Treatment Of Leiomyosarcoma Research Articles

Inhibition of Aberrantly Overexpressed Polo-like Kinase 4 Is a Potential Effective Treatment for DNA Damage Repair-Deficient Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment. Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. A PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) was tested in vitro on gynecologic sarcoma cell lines SK-UT-1, SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in the Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2-knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay. Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining DNA repair. Compared with wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repairs were impaired. Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacologic inhibition of ATM enhanced the efficacy of the PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.

Efficacy and safety of anthracycline combined with alkylating agent for treatment of advanced leiomyosarcoma.

e23558 Background: Leiomyosarcoma(LMS) accounts for 12-14% of all soft tissue sarcomas(STSs) and this STS subtype has high metastatic potential. We evaluated the efficacy and safety of epirubicin combined with temozolomide(EPI-TMZ) for treatment of advanced LMS. Methods: Oral TMZ(200 or 300 mg) was administered each day on days 1-5, and intravenous EPI(60 mg/m2) was administered on days 1-4, with even distribution over these 96h within a 21‐day cycle. After 8 cycles of intensive chemotherapy, monodrug maintenance therapy consisted of TMZ alone(dosing as in the primary therapy, most choices, stop taking medication after 1 year control), and two-drug maintenance therapy consisted of TMZ with thalidomide(only 3 patients). All patients-initiated EPI-TMZ treatment between January 2018 and January 2024. Results: We examined 31 patients who received EPI-TMZ. There were 25 females and 6 males, with average age 50.5 years old. All were unresectable patients derived from abdominal retroperitoneum, uterus, inferior vena cava, mesentery, small intestine, stomach, thighs, elbows, wrists, pancreas, nasal cavity, meantime with distant metastasis. Average Ki67 is above 40%. This was a first-line treatment in 16 patients, a second- or third-line in 13, and a fourth-line in 2. At the time of data cutoff (January 31, 2024), the median PFS was 12.6 months, 1 patient had cCR, 9 PR and 20 SD. The ORR was 32.3%(10/31) and DCR was 96.8%(30/31). The only patient who progressed after two cycles of medication had PMS2 deficiency, and studies have reported that it may have a primary resistance mechanism. Even the shortest disease control period is also 5 months, indicating this regime has significant clinical benefit. Some patients have undergone tumor reduction surgery to improve quality of life after achieving significant tumor relief. The current longest PFS is 42 months up to now and under continuous tumor control. Previous retrospective studies indicated the best mPFS was 9.2 months and the best ORR was 30.9%. 2023 ESMO declared prospective doxorubicin with trabectedin obtained mPFS of 12.19 months. The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. Two patients had severe febrile neutropenia, but there were no treatment-related deaths, survival data follow-up. Conclusions: EPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ may provide better outcomes than reported in previous studies of other treatments for advanced LMS, worth further prospective research.

The Future of Targeted Therapy for Leiomyosarcoma.

Leiomyosarcoma (LMS) is an aggressive subtype of soft tissue sarcoma that arises from smooth muscle cells, most commonly in the uterus and retroperitoneum. LMS is a heterogeneous disease with diverse clinical and molecular characteristics that have yet to be fully understood. Molecular profiling has uncovered possible targets amenable to treatment, though this has yet to translate into approved targeted therapies in LMS. This review will explore historic and recent findings from molecular profiling, highlight promising avenues of current investigation, and suggest possible future strategies to move toward the goal of molecularly matched treatment of LMS. We focus on targeting the DNA damage response, the macrophage-rich micro-environment, the PI3K/mTOR pathway, epigenetic regulators, and telomere biology.

Treatment outlines for the management of primary leiomyosarcoma of the inferior vena cava.

Primary venous Leiomyosarcoma (LMSs) are extremely rare tumours with poor survival rates. Surgery is currently the only potentially curative therapy in non-metastatic disease, but it consists in challenging interventions. The authors report the experience of one single centre in the treatment of LMS and a literature overview focusing on the diverse methods of vessels repair. Outcomes achieved are also outlined.

Multiomic analysis to reveal distinct molecular profiles of uterine and nonuterine leiomyosarcoma.

