Soft Tissue Sarcoma Patients Research Articles

Pandemic driven preoperative moderate hypofractionated radiotherapy for soft tissue sarcomas.

Moderate hypofractionation was adopted to reduce hospital visits during the COVID-19 pandemic aiming to maintain treatment efficacy for soft tissue sarcoma (STS) patients, shifting preoperative schedules from 25 fractions of 2 Gy to 14-15 fractions of 3 Gy. This study evaluates the clinical implications and outcomes of this schedule, focusing on wound complications, radiation toxicity, local tumour control, and distant metastases. Data was collected from patients treated between 01 and 01-2020 and 31-12-2023. Outcomes included wound complications within 120 days post-surgery, local-recurrence, distant metastases and radiation toxicity. Logistic regression was performed to identify factors associated with wound complications. The cumulative incidence of local recurrence and distant metastases were estimated with a competing risk model. Sixty-six patients were analysed, with a mean age of 74 years (standard deviation (SD)± 11). Tumours were mainly localized in the lower extremities (64 %), mean size 103 mm (SD±58). Median follow-up was 29 months (range 2-50). A R0 resection margin was achieved in 77 % of the operated patients. The wound complication rate was 33 %, with moderate complications in 13 patients and severe in 6. The cumulative incidences of local recurrence and distant metastases at 2 years were 7.6 % (standard error (SE) 3.7 %) and 29 % (SE 6 %, Fig. 1) respectively. Acute grade 3 dermatitis occurred in one patient (1.5 %)and two patients experienced late grade 3 toxicity (fractures, 3.0 %). Twenty patients developed distant metastases, two diagnosed before start of the treatment. Eighteen patients died, with six deaths from distant metastases and one from the primary tumour. Preoperative moderate hypofractionation for STS during COVID-19 showed promising results, with no increase in postoperative wound complications and favourable local failure rates.

Gemcitabine-Based Chemotherapy for Advanced Soft Tissue Sarcoma: Identifying the Appropriate Dose and Schedule.

Background In 2024, reimbursement for gemcitabine-docetaxel therapy (GEM-DOC; gemcitabine 900 mg/m2on days 1 and 8 and docetaxel 70 mg/m2on day 8 every 21 days, GEM 900-DOC 70) to treat recurrent/metastatic soft tissue sarcoma (STS) was made in Japan. Methods We retrospectively reviewed clinical records of advanced/metastatic STS patients who underwent off-label gemcitabine-containing chemotherapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Researchbetween February 2007 and October 2019. Results Of 115 enrolled patients, 51 were treated with GEM-DOC (26 patients received the dose as previously stated) and the other 64 with gemcitabine monotherapy. Objective response rates (ORR; 9.8% versus 4.7%), progression-free survival (PFS; 3.8 months versus 2.1 months), and overall survival (OS; 21.5 months versus 11.8 months) tended to be superior in GEM-DOC; the difference of the rate of following salvage treatment (GEM-DOC, 82.4%; gemcitabine monotherapy, 48.4%) could affect the OS. As for safety, severe adverse events (grade 3 {G3} or more) were more frequent in patients with GEM-DOC (hematologic, 80.4% versus 40.6%; non-hematologic, 19.6% versus 15.6%), including those using the stated dose (hematologic, 96.1%; non-hematologic, 26.9%). Conclusion The stated dose of GEM-DOC could be effective for STSbut shows more toxicity compared to other dose settings or gemcitabine monotherapy. An investigation of appropriate dose settings by prospective clinical trial may be needed.

Selective Synergy of Recombinant Methioninase Plus Docetaxel Against Docetaxel-resistant and -sensitive Fibrosarcoma Cells Compared to Normal Fibroblasts.

