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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Extent of macroscopic vascular invasion predicts distant metastasis in primary leiomyosarcoma of the inferior vena cava.

BACKGROUND: In retroperitoneal leiomyosarcoma (RP LMS), the predominant issue is distant metastasis (DM). We sought to determine variables associated with this outcome and disease-specific death (DSD). METHODS: Data were retrospectively collected on patients with primary RP LMS treated at a high-volume center from 2002 to 2023. For inferior vena cava (IVC)-origin tumors, the extent of macroscopic vascular invasion was re-assessed on each resection specimen and correlated with preoperative cross-sectional imaging. Crude cumulative incidences were estimated for DM and DSD and univariable and multivariable models were performed. RESULTS: Among 157 study patients, median tumor size was 11.0 cm and 96.2% of cases were intermediate or high grade. All patients underwent complete resection, 56.7% received chemotherapy (43.9% neoadjuvant) and 14.6% received radiation therapy. Only tumor size and grade and not site of tumor origin (e.g., IVC vs. other) were associated with DM and DSD (p < 0.05). Among 64 patients with IVC-origin tumors, a novel 3-tier classification was devised based on the level of intimal disruption, which was associated with both DM (p = 0.007) and DSD (0.002). CONCLUSION: In primary RP LMS, only tumor size and grade are predictive of DM and DSD. In IVC-origin tumors, the extent of macroscopic vascular invasion is also strongly predictive of these outcomes.

Effect of Anti-CD4 Antibody UB-421 on HIV-1 Rebound after Treatment Interruption.

BACKGROUND: Administration of a single broadly neutralizing human immunodeficiency virus (HIV)-specific antibody to HIV-infected persons leads to the development of antibody-resistant virus in the absence of antiretroviral therapy (ART). It is possible that monotherapy with UB-421, an antibody that blocks the virus-binding site on human CD4+ T cells, could induce sustained virologic suppression without induction of resistance in HIV-infected persons after analytic treatment interruption. METHODS: We conducted a nonrandomized, open-label, phase 2 clinical study evaluating the safety, pharmacokinetics, and antiviral activity of UB-421 monotherapy in HIV-infected persons undergoing analytic treatment interruption. All the participants had undetectable plasma viremia (<20 copies of HIV RNA per milliliter) at the screening visit. After discontinuation of ART, participants received eight intravenous infusions of UB-421, at a dose of either 10 mg per kilogram of body weight every week (Cohort 1) or 25 mg per kilogram every 2 weeks (Cohort 2). The primary outcome was the time to viral rebound (≥400 copies per milliliter). RESULTS: A total of 29 participants were enrolled, 14 in Cohort 1 and 15 in Cohort 2. Administration of UB-421 maintained virologic suppression (<20 copies per milliliter) in all the participants (94.5% of measurements at study visits 2 through 9) during analytic treatment interruption, with intermittent viral blips (range, 21 to 142 copies per milliliter) observed in 8 participants (28%). No study participants had plasma viral rebound to more than 400 copies per milliliter. CD4+ T-cell counts remained stable throughout the duration of the study. Rash, mostly of grade 1, was a common and transient adverse event; one participant discontinued the study drug owing to a rash. A decrease in the population of CD4+ regulatory T cells was observed during UB-421 monotherapy. CONCLUSIONS: UB-421 maintained virologic suppression (during the 8 to 16 weeks of study) in participants in the absence of ART. One participant discontinued therapy owing to a rash. (Funded by United Biomedical and others; ClinicalTrials.gov number, NCT02369146.).

Management of Locally Recurrent Retroperitoneal Sarcoma in the Adult: An Updated Consensus Approach from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly among histologic types of RPS, with implications for management. The Transatlantic Australasian RPS Working Group (TARPSWG) published a consensus approach to primary RPS, and to complement this, one for recurrent RPS in 2016. Since then, additional studies have been published, and collaborative discussion is ongoing to address the clinical challenges of local recurrence in RPS. METHODS: An extensive literature search was performed, and the previous consensus statements for recurrent RPS were updated after review by TARPSWG members. The search included the most common RPS histologic types: liposarcoma, leiomyosarcoma, solitary fibrous tumor, undifferentiated pleomorphic sarcoma, and malignant peripheral nerve sheath tumor. RESULTS: Recurrent RPS management was evaluated from diagnosis to follow-up evaluation. For appropriately selected patients, resection is safe. Nomograms currently are available to help predict outcome after resection. These and other new findings have been combined with expert recommendations to provide 36 statements, each of which is attributed a level of evidence and grade of recommendation. In this updated document, more emphasis is placed on histologic type and clarification of the intent for surgical treatment, either curative or palliative. Overall, the fundamental tenet of optimal care for patients with recurrent RPS remains individualized treatment after multidisciplinary discussion by an experienced team with expertise in RPS. CONCLUSIONS: Updated consensus recommendations are provided to help guide decision-making for treatment of locally recurrent RPS and better selection of patients who would potentially benefit from surgery.

