High-grade Soft Tissue Sarcomas Research Articles

Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma

BackgroundSoft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS.MethodsPhase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies.DiscussionThis is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS.Trial registrationNCT05301283.Trial statusThe trial started recruitment on March 17, 2022.

Ultra-low-dose computed tomography and chest X-ray in follow-up of high-grade soft tissue sarcoma—a prospective comparative study

Ultra-low-dose computed tomography (ULD-CT) may combine the high sensitivity of conventional computed tomography (CT) in detecting sarcoma pulmonary metastasis, with a radiation dose in the same magnitude as chest X-ray (CXR). Fifty patients with non-metastatic high-grade soft tissue sarcoma treated with curative intention were recruited. Their follow-up involved both CXR and ULD-CT to evaluate their different sensitivity. Suspected findings were confirmed by conventional CT if necessary. Patients with isolated pulmonary metastases were treated with surgery or stereotactic body radiation therapy (SBRT) with curative intent if possible. The median effective dose from a single ULD-CT study was 0.27 mSv (range 0.12 to 0.89 mSv). Nine patients were diagnosed with asymptomatic lung metastases during the follow-up. Only three of them were visible in CXR and all nine in ULD-CT. CXR had therefore only a 33% sensitivity compared to ULD-CT. Four patients were operated, and one had SBRT to all pulmonary lesions. Eight of them, however, died of the disease. Two patients developed symptomatic metastatic recurrence involving extrapulmonary sites+/−the lungs between two imaging rounds. ULD-CT has higher sensitivity for the detection of sarcoma pulmonary metastasis than CXR, with a radiation dose considerably lower than conventional CT.Clinical trial registration: NCT05813808. 04-14-2023.

Can DNA Methylation Profiling Classify Histologic Subtypes and Grades in Soft Tissue Sarcoma?

A clear classification of the subtype and grade of soft tissue sarcoma is important for predicting prognosis and establishing treatment strategies. However, the rarity and heterogeneity of these tumors often make diagnosis difficult. In addition, it remains challenging to predict the response to chemotherapy and prognosis. Thus, we need a new method to help diagnose soft tissue sarcomas and determine treatment strategies in conjunction with traditional methods. Genetic alterations can be found in some subtypes of soft tissue sarcoma, but many other types show dysregulated gene expression attributed to epigenetic changes, such as DNA methylation status. However, research on DNA methylation profiles in soft tissue sarcoma is still insufficient to provide information to assist in diagnosis and therapeutic decisions. (1) Do DNA methylation profiles differ between normal tissue and soft tissue sarcoma? (2) Do DNA methylation profiles vary between different histologic subtypes of soft tissue sarcoma? (3) Do DNA methylation profiles differ based on tumor grade? Between January 2019 and December 2022, we treated 85 patients for soft tissue sarcomas. We considered patients whose specimens were approved for pilot research by the Human Biobank of St. Vincent's Hospital, The Catholic University of Korea, as potentially eligible. Based on this, 41% (35 patients) were eligible; 1% (one patient) was excluded because of gender mismatch between clinical and genetic data after controlling for data quality. Finally, 39 specimens (34 soft tissue sarcomas and five normal samples) were included from 34 patients who had clinical data. All tissue samples were collected intraoperatively. The five normal tissue samples were from muscle tissues. There were 20 female patients and 14 male patients, with a median age of 58 years (range 19 to 82 years). Genomic DNA was extracted from frozen tissue, and DNA methylation profiles were obtained. Genomic annotation of DNA methylation sites and hierarchical cluster analysis were performed to interpret results from DNA methylation profiling. A t-test was used to analyze different methylation probes. Benjamini-Hochberg-adjusted p value calculations were used to account for bias resulting from evaluating thousands of methylation sites. The most common histologic subtypes were liposarcoma (n = 10) and leiomyosarcoma (n = 9). The tumor grade was Fédération Nationale des Centres de Lutte Contre Le Cancer Grades 1, 2, and 3 in 3, 15, and 16 patients, respectively. DNA methylation profiling demonstrated differences between soft tissue sarcoma and normal tissue as 21,188 cytosine-phosphate-guanine sites. Despite the small number of samples, 72 of these sites showed an adjusted p value of < 0.000001, suggesting a low probability of statistical errors. Among the 72 sites, 70 exhibited a hypermethylation pattern in soft tissue sarcoma, with only two sites showing a hypomethylation pattern. Thirty of 34 soft tissue sarcomas were distinguished from normal samples using hierarchical cluster analysis. There was a different methylation pattern between leiomyosarcoma and liposarcoma at 7445 sites. Using the data, hierarchical clustering analysis showed that liposarcoma was distinguished from leiomyosarcoma. When we used the same approach and included other subtypes with three or more samples, only leiomyosarcoma and myxofibrosarcoma were separated from the other subtypes, while liposarcoma and alveolar soft-part sarcoma were mixed with the others. When comparing DNA methylation profiles between low-grade (Grade 1) and high-grade (Grades 2 and 3) soft tissue sarcomas, a difference in methylation pattern was observed at 144 cytosine-phosphate-guanine sites. Among these, 132 cytosine-phosphate-guanine sites exhibited hypermethylation in the high-grade group compared with the low-grade group. Hierarchical clustering analysis showed a division into two groups, with most high-grade sarcomas (28 of 31) separated from the low-grade group and few (3 out of 31) clustered together with the low-grade group. However, three high-grade soft tissue sarcomas were grouped with the Grade 1 cluster, and all of these sarcomas were Grade 2. When comparing Grades 1 and 2 to Grade 3, Grade 3 tumors were separated from Grades 1 and 2. We observed a different DNA methylation pattern between soft tissue sarcomas and normal tissues. Liposarcoma was distinguished from leiomyosarcoma using methylation profiling. High-grade soft tissue sarcoma samples showed a hypermethylation pattern compared with low-grade ones. Our findings indicate the need for research using methylation profiling to better understand the diverse biological characteristics of soft tissue sarcoma. Such research should include studies with sufficient samples and a variety of subtypes, as well as analyses of the expression and function of related genes. Additionally, efforts to link this research with clinical data related to treatment and prognosis are necessary. Level III, diagnostic study.