Docetaxel combined with gemcitabine is a second-line treatment for soft-tissue sarcoma; however, its effectiveness is limited because of docetaxel resistance. The objective of the present study was to determine the potential of recombinant methioninase (rMETase) to enhance the efficacy of docetaxel on high-docetaxel-resistant human fibrosarcoma cells in vitro. Docetaxel-resistant HT1080 (DTR-HT1080) human fibrosarcoma cells were established by culturing them in by progressively increasing concentrations of docetaxel from 0.02 to 9 nM in vitro. The IC50 values for docetaxel and rMETase, as well as the efficacy of their combination, in inhibiting HT1080 human fibrosarcoma cells, DTR-HT1080 cells, and Hs27 normal human fibroblasts were determined. Four experimental groups were examined in vitro: control group without treatment; docetaxel alone; rMETase alone; docetaxel combined with rMETase. The IC50 of docetaxel for DTR-HT1080 cells was 7.57 nM, compared to the parental HT1080 cells with an IC50 of 1.68 nM, a 4.5-fold increase. The IC50 of docetaxel on Hs27 fibroblasts was 4.46 nM. The IC50 of rMETase on HT1080 cells was 0.75 U/ml (data from [6]). The IC50 of rMETase on DTR-HT1080 cells was 0.55 U/ml. The IC50 of rMETase on Hs27 fibroblasts was 0.93 U/ml (data from [6]). Docetaxel (1.68 nM [IC50]) plus rMETase (0.75 U/ml [IC50]) synergistically reduced the viability of HT1080 cells (p<0.05). In contrast, docetaxel (4.46 nM) plus rMETase (0.93 U/ml) did not reduce the viability of Hs27 fibroblasts, compared to either agent alone. The combination of rMETase (0.55 U/ml [IC50]) and docetaxel (1.68 nM [IC50 of the parental cells]) overcame docetaxel resistance of DTR-HT1080 cells, resulting in an inhibition of 48.1% compared to docetaxel alone (6.8%) or rMETase alone (37.5%) (p<0.05). rMETase thus increased the efficacy of docetaxel 7-fold on docetaxel-resistant human fibrosarcoma cells. The combination of docetaxel and rMETase was synergistic on HT1080 fibrosarcoma cells, but not normal fibroblasts. rMETase plus docetaxel synergistically reduced the high docetaxel resistance of DTR-HT1080 cells. The present results indicate the clinical potential of rMETase to reduce docetaxel resistance in soft-tissue sarcoma patients in the future.

Study protocol: randomized phase III trial of neo-adjuvant and adjuvant chemotherapy vs. immediate surgery and adjuvant chemotherapy for localized soft tissue sarcoma: Japan Clinical Oncology Group study JCOG2102 (NACLESS).

The optimal timing of surgery and the number of courses of perioperative chemotherapy for high-risk soft tissue sarcoma patients are still controversial. Tumour growth during neoadjuvant chemotherapy led to limb amputation in some patients. This study aims to confirm the non-inferiority of surgery and three courses of adjuvant chemotherapy with adriamycin (30mg/m2, days 1 and 2) plus ifosfamide (2g/m2, days 1-5) compared with our standard treatment of three courses of neoadjuvant chemotherapy and surgery followed by two courses of adjuvant chemotherapy with adriamycin plus ifosfamide for localized high-risk soft tissue sarcoma patients. This is a multi-center, two-arm, open-label, randomized phase III trial. The primary aim is to confirm the non-inferiority in overall survival (margin: hazard ratio of 1.61). This is the first randomized controlled trial to compare neoadjuvant chemotherapy and immediate surgery for soft tissue sarcoma. This trial was initiated on 16 November 2022 and registered with the Japan Clinical Trials Registry (jRCTs031220446).

Peripheral immune profiling of soft tissue sarcoma: perspectives for disease monitoring.

