as potential treatment options for both dogs and humans with STSs. In conclusion, this review provides an overview of the current understanding of STSs in dogs and humans, emphasizing the importance of the TME and potential treatment strategies.

Perfusion-weighted imaging with dynamic contrast enhancement (PWI/DCE) morphologic, qualitative, semiquantitative, and radiomics features predicting undifferentiated pleomorphic sarcoma (UPS) treatment response.

Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft tissue sarcomas. This study determined the value of perfusion-weighted imaging with dynamic-contrast-enhancement (PWI/DCE) morphologic, qualitative, and semiquantitative features for predicting UPS pathology-assessed treatment effect (PATE). This retrospective study included 33 surgically excised extremity UPS patients with pre-surgical MRI. Volumetric tumor segmentation from PWI/DCE was obtained at Baseline (BL), Post-Chemotherapy (PC), and Post-Radiation Therapy (PRT). The surgical specimens' PATE separated cases into Responders (R) (≥ 90%, 16 patients), Partial-Responders (PR) (89 - 31%, 10 patients), and Non-Responders (NR) (≤ 30%, seven patients). Seven semiquantitative kinetic parameters and maps were extracted from time-intensity curves (TICs), and 107 radiomic features were derived. Statistical analyses compared R vs. PR/NR. At PRT, 79% of R displayed a "Capsular" morphology (P = 1.49 × 10-7), and 100% demonstrated a TIC-type II (P = 8.32 × 10-7). 80% of PR showed "Unipolar" morphology (P = 1.03 × 10-5), and 60% expressed a TIC-type V (P = 0.06). Semiquantitative wash-in rate (WiR) was able to separate R vs. PR/NR (P = 0.0078). The WiR radiomics displayed significant differences in the first_order_10 percentile (P = 0.0178) comparing R vs. PR/NR at PRT. The PWI/DCE TIC-type II curve, low WiR, and "Capsular" enhancement represent PRT patterns typically observed in successfully treated UPS and demonstrate potential for UPS treatment response assessment.

New strategies in soft tissue sarcoma treatment.

Soft tissue sarcomas (STS) have long been a formidable challenge in oncology, partly because of their rarity and diversity, which complicates large-scale studies and slows the advent of new treatments. Traditionally anchored by anthracycline-based chemotherapy, the landscape of STS treatment hasn't shifted dramatically in the past twenty years. However, recent strides in research are starting to paint a more hopeful picture. Leveraging advanced molecular profiling, researchers are now tailoring treatments to the unique genetic makeup of tumors, with targeted therapies showing promise. Innovations such as NTRK inhibitors for NTRK-rearranged sarcomas and gamma-secretase inhibitors for desmoid tumors are changing clinical practices. The rise of immunotherapy, including novel agents like LAG-3 inhibitors and bifunctional proteins that target both TGF-ß and PD-L1, offers new avenues for treatment, particularly when combined with traditional therapies like chemotherapy. Meanwhile, the approval of epigenetic treatments for specific sarcoma subtypes heralds a new wave of strategy based on histological specificity, which could lead to more personalized and effective care. While challenges remain, the field of STS treatment is evolving, driven by a deeper understanding of the disease's biological underpinnings and a commitment to innovative research approaches.

Patient-reported outcomes in randomized clinical trials of systemic therapy for advanced soft tissue sarcomas in adults: A systematic review.

BACKGROUND: This systematic review evaluates reporting of patient-reported outcomes (PROs) within randomized clinical trials (RCTs) for advanced soft tissue sarcoma (STS) patients. METHODS: A systematic literature search from January 2000 - August 2022 was conducted for phase II/III RCTs evaluating systemic treatments in adult patients with advanced STS. Quality of PRO reporting was assessed using the CONSORT PRO extension. RESULTS: Out of 7294 abstracts, 59 articles were included; comprising 43 RCTs. Only 15 RCTs (35%) included PROs, none as primary endpoints. Only 10 of these RCTs reported PROs, either in the primary (6/10) or secondary publication (1/10) or in both (3/10), with a median time interval of 23 months. The median CONSORT PRO adherence score was 5.5/14, with higher scores in publications focusing exclusively on PROs. CONCLUSION: These results highlight the need for improved and more consistent PRO reporting to inform patient care in the setting of advanced STS.