Do Patients Treated With an Unplanned Resection for Small Superficial Soft Tissue Sarcomas Have Worse Long-term Survival Than Those Initially Treated With an Oncologic Resection?

Histologic grade, size, and depth are well-known prognostic factors in soft tissue sarcomas (STS). Small (< 5 cm) and superficial STS generally have an excellent prognosis when treated with appropriate surgery. However, they are often misdiagnosed and mistreated. We reported that in midterm follow-up (5 to 7 years), patients with unplanned resections of tumors with positive margins who immediately underwent a reoperation with margin-widening re-resection and postoperative radiotherapy had survival comparable to that of patients who were initially treated correctly. In that article, we included STS larger than 5 cm, deep STS, and individuals with local recurrence. However, we wanted to evaluate the impact of unplanned resection on the survival of patients who had STS with the best prognosis, small and superficial STS, with two groups that were as homogeneous as possible. Do patients with small and superficial STS who underwent an unplanned resection have worse prognosis in the long term than those who were initially treated correctly? We exclusively evaluated patients with small (< 5 cm) and superficial (to the deep fascia) STS. We systematically excluded deep STS. Among this subset, we identified 93 patients with superficial STS. We excluded patients with local relapse, metastatic disease, superficial STS of the head or neck, those with insufficient clinical or dosimetric information, and patients with follow-up of less than 2 years. Furthermore, our focus on investigating the most benign and homogeneous STS prompted us to exclude patients with superficial tumors greater than or equal to 5 cm. This selection was driven by the presumed better prognosis associated with smaller tumors, inevitably leading to a smaller pool of patients for direct comparison with patients who had unplanned resections. The initial expectation was to observe similar survival outcomes between cohorts. Between 1990 and 2019, a total of 17 patients underwent surgical treatment at our private, medium-size center. Of those, 29% (5 patients) were lost to follow-up before 2 years without meeting a study endpoint (relapse, metastasis or revision, reoperation, or death), leaving a total of 71% (12 patients) of the original group who had either follow-up of at least 2 years or who met a study endpoint before that minimum surveillance duration. They were treated with surgery alone. During that same period, another 51 patients were referred to us after undergoing an unplanned resection of a lesion that subsequently was determined to be a soft tissue malignancy. Of those, 18% (9 patients) were lost to follow-up before 2 years without meeting a study endpoint, leaving 82% (42 patients) of the original group who had either follow-up of at least 2 years or who met a study endpoint before that minimum surveillance duration. They were treated with re-excision and postoperative radiotherapy. Patients with unplanned resections had an older mean age (51± 5 versus 44 ± 7 years; p = 0.1) and a higher proportion of female patients (58% versus 38%; p = 0.07), but the groups did not differ in terms of largest diameter, histologic type, or tumor location. However, patients with planned resections had a higher proportion of high-grade STS (75% versus 55%; p = 0.07). No metastases were present in either group at diagnosis. We performed a univariate analysis of the groups. We could not perform a multivariate analysis because of the small sample. We compared the groups in terms of local recurrence and all-cause mortality using the Kaplan-Meier survivorship estimator. According to the Kaplan-Meier survivorship estimator, survivorship free from local recurrence at a mean of 20 years of follow-up was better in the planned resection group than in the unplanned resection group (92% [95% CI 63% to 100%] versus 69% [95% CI 54% to 81%]; p = 0.04). Furthermore, overall survivorship at 5 years was higher in the planned resection group than in the unplanned resection group (100% [95% CI 72% to 100%] versus 70% [95% CI 54% to 81%]; p = 0.04). Similarly, the planned resection group exhibited superior survivorship at 20 years of follow-up (100% [95% CI 72% to 100%] versus 62% [95% CI 47% to 75%]; p = 0.01). Metastatic disease was absent in the planned resection group, while it occurred in 12 patients in the unplanned resection group (28% [95% CI 17% to 44%]). Unplanned resection for patients with small and superficial STS was associated with a decrease in overall survival in the long term, despite the use of postoperative radiotherapy. An unplanned resection may be an important prognostic factor. Nevertheless, larger and prospective studies are needed to validate our findings. Although small and superficial lumps are usually benign, nonsarcoma surgeons should be aware that some masses may be malignant, and if in doubt, MR imaging, a biopsy before excision, or consultation with or referral to a sarcoma center should be considered before removing the mass. Level III, therapeutic study.

