Purpose: This study aimed to determine the relevance of first- and high-order radiomic features derived from Diffusion-Weighted Imaging (DWI) and Apparent Diffusion Coefficient (ADC) maps for predicting treatment response in patients with Undifferentiated Pleomorphic Sarcoma (UPS). Methods: This retrospective study included 33 extremity UPS patients with pre-surgical DWI/ADC and surgical resection. Manual volumetric tumor segmentation was performed on DWI/ADC maps acquired at Baseline (BL), Post-Chemotherapy (PC), and Post-Radiation Therapy (PRT). The percentage of pathology-assessed treatment effect (PATE) in surgical specimens categorized patients into responders (R; PATE ≥ 90%; 16 patients), partial-responders (PR; 89% - 31% PATE; 10 patients), and non-responders (NR; PATE ≤ 30%; 7 patients). 107 radiomic features were extracted from BL, PC, and PRT ADC maps. Statistical analyses compared R vs. PR/NR. Results: Pseudo-progression at PC and universal stability at PRT were observed in R and PR/NR based on RECIST, WHO, and volumetric assessments. At PRT, responders displayed a 35% increase in ADC mean (p = 0.0034), a 136% decrease in skewness (p = 0.0001), and a 363% increase in the 90th percentile proportion (p = 0.0009). Comparing R vs. PR/NR at BL, statistically significant differences were observed in glrlm_highgraylevelrunemphasis (p = 0.0081), glrlm_shortrunhighgraylevelemphasis (p = 0.0138), gldm_highgraylevelemphasis (p = 0.0138), glcm_sumaverage (p = 0.0164), glcm_jointaverage (p = 0.0164), and glcm_autocorrelation (p = 0.0193). At PC, firstorder_meanabsolutedeviation (p = 0.0078), firstorder_interquartilerange (p = 0.0109), firstorder_variance (p = 0.0109), and firstorder_robustmeanabsolutedeviation (p = 0.0151) provided statistically significant differences. Conclusion: Observing a high post-therapeutic ADC mean, low skewness, and high 90th percentile proportion with respect to baseline is predictive of successfully treated UPS patients presenting > 90% PATE. Highly significant higher-order radiomic results include glrlm-highgraylevelrunemphasis (BL) and first-order-mean absolute deviation (PC).

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

Chordomas are rare neoplasms of notochord origin that can affect the skull base and mobile spine. While surgery and radiation are effective means to treat localized disease, there are no standard systemic therapies to treat locally advanced/metastatic chordomas. We previously published a series of chordoma patients treated with immune checkpoint inhibitors demonstrating limited activity. Here we begin to evaluate the immune microenvironment of chordomas by transcriptional analysis. 57 tissue samples (30 spine chordoma, 21 skull base chordoma, 6 normal), previously analyzed by RNA-sequencing analysis and published (PMID: 28844110), were used. Hierarchical clustering was used to evaluate expression of immune-related genes. Gene ontology analysis was performed with GeneAnalytics. Microenvironment Cell Populations-counter (MCP-counter) was used for quantification of immune cell populations. Spearman's rank correlation coefficient and t-tests were used for statistical purposes. Populations of endothelial cells were significantly different in skull base (SB) samples (p<0.05) and mobile spine (MS) samples (p<0.01) compared to normal. B cells were significantly different in MS compared to normal (p<0.05), and monocytes were significantly different in SB samples compared to normal (p<0.001). 19 genes of the Interferon gamma (IFNG) gene pathway were significantly altered (p<0.05) in SB samples compared to MS samples but only 4 genes of the IFNG pathway were significantly altered (p<0.05) in SB samples compared to normal samples. 9 genes of the IFNG pathway were significantly altered in MS samples compared to normal (p<0.05). Hierarchical clustering of immune-related gene expression revealed 3 distinct groups. Gene ontology analysis revealed that group 1 favored NF-kappa B signaling pathway, group 2 favored the phagosome pathway, and group 3 represented dendritic cell development lineage pathway. Chordomas of the skull base and mobile spine exhibit diverse immune cell populations and differential expression of mediators of immune response. A comprehensive analysis is needed to further our understanding of the immune microenvironment of chordoma to develop ideal immunotherapeutic strategies.

