Soft Tissue Sarcomas: Treatment and Management

Background: To report the final results of a prospective, one-armed, single-center phase I/II trial (NCT01566123). Methods: Between 2007 and 2017, 37 patients with primary or recurrent (N = 6) retroperitoneal sarcomas were enrolled. Treatment included preoperative IMRT of 45–50 Gy with a simultaneous integrated boost of 50–56 Gy, surgery and IORT. The primary endpoint was local control (LC) at 5 years. The most common histology was dedifferentiated liposarcoma (51%), followed by leiomyosarcoma (24%) and well-differentiated liposarcoma (14%). The majority of lesions were high-grade (FNCLCC G1: 30%, G2: 38%, G3: 27%, two missing). Five patients were excluded from LC analysis per protocol. Results: The minimum follow-up of the survivors was 62 months (median: 109; maximum 162). IORT was performed for 27 patients. Thirty-five patients underwent gross total resection; the pathological resection margin was mostly R+ (80%) and, less often, R0 (20%). We observed 10 local recurrences. The 5-year LC of the whole cohort was 59.6%. Eleven patients received a dose > 50 Gy plus IORT boost; LC was 64.8%; the difference, however, was not significant (p = 0.588). Of 37 patients, 15 were alive and 22 deceased at the time of final analysis. The 5-year OS was 59.5% (68.8% per protocol). Conclusions: The primary endpoint of a 5-year LC of 70% was not met. This might be explained by the inclusion of recurrent disease and the high rate of G3 lesions and leiomyosarcoma, which have been shown to profit less from radiotherapy. Stratification by grading and histology should be considered for future studies. Full article

This retrospective multicenter study aimed to analyze the clinical features and prognosis of 24 patients diagnosed with LGMS between 2002 and 2019 in the Japanese sarcoma network. Twenty-two cases were surgically treated and two cases were treated with radical radiotherapy (RT). The pathological margin was R0 in 14 cases, R1 in 7 cases, and R2 in 1 case. The best overall response in the two patients who underwent radical RT was one complete response and one partial response. Local relapse occurred in 20.8% of patients. Local relapse-free survival (LRFS) was 91.3% at 2 years and 75.4% at 5 years. In univariate analysis, tumors of 5 cm or more were significantly more likely to cause local relapse (p < 0.01). In terms of the treatment of relapsed tumors, surgery was performed in two cases and radical RT was performed in three cases. None of the patients experienced a second local relapse. Disease-specific survival was 100% at 5 years. A wide excision aimed at the microscopically R0 margin is considered the standard treatment for LGMS. However, RT may be a viable option in unresectable cases or in cases where surgery is expected to cause significant functional impairment. Full article

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

The PazoQoL prospective, randomized, controlled, multicenter study was designed to continuously assess global health related quality of life (HRQoL) during treatment with pazopanib or physician-preferred chemotherapy over a 9-week period. The questionnaires were completed by the patients at home with great reliability during this time period. Continuous electronic patient reported outcome (ePRO) enabled early detection of the onset of deterioration and timely initiation of countermeasures. The Cancer Therapy Satisfaction Questionnaire (CTSQ) showed high interindividual variability and decline over a 9-week period, whereas the Time Trade-off (TTO) proved to be an efficient method for assessing individual benefit from cancer therapy. In our cohort, the TTO clearly demonstrated that the prolongation of life and the side effect profile of continued therapy were not as satisfactory as expected by patients when starting a new therapy. Although the study had to be stopped early due to the pandemic, our findings could translate into clinical practice without much effort and outside of a trial. Full article

Soft tissue sarcomas are highly aggressive malignant neoplasms of mesenchymal origin, accounting for less than 1% of adult cancers, but comprising over 20% of paediatric solid tumours. In locally advanced, unresectable, or metastatic disease, outcomes from even the first line of systemic treatment are invariably poor. MicroRNAs (miRNAs), which are short non-coding RNA molecules, target and modulate multiple dysregulated target genes and/or signalling pathways within cancer cells. Accordingly, miRNAs demonstrate great promise for their utility in diagnosing, prognosticating and improving treatment for soft tissue sarcomas. This review aims to provide an updated discussion on the known roles of specific miRNAs in the pathogenesis of sarcomas, and their potential use in prognosticating outcomes and prediction of therapeutic resistance. Full article

