Loss of the DNA Repair Gene RNase H2 Identifies a Unique Subset of DDR-Deficient Leiomyosarcomas.

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR targeted treatments. Therefore, we designed a protein and genomic based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor tissue microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS) (30%, 39/102). In the TCGA database, RNASEH2B homozygous deletions (HomDels) were found in 6% (5/80) of LMS cases, with a higher proportion in U-LMS (15%; 4/27) compared to ST-LMS (2%; 1/53). Using the SNiPDx targeted-NGS sequencing assay to detect biallelic loss of function in select DDR related genes, we found RNASEH2B HomDels in 54% (19/35) of U-LMS cases with RNase H2 loss by IHC, and 7% (3/43) HomDels in RNase H2 intact cases. No RNASEH2B HomDels were detected in ST-LMS. In U-LMS patient cohort (n = 109), no significant overall survival difference was seen in patients with RNase H2 loss versus intact, or RNASEH2B HomDel (n=12) vs Non-HomDel (n=37). The overall diagnostic accuracy, sensitivity, and specificity of RNase H2 IHC for detecting RNASEH2B HomDels in U-LMS was 76%, 93% and 71% respectively, and it is being developed for future predictive biomarker driven clinical trials targeting DDR in U-LMS.

Safety and efficacy of percutaneous image-guided ablation for soft tissue sarcoma metastases to the liver.

PURPOSE: To evaluate outcomes following percutaneous image-guided ablation of soft tissue sarcoma metastases to the liver. MATERIALS AND METHODS: A single-institution retrospective analysis of patients with a diagnosis of metastatic soft tissue sarcoma who underwent percutaneous image-guided ablation of hepatic metastases between January 2011 and December 2021 was performed. Patients with less than 60 days of follow-up after ablation were excluded. The primary outcome was local tumor progression-free survival (LPFS). Secondary outcomes included overall survival, liver-specific progression-free survival. and chemotherapy-free survival. RESULTS: Fifty-five patients who underwent percutaneous ablation for 84 metastatic liver lesions were included. The most common histopathological subtypes were leiomyosarcoma (23/55), followed by gastrointestinal stromal tumor (22/55). The median treated liver lesions was 2 (range, 1-8), whereas the median size of metastases were 1.8 cm (0.3-8.7 cm). Complete response at 2 months was achieved in 90.5% of the treated lesions. LPFS was 83% at 1 year and 80% at 2 years. Liver-specific progression-free survival was 66% at 1 year and 40% at 2 years. The overall survival at 1 and 2 years was 98% and 94%. The chemotherapy-free holiday from the start of ablation was 71.2% at 12 months. The complication rate was 3.6% (2/55); one of the complications was Common Terminology Criteria for Adverse Events grade 3 or higher. LPFS subgroup analysis for leiomyosarcoma versus gastrointestinal stromal tumor suggests histology-agnostic outcomes (2 years, 89% vs 82%, p = .35). CONCLUSION: Percutaneous image-guided liver ablation of soft tissue sarcoma metastases is safe and efficacious.

When to ditch the ladder and take the elevator: The Anderson SArcoma Risk of Complications (A-SARC) score to guide reconstructive decision-making in extremity soft tissue sarcoma patients.

BACKGROUND: The reconstructive ladder relies mostly on defect size and depth to determine reconstructive technique, however, in actuality, many more variables ultimately inform reconstructive decision making, especially regarding extremity soft tissue sarcoma (eSTS) defects. The purpose of this study was to describe eSTS patients who will most optimally benefit from an advanced method of reconstruction (defined as a pedicled regional flap or free flap) and to create a simple risk assessment scale that can be employed in clinical practice. STUDY DESIGN: A single-institution retrospective cohort study examined patients undergoing resection of soft tissue sarcoma affecting the upper or lower extremities between 2016 and 2021. We categorized patients who required a pedicled or free flap as having had advanced reconstruction, and all other techniques were considered simple reconstruction. A regression was used to create a risk scale to guide reconstructive decision-making. RESULTS: The following variables were identified as independent predictors of complications and used to create our risk scale: lower extremity tumor location, preoperative radiotherapy, tumor bed excision, male sex, hypertension, and tumor volume. Intermediate and high-risk patients reconstructed using simple techniques had significantly greater overall complication rates compared to those reconstructed with advanced techniques. Major complications were significantly greater in low-risk patients reconstructed with advanced techniques. CONCLUSIONS: To minimize postoperative wound complications, low-risk patients should receive simple methods of reconstruction, whereas high-risk patients should be reconstructed using advanced techniques.

