Primary Tumor Resection in Leiomyosarcoma Patients With Synchronous Isolated Lung Metastases: A National Cancer Database Study.

INTRODUCTION: Up to half of patients with leiomyosarcoma (LMS) present with distant metastases, most commonly in the lungs. Despite guidelines around managing metachronous oligometastatic disease, limited evidence exists for synchronous isolated lung metastases (SILMs). Our histology-specific study describes management patterns and outcomes for patients with LMS and SILM across disease sites. METHODS: We used the National Cancer Database to analyze patients with LMS of the retroperitoneum, extremity, trunk/chest/abdominal wall, and pelvis with SILM. Patients with extra-pulmonary metastases were excluded. We identified factors associated with primary tumor resection and receipt of metastasectomy. Outcomes included median, 1-year, and 5-year overall survival (OS) across treatment approaches using log-rank tests, Kaplan-Meier curves, and Cox proportional hazard models. RESULTS: We identified 629 LMS patients with SILM from 2004 to 2017. Patients were more likely to have resection of their primary tumor or lung metastases if treated at an academic center compared to a community cancer center. Five year OS for patients undergoing both primary tumor resection and metastasectomy was 20.9% versus 9.2% for primary tumor resection alone, and 2.6% for nonsurgical patients. Median OS for all-comers was 15.5 mo. Community treatment site, comorbidity score, and larger primary tumors were associated with worse survival. Chemotherapy, primary resection, and curative intent surgery predicted improved survival on multivariate Cox regression. CONCLUSIONS: An aggressive surgical approach to primary LMS with SILM was undertaken for select patients in our population and found to be associated with improved OS. This approach should be considered for suitable patients at high-volume centers.

Uterine MEIS1::NCOA2 Fusion Sarcoma With Lung Metastasis: A Case Report and Review of the Literature.

MEIS1::NCOA1/2 fusion sarcomas are a recently described novel entity arising in a variety of locations with a predilection for the genitourinary tract and gynecologic organs. Despite multiple locoregional recurrences, these tumors are thought to behave in a low-grade malignant manner. Here we report a uterine MEIS1::NCOA2 fusion sarcoma with lung metastasis. The patient was a 47-yr-old woman with a history of abnormal uterine bleeding who was found to have a myometrial mass confirmed by pathology to be uterine sarcoma. The tumor was predominantly composed of monotonous spindle cells with scant cytoplasm, crowded nuclei, and brisk mitotic activity, growing in a fascicular and streaming pattern. The morphologic and immunophenotypic features were nonspecific and a diagnosis of high-grade uterine sarcoma with a differential of leiomyosarcoma versus high-grade endometrial stromal sarcoma was rendered. At the 27-mo follow-up, the patient was found to have a lung metastasis consisting of a monotonous round cell sarcoma. A retrospective RNA-based and DNA-based next-generation sequencing of the primary uterine sarcoma revealed a MEIS1::NCOA2 gene fusion, a c.94G>C/p.D32H mutation in exon 3 of CTNNB1 gene, HMGA2 , and CDK4 gene amplification, and an intermediate/marginal level of MDM2 gene amplification. Polymerase chain reaction-based molecular analysis further demonstrated that the MEIS1::NCOA2 gene fusion and CTNNB1 somatic mutation were also present in the lung metastasis. This case represents the first case of such gynecologic sarcoma with distant (lung) metastasis, and the second metastatic case among all reported MEIS1::NCOA1/2 fusion sarcomas, highlighting the malignant metastatic potential of this emerging entity. Our case also indicates that HMGA2/CDK4/MDM2 region amplification and CTNNB1 somatic mutation might be recurrent genetic events in this rare sarcoma subtype.

Ocular adnexal sebaceous carcinoma in a patient with Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is caused by a pathogenic germline variant at the TP53 locus and is associated with an increased predisposition to a variety of cancers. The neoplasms most frequently associated with LFS are sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. In this case report, we present a 43-year-old male diagnosed with an ocular adnexal sebaceous carcinoma of the right upper eyelid who was confirmed to have LFS with subsequent genetic testing. The mutational profile of both the patient's genetic screen and tumor sequencing were congruent, demonstrating the same pathogenic loss-of-function TP53 variant. This case report highlights the importance of pursuing genetic testing in patients with a history of multiple tumor types, particularly those with uncommon diagnoses. In this case, confirmation of LFS had important implications for personalized patient care, including identification of contraindicated treatment interventions and the imaging modalities necessary for vigilant follow-up screening.