Defining the role of neoadjuvant systemic therapy in high-risk retroperitoneal sarcoma: A multi-institutional study from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: In patients with retroperitoneal sarcoma (RPS), the incidence of recurrence after surgery remains high. Novel treatment approaches are needed. This retrospective study evaluated patients with primary, high-risk RPS who received neoadjuvant systemic therapy followed by surgery to 1) determine the frequency and potential predictors of radiologic tumor responses and 2) assess clinical outcomes. METHODS: Clinicopathologic data were collected for eligible patients treated at 13 sarcoma referral centers from 2008 to 2018. Univariable and multivariable logistic models were performed to assess the association between clinical predictors and response. Overall survival (OS) and crude cumulative incidences of local recurrence and distant metastasis were compared. RESULTS: Data on 158 patients were analyzed. A median of 3 cycles of neoadjuvant systemic therapy (interquartile range, 2-4 cycles) were given. The regimens were mostly anthracycline based; however, there was significant heterogeneity. No patients demonstrated a complete response, 37 (23%) demonstrated a partial response (PR), 88 (56%) demonstrated stable disease, and 33 (21%) demonstrated progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Only a higher number of cycles given was positively associated with PR (P = .005). All patients underwent complete resection, regardless of the tumor response. Overall, patients whose tumors demonstrated PD before surgery showed markedly worse OS (P = .005). An indication of a better clinical outcome was seen in specific regimens given for grade 3 dedifferentiated liposarcoma and leiomyosarcoma. CONCLUSIONS: In patients with high-risk RPS, the response to neoadjuvant systemic therapy is fair overall. Disease progression on therapy may be used to predict survival after surgery. Subtype-specific regimens should be further validated.

Micrometastatic cancer cells in lymph nodes, bone marrow, and blood: Clinical significance and biologic implications.

Cancer metastasis may be regarded as a progressive process from its inception in the primary tumor microenvironment to distant sites by way of the lymphovascular system. Although this type of tumor dissemination often occurs in an orderly fashion via the sentinel lymph node (SLN), acting as a possible gateway to the regional lymph nodes, bone marrow, and peripheral blood and ultimately to distant metastatic sites, this is not a general rule as tumor cells may enter the blood and spread to distant sites, bypassing the SLN. Methods of detecting micrometastatic cancer cells in the SLN, bone marrow, and peripheral blood of patients have been established. Patients with cancer cells in their SLN, bone marrow, or peripheral blood have worse clinical outcomes than patients with no evidence of spread to these compartments. The presence of these cells also has important biologic implications for disease progression and the clinician's understanding of the process of cancer metastasis. Further characterization of these micrometastatic cancer cells at each stage and site of metastasis is needed to design novel selective therapies for a more "personalized" treatment.

Dedifferentiation within well-differentiated liposarcoma of the extremity or trunk: Implications for clinical management.

BACKGROUND: In extremity or trunk liposarcoma, the implications of a dedifferentiated (DD) component within a well-differentiated (WD) tumor are unclear. We evaluated outcomes after surgery and identified potential predictors of survival in these patients compared to those with an entirely WD tumor. METHODS: Retrospective data were collected for patients who underwent complete resection from 2009 to 2019. Cumulative incidences of local recurrence (LR) and distant metastasis (DM) were calculated, and overall survival (OS) was estimated. Associations between OS and clinicopathologic variables were evaluated by univariable models. RESULTS: A total of 210 patients with MDM2-verified tumors were studied, including 58 (27.6%) with DD. In primary disease, LR occurred only in DD and worse OS was observed versus WD (p < 0.001). In recurrent disease, the LR incidences were similar between WD and DD (p = 0.559); however, worse OS persisted in DD (p = 0.004). The incidence of DM was extremely low (3.8%) and limited to DD. Higher grade (p < 0.001) and DD size (p = 0.043), but not overall tumor size were associated with worse OS. CONCLUSIONS: In extremity or trunk liposarcoma, the presence of DD leads to significantly worse outcomes in both primary and recurrence diseases. Further study is needed to determine if these patients benefit from adjunct therapies (e.g., radiation).