Therapeutic advances in leiomyosarcoma.

Leiomyosarcoma is an aggressive mesenchymal malignancy and represents one of the most common subtypes of soft tissue sarcomas. It is characterized by significant disease heterogeneity with variable sites of origin and diverse genomic profiles. As a result, the treatment of advanced leiomyosarcoma is challenging. First-line therapy for metastatic and/or unresectable leiomyosarcoma includes anthracycline or gemcitabine based regimens, which provide a median progression-free survival time of about 5 months and overall survival time between 14-16 months. Effective later-line therapies are limited. Molecular profiling has enhanced our knowledge of the pathophysiology driving leiomyosarcoma, providing potential targets for treatment. In this review, we explore recent advances in our understanding of leiomyosarcoma tumor biology and implications for novel therapeutics. We describe the development of clinical trials based on such findings and discuss available published results. To date, the most promising approaches for advanced leiomyosarcoma include targeting DNA damage repair pathways and aberrant metabolism associated with oncogenesis, as well as novel chemotherapy combinations. This review highlights the recent progress made in the treatment of advanced leiomyosarcoma. Ongoing progress is contingent upon further development of clinical trials based on molecular findings, with careful consideration for clinical trial design, strong academic collaborations, and prospective correlative analyses.

Telemedicine in Care of Sarcoma Patients beyond the COVID-19 Pandemic: Challenges and Opportunities.

BACKGROUND: The COVID-19 pandemic has created a challenging environment for sarcoma patients. Most oncology societies published guidelines or recommendations prioritizing sarcoma patients and established telehealth as an efficient method of approaching them. The aim of this review is the assessment of current evidence regarding the utilization of telemedicine in diagnosis, treatment modalities, telerehabilitation and satisfaction among sarcoma patients and healthcare providers (HP). METHODS: This systematic review was carried out using the databases PubMed and Ovid MEDLINE according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: The application of telemedicine to the management of sarcoma has yielded improved clinical and psychological outcomes. Specifically, significant progress has been demonstrated in the areas of tele-oncology and telerehabilitation during the last decade, and the COVID-19 outbreak has accelerated this transition toward them. Telehealth has been proven efficient in a wide spectrum of applications from consultations on physical therapy and psychological support to virtual care symptom management. Both HP and patients reported satisfaction with telehealth services at levels comparable to in-person visits. CONCLUSIONS: Telehealth has already unveiled many opportunities in tailoring individualized care, and its role in the management of sarcoma patients has been established in the post-COVID-19 era, as well.

Correlation between 18F-FDG PET-derived parameters and quantitative pathological characteristics of soft tissue sarcoma.

Background: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) has been widely used for evaluating patients with soft tissue sarcoma (STS). However, uncertainties and overlap among individuals may be observed, and the relevance of these findings remains to be further explored. The present study was aimed at investigating the correlation between PET metabolic parameters and quantitative pathological characteristics in STS. Methods: We retrospectively collected 39 patients with STS who underwent 18F-FDG PET/computed tomography (CT) examination before treatment. Metabolic parameters including the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and intratumoral FDG uptake heterogeneity (IFH) were measured. Histological grading was performed according to the French Federation of Cancer Centers grading system. Continuous staining of tissue sections and digital quantitative analysis methods were used, the characteristics of tumor nucleated cells were observed through hematoxylin-eosin staining, and the expression of CD163, CD68, CD8, and CD4 in tumor tissues was determined by immunohistochemistry (IHC), then the correlation between FDG metabolic parameters and the above quantitative pathological characteristics in patients with STS were evaluated. Results: The SUVmax of 18F-FDG PET/CT in STS was positively correlated with the total nuclear area (r=0.355, P=0.027). SUVmax was also positively correlated with the expression levels of CD163, CD68, CD8, and CD4 (r=0.582, 0.485, 0.343, and 0.324, with P<0.001, 0.002, 0.032, and 0.044, respectively), but was not significantly correlated with cell count and mean nuclear area (all P>0.05). However, MTV, TLG, and IFH were not significantly correlated with the above quantitative pathological characteristics. Further multivariate logistic regression analysis indicated that only CD163 expression and histological grade were independently correlated with SUVmax. Moreover, SUVmax remained positively correlated with CD163 expression in the low-grade STS (r=0.820, P=0.001) and high-grade STS groups (r=0.430, P=0.028). Conclusions: 18F-FDG uptake was positively correlated with the quantitative pathological features of soft tissue tumors. SUVmax may be a meaningful method reflecting the level of M2 macrophage infiltration and may provide additional valuable information for preclinical evaluation of STS.