Sarcoma Size and Limb Dimensions Predict Complications, Recurrence, and Death in Patients with Soft Tissue Sarcoma in the Thigh: A Multidimensional Analysis.

BACKGROUND: Limb-sparing resections of thigh soft tissue sarcomas (STSs) can result in adverse outcomes. Identifying preoperative predictors for wound healing complications, tumor recurrence, and mortality is crucial for informed reconstructive decision-making. We hypothesized that preoperative measurements of thigh and tumor dimensions could serve as reliable indicators for postoperative complications, recurrence, and death. PATIENTS AND METHODS: In this retrospective cohort study conducted from March 2016 to December 2021, we analyzed patients undergoing thigh STS excisions followed by reconstruction. Preoperative magnetic resonance imaging or computed tomography scans provided necessary thigh and tumor dimensions. Univariate and multivariate regression assessed relationships between these dimensions and postoperative outcomes, including complications, recurrence, and death. RESULTS: Upon the analysis of 123 thighs, we found thigh width to be highly predictive of postoperative complications, even surpassing body mass index (BMI) and retaining significance in multivariate regression [odds ratio (OR) 1.19; 95% CI 1.03-1.39; p = 0.03]. Sarcoma-to-thigh width and thickness ratios predicted STS recurrence, with the thickness ratio retaining significance in multivariate regression (OR 1.03; 95% CI 1.001-1.05; p = 0.041). Notably, greater thigh thickness was independently protective against mortality in multivariate analysis (OR 0.80; 95% CI 0.65-0.98; p = 0.030). CONCLUSIONS: Thigh width outperformed BMI in association with postoperative complications. This may create an opportunity for intervention, where weight loss can play a role during the neoadjuvant therapy period to potentially reduce complications. Sarcoma-to-thigh width and thickness ratios, particularly the latter, hold substantial predictive value in terms of STS recurrence. Moreover, thigh thickness is an independent predictor of survival.

High Community-Level Social Vulnerability is Associated with Worse Recurrence-Free Survival (RFS) After Resection of Extremity and Truncal Soft Tissue Sarcoma.

BACKGROUND: Although social vulnerability has been associated with worse postoperative and oncologic outcomes in other cancer types, these effects have not been characterized in patients with soft tissue sarcoma. This study evaluated the association of social vulnerability and oncologic outcomes. METHODS: The authors conducted a single-institution cohort study of adult patients with primary and locally recurrent extremity or truncal soft tissue sarcoma undergoing resection between January 2016 and December 2021. The social vulnerability index (SVI) was measured on a low (SVI 1-39%, least vulnerable) to high (60-100%, most vulnerable) SVI scale. The association of SVI with overall survival (OS) and recurrence-free survival (RFS) was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. RESULTS: The study identified 577 patients. The median SVI was 44 (interquartile range [IQR], 19-67), with 195 patients categorized as high SVI and 265 patients as low SVI. The median age, tumor size, histologic subtype, grade, comorbidities, stage, follow-up time, and perioperative chemotherapy and radiation utilization were similar between the high and low SVI cohorts. The patients with high SVI had worse OS (p = 0.07) and RFS (p = 0.016) than the patients with low SVI. High SVI was independently associated with shorter RFS in the multivariate analysis (hazard ratio, 1.64; 95% confidence interval, 1.06-2.54) but not with OS (HR, 1.47; 95% CI 0.84-2.56). CONCLUSION: High community-level social vulnerability appears to be independently associated with worse RFS for patients undergoing resection of extremity and truncal soft tissue sarcoma. The effect of patient and community-level social risk factors should be considered in the treatment of patients with extremity sarcoma.

A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

Immuno-Oncology: New Insights into Targets and Therapies.

The role of immunotherapy in the care of surgical oncology patients promises to expand as investigators and clinicians evaluate new targets and approaches. Currently active clinical trials evaluate new immune checkpoints, including lymphocyte activation gene 3, T cell immunoreceptor with Ig and ITIM domains, and killer Ig-like receptor 2DL1/2L3. Vaccines delivered through mRNA have demonstrated exciting results in early clinical trials and hold promise for expanded application. Investigational approaches include dendritic cell vaccines, peptide vaccines, cytokines therapies, and cellular therapies. These studies have the potential to revolutionize the management of surgical oncology patients and promote durable cures following surgical resection.

Identifying risk factors and analyzing reconstructive outcomes in patients with lower-extremity soft-tissue sarcoma.

PURPOSE: Reconstructing defects after resecting soft-tissue sarcoma (STS) can be challenging. The aim of this retrospective study was to analyze the reconstructive outcomes and identify the potential risk factors in patients undergoing reconstruction after excision of lower-extremity STS. METHODS: Patients with lower-extremity STS were included. This database was compiled of patients from a single, large National Cancer Institute-accredited academic hospital. In total, 302 patients were included between January 2016 to January 2022. Univariate and multivariate analyses were performed to calculate odds ratios (ORs) for developing complications for each patient and surgical characteristic. RESULTS: The following factors were independent predictors of any complication: benign pulmonary disease (OR = 4.2; p = 0.02), preoperative radiotherapy (RT; OR = 2.5; p = 0.047), a tumor in the medial thigh (OR = 1.9; p = 0.03), body mass index (BMI) > 30 kg/m2 (OR = 1.05; p = 0.037), and full-thickness skin graft (OR = 5.4; p = 0.01). In the preoperative RT subgroup, reconstructing a defect via undermining and layered closure alone was an independent predictor of dehiscence (OR = 2.1; p = 0.02) and seroma (OR = 3.1; p = 0.02), whereas pedicled flaps (OR = 0.08; p = 0.001) and free flaps (OR = 0.05; p = 0.001) were independent protectors against any complication. CONCLUSION: Information derived from this analysis will assist with accurate preoperative patient counseling, which is crucial for informed decision-making and expectation management in lower-extremity STS. BMI and pulmonary function should be optimized to the extent possible to reduce postoperative complications. Patients treated preoperatively with RT should be reconstructed with a pedicled or free flap to optimize recovery.

BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors.

AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.5 × 1011, 5.0 × 1011, 1.0 × 1012 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 1012 vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 1012 vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling.

Data Dissemination of the Role of Neoadjuvant Radiation in Retroperitoneal Sarcoma: A CTOS and CSSO Survey.

Consensus guidelines call for complete resection of retroperitoneal sarcoma with consideration of neoadjuvant radiation for curative-intent treatment. The 15-month delay from the initial presentation of an abstract to the final publication of the STRASS trial results assessing the impact of neoadjuvant radiation led to a dilemma of how patients should be managed in the interim. This study aims to (1) understand perspectives regarding neoadjuvant radiation for RPS during this period; and (2) assess the process of integrating data into practice. A survey was distributed to international organizations including all specialties treating RPS. Eighty clinicians responded, including surgical (60.5%), radiation (21.0%) and medical oncologists (18.5%). Low kappa correlation coefficients on a series of clinical scenarios querying individual recommendations before and after initial presentation as an abstract indicate considerable change. Over 62% of respondents identified a practice change; however, most also noted discomfort in adopting changes without a manuscript available. Of the 45 respondents indicating discomfort with practice changes without a full manuscript, 28 (62%) indicated that their practice changed in response to the abstract. There was substantial variability in recommendations for neoadjuvant radiation between the presentation of the abstract and the publication of trial results. The difference in the proportion of clinicians describing comfort with changing practice based on the presentation of the abstract versus those that had done so shows that indications for proper integration of data into practice are not clear. Endeavors to resolve this ambiguity and expedite availability of practice-changing data are warranted.