Background and Objectives: Small gastrointestinal stromal tumors (GISTs) are defined as tumors less than 2 cm in diameter, which are often found incidentally during gastroscopy. There is controversy regarding the management of small GISTs, and a certain percentage of small GISTs become malignant during follow-up. Previous studies which used Sanger targeted sequencing have shown that the mutation rate of small GISTs is significantly lower than that of large tumors. The aim of this study was to investigate the overall mutational profile of small GISTs, including those of wild-type tumors, using whole-exome sequencing (WES) and Sanger sequencing. Methods: Thirty-six paired small GIST specimens, which were resected by endoscopy, were analyzed by WES. Somatic mutations identified by WES were confirmed by Sanger sequencing. Sanger sequencing was performed in an additional 38 small gastric stromal tumor samples for examining hotspot mutations in KIT, PDGFRA, and BRAF. Results: Somatic C-KIT/PDGFRA mutations accounted for 81% of the mutations, including three novel mutation sites in C-KIT at exon 11, across the entire small gastric stromal tumor cohort (n = 74). In addition, 15% of small GISTs harbored previously undescribed BRAF-V600E hotspot mutations. No significant correlation was observed among the genotype, pathological features, and clinical classification. Conclusions: Our data revealed a high overall mutation rate (~96%) in small GISTs, indicating that genetic alterations are common events in early GIST generation. We also identified a high frequency of oncogenic BRAF-V600E mutations (15%) in small GISTs, which has not been previously reported. Full article

This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile. Full article

(1) Background: The management of gastrointestinal stromal tumors (GIST) has significantly evolved over the last two decades, with the introduction of tyrosine kinase inhibitors (TKI). We aim to report 10 years of experience of GIST management at a regional cancer center in Canada. (2) Methods: We retrospectively analyzed the records of 248 consecutive patients diagnosed with GIST between 2011 and 2021. We describe the clinical and pathological data, management, and outcome, including survival. (3) Results: The most common GIST sites were the stomach 63% (156), followed by the small bowel 29% (73). At diagnosis, 83% (206) of patients had localized disease (stage I–III). According to the modified National Institutes of Health consensus criteria (NIH) for GIST, around 45% (90) had intermediate or high-risk disease. Most patients, 86% (213), underwent curative surgical resection. Forty-nine patients received adjuvant imatinib, while forty-three patients had advanced disease and received at least one line of TKI. With a median follow-up of 47 months, the 5-year recurrence-free survival (RFS) rates for very low and low risk were 100% and 94%, respectively, while those for intermediate and high risk were 84% and 51%, respectively. The 5-year overall survival (OS) rates for very low and low risk were 100% and 94%, while intermediate, high risk, and advanced were 91%, 88%, and 65%, respectively. Using the Kaplan–Meier method, there were statistically significant differences in RFS and OS between NIH risk groups, p < 0.0005. In univariate analysis, ECOG, site, mitosis, secondary malignancy, and size were predictors for OS. High mitosis and large size (>5 cm) were associated with worse RFS. (4) Conclusions: Curative surgical resection remains the gold standard management of GIST. Our results are comparable to the reported literature. Further research is needed to explore histology’s role in risk stratification and initiating adjuvant TKI. Full article

Preoperative radiotherapy increases the risk of postoperative wound complication in the treatment of soft tissue sarcoma (STS). This study aims to develop a nomogram for predicting major wound complication (MaWC) after surgery. Using the Oxford University Hospital (OUH) database, a total of 126 STS patients treated with preoperative radiotherapy and surgical resection between 2007 and 2021 were retrospectively reviewed. MaWC was defined as a wound complication that required secondary surgical intervention. Univariate and multivariate regression analyses on the association between MaWC and risk factors were performed. A nomogram was formulated and the areas under the Receiver Operating Characteristic Curves (AUC) were adopted to measure the predictive value of MaWC. A decision curve analysis (DCA) determined the model with the best discriminative ability. The incidence of MaWC was 19%. Age, tumour size, diabetes mellitus and metastasis at presentation were associated with MaWC in the univariate analysis. Age, tumour size, and metastasis at presentation were independent risk factors in the multivariate analysis. The sensitivity and specificity of the predictive model is 0.90 and 0.76, respectively. The AUC value was 0.86. The nomogram constructed in the study effectively predicts the risk of MaWC after preoperative radiotherapy and surgery for STS patients. Full article

