FNCLCC Grade Research Articles

Pleomorphic Liposarcoma of the Extremity and Trunk: Multimodality Therapy for Some but Not All?

Pleomorphic liposarcoma (PLPS) is an ultra-rare malignancy distinct from well-differentiated/dedifferentiated and myxoid liposarcoma. In this study, we sought to (1) assess outcomes after surgery for primary, non-metastatic PLPS and (2) explore potential indications for multimodality therapy. Clinicopathologic data were retrospectively collected for patients treated from 2002 to 2019 at our sarcoma referral center. Descriptive data were summarized and Kaplan-Meier plots were constructed for overall survival (OS) and crude cumulative incidences (CCI) of disease-specific death (DSD), local recurrence (LR), and distant metastasis (DM). Univariable models were performed to assess the association of specific variables of interest on outcome. Forty-four pathology-verified PLPS cases were included in this study. Median tumor size was 8.5 cm; 75% were FNCLCC Grade 3. All patients underwent complete resection, including 15 patients (34%) who required re-excision to secure microscopic negative margins. Radiation therapy was given to 75% of patients, chemotherapy in 36%. At 5 years, OS was 75.3%; CCI of DSD, LR, and DM were 17.5%, 2.3%, and 32.5%. Larger tumor size was strongly associated with worse OS (p = 0.028) and DSD (p ≤ 0.001). A subgroup of patients (n = 10, 23%) with smaller, predominantly Grade 2 tumors underwent surgery alone without any LR or DM event at a median follow-up of 7.9 years. In PLPS, aggressive surgery and when appropriate, radiation therapy, results in excellent local control. Chemotherapy can be considered for larger tumors. Patients with smaller, Grade 2 tumors may be potentially cured with surgery alone.

Survival and prognostic factors of primary retroperitoneal sarcomas after surgery: a single-center experience.

The percentage of retroperitoneal sarcomas (RPS) among all soft tissue sarcomas ranges from 10 to 15%. Surgery remains the gold standard for RPS. In this study, we analyzed the impact of surgical treatment for primary RPS on recurrence and overall mortality at a Chinese institution and identified and evaluated prognostic variables. Data from patients with RPS who underwent surgical treatment were retrospectively analyzed. The patients were treated at a single center from January 2000 to June 2018. Retrospectively collected demographic, clinicopathological, and surgical factors were examined. Overall survival (OS) and disease-free survival (DSF) were used as the primary endpoints. Predicted 5-year survival rates, encompassing both DFS and OS, were derived from the Sarculator prognostic nomogram. A total of 110 patients met the inclusion criteria. The median follow-up time after surgery for patients with primary RPS was 5.3 years. During this period, 59 patients died. The 5-year OS and DFS estimates were 63.5% and 35.3%, respectively. In a multivariate analysis, poor OS following surgical treatment of primary RPS was independently correlated with FNCLCC grade (p < 0.001) and surgical margin status (p = 0.016). FNCLCC grade (p = 0.001) and surgical margin status (p = 0.002) were also independently associated with poor DFS. The C-indices for 5-year OS and DFS survival utilizing the Sarculator prognostic nomogram were 0.71 and 0.73 respectively. The overall mortality rate of patients with RPS was considered acceptable. OS and DFS prognostic markers were established for primary RPS. Tumor grade and intraregional margins are other factors that affect survival and recurrence.

Vena cava leiomyosarcoma surgery results in a retrospective cohort of 41 patients from two centers.

Leiomyosarcoma of the vena cava (LMS-VC)is a rare entity with poor oncological outcomes and a lack of histological staging prognostic factors. Outcomes of consecutive patients operated on LMS-VCbetween March 2003 and May 2022, in two specialized sarcoma centers were reported. Forty-one patients were identified. Median size of LMS-VCwas 9 cm with 68% of complete obstruction. After surgery, severe complication rate was 30%. No postoperative mortality was reported. Microscopic complete excision was obtained for 71% of patients, R1 for 27% and one patient presented an R2 resection. Grade 3 was found in 24%. After a median follow-up of 70 months, 3 years disease-freesurvival (DFS) and 5 years DFS were 34% and 17%, and 3 yearsoverall survival (OS)and 5 years OS were 74% and 50%. Distant metastasis concerned 54% of recurrences, local 7% and local and distant 5%. Multivariate analysis showed that FNCLCC grade (p < 0.001) and perioperative chemotherapy (p = 0.026) were significant factors for DFS. In multivariate analysis, FNCLCC grade was a significant factor for OS (p = 0.004). Perioperative chemotherapy may have a role to play in lowering the risk of recurrence for LMS-VC,particularly in high-grade tumor.

Final results of a randomized phase II/III study comparing perioperative adriamycin plus ifosfamide and gemcitabine plus docetaxel for high-grade soft tissue sarcomas: Japan Clinical Oncology Group study JCOG1306.

11503 Background: We have previously reported long-term follow-up results of the favorable efficacy of perioperative chemotherapy with adriamycin plus ifosfamide (AI) for high-grade soft tissue sarcomas (STS) (JCOG0304). We have also reported the results of the second interim analysis of a phase II/III trial to confirm the non-inferiority of perioperative gemcitabine plus docetaxel (GD) to AI for high-grade STS (JCOG1306) in 2020 ASCO Annual Meeting. This study was terminated at the preplanned second interim analysis based on the point estimate of hazard ratio (HR) being above the pre-specified allowable HR of 1.61. The estimated 2-year overall survival (OS) was 94.3% (95% confidence interval (CI) 83.4–98.1%) in AI and 91.6% (80.9–96.4%) in GD (HR 2.55, 95% CI 0.80–8.14) in the analysis. We herein report the final results of JCOG1306 at 5-year follow-up. Methods: Patients with operable, FNCLCC grade 2/3 STS primary tumor (T2bN0M0 or anyTN1M0, AJCC 7th edition) or first local recurrent tumor in the extremities or trunk were randomized to AI or GD. Chemotherapy consisted of adriamycin 60 mg/m2 plus ifosfamide 10 g/m2 for AI or gemcitabine 1,800 mg/m2 plus docetaxel 70 mg/m2 for GD. The treatments were repeated for 3 courses preoperatively and 2 courses postoperatively in a 3-week interval. The primary endpoint in phase III part was OS. Planned sample size was 140 with a one-sided alpha of 0.1, power of 0.7 and a non-inferiority margin of 8% at 3-year OS (HR of 1.61), assuming 3-year OS of AI to be 85% and that of GD as 87%. Results: A total of 143 patients were enrolled between February 2014 and September 2018, and 5-year follow-up has finished in September 2023. Seventy and 73 patients were assigned to AI and GD, respectively, and included in the efficacy analysis. At the final analysis with a median follow-up of 6.0 years, the estimated 5-year OS was 90.0% (95% CI 80.1–95.1%) in AI and 76.1% (64.5–84.4%) in GD (HR 2.67, 95% CI 1.23–5.80). The estimated 5-year progression-free survival was 65.2% (95% CI: 52.7–75.2%) in AI and 57.4% (45.2–67.8%) in GD (HR: 1.33, 95% CI 0.81–2.18). At the 5-year follow-up analysis, there were no treatment-related deaths in both arms. Conclusions: The results of the second interim analysis were confirmed in the final analysis after five-year follow-up, i.e., non-inferiority of GD to AI in terms of OS could not be confirmed. In the perioperative chemotherapy for high-grade STS in the extremities and trunk, AI remains the standard regimen. Clinical trial information: jRCTs031180003 .

SU2C-SARC032: A randomized trial of neoadjuvant RT and surgery with or without pembrolizumab for soft tissue sarcoma.

11504 Background: Surgery &amp; radiation therapy (RT) yield high local control rates for soft tissue sarcoma (STS) of the extremity and limb girdle. However, patients (pts) with high-grade stage III STS are at significant risk for developing metastasis. Median survival for pts with metastatic STS is &lt; 2 years. SARC028 (NCT02301039) evaluated the efficacy of pembrolizumab (pembro) for metastatic STS, showing 20% and 8.7% response rates in undifferentiated pleomorphic sarcoma (UPS) and pleomorphic/dedifferentiated liposarcoma (LPS), respectively. We hypothesized that neoadjuvant pembro with concurrent RT followed by surgery and adjuvant pembro for stage III UPS, including myxofibrosarcoma, or LPS would stimulate an anti-tumor immune response to eliminate micrometastatic disease &amp; improve disease-free survival (DFS). SU2C-SARC032 (NCT03092323) is a multi-institutional, international, randomized phase 2 trial evaluating the safety and efficacy of adding pembro to standard of care (SOC) RT &amp; surgery for pts with stage III UPS or LPS. Methods: Pts aged &gt; 12 yo with stage III (FNCLCC grade 2 or 3) UPS or LPS of the extremity and limb girdle were enrolled. Pts were randomized (1:1, stratified by grade) to neoadjuvant RT (50 Gy/25 fx) then surgery (SOC arm) or neoadjuvant pembro and RT then surgery &amp; adjuvant pembro (EXP arm). Pembro was given 200 mg IV Q3 wk for 3 doses (before, during &amp; after RT) &amp; up to 14 adjuvant cycles. The primary endpoint was 2-yr DFS. Secondary endpoints included local recurrence-free survival (LRFS), distant disease-free survival (DDFS), &amp; overall survival (OS). Target enrollment of 126 evaluable patients (max 144 total) provided 80% power (1-sided α = 0.05) to distinguish between a null hypothesis of 50% 2-yr DFS rate &amp; alternative hypothesis of 75% 2-yr DFS rate by log-rank test, with initial analysis at 45 DFS events. Cox models were stratified by grade; primary analysis was a one-sided stratified log-rank test. Results: Between July 2017-November 2023, 143 patients were enrolled, predominantly with UPS (85%) &amp; grade 3 (64%) histology. Median follow-up for alive patients is 24.1 mo. DFS in the EXP arm is significantly higher than the SOC arm (p = 0.023; HR 0.57, 90% CI: 0.35, 0.91). Estimated 2-yr DFS is 53% (90% CI: 43, 66%) for SOC vs 70% (90% CI: 61, 81%) for EXP arm. Currently, there is no statistically significant difference in LRFS (HR 0.55, 95% CI: 0.21, 1.42), DDFS (HR 0.57, 95% CI: 0.32, 1.01), or OS (HR 0.39, 95% CI: 0.14, 1.12). Pts with grade 3 sarcomas had improved DFS with pembro (HR 0.47, 95% CI: 0.25, 0.89), but no difference in DFS was observed in grade 2 tumors (HR 1.21, 95% CI: 0.35, 4.18). The proportion of patients with grade 3+ adverse events was significantly higher in EXP (52%) vs SOC arm (26%) (p = 0.002). Conclusions: Theaddition of neoadjuvant &amp; adjuvant pembro to RT and surgery significantly improves DFS for pts with stage III UPS and LPS of the extremity and limb girdle. Clinical trial information: NCT03092323 .

Abstract 1622: Characterization of the phylogenetic relationships in bilateral breast angiosarcoma

Abstract Background: Breast angiosarcoma represents around 20% of all angiosarcomas, and often spread to lung, liver, and bones. Driver mutations of angiosarcoma, specifically PTPRB, and PLCG1, are well-known as reported previously. Notably, contralateral breast is another metastatic site of the breast angiosarcoma, where an unusual location for other soft tissue sarcomas. However, it remains uncertain whether the contralateral disease originates from the primary tumor or emerges independently. Here, we present a 75-year-old woman with bilateral breast angiosarcomas to investigate the genetic relationship between the tumors. Methods: Irregular and heterogeneous masses were synchronously detected through breast sonography. Whole genome sequencing (WGS) was conducted at 60X coverage using bilateral total mastectomies, along with a matched normal blood sample (n=1). Single nucleotide variants (SNVs) and small indels were identified using Strelka2 and Varscan2. Subsequent filtering was performed using custom Python scripts to establish high-confidence variants. A phylogenetic tree was then reconstructed based on SNVs to trace clonal evolution and distinguish between de novo primary and metastasis. Following this, COSMIC mutational signatures were analyzed to characterize the genomic profile. Results: For the left breast angiosarcoma, we found 1,086 SNVs and 101 indels, while the right breast angiosarcoma had 921 SNVs and 92 indels. Despite their small size (&amp;lt;1.0 cm) and low FNCLCC grade (G1), these two cancers shared 600 SNVs and 135 indels as “truncal events”, indicating that one side metastasized from the other. According to the phylogenetic tree and the molecular clock of the two angiosarcomas, we estimated that the metastasis occurred during the middle stages of cancer evolution. Additionally, we identified 7 nonsynonymous SNVs (ADAMTS7, RPS15, CYP2A6, OR1S2, ARHGAP23, GNAQ, UGT2B7), five of which were shared. Remarkably, the GNAQ driver mutation exhibited a mutation at codon 209, a hotspot mutation not previously reported in breast angiosarcoma. The dominant Cosmic mutational signatures were SBS1/5 and ID1/2, all of which were associated with aging. Conclusion: Our findings demonstrate that bilateral breast angiosarcomas metastasized from one side to the other, as evidenced by the WGS data. This study underscores that the capability of WGS to distinguish between oligometastatic disease and multiple primary cancers, which has implications for predicting patients’ prognosis. Citation Format: Minju Kim, Jeonghwan Youk, Soyeon Kim, Miso Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Myung Geun Song, Jiwon Koh, Jeong Mo Bae, Hyeong-Gon Moon, Seock-Ah Im. Characterization of the phylogenetic relationships in bilateral breast angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1622.

Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma.

Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model. We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least 1-year follow-up. In STLMS, French Federation of Cancer Centers (FNCLCC) grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate, and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk: co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk: presence of RB1 mutation, ATRX mutation, or del12q; low risk: lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk: concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk: presence of TP53 mutation, ATRX mutation, or amp20q; low risk: lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression. Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

Myxofibrosarcoma with false-positive EWSR1 FISH

Abstract Introduction/Objective Myxofibrosarcoma is a common sarcoma in elderly patients. It comprises a spectrum of malignant fibroblastic neoplasms with variable myxoid stroma, pleomorphism, and a distinctive curvilinear vascular pattern. As soft tissue tumors frequently exhibit overlapping histologic features, immunohistochemical stains and fluorescent in situ hybridization (FISH) studies are utilized to determine accurate diagnosis. The purpose of this case is to report a false-positive EWSR1 FISH in a myxofibrosarcoma. Methods/Case Report A 54-year-old male presented with a mass in his left forearm that had been present for four months. The mass was as painless and had not grown larger since it was initially noticed. A resection of the mass was performed which revealed monotonous, spindled to focally epithelioid cell population in a myxoid background that bordered on chondroid in some foci. While this raised concern for a translocation-associated sarcoma, particularly extraskeletal myxoid chondrosarcoma, the scattered pleomorphism expected in a myxofibrosarcoma was still present. Immunohistochemistry revealed diffuse reactivity for CD34 and negativity for pancytokeratin, EMA, S100, SOX10, desmin, SMA, CD117, TLE1, and STAT6 stains. FISH for EWSR1 gene arrangement to exclude extraskeletal myxoid chondrosarcoma was positive. However, a follow-up NGS study was negative for gene rearrangement, indicating a false-positive FISH result. The diagnosis of myxofibrosarcoma, FNCLCC grade 1 or 3 was rendered. Results (if a Case Study enter NA) NA Conclusion EWSR1 gene rearrangements represent one of the most commonly involved genes in sarcoma. FISH has a reported sensitivity and specificity for this rearrangement of 100% and 87% respectively. This case highlights a false-positive FISH result in a soft tissue tumor and the importance of correlating results with histology and molecular genetics for accurate diagnosis to guide appropriate management for patients.

Myxofibrosarcoma in adolescents and young adults: a clinicopathologic study of 17 cases

Myxofibrosarcoma is a locally aggressive sarcoma that characteristically arises in the extremities of older patients. Cases arising at a younger age are rare, leading to diagnostic challenges. Our aim was to study the clinicopathologic features of myxofibrosarcoma in patients aged ≤40 years. Cases of myxofibrosarcomaand myxoid malignant fibrous histiocytomaarising in patients aged ≤40 yearswith clinical follow-up were collected from multiple institutions. Hematoxylin and eosin slides were evaluated for mitoses, necrosis, and epithelioid areas. Seventeen cases were identified (13 females, 4 males; 16-39 years; median 32 years), tumors ranged from 2.2 to 34cm (median 4.1cm). Anatomic sites includedproximal extremity (9), distal extremity (4), trunk (1), and head/neck (3). Ten were superficial, and 6 were deep-seated. Three cases were predominantly epithelioid. In untreated resection specimens, 6 were FNCLCC grade 1, 4 grade 2, and 2 grade 3. Follow-up (6-204 months, median 36 months) revealed that 2 patients experienced local recurrences, 1 distant metastasis, and 2 patients both. The 5-year overall survival (OS) and event-free survival (EFS) were 84% and 55.9%, respectively. Tumor depth and necrosis were correlated with inferior OS (P=.025, P=.005), while tumor depth was also associated with worse EFS (P=<.001). We conclude that myxofibrosarcomas arising in adolescents and young adults show similar behavior compared to their older adult counterparts. Tumor depth and necrosis are poor prognostic factors in myxofibrosarcoma in this age group. Awareness that myxofibrosarcoma can rarely present in this population is important for accurate diagnosis.

173 Performance of PERSARC as Prognostic Tool of Extremity Soft Tissue Sarcoma

Abstract Aim To review extremity soft tissue sarcoma (ESTS) in MSK sarcoma unit in Glasgow Royal Infirmary. To assess reliability of PERSARC nomogram in estimating outcomes of FNCLCC Grade II and III ESTS. Method A retrospective study of 72 patients with primary ESTS, treated surgically at GRI from 2010-2015 was performed. Patients were followed up as per local sarcoma protocol up to 10 years. Overall survival (OS), Local recurrence (LR) and Distant metastasis (DM) at 3 years and 5 years post-op were calculated and PERSARC nomogram was used to estimate predicted OS, LR and DM at 3 years and 5 years post-op. The reliability of PERSARC to estimate ESTS outcomes was assessed using discrimination and calibration. Concordance index was used to assess discrimination. Calibration plot was used to assess calibration. Results Observed 5-year OS, LR and DM were 77.78%, 12.5% and 27.77% respectively. Concordance indices for 3-year OS, LR and DM were 0.82, 0.68 and 0.70 respectively. Concordance indices for 5-year OS, LR and DM were 0.77, 0.69 and 0.66 respectively. Calibration plot showed PERSARC underestimated 3-year and 5-year OS. Calibration plot showed good calibration for 3-year and 5-year LR and DM. Conclusions PERSARC nomogram showed good discriminative ability for 3-year OS, 3-year DM, and 5-year OS as the concordance indices were &amp;gt;0.7 and good calibration for 3-year and 5-year LR and DM. PERSARC could be beneficial to guide shared decision making between patients and healthcare professionals, leading to focused and personalised care for patients with ESTS.

Which modality is better to diagnose high-grade transformation in retroperitoneal liposarcoma? Comparison of computed tomography, positron emission tomography, and magnetic resonance imaging.

Survival in patients with retroperitoneal liposarcoma (RPLS) depends on the surgical management of the dedifferentiated foci. The present study investigated the diagnostic yield of contrast-enhanced CT, 18F-fluorodeoxyglucose positron emission tomography (PET), and diffusion-weighted MRI in terms of dedifferentiated foci within the RPLS. Patients treated with primary or recurrent RPLS who underwent the above imaging between January 2010 and December 2021 were retrospectively reviewed. The diagnostic accuracy of the three modalities for histologic subtype of dedifferentiated liposarcoma (DDLS) and French Federation of Cancer Center (FNCLCC) grade 2/3 were compared using receiver operating characteristic curves and areas under the curves (AUCs). The cohort involved 32 patients with 53 tumors; 30 of which exhibited DDLS and 31 of which did FNCLCC grades 2/3. The optimal thresholds for predicting DDLS were mean CT value of 31 Hounsfield Unit (HU) (AUC = 0.880, 95% CI 0.775-0.984; p < 0.001), maximum standardized uptake value (SUVmax) of 2.9 (AUC = 0.865 95% CI 0.792-0.980; p < 0.001), while MRI failed to differentiate DDLS. The cutoff values for distinguishing FNCLCC grades 1 and 2/3 were a mean CT value of 24 HU (AUC = 0.858, 95% CI 0.731-0.985; p < 0.001) and SUVmax of 2.9 (AUC = 0.885, 95% CI 0.792-0.978; p < 0.001). MRI had no sufficient power to separate these grades. Contrast-enhanced CT and PET were useful for predicting DDLS and FNCLCC grade 2/3, while MRI was inferior to these two modalities.

Prevalence and detection of actionable BRAF V600 and NRAS Q61 mutations in malignant peripheral nerve sheath tumor by droplet digital PCR

Malignant peripheral nerve sheath tumors ( MPNSTs) are aggressive tumors with poor prognosis that do not typically respond well to standard chemotherapy. Recently, point mutations involving BRAF V600E have been demonstrated in a subset of MPNST, offering the possibility of targeted treatment. However, the reported prevalence of these alterations is variable. Mutations involving NRAS, which is also involved in the MAPK/ERK pathway and amenable to targeted inhibitors, have not been well characterized in MPNST. In this study, we validated droplet digital polymerase chain reactionfor the detection of BRAF V600E and NRAS Q61 mutations and evaluate the prevalence of BRAF V600E and NRAS Q61 mutations in 79 cases of MPNST, including 45 sporadic, 27 NF-1 associated, and 7 radiation-associated tumors. We detected actionable BRAF or NRAS mutations in 3 of 44sporadic MPNSTs (6.8%), including 2 BRAFV600 and 1 NRAS Q61 mutations, as well as 1 NRAS Q61 mutation in a tumor that was ultimately considered to represent melanoma. These 3 cases with positive mutations were exclusively in sporadic, high-grade MPNST (FNCLCC grade 3 of 3), with a prevalence of 11.5% in this group (3.8% NRAS Q61 mutations and 7.7% BRAF V600 mutations). None of the tumors associated with NF-1 or prior radiation had detectable mutations in the genes tested. Overall, the prevalence of these alterations offers the possibility of targeted therapy in this aggressive type of sarcoma and suggests the potential benefit of routine clinical testing.

Outcomes following preoperative chemoradiation +/- pazopanib in non-rhabdomyosarcoma soft tissue sarcoma (NRSTS): A report from Children's Oncology Group (COG) and NRG Oncology.

11504 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity in advanced soft tissue sarcoma. ARST1321 was a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) following preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive body wall/extremity NRSTS. Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary analysis of the study, we now report the outcome data for this cohort. Methods: ARST1321 was a jointly designed COG and NRG Oncology study open to enrollment July 2014-October 2018. Eligible adult (≥18 years) and pediatric (&lt; 18 years) patients with newly-diagnosed unresected body wall/extremity NRSTS were enrolled into the Chemotherapy Cohort (&gt; 5 cm, FNCLCC grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib (&lt; 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then further chemotherapy to week 25. Results: Eighty-five eligible patients were enrolled in the Chemotherapy Cohort and randomized to receive or not receive pazopanib. Median age 22.1 years (range: 5.7-64.2 years); 30 patients &lt; 18 years. Most common histologies were synovial sarcoma (n = 42) and undifferentiated pleomorphic sarcoma (n = 19). As of December 31, 2021, at a median survivor follow-up of 3.3 years (range: 0.1 – 5.8 years), the 3-year event-free survival (EFS) for all patients in the intent-to-treat analysis was 52.5% (95% CI: 34.8%-70.2%) for Regimen A and 50.6% (32%-69.2%) for Regimen B (p = 0.8677); 3-year overall survival (OS) was 75.7% (59.7%-91.7%) for Regimen A and 65.4% (48.1%-82.7%) for Regimen B (p = 0.1919). Conclusions: Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk body wall/extremity NRSTS, outcomes were not statistically significantly different between the two regimens. Pathologic response could be a TKI-related phenomenon and may not be a good surrogate marker of outcome in future studies. Clinical trial information: NCT02180867.

A nomogram to predict the prognosis of advanced soft tissue sarcoma patients treated with anlotinib: A real-world population-based study.

e23550 Background: The ALTER0203 randomized controlled trial proved the antitumor activity of anlotinib, a multitargeted tyrosine kinase inhibitor, in 8 subtypes of advanced refractory soft tissue sarcoma (STS). Our previous studies have shown that anlotinib showed antitumor activity in more than 30 STS pathological subtypes in the real world. This study further constructed a nomogram to predict the prognosis of advanced STS patients treated with anlotinib based on real-world data. Methods: We retrospectively analyzed the data of patients with unresectable locally advanced or metastatic STS who received at least one dose of anlotinib from June 2018 to March 2021. A nomogram was developed to predict the survival probability based on the multivariate analysis. The performance of the nomogram was evaluated by concordance index, bootstrap resampling calibration curve and time-dependent ROC curve. Results: A total of 209 patients were included in this study. The median age was 48 years (range 11-85 years), and the median follow-up time was 18.7 months. Based on five independent prognostic factors including ECOG performance status, FNCLCC grade G2-3, poor nutrition, increased neutrophil count, and treatment patterns according to the multivariate analysis, we constructed a nomogram to predict the prognosis of advanced STS patients treated with anlotinib. The concordance index was 0.780. For the prediction of 1-year and 2-year overall survival probability according to the nomogram, the area under the receiver operating characteristic curve was 0.833 and 0.829, respectively. Conclusions: The nomogram based on ECOG performance status, FNCLCC grade, nutritional status, neutrophil count, and treatment patterns can accurately predict the 1-year and 2-year OS probability for advanced STS patients treated with anlotinib.

Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation.

Malignant peripheral nerve sheath tumor (MPNST) is a very aggressive peripheral nerve sheath-derived sarcoma, which is one of the most difficult tumors to diagnose due to its wide spectrum of histological findings and lack of specific immunohistochemical markers. Recently, it has been reported that losses of expression of H3K27me3 and H3K27me2 caused by PRC2 dysfunction may be useful diagnostic markers for MPNST, but there is no consensus on their clinicopathological significance. Here, we investigated the relationship between loss of H3K27 methylation and various parameters and clarified the clinicopathological significance of such loss. We analyzed the clinicopathological and immunohistochemical features in 84 MPNST cases. Complete losses of H3K27me3 and H3K27me2 were observed in 37 (44%) and 29 (35%) cases, respectively. Losses of H3K27me3 and H3K27me2 were significantly correlated with myogenic immunopositivity (H3K27me3 vs. desmin, P = 0.0051; H3K27me3 vs. myogenin, P = 0.0009; H3K27me2 vs. myogenin, P = 0.042). Meanwhile, there were significant correlations between preservation of immunohistochemical neurogenic markers and intact H3K27me3 and H3K27me2 (H3K27me3 vs. S-100 protein, P = 0.0019; H3K27me3 vs. SOX10, P = 0.014; H3K27me2 vs. S-100 protein, P = 0.0011; H3K27me2 vs. SOX10, P = 0.0087). In multivariate analysis, local recurrence, distant metastasis, high FNCLCC grade, and loss of SOX10 expression were independent prognostic factors for overall survival. H3K27me3 and H3K27me2 expression was retained in all 26 cases of rhabdomyosarcoma non-alveolar subtype. In conclusion, we suggest that H3K27me3 and H3K27me2 immunonegativity is useful but not definitive for diagnosing MPNST. Complete loss of H3K27 methylation may be involved in aggressive transdifferentiation from neural differentiation to skeletal muscle differentiation in MPNST.

Development and Validation of a Nomogram for Predicting Recurrence-Free Survival of Surgical Resected Retroperitoneal Liposarcoma.

Background and ObjectivesSurgical treatment is still the mainstay of curative therapy for retroperitoneal liposarcoma (RLPS), but often recurs after surgical resection. We aimed to establish a nomogram for postoperative recurrence of RLPS based on the Asian population.MethodsPatients after surgical resection at the South Hospital of Zhongshan Hospital/Shanghai Public Health Clinical Center between August 2011 and December 2020 were included. The enrolled patients are randomly divided into training set and test set according to the ratio of 7:3. Prognostic factors were chosen based on Akaike Information Criterion, and the nomogram was built based on Cox regression and then internally validated through calibration plots and concordance index (C-index).ResultsA total of 447 patients were included. Gender, age, presentation status, organ invasion and FNCLCC grade were used to build nomogram. The calibration plots showed that RFS predicted probabilities are identical to the actual RFS rates. The C-index of the nomogram was 0.703 (95% CI 0.623–0.783) in the training set and 0.695 (95% CI 0.565–0.825) in test set.ConclusionThe nomogram we established can accurately predict postoperative recurrence of RLPS patients for Asian population.

Impact of surgical margins on survival in cutaneous sarcomas: A nationwide study of French Sarcoma Group (FSG) from NETSARC Database.

e23537 Background: R0 surgery in reference centers is the cornerstone for sarcomas treatment with better local control and survival and is mandatory for ESMO-EURACAN and NCCN guidelines. The medical community is out on this issue for cutaneous sarcomas, if they have to follow suit. This retrospective descriptive study focused on margin status and local relapse-free survival (LRFS) and overall survival (OS) of patients (pts) with cutaneous sarcomas. Methods: Between 01/01/10 and 30/12/17, surgery was performed on 2044 pts with cutaneous sarcomas from 20 centers. Data were collected from the NETSARC national network database ( http://netsarc.sarcomabcb.org ). Diagnosis of cutaneous sarcoma was reviewed and histologically confirmed by a local expert pathologist of RRePS (“Network for expert pathology diagnosis in sarcoma”). Dermatofibrosarcoma, Kaposi sarcoma and rare subtypes (&lt; 20 cases in the database) were excluded. Univariate analyses were conducted using log rank test or Cox test. Multivariate analyses were conducted using Cox test. Age and tumor size were analyzed as continuous values. Two-sided significant p level was set at &lt; 0.05. Results: Mean age was 66 years. Primary tumor was localized in lower limb, trunk wall, head and neck and upper limb for 30%, 26%, 26% and 18% pts respectively. Main subtypes were leiomyosarcoma, undifferentiated sarcoma, and myxofibrosarcoma for 29%, 29%, and 14% pts respectively. Angiosarcoma was the subtype of 9% of the patients (n = 193). Mean size was 45 mm. FNCLCC grade was 1, 2, and 3 for 14%, 29.5%, and 24% tumors respectively. Before surgery, imaging and biopsy were performed for 21% and 51% pts respectively. Surgery was carried out in a NETSARC center for 26% of the pts. Margin status after initial surgery was R0, R1, and R2 for 35% (n = 724), 34% (n = 696), and 12% pts (n = 246) respectively. Re-excision was performed for 34% (703/2044 pts), leading to a subsequent R0 margin for 74% of them (523/703 pts, equivalent to 26% of the overall population). Local relapse occurred for 21% of pts after a median time of 10 months. Metastatic relapse occurred for 13% of pts after a median time of 11 months. One hundred and ninety-three pts (9%) died. Median follow-up was 12 months. In multivariate analyses, statistically significant favorable prognostic factors for LRFS were: young age, small tumor size and non-angiosarcoma subtype. Significant prognostic factors associated with longer OS were: young age, small tumor size, non-angiosarcoma subtype, FNCLCC grade (1 vs 2 and 1 vs 3) and initial R0 surgery. Conclusions: Cutaneous sarcomas share same favorable clinical prognostic factors than non-cutaneous sarcomas. Quality of surgery remains the mainstay for OS.

Conditional survival after surgical resection of primary retroperitoneal tumors: a population-based study

BackgroundThe purpose of this study was to assess conditional survival (CS) after resection of primary retroperitoneal tumors (RPTs).MethodsThe data of 1594 patients with primary RPTs who underwent surgery between 2004 and 2016 were retrieved from the Surveillance Epidemiology and End Results (SEER) database. Multivariate Cox analysis was used to identify prognostic factors affecting overall survival (OS) and cancer-specific survival (CSS). CS was used to calculate the probability of survival for an additional 3 years after the patient had survived x years, according to the formulas: COS3 = OS (x + 3) /OS (x) and CCSS3 = CSS (x + 3)/CSS (x).ResultsThe 1-, 3-, and 5-year OS rates of all patients were 89.8, 71.8, and 60.8%, while the 1-, 3-, and 5-year CSS rates were 91.9, 77.1, and 67.8%, respectively. Age, sex, FNCLCC grade, size, multifocality, histology, and chemotherapy were independent prognostic factors for OS and CSS. Among patients who survived for 1, 3, and 5 years, the COS3 rates were 72.9, 77.9, and 79.3%, and the CCSS3 rates were 78.1, 82.7, and 85.8%, respectively. Patients with poor clinicopathological characteristics achieved greater improvements in COS3 and CCSS3 rates, and the survival gaps between OS and COS3, as well as CSS and CCSS3 were more obvious.ConclusionPostoperative CS of RPTs was dynamic and increased over time. CS increased more significantly in patients with poor clinicopathological characteristics.

Prediction of Histologic Subtype and FNCLCC Grade by SUVmax Measured on 18F-FDG PET/CT in Patients with Retroperitoneal Liposarcoma

This study aimed to evaluate the usefulness of maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) in differentiating the subtypes and tumor grades of retroperitoneal liposarcoma (RPLS). The data of RPLS patients who underwent surgical resection from November 2013 to December 2019 at the sarcoma center of our institute were reviewed. The demographics, clinical features, and SUVmax of 84 patients who underwent preoperative 18F-FDG PET/CT scans were analyzed. Of these, 19 patients (22.6%) were with well-differentiated liposarcoma (WDLPS), 60 patients (71.4%) were with dedifferentiated liposarcoma (DDLPS), and 5 patients (6.0%) were with pleomorphic liposarcoma (PMLPS). The median SUVmax of WDLPS, DDLPS, and PMLPS groups was 2.8 (IQR: 1.9–3.2), 6.2 (IQR: 4.1–11.3), and 4.5 (IQR: 4.0–7.4). The ROC curve suggested 3.8 as an approximate cutoff value of SUVmax for distinguishing WDLPS and non-WDLPS (sensitivity = 0.769; specificity = 0.895). The median SUVmax for FNCLCC Grades 1, 2, and 3 of RPLS was 2.5 (IQR: 1.9–3.2), 4.5 (IQR: 3.2–6.7), and 9.0 (IQR: 6.0–13.3). The ROC curves suggest that SUVmax of ≤3.8 and >5.3 can be used for predicting FNCLCC Grades 1 and 3, respectively. The result showed that 18F-FDG PET/CT exhibited high sensitivity and specificity for identifying the subtypes and FNCLCC grades of RPLS. Additionally, 18F-FDG PET/CT might be a useful complementary imaging modality for guiding suitable biopsy location of RPLS.

A novel nomogram for predicting local recurrence-free survival after surgical resection for retroperitoneal liposarcoma from a Chinese tertiary cancer center.

Local recurrence is the most difficult postoperative challenge and the leading cause of death in patients with retroperitoneal liposarcoma (RLPS). We aimed to establish a postoperative nomogram exclusively focused on RLPS for predicting local recurrence-free survival (LRFS). A cohort of 124 patients after surgical resection with curative intent in the Peking University Cancer Hospital Sarcoma Center were included in the study. Demographic, clinicopathologic, and treatment variables were analyzed using the Cox regression model. Significant clinically relevant variables in multivariable analysis were incorporated into the RLPS-specific nomogram. The discriminative ability and predictive accuracy of the nomogram were assessed by calculating the concordance index and drawing a calibration plot. At a median follow-up of 26.5 (interquartile range 10.9-39.4) months, 71 patients had recurrent disease. The 3-year and 5-year LRFS rates were 35.6% (95% confidence interval, 27.0-46.9%) and 28.2% (95% CI 15.8-38.6%), respectively. Multivariate analysis identified the French Federation of Cancer Centers Sarcoma Group (FNCLCC) grade and completeness of resection as independent predictors of LRFS. Variables included in our nomogram were: presentation status, multifocality, completeness of resection, histologic subtypes, and FNCLCC grade. The concordance index of our nomogram was 0.732 (95% CI 0.667-0.797) and the calibration plot was excellent. Our novel nomogram for patients with resected RLPS could improve recurrence risk stratification to explore molecular analysis associated with recurrence.