11555 Background: Leiomyosarcoma (LMS) is a rare group of mesenchymal malignancies found in the uterus, retroperitoneum, skin, or other soft-tissue sites. Treatment for LMS is extrapolated from trials including both uterine (uLMS) and non-uLMS subtypes, although whether they respond similarly and have similar outcomes from treatment is not clear. We examined the molecular composition of LMS by site of origin to better inform future drug development and trial design. Methods: We reviewed 1115 specimens with LMS histology tested by Caris Life Sciences for targeted exome (NextSeq, 592 gene panel), whole exome, and whole transcriptome sequencing (NovaSeq). Specimens were stratified into uLMS, rpLMS (retroperitoneal), and otherLMS (non-uterine/retroperitoneal) subgroups based on tumor origin sites. Genomic data was analyzed for mutations, copy number aberrations, and fusions. RNA expression profiling included evaluation of individual genes and gene set enrichment analysis (GSEA). P-value adjustment performed by the Benjamini-Hochberg procedure. Results: The study cohort was comprised of 62.9% uLMS (n = 701), 14.9% rpLMS (n = 166) and 22.2% otherLMS (n = 248) specimens. Overall, LMS specimens most frequently harbored TP53 (64%, n = 612), ATRX (30%, n = 219), RB1 (22%, n = 156), and MED12 (16%, n = 94) mutations, with these genes accounting for 74.4% (n = 1044) of all observed pathogenic/likely pathogenic mutations. RB1 mutations were significantly less common in uLMS (15%) compared to rpLMS (30%, p < 0.05) and otherLMS (33%, p < 0.01), whereas MED12 mutations were almost exclusive to uLMS (22% vs 1% rpLMS, 3% otherLMS, p < 0.05). MAP2K4 copy number amplification were more common in rpLMS (22%, p < 0.001) and otherLMS (14%, p < 0.182) compared to uLMS (7%), with frequent co-amplification of nearby genes ( FLCN, GID4, SPECC1, GAS7, PER1, and AURKB) located at chr17p11-13. Actionable gene fusions involving ALK (2.1%, n = 11), FGFR1 (0.2%, n = 1), and NTRK1/2 (0.2%, n = 1 each) were rare overall, with similar prevalence across subtypes. Genomic alteration rates were not significantly different between rpLMS and otherLMS subtypes . RNA expression profiling identified significant upregulation of PI3K/AKT/mTOR, DDR, WNT/Beta-Catenin pathway genes in non-uLMS. GSEA indicated several immune-related gene sets were enriched in rpLMS and otherLMS compared to uLMS. Conclusions: Comprehensive molecular profiling suggests that LMS originating from the uterus represents a molecularly distinct disease compared to other primary sites of origin. We identified key genomic patterns which have potential for targeted therapy. These data provide insight for the framework of future clinical trials designed to separate uLMS from non-uLMS histologies, although further subdivision does not appear to be warranted.

Metastatic leiomyosarcoma of the excluded stomach: a case report

Background: Leiomyosarcoma (LMS) represents about 1% of primary malignancies of the stomach, usually evolves with hepatic implants in 2-thirds of cases, and the outcome is frequently poor. With an insidious course, late diagnosis and misdiagnosis with other gastric neoplasia occur. Immunohistochemical evaluations are mandatory to confirm the diagnostic hypothesis. Surgical resection has been the more effective treatment of gastric LMS; however, recurrences after resections and distant metastases may develop in up to 50% of the patients. Doxorubicin, gemcitabine, and docetaxel are therapeutic options, with variable responses. Case presentation: The 52-year-old male herein described with a diagnosis of LMS in the gastric pouch and liver metastasis underwent a Roux-en-Y bypass to treat morbid obesity more than a decade ago. Persistent abdominal pain was a unique symptom, and he had liver metastasis at diagnosis. The initial hypothesis was a metastatic gastrointestinal stromal tumor (GIST) of the excluded stomach and the patient underwent a schedule with imatinib without significant response. After a complete revision of the anatomopathological findings, the patient underwent a new biopsy of the gastric mass, and the immunohistochemical data were consistent with LMS. Then doxorubicin replaced imatinib, later changed by gemcitabine associated with docetaxel. As last control found lesions in the central nervous system, he is under radiotherapy sessions. Conclusion: The diagnosis of gastric LMS often occurs at late stages because of the insidious clinical course. The rate of liver metastasis at diagnosis is high. Besides, the relatively poor response to the alternative management for non-surgical stages of the disease yields severe outcomes.