Adult Granulosa Cell Tumor With Sarcomatous Transformation: A Case Study With Emphasis on Molecular Alterations.

Adult granulosa cells tumors (AGCTs) are typically low-grade indolent tumors. On rare occasions, they undergo high-grade/sarcomatous transformation and behave aggressively. This transformation is postulated to occur as the result of acquired genetic alterations, some of which may be eligible for targeted therapy. Here we report a rare case of AGCT with sarcomatous transformation that harbored distinct molecular alterations from those typically seen with AGCTs supporting a molecularly driven approach to these malignancies. The patient is a 56-yr-old G3P3 woman with a history of multiple recurrences of ovarian AGCT for which the first diagnosis was made at the age of 25 when she was evaluated for infertility. The ovarian tumor displayed typical features of AGCT with low-grade, bland morphology. The first extraovarian spread of tumor involving the cul-de-sac was reported at the age of 39. After that, recurrences occurred every 2 to 3 yr with involvement of multiple anatomic sites and repeated surgical resections. At the age of 55 she developed a symptomatic recurrence in the pelvis and underwent resection of an isolated lesion (specimen 1) to no gross residual disease. Within 4 wk of resection she developed significant pelvic pain and imaging showed recurrence of the mass. Therefore, in 5 mo after the initial resection she underwent repeat excision of the lesion (specimen 2) and associated bowel. The sections from specimen 1 showed a biphasic morphology: a low-grade component with morphology and immunophenotype consistent with a typical AGCT and a high-grade spindle cell component with features consistent with a high-grade sarcoma. Specimen 2 featured a pure high-grade sarcoma characterized by coagulative tumor cell necrosis, readily recognizable mitoses, highly atypical cells with vesicular nuclei and prominent nucleoli. SF-1 positivity and the presence of FOXL2 C134W mutation in the sarcomatous component support the notion of transformation of typical AGCT. While detected TERT promoter C228T mutation may play a role in this process, we further identified genetic alterations affecting PI3K/AKT/mTOR pathway, including mutations in PIK3CA , PIK3R1 , AKT1 , and NF2 , which may also contribute to tumor progression/transformation. These findings provide rationale for molecular/pathway-based targeted therapy for patients with advanced AGCT.

Can Posttransarterial Chemoembolization Volumetric Oil Deposition on Computed Tomography Predict Treatment Response on Magnetic Resonance Imaging in Leiomyosarcoma Metastases to the Liver?

OBJECTIVE: To predict early tumor response to transarterial chemoembolization (TACE) based on volumetric oil deposition on posttreatment computed tomography (CT) in patients with leiomyosarcoma liver metastases. METHODS: This retrospective lesion-by-lesion based study included 32 lesions. The volumetric percent enhancing tumor on pre-TACE and 1-month post-TACE venous phase magnetic resonance imaging (MRI), and the percent oil deposition on CT 1 day after TACE were calculated. The predicted post-TACE enhanced percentage was computed by subtracting percent oil deposition from baseline percent enhanced. RESULTS: Mean percentage of viable tumor on pre-TACE MRI was 90.6% ± 9.3%. Mean oil deposition was calculated as 51.4% ± 26.2%. Mean percentage of measured residual tumor enhancement 1 month after TACE was 58.3% ± 27%, which correlates with predicted enhancement percentage of 43.9% ± 25.1% (r = 0.72, P < 0.001). A threshold of 35.5% for enhancement reduction was determined to predict tumor response with an accuracy of 78.1%. CONCLUSION: Volumetric oil deposition on CT can predict residual enhancement on post-TACE MRI.

A randomized, open-label, phase 2, multicenter trial of gemcitabine with pazopanib or gemcitabine with docetaxel in patients with advanced soft-tissue sarcoma.

BACKGROUND: Therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS. METHODS: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline-based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression-free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent-to-treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). RESULTS: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P = .3, log-rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively). CONCLUSIONS: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS.

Desmoid tumor mimics local recurrence of extremity sarcoma on MRI.

