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International Journal of Gynecological... Oct 2020Uterine sarcomas are a group of rare tumors that include different subtypes. Patients with histopathological high-grade diseases are at high-risk of recurrence or...
A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in high-grade uterine sarcoma after stabilization or response to doxorubicin ± ifosfamide following surgery or in metastatic first line treatment (EORTC62113).
BACKGROUND
Uterine sarcomas are a group of rare tumors that include different subtypes. Patients with histopathological high-grade diseases are at high-risk of recurrence or progression, and have a poor prognosis. We aim to explore the most appropriate management in patients with uterine high-grade sarcomas.
PRIMARY OBJECTIVE
To assess the efficacy of maintenance treatment with cabozantinib in patients with high-grade uterine sarcomas who achieved clinical benefit after standard chemotherapy.
STUDY HYPOTHESIS
Maintenance treatment with cabozantinib after standard chemotherapy given as an adjuvant treatment after curative surgery, or in locally advanced or metastatic disease, increases progression-free survival compared with placebo TRIAL DESIGN: This is a randomized double blinded phase II trial.
MAJOR INCLUSION/EXCLUSION CRITERIA
The study is enrolling adult patients with high-grade undifferentiated uterine sarcomas, high-grade endometrial stromal sarcomas, high-grade leiomyosarcoma, and high-grade adenosarcoma, FIGO (Federation International gynecologue Obstétricien) stage II/III to IV in stable disease or who achieved complete or partial response with doxorubicin ± ifosfamide, who are assigned 1:1 to 60 mg daily cabozantinib (experimental arm) or placebo (control arm), as maintenance therapy. Exclusion criteria include low-grade sarcoma.
PRIMARY ENDPOINT
Progression-free survival at 4 months.
SAMPLE SIZE
The study plans to enroll 90 patients to allow the randomization of 54 patients to detect an improvement in 4-month progression-free survival from 50% to 80% with 15% significance level and 85% power. Estimated dates for accrual completion: recruitment for the trial started in February 2015, and has currently enrolled 83 patients, of whom 35 patients have been randomized. The end of recruitment is anticipated for December 2020.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov, number NCT01979393.
Topics: Anilides; Clinical Trials, Phase II as Topic; Double-Blind Method; Doxorubicin; Female; Humans; Progression-Free Survival; Pyridines; Randomized Controlled Trials as Topic; Sarcoma, Endometrial Stromal; Uterine Neoplasms
PubMed: 32546554
DOI: 10.1136/ijgc-2020-001519 -
Frontiers in Oncology 2019[This corrects the article DOI: 10.3389/fonc.2019.00237.].
[This corrects the article DOI: 10.3389/fonc.2019.00237.].
PubMed: 31396483
DOI: 10.3389/fonc.2019.00657 -
Journal of Gynecologic Oncology May 2020Primary sarcoma of the cervix is rare and is associated with worse outcomes as compared to other histologies. The purpose of this study was to identify national...
OBJECTIVE
Primary sarcoma of the cervix is rare and is associated with worse outcomes as compared to other histologies. The purpose of this study was to identify national treatment patterns and outcomes based on histological subtype using the National Cancer Database (NCDB).
METHODS
The NCDB was queried for patients with cervical cancer from 2004-2015. Clinico-demographic treatment details were obtained and compared between patients with squamous cell carcinoma (SCC), adenocarcinoma, and sarcoma of the cervix. Multivariable Cox regression and the Kaplan-Meier method was used to examine survival.
RESULTS
107,177 patients met inclusion criteria including 81,245 (75.8%) women with SCC, 24,562 (22.9%) women with adenocarcinoma, and 1,370 (1.3%) women with sarcoma. Of the patients with cervical sarcoma, 680 (49.6%) patients had carcinosarcoma or malignant mixed Müllerian tumor, 255 (18.6%) patients had leiomyosarcoma, 197 (14.4%) patients had adenosarcoma, 28 (2.0%) patients had endometrial stromal sarcoma (ESS), 85 (6.2%) patients had rhabdomyosarcoma, and 125 (9.1%) patients had sarcoma not otherwise specified (NOS). Patients with sarcoma were older and more likely to be treated primarily with surgery. On multivariable Cox regression, sarcoma had decreased overall survival (OS) as compared to patients with SCC (hazard ratio=2.17; 95% CI=1.99-2.37; p<0.001). Among patients with sarcoma, 5-year OS was 89.2% for adenosarcoma, 66.2% for rhabdomyosarcoma, 55.6% for leiomyosarcoma, 45.8% for ESS, 31.6% for carcinosarcoma, and 29.2% for sarcoma NOS.
CONCLUSIONS
Primary cervical sarcomas have inferior outcomes compared to SCC and adenocarcinoma. Sarcoma NOS and carcinosarcoma have the worst prognosis among sarcoma subtypes.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Medicare; Middle Aged; Prognosis; Sarcoma; United States; Uterine Neoplasms; Young Adult
PubMed: 31912680
DOI: 10.3802/jgo.2020.31.e25 -
Pathologica Dec 2020Mullerian adenosarcoma is an uncommon biphasic malignant uterine tumor. It is composed of benign epithelial and malignant stromal elements. We present a case of a...
Mullerian adenosarcoma is an uncommon biphasic malignant uterine tumor. It is composed of benign epithelial and malignant stromal elements. We present a case of a 45-year-old woman who presented with post-menopausal bleeding for three months. She had a significant past medical history of pelvic irradiation for squamous carcinoma of cervix 20 years ago. Pathology revealed adenosarcoma with sarcomatous overgrowth. The patient had a recurrence of pure sarcoma three months later and unfortunately succumbed to her disease. The role of radiation in the pathogenesis of adenosarcoma has been uncommonly described compared to its well established role in the development of carcinosarcoma. Our case fulfils the criteria for a radiation induced sarcoma. We review the salient clinical and pathological features of this uncommon lesion highlighting the importance of sarcomatous overgrowth in these lesions and the possible role of radiation in the development of these tumors.
Topics: Adenosarcoma; Cervix Uteri; Female; Humans; Middle Aged; Mixed Tumor, Mullerian; Neoplasms, Radiation-Induced; Radiotherapy; Uterine Cervical Neoplasms; Uterine Neoplasms
PubMed: 33393526
DOI: 10.32074/1591-951X-114 -
International Journal of Gynecological... Jul 2024SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular...
SMARCA4 / BRG1 -deficient Uterine Neoplasm With Hybrid Adenosarcoma and Carcinoma Features: Expanding the Molecular-morphologic Spectrum of SMARCA4 -driven Gynecologic Malignancies.
SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.
Topics: Humans; Female; DNA Helicases; Transcription Factors; Nuclear Proteins; Adult; Adenosarcoma; Uterine Neoplasms; Immunohistochemistry; Carcinoma
PubMed: 38113031
DOI: 10.1097/PGP.0000000000000996 -
JNMA; Journal of the Nepal Medical... Feb 2021Uterine adenosarcoma is a rare variant of mