Liposarcoma Research Articles

A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS).

3004 Background: The highly potent MDM2–p53 antagonist BI 907828 showed antitumor efficacy in vivo, particularly in TP53 wild-type, MDM2-amplified de-differentiated LPS (DDLPS) patient-derived xenografts and syngeneic models. This phase I study (NCT03449381) is assessing BI 907828 monotherapy in patients with advanced solid tumors, including LPS. In Part A (dose escalation), patients received one of two BI 907828 dosing schedules: Arm A, day 1 of 21-day cycles (q3w); Arm B, days 1 and 8 of 28-day cycles. Based on previously reported results from Part A (LoRusso ASCO 2021), the MTD was 60 mg q3w and the recommended dose for expansion (RDE) was selected as 45 mg q3w. Methods: In Part B (dose expansion), patients received BI 907828 45 mg q3w. The primary endpoint was PFS. Secondary endpoints/objectives included objective response rate, overall survival, the number of patients with grade ≥3 treatment-related AEs, and PK parameters. Here, we report overall safety data and efficacy data in the subgroup of patients with advanced LPS. Results: As of January 10, 2022, 90 patients had been enrolled; 49 (54.4%) were male, 55 (61.1%)/34 (37.8%) were ECOG PS 0/1, the median number of prior systemic therapies was 2 (range, 0–11), 44 had advanced LPS (28 DDLPS, 16 well-differentiated LPS [WDLPS]). At data cut-off, 31/90 patients (34.4%) had received treatment for ≥6 months. In the 41 evaluable patients with advanced LPS, best response of PR or SD was observed in 24/27 patients with DDLPS (88.9%) and 13/14 patients with WDLPS (92.9%). Two DDLPS and 4 WDLPS patients achieved a PR; all had MDM2-amplified disease. In Part A, 5/11 DDLPS patients and 4/8 WDLPS patients have achieved PFS ≥10.5 months. In the 42 patients who received the RDE of 45 mg q3w, 18 patients (42.9%) had grade ≥3 AEs; the most common grade ≥3 AEs were neutropenia (23.8%), thrombocytopenia (21.4%), and anemia (11.9%). Seven patients (16.7%) had SAEs; the most common were thrombocytopenia (4.8%) and pyrexia (4.8%). PK analysis showed that mean plasma exposures (Cmax and AUC0-inf) increased with dose and showed no significant deviation from linearity in the dose range 10–60 mg. A correlation was observed between exposure and GDF-15 levels in plasma, as a target engagement marker. Conclusions: BI 907828 showed a manageable safety profile, high plasma exposure, target engagement and encouraging signs of antitumor activity in patients with advanced DDLPS and WDLPS. The Part B dose expansion is ongoing. Clinical trial information: NCT03449381.

A phase II study, with a safety lead-in, to evaluate ATX-101, a peptide drug targeting PCNA, in advanced dedifferentiated liposarcoma and leiomyosarcoma.

TPS11587 Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of mesenchymal origin; leiomyosarcoma (LMS) and liposarcoma (LPS), two of the most common adult STS, are treated with first-line chemotherapy with objective response rates (ORRs) of 15-20%. There is an urgent need for novel therapeutics. ATX-101 is a small peptide comprised of a novel human AlkB homolog 2 proliferating cell nuclear antigen (PCNA) interacting motif termed APIM coupled to cellular and nuclear delivery domains. Via APIM, PCNA interacts with many cellular proteins important in the cellular stress and DNA damage responses, as well as intracellular signaling, apoptosis, metabolism, and anti-tumor immunity. In preclinical studies, ATX-101 demonstrated single-agent activity and potentiated other cytotoxic and targeted agents across multiple cancer models in vitro and in vivo, including LMS and LPS. In a phase I safety and pharmacokinetic study in solid tumors, ATX-101 was well tolerated and demonstrated prolonged disease stabilization in patients (pts) with heavily pretreated malignancies. This study will evaluate preliminary efficacy and further establish the safety profile of ATX-101 in advanced LMS and LPS. Methods: This is a single-arm, open-label, Simon 2-stage, phase II clinical trial of ATX-101 in pts with advanced LMS and LPS. Eligible pts have ECOG PS ≤2, progression on ≥1 prior line of therapy and disease measurable by RECIST v1.1 and amenable to image-guided biopsy. Pts receive ATX-101 60 mg/m2 IV weekly in continuous 21-day cycles. The 1° endpoint is progression free rate at 12 weeks (PFR12). A Simon 2-stage design is used to evaluate for improvement in PFR12 of ≤ 30% (null hypothesis) versus ≥ 55% (alternative hypothesis). The design calls for 34 pts with a safety lead-in among the first 10 pts enrolled. If 15/34 meet the PFR12 endpoint, the treatment is promising. This design yields 85% power and 1-sided type I error of 5%. 2° endpoints include progression free survival, ORR, and safety. 10 pts undergo tumor biopsies pre-treatment and during cycle 2. Tissue is used for correlative analysis interrogating ATX-101’s effects on the immune microenvironment through multiplex immunohistochemistry, DNA damage response through whole exome sequencing/RNAseq to evaluate for alterations in HR pathway component genes, and intracellular signaling pathways by Western blot for AKT/mTOR components. The study opened to accrual 12/2021. Clinical trial information: NCT05116683.

Using pan-sarcoma multiomic analysis for identifying sarcoma subtypes with immunogenic potential.

11551 Background: Immune checkpoint inhibitors (ICI) have limited efficacy for most sarcomas. Yet, responses are seen in particular sarcoma subtypes, highlighting the need for better predictive biomarkers. The T cell inflamed score (TIS), a gene expression signature reflective of an active tumor immune microenvironment, is associated with ICI response in multiple solid tumors. We evaluated the TIS across a large database of sarcomas to identify which histologic subtypes may benefit from ICI. Methods: Next generation sequencing of DNA (592 gene or whole exome)/RNA (whole transcriptome) was performed for 3605 sarcoma patient samples, representing 45 histologic subtypes (Caris Life Sciences, Phoenix, AZ). TIS (18 gene weighted coefficient composite value; Cristescu 2018) was calculated and the Microenvironment Cell Populations-counter tool (Becht 2016) was used to quantify immune cell populations. Results were compared to melanoma (n = 1255), a representative immunogenic tumor type. High TIS was defined as a score within the upper quartile of melanoma TIS (> 5.5). Percentage with high TIS are reported with 95% CI. Results: Median TIS was highest in inflammatory myofibroblastic tumor (IMT), epithelioid sarcoma (EPIS), myxofibrosarcoma (MFS), well differentiated liposarcoma, and solitary fibrous tumor (SFT). These did not differ significantly from melanoma (p > 0.06). Median TIS was lowest in embryonal rhabdomyosarcoma, desmoid tumor (DES), synovial sarcoma (SYNS), and Ewing sarcoma (ES). Histologic subtypes where > 10% of samples had a high TIS included IMT (29.9% ± 21.7%), MFS (23.3% ± 12.6%), pleomorphic sarcoma (PLSARC) (21.9% ± 5.8%), cutaneous angiosarcoma (ANGS) (18.4% ± 13.9%), spindle cell sarcoma (17.5% ± 7.6%), liposarcoma (LPS) (17% ± 10.7%), EPIS (15.4% ± 19.6%), visceral ANGS (13.2% ± 10.7%), pleomorphic LPS (13.6% ± 14.3%), fibrosarcoma (12.5% ± 13.2%), leiomyosarcoma (11.6%± 3.4%), malignant peripheral nerve sheath tumor (MPNST) (10.2% ± 7.7%), and perivascular epithelioid cell tumor (PEComa) (10% ± 10.7%). The relative abundance of immune and stromal cell populations was highly variable across sarcoma subtypes, yet a strong positive correlation between TIS and immune cell populations was observed for most subtypes (e.g. T cells, Spearman R range: 0.56 [P = 0.08] - 0.96 [P < 0.0001]). A notable exception was SFT, which had a relatively high median TIS but low abundance of CD8+ T cells and B cells. Conclusions: We found high median TIS and/or significant proportions of samples with a high TIS in sarcoma subtypes with previously demonstrated responsiveness to ICI, including MFS, PLSARC, LPS, and ANGS, while unresponsive tumor types such as RMS, DES, SYNS, and ES had low TIS. We further identified subtypes with high TIS but limited prior clinical data supporting ICI use, such as IMT, EPIS, MPNST, SFT, and PEComa. Our results warrant prospective exploration of TIS as a predictive biomarker for ICI use in sarcoma.

Comparison of prognostic reliability of TNM staging systems version 7/8 and SARCULATOR in primary localized liposarcomas of the extremity or trunk wall.

e23529 Background: The oncological staging system should provide meaningful information regarding the patients’ prognosis. For soft tissue sarcomas, available staging systems include AJCC version 8, AJCC version 7, and nomogram-based approaches such as SARCULATOR (which additionally includes age and subtype). This work compares these systems using a group of extremity/trunk wall cases of liposarcoma (LPS). Methods: We have included all (N = 147) consecutive, newly diagnosed LPS patients treated in our institution between 2010 and 2021. We have excluded atypical lipomatous tumors. Patients’ and tumor characteristics were collected, and AJCC staging and SARCULATOR risk assessment were performed. Appropriate Cox proportional hazard models were fitted. The results were compared using the concordance index, Akaike information criterion (AIC), and partial likelihood ratio (PLR) test for non-nested Cox models. Results: In this group, 81 (55.1%) patients were male; the mean age in the group was 54 years (SD:16). Most tumors (83%) were localized on the lower extremity, with 8.8% on the upper extremity and 8.2% on the trunk. 66% of cases were myxoid LPS, 17.7% - dedifferentiated and 16.3% - pleomorphic. The median tumor size was 12 cm (IQR 9 – 18). Patients’ prognostic groups are summarized in Table. The median follow-up was 43 months (95%CI:38-51). The median overall survival (OS) was not reached. The 5-year survival rate was 68% (95%CI:62-75). The concordance for AJCC version 7, AJCC version 8, and SARCULATOR were respectively 0.625, 0.705, and 0.778. The AIC in the same order were: 311, 301, 274. The PLR test showed that AJCC version 8 fits better than AJCC version 7 (p for superiority = 0.036) while SARCULATOR fits better than AJCC version 8 (p for superiority = 0.028). Conclusions: New staging systems improve in better predicting patients outcome. In rare diseases such as sarcomas, it is crucial to have access to more personalized nomograms such as SARCULATOR.[Table: see text]