Recurrences are common after resection of DDLPS and UPS. We conducted a neoICB trial in resectable UPS and DDLPS pts and assessed peripheral immune biomarkers. DDLPS (n=17) and UPS (n=10) patients (pts) were treated with neoICB; UPS pts received concurrent radiation. We performed RNA sequencing of peripheral blood mononuclear cells (PBMCs) and tumor specimens collected at baseline, on treatment and at surgery and single sample gene set enrichment analysis (ssGSEA) to quantify 30 immune cell types/signatures. The peripheral TCR repertoire (richness, clonality, density) was assessed by TCR-sequencing of DNA extracted from PBMCs. Correlation between peripheral and tumor immune scores were calculated by Spearman correlation test. Longitudinal comparisons between variables were done using ANOVA tests. Progression-free survival (PFS) was defined from time of neoICB start to progression on neoICB or relapse after surgery. Survival curves were compared using log-rank tests. Median follow-up was 30 months from start of ICB treatment. Median PFS was 20 months (DDLPS: 18 months; UPS: Not Reached), with 15 progression events (12 DDLPS, 3 UPS). None of the peripheral ssGSEA scores correlated with their tumor counterparts at any time point. There was no significant change in any peripheral ssGSEA score nor TCR richness or clonality upon ICB treatment. Peripheral TCR density decreased with ICB treatment (p<0.001; DDLPS: p=0.0037; UPS: p=0.0027). Pts with higher peripheral TCR densities (above median) on treatment had improved PFS (p=0.049). Higher peripheral TCR richness (above median) at baseline showed a trend towards better PFS (p=0.1) and was also seen on treatment (p=0.08) but not at surgery (p=0.81). In UPS and DDLPS patients undergoing neoICB, we were unable to identify a correlation between peripheral and tumor immune cells and signatures. However, peripheral TCR richness and density at baseline and during treatment may identify pts with better prognosis.

BackgroundThe fecal microbiome is associated with toxicity and efficacy of ICB in multiple malignancies, although little is known about its role in STS. We examined the impact of the fecal microbiome on toxicity and early relapse in a phase II trial of neoadjuvant ICB for extremity/truncal undifferentiated pleomorphic sarcoma (UPS) and retroperitoneal dedifferentiated liposarcoma (DDLPS).MethodsPatients (DDLPS, n=17; UPS, n=10) were randomized to receive neoadjuvant nivolumab or nivolumab/ipilimumab, with UPS patients receiving ICB/radiation therapy concurrently. Fecal samples were collected at baseline, after 1 cycle of ICB, and at surgery. Fecal microbiomes were profiled via 16S rRNA gene sequencing and operational taxonomic units determined with UPARSE and the SILVA database. Comparisons were made using alpha and beta diversity scores and taxonomic relative abundances to evaluate differences between the two sarcoma types, patients with early or late relapse, and for those with immune-mediated toxicity, carried out with non-parametric statistical tests.ResultsFecal microbiomes from DDLPS and UPS patients were found to have similar diversity, composition, and structure at baseline (p=0.431). Fecal microbiomes from both histotypes were characterized by an abundance of Bacteroides sp. and Blautia sp; however, baseline samples from patients with UPS had a higher relative abundance of Faecalibaterium sp. when compared to DDLPS (7.5% vs. 4.7%; p=0.038). Patients that experienced immune-mediated diarrhea or colitis had lower Inverse Simpson scores, although this was not statistically significant (p=0.145). We did not observe taxonomic or compositional differences between patients that experienced immune-mediated adverse events compared to those that did not. Interestingly, patients who relapsed during the first year after surgery had lower Inverse Simpson Scores following one cycle of ICB (p=0.039). In contrast, patients who did not relapse during the first year had a higher relative abundance of Ruminococcus at baseline (p=0.011).ConclusionsThis study strongly suggests an impact of the fecal microbiome on toxicity and relapse in STS patients treated with ICB which can be further explored with larger cohorts.Clinical trial identificationNCT03307616.Legal entity responsible for the studyMD Anderson Cancer Center.FundingMD Anderson Cancer Center.DisclosureAll authors have declared no conflicts of interest. BackgroundThe