Author Correction: The Adaptive and Innate Immune Cell Landscape of Uterine Leiomyosarcomas (original) (raw)
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The Adaptive and Innate Immune Cell Landscape of Uterine Leiomyosarcomas
Scientific Reports, 2020
Reactivation of the anti-tumor response has shown substantial progress in aggressive tumors such as melanoma and lung cancer. Data on less common histotypes are scanty. Immune checkpoint inhibitor therapy has been applied to few cases of uterine leiomyosarcomas, of which the immune cell composition was not examined in detail. We analyzed the inflammatory infiltrate of 21 such cases in high-dimensional, single cell phenotyping on routinely processed tissue. T-lymphoid cells displayed a composite phenotype common to all tumors, suggestive of antigen-exposure, acute and chronic exhaustion. To the contrary, myelomonocytic cells had case-specific individual combinations of phenotypes and subsets. We identified five distinct monocyte-macrophage cell types, some not described before, bearing immunosuppressive molecules (TIM3, B7H3, VISTA, PD1, PDL1). Detailed in situ analysis of routinely processed tissue yields comprehensive information about the immune status of sarcomas. The method empl...
New insights into the cellular pathways affected in primary uterine leiomyosarcoma
Resistance to chemotherapeutic agents and radiotherapy has kept surgery the primary treatment of uterine leiomyosarcoma (ULMS). In search of leads for potential therapeutic targets, array CGH (aCGH) was used to obtain a genomewide pattern of ULMS-specific genetic imbalances and to define the affected biological processes. Fine-resolution genomewide aCGH analysis was performed using customised 16K cDNA microarrays on 18 primary ULMS cases. Furthermore, patterns of DNA copy number changes were assessed for associations with clinical parameters, i.e., tumour grade, tumour size and patient status at last follow-up. Our aCGH results demonstrated extensive DNA copy number changes in all chromosomes. Of the 10,590 gene loci included in the analysis, 4,387 were found to be affected by DNA copy number gains and 4,518 by DNA copy number losses in at least one case. Further analyses revealed that 231 of these were commonly gained, and 265 lost in at least 20% of the cases. The gains affected loci at 1p, 1q, 2p, 3p, 6p, 8q, 10q and 18q, whereas losses were observed at 2q, 4q, 6p, 6q, 7p, 7q, 13q, 14p, 16q, 19p, Xp and Xq. Enrichment analysis of biological processes revealed the gained genes to be involved in the G1/S transition of mitotic cell cycle, co-translational protein targeting to membrane, actin filament polymerisation and positive regulation of cytokine biosynthesis, whereas the genes affected by losses were associated with DNA replication, chromatin modification, telomere maintenance, meiosis, mitosis and angiogenesis. These biological processes featured prominently two well-established tumour suppressors (BRCA2, EREG) and one proto-oncogene (GFI1). No statistically significant associations were found between the aberration patterns and clinical variables. Analysis of gene pathways using aCGH uncovered the biological networks involved in malignant progression of ULMS.
Uterine Leiomyosarcoma (uLMS): A Malignancy in Disguise
Bangladesh Journal of Obstetrics & Gynaecology, 2023
Uterine leiomyosarcoma is an aggressive tumour biologically and a relatively chemoresistant disease. Uterine sarcomas are of four main types: Uterine Leiomyosarcoma, Endometrial stromal sarcoma (Low grade and High grade), Malignant mixed Mullerian tumour and Undifferentiated Sarcoma. Most of the leiomyosarcoma that occur in the uterus are presumed to be fibroid because they look like fibroid on imaging scan. These uncommon malignant neoplasms are thought to arise from the myometrium or endometrial stromal precursor cells, rather than from leiomyomas. In contrast to leiomyomas, leiomyosarcomas have complex, highly variable karyotypes that frequently include deletions. Like leiomyomas, a subset contains MED12 mutations, a genetic aberration that appears to be virtually unique to uterine smooth muscle tumors. Leiomyosarcomas occur both before and after menopause, with a peak incidence at 40 to 60 years of age. These tumors often recur following surgery, and more than half eventually metastasize haematogenously to distant organs, such as lungs, bone, and brain. Dissemination throughout the abdominal cavity is also encountered. The overall 5year survival rate is about 40%, but the anaplastic lesions have a 5-year survival rate of only 10% to 15%. 1
Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma
Anticancer research, 2016
Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. Radiographic evaluation with combined positron-emission tomography/computed tomography may assist in diagnosis and surveillance in women with uterine LMS; these are commonly used with stage and tumour grade as prognostic indicators and a recently developed risk-assessment index to predict disease-specific survival. Recent studies have shown that the addition of adjuvant therapy after surgical management does not seem to improve survival, and ovarian preservation does not appear to negatively impact outcome. Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/β1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of ~37% by 12 months of age. Furthermore, a recent report showed the loss of ability to induce PSMB9/β1i expression, that is up...