Efficacy and safety of eribulin in the treatment of advanced adult soft tissue sarcoma (STS): First real-world data in Chinese population.

11577 Background: Eribulin has shown efficacy in STS, especially for the L-type sarcomas, including liposarcoma (LPS) and leiomyosarcoma (LMS). We investigated the efficacy and safety of eribulin in the treatment of advanced adult STS in Chinese population. Methods: The study retrospectively analyzed data from patients diagnosed as advanced STS and received eribulin monotherapy or combination regimens in the Department of Oncology, Zhongshan Hospital affiliated to Fudan University from January 2020 to February 2021. Primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints included disease control rate (DCR), progress-free survival (PFS) and treatment-related adverse events (TRAE) by CTCAE v5.0. Results: A total of 40 patients who received at least two doses of eribulin and underwent at least one post-baseline response assessment were included in analysis. The mean age was 48 years. 82.5% (33/40) had L-type sarcomas, and 17.5% (7/40) had non-L-type sarcomas. Overall, 25% (10/40) of patients received eribulin alone; and 75% (30/40) received combination regimens. Drugs used with eribulin included gemcitabine, tyrosine kinase inhibitors (TKIs), anti-PD-1 antibodies, or TKIs plus anti-PD-1 antibodies. For the 40 patients, the ORR was 27.5% (11/40) and the DCR was 60% (24/40). The ORR for myxoid liposarcoma was especially encouraging: 54.5% (6/11) and the DCR was 72.7% (8/11). 10 patients received the combined therapy of anti-PD-1 antibodies, TKIs, and eribulin and showed a likely better ORR of 30% (3/10) and DCR of 70% (7/10). After a median follow-up time of 12.57 months (IQR, 8.43-16.30), the median PFS was 4.13 months (95% CI, 2.17-8.40). 10 out of 33 (30.3%) patients with L-type sarcomas had achieved PR and the median PFS was 4.45 months, 1 out of 7 (14.3%) patients with non-L-type sarcomas had achieved PR and the median PFS is 2.67 months. Common TRAEs were bone marrow suppression (42.5%), hypertriglyceridemia (25%), fatigue (10%), hypertension (7.5%). No treatment-related death happened. Logistic regression analysis of the multiple factors influencing ORR revealed no difference between taxane-treated and taxane-naïve patient groups. Conclusions: This study presents the first real-world data on the use of eribulin in STS in Chinese population. Eribulin monotherapy or combination therapy were likely more effective in this population, as well-tolerated as with Study 309, especially in treating liposarcoma. Eribulin used in combination with TKI and anti-PD-1 antibody showed potential efficacy in STSs. Further clinical exploration of front-line eribulin monotherapy and combination strategies in this setting is warranted.

Long-term efficacy and safety of anlotinib in advanced sarcomas.

e23564 Background: Treatment of sarcomas has advanced in recent years partly because of the application of multitarget tyrosine kinase inhibitor (TKI) drugs. Anlotinib is an oral TKI with the dual effects of antiproliferation and antiangiogenesis, and it has a therapeutic effect with good tolerance and low side effects. In theory, physicians can gain long-term tumor control with anlotinib in certain advanced sarcomas. Methods: We conducted a retrospective analysis of patients with advanced sarcomas with measurable target lesions who had been treated in our ward since 2018. There were 22 patients who had taken anlotinib regularly for more than 12 months. Their general information, clinical efficacy, and toxicities were statistically analyzed. We used a swimmer plot to observe the efficacy and duration of the drugs and a waterfall plot to express the best treatment effect. Results: There were 14 male and 8 female patients, ranging in age from 14 to 75 (44.77 on average) years. The primary sarcomas were ASPS in five cases; synovial sarcoma (SS) in four cases; LMS in three cases; epithelioid sarcoma (ES) and UPS in two cases each; and clear cell sarcoma, RMS, angiosarcoma (AS), fibrosarcoma (FS), pleomorphic liposarcoma (LS), and osteosarcoma (OS) in one case each. The sites of metastasis were the lung in 15 cases, lymph nodes in 4 cases, and multiple sites in 3 cases. Therapies were as follows: first-line therapy (6 cases), second-line therapy (9 cases), third-line therapy (5 cases), and more than third-line therapy (2 cases). The current therapy protocols were nine cases with oral anlotinib alone, nine cases with combination chemotherapy, and four cases with combination immunotherapy (anti-PD1). The best clinical efficacy of this group was complete response (CR) in four cases (18.18%), partial response (PR) in five cases (22.73%), and stable disease in 13 cases (59.09%), with an overall response rate of 40.91% and the longest lasting time of 26, 16, 38 months in different response groups. The mean of progression-free survival (PFS) was 23.32 months. The main adverse effects included myelosuppression in seven cases (31.82%), hypertension in three cases (13.64%), and hand-foot syndrome and weakness in two cases (9.10%). Severe adverse effects included hypothyroidism with weakness in one case and wound ulceration with pneumothorax formation in another case. Conclusions: Anlotinib monotherapy or combination therapy can be an effective and safe choice for some advanced sarcomas with a longer maintenance time and acceptable side effects. Besides, anlotinib combined with anti-PD1 therapy has better therapeutic efficacy for specific diseases such as ASPS and ES. Anlotinib combined with chemotherapy has therapeutic efficacy for SS, LMS, FS, and RMS. Clinical efficacy such as CR and PR may be a prediction of long-term PFS in some advanced sarcomas.