Studying the tumor microenvironment and surrounding lymph nodes is the main focus of current immunological research on soft tissue sarcomas (STS). However, due to the restricted opportunity to examine tumor samples, alternative approaches are required to evaluate immune responses in non-surgical patients. Therefore, the purpose of this study was to evaluate the peripheral immune profile of STS patients, characterize patients accordingly and explore the impact of peripheral immunotypes on patient survival. Blood samples were collected from 55 STS patients and age-matched healthy donors (HD) controls. Deep immunophenotyping and gene expression analysis of whole blood was analyzed using multiparametric flow cytometry and real-time RT-qPCR, respectively. Using xMAP technology, proteomic analysis was also carried out on plasma samples. Unsupervised clustering analysis was used to classify patients based on their immune profiles to further analyze the impact of peripheral immunotypes on patient survival. Significant differences were found between STS patients and HD controls. It was found a contraction of B cells and CD4 T cells compartment, along with decreased expression levels of ICOSLG and CD40LG; a major contribution of suppressor factors, as increased frequency of M-MDSC and memory Tregs, increased expression levels of ARG1, and increased plasma levels of IL-10, soluble VISTA and soluble TIMD-4; and a compromised cytotoxic potential associated with NK and CD8 T cells, namely decreased frequency of CD56dim NK cells, and decreased levels of PRF1, GZMB, and KLRK1. In addition, the patients were classified into three peripheral immunotype groups: "immune-high," "immune-intermediate," and "immune-low." Furthermore, it was found a correlation between these immunotypes and patient survival. Patients classified as "immune-high" exhibited higher levels of immune-related factors linked to cytotoxic/effector activity and longer survival times, whereas patients classified as "immune-low" displayed higher levels of immune factors associated with immunosuppression and shorter survival times. In conclusion, it can be suggested that STS patients have a compromised systemic immunity, and the correlation between immunotypes and survival emphasizes the importance of studying peripheral blood samples in STS. Assessing the peripheral immune response holds promise as a useful method for monitoring and forecasting outcomes in STS.

Targeting KIFC1 Promotes Senescence in Soft Tissue Sarcoma via FXR1-Dependent Regulation of MAD2L1 mRNA Stability.

Patients diagnosed with soft tissue sarcoma (STS) often present at intermediate to advanced stages, with inherently limited therapeutic options available. There is an urgent need to identify novel therapeutic targets. In this study, by screening STS data from the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases, KIFC1 is identified as a potential biomarker and a promising therapeutic target for STS. Notably, a significant increase in KIFC1 levels, which exhibited a strong correlation with a poor prognosis in STS patients is observed. The findings revealed that knockout of KIFC1 suppressed STS growth both in vitro and in vivo. Furthermore, KIFC1 is found to regulate cellular senescence in STS, which has not been reported before. that targeting KIFC1 induced cellular senescence via interacting with FXR1, an RNA-binding protein is discovered, thereby further stabilizing MAD2L1 mRNA in an m6A-dependent manner. Additionally, the suppression of KIFC1 markedly diminished the growth of patient-derived xenografts (PDX) and triggered senescence. This study provides the first evidence that KIFC1 inhibition induces cellular senescence through MAD2L1, underscoring KIFC1 as a novel prognostic biomarker and a potential therapeutic target for STS.

A study of pre- and post-treatment hematologic markers of immune response in patients undergoing radiotherapy for soft tissue sarcoma.

This study investigates the impact of pre- and post-treatment hematologic markers, specifically neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), on treatment outcomes in soft tissue sarcoma (STS) patients undergoing radiation therapy (RT). Data from 64 patients who underwent RT for curative management of STS were reviewed. Pre-RT and post-RT hematologic measures were evaluated for associations with survival outcomes. A normal tissue complication probability (NTCP) curve for predicting ΔPLR ≥ 75 was modeled using a probit function. Elevated baseline NLR was associated with worse overall survival (OS) and disease-free survival (DFS), while elevated PLR was associated with worse DFS. Post-RT, elevated PLR was linked to worse OS and DFS. Increasing PLR change post-RT was associated with worse OS and DFS. Receiver operating characteristics analysis determined ΔPLR ≥ 75 to be a robust cutoff associated with worse DFS. Bone V10Gy ≥362 cc corresponded to a 50% risk of developing ΔPLR ≥ 75. These results suggest that hematologic markers could serve as prognostic biomarkers in both pre- and post-treatment settings for STS patients undergoing RT. Future studies can consider using bone V10Gy < 362 cc as a potential cutoff to reduce the risk of increased PLR after RT.

Optimal Setup and Parameters of Diffusion-Weighted Magnetic Resonance Imaging for Translational Evaluation of a Tumor Progression Model for Soft Tissue Sarcomas

PurposeDefining a microscopic tumor infiltration boundary is critical to the success of radiation therapy. Currently, radiation oncologists use margins to geometrically expand the visible tumor for radiation treatment planning in soft tissue sarcomas (STS). Image-based models of tumor progression would be critical to personalize treatment radiation field to the pattern of sarcoma spread. Evaluation of these models is necessary to demonstrate feasibility in the clinical setting. This study presents an imaging protocol for the preclinical evaluation of a tumor progression model in extremity STS. MethodsWe recruited seven healthy volunteers and acquired diffusion-weighted MRI (DW-MRI) images of the thigh on an MRI scanner used for imaging cancer patients in a radiation oncology department. We developed a protocol, which includes positioning the patient, configuring the RF coils, and setting the diffusion-weighted MRI sequence parameters. To find the optimal parameter configuration, the image signal-to-noise ratio (SNR) and the directional variability (DV) of the principal eigenvector of the diffusion tensor were calculated. ResultsThe mean SNR across all trials and 12 thigh muscles was 41 with a range of 12 to 72. The mean DV was 13° and ranged from 11° to 23°. The longest scan time was 22 min 58 s and the shortest 11 min 46 s. For the high-resolution image with a voxel volume of 1.3×1.3×6 mm3 and 38 slices, the optimal parameters were found to be a repetition time of 8000 ms, 12 signal averages, and 6 gradient directions. This configuration resulted in a scan time of 11 min 46 s, an SNR of 34, and a DV of 13°. ConclusionsA DW-MRI scan duration acceptable for imaging cancer patients was achieved with an image quality suitable for reproducible modeling of tumor infiltration. The developed protocol can be used for preclinical evaluation in STS patients.

The application of lung immune prognostic index in predicting the prognosis of 302 STS patients.

Soft tissue sarcoma (STS) are heterogeneous and rare tumors, and few studies have explored predicting the prognosis of patients with STS. The Lung Immune Prognostic Index (LIPI), calculated based on baseline serum lactate dehydrogenase (LDH) and the derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR), was considered effective in predicting the prognosis of patients with pulmonary cancer and other malignancies. However, the efficacy of the LIPI in predicting the prognosis of patients with STS remains unclear. This study retrospectively reviewed patients with STS admitted to our center from January 2016 to January 2021. Their hematological and clinical characteristics were collected and analyzed to construct the LIPI specific to STS. The correlations between various predictive factors and overall survival (OS) were examined using Kaplan-Meier and Cox regression analyses. Independent risk factors for OS were identified using univariate and multivariate analyses. Finally, a LIPI nomogram model for STS was established. This study enrolled 302 patients with STS, of which 87 (28.9%), 162 (53.6%), and 53 (17.5%) were classified into three LIPI-based categories: good, moderate, and poor, respectively (P < 0.0001). The time-dependent operator curve showed that the LIPI had better prognostic predictive ability than other hematological and clinical characteristics. Univariate and multivariate analyses identified the Fédération Nationale des Centres de Lutte Contre le Cancer grade (FNCLCC/G), tumor size, and LIPI as independent risk factors. Finally, a nomogram was constructed by integrating the significant prognostic factors. Its C-index was 0.72, and the calibration curve indicated that it could accurately predict the three- and five-year OS of patients with STS. The decision and clinical impact curves also indicated that implementing this LIPI-nomogram could significantly benefit patients with STS. This study explored the efficacy of the LIPI in predicting the prognosis of 302 patients with STS, classifying them into three categories to evaluate the prognosis. It also reconstructed a LIPI-based nomogram to assist clinicians in predicting the three- and five-year OS of patients with STS, potentially enabling timely intervention and customized management.

Impact of COVID-19 pandemic on bone and soft tissue sarcoma patients’ consultation and diagnosis

The coronavirus disease (COVID-19) pandemic negatively affected the diagnosis and treatment of several cancer types. However, this pandemic’s exact impact and extent on bone and soft tissue sarcomas need to be clarified. We aimed to investigate the effect of the COVID-19 pandemic and emergency declaration by the local government on consultation behavior and clinical stage at diagnosis of bone and soft tissue sarcoma. A total of 403 patients diagnosed with bone and soft tissue sarcoma who initially visited three sarcoma treatment hospitals between January 2018 and December 2021 were included. The monthly number of newly diagnosed soft tissue sarcoma patients was reduced by 25%, and the proportion of soft tissue patients with stage IV disease at diagnosis significantly increased by 9% during the COVID-19 pandemic compared to before the COVID-19 pandemic. Furthermore, the monthly number of new primary bone and soft tissue sarcoma patients significantly decreased by 43% during the state of emergency declaration. The COVID-19 pandemic had a negative impact on soft tissue sarcoma patients’ consultation behavior and increased the proportion of advanced-stage patients at initial diagnosis. An emergency declaration by the local government also negatively affected primary bone and soft tissue sarcoma patients’ consultation behavior.