Systemic Treatment of Metastatic/Recurrent Uterine Leiomyosarcoma: A Changing Paradigm
The Oncologist
The treatment of metastatic and recurrent uterine leoimyosarcoma (uLMS) has evolved rapidly in the past several years. Leoimyosarcoma is extremely aggressive and responds poorly to traditional chemotherapeutics. Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these new compounds. Additionally, the potential role of immunotherapy is being assessed in current uLMS clinical trials. Given the increasing number of agents available both in the U.S. and globally, a treatment template that addresses optimal sequencing based upon expert consensus would be useful. Current guidelines, although listing various options, lack granularity by line of therapy. Most patients with leiomyosarcoma, even in early stage, are treated with surgery followed by adjuvant chemotherapy despite uLMS being relatively chemoresistant. Adjuvant chemotherapy oft...
Cancer, 2017
Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1) inhibition with nivolumab in this patient population. This single-center phase 2 trial completed enrollment between May and October 2015. Patients received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. We assessed PD-1, PD-ligand 1 (PD-L1), and PD-2 expression in archival tumor samples and variations in immune-phenotyping of circulating immune cells during treatment. Twelve patients were enrolled in the first stage of the 2-stage design. A median of 5 (range, 2-6) 2-week cycles of nivolumab were administered. Of the 12 patients, none responded to treatment. The overal...
Gynecologic Oncology, 1997
leiomyoma) and malignant uterine smooth muscle tumors Objective. To investigate the differences of biological aggressive-(leiomyosarcoma). Uterine myoma is usually benign lesions ness in terms of proliferating cell nuclear antigen (PCNA) expreswith less than 5 mitoses per 10 HPFs. In contrast, if ú10 sion, cell proliferation, and microvessel density between uterine mitoses per 10 HPFs are found, the tumor is considered leiomyosarcoma and leiomyoma. malignant [1]. Uterine sarcomas, as a group, are character-Study design. All patients with uterine leiomyosarcoma undergoized by rapid clinical progression, and they carry a poor ing surgery at National Cheng Kung University Hospital were overall prognosis. It is generally believed that the number eligible. Forty-four patients with uterine myoma were also studied of mitoses per 10 HPFs seems to be the most reliable preas the benign counterpart. The paraffin-embedded slides were dictor of biological behavior. However, the mitotic count is stained with hematoxylin and eosin to confirm the presence of still considered to be a fairly crude index of proliferation, tumor and to quantitate mitoses, PC 10 for measurement of PCNA and suffers from limitations [2]. expression, MIB 1 for measurement of cell proliferation, and factor VIII for quantitation of microvessel density. The immunohisto-Proliferating cell nuclear antigen (PCNA), a 36-kDa nuchemical findings of the slides were correlated with clinocopathoclear protein, is a necessary component of the machinery logic findings of the patients, and the data were analyzed by either that copies DNA so that cell division can take place [3, 4].
Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile
Cancers
Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in either TP53, RB1, ATRX or PTEN. The most frequently mutated gene was TP53, with 61% of the patients harboring at least one mutation, followed by RB1 at 48%. PTEN alteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend for TP53 and RB1 mutations to occur together, while both TP53 and RB1 were mutually exclusive with respect to CDKN2A/B inactivation. Overall surviva...