Enhancing local recurrence detection in patients with high-grade soft tissue sarcoma: value of short-term Ultrasonography added to post-operative MRI surveillance

BackgroundLimited data exist on the optimal postoperative surveillance protocol for high-grade soft tissue sarcoma, particularly regarding the optimal imaging modality and imaging interval for detecting local recurrence. This study aimed to assess the benefit of short-term postoperative ultrasonography (USG) for detecting local recurrence in patients with high-grade soft tissue sarcoma.MethodsPatients with newly diagnosed high-grade soft tissue sarcoma who underwent surgical resection between January 2010 and June 2020 were included. Short-term USG was added to the follow-up protocol as a surveillance tool alongside routine magnetic resonance imaging (MRI). The primary outcome was the additional detection rate of short-term USG compared with routine MRI surveillance for early local recurrence detection. Subgroup analysis was performed to evaluate factors influencing USG detection rate. The additional detection rate of short-term USG for detection of metastatic lymph nodes was also evaluated. The secondary outcome was the false referral rate of short-term USG.ResultsIn total, 198 patients (mean age ± standard deviation: 52.1 ± 15.8 years; 94 women) were included. Local recurrence occurred in 20 patients (10.1%; 20/198). Short-term USG detected local recurrence in advance of routine MRI visits in 7 out of 198 patients, resulting in an additional detection rate of 3.5% (95% CI: 1.7–7.1%). Subgroup analysis showed no significant difference in the short-term USG detection rate based on initial tumor characteristics, and receipt of radiotherapy or chemotherapy. Short-term USG additionally detected five of seven patients with metastatic lymph nodes [2.5% (95% CI, 1.1–5.8%, 5/198)]. The false referral rate of short-term USG was 3.5% (95% CI: 1.7–7.1%; 7/198).ConclusionsShort-term USG as part of postoperative surveillance for high-grade soft tissue sarcoma can enhance early detection of local tumor recurrence and metastatic lymphadenopathy. Early detection of local tumor recurrence could lead to a prompt surgical resection and aid in local disease control.

Radiotherapy versus limb-sparing surgery alone in low-grade soft-tissue sarcoma of the extremity and trunk wall: a systematic review and meta-analysis.