Telomere as a Therapeutic Target in Dedifferentiated Liposarcoma.

Simple SummaryDDLPS is a non-lipogenic tumor with aggressive clinical behavior. DDLPS patients have limited therapeutic options, especially those with retroperitoneal tumors, and their outcome remains largely unsatisfactory, highlighting the need for novel treatment strategies. Gene expression analysis carried out in clinical samples from primary retroperitoneal DDLPS indicated that these tumors highly express genes involved in telomere maintenance, the cellular process that guarantees immortality to tumor cells. In this study, we evaluated the effect of RHPS4, a molecule able to alter telomere by binding to telomeric structures called G-quadruplexes, in patient-derived DDLPS cell lines. Exposure to RHPS4 induced DNA damage and decreased cell proliferation and migration, thus suggesting telomere as a novel target and G-quadruplex binders as innovative therapeutic agents in DDLPS.Background: Well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS) accounts for ~60% of retroperitoneal sarcomas. WDLPS and DDLPS divergently evolve from a common precursor and are both marked by the amplification of the 12q13–q15 region, leading to the abnormal expression of MDM2, CDK4, and HMGA2 genes. DDLPS is a non-lipogenic disease associated with aggressive clinical behavior. Patients have limited therapeutic options, especially for advanced disease, and their outcome remains largely unsatisfactory. This evidence underlines the need for identifying and validating DDLPS-specific actionable targets to design novel biology-driven therapies. Methods: Following gene expression profiling of DDLPS clinical specimens, we observed the up-regulation of “telomere maintenance” (TMM) pathways in paired DD and WD components of DDLPS. Considering the relevance of TMM for LPS onset and progression, the activity of a telomeric G-quadruplex binder (RHPS4) was assessed in DDLPS patient-derived cell lines. Results: Equitoxic concentrations of RHPS4 in DDLPS cells altered telomeric c-circle levels, induced DNA damage, and resulted in the accumulation of γ-H2AX-stained micronuclei. This evidence was paralleled by an RHPS4-mediated reduction of in vitro cell migration and induction of apoptosis/autophagy. Conclusions: Our findings support telomere as an intriguing therapeutic target in DDLPS and suggest G-quadruplex binders as innovative therapeutic agents.

Lipomatous Tumors: A Comparison of MRI-Reported Diagnosis with Histological Diagnosis.

Lipomatous tumors are among the most common soft tissue tumors (STTs). Magnetic resonance imaging (MRI) is a state-of-the-art diagnostic tool used to differentiate and characterize STTs. Radiological misjudgment can lead to incorrect treatment. This was a single-center retrospective study. Two hundred and forty lipomatous tumors were included. MRI diagnoses were categorized as benign, intermediate, or malignant and were compared with histological diagnoses. Tumor volumes were measured by MRI and from surgical specimens. The tumor was correctly categorized 73.3% of the time. A total of 21.7% of tumors were categorized as more malignant in MRI reports than they were by histology, and vice versa for 5.0% of tumors. Volume measured by MRI was not different from actual tumor size in pathology. Atypical lipomatous tumors (ALTs) and liposarcomas (LPSs) were larger when compared with lipomata and occurred in older patients. Based on the MRI-suspected tumor entity, surgical treatment can be planned. Large lipomatous tumors in elderly patients are more likely to be ALTs. However, a safe threshold size or volume for ALTs cannot be determined.