Axillary soft tissue sarcoma (STS) is challenging due to its proximity to vital neurovascular bundles. We conducted a prospective observational pilot study to explore whether 3D multimodality imaging (3DMMI) can improve preoperative planning for and surgical outcomes of patients with axillary STS. Twenty-one patients with STS (diameter > 5 cm) of the axilla were allocated, at their discretion, to either a control group undergoing traditional preoperative planning with separate computed tomography angiography, magnetic resonance imaging, and magnetic resonance neurography, or an intervention group where 3DMMI, digitally created based on these images, revealed the tumour and adjacent skeletomuscular and neurovascular structures in three dimensions. Primary outcome measures were surgical margins and surgical complications. Secondary outcomes included operative time, blood loss, serum C-reactive protein and interleukin-6, length of hospital stay, and limb function. The 3DMMI group had a lower, although not significantly different, inadvertent positive margin rate (1/12 vs. 3/9, p = 0.272), a significantly shorter operative time (p = 0.048), reduced blood loss (p = 0.038), and reduced length of hospital stay (p = 0.046). This endorses larger trials to improve complex surgical procedures and study how preoperative planning could be performed in the future. Full article

Gastrointestinal stromal tumors (GISTs) are considered insensitive to radiotherapy. However, a growing number of case reports and case series have shown that some lesions treated by radiotherapy achieved an objective response. The aim of the study was to perform a systematic review of all reported cases, case series, and clinical studies of GISTs treated with radiotherapy to reevaluate the role of radiotherapy in GISTs. A systematic search of the English-written literature was conducted using PubMed, Web of Science, and Embase databases. Overall, 41 articles describing 112 patients were retrieved. The included articles were of low to moderate quality. Bone was the most common site treated by radiotherapy, followed by the abdomen. In order to exclude the influence of effective tyrosine kinase inhibitors (TKIs), a subgroup analysis was conducted on whether and which TKIs were concurrently applied with radiotherapy. Results showed that radiotherapy alone or combined with resistant TKIs could help achieve objective response in selected patients with advanced or metastatic GISTs; however, survival benefits were not observed in the included studies. Pain was the most common symptom in symptomatic GISTs, followed by neurological dysfunction and bleeding. The symptom palliation rate was 78.6% after excluding the influence of effective TKIs. The adverse reactions were mainly graded 1–2. Radiotherapy was generally well-tolerated. Overall, radiotherapy may relieve symptoms for GIST patients with advanced or metastatic lesions and even help achieve objective response in selected patients without significantly reducing the quality of life. In addition to bone metastases, fixed abdominal lesions may be treated by radiotherapy. Publication bias and insufficient quality of included studies were the main limitations in this review. Further clinical studies are needed and justified. Full article

This study assesses the survival in patients undergoing metastasectomy for leiomyosarcoma (LMS) and compares the outcomes by the site of metastasectomy. We conducted a systematic review and pooled survival analysis of patients undergoing metastasectomy for LMS. Survival was compared between sites of metastasectomy. We identified 23 studies including 573 patients undergoing metastasectomy for LMS. The pooled median survival was 59.6 months (95% CI 33.3 to 66.0). The pooled median survival was longest for lung metastasectomy (72.8 months 95% CI 63.0 to 82.5), followed by liver (34.8 months 95% CI 22.3 to 47.2), spine (14.1 months 95% CI 8.6 to 19.7), and brain (14 months 95% CI 6.7 to 21.3). Two studies compared the survival outcomes between patients who did, versus who did not undergo metastasectomy; both demonstrated a significantly improved survival with metastasectomy. We conclude that surgery is currently being utilized for LMS metastases to the lung, liver, spine, and brain with acceptable survival. Although low quality, comparative studies support a survival benefit with metastasectomy. In the absence of randomized studies, it is impossible to determine whether the survival benefit associated with metastasectomy is due to careful patient selection rather than a surgical advantage; limited data were included about patient selection. Full article

The aim of this study was to investigate the influence of systemic chemotherapy on the skeletal growth of young osteosarcoma patients as a treatment-related late adverse effect. We reviewed the height data of 20 osteosarcoma patients (13 males and 7 females) aged ≤18 years. The average (±SD) age at diagnosis was 14.5 (±3.3) years. The average follow-up interval was 89.6 months. After wide resection of the affected bones, reconstruction with tumor prostheses and auto-bone grafting was carried out in 11 and 9 cases, respectively. Pearson’s correlation coefficient was calculated to evaluate the association between actual and predicted (using Paley’s multiplier method) heights. Z-scores were used to compare the initial and final heights with the Japanese national growth curve. Actual and predicted heights were correlated according to Pearson’s correlation coefficient (R = 0.503). Z-analysis showed that statistical significance (p = 0.04) was noted for the height data Z-scores of patients between ≤10 years and >10 years at the final follow-up. Systemic chemotherapy did not reduce skeletal growth in young osteosarcoma patients as a late adverse effect based on two different evaluation methods. However, patients aged ≤10 years at diagnosis may develop a short stature after systemic chemotherapy. Full article