1740P Surufatinib combined with gemcitabine in soft tissue sarcoma (STS) patients failed with anthracyclines chemotherapy or monotherapy post-anlotinib progression: A multi-center, phase II trial

1740P Surufatinib combined with gemcitabine in soft tissue sarcoma (STS) patients failed with anthracyclines chemotherapy or monotherapy post-anlotinib progression: A multi-center, phase II trial

1718O EREMISS trial: A double-blind placebo (PBO)-controlled randomised trial assessing efficacy/safety of regorafenib (REGO) as maintenance therapy after 1st line doxorubicin-based chemotherapy in advanced soft-tissue sarcoma (ASTS) patients (pts)

1718O EREMISS trial: A double-blind placebo (PBO)-controlled randomised trial assessing efficacy/safety of regorafenib (REGO) as maintenance therapy after 1st line doxorubicin-based chemotherapy in advanced soft-tissue sarcoma (ASTS) patients (pts)

Clear cell sarcoma in Japan: an analysis of the population-based cancer registry in Japan.

Clear cell sarcoma is rare, so no reports have previously characterized its national profiles. We examined the nationwide epidemiology and clinical outcomes of patients with clear cell sarcoma based on the National Cancer Registry in Japan. Overall, 23 522 patients with soft tissue sarcoma-entered in the National Cancer Registry in 2016-2019 using the International Classification of Diseases for Oncology, Third Edition cancer topography and morphology codes-were enrolled in either the clear cell or the non-clear cell sarcoma group. Data extracted included: demographics (sex and age), tumor details (reason for diagnosis, tumor location, histology and stage), hospital volume and facility type, treatment and prognosis for each patient. Of 23 522 soft tissue sarcoma patients, 122 were enrolled in the clear cell sarcoma group and 23 400 in the non-clear cell sarcoma group. The incidence of clear cell sarcoma was 0.52% of all soft tissue sarcoma, with an age-adjusted incidence of 0.024/100 000/year. The age at diagnosis was significantly younger, and more tumors were at the localized stage in the clear cell than the non-clear cell sarcoma group. In addition, the overall survival in the clear cell group was worse than in the non-clear cell group (P<0.001). Of 122 patients with clear cell sarcoma, the localized stage, surgical treatment and treatment without chemotherapy were associated with better overall survival in the univariate analyses. The present study is the first to have clarified the epidemiology, clinical features, treatment, prognosis and significant factors affecting the prognosis of patients with clear cell sarcoma in Japan.

Unraveling the role of local ablative therapies for patients with metastatic soft tissue sarcoma – A retrospective multicenter study of the Bavarian university hospitals

BackgroundLocal ablative therapies (LAT) are increasingly used in patients with metastatic soft tissue sarcoma (STS), yet evidence-based standards are lacking. This study aimed to assess the impact of LAT on survival of metastatic STS patients and to identify prognostic factors. MethodsIn this retrospective multicenter study, 246 STS patients with metastatic disease who underwent LAT on tumor board recommendation between 2017 and 2021 were analyzed. A mixed effects model was applied to evaluate multiple survival events per patient. ResultsMedian overall survival (OS) after first metastasis was 5.4 years with 1-, 2- and 5-year survival rates of 93.7, 81.7, and 53.1 %, respectively. A treatment-free interval ≥12 months and treatment of liver metastases were positively correlated with progression-free survival (PFS) after LAT (HR = 0.61, p = 0.00032 and HR = 0.52, p = 0.0081, respectively). A treatment-free interval ≥12 months and treatment of metastatic lesions in a single organ site other than lung and liver were positive prognostic factors for OS after first LAT (HR = 0.50, p = 0.028 and HR = 0.40, p = 0.026, respectively) while rare histotypes and LAT other than surgery and radiotherapy were negatively associated with OS after first LAT (HR = 2.56, p = 0.020 and HR = 3.87, p = 0.025). Additional systemic therapy was independently associated with a PFS benefit in patients ≤60 years with ≥4 metastatic lesions (for max. diameter of treated lesions ≤2 cm: HR = 0.32, p = 0.02 and >2 cm: HR = 0.20, p = 0.0011, respectively). ConclusionThis multicenter study conducted at six German university hospitals underlines the value of LAT in metastatic STS. The exceptionally high survival rates are likely to be associated with patient selection and treatment in specialized sarcoma centers.