fecal microbiome is associated with toxicity and efficacy of ICB in multiple malignancies, although little is known about its role in STS. We examined the impact of the fecal microbiome on toxicity and early relapse in a phase II trial of neoadjuvant ICB for extremity/truncal undifferentiated pleomorphic sarcoma (UPS) and retroperitoneal dedifferentiated liposarcoma (DDLPS). The fecal microbiome is associated with toxicity and efficacy of ICB in multiple malignancies, although little is known about its role in STS. We examined the impact of the fecal microbiome on toxicity and early relapse in a phase II trial of neoadjuvant ICB for extremity/truncal undifferentiated pleomorphic sarcoma (UPS) and retroperitoneal dedifferentiated liposarcoma (DDLPS). MethodsPatients (DDLPS, n=17; UPS, n=10) were randomized to receive neoadjuvant nivolumab or nivolumab/ipilimumab, with UPS patients receiving ICB/radiation therapy concurrently. Fecal samples were collected at baseline, after 1 cycle of ICB, and at surgery. Fecal microbiomes were profiled via 16S rRNA gene sequencing and operational taxonomic units determined with UPARSE and the SILVA database. Comparisons were made using alpha and beta diversity scores and taxonomic relative abundances to evaluate differences between the two sarcoma types, patients with early or late relapse, and for those with immune-mediated toxicity, carried out with non-parametric statistical tests. Patients (DDLPS, n=17; UPS, n=10) were randomized to receive neoadjuvant nivolumab or nivolumab/ipilimumab, with UPS patients receiving ICB/radiation therapy concurrently. Fecal samples were collected at baseline, after 1 cycle of ICB, and at surgery. Fecal microbiomes were profiled via 16S rRNA gene sequencing and operational taxonomic units determined with UPARSE and the SILVA database. Comparisons were made using alpha and beta diversity scores and taxonomic relative abundances to evaluate differences between the two sarcoma types, patients with early or late relapse, and for those with immune-mediated toxicity, carried out with non-parametric statistical tests. ResultsFecal microbiomes from DDLPS and UPS patients were found to have similar diversity, composition, and structure at baseline (p=0.431). Fecal microbiomes from both histotypes were characterized by an abundance of Bacteroides sp. and Blautia sp; however, baseline samples from patients with UPS had a higher relative abundance of Faecalibaterium sp. when compared to DDLPS (7.5% vs. 4.7%; p=0.038). Patients that experienced immune-mediated diarrhea or colitis had lower Inverse Simpson scores, although this was not statistically significant (p=0.145). We did not observe taxonomic or compositional differences between patients that experienced immune-mediated adverse events compared to those that did not. Interestingly, patients who relapsed during the first year after surgery had lower Inverse Simpson Scores following one cycle of ICB (p=0.039). In contrast, patients who did not relapse during the first year had a higher relative abundance of Ruminococcus at baseline (p=0.011). Fecal microbiomes from DDLPS and UPS patients were found to have similar diversity, composition, and structure at baseline (p=0.431). Fecal microbiomes from both histotypes were characterized by an abundance of Bacteroides sp. and Blautia sp; however, baseline samples from patients with UPS had a higher relative abundance of Faecalibaterium sp. when compared to DDLPS (7.5% vs. 4.7%; p=0.038). Patients that experienced immune-mediated diarrhea or colitis had lower Inverse Simpson scores, although this was not statistically significant (p=0.145). We did not observe taxonomic or compositional differences between patients that experienced immune-mediated adverse events compared to those that did not. Interestingly, patients who relapsed during the first year after surgery had lower Inverse Simpson Scores following one cycle of ICB (p=0.039). In contrast, patients who did not relapse during the first year had a higher relative abundance of Ruminococcus at baseline (p=0.011). ConclusionsThis study strongly suggests an impact of the fecal microbiome on toxicity and relapse in STS patients treated with ICB which can be further explored with larger cohorts. This study strongly suggests an impact of the fecal microbiome on toxicity and relapse in STS patients treated with ICB which can be further explored with larger cohorts.