The role of 18 F-FDG PET/CT in retroperitoneal sarcomas-A multicenter retrospective study.

BACKGROUND: The role of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) in the evaluation of retroperitoneal sarcomas is poorly defined. We evaluated the correlation of maximum standardized uptake value (SUVmax) with pathologic tumor grade in the surgical specimen of primary retroperitoneal dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS). METHODS: Patients with the above histological subtypes in three participating institutions with preoperative 18 F-FDG PET/CT scan and histopathological specimen available for review were included. The association between SUVmax and pathological grade was assessed. Correlation between SUVmax and relapse-free survival (RFS) and overall survival (OS) were also studied. RESULTS: Of the total 58 patients, final pathological subtype was DDLPS in 44 (75.9%) patients and LMS in 14 (24.1%) patients. The mean SUVmax was 8.7 with a median 7.1 (range, 2.2-33.9). The tumors were graded I, II, III in 6 (10.3%), 35 (60.3%), and 17 (29.3%) patients, respectively. There was an association of higher histological grade with higher SUVmax (rs = 0.40, p = .002). Increasing SUVmax was associated with worse RFS (p = .003) and OS (p = .003). CONCLUSION: There is a correlation between SUVmax and pathologic tumor grade; increasing SUVmax was associated with worse OS and RFS, providing a preoperative noninvasive surrogate marker of tumor grade and biological behavior.

Primary mesenteric sarcomas: Collaborative experience from the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

BACKGROUND: Primary mesenteric soft tissue sarcomas (STS) are rare and limited evidence is available to inform management. Surgical resection is challenging due to the proximity of vital structures and a need to preserve enteric function. OBJECTIVES: To determine the overall survival (OS) and recurrence-free survival (RFS) for patients undergoing primary resection for mesenteric STS. METHODS: The Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) is an intercontinental collaborative comprising specialist sarcoma centers. Data were collected retrospectively for all patients with mesenteric STS undergoing primary resection between 2000 and 2019. RESULTS: Fifty-six cases from 15 institutions were included. The spectrum of pathology was similar to the retroperitoneum, although of a higher grade. R0/R1 resection was achieved in 87%. Median OS was 56 months. OS was significantly shorter in higher-grade tumors (p = .018) and extensive resection (p < .001). No significant association between OS and resection margin or tumor size was detected. Rates of local recurrence (LR) and distant metastases (DM) at 5 years were 60% and 41%, respectively. Liver metastases were common (60%), reflecting portal drainage of the mesentery. CONCLUSION: Primary mesenteric sarcoma is rare, with a modest survival rate. LR and DM are frequent events. Liver metastases are common, highlighting the need for surveillance imaging.

Risk Factors for Wound Complications After Soft Tissue Sarcoma Resection.

ABSTRACT: Soft tissue sarcomas are a heterogenous group of malignant tumors that represent approximately 1% of adult malignancies. Although these tumors occur throughout the body, the majority involved the lower extremity. Management may involve amputation but more commonly often includes wide local resection by an oncologic surgeon and involvement of a plastic surgeon for reconstruction of larger and more complex defects. Postoperative wound complications are challenging for the surgeon and patient but also impact management of adjuvant chemotherapy and radiation therapy. To explore risk factors for wound complications, we reviewed our single-institution experience of lower-extremity soft tissue sarcomas from April 2009 to September 2016. We identified 127 patients for retrospective review and analysis. The proportion of patients with wound complications in the cohort was 43.3%. Most notably, compared with patients without wound complications, patients with wound complications had a higher proportion of immediate reconstruction (34.5% vs 15.3%; P = 0.05) and a marginally higher proportion who received neoadjuvant radiation (30.9% vs 16.7%; P = 0.06).

Historical perspectives and future directions in the surgical management of retroperitoneal sarcoma.

Retroperitoneal sarcomas (RPS) have fascinated and intrigued physicians both past and present. Operative mortality rates were historically very high and complete resection was not possible for the majority of patients until only the last 2 decades. More recently, changes to the surgical approach and clinical decision-making in RPS have improved patient outcomes. With select integration of nonsurgical therapies, continued RPS-specific research, and ongoing collaborative efforts among major referral centers, the future appears promising.