The mitotic rate as a prognostic biomarker after preoperative radiotherapy for high-grade limb/trunk soft tissue sarcoma

PurposeCurrently there is no generally accepted standardized approach for the pathological evaluation of soft tissue sarcoma (STS) histology appearance after preoperative radiotherapy (PORT). This study aimed to investigate the prognostic value of pathological appearance after PORT for patients with high-grade limb/trunk STS. MethodsA cohort of 116 patients with high-grade STS of the limb/trunk treated with PORT followed by resection were evaluated. Patient characteristics, imaging tumor morphology (size, volume), and histopathology (mitotic and necrosis rate, viable cell, hyalinization/fibrosis cytopathic effect) were reviewed and reassessed. Disease free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the hazard ratio was derived from Cox proportional hazard models. Two predictive nomograms were calculated based on significant predictors identified. ResultsThe 5-year DFS and OS were 52.9% and 70.3%, respectively. Tumor size before (HR:1.07, 95%CI: 1.01–1.14) and after PORT (HR:1.08, 95%CI: 1.01–1.14), tumor volume (HR:1.06, 95%CI: 1.01–1.12), mitotic rate after PORT (HR: 1.06, 95%CI: 1.02–1.11), mitotic rate change after PORT (HR:1.04, 95%CI:1.00–1.09) were independent risk factors for DFS. Tumor size before (HR:1.08, 95%CI: 1.03–1.14) and after PORT (HR:1.09, 95%CI: 1.04–1.15), tumor volume (HR:1.05, 95%CI: 1.01–1.09), mitotic rate after PORT (HR: 1.09, 95%CI: 1.04–1.13), mitotic rate change after PORT (HR:1.05, 95%CI:1.01–1.09) were independent risk factors for OS. The C-index of pathologic predictive nomogram based on mitotic rate for DFS and OS were 0.67 and 0.73, respectively. The C-index of morphology-pathology predictive nomogram for OS was 0.79. ConclusionTumor size before and after PORT, tumor volume, mitotic rate after PORT, mitotic rate change after PORT were independent risk factors for DFS and OS in high-grade STS patients treated with PORT. The mitotic rate, independent of tumor morphology, showed its potential as a prognostic biomarker for pathologic evaluation in patients treated with PORT.

Understanding how a personalized risk prediction tool (VALUE-PERSARC) supports informed treatment decisions of soft-tissue sarcomas patients in daily clinical practice – A mixed methods study

IntroductionRisk prediction models (RPM) can help soft-tissue sarcoma(STS) patients and clinicians make informed treatment decisions by providing them with estimates of (disease-free) survival for different treatment options. However, it is unknown how RPMs are used in the clinical encounter to support decision-making. This study aimed to understand how a PERsonalised SARcoma Care (PERSARC) RPM is used to support treatment decisions and which barriers and facilitators influence its use in daily clinical practice. MethodsA convergent mixed-methods design is used to understand how PERSARC is integrated in the clinical encounter in three Dutch sarcoma centers. Data were collected using qualitative interviews with STS patients (n = 15) and clinicians (n = 8), quantitative surveys (n = 50) and audiotaped consultations (n = 30). Qualitative data were analyzed using thematic analysis and integrated with quantitative data through merging guided by the SEIPS model. ResultsPERSARC was generally used to support clinicians’ proposed treatment plan and not to help patients weigh available treatment options. Use of PERSARC in decision-making was hampered by clinician’s doubts about whether there were multiple viable treatment options,the accuracy of risk estimates, and time constraints. On the other hand, use of PERSARC facilitated clinicians to estimate and communicate the expected benefit of adjuvant therapy to patients. ConclusionPERSARC was not used to support informed treatment decision-making in STS patients. Integrating RPMs into clinical consultations requires acknowledgement of their benefits in facilitating clinicians' estimation of the expected benefit of adjuvant therapies and information provision to patients, while also considering concerns regarding RPM quality and treatment options' viability.

