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A non-randomised, phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma. In this phase 3 study, we aimed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine (an active control). We did this randomised, open-label, phase 3 study across 110 study sites in 22 countries. We enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Using an interactive voice and web response system, an independent statistician randomly assigned (1:1) patients to receive eribulin mesilate (1·4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850 mg/m2, 1000 mg/m2, or 1200 mg/m2 [dose dependent on centre and clinician] intravenously on day 1) every 21 days until disease progression. Randomisation was stratified by disease type, geographical region, and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT01327885, and is closed to recruitment, but treatment and follow-up continue. Between March 10, 2011 and May 22, 2013, we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13·5 months [95% CI 10·9–15·6] vs 11·5 months [9·6–13·0]; hazard ratio 0·77 [95% CI 0·62–0·95]; p=0·0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in patients who received eribulin (152 [67%]) than in those who received dacarbazine (126 [56%]), as were deaths (10 [4%] vs 3 [1%]); one death (in the eribulin group) was considered treatment-related by the investigators. Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma. Eisai.

Among patients with leiomyosarcoma, a combination of doxorubicin and trabectedin with prolonged trabectedin maintenance therapy led to longer overall survival than doxorubicin alone (median, 33 vs. 24 months).

Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy of uterine smooth muscle, associated with early metastasis, frequent recurrence, and poor prognosis. Accurate preoperative diagnosis remains difficult given that clinical and radiologic features often overlap with benign leiomyomas, and no reliable biomarkers are currently available. This review summarizes recent evidence on the role of microRNAs (miRNAs) in the biology and clinical management of uLMS. Literature from molecular and translational studies was examined to identify dysregulated miRNAs, their target pathways, and potential diagnostic and therapeutic applications. uLMS displays a characteristic miRNA profile, including downregulation of tumor-suppressive miRNAs such as the miR-29 and miR-200 families and upregulation of oncogenic miRNAs including miR-21 and the miR-183~96~182 cluster, leading to activation of PI3K/AKT/mTOR signaling and epithelial–mesenchymal transition (EMT). Circulating and tissue miRNAs show promise as minimally invasive biomarkers for differentiating uLMS from leiomyomas, predicting prognosis, and guiding therapy. Emerging therapeutic approaches aim to restore the tumor-suppressive miRNAs or inhibit oncogenic ones using mimics or antagomiRs. Overall miRNAs represent critical regulators of uLMS pathogenesis and hold significant potential for precision diagnosis, prognostication, and targeted therapy, though larger validation studies and improved delivery systems are required before clinical translation.

Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. They have a poor prognosis with high rates of recurrence and metastasis. The five-year survival for uLMS patients is between 25 and 76%, with survival rates approaching 10–15% for patients with metastatic disease at the initial diagnosis. Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. Notably, drugs that block abnormal functions of these pathways remarkably improve survival in uLMS patients. However, due to chemotherapy resistance, there remains a need for novel drugs that can target these pathways effectively. In this review article, we provide an overview of the recent progress in ascertaining the biological functions and regulatory mechanisms in uLMS from the perspective of aberrant biological pathways, including DNA repair, immune checkpoint blockade, protein kinase and intracellular signaling pathways, and the hedgehog pathway. We review the emerging role of epigenetics and epitranscriptome in the pathogenesis of uLMS. In addition, we discuss serum markers, artificial intelligence (AI) combined with machine learning, shear wave elastography, current management and medical treatment options, and ongoing clinical trials for patients with uLMS. Comprehensive, integrated, and deeper insights into the pathobiology and underlying molecular mechanisms of uLMS will help develop novel strategies to treat patients with this aggressive tumor.

Background Retroperitoneal vascular leiomyosarcoma (RVLMS), which originates from vascular wall smooth muscle cells, typically requires inferior vena cava (IVC) reconstruction during radical surgery. Methods A retrospective cohort study was conducted on 24 patients who underwent primary resection of RVLMS from June 2015 to November 2023 in one institution. The patient details, operative management, and follow-up data were assessed. Results Regarding the imaging classification of RVLMS, 6 patients were intraluminal type, 9 patients were intermediate type, 4 patients were extraluminal type, and 5 patients were peripheral type. The median tumor size was 80 mm (interquartile range, IQR 63–105 mm). The median operative time was 294 min. The median blood loss was 650 ml. There were significant differences in operation time, blood loss, blood transfusion, and Intensive Care Unit admission rate among the four types of RVLMS. The procedures of vascular reconstruction included primary repair ( n  = 15), patch angioplasty ( n  = 2), and IVC ligation ( n  = 4). 3 patients suffered an R1/R2 margin. With a median follow-up time of 12.5 months, 5 patients developed local recurrence while 7 patients developed distant metastasis. 1 patient had both local recurrence and distant metastasis. The median disease-free survival was 19.0 months (IQR 7.0–59.0 months). Conclusion A reasonable surgical strategy of vascular resection and reconstruction in the context of RVLMS surgery was of value in achieving good postoperative outcomes and long-term survival. The imaging classification of RVLMS might help to evaluate the surgical complexity and the prognosis.

Background Morcellation may lead to intraperitoneal spread of tumor cells, thus making prognosis of undiagnosed uterine leiomyosarcoma (ULMS) worse. However, preoperative diagnosis of ULMS remains challenging. This study aimed to design a preoperative clinical characteristics scoring system for differentiating ULMS from uterine fibroid. Methods This study enrolled 45 ULMS patients and 180 uterine fibroid patients in Peking Union Medical College Hospital from January 2013 to December 2018. Results The incidence of occult ULMS was 0.59% (95% CI, 0.39–0.71%). Age ≥ 40 years old (OR 2.826, 95%CI 1.326–5.461), tumor size ≥7 cm (OR 6.930, 95% CI 2.872–16.724), neutrophil-to-lymphocyte ratio (NLR) ≥ 2.8 (OR 3.032, 95%CI 1.288–7.13), number of platelet ≥298 × 10 9 /L (OR 3.688, 95%CI 1.452–9.266) and lactate dehydrogenase (LDH) ≥ 193 U/L (OR 6.479, 95%CI 2.658–15.792) were independent predictors of ULMS. A preoperative clinical characteristics scoring system was designed based on OR values, with a total score of 7 points. Tumor size ≥7 cm, LDH ≥ 193 U/L were assigned 2 points, while age ≥ 40 years old, NLR ≥ 2.8 and number of platelet ≥298 × 10 9 /L were assigned 1 point. Score ≥ 4 points was a useful predictor in diagnosing ULMS from fibroid (sensitivity 0.800, specificity 0.778). Conclusions The incidence of occult ULMS was low. Age ≥ 40 years old, tumor size ≥7 cm, LDH ≥ 193 U/L, NLR ≥ 2.8 and number of platelet ≥298 × 10 9 /L were independent predictors of ULMS. The preoperative clinical characteristics scoring system could be helpful in preoperative diagnosis of occult ULMS.

Abstract Background Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. Methods To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. Clinical Report and Results We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered. Conclusion uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations. This Molecular Tumor Board report describes a remarkably response achieved with the use of Niraparib in a patients affected by uterine leiomyosarcoma carrying a somatic biallelic BRCA2 alteration. In the accompanying genomic analysis, an enrichment of BRCA2 somatic alterations were observed among uterine leiomyosarcoma, confirming their prevalence and potential clinical actionability.