Neoadjuvant radiotherapy for soft tissue sarcoma in China: a preliminary result.

Background: Neoadjuvant radiotherapy (RT) for soft tissue sarcoma (STS) is widely used abroad, but rarely reported in China. We assessed the preliminary clinical outcomes of preoperative RT followed by surgery in patients with STS. Methods: A total of 19 patients (14 male, 5 female) with intermediate- or high-grade primary STS were treated with neoadjuvant RT in 2-Gy fractions over 25 sessions for a total dose of 50 Gy. Surgical resection was then performed. The pathologic specimens were reviewed for percentage of residual tumor cells. And the skin complications, wound complications and local recurrence and distant metastasis were also evaluated. Results: After neoadjuvant RT, 2 patients had progressive disease (PD), 6 showed a partial remission (PR), and 11 demonstrated stable disease (SD). The objective response rate (ORR) was 31.6%, and the disease control rate (DCR) was 89.5%. The median follow-up was 14.3 months (11.9-24.7 months). Six patients (31.6%) had wound complications: 3 cases of epidermal complications and 3 of severe complications (15.8%) comprising 2 cases of skin flap necrosis, and 1 case of local hematoma. The European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) histopathological response score was used to evaluate the post-RT response. A total of 9 patients (47.4%) achieved pathological complete remission (pCR). No recurrence was found, but metastasis occurred in 2 patients (10.5%) in the preliminary follow-up. Conclusions: Neoadjuvant RT for STS has a quietly high DCR and pathological remission rate. Surgical wound complications can be controlled after neoadjuvant RT.

Gemcitabine Plus Anlotinib Is Effective and Safe Compared to Gemcitabine Plus Docetaxel in Advanced Soft Tissue Sarcoma.

Objective: The aim of this study is to compare gemcitabine (G) plus docetaxel (D) versus G plus anlotinib (A) for advanced soft tissue sarcoma (STS). Methods: We retrospectively investigated 122 patients with locally advanced or metastatic STS who were treated with either G+D or G+A between July 2016 and October 2021 and compared the efficacy and toxicity of G+D and G+A. The primary endpoints were median progression-free survival (PFS) and the proportion of patients with grade ≥3 adverse events. We also analyzed differences in the clinical efficacy of G+D and G+A in leiomyosarcoma, and the differences in the clinical efficacy of G+D and G+A as first-line therapy. Results: Overall, 122 patients were included (81 patients receiving G+D and 41 patients receiving G+A) with a median age of 55 years. The main histological types are leiomyosarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma. After a median follow-up of 25 months, PFS did not differ between patients treated with G+D and those treated with G+A (median PFS: 5.8 months and 6.8 months, p = 0.39), and overall survival (OS) was similar (median OS: 14.7 vs. 13.3 months, p = 0.75) with a similar objective response rate (18.5% vs. 14.6%, p = 0.17), whereas the proportion of patients with grade ≥3 adverse events treated with G+D was significantly higher than those treated with G+A (68% vs. 44%, p < 0.05). Subgroup analysis of leiomyosarcoma patients (47.5% of the patients) and first-line treatment patients (46.7% of the patients) shows that PFS was not significantly different between the two groups (LMS: median PFS: 6.5 months vs. 7.5 months, p = 0.08; first-line treatment: median PFS: 6.2 months vs. 7.1 months, p = 0.51). Conclusion: Compared with gemcitabine plus docetaxel for advanced STS, gemcitabine plus anlotinib achieved a similar response rate on median PFS and OS, but lower toxicity. These results suggest that gemcitabine plus anlotinib may be an effective and safe strategy for advanced STS.

Intratumoral injection of holmium-166 microspheres as neoadjuvant therapy of soft tissue sarcomas in dogs.