Background: To determine the risk of mortality and factors associated with survival amongst patients diagnosed with primary hepatic angiosarcoma (PHA). Methods: All patients diagnosed with hepatocellular carcinoma (HCC) or PHA from 2004 to 2014 were identified from the National Cancer Database (NCDB). Further analysis was performed within the cohort of patients with PHA to assess the impact of surgery, chemotherapy, radiation, and facility type on overall survival (OS). A multivariable analysis using the Cox proportional methods and a survival analysis using the Kaplan–Meier method were used. Results: A total of 117,633 patients with HCC were identified, out of whom 346 patients had PHA. Patients with PHA had a mean age of 62.9 years (SD 13.7), the majority were men (64.7%), white (85.8%), and had a Charlson comorbidity index (CCI) of zero (66.2%). A third of the patients with PHA (35.7%) received chemotherapy, and 14.6% underwent a surgical resection. The median survival was 1.9 months (1.8–2.4 months) compared to patients with HCC (10.4 months, 10.2–10.5) (aHR-2.41, 95% CI: 2.10–2.77, p < 0.0001). Surgical resection was associated with a higher median survival (7.7 versus 1.8 months, aHR-0.23, 95% CI: 0.15–0.37, p < 0.0001). A receipt of chemotherapy was associated with a higher median survival than no chemotherapy (5.1 versus 1.2 months, aHR-0.44, 95% CI: 0.32–0.60, p < 0.0001), although the survival benefit did not persist long term. Conclusion: PHA is associated with poor outcomes. A surgical resection and chemotherapy are associated with improved survival outcomes; however, the long-term benefits of chemotherapy are limited. Full article

The development of appropriate photothermal detection of skin diseases to meet complex clinical demands is an urgent challenge for the prevention and therapy of skin cancer. An extensive body of literature has ignored all high-order harmonics above the second order and their influences on low-order harmonics. In this paper, a new iterative numerical method is developed for solving the nonlinear thermal diffusion equation to improve nonlinear photothermal detection for the noninvasive assessment of the thickness of port-wine stain (PWS). First, based on the anatomical and structural properties of skin tissue of PWS, a nonlinear theoretical model for photothermal detection is established. Second, a corresponding nonlinear thermal diffusion equation is solved by using the new iterative numerical method and taking into account harmonics above the second-order and their effects on lower-order harmonics. Finally, the thickness and excitation light intensity of PWS samples are numerically simulated. The simulation results show that the numerical solution converges fasterand the physical meaning of the solution is clearerwith the new method than with the traditional perturbation method. The rate of change in each harmonic with the sample thickness for the new method is higher than that for the conventional perturbation method, suggesting that the proposed numerical method may provide greater detection sensitivity. The results of the study provide a theoretical basis for the clinical treatment of PWS. Full article

Due to the rarity of primary angiosarcoma of the breast, optimal management is based on expert opinion. The aim of this study was to review all primary angiosarcomas of the breast obtained from a single center in terms of clinicopathologic characteristics, treatment, and survival outcomes. From 1997 to 2020, 15 patients with primary angiosarcoma of the breast underwent either mastectomy or wide excision. We analyzed the clinicopathologic data to assess disease-free survival and overall survival. Fifteen women with primary angiosarcoma of the breast were identified. The mean age at diagnosis was 33 years (range: 14–63 years). The overall mean tumor size was 7.7 cm (range 3.5–20 cm). Upon histological grading, there were three cases of low grade, five intermediate grade, six high grade, and one unidentified grade. The five-year disease-free survival rate was 24.4%, and the five-year survival rate was 37.2%. The survival rate of the low-grade patient group was statistically higher than that of the intermediate- or high-grade patient groups (p = 0.024). Primary angiosarcoma of the breast is a rare aggressive tumor characterized by high grade and poor outcome. Histologic grade appears to be a reliable predictor of survival. There are no standard treatment guidelines; thus, optimal R0 surgical resection remains the best approach. The roles of neoadjuvant, adjuvant chemotherapy, and radiotherapy remain unclear. Full article