Potential use of homologous recombination deficiency score as an indicator of therapy selection in leiomyosarcoma patients.

e23539 Background: Leiomyosarcoma (LMS) is one of the most frequent sarcoma subtypes. While surgical resection is the standard treatment of LMS, chemotherapy and radiation have shown additional survival benefit. However, the treatment response is variable and selection of appropriate agents is difficult due to the great heterogeneity of LMS. Matching DNA damaging reagents or PARP inhibitors, to tumors with a general homologous recombination deficit (HRD), can help to deploy these reagents more precisely. We explored the correlation of HRD score with the activation of PARP signaling pathway and retrospectively tested the effect of platinum-based therapy on an LMS patient with high HRD score. Methods: Nineteen LMS samples were subjected to whole exome sequencing and their HRD scores were calculated using a published algorithm. Nine of the LMS samples were also subjected to RNA-seq analysis and undergone GSEA to profile PARP pathway expression. CIBERSORT was employed to profile infiltrating immune cells. Results: The 19 LMS samples are defined as HRD-high (11 samples) or HRD-low (8 samples) if their HRD score is above or equal to, or below the medium respectively. For the 9 samples undergone RNA-seq, 97 genes have differential expression between the two groups (p-value < 0.05, fold change≥ 2). GSEA revealed 23 enriched pathways. Interestingly, PPAR signaling pathway is the most highly enriched one (EnrichmentScore = 0.506, P.adj = 0.005). No other pathogenic germline or somatic mutation in HRD related genes, for example BRCA1/2, is enriched. Additionally, high HRD score is significantly correlated with infiltrating Tregs, monocyte, and M0 macrophages as found in CIBERSORT analysis. To retrospectively test whether HRD score can be used to predict the response to inhibitors of DNA repair pathway, we identified one patient who had received platinum-based combination therapy after failure of first-line chemotherapy. The patient is a 40-year-old female with stage IV LMS and has a high HRD score. She achieved PR with 6-month PFS and remains progression free up to the abstract date, supporting a good correlation between high HRD score and advanced chemotherapy in LMS patients. Conclusions: High HRD score is correlated with activated PPAR pathway and infiltrating Tregs, monocytes and M0 macrophages, and can potentially be used to identify LMS patients with good response to platinum-based chemotherapy even though they have no obvious germline and somatic mutation in genes involved in DNA repair.

Identification of Prognostic Genes in Leiomyosarcoma by Gene Co-Expression Network Analysis.

Background/AimsLeiomyosarcoma (LMS) is a tumor derived from malignant mesenchymal tissue associated with poor prognosis. Determining potential prognostic markers for LMS can provide clues for early diagnosis, recurrence, and treatment.Methods RNA sequence data and clinical features of 103 LMS were obtained from the Cancer Genome Atlas (TCGA) database. Application Weighted Gene Co-Expression Network Analysis (WGCNA) was used to construct a free-scale gene co-expression network, to study the interrelationship between its potential modules and clinical features, and to identify hub genes in the module. The hub gene function was verified by an external database.ResultsTwenty-four co-expression modules were constructed using WGCNA. A dark red co-expression module was found to be significantly associated with disease recurrence. Functional enrichment analysis and GEPIA and ONCOMINE database analyses demonstrated that hub genes CDK4, CCT2, and MGAT1 may play an important role in LMS recurrence.ConclusionOur study constructed an LMS co-expressing gene module and identified prognostic markers for LMS recurrence detection and treatment.

Leiomyosarcoma of the skin: review of the literature with an emphasis on prognosis and management.

Leiomyosarcoma (LMS) of the skin is rare, and no management guideline currently exists. Although LMS is historically classified as either dermal (cutaneous) or subcutaneous, definition for its classfication is inconsistent in the literature. Studies on the managenent of LMS are scarce, and there is no consensus on the appropriate surgical margin for the treatment of LMS. While a 1cm margin may be sufficient in cutaneous LMS, wider margins may be required for subcutaneous tumors. Mohs micrographic surgery is a promising surgical modality for the treatment of cutaneous LMS. In this review, current knowledge on LMS is summarized and a practical approach to the management of this rare neoplasm is proposed.