Introduction: Minimally invasive microbrachytherapy is in development to treat solid tumors by intratumoral injection of (radioactive) holmium-166 (166Ho) microspheres (MS). A high local dose can be administered with minimal damage to surrounding tissue because of the short soft tissue penetration depth of 166Ho beta radiation. We aimed to prospectively evaluate the safety and efficacy of 166Ho microbrachytherapy in client-owned canine patients with soft tissue sarcomas (STS). Methods: We included seven dogs with STS not suitable for local excision due to tumor size and/or location. 166HoMS were suspended in a carrier fluid and multiple needle-injections were performed in predetermined tumor segments to maximize tumor coverage. Tumor response was evaluated using 3D caliper and CT measurements. Follow-up further included monitoring for potential side effects and registration of subsequent treatments and survival, until at least two years after treatment. Results: Delivered radioactive doses ranged from 70 to 969 Gy resulting in a mean tumor volume reduction of 49.0 ± 21.3% after 33 ± 25 days. Treatment-related side effects consisted of local necrosis (n = 1) and ulceration of the skin covering the tumor (n = 1), which resolved with basic wound care, and surgical excision of residual tumor, respectively. Residual tumor was surgically resected in six patients after 22-93 days. After a mean follow-up of 1,005 days, four patients were alive, two patients were euthanized because of unrelated causes, and one patient was euthanized because of disease progression after the owner(s) declined subsequent surgical treatment. Conclusion: 166Ho microbrachytherapy was a safe and effective neoadjuvant treatment option for canine patients with STS.

Efficacy and safety of apatinib in patients with untreated or chemotherapy-refractory soft tissue sarcoma: a multicenter, phase 2 trial.

Background: Anti-angiogenic agents have been reported to exert promising clinical activity for advanced soft tissue sarcoma (STS). Apatinib, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, is effective and safe for various solid tumors, but its role in STS remains unclear. The aim of this study was to explore the efficacy and safety of apatinib in patients with untreated or chemotherapy-refractory STS. Methods: In this multicenter, single-arm, phase 2 trial, patients aged 18-70 years with untreated or chemotherapy-refractory STS were enrolled and received 500 mg apatinib per day. During treatment, patients were followed up with imaging every 8 weeks. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), overall survival (OS), and adverse events (AEs), which were graded following the National Cancer Institute common terminology criteria for AEs version 4.03. Results: From June 2017 to October 2018, 53 patients were enrolled, 51 of whom received at least one dose of apatinib. Of the 53 patients, 41 (77.4%) had chemotherapy-refractory disease. The median follow-up was 13.3 months. The 6- and 12-month PFS rates were 46.8% and 25.2%, respectively, with a median PFS of 5.6 months [95% confidence interval (CI): 3.8-9.2 months]. The median PFS was 5.5 months for chemotherapy-refractory patients, 9.1 months for untreated patients, 13.9 months for patients with alveolar soft part sarcoma (ASPS), and 3.7 months for patients with clear cell sarcoma (CCS). The 12- and 24-month OS rates were 58.6% and 44.9%, respectively, with a median OS of 20.0 months (95% CI: 9.2-31.1 months). The median OS was 10.7 months for chemotherapy-refractory patients and not estimated for untreated, ASPS, nor CCS patients. In 50 evaluable patients, the ORR was 18.0% and the disease control rate was 86.0%. These results were similar to those of the per-protocol set. The most common grade 3 or 4 AEs included hypertension [30 (58.8%) of 51 patients], leukopenia [12 (23.5%)], proteinuria [8 (15.69%)], and hematuria [8 (15.69%)]. One patient died of unknown cause. Conclusions: This study suggested that apatinib might be effective and tolerable in patients with untreated or chemotherapy-refractory STS (NCT03064243).

PET/MR fusion texture analysis for the clinical outcome prediction in soft-tissue sarcoma.