Radiation-induced fibrosis (RIF) is a severe side effect related with soft tissues sarcomas (STS) radiotherapy. RIF is a multicellular process initiated primarily by TGF-β1 that is increased in irradiated tissue, whose signaling leads to intracellular Smad2/3 phosphorylation and further induction of profibrotic target genes. P144 (Disetertide©) is a peptide inhibitor of TGF-β1 and is proposed as a candidate compound for reducing RIF associated wound healing problems and muscle fibrosis in STS. Methods: A treatment and control group of WNZ rabbits were employed to implement a brachytherapy animal model, through catheter implantation at the lower limb. Two days after implantation, animals received 20 Gy isodosis, intended to induce a high RIF grade. The treatment group received intravenous P144 administration following a brachytherapy session, repeated at 24–72 h post-radiation, while the control group received placebo. Four weeks later, affected muscular tissues underwent histological processing for collagen quantification and P-Smad2/3 immunohistochemistry through image analysis. Results: High isodosis Brachytherapy produced remarkable fibrosis in this experimental model. Results showed retained macro and microscopical morphology of muscle in the P144 treated group, with reduced extracellular matrix fibrosis, with a lower area of collagen deposition measured through Masson’s trichrome staining. Intravenous P144 also induced a significant reduction in Smad2/3 phosphorylation levels compared with the placebo group. Conclusions: P144 administration clearly reduces RIF and opens a new potential co-treatment approach to reduce complications in soft tissue sarcoma (STS) radiotherapy. Further studies are required to establish whether the dosage and timing optimization of P144 administration, in different RIF phases, might entirely avoid fibrosis associated with STS brachytherapy. Full article

Background/Aim: Patients with uterine sarcoma comprise 2–5% of all patients with uterine malignancies; however, the morbidity of uterine sarcoma is low compared with that of other gynecological cancers. For many cases, malignant uterine tumors are diagnosed during follow-up of benign uterine leiomyoma. Of the uterine sarcomas, rhabdomyosarcoma is considered a mixed tumor containing components of epithelial cells and mesenchymal cells. Therefore, the onset of primary uterine rhabdomyosarcoma during follow-up of uterine leiomyoma is extremely rare. Rhabdomyosarcoma is a relatively common malignant tumor in children, but rhabdomyosarcoma in adults is extremely rare, accounting for approximately 3% of all patients with soft tissue sarcoma. Rhabdomyosarcoma in children is highly sensitive to chemotherapy and radiation therapy; however, the response to chemotherapy and radiation therapy in adult rhabdomyosarcoma is low and survival in adult rhabdomyosarcoma with metastatic lesions to other organs is approximately 14 months. We experienced a case of pleomorphic rhabdomyosarcoma during the follow-up of a uterine leiomyoma. Materials and Methods: We examined the oncological properties of uterine rhabdomyosarcoma in adults using molecular pathological techniques on tissue excised from patients with uterine leiomyoma. Result: A differential diagnosis was made for this case by molecular pathology, which included candidate biomarkers for uterine smooth muscle tumors. The oncological nature of uterine rhabdomyosarcoma was found to be similar to the oncological properties of uterine leiomyosarcoma. However, in uterine rhabdomyosarcoma, LMP2/β1i-positive cells were clearly observed. Conclusion: It is expected that establishing a diagnostic and treatment method targeting characteristics of mesenchymal tumor cells will lead to the treatment of malignant tumors with a low risk of recurrence and metastasis. Full article

Background: Few studies have described the characteristics and prognostic factors of patients with metastatic extrauterine leiomyosarcoma (euLMS). Therefore, we retrospectively investigated the clinicopathological features, clinical outcomes, and prognostic factors of patients with euLMS. Methods: We recruited 61 patients with metastatic euLMS treated from 2006 to 2020 and collected and statistically analyzed information on patient-, tumor-, and treatment-related factors. The median follow-up period was 21.1 months. Results: Sixty-one patients with euLMS and a median age of 59 years were included. Furthermore, their five-year overall survival (OS) rate was 38.3%. Univariate analysis revealed that primary tumor size >10 cm, synchronous metastasis, initial metastatic sites >1, and no metastasectomy with curative intent were significantly associated with poor OS rate. Multivariate analysis identified primary tumor size >10 cm as an independent prognostic factor for poor OS. Among 24 patients who received metastasectomy with curative intent, the interval from the initial diagnosis to development of metastasis ≤6 months was significantly correlated with unfavorable OS. Among 37 patients who did not receive metastasectomy, chemotherapy after metastasis development was significantly related to better OS. Conclusions: Complete metastasectomy should be considered for metastatic euLMS treatment. Moreover, chemotherapy could prolong survival in patients with metastasis who are ineligible for metastasectomy. Full article