Current guidelines recommend the use of radiotherapy in the management of intermediate and high-grade soft-tissue sarcoma of the extremity and trunk wall. Its use in low-grade sarcoma is less clear. To date there have been no pooled data analyses regarding its role in this context. Its use is not without complications and therefore must be justified. We aim to assess the oncological impact of radiotherapy versus limb-sparing surgery alone in this subset of sarcoma. Medline, EMBASE and Cochrane's databases were searched from 1982 to present. Studies on or having a subgroup analysis of low-grade soft tissue sarcoma, with a radiotherapy and a surgery only arm were included. Outcomes included local recurrence and overall survival. Patients were at least 16 years of age with primary de-novo sarcoma who had not undergone prior resection or treatment. Those undergoing concomitant therapy were excluded. Data extraction was performed independently by two reviewers. Results were pooled using a random-effects model and presented as a forest plot. Primary outcome measures included local recurrence and overall survival. Eleven unique studies were included, consisting of two RCTs and nine non-randomized studies. Overall, there were 12 799 patients. Four studies were included in meta-analysis and the overall pooled effect showed a limited role of radiotherapy in overall survival outcomes when compared to limb-sparing surgery alone HR 1.00 [0.83-1.20] P = 0.41. Descriptive analysis suggests there is limited role of radiotherapy in improving local recurrence outcomes. This study suggests there is limited role for radiotherapy versus limb-sparing surgery alone in low-grade soft-tissue sarcoma. These findings strongly suggest there is lack of high-quality data and that further research must be undertaken prior to forming any strong conclusions regarding the management of low-grade soft-tissue sarcoma. Demonstrating a role for radiotherapy may help improve the quality of excisional margins and thus potentiate limb-sparing surgery.

Prognostic factors and treatment outcomes in patients with pleomorphic rhabdomyosarcoma: a population-based cohort study.

Pleomorphic rhabdomyosarcoma is a rare sarcoma in adults. The clinical characteristics, outcomes and prognostic factors associated with pleomorphic rhabdomyosarcoma remain unclear. We retrospectively analyzed data from the Bone and Soft Tissue Tumor Registry of Japan, and enrolled patients with pleomorphic rhabdomyosarcoma. Disease-specific overall survival, local recurrence-free survival and distant metastasis-free survival were estimated using the Kaplan-Meier method; Cox regression model was used to identify prognostic factors. In total, 182 patients with pleomorphic rhabdomyosarcoma were included. Median age was 63 (range 20-95) years. The lower extremity (48%) was the most frequent tumor origin site, while head and neck were rare (4%). A total of 43 patients (24%) had distant or regional nodal metastases at first presentation. In all cases, the 2-year and 5-year survival rates were 66.3% and 54.1%, respectively. Distant metastasis was a significant poor prognostic factor (Hazard ratio 6.65; 95% confidence intervals, 3.00-14.75, P<0.0001), with median survival of such patients being 9.4 (95% confidence intervals: 5.3-12.2) months. In 134 localized cases, the 2-year and 5-year survival rates were 91.5% and 68.3%, respectively. Large tumor size and older age were associated with poorer prognosis. Through data from localized and locally curative cases extracted and adjusted by propensity score matching, we found that perioperative chemotherapy did not improve disease-specific overall survival, distant metastasis-free survival or local recurrence-free survival. Clinical characteristics and outcomes of pleomorphic rhabdomyosarcoma are similar to those of other high-grade soft tissue sarcomas. Pleomorphic rhabdomyosarcoma may be less chemosensitive, and a strategy other than the standard cytotoxic chemotherapy is required to improve its prognosis.

Neoadjuvant Radiotherapy Is Associated with Fewer Acute Adverse Skin Reactions Without Increased Risk of Postoperative Wound Complications in High-Grade Extremity Soft Tissue Sarcoma - A Retrospective Comparative Study with A Mean Follow-Up of 7 Years

Aim: In this study, we aim to compare the adverse effects and oncological outcomes of patients with high-grade extremity soft tissue sarcoma receiving neoadjuvant or adjuvant RT. Methods: From 2008 to 2022, Sixty-four patients underwent limb-preserving surgery in our institute for localized high-grade extremity soft tissue sarcoma were included. Thirty-nine patients received adjuvant radiotherapy while twenty-five patients received neoadjuvant RT before surgery if the soft tissue sarcomas were close to the neurovascular bundles, bones or histological types of myxoid liposarcoma or rhabdomyosarcoma. Primary outcomes were acute RT-related skin adverse reactions and significant side effects comprising postoperative wound complications, pathological fractures and RT-induced sarcoma. Secondary outcomes included surgical margin quality, Local-Recurrence (LR)-free survival, metastasis-free survival and overall survivorship. Results and Discussion: Patients in the neoadjuvant RT group had significantly fewer acute RT-induced adverse skin reactions than the adjuvant RT group (p=0.044, Table 2). None in the neoadjuvant RT group suffered severe acute skin reaction (RTOG grade 3-4). Wound infection (n=2) and pathological fracture (n=1) were rare in both adjuvant and neoadjuvant RT groups (P=0.640 &amp; 1.000 respectively). Survival curves for local-recurrence-free survival, metastasis-free survival and overall survivorship of both neoadjuvant and adjuvant groups were analyzed via Kaplan-Meier Curve. All results are statistically insignificant, with p=0.835, 0.948 and 0.540, respectively. Presence of metastasis was the only statistically significant predictor of the overall survival-adjusted hazard ratio of 8.7 (95%CI 2.7-28), p&lt;0.001. Conclusion: Patients with neoadjuvant RT had lower cumulative radiation doses and fewer acute adverse skin reactions. There was no increased risk of postoperative wound complication compared to adjuvant RT. The LR-free survival, metastasis-free survival and overall survival were comparable in both groups. Our results suggested that postponing surgery to eight weeks after neoadjuvant RT and primary wound closure were associated with fewer wound complications, but further studies were warranted.