Mocetinostat combined with gemcitabine for the treatment of leiomyosarcoma: Preclinical correlates.

Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastatic disease. Chemotherapeutic intervention has demonstrated to have modest clinical efficacy with no curative potential in LMS patients. Previously, we demonstrated pan-HDAC inhibition to have a superior effect in various complex karyotypic sarcomas. In this study, our goal is to evaluate the therapeutic efficacy of mocetinostat alone and in combination with gemcitabine in LMS. Human leiomyosarcoma (LMS) cell lines were used for in vitro and in vivo studies. Compounds tested included the class I HDAC inhibitor, mocetinostat, and nucleoside analog, gemcitabine. MTS and clonogenic assays were used to evaluate the effect of mocetinostat on LMS cell growth. Cleaved caspase 3/7 analysis was used to determine the effects of mocetinostat on apoptosis. Compusyn software was used to determine in vitro synergy studies for the combination of mocetinostat plus gemcitabine. A LMS xenograft model in SCID mice was used to test the impact of mocetinostat alone, gemcitabine alone and the combination of mocetinostat plus gemcitabine. Mocetinostat abrogated LMS cell growth and clonogenic potential, and enhanced apoptosis in LMS cell lines. The combination of mocetinostat plus gemcitabine exhibited a synergistic effect in LMS cells in vitro. Similarly, mocetinostat combined with gemcitabine resulted in superior anti-LMS effects in vivo. Mocetinostat reduced the expression of gemcitabine-resistance markers RRM1, RRM2, and increased the expression of gemcitabine-sensitivity marker, hENT1, in LMS cells. LMS are aggressive, metastatic tumors with poor prognosis where effective therapeutic interventions are wanting. Our studies demonstrate the potential utility of mocetinostat combined with gemcitabine for the treatment of LMS.

Management of Leimyosarcoma: A Survey Among Members of the Korean Gynecologic Oncology Group.

This study aimed to investigate current clinical management of leiomyosarcoma (LMS) in Korea. We conducted a Web-based survey among members of the Korean Gynecologic Oncology Group regarding their treatment of LMS. In total, 77 (27.8%) of 277 members responded to the survey. For surgical treatment of stage I LMS, 26.8% indicated total hysterectomy only and 16.9% indicated total hysterectomy with bilateral salpingo-oophorectomy. Also, lymph node dissection was indicated by 54.9% of respondents, whereas 46.5% stated that bilateral salpingo-oophorectomy could be omitted in young patients. More than half (57.7%) of the respondents recommended against adjuvant treatment. For stage I LMS diagnosed after morcellation, 79.2% of the respondents recommended lymph node dissection and 56.4% recommended adjuvant therapy. As for advanced-stage LMS, in cases of complete resection, adjuvant chemotherapy was preferred by 63.1%. For incomplete resection, combined radiotherapy/chemotherapy was the most preferred adjuvant therapy (63.1%). Among Korean Gynecologic Oncology Group members, there are many discrepancies in the clinical management of LMS. A large-scale prospective study to establish treatment guidelines is needed.