Imaging of liposarcomas for clinicians: Characteristic features and differential considerations.

Liposarcoma (LPS) is a malignancy of fat and one of the most common soft tissue sarcomas. There are three major subtypes of LPS: Well-differentiated / dedifferentiated, myxoid, and pleomorphic. We review the imaging features of LPS in the abdomen and extremities, describe features that help differentiate the subtypes, and provides alternative considerations for fat-containing lesions (many benign) that can mimic LPS.

The role of margins in extremity soft tissue sarcoma.

For extremity soft tissue sarcomas, limb salvage is now standard of care. The extent of surgical margins is balanced with functionality of the resected limb. Although negative margins are the goal, the necessary width is unclear. Additional considerations for margin adequacy include presence of anatomic barriers such as fascia and periosteum, proximity of critical structures, receipt of adjuvant and neoadjuvant therapies, and histologic subtype. Multidisciplinary team discussion is critical for treatment planning.

Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter.

E26 transformation-specific sequence 1 (Ets-1), the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 by murine Th cells; however, its mechanism of action is still unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by primary human Th cells. Although Ets-1 negatively regulates the expression of Blimp1, a known suppressor of IL-2 expression, ablation of B lymphocyte-induced maturation protein 1 (Blimp1) does not rescue the expression of IL-2 by Ets-1-deficient Th cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) and is required for the recruitment of NFAT to the IL-2 promoter. In addition, Ets-1 is located in both the nucleus and cytoplasm of resting Th cells. Nuclear Ets-1 quickly exits the nucleus in response to calcium-dependent signals and competes with NFAT proteins for binding to protein components of noncoding RNA repressor of NFAT complex (NRON), which serves as a cytoplasmic trap for phosphorylated NFAT proteins. This nuclear exit of Ets-1 precedes rapid nuclear entry of NFAT and Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT.

Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma.

BACKGROUND: This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS). METHODS: Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS: Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m(2). At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85%, 80%, and 86%, respectively. CONCLUSIONS: The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging.

Accuracy of preoperative percutaneous biopsy for the diagnosis of retroperitoneal liposarcoma subtypes.

BACKGROUND: Surgery is the primary treatment for all subtypes of retroperitoneal liposarcoma, but neoadjuvant therapy may be warranted in cases of dedifferentiated liposarcoma (DDLS), which has an increased risk of recurrence and metastasis. Therefore, an accurate subtype-specific diagnosis is vital for appropriate consideration of neoadjuvant therapy. Previous studies assessing the subtype-specific accuracy of percutaneous biopsy are limited. We aimed to analyze the accuracy of preoperative percutaneous biopsy in the subtype-specific diagnosis of retroperitoneal liposarcoma and thus the reliability of percutaneous biopsy in guiding decisions about neoadjuvant treatment. METHODS: We retrospectively reviewed the medical records, including the pathologic reports, interventional radiology reports, and operative reports, of patients registered in the retroperitoneal/well-differentiated liposarcoma (WDLS/DDLS) database at The University of Texas MD Anderson Cancer Center between 1993 and 2013. RESULTS: We identified 120 patients who underwent 137 preoperative percutaneous biopsies followed by surgical resections. Pathologic examination following resection indicated that 74 of the patients had WDLS and 63 had DDLS. The overall diagnostic accuracy of percutaneous biopsy for identifying the subtype of liposarcoma was 62.8 % (86/137); the accuracy for identifying WDLS was significantly higher (85.1 %; 63/74) than that for identifying DDLS (36.5 %; 23/63) (p < 0.01). CONCLUSIONS: Percutaneous biopsy has low accuracy in the diagnosis of retroperitoneal DDLS. This can potentially mislead physicians in the decision to implement neoadjuvant treatment. When developing treatment strategies, including clinical trials for patients with retroperitoneal liposarcoma, physicians should carefully consider the low accuracy of percutaneous biopsy in detecting DDLS.

Follow-up of the soft tissue sarcoma patient.

Despite optimal treatment, patients with soft tissue sarcoma are at risk for recurrence and therefore appropriate surveillance is critical. At minimum, regularly scheduled clinical assessments and chest X-rays are necessary. Consensus guidelines are available; however, surveillance strategies must be personalized based on the risk for recurrence and inherent disease biology. Further research is needed on a number of issues, including the impact of surveillance on clinical outcome and the utility of molecular surveillance.