How to treat liposarcomas located in retroperitoneum

Almost half of retroperitoneal (RP) sarcomas are liposarcomas (LPS). The large majority of RP LPS are either well-differentiated LPS (WDLPS) or dedifferentiated LPS (DDLPS), these latter further classified according to grading in G2 and G3 DDLPS.Surgery is the only potentially curative treatment to achieve local control and possibly cure in primary localized disease. Over the last decade, a better delineation of the different histology-specific patterns of failure and the development of nomograms predictors of outcome has led to a better management of these rare tumors, with a special focus on non-surgical treatments. Available evidences – although far from exhaustive – show that radiation therapy might have a role, if any, as neoadjuvant treatment in locally aggressive histologies (i.e. WDLPS and G2 DDLPS), while it does not seem beneficial for histologies with a higher metastatic risk (i.e. G3 DDLPS and leiomyosarcoma). Neoadjuvant chemotherapy, instead, can be considered to reduce the risk of distant metastasis while waiting for the results of an ongoing RCT (STRASS-2) evaluating its effect in these tumors.However, given the rarity of these diseases and the subsequent lack of strong evidences to guide treatment, outcome improvement in these patients remains a challenge. Patients' referral to a sarcoma center where a dedicated specialized multidisciplinary team tailor optimal treatment on a case-by-case basis is crucial to ensure these patients the best outcome. Refining available nomograms – e.g including molecular variables – and identifying predictors of response/toxicity to chemotherapy and immunotherapy might be significantly helpful in tailoring treatments to the patient's characteristics. Also, new systemic agents are eagerly awaited for improving the management further.

Pleomorphic liposarcoma: A clinicopathologic study of 20 FNA cases.

Pleomorphic liposarcoma (PLPS) is the least common but most aggressive of all forms of liposarcoma (LPS). Its diagnosis relies on the recognition of pleomorphic lipoblasts (PLBs), whose numbers vary considerably. Because few large fine-needle aspiration (FNA) biopsy studies exist, the authors review their experience with PLPS. The authors' cytopathology files were searched for PLPS with histopathologic verification. FNA biopsy smears were performed via standard techniques. Twenty cases from 20 patients (male/female ratio, 2.3/1; age range, 22-77 years; mean age, 58 years) met the inclusion criteria. All had tissue confirmation. Biopsy sites included the following: thigh (11 [55%]), upper extremity (4 [20%]), axilla (2 [10%]), neck (1 [5%]), chest wall (1 [5%]), and mediastinum (1 [5%]). Aspirates were from primary (17 [85%]), locally recurrent (2 [10%]), and metastatic neoplasms (1 [5%]). The FNA diagnoses were PLPS (10 [50%]), myxofibrosarcoma (4 [20%]), LPS (2 [10%]), sarcoma (2 [10%]), and high-grade malignant neoplasm (2 [10%]). Smears showed thick cell clusters and dissociated single forms. Pleomorphic, epithelioid, and bizarre cell/nuclear shapes were common. PLBs were absent, rare, or unnoticed in 45%. In 25%, smears dominated by myxoid stroma were diagnosed as high-grade myxofibrosarcoma or myxoid LPS. Ancillary testing performed in 5 cases had limited diagnostic efficacy. FNA biopsy of PLPS, although able to successfully recognize malignancy, suffers from a sampling bias due to an inability to capture or recognize PLBs in a significant proportion of cases secondary to the heterogeneous composition of this neoplasm.

Neoadjuvant Therapy for Primary Resectable Retroperitoneal Sarcomas-Looking Forward.

Simple SummaryThis review summarizes the current evidence around neoadjuvant radiotherapy and systemic therapy for retroperitoneal sarcoma (RPS). While surgery is the cornerstone of treatment for these tumors, data from prospective studies, retrospective studies, early phase trials, and—most recently—our first phase III randomized trial for RPS suggest there are clinical scenarios in which neoadjuvant therapy may provide benefit. This review evaluates the STRASS results in the setting of other recent studies, identifies active trials of interest, and suggests future directions of study in this field. The intersection of STRASS and STRASS2 is considered and a summary of current acceptable approaches to neoadjuvant therapy for RPS is provided. The cornerstone of therapy for primary retroperitoneal sarcomas (RPS) is complete surgical resection, best achieved by resecting the tumor en bloc with adherent structures even if not overtly infiltrated. Until recently, trials designed to elucidate the role of neoadjuvant radiation or chemotherapy for RPS have been unable to achieve sufficient enrollment. The completion of the STRASS trial, which explored neoadjuvant radiotherapy for primary resectable RPS, is a major milestone in RPS research, but has prompted further questions about histology-driven treatment paradigms for RPS. Though it was ultimately a negative trial with respect to its primary endpoint of abdominal recurrence-free survival, STRASS produced a signal that suggested improved abdominal recurrence-free survival with neoadjuvant radiotherapy (RT) for patients with liposarcoma (LPS). No effect was seen for leiomyosarcoma (LMS) or high-grade dedifferentiated (DD) LPS, consistent with recent literature suggesting LMS and high-grade DD-LPS have a predominant pattern of distant rather than local failure. These results, along with those from other recent studies conducted at the bench and the bedside, emphasize the importance of a histology-specific approach to RPS research. Recent evidence for patterns of distant failure in LMS and high-grade DD-LPS has prompted the initiation of STRASS2, a study of neoadjuvant chemotherapy for these histologies. As this study unfolds, evidence may emerge for novel systemic therapy options in specific sarcoma histotypes given the explosion in targeted and immunotherapeutic applications over the last decade. This article reviews current and recent evidence around neoadjuvant radiation and chemotherapy as well as avenues for future study to optimize these treatment approaches.