Primary Gastric Leiomyosarcoma: A Rare Entity

Introduction: In the post c-KIT era, true smooth muscle neoplasms of GI tract have received little attention and are an extremely rare tumor. Here we report a case of primary gastric leiomyosarcoma (LMS) in an adult presenting with anemia. Case Report: A 54-year-old Caucasian male with past medical history of interstitial lung disease presented to the hospital for evaluation of lighheadness and multiple episodes of black tarry stool. On examination, patient's stool was guaiac positive with positive orthostatic vital signs. Patient underwent EGD which revealed a 3 cm bull's eye lesion in mid-gastric body with central depression (Fig 1). Endoscopic ultrasound showed a16 mm hypoechoic lesion in mid-gastric body, appeared to be arising from muscularis propria without any lymphadenopathy. Pathologic examination classified the tumor as LMS grade 2 of 3 based on immunohistochemical staining (negative c-Kit and DOG-1, positive desmin and actin), confirmed by 2 pathologists at different institutions (Fig 2). Patient underwent computed tomography and PET scan, which was negative for any metastasis and showed only positive uptake in mid-gastric body. On repeat EGD, his lesion has grown in size to 3 cm and appeared to invade serosa. At that point, surgical resection was undertaken and patient underwent partial gastrectomy with frozen section showing clear margins. The patient had uneventful recovery.Figure: EGD showing Bull'e eye like lesion in mid-gastric body.Figure: Immunohistochemical staining showing positivity for Actin (A), Desmin (B) in sheets of spindle cell (C).Discussion: LMS of the gastrointestinal (GI) tract are rare entity in the post-GIST era since c-kit was described in 1998 representing only 1% of true smooth muscle neoplasm of the GI tract. There are approximately 100 reported cases of GI LMS, with small intestine being the commonest site and stomach being the least common site. There are only 10 reported cases of gastric leiomyosarcoma in post-GIST era. The median age of gastric LMS is 37 years with males (70%) more commonly affected than females (30%). The most common reported symptom was GI bleeding, followed by abdominal pain, weight loss, and gastroesophageal reflux. The mean tumor size is 6.45 cm +/- 3. GISTs are positive for CD-117 and CD-34, which are negative in LMS. Moreover, LMS are positive for vimentin, smooth muscle actin and desmin. There is no consensus on treatment of LMS as they are rarely encountered. Our patient's LMS grew from 16mm to 30 mm within a month, demonstrating the aggressiveness of the tumor. Complete surgical resection with negative margins remains the gold standard treatment.

Uterine leiomyosarcoma: a review of recent advances in molecular biology, clinical management and outcome.

The diagnosis and treatment of uterine LMS is challenging. Novel biomarkers offer hope for future therapies.

Survival of patients with metastatic leiomyosarcoma: the MD Anderson Clinical Center for targeted therapy experience.

Advanced stage leiomyosarcoma (LMS) is incurable with current systemic antitumor therapies. Therefore, there is clinical interest in exploring novel therapeutic regimens to treat LMS. We reviewed the medical records of 75 consecutive patients with histologically confirmed metastatic LMS, who had been referred to the Clinical Center for Targeted Therapy at MD Anderson Cancer Center. To lay the foundation for potential phase I trials for the treatment of advanced LMS, we analyzed tumor response and survival outcome data. The frequent hotspot gene aberrations that we observed were the TP53 mutation (65%) and RB1 loss/mutation (45%) detected by Sequenom or next‐generation sequencing. Among patients treated with gene aberration‐related phase I trial therapy, the median progression‐free survival was 5.8 months and the median overall survival was 15.9 months, significantly better than in patients without therapy (1.9 months, P = 0.001; and 8.7 months, P = 0.013, respectively). Independent risk factors that predicted shorter overall survival included hemoglobin <10 g/dL, body mass index <30 kg/m2, serum albumin <3.5 g/dL, and neutrophil above upper limit of normal. The median survivals were 19.9, 7.6, and 0.9 months for patients with 0, 1 or 2, and ≥3 of the above risk factors, respectively (P < 0.001). A prognostic scoring system that included four independent risk factors might predict survival in patients with metastatic LMS who were treated in a phase I trial. Gene aberration‐related therapies led to significantly better clinical benefits, supporting that further exploration with novel mechanism‐driven therapeutic regimens is warranted.

Abstract 286: Preclinical study: HDAC inhibition combined with gemcitabine for the treatment of leiomyosarcoma