Targeting the Molecular and Immunologic Features of Leiomyosarcoma.

Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies.

Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101).

PURPOSE: Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma. EXPERIMENTAL DESIGN: In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021. RESULTS: Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, 60 gastrointestinal stromal tumor (GIST); median of three prior lines of therapy]. Most common subtypes were leiomyosarcoma (17.2%), liposarcoma (14.0%), and GIST (10.2%). Molecular testing was available for 511 patients (87.1%); 221 patients (37.6%) were treated in matched trials. Overall response rate was 13.1% matched compared with 4.9% in unmatched (P < 0.001); the clinical benefit rate at 6 months was 43.9% vs. 19.9% (P < 0.001). Progression-free survival was longer for patients in matched trials (median, 5.5 vs. 2.4 months; P < 0.001), and overall survival was also superior for patients in matched trials (median, 21.5 vs. 12.3 months; P < 0.001). The benefit of enrollment in matched trials was maintained when patients with GIST were excluded from the analysis. CONCLUSIONS: Enrollment in biomarker-matched early-phase trials is associated with improved outcomes in heavily pretreated patients with metastatic sarcoma. Molecular testing of tumors from patients with advanced sarcoma and enrollment in matched trials is a reasonable therapeutic strategy.

The Landscape of Immunotherapy for Retroperitoneal Sarcoma.

Significant multidisciplinary scientific effort has been undertaken to understand the heterogeneous family of neoplasms that comprise soft tissue sarcomas. Within this family of neoplasms, outcomes for retroperitoneal sarcomas (RPS) are currently limited given a lack of effective therapies. In this review, we focus on immunotherapy and its relationship with the common RPS histologic subtypes. Although initial outcomes for RPS patients with immune checkpoint inhibition alone have been somewhat disappointing, subsequent analyses on histologies, the tumor microenvironment, sarcoma immune class, tumor infiltrating lymphocytes and genetic analysis for tumor mutational burden have yielded insight into the interplay between sarcomas and immunotherapy. Such approaches have all provided critical insight into the environment and characterization of these tumors, with targets for potential immunotherapy in future clinical trials. With this insight, molecularly tailored combination treatments for improving response rates and oncologic outcomes for RPS are promising.

Practice Pattern Variability in the Management of Regional Lymph Node Metastasis in Extremity and Trunk Soft Tissue Sarcoma: A Survey of the Society of Surgical Oncology and Musculoskeletal Tumor Society Membership.

BACKGROUND: Regional lymph node metastasis in extremity and trunk soft tissue sarcoma (ETSTS) is rare with no standardized management. We sought to determine management patterns for regional lymph node metastasis in ETSTS. METHODS: A survey regarding the management of ETSTS lymph node metastasis was distributed to the membership of the Musculoskeletal Tumor Society (MSTS) and the Society of Surgical Oncology (SSO) in January 2022. The survey queried the type of training (surgical oncology, orthopedic oncology), details of their practice setting, and management decisions of hypothetical ETSTS scenarios that involved potential or confirmed lymph node metastasis. RESULTS: The survey was distributed to 349 MSTS members (open rate of 63%, completion rate 21%) and 3026 SSO members (open rate of 55%, completion rate 4.7%) and was completed by 214 respondents, of whom 73 (34.1%) and 141 (65.9%) were orthopedic oncology and surgical oncology fellowship-trained, respectively. The majority of respondents practiced in an academic setting (n = 171, 79.9%) and treat >10 extremity sarcoma cases annually (n = 138, 62.2%). In scenarios with confirmed nodal disease for clear cell and epithelioid sarcoma, surgical oncologists were inclined to perform lymphadenectomy, while orthopedic oncologists were inclined to offer targeted lymph node excision with adjuvant radiation (p < 0.001). There was heterogeneity of responses regarding the management of nodal disease regardless of training background. CONCLUSION: Self-reported management of nodal disease in ETSTS was variable among respondent groups with differences and similarities based on training background. These data highlight the variability of practice for nodal disease management and the need for consensus-based guidelines.