BACKGROUND: Various fusion strategies (feature-level fusion, matrix-level fusion, and image-level fusion) were used to fuse PET and MR images, which might lead to different feature values and classification performance. The purpose of this study was to measure the classification capability of features extracted using various PET/MR fusion methods in a dataset of soft-tissue sarcoma (STS). METHODS: The retrospective dataset included 51 patients with histologically proven STS. All patients had pre-treatment PET and MR images. The image-level fusion was conducted using discrete wavelet transformation (DWT). During the DWT process, the MR weight was set as 0.1, 0.2, 0.3, 0.4, …, 0.9. And the corresponding PET weight was set as 1- (MR weight). The fused PET/MR images was generated using the inverse DWT. The matrix-level fusion was conducted by fusing the feature calculation matrix during the feature extracting process. The feature-level fusion was conducted by concatenating and averaging the features. We measured the predictive performance of features using univariate analysis and multivariable analysis. The univariate analysis included the Mann-Whitney U test and receiver operating characteristic (ROC) analysis. The multivariable analysis was used to develop the signatures by jointing the maximum relevance minimum redundancy method and multivariable logistic regression. The area under the ROC curve (AUC) value was calculated to evaluate the classification performance. RESULTS: By using the univariate analysis, the features extracted using image-level fusion method showed the optimal classification performance. For the multivariable analysis, the signatures developed using the image-level fusion-based features showed the best performance. For the T1/PET image-level fusion, the signature developed using the MR weight of 0.1 showed the optimal performance (0.9524(95% confidence interval (CI), 0.8413-0.9999)). For the T2/PET image-level fusion, the signature developed using the MR weight of 0.3 showed the optimal performance (0.9048(95%CI, 0.7356-0.9999)). CONCLUSIONS: For the fusion of PET/MR images in patients with STS, the signatures developed using the image-level fusion-based features showed the optimal classification performance than the signatures developed using the feature-level fusion and matrix-level fusion-based features, as well as the single modality features. The image-level fusion method was more recommended to fuse PET/MR images in future radiomics studies.

Transcriptome Analysis of Tumor-Infiltrating Lymphocytes Identifies NK Cell Gene Signatures Associated With Lymphocyte Infiltration and Survival in Soft Tissue Sarcomas.

Purpose: Clinical successes using current T-cell based immunotherapies have been limited in soft tissue sarcomas (STS), while pre-clinical studies have shown evidence of natural killer (NK) cell activity. Since tumor immune infiltration, especially tumor-infiltrating lymphocytes, is associated with improved survival in most solid tumors, we sought to evaluate the gene expression profile of tumor and blood NK and T cells, as well as tumor cells, with the goal of identifying potential novel immune targets in STS. Experimental Design: Using fluorescence-activated cell sorting, we isolated blood and tumor-infiltrating CD3-CD56+ NK and CD3+ T cells and CD45- viable tumor cells from STS patients undergoing surgery. We then evaluated differential gene expression (DGE) of these purified populations with RNA sequencing analysis. To evaluate survival differences and validate primary DGE results, we also queried The Cancer Genome Atlas (TCGA) database to compare outcomes stratified by bulk gene expression. Results: Sorted intra-tumoral CD3+ T cells showed significant upregulation of established activating (CD137) and inhibitory genes (TIM-3) compared to circulating T cells. In contrast, intra-tumoral NK cells did not exhibit upregulation of canonical cytotoxic genes (IFNG, GZMB), but rather significant DGE in mitogen signaling (DUSP4) and metabolic function (SMPD3, SLC7A5). Tumors with higher NK and T cell infiltration exhibited significantly increased expression of the pro-inflammatory receptor TLR4 in sorted CD45- tumor cells. TCGA analysis revealed that tumors with high TLR4 expression (P = 0.03) and low expression of STMN1 involved in microtubule polymerization (P < 0.001) were associated with significantly improved survival. Conclusions: Unlike T cells, which demonstrate significant DGE consistent with upregulation of both activating and inhibiting receptors in tumor-infiltrating subsets, NK cells appear to have more stable gene expression between blood and tumor subsets, with alterations restricted primarily to metabolic pathways. Increased immune cell infiltration and improved survival were positively correlated with TLR4 expression and inversely correlated with STMN1 expression within tumors, suggesting possible novel therapeutic targets for immunotherapy in STS.

Molecular profiling of gene fusions in soft tissue sarcomas by Ion AmpliSeqTM: a study of 35 cases.

Background: The accurate diagnosis of sarcoma can be difficult as there are over 70 different subtypes. While molecular profiling in soft tissue sarcoma (STS) has gradually been incorporated into routine diagnostics, conventional methods such as fluorescence in situ hybridization (FISH), reverse transcriptase-PCR (RT-PCR), and Sanger sequencing have several drawbacks. By allowing simultaneous analysis of multiple targets and increasing sequencing depth to achieve ultra-sensitivity, next-generation sequencing (NGS) can not only detect common genetic abnormalities without prior assumptions but also identify uncommon or even new variants. Methods: In this study, the applicability of NGS in assessing STS using the Ion Torrent Proton was evaluated and compared with other methods. A cohort of 35 tissue specimens from STS patients, including alveolar soft-part sarcoma (ASPS), Ewing's sarcoma (ES), synovial sarcoma (SS), dermatofibrosarcoma protuberans (DFSP), and myxoid liposarcoma (MLPS) patients, were subjected to NGS by an Ion AmpliSeqTM Custom panel. Results: A proportion of 97.14% (34/35) were successfully conducted to detect gene fusion positive events and met all criteria for good quality. The concordance between NGS and conventional techniques was 94.12% (32/34). NGS also showed superior results, as Sanger sequencing and FISH in two cases were false negatives, demonstrating the excellent diagnostic utility of NGS for translocation detection in STS. Conclusions: The results in this study show the potential for NGS to aid in diagnosis and clinical monitoring of STS and warrant additional studies in larger cohorts.

Virtual Biopsy in Soft Tissue Sarcoma. How Close Are We?

A shift in radiology to a data-driven specialty has been unlocked by synergistic developments in imaging biomarkers (IB) and computational science. This is advancing the capability to deliver "virtual biopsies" within oncology. The ability to non-invasively probe tumour biology both spatially and temporally would fulfil the potential of imaging to inform management of complex tumours; improving diagnostic accuracy, providing new insights into inter- and intra-tumoral heterogeneity and individualised treatment planning and monitoring. Soft tissue sarcomas (STS) are rare tumours of mesenchymal origin with over 150 histological subtypes and notorious heterogeneity. The combination of inter- and intra-tumoural heterogeneity and the rarity of the disease remain major barriers to effective treatments. We provide an overview of the process of successful IB development, the key imaging and computational advancements in STS including quantitative magnetic resonance imaging, radiomics and artificial intelligence, and the studies to date that have explored the potential biological surrogates to imaging metrics. We discuss the promising future directions of IBs in STS and illustrate how the routine clinical implementation of a virtual biopsy has the potential to revolutionise the management of this group of complex cancers and improve clinical outcomes.

A three-dimensional visualization of the full-field surgical region based on thin-slice MRI: A helpful approach for simultaneously guiding tumor resection and perforator flap elevation.

Background: The goal of the current study was to explore the application of preoperative three-dimensional reconstruction (3DR) based on thin-slice magnetic resonance imaging (MRI) in the simultaneous guidance of en bloc tumor resection and adjacent perforator flap elevation. Methods: The prospective cohort included 35 patients diagnosed with either soft tissue sarcoma or squamous cell skin cancer between 2019 and 2021. The preoperative 3DR based on thin-slice MRI illustrated the spatial anatomical relationship among the tumor, underlying muscle, adjacent perforator vessels, and bone around the surgical region. The accuracy of preoperative imaging data was verified by intraoperative vessel dissection and postoperative pathological measurements. Results: Tumor size from 3DR data showed relatively high concordance rates with pathological measurements within the 95% limits of agreement. An average of three perforators (range: 1-7) with a mean diameter of 0.32 cm (range: 0.18-0.74 cm) from the 3DR were present in our study. The average distance between tumor boundary and perforator piercing sites on the 3DR was 2.2 cm (range: 1.2-7.7 cm). The average length of artery perforator coursing along the subcutaneous tissue was 5.8 cm (range: 3.3-25.1 cm). The mean flap harvest time was 55 mins (range: 36-97 min). The average flap size was 92.2 cm2 (range: 32-126 cm2). One perforator flap occurred distal partial necrosis. Conclusion: A thorough understanding of anatomical structures in the surgical region according to full-field 3DR based on thin-slice MRI can improve the performance of radical resection of the tumor and adjacent perforator flap transfer, especially for junior surgeons with a poor experience.