Abstract Objective Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastasic disease. Chemotherapeutic intervention has demonstrated to have modest clinical efficacy with no curative potential in LMS patients. Previously, we demonstrated pan-HDAC inhibition to have a superior effect in various complex karyotypic sarcomas. In this study, our goal is to evaluate the therapeutic efficacy of pan-HDACi alone and in combination with gemcitabine in LMS. Methods Human leiomyosarcoma (LMS) cell lines were used for in vitro and in vivo studies. Compounds tested included a pan-HDAC inhibitor (HDACi) and nucleoside analog, gemcitabine (Gem). MTS and clonogenic assays were used to evaluate the effect of HDACi on LMS cell growth. Cell cycle FACS and annexin V PI/FACS analysis were used to determine the effects of HDACi on cell cycle and apoptosis, respectively. Compusyn software was used to determine in vitro synergy studies for the combination of HDACi + Gem. A LMS xenograft model in SCID mice was used to test the impact of HDACi alone, Gem alone and the combination of HDACi + Gemcitabine. Results Pan-HDAC inhibition abrogated LMS cell growth and clonogenic potential. HDACi induced G2/M cell cycle growth arrest and enhanced apoptosis in LMS cell lines. The combination of HDACi + Gem exhibited a synergistic effect in LMS cells in vitro. Similarly, HDACi combined with Gem resulted in superior anti-LMS effects in vivo. Conclusion LMS are aggressive, metastatic tumors with poor prognosis where effective therapeutic interventions are wanting. Our studies demonstrate the potential utility of pan-HDAC inhibition combined with gemcitabine for the treatment of LMS. Citation Format: Gonzalo Lopez, Edwin Choy, Shreyaskumar Patel, Hemant Bid, Danielle Braggio, Dina Lev, Raphael Pollock. Preclinical study: HDAC inhibition combined with gemcitabine for the treatment of leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 286.

Patient-reported outcomes from randomized, phase-3 study of trabectedin (T) vs. dacarbazine (D) in advanced leiomyosarcoma (LMS) or liposarcoma (LPS).

11061Background: T is recently approved in the US for treatment of advanced LMS or LPS after prior chemotherapy failure based on results from a randomized, phase-3 study (Demetri et al, 2015, J Cli...

Role of surgery in the multimodal treatment of primary and recurrent leiomyosarcoma of the inferior vena cava.

The optimal treatment of leiomyosarcoma (LMS) of the inferior vena cava (IVC) is still unclear, especially in the metastatic and/or recurrent setting. We herein evaluated the long-term outcome after aggressive management. Eleven patients underwent surgery for primary LMS of the IVC between 2000 and 2012. The clinical, pathological, and survival data were reviewed. The IVC was managed by graft replacement in four cases, primary repair in four, and ligation in three. The R0 resection rate was 64%. The median follow-up was 60 months. Nine patients developed distant relapse, two of them concomitant local recurrence; no exclusive local recurrence was observed. The 3- and 5-year distant recurrence free survival were 30% and 10%, respectively. The 3- and 5-year overall-survival (OS) were 77.8%. The presence of residual disease after surgery (P = 0.024) and the time to recurrence (P = 0.033) were associated with the OS in a univariate analysis. The time to recurrence was related to the post-metastases survival (P = 0.032). An adequate surgery minimizes the risk of local recurrence and remains the main treatment for primary LMS of the IVC. Nevertheless, the rate of distant metastases remains extremely high. An aggressive surgical policy may be of benefit to selected patients with metastatic disease. J. Surg. Oncol. 2016;114:44-49. © 2016 Wiley Periodicals, Inc.

Use of first-line trabectedin in advanced leiomyosarcoma: a review of clinical data and future perspectives

Leiomyosarcomas (LMS) represent a large subgroup of soft-tissue sarcoma (STS) generally considered moderately sensitive to conventional chemotherapy. Single-agent doxorubicin is the standard first-line therapy for advanced non-selected STS, although combination with ifosfamide appears to be superior in terms of objective response. Gemcitabine-based regimes, dacarbazine, trabectedin and pazopanib seem to be especially active in patients with advanced LMS, while the activity of ifosfamide in this histotype is low. Data derived from clinical trials and retrospective series show that trabectedin is especially active in L-sarcomas including non-gynecological and uterine LMS as well as liposarcomas, in particular myxoid liposarcomas. Trabectedin has also been tested in the first-line setting, alone or in combination with doxorubicin, for the treatment of LMS of uterine and non-uterine origin in a trial by the French Sarcoma Group (phase II study LMS-02) with encouraging results in terms of median progression-free survival and objective response. The toxicity profile of trabectedin appears to be comparable to, or even more manageable than, that of other chemotherapy combinations in the first-line setting. Designing new clinical trials based on specific histologic subtypes is feasible, and the results of such studies would help to optimize the management of patients with STS.

Verticillin A Inhibits Leiomyosarcoma and Malignant Peripheral Nerve Sheath Tumor Growth via Induction of Apoptosis.