BACKGROUND AND OBJECTIVES: The development of desmoid fibromatosis after tumor resection may mimic local recurrence. To our knowledge, this phenomenon has not been reported after extremity sarcoma resection. We report four cases of desmoid-type fibromatosis ("desmoid tumors") mimicking local recurrence after extremity sarcoma resection. METHODS: We retrospectively reviewed the records of patients treated for extremity sarcoma by our orthopedic oncology service from 2014 to 2019 and identified four patients with biopsy-proven desmoid tumors. We extracted clinical, pathologic, radiographic, and operative data for the primary neoplasms and desmoid tumors. RESULTS: Four patients with postresection surveillance magnetic resonance imaging suspicious for local recurrence underwent further analysis showing desmoid tumors. Patients underwent image-guided needle biopsy, with specimens demonstrating fibromatosis-type histologic characteristics. Two cases were ß-catenin positive. Desmoid tumors were managed with observation. No patient had experienced local or distant recurrence of the primary tumor at a mean follow-up of 30 months after resection (range, 23-34 months); none underwent surgery for symptoms of desmoid tumors. CONCLUSIONS: Desmoid tumors should be considered part of the differential diagnosis when assessing patients with radiographic concern for postresection local recurrence of extremity bone and soft-tissue sarcoma. An image-guided needle biopsy can inform diagnosis and management.

BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma.

BACKGROUND: Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for BRCA1/2 gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS). MATERIALS AND METHODS: DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional BRCA2 loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition. RESULTS: In an unselected STS study population, BRCA2 alterations were identified in 15 (1%) patients, and homozygous BRCA2 loss was detected in 9 (<1%). However, subset analysis revealed that these BRCA2 alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a BRCA2 alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with BRCA2 loss. CONCLUSION: HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for BRCA2 loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic BRCA2 profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS. IMPLICATIONS FOR PRACTICE: Soft-tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional BRCA1/2 loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and BRCA2 loss who achieved durable clinical benefit from poly (ADP-ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for BRCA1/2 alterations and may benefit from treatment targeted to these alterations.

A national analysis of patterns of care and outcomes for adults diagnosed with desmoplastic small round cell tumors in the United States.

BACKGROUND: Because of the rarity of desmoplastic small round cell tumors (DSRCT), there is a lack of data describing patterns of care and survival for these patients. Using a national tumor registry, the current study sought to describe patterns of care and clinical outcomes for patients with DSCRT. METHODS: Data from the National Cancer Database were used to identify 491 patients aged 18 years or older diagnosed with DSRCT between 2004 and 2014. Multivariable Cox proportional hazards regression analysis was used to identify factors associated with overall survival (OS). RESULTS: Among all patients, 41.2% (n = 200), underwent surgical resection of their primary tumor, chemotherapy was administered to 86.5% (n = 415) of patients, while radiation therapy was administered to 13.0% (n = 63) of patients. Over the study, 69.7% of patients died with a median OS of 25.9 months (interquartile range [IQR]: 22.7-27.5); 1-, 3-, and 5-year OS were 78.6%, 32.3%, and 18.4%, respectively. On multivariable analysis, stage IV disease (Hazard Ratio [HR] = 2.12, 95% CI: 1.41-3.18), receipt of surgery (HR = 0.68, 95% CI: 0.50-0.91), chemotherapy (HR = 0.52, 95% CI: 0.35-0.78), or radiation therapy (HR = 0.55, 95% CI: 0.33-0.92) were independently associated with OS. CONCLUSIONS: Although receipt of multimodality treatment may lead to improved survival, further research and clinical trials are required to establish best practices for the care of DSRCT.

Call for improved design and reporting in soft tissue sarcoma studies: A systematic review and meta-analysis of chemotherapy and survival outcomes in resectable STS.

New evidence and systemic therapies demand an updated analysis of chemotherapy for soft tissue sarcoma. We completed a meta-analysis of chemotherapy in localized STS, assessing OS, PFS, and local and distant recurrence (local recurrence-free survival [LRFS] and distant recurrence-free survival [DRFS]). Ten studies, totaling 3157 patients, were included. A pooled analysis for 5-year OS, progression-free survival, LRFS, and DRFS showed no benefit of chemotherapy over locoregional therapy alone for all-comers or site-specific STS. We make recommendations to improve outcome reporting and quality indices.