Differentiation Between Lipomas and Atypical Lipomatous Tumors of the Extremities Using Radiomics.

The differentiation of soft tissue lipomas from atypical lipoma tumors (ALTs) of the extremities is important because of the distinction of the cytogenetic profiles and the treatment decisions. To investigate a radiomics method to differentiate between lipomas and ALTs of the extremities. Retrospective. Imaging data of 122 patients including 90 cases of lipomas and 32 cases of ALTs. Axial T1-weighted imaging and fat suppressed T2-weighted imaging at 3.0T MRI. Analysis of variance and the least absolute shrinkage and selection operator methods were used for feature selection and the random forest method was used to build three radiomics models based on T1WI, FS T2WI, and their combination (T1&T2WI). Three independent radiologists classified the tumors based on the subjective assessments. The area under the curve (AUC) of the receiver operating characteristic curve, accuracy, F1-score, specificity, and sensitivity were employed. The differences of the classifiers and discriminating ability of the radiologists and the radiomics model were compared by Delong test. A P value <0.05 was considered significant. Kappa test was used to determine the inter-reader agreements between the radiologists. The AUCs were 0.952 (95% confidence interval [CI]: 0.785-0.998), 0.944 (95% CI: 0.774-0.997), and 0.968 (95% CI: 0.809-1) for T1WI, FS T2WI, and T1&T2WI models in testing sets respectively. Delong test showed there were no significant difference between the different radiomics models (P > 0.05). The AUCs of the radiologists were 0.893 (95% CI: 0.824-0.942), 0.831 (95% CI: 0.752-0.893), and 0.893 (95% CI: 0.824-0.94), respectively. There were significant difference between radiomics model and radiologists' model in the training and entire cohorts (P < 0.05) while there were no significant difference in the testing sets (P > 0.05). Radiomics has the potential to distinguish between lipomas and ALTs of the extremities and their discrimination ability is no weaker than the senor radiologists. 3 TECHNICAL EFFICACY STAGE: 2.

Targetable Pathways in the Treatment of Retroperitoneal Liposarcoma.

Simple SummaryThis review discusses current and prospective treatment strategies for retroperitoneal liposarcoma, a rare type of sarcoma with a high propensity for locoregional recurrence and low survival rate. Chemo- and radiotherapy regimens, as well as molecular targets, are highlighted as important tools to better explore the mechanisms underlying this disease and to pursue new possible targetable pathways.Liposarcoma (LPS) is the most prevalent soft tissue sarcoma histological subtype. When it occurs in the abdomen the overall survival rate is as low as 10% at 10 years and is fraught with high rates of recurrence, particularly for the more aggressive dedifferentiated subtype. Surgery remains the mainstay of treatment. Systemic therapies for the treatment of metastatic or unresectable disease have low response rates. Deep understanding of well-differentiated and de-differentiated LPS (WDLPS and DDLPS, respectively) oncologic drivers is necessary for the development of new efficacious targeted therapies for the management of this disease. This review discusses the current treatments under evaluation for retroperitoneal DDLPS and the potential targetable pathways in DDLPS.

Liposarcoma subtype recurrence and survival: A UK regional cohort study

<h2>Summary</h2><h3>Background</h3> Clinical outcome data in the United Kingdom, Europe, and the United States have yet to facilitate appropriately specific surveillance for liposarcoma histological subtypes, despite being one of the most common soft tissue sarcomas. Therefore, this study aims to demonstrate histologic-specific differences in liposarcoma recurrence, disease progression, and survival and discuss the implications. <h3>Methods and findings</h3> This cohort study involves patients from a regional sarcoma service in the UK who have had a primary surgical excision of liposarcoma between October 2002 and September 2019. The median follow-up is five years. Confirmed histopathological diagnoses of liposarcoma (<i>n</i> = 193) are organised according to the World Health Organisation recognised subtypes: atypical lipomatous tumours (ALT), myxoid, pleomorphic, and dedifferentiated liposarcomas. In addition, retroperitoneal variants (<i>n</i> = 34) are included to illustrate the broader spectrum of phenotypes. The primary outcomes were local recurrence, distant disease progression, and disease-specific death, and compared using Kaplan–Meier analyses and tumour variables using Cox proportional hazard analyses. All three primary outcomes significantly differed (<i>P</i> < 0.0001, <i>n</i> = 193). There were no metastases or disease-specific death in patients with ALT (<i>n</i> = 92) and no metastases of their retroperitoneal counterparts (<i>n</i> = 17). Amongst the metastasising cases of rarer subtypes, there were pulmonary spread of pleomorphic (8/9, <i>n</i> = 20), dedifferentiated (4/5, <i>n</i> = 18), and myxoid (2/3, <i>n</i> = 29) liposarcomas. <h3>Conclusion</h3> An absence of metastases of ALT should be considered alongside global evidence. Surveillance protocols could better differentiate between these subtypes and, in doing so, save patients a considerable amount of irradiation, time, fear, and anxiety.

Utilization of radiation therapy and impact on outcomes in spermatic cord sarcomas in the United States.

419 Background: Spermatic cord sarcomas are a rare entity with management consisting of radical orchiectomy and the value of adjuvant radiation being unclear, as the literature consists of heterogeneous case series spanning multiple decades with limited numbers of patients. Methods: The National Cancer Data Base was queried for men who underwent orchiectomy for spermatic cord sarcomas between 2004 and 2018 with known surgical margin status. Kaplan-Meier with log-rank test and Cox proportional hazards tests were utilized for overall survival (OS) calculations. Associations were determined with bivariate regression analysis. Results: A total of 912 men were identified who met inclusion criteria. Six hundred seventeen (67.7%) had liposarcomas (LS) while 32.3% had non-lipsarcomatous (NLS) histologies. 5/10-year OS for men with LS was 85.1%/67.4% and 74.1%/58.4% for NLS, respectively (p &lt; 0.001). 238 (26.1%) men were treated with adjuvant radiation therapy with similar distributions between LS and NLS. Utilization of radiation was significantly associated with moderate-poorly differentiated histology (HR 3.228 [95%CI 2.241-4.649] p &lt; 0.001), radical orchiectomy (HR 1.477 [1.062-2.054] p = 0.020), positive surgical margins (HR 1.826 [95%CI 1.257-2.652] p = 0.002), but not histologic subtype or tumor size. There was no difference in OS for LS nor NLS with respect to the application of adjuvant radiation, but in men with moderately-poorly differentiated LS treated with adjuvant radiation, 5-year OS was 86.8% vs. 68.6% (p = 0.148). In men with well-differentiated LS, 5-year OS was 93.6% with XRT vs 89.5% (p = 0.623). Adjuvant XRT did not impact OS in men with positive surgical margins, nor did it have an impact on OS for NLS regardless of disease grade or margins. Conclusions: Adjuvant radiation therapy is utilized for approximately one quarter of men diagnosed with spermatic cord sarcomas. XRT may impact OS for men with moderately-poorly differentiated liposarcomas; further research with patient-level data is required.

Evaluation of PD-L1 Expression in Undifferentiated Pleomorphic Sarcomas, Liposarcomas and Chondrosarcomas.

Immune checkpoint inhibitors (ICIs) such as PD1/PD-L1 blockers are an established treatment for many solid cancers. There are currently no approved ICIs for sarcomas, but satisfactory results have been seen in some patients with disseminated disease in certain histological types. Most studies on PD-L1 in sarcoma have used small specimens and there are no clear cutoff values for scoring. We investigated PD-L1 immunoreactivity in high-grade chondrosarcomas (CS), abdominal liposarcoma (LS) and undifferentiated pleomorphic sarcomas (UPS). In total, 230 tumors were stained with SP142 and SP263 assays and evaluated by two clinical pathologists. Immunoreactivity in tumor and immune cells was correlated with clinical outcome. Overall, ≥1% PD-L1 immunoreactivity in tumor cells was found in 11 CS, 26 LS and 59 UPS (SP142 assay) and in 10 CS, 26 LS and 77 UPS (SP263 assay). Most tumors exhibited ≤10% PD-L1 immunoreactivity, but a subset across all three subtypes had >50%. Kaplan–Meier survival analysis showed no significant difference in metastasis-free or overall survival in relation to PD-L1 immunoreactivity in tumor or immune cells for any subtype. As there is a lack of clinical data regarding PD-L1/PD-1 status and therapy response, it is not currently possible to establish clear cutoff values. Patients with high (>50%) PD-L1 immunoreactivity in tumor cells (TC) with the SP263 assay would be a logical group to investigate for potentially beneficial PD1/PD-L1-targeted treatment.

Detection of MDM2 gene amplification on tissue microarray-based Fluorescence In-Situ Hybridization (FISH) in well-differentiated and dedifferentiated liposarcomas, displaying a wide morphological spectrum: A validation study at a tertiary cancer referral centre.