Metastatic leiomyosarcomas have a poor prognosis, and currently doxorubicin alone is used as the standard first-line treatment. Doxorubicin combined with trabectedin has shown promising results in phase 1 and 2 studies. We aimed to identify and compare the progression-free survival of patients with metastatic or unresectable uterine or soft tissue leiomyosarcoma treated with doxorubicin and trabectedin combined as first-line therapy versus doxorubicin alone in a phase 3 trial. LMS-04 was a randomised, multicentre, open-label, superiority phase 3 trial, which included patients from 20 centres of the French Sarcoma Group (anticancer centers or hospitals with an oncological unit) in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–1, and had metastatic or relapsed unresectable leiomyosarcomas that had not previously been treated with chemotherapy. Patients were randomly assigned (1:1), by means of an interactive web response system (permuted blocks of different sizes from two to six), to receive either intravenous doxorubicin alone (75 mg/m2) once every 3 weeks for up to six cycles or of intravenous doxorubicin (60 mg/m2) plus intravenous trabectedin (1·1 mg/m2) once every 3 weeks up to six cycles followed by maintenance with trabectedin alone. Surgery for residual disease was allowed in both groups after six cycles of treatment. Randomisation was stratified by tumour location (uterine vs soft tissue) and disease (locally advanced vs metastatic). The primary endpoint was progression-free survival assessed by blinded independent central review and according to Response Evaluation Criteria in Solid Tumours 1.1 criteria. Efficacy analyses were performed on all randomly assigned patients, based on the intention-to-treat principle. The safety population included all randomly assigned patients who received at least one cycle of treatment. This trial is registered with ClinicalTrials.gov, NCT02997358, and is closed to enrolment. Between Jan 18, 2017, and March 21, 2019, 150 patients were enrolled (67 with uterine leiomyosarcomas and 83 with soft tissue leiomyosarcomas) and included in the intention-to-treat population: 76 in the doxorubicin alone group and 74 in the doxorubicin plus trabectedin group. The median duration of follow-up was 36·9 months (IQR 30·0–43·2) in the doxorubicine group and 38·8 months (32·7–44·2) in the doxorubicin plus trabectedin group. Median progression-free survival was significantly longer with doxorubicin plus trabectedin versus doxorubicin alone (12·2 months [95% CI 10·1–15·6] vs 6·2 months [4·1–7·1]; adjusted hazard ratio 0·41 [95% CI 0·29–0·58]; p<0·0001). The most common grade 3–4 adverse events were neutropenia (ten [13%] of 75 patients in the doxorubicin alone group vs 59 [80%] in the doxorubicin plus trabectedin group), anaemia (four [5%] vs 23 [31%]), thrombocytopenia (0 vs 35 [47%]), and febrile neutropenia (seven [9%] vs 21 [28%]). Nine (12%) patients in the doxorubicin alone group and 15 (201%) patients in the doxorubicin plus trabectedin group has serious adverse events. There was only one treatment-related death, reported in the doxorubicin alone group (cardiac failure). Doxorubicin plus trabectedin in first-line therapy was found to significantly increase progression-free survival in patients with metastatic or unresectable leiomyosarcomas compared with doxorubicin alone, despite a higher but manageable toxicity, and could be considered an option for the first-line treatment of metastatic leiomyosarcomas. PharmaMar.

Background Uterine myxoid leiomyosarcoma (MLMS) is an extremely rare and highly aggressive subtype of uterine leiomyosarcoma. Its rarity poses challenges to clinical diagnosis and treatment. Case presentation A 48-year-old Chinese woman, gravida 2, para 2, presented with vaginal bleeding lasting half a month. Pelvic ultrasonography and magnetic resonance imaging scans led to a preliminary diagnosis of uterine leiomyomas and adnexa cyst. She subsequently underwent an elective laparoscopic myomectomy and adnexal cysts enucleation. Postoperative pathological examination confirmed the diagnosis of uterine MLMS. Prior to her scheduled second surgery, she developed a pulmonary embolism. Following one month of heparin anticoagulation, she received total laparoscopic hysterectomy and bilateral salpingo-oophorectomy therapy, followed by 4 courses of intravenous gemcitabine plus doxorubicin chemotherapy. Additionally, she received letrozole as long-term maintenance therapy. To date, one and a half years of follow-up has shown no evidence of tumor recurrence or metastasis. Conclusions This is a case of uterine MLMS complicated by pulmonary embolism. Adjuvant gemcitabine plus doxorubicin chemotherapy combined with letrozole maintenance therapy achieved progression-free survival for one and a half years. Through systematic literature reviewing, we conduct an in-depth discussion on diagnostic challenges, surgical approaches considerations, venous thromboembolism (VTE) risk, and value of adjuvant therapy of this disease. Given the known risk of late recurrence in uterine MLMS, long-term clinical monitoring is essential to confirm the durability of this treatment response.