Minimally Invasive Versus Open Primary Resection for Retroperitoneal Soft Tissue Sarcoma: A Propensity-Matched Study From the National Cancer Database.

BACKGROUND: Although well described for gastrointestinal and pelvic cancers, use of minimally invasive surgery (MIS) for the management of retroperitoneal soft tissue sarcoma (RPS) remains unknown. The current study aimed to describe patterns of MIS use and assess the association between MIS and clinical outcomes among patients undergoing surgery for RPS. METHODS: Patients undergoing a primary resection for RPS between 2010 and 2014 were identified using the National Cancer Database. Multivariable logistic and Cox proportional hazards models were used to assess the association between use of MIS and clinical outcomes. Sensitivity analysis was performed using propensity score-matching (PSM). RESULTS: This study identified 3844 patients who met the inclusion criteria. Of these patients, 89.3% (n = 3432) underwent an open surgery, whereas 10.7% (n = 412) underwent MIS. The patients undergoing MIS were more likely to present with smaller tumors (open vs MIS: median tumor size, 17 cm; interquartile range [IQR, 9.8-26.0] vs 10.5 cm [IQR, 6.5-18.0]) and to undergo surgery at community hospitals (26.8% vs 36.1%; both P < 0.001). Although MIS was associated with a shorter hospital length of stay [LOS] (median LOS, 6 days [IQR, 5-9 days] vs 4 days [IQR, 2-7]; P < 0.001), postoperative mortality and overall survival were comparable between the two treatment groups (all P > 0.05). These findings were confirmed using PSM. CONCLUSIONS: MIS was associated with a shorter LOS, however, postoperative mortality and overall survival were comparable by operative approach. Future research is required to evaluate the use of MIS for the management of RPS. Policies are required to ensure that patients receive care in accordance with best practices and recommended guidelines.

Highly personalized detection of minimal Ewing sarcoma disease burden from plasma tumor DNA.

BACKGROUND: Even though virtually all patients with Ewing sarcoma achieve a radiographic complete response, up to 30% of patients who present with localized disease and up to 90% of those who present with metastases experience a metastatic disease recurrence, highlighting the inability to identify patients with residual disease at the end of therapy. Up to 95% of Ewing sarcomas carry a driving EWS-ETS translocation that has an intronic breakpoint that is specific to each tumor, and the authors developed a system to quantitatively detect the specific breakpoint DNA fragment in patient plasma. METHODS: The authors used a long-range multiplex polymerase chain reaction (PCR) technique to identify tumor-specific EWS-ETS breakpoints in Ewing sarcoma cell lines, patient-derived xenografts, and patient tumors, and this sequence was used to design tumor-specific primer sets to detect plasma tumor DNA (ptDNA) by droplet digital PCR in xenograft-bearing mice and patients. RESULTS: Tumor-specific breakpoint DNA fragments were detected in the plasma of xenograft-bearing mice, and the signal correlated with tumor burden during primary tumor growth, after surgical resection, and at the time of metastatic disease recurrence. Furthermore, the authors were able to detect the specific breakpoint in plasma DNA obtained from 3 patients with Ewing sarcoma and in 2 patients the authors were able to detect ptDNA when there was radiographically undetectable disease present. CONCLUSIONS: The use of droplet digital PCR to detect tumor-specific EWS-ETS fusion gene breakpoint ptDNA fragments can be developed into a highly personalized biomarker of disease recurrence that can be optimized in animal studies for ultimate use in patients. Cancer 2016;122:3015-3023. © 2016 American Cancer Society.

Clinical outcomes of patients with CIC-rearranged sarcoma: a single institution retrospective analysis.