ObjectiveThe heterogeneity of soft tissue sarcoma (STS) represents a major challenge for the development of effective therapeutics. Comprised of over 50 different histology subtypes of various etiologies, STS subsets are further characterized as either karyotypically simple or complex. Due to the number of genetic anomalies associated with genetically complex STS, development of therapies demonstrating potency against this STS cluster is especially challenging and yet greatly needed. Verticillin A is a small molecule natural product with demonstrated anticancer activity; however, the efficacy of this agent has never been evaluated in STS. Therefore, the goal of this study was to explore verticillin A as a potential STS therapeutic.MethodsWe performed survival (MTS) and clonogenic analyses to measure the impact of this agent on the viability and colony formation capability of karyotypically complex STS cell lines: malignant peripheral nerve sheath tumor (MPNST) and leiomyosarcoma (LMS). The in vitro effects of verticillin A on apoptosis were investigated through annexin V/PI flow cytometry analysis and by measuring fluorescently-labeled cleaved caspase 3/7 activity. The impact on cell cycle progression was assessed via cytometric measurement of propidium iodide intercalation. In vivo studies were performed using MPNST xenograft models. Tumors were processed and analyzed using immunohistochemistry (IHC) for verticillin A effects on growth (Ki67) and apoptosis (cleaved caspase 3).ResultsTreatment with verticillin A resulted in decreased STS growth and an increase in apoptotic levels after 24 h. 100 nM verticillin A induced significant cellular growth abrogation after 24 h (96.7, 88.7, 72.7, 57, and 39.7% reduction in LMS1, S462, ST88, SKLMS1, and MPNST724, respectively). We observed no arrest in cell cycle, elevated annexin, and a nearly two-fold increase in cleaved caspase 3/7 activity in all MPNST and LMS cell lines. Control normal human Schwann (HSC) and aortic smooth muscle (HASMC) cells displayed higher tolerance to verticillin A treatment compared to sarcoma cell lines, although toxicity was seen in HSC at the highest treatment dose. In vivo studies mirrored the in vitro results: by day 11, tumor size was significantly reduced in MPNST724 xenograft models with treatment of 0.25 and 0.5 mg/kg verticillin A. Additionally, IHC assessment of tumors demonstrated increased cleaved caspase 3 and decreased proliferation (Ki67) following treatment with verticillin A.ConclusionAdvancement in the treatment of karyotypically complex STS is confounded by the high level of genetic abnormalities found in these diseases. Consequently, the identification and investigation of novel therapies is greatly needed. Our data suggest that verticillin A selectively inhibits MPNST and LMS growth via induction of apoptosis while exhibiting minimal to moderate effects on normal cells, pointing to verticillin A as a potential treatment for MPNST and LMS, after additional preclinical validation.

Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma.

Leiomyosarcoma (LMS) represents a highly malignant, rare soft tissue sarcoma with high rates of morbidity and mortality. Previously, we demonstrated that tissue-isolated human LMS xenografts perfused in situ are highly sensitive to the direct anticancer effects of physiological nocturnal blood levels of melatonin which inhibited tumour cell proliferative activity, linoleic acid (LA) uptake and metabolism to 13-hydroxyoctadecadienoic acid (13-HODE). Here, we show the effects of low pharmacological blood concentrations of melatonin following oral ingestion of a melatonin supplement by healthy adult human female subjects on tumour proliferative activity, aerobic glycolysis (Warburg effect) and LA metabolic signalling in tissue-isolated LMS xenografts perfused in situ with this blood. Melatonin markedly suppressed aerobic glycolysis and induced a complete inhibition of tumour LA uptake, 13-HODE release, as well as significant reductions in tumour cAMP levels, DNA content and [(3) H]-thymidine incorporation into DNA. Furthermore, melatonin completely suppressed the phospho-activation of ERK 1/2, AKT, GSK3β and NF-kB (p65). The addition of S20928, a nonselective melatonin antagonist, reversed these melatonin inhibitory effects. Moreover, in in vitro cell culture studies, physiological concentrations of melatonin repressed cell proliferation and cell invasion. These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA uptake and other related signalling mechanisms. An understanding of these novel signalling pathway(s) and their association with aerobic glycolysis and LA metabolism in human LMS may lead to new circadian-based therapies for the prevention and treatment of LMS and potentially other mesenchymally derived solid tumours.