OBJECTIVES We reviewed our experience treating patients with localized extraskeletal Ewing sarcoma (EES) to determine optimal local management strategies for this rare disease. METHODS Sixty patients with localized EES treated at our institution between 1994 and 2018 were reviewed. The Kaplan-Meier method was used to estimates disease outcomes. RESULTS The median follow-up time was 74 months (interquartile range [IQR], 17-121). Half the patients (n=30) received combined modality local therapy (CMT) with both surgery and radiation therapy (RT), whereas the other half received single modality local therapy (SMT) with either surgery or RT. All patients received chemotherapy. The 5-year OS was 76%. Twenty-two patients (37%) developed recurrence at a median time of 15 months (IQR, 5-56 months) resulting in 3-year PFS 65%. On univariate analysis, the use of both neoadjuvant and adjuvant chemotherapy was associated with improved 5-year PFS (71% vs 50%, p=0.04) compared to those who received one or the other. Furthermore, eleven patients (18%) developed local recurrences at a median time of 14 months (IQR, 2-19 months) resulting in 5-year LC rate of 77%. Use of CMT was not associated with improved LC (83% vs. 72% SMT, P=0.41). Also, use of CMT was the only factor associated with poorer DSS (vs. SMT; HR 3.4, p=0.047, 95% CI 1.01-11.4). CONCLUSION For patients with EES, CMT was not associated with a decreased rate of local relapse. These data suggest that SMT alone may be sufficient for LC in select patients. A multi-institutional collaborative effort should be considered to validate these findings. IMPLICATIONS FOR PRACTICE Extraskeletal Ewing sarcoma is a rare chemo-sensitive sarcoma whose clinical course more closely follows Ewing's sarcoma of bone rather than that of other soft tissue sarcomas. Based on our study, combined modality local therapy did not confer a local control advantage compared to single modality local therapy. Therefore, single modality local therapy is likely adequate in select patients with favorable disease features, which has the advantage of ensuring prompt administration of systemic therapy. A multi-institutional collaborative effort is warranted to determine which patients may benefit from de-escalated local therapy.