PURPOSE: CIC-rearranged sarcomas represent a type of undifferentiated small round cell sarcoma (USRCS) characterized by poor survival, rapid development of chemotherapy resistance, and high rates of metastasis. We aim to contribute to the growing body of knowledge regarding diagnosis, treatment, clinical course, and outcomes for these patients. METHODS: This case series investigates the clinical courses of ten patients with CIC-rearranged sarcoma treated at the Johns Hopkins Hospital from July 2014 through January 2024. Clinical data were retrospectively extracted from electronic medical records. RESULTS: Patients ranged from 10 to 67 years of age at diagnosis, with seven patients presenting with localized disease and three with metastatic disease. Tumors originated from soft tissues of various anatomic locations. Mean overall survival (OS) was 22.1 months (10.6-52.2), and mean progression-free survival (PFS) was 16.7 months (5.3-52.2). Seven patients received intensive systemic therapy with an Ewing sarcoma-directed regimen or a soft tissue sarcoma-directed regimen. Three patients experienced prolonged disease-free survival without systemic treatment. CONCLUSION: Most patients in this case series demonstrated aggressive clinical courses consistent with those previously described in the literature, although we note a spectrum of clinical outcomes not previously reported. The diversity of clinical courses underscores the need for an improved understanding of individual tumor biology to enhance clinical decision-making and patient prognosis. Despite its limitations, this article broadens the spectrum of reported clinical outcomes, providing a valuable addition to the published literature on this rare cancer.

Treatment patterns and outcomes for primary uterine leiomyosarcoma with synchronous isolated lung metastases: A National Cancer Database study of primary resection and metastasectomy.

Background: One third of patients with uterine leiomyosarcomas (uLMS) present with distant metastases. Current guidelines do not include recommendations around surgery for metastatic uLMS. Patients with distant metastases commonly receive primary tumor resection for symptoms and so oncologic outcomes after surgery warrant exploration. We describe treatment patterns and outcomes for uLMS patients with synchronous isolated lung metastases (SILM). Methods: This retrospective analysis of the National Cancer Database identified patients with uLMS and SILM. Patients with non-pulmonary metastases were excluded. We collected demographic, disease, and treatment characteristics and assessed clinicopathologic factors associated with the receipt of surgery on multivariate regression. Median, 1-year, and 5-year overall survival (OS) across treatment approaches were compared using Kaplan-Meier curves and log-rank tests. Multivariate Cox proportional hazard regressions identified independent predictors of survival. Results: We identified 905 patients with uLMS and SILM between 2004 and 2017. 600 patients had primary tumor resection; 63 also had curative intent surgery with metastasectomy. Patients who did not receive chemotherapy were older (p<0.01) with a higher comorbidity index (p<0.05). Women with private health insurance were more likely to receive chemotherapy (p<0.01) and primary tumor resection (p<0.01). Patients who underwent curative intent surgery had 1-year OS of 71.2% and 5-year survival of 18% compared to 1-year survival of 35.6 % and 5-year survival of 5.16 % for patients who had no surgery. Black women had poorer survival on multivariate regression. Conclusions: Primary tumor resection and curative intent surgery are associated with improved OS in uLMS with SILM and may be a reasonable treatment option in appropriately selected patients.

Impact of Consolidative Radiation on Overall and Progression-Free Survival in Pediatric, Adolescent, and Young Adult Metastatic Bone and Soft Tissue Sarcoma.

PURPOSE: To determine the association between consolidative radiation (RT) and survival in children, adolescents, and young adults with metastatic sarcoma. METHODS AND MATERIALS: Eligibility criteria included patients aged ≤39 years with newly diagnosed metastatic bone or soft tissue sarcoma who completed local control of the primary tumor without disease progression. Consolidative RT was defined as RT to all known sites of metastatic disease. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). The least absolute shrinkage and selection operator Cox provided adjusted estimates. To account for immortal time bias, consolidative RT was used as a time-varying covariate in a time dependent Cox model. Distant failure was estimated using the Fine-Gray model. RESULTS: Patients (n = 85) had a median age at diagnosis of 14.8 years. Most common histology was Ewing Sarcoma (45.9%) followed by rhabdomyosarcoma (40.0%). Receipt of consolidative RT was associated with Ewing Sarcoma (P < .001) and local control modality as those who underwent local control with surgery and RT compared with surgery alone were more likely to be treated with consolidative RT (P = .034). Consolidative RT was independently associated with improved OS (hazard ratio [HR], 0.41; 95% CI, 0.17-0.98; P = .045) and improved PFS (HR, 0.37; 95% CI, 0.16-0.88; P = .024) after adjusting for confounding variables and immortal time bias. Patients treated with consolidative RT also experienced a lower risk of distant failure (HR, 0.33; 95% CI, 0.17-0.64; P = .001). In an independent data set of patients with metachronous progression (n = 36), consolidative RT remained independently associated with improved OS. CONCLUSIONS: Consolidative RT was independently associated with improved OS and PFS and decreased risk of distant failure in child, adolescent, and young adult patients with metastatic sarcoma. Future work should evaluate biomarkers to optimize patient selection, timing, and dose for consolidative RT.