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

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. 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. 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). 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.

(Cost-)effectiveness of an individualised risk prediction tool (PERSARC) on patient’s knowledge and decisional conflict among soft-tissue sarcomas patients: protocol for a parallel cluster randomised trial (the VALUE-PERSARC study)

IntroductionCurrent treatment decision-making in high-grade soft-tissue sarcoma (STS) care is not informed by individualised risks for different treatment options and patients’ preferences. Risk prediction tools may provide patients and professionals...

Non-invasive monitoring of neoadjuvant radiation therapy response in soft tissue sarcomas by multiparametric MRI and quantification of circulating tumor DNA-A study protocol.

Wide resection remains the cornerstone of localized soft-tissue sarcomas (STS) treatment. Neoadjuvant radiation therapy (NRT) may decrease the risk of local recurrences; however, its effectiveness for different histological STS subtypes has not been systematically investigated. The proposed prospective study evaluates the NRT response in STS using liquid biopsies and the correlation of multiparametric magnetic resonance imaging (mpMRI) with histopathology and immunohistochemistry. Patients with localized high-grade STS, who qualify for NRT, are included in this study. Quantification of circulating tumor DNA (ctDNA) in patient blood samples is performed by targeted next-generation sequencing. Soft-tissue sarcoma subtype-specific panel sequencing in combination with patient-specific exome sequencing allows the detection of individual structural variants and point mutations. Circulating free DNA is isolated from peritherapeutically collected patient plasma samples and ctDNA quantified therein. Identification of breakpoints is carried out using FACTERA. Bioinformatic analysis is performed using samtools, picard, fgbio, and the MIRACUM Pipeline. Combination of conventional MRI sequences with diffusion-weighted imaging, intravoxel-incoherent motion, and dynamic contrast enhancement. Multiparametric MRI is performed before, during, and after NRT. We aim to correlate mpMRI data with the resected specimen's macroscopical, histological, and immunohistochemical findings. Preliminary data support the notion that quantification of ctDNA in combination with tumor mass characterization through co-registration of mpMRI and histopathology can predict NRT response of STS. The methods presented in this prospective study are necessary to assess therapy response in heterogeneous tumors and lay the foundation of future patient- and tumor-specific therapy concepts. These methods can be applied to various tumor entities. Thus, the participation and support of a wider group of oncologic surgeons are needed to validate these findings on a larger patient cohort.

Novel Postoperative Hypofractionated Accelerated Radiation Dose-Painting Approach for Soft Tissue Sarcoma

Background: Hypofractionated radiotherapy (RT) offers benefits in the treatment of soft tissue sarcomas (STS), including exploitation of the lower α/β, patient convenience, and cost. This study evaluates the acute toxicity of a hypofractionated accelerated RT dose-painting (HARD) approach for postoperative treatment of STS. Materials and Methods: This is a retrospective review of 53 consecutive patients with STS who underwent resection followed by postoperative RT. Standard postoperative RT dosing for R0/R1/gross disease with sequential boost (50Gy + 14/16/20Gy in 32-35 fractions) were replaced with dose-painting, which adapts dose based on risk of disease burden, to 50.4 and 63/64.4/70 Gy in 28 fractions, respectively. The first 10 patients were re-planned with a sequential boost RT approach and dosimetric indices were compared. Time-to-event outcomes, including local control (LC), regional control (RC), distant control (DC), and overall survival (OS), were estimated with Kaplan-Meier (KM) analysis. Results: Median follow up was 25.2 months. Most patients had high grade (59%) STS of the extremity (63%) who underwent resection with either R1 (40%) or close (36%) margins. Four patients experienced grade 3 acute dermatitis which resolved by the 3-month follow up visit. The 2-year LC, RC, DC, and OS were 100%, 92%, 68%, and 86%, respectively. Compared to the sequential boost plan, HARD had a significantly lower field size (total V50Gy) (p=0.002), bone V50 (p=0.031), and maximum skin dose (p=0.008). Overall treatment time was decreased by 4-7 fractions, which translated to a decrease in estimated average treatment cost of $3,056 (range: $2,51-$4,335, p<0.001). Conclusions: In addition to benefits in cost, convenience, and improved biological effect in STS, hypofractionated accelerated RT dose-painting (HARD) regimen offers a safe treatment approach with dosimetric advantages compared to conventional sequential boost, which may translate to improved long-term toxicity.