Liposarcomas including atypical lipomatous tumors (ALT)/well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPSs) display a histomorphological spectrum with their several diagnostic mimics. Murine double minute 2(MDM2) gene amplification characterizes ALT/WDLPS and DDLPS. Presently, there is no documented study from our subcontinent on the validation of MDM2 gene testing in these tumors. Twenty-eight cases, diagnosed as ALT/WDLPS (n = 5) and DDLPSs (n = 23), along with 10 other tumors were tested for MDM2 gene amplification, using fluorescence in situ hybridization (FISH) on tissue microarrays (TMAs). Fourteen cases, diagnosed as ALT/WDLPS and DDLPS, along with 49 other tumors were tested for MDM2 immunostaining. Twenty tumors were tested for p16INK4a immunostaining. FISH was interpretable in 25 (89.2%) cases. Among the 20 cases diagnosed as DDLPSs, 19 displayed MDM2 gene amplification. Among the 5 cases diagnosed as ALT/WDLPS, four showed MDM2 gene amplification. Finally, 19 cases were confirmed as DDLPS and 4 as ALT/WDLPS. Furthermore, 7/19 cases confirmed as DDLPS and all 4 cases as ALT/WDLPS tested for MDM2 immunostaining, displayed its diffuse immunoexpression, while a single case of DDLPS showed its focal immunostaining. None of the 49 control cases displayed diffuse MDM2 immunoexpression. ALL 16 DDLPSs and 4 cases of ALT/WDLPS displayed p16INK4a immunostaining. The sensitivity for diffuse MDM2 immunostaining was 87.5% in cases of DDLPS, 100% in ALT/WDLPS, and specificity was 100%. The sensitivity for MDM2 gene amplification was 94.7% in cases of DDLPS and 100% in cases of ALT/WDLPS. The sensitivity for p16INK4a was 100%. This constitutes the first sizable study on MDM2 testing in ALT/WDLPS and DDLPS from our subcontinent using TMAs. MDM2 gene amplification testing continues as the diagnostic gold standard for ALTs/WDLPSs and DDLPSs and is useful in cases of diagnostic dilemmas. Diffuse MDM2 (IF2 clone) and p16INK4a immunostaining, together seem useful for triaging cases for FISH.

Jejunal intussusception due to an atypical lipomatous tumor: a rare case report.

Intussusception in adults is rare, and the clinical symptoms of intussusception are subtle, making the diagnosis quite challenging. Gastrointestinal lipomas are rare benign tumors and are essentially adipose growths, most frequently found within the small intestine wall or mesentery. Limited up-to-date evidence exists regarding such lipomas. Intussusception due to a gastrointestinal lipoma constitutes an infrequent clinical entity, and the diagnosis of duodenal lipoma mainly depends on endoscopy examination, supplemented by computed tomography and magnetic resonance imaging. The present report describes a case of jejunal intussusception in an adult with a history of intermittent colicky abdominal pain located in the left upper quadrant over the last month. Contrast-enhanced computed tomography of the abdomen showed the typical target sign of a small intestinal intussusception along the left upper quadrant and a well-defined, low-density tumor in the intussusception. Exploratory laparotomy revealed jejuno-jejunal intussusception secondary to a lipoma, which was successfully treated with segmental intestinal resection.

A scoring system combining clinical, radiological, and histopathological examinations for differential diagnosis between lipoma and atypical lipomatous tumor/well-differentiated liposarcoma

This study evaluated the diagnostic accuracy of clinical, radiological, and histopathological examinations for differential diagnosis between atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLS) and lipoma, and aimed to develop a new combined scoring system for the preoperative diagnosis of ALT/WDLS. Eighty-nine lipomas and 56 ALT/WDLS were included and their clinical characteristics, magnetic resonance imaging (MRI) findings, histological findings by hematoxylin and eosin (HE) staining were investigated. Then, univariate and multivariate logistic regression analyses were performed for the findings, and a combined scoring system consisted of predictive factors of ALT/WDLS was developed. The univariate and multivariate logistic regression analyses revealed that tumor location (lower extremity), deep site, size (> 11 cm), thick septa (> 2 mm), enhancement of septa or nodular lesions, and lipoblasts were significantly different for the diagnosis of ALT/WDLS. We developed a combined scoring system based on the six predictive factors (total 0–16 points, the cutoff was 9 points). The area under the curve was 0.945, and sensitivity was 87.6% and specificity was 91.1% by the receiver operating characteristics curve. This combined scoring system does not require special equipment and reagents such as fluorescence in situ hybridization (FISH), and anyone can use it easily in many medical institutions with high diagnostic accuracy.

Overview of systemic therapy options in liposarcoma, with a focus on the activity of selinexor, a selective inhibitor of nuclear export in dedifferentiated liposarcoma.

Liposarcoma (LPS) is a common soft tissue sarcoma that encompasses diverse subtypes of well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic LPS. There is heterogeneity among the various LPS types with regard to prognosis, molecular pathogenesis, and response to treatment. Well-differentiated (WDLPS) and dedifferentiated liposarcoma (DDLPS) are most common types, which share common genetic alteration of chromosome 12q13-15 amplification resulting in amplification of oncogenes, including MDM2 (Mouse double minute 2), CDK4 (cyclin-dependent kinase 4), and HMGA2 (High mobility group protein AT-hook 2). Despite sharing the same molecular alteration, DDLPS has a worse prognosis, with a higher recurrence rate and higher propensity for metastases compared to WDLPS. Here we provide an overview of the LPS treatment landscape focusing on recent developments in the treatment of DDLPS with a focus on selinexor. Selinexor, a selective inhibitor of XPO1, was recently evaluated in a phase 3 trial, the first prospective randomized trial in DDLPS, and we discuss its efficacy in context of other available agents for DDLPS.