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma.

PURPOSE: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS). PATIENTS AND METHODS: Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m2 intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D. RESULTS: Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m2 IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%. CONCLUSION: Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics.

PURPOSE: Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of PNST in cancer predisposition syndrome NF1. EXPERIMENTAL DESIGN: cfDNA was isolated from plasma samples of a novel cohort of 101 NF1 patients and 21 healthy controls and underwent whole genome sequencing. We investigated diagnosis-specific signatures of copy number alterations (CNA) with in silico size selection as well as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end-motifs, and fragment non-negative matrix factorization (NMF) signatures. RESULTS: The novel cohort of NF1 patients validated that our previous cfDNA CNA-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. CONCLUSIONS: Novel cfDNA fragmentomic signatures distinguish atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 and provides a blueprint for de-centralizing non-invasive cancer surveillance in hereditary cancer syndromes.

Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics.

Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.

Pazopanib in sarcomas: expanding the PALETTE.

PURPOSE OF REVIEW: After failure of standard therapy, few effective treatment options exist for adult patients with metastatic sarcomas, and median survival remains dismal at approximately 1 year. Pazopanib, a multitargeted tyrosine kinase inhibitor, has recently been approved for nonadipocytic soft tissue sarcomas refractory to chemotherapy. In this review, we will revisit the efficacy of pazopanib in sarcomas, and present a patient case that illustrates two of many unanswered questions: which sarcoma patients are most likely to benefit from pazopanib therapy, and what criteria are best suited to accurately detect benefit in clinical trials? RECENT FINDINGS: Pazopanib has been tested in sarcoma patients in a phase II and phase III study, and was shown to prolong progression-free survival by 3 months relative to placebo. Although histology has been the primary stratification variable for subgroup analysis in large sarcoma trials, the PALETTE study did not demonstrate superior response within histologic cohorts. Ongoing trials seek to explore efficacy of pazopanib in previously excluded histologies, as well as include correlative studies to identify histologic and molecular biomarkers to predict patients likely to benefit. SUMMARY: Pazopanib has been proven to provide modest benefit overall to nonadipocytic soft tissue sarcoma patients, but we have yet to identify the molecular basis for those patients who derive exceptional benefit.

Extrathoracic location and "borderline" histology are associated with recurrence of solitary fibrous tumors after surgical resection.

BACKGROUND: Most solitary fibrous tumors (SFTs) are cured by complete resection, but many recurrent and metastatic SFTs do not respond to treatment and are fatal. Malignant histology, defined by England's pathologic criteria, is strongly associated with recurrence, but some benign SFTs still behave aggressively. Several studies have suggested that extrathoracic SFTs have a worse prognosis. We reviewed thoracic and extrathoracic SFTs from our institution to determine if extrathoracic location is associated with recurrence, independent of malignant histology. METHODS: With IRB approval, we retrieved patient pathology reports from the Johns Hopkins Surgical Pathology database between 1991 and 2011 and included 83 SFT patients in our analysis. Patient history and outcomes were obtained from the medical record and primary care physicians. Predictors of recurrence were analyzed by univariate and multivariate analysis and survival determined by the Kaplan-Meier method. RESULTS: Of the 83 patients, 59 had extrathoracic SFTs in neurologic (n = 24), extremity or head/neck (n = 13), or visceral/intraabdominal (n = 22) sites. A total of 74 SFTs were classified benign and 9 as malignant. Of the 14 recurrences, 13 occurred in extrathoracic SFTs; only 7 were classified as malignant. Multivariate analysis confirmed that malignant histology had the strongest association with recurrence, but extrathoracic location also independently predicted recurrence. A total of 20 benign SFTs possessed 1 or more of England's criteria but to an insufficient degree for malignant classification. These "borderline" SFTs were more likely to recur than benign SFTs without these features. CONCLUSIONS: Extrathoracic and "borderline" SFTs with any of England's criteria have a higher risk of recurrence.