Intratumoral and peritumoral MRI-based radiomics prediction of histopathological grade in soft tissue sarcomas: a two-center study

ObjectivesThis study aims to develop a model based on intratumoral and peritumoral radiomics from fat-suppressed T2-weighted(FS-T2WI) images to predict the histopathological grade of soft tissue sarcoma (STS).MethodsThis retrospective study included 160 patients with STS from two centers, of which 82 were low-grade and 78were high-grade. Radiomics features were extracted and selected from the region of tumor mass volume (TMV) and peritumoral tumor volume (PTV) respectively. The TMV, PTV, and combined(TM-PTV) radiomics models were established in the training cohort (n = 111)for the prediction of histopathological grade. Finally, a radiomics nomogram was constructed by combining the TM-PTV radiomics signature (Rad-score) and the selected clinical-MRI predictor. The ROC and calibration curves were used to determine the performance of the TMV, PTV, and TM-PTV models in the training and validation cohort (n = 49). The decision curve analysis (DCA) and calibration curves were used to investigate the clinical usefulness and calibration of the nomogram, respectively.ResultsThe TMV model, PTV model, and TM-PTV model had AUCs of 0.835, 0.879, and 0.917 in the training cohort and 0.811, 0.756, 0.896 in the validation cohort. The nomogram, including the TM-PTV signatures and peritumoral hyperintensity, achieved good calibration and discrimination with a C-index of 0.948 (95% CI, 0.906 to 0.990) in the training cohort and 0.921 (95% CI, 0.840 to 0.995) in the validation cohort. Decision curve analysis demonstrated the clinical usefulness of the nomogram.ConclusionThe proposed model based on intratumoral and peritumoral radiomics showed good performance in distinguishing low-grade from high-grade STSs.

Bioinformatic Analysis of Recurrent Genomic Alterations and Corresponding Pathway Alterations in Ewing Sarcoma.

Ewing Sarcoma (ES) is an aggressive, mesenchymal malignancy associated with a poor prognosis in the recurrent or metastatic setting with an estimated overall survival (OS) of <30% at 5 years. ES is characterized by a balanced, reciprocal chromosomal translocation involving the EWSR1 RNA-binding protein and ETS transcription factor gene (EWS-FLI being the most common). Interestingly, murine ES models have failed to produce tumors phenotypically representative of ES. Genomic alterations (GA) in ES are infrequent and may work synergistically with EWS-ETS translocations to promote oncogenesis. Aberrations in fibroblast growth factor receptor (FGFR4), a receptor tyrosine kinase (RTK) have been shown to contribute to carcinogenesis. Mouse embryonic fibroblasts (MEFs) derived from knock-in strain of homologous Fgfr4G385R mice display a transformed phenotype with enhanced TGF-induced mammary carcinogenesis. The association between the FGFRG388R SNV in high-grade soft tissue sarcomas has previously been demonstrated conferring a statistically significant association with poorer OS. How the FGFR4G388R SNV specifically relates to ES has not previously been delineated. To further define the genomic landscape and corresponding pathway alterations in ES, comprehensive genomic profiling (CGP) was performed on the tumors of 189 ES patients. The FGFR4G388R SNV was identified in a significant proportion of the evaluable cases (n = 97, 51%). In line with previous analyses, TP53 (n = 36, 19%), CDK2NA/B (n = 33, 17%), and STAG2 (n = 22, 11.6%) represented the most frequent alterations in our cohort. Co-occurrence of CDK2NA and STAG2 alterations was observed (n = 5, 3%). Notably, we identified a higher proportion of TP53 mutations than previously observed. The most frequent pathway alterations affected MAPK (n = 89, 24% of pathological samples), HRR (n = 75, 25%), Notch1 (n = 69, 23%), Histone/Chromatin remodeling (n = 57, 24%), and PI3K (n = 64, 20%). These findings help to further elucidate the genomic landscape of ES with a novel investigation of the FGFR4G388R SNV revealing frequent aberration.