Extraskeletal myxoid chondrosarcomas (EMC) are rare soft tissue sarcomas of uncertain lineage that have an indolent course yet high risk of relapse. Due to a paucity of data, the role of radiation therapy (RT) in their management is poorly defined. Therefore, given our comparatively large experience managing patients with EMC, we sought to evaluate outcomes in this rare tumor type for patients with localized disease. We reviewed the records of 41 patients with primary ECM treated at our institution from 1990 to 2016. The Kaplan-Meier method was used to estimate rates of overall survival (OS), disease-specific survival (DSS), local control (LC), and distant metastatic free survival (DMFS). Median follow-up time was 94 months (range, 8-316). The median patient age was 53 years (range, 20-84) and predominantly male (n=34, 83%). The most common tumor location was the lower extremities (n=22, 54%; UE n=10, 24%; trunk n=8, 20%; H&N n=1, 2%) with a median tumor size of 7.5 cm (range, 2-38), and the majority were >5cm (n=32, 78%). Most patients (n=33, 80%) received combined modality therapy (CMT) with surgery and RT, whereas only 8 (20%) underwent surgery alone. Median OS was 89 months (range, 8-316 months) with a 5- and 10-year OS rate of 88% and 66%, respectively. There were 5 deaths (12%) that were attributable to disease with a median survival of 74 months (range, 65-122 months) which resulted in a 5- and 10-year DSS of 100% and 85%, respectively. There were no patient or treatment-related factors associated with DSS, but distant relapse did negatively impact DSS (10-yr 62% vs. 100% if no DM, P=0.002) without influencing OS (10-yr 62% vs. 68% if no DM, P=0.52). The 5- and 10-year LC rates were 94% and 90%, respectively. There were 5 patients (12%) with local relapse at a median time of 75 months (range 13-176 months). On univariate analysis, the only significant factor associated with poorer LC was the use of surgery alone (10-year LC 63% vs. 100% for CMT, P=0.004), which remained the only factor also significant on multivariable analysis (P=0.02, HR 12.7, 95% CI 1.4 -115.3). Thirteen patients (32%) developed DM at a median time of 28 months (range, 3-154 months). The 5- and 10-year DMFS rates were 73% and 69%, respectively. Two factors were associated with poorer DMFS on univariate analysis including tumor size >5cm (5-yr 59% vs. 100% ≤5cm, P=0.02) and local relapse (5-yr 60% vs 74% no local relapse, P=0.05). Interestingly, local recurrence was the only factor associated with poorer DMFS on multivariate analysis (P=0.04, HR 3.9, 95% CI 1.1-14.7). Following disease relapse, the median DSS was 59 months (range, 25-241 months) with a 5- and 10-year DSS after relapse of 75% and 50%, respectively. For patients with EMC, CMT resulted in improved LC, which was important given that local relapse was associated with poorer DMFS. Achieving upfront LC with CMT may reduce the risk of DM. Despite the high risk for metastatic relapse, patients survive for long periods of time with distant disease.

To evaluate treatment outcomes in patients with desmoid tumors (DT) receiving surgery alone, radiation therapy (RT) alone, or combined RT and surgery (CMT). We reviewed the records of 412 consecutive patients with DTs who received local therapy at our institution between 1965 and 2018. Local control was defined as stable disease or regression of gross tumor on serial imaging in cases where there was tumor present at the time of RT or no disease recurrence in patients receiving surgery or CMT. Median follow-up time was 95 months (range, 1-509) with a 10-year OS of 95%. The median age was 35 years (range, 1-85), and the median tumor size was 6cm (range, 1-24) with a majority of tumors located in the trunk (n=253, 61%; extremities n=106, 26%). Local therapy was surgery in 218 patients (52%), RT in 109 (27%) and CMT in 85 (21%). Patients who received surgery had smaller DTs (≤5cm 48% vs 18% RT vs 33% CMT, P<0.001) and were more commonly truncal (72% vs 49% RT vs 51% CMT, P<0.001), whereas patients who received CMT were younger (≤30 yrs 54% vs 36% surgery vs 34% RT, P=0.007). Local relapse occurred in 127 patients (31%) at a median time of 21 months (range, 3-295). The 5- and 10-year LC was 67% and 65%, respectively. On univariate analysis, patient and tumor factors associated with inferior 5-year LC included: younger age (≤30 yrs 57% vs >30 yrs 75%, P=0.001), extremity location (57% vs non-extremities 71%, P=0.002), and larger tumors (>10cm 59% vs 5-10cm 65% vs ≤5cm 76%, P=0.02). When these factors were included in multivariable analyses along with treatment strategy, they remained significantly associated with LC. Additionally, surgery alone was inferior to CMT (reference group) (HR 2.35, P=0.001, 95% CI 1.40-3.97) and RT was not significantly different than CMT (HR 1.72, P=0.06, 95% CI 0.99-3.01). However, an interaction was identified between tumor site and treatment. When this interaction term was included in the adjusted Cox regression model, neither treatment nor tumor site were significant, whereas age and larger size remained associated with higher risk of relapse: ≤30 yrs (HR 1.68, 95% CI 1.16-2.42) and 5-10cm (HR 1.66, 95% CI 1.07-2.58), >10cm (HR 2.26, 95% CI 1.35-3.77). Stratified analyses by extremity versus non-extremity were performed. In analyses adjusting for age, size, and treatment, tumor size (5-10cm: HR 3.22, 95% CI 1.47-7.05; >10 cm: HR 5.49, 95% CI 2.26-13.32) and treatment with surgery (HR 5.15, 95% CI 2.24-11.85) were the only factors associated with poorer LC for patients with extremity tumors. For non-extremity tumors, young age (≤30 yrs, HR 1.91, 95% CI 1.20-3.04) was the only significant predictor of LC. Local control for patients with symptomatic or progressive desmoid tumors remains a challenge for patients of young age, or with large tumors, or extremity locations. When local therapy is recommended for large tumors of the extremity, patients may benefit from combined modality therapy.

Benefit from chemotherapy for well-differentiated/de-differentiated (WD/DD) liposarcomas has been reported to be minimal, however traditional response criteria may not adequately capture positive treatment effect. In this study, we evaluate benefit from first-line chemotherapy and characterize imaging response characteristics in patients with retroperitoneal (RP) WD/DD liposarcoma treated at The University of Texas MD Anderson Cancer Center. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) and an exploratory analysis of vascular response was characterized. Among 82 patients evaluable for response to first-line therapy, 31 patients received neoadjuvant chemotherapy for localized/locally advanced disease; 51 received chemotherapy for unresectable recurrent/metastatic disease. Median overall survival from the start of chemotherapy was 29 months (95% CI 24–40 months). Response rates by RECIST: partial response (PR) 21% (17/82), stable disease (SD) 40%, and progression (PD) 39%. All RECIST responses were in patients receiving combination chemotherapy. A qualitative vascular response was seen in 24 patients (31%). Combination chemotherapy yields a response rate of 24% and a clinical benefit rate (CR/PR/SD > 6 months) of 44%, higher than previously reported in DD liposarcoma. A higher percentage of patients experience a vascular response with chemotherapy that is not adequately captured by RECIST in these large heterogeneous tumors.

AimsEpithelioid haemangioendothelioma (EHE) is a malignant vascular neoplasm. Subsets have been characterized previously by translocations resulting in either WWTR1-CAMTA1 or YAP1-TFE3 fusion. We sought to develop molecular and immunohistochemical (IHC) assays to aid in the diagnosis and characterization of EHE.Methods and resultsFifty-two formalin-fixed, paraffin-embedded (FFPE) cases diagnosed between 2002 and 2014 were retrieved from the pathology files of our institutions. Reverse transcription-polymerase chain reaction (RT-PCR) assays were optimized to detect WWTR1-CAMTA1 and YAP1-TFE3 fusion transcripts in FFPE tissue and transcription factor E3 (TFE3) protein accumulation was examined by immunohistochemistry (IHC). RNA was extracted from 33 adequate samples, with more recent cases providing a greater yield of high quality RNA. Fourteen of 18 informative cases were positive for WWTR1-CAMTA1 fusion transcripts, four of which showed higher-grade cytological features termed by some as malignant EHE'. Novel in-frame fusion transcripts were identified in four cases by direct sequencing. IHC revealed variable nuclear TFE3 staining in six of 17 cases; three with patchy staining showed WWTR1-CAMTA1 fusion. One of 18 informative cases was positive for YAP1-TFE3 fusion and showed strong nuclear TFE3 staining by IHC.ConclusionsThis study confirms the high incidence of WWTR1-CAMTA1 and YAP1-TFE3 rearrangements in EHE and indicates that the staining pattern for TFE3 IHC is critical for specificity.