Risk Stratification Tools to Aid Decisions on Adjuvant Chemotherapy Usage in Resected Soft Tissue Sarcomas: A Ten-Year Review of an Irish Sarcoma Center Experience.

Soft tissue sarcoma (STS) is comprised of approximately 80 subtypes, with an incidence of 4 - 5 per 100,000 annually in Europe. The National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of neoadjuvant/adjuvant chemotherapy in tumors at high risk of recurrence based on the American Joint Committee on Cancer (AJCC) staging. Alternatively, the Sarculator is a risk prediction tool that has identified a threshold of risk, above which chemotherapy may provide an overall survival (OS) benefit. Using this nomogram, patients with a 10-year predicted OS < 60% are classified as high risk and should be considered for chemotherapy. The aim of this study was to assess the prognostic accuracy of these two risk prediction methods in an Irish population. All newly diagnosed patients with resected STS discussed in the STS tumor board in Cork University Hospital between January 2012 and December 2021 were identified. Clinicopathological data were collected. Risk assessment using AJCC and Sarculator nomogram was performed on all patients with an extremity/trunk sarcoma. The OS was calculated including Kaplan-Meier method for time to event analysis. In total, 200 STS patients were reviewed, of whom 134 had truncal or extremity tumors. Sarculator score was calculated for 60 of these (well differentiated liposarcomas, desmoid tumors and dermatofibrosarcoma protuberans were excluded). Using the Sarculator nomogram to calculate 10-year predicted OS, 19 patients were categorized as high risk and 41 were categorized as low risk. Using AJCC staging, 25 patients were categorized as high risk and 35 as low risk. The 5-year OS rate in the Sarculator high-risk group was 60.2%, compared with 87.1% in the low-risk group (P = 0.009). The 5-year OS rate in the AJCC high-risk group was 67.6%, compared with 86.3% in the low-risk group (P = 0.083). Our cohort is representative of the broad histological subtypes expected. In our population, Sarculator score results correlate with international outcomes and higher scores were associated with increased mortality. The Sarculator was more predictive of clinical outcome than AJCC staging, and its use would lower the proportion of patients being considered for adjuvant chemotherapy thereby sparing toxicity, which is important in the setting of uncertain clinical benefit.

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). TDM reduced the proportion of patients with subtherapeutic exposure levels by ~50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

Spatial distribution of tumour immune infiltrate predicts outcomes of patients with high-risk soft tissue sarcomas after neoadjuvant chemotherapy

BackgroundAnthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. MethodsThe ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). FindingsTumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. InterpretationThe different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS.Funding: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5x1000 Funds—2016, Italian Ministry of Health; AIRC Grant [ID#28546].

Interleukin-6 in relation to early recurrence in primary, localized soft tissue sarcoma: An addition for existing risk classification systems?

BackgroundSeveral inflammatory markers have gained interest as prognostic factors for cancer. The aim of this study is to evaluate the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as predictive markers for aggressive behavior and early recurrences in primary, localized soft tissue sarcoma (STS). Methods115 STS patients were retrospectively reviewed. IL-6 and CRP blood levels, NLR and PLR were obtained prior to treatment. Early recurrence was defined as disease relapse (local or distant) within the first year after surgery. Cox regression analysis was used to identify prognostic factors for early recurrence. ResultsIL-6 elevation was associated with a higher tumor grade, increased size, tumor necrosis and a higher mitotic count. NLR elevation was associated with a higher tumor grade, PLR elevation with a larger tumor size. Early recurrences were found in 24 patients (21 %). Univariable analysis revealed that tumor grade (p = 0.029), tumor size (p = 0.030, >10 cm vs < 5 cm), tumor depth (p = 0.036), necrosis on imaging (p = 0.008), mitotic count (p = 0.045, ≥20 mitoses vs 0–9 mitoses), and IL-6 level (p = 0.044) were associated with early recurrence. The factors age at diagnosis, tumor location, necrosis at pathology, (neo)adjuvant radio- or chemotherapy, resection margin, CRP level, NLR and PLR were not related to early disease recurrence. ConclusionsIncreased inflammatory markers in STS are associated with an aggressive phenotype. STS patients with elevation of IL-6 may be at risk for early disease recurrence.