Racial and ethnic variation in presentation and outcomes of high-grade soft tissue sarcoma at a Southeastern United States comprehensive cancer center

BackgroundHigh-grade soft tissue sarcoma is rare and associated with poor prognosis. This study examines racial and ethnic variation in presentation and outcomes at a Southeastern US cancer center. MethodsAmong an institutional cohort of patients seen between January 2016–December 2021, racial and ethnic differences were evaluated using chi-squared tests, Kaplan Meier curves, and Cox proportional hazards models. ResultsThere were 295 patients (71 ​% Non-Hispanic White, 24 ​% Black, 3 ​% Hispanic White, 2 ​% Other). Black representation was greater than national cohorts (24 ​% vs. 12 ​%). Histological subtype varied by race/ethnicity (p ​= ​0.007). Adjusting for histology and stage, survival was worse for Black vs. White patients (HR 1.71, 95 ​% CI 1.07–2.76) and those with metastatic disease (5.47, 3.54–8.44). In non-metastatic patients, survival differences for Black vs. White patients were attenuated by receipt of multi-modal treatment (1.53, 0.82–2.88). ConclusionObserved racial disparities in survival of high-grade sarcoma may be addressed by early, multidisciplinary management.

Recurrence of follicular dendritic cell sarcoma in tonsils after 7 years: a rare case report

Follicular dendritic cell sarcoma (FDCS) is a rare mesenchymal neoplasm. It arises from not only from lymph nodes but also from extra nodal tissues, either as acquired lymphoid tissue or as part of the organized constitutive lymphoid tissue. We here report this rare entity which developed again after 7 years post tonsillectomy in a 5-year old male patient. Patient underwent radical tonsillectomy and adjuvant treatment is awaited. Differential diagnosis includes large cell lymphoma, peripheral nerve sheath tumor, extracranial meningioma, malignant melanoma, metastatic carcinoma, ectopic thymoma, malignant fibrous histiocytoma, and interstitial reticulum cell sarcoma. Currently, the management of FDCS includes the therapeutic guidelines similar to that of high-grade soft tissue sarcomas that is complete surgical resection of the lesion with possibility of adjuvant radiotherapy and/or chemotherapy. The ideal combination of management of FDCS has yet to be defined.

Clinical features and prognostic factors of extraskeletal osteosarcoma: A single-center retrospective study from China

ObjectiveExtraskeletal osteosarcoma (EO) represents a rare manifesting variant of soft tissue sarcoma. This study aims to analyze clinical characteristics, natural course, and potential prognostic factors of EO based on literature review. MethodsClinical data of 12 patients with EO admitted to Department of Orthopedic Oncology Surgery of Beijing Ji Shui Tan Hospital from March 1995 to October 2019 were retrospectively analyzed, and clinical profile, therapies, and endpoints were summarized. ResultsEight patients were previously untreated, and four cases were recurrent. The median age on diagnosis was 53 years, and the mean follow-up time was 41.4 (range: 25 to 72) months. The lesions were located in the thigh of 5 patients, calf in 3, buttock in 2 and upper arm in 2. The lesions were located in the deep layer of fascia in 10 cases and in the superficial layer in 2, with a maximum diameter of 13 (4–19) cm on average, and Ennecking stage was IIB for 10 patients and III for 2. All patients underwent surgery, with a marginal resection in 8 cases, and wide resection in 4. Eight patients received chemotherapy, including two patients with neoadjuvant chemotherapy and 7 with postoperative adjuvant chemotherapy. Three patients with marginal resection had local recurrence and two of them underwent radical amputation. Five patients died from lung metastases, including two patients with pre-existing metastasis at presentation. ConclusionsEO is a rare high-grade soft tissue sarcoma. Age<50 years, no metastasis at presentation, superficial location of the tumor, and negative resection margin are favourable prognostic factors. For patients with positive margins, adjuvant radiotherapy is recommended to improve local control rates. High-risk patients may benefit from platinum-based chemotherapy regimens.

Prediction of high-grade soft-tissue sarcoma using a combined intratumoural and peritumoural MRI-based radiomics nomogram

To develop an intratumoural and peritumoural magnetic resonance imaging (MRI)-based radiomics nomogram for predicting tumour grade to improve clinical treatment and long-term prognosis. MRI (3 T) features and T2-weighted imaging with fat-saturation (T2WI-FS)-based radiomics features of 57 patients with soft-tissue sarcoma (STS) were analysed retrospectively. Tumour size, ratio of width and length, relative depth to the peripheral fascia, peritumoural oedema, heterogeneity on T2WI, necrosis signal, enhancement model, and peritumoural enhancement were obtained. Independent risk factors were screened to construct an MRI feature nomogram. Radiomics features were obtained from intratumoural and peritumoural images on T2WI-FS. The optimal radiomics model was selected by the four-step dimensionality reduction method of minimum and maximum normalisation, optimal feature selection, selection based on support vector machine with L1-norm regularisation model, and iterative feature selection. MRI features and optimal radiomics features were used to construct a radiomics nomogram. The MRI feature nomogram model, the radiomics model, and the radiomics nomogram model were assessed by receiver operating characteristic (ROC) curves and calibration curves of the training and validation sets. Heterogeneity on T2WI and peritumoural enhancement were independent risk factors for predicting high-grade STS. The areas under the curves of the training set and verification set of the three models were as follows: MRI feature nomogram, 0.86 and 0.83, respectively; intratumoural and peritumoural combined radiomics model, 0.99 and 0.86, respectively; and radiomics nomogram model, 0.98 and 0.96, respectively. The radiomics nomogram model based on MRI features and combined intratumoural and peritumoural radiomic features was best able to predict high-grade STS.

Oclacitinib and Myxoma Virus Therapy in Dogs with High-Grade Soft Tissue Sarcoma.

Human rhabdomyosarcomas are rarely cured by surgical resection alone. This is also true for high-grade soft tissue sarcomas in dogs. Dogs with spontaneous sarcoma are good models for clinical responses to new cancer therapies. Strategic combinations of immunotherapy and oncolytic virotherapy (OV) could improve treatment responses in canine and human cancer patients. To develop an appropriate combination of immunotherapy and OV for dogs with soft tissue sarcoma (STS), canine cancer cells were inoculated with myxoma viruses (MYXVs) and gene transcripts were quantified. Next, the cytokine concentrations in the canine cancer cells were altered to evaluate their effect on MYXV replication. These studies indicated that, as in murine and human cells, type I interferons (IFN) play an important role in limiting MYXV replication in canine cancer cells. To reduce type I IFN production during OV, oclacitinib (a JAK1 inhibitor) was administered twice daily to dogs for 14 days starting ~7 days prior to surgery. STS tumors were excised, and MYXV deleted for serp2 (MYXV∆SERP2) was administered at the surgical site at two time points post-operatively to treat any remaining microscopic tumor cells. Tumor regrowth in dogs treated with OV was decreased relative to historical controls. However, regrowth was not further inhibited in patients given combination therapy.

Indicators of clinical performance in monitoring soft tissue sarcoma management: a population-based perspective.

Soft tissue sarcomas (STS) are rare malignancies which prognosis varies significantly by primary site, histological subtype, and tumor stage. Their low incidence, and the complexity of their clinico-pathological characteristics demand standardized, cancer-tailored diagnostics and therapies managed at high-volume, multidisciplinary care centers. This study evaluates the quality of STS management in north-east Italy (Veneto Region) through a list of ad hoc defined clinical indicators. This population-based study concerns all incident cases of STS in 2018 (214 cases) recorded in the adult population censored by the Veneto's regional Cancer Registry. Based on the international literature, a multidisciplinary working group of experts identified a set of indicators for monitoring the quality of diagnostic, therapeutic, and end-of-life clinical interventions. The quality of care was assessed by comparing the reference thresholds with the indicators' values achieved in clinical practice. Diagnostic procedures showed poor adherence to the thresholds, with a low percentage of histological diagnoses validated by a second opinion. The indicators relating to the surgical treatment of superficial, small, low-grade STS, or of medium, high-grade STS of the head-neck, trunk, or limbs were consistent with the thresholds, while for intermediate, high-grade (large-sized, deep) and retroperitoneal STS they fell significantly below the thresholds. A critical evaluation of the clinical indicators allowed to uncover the procedures needing corrective action. Monitoring clinical care indicators improves cancer care, confirms the importance of managing rare cancers at highly specialized, high-volume centers, and promotes the ethical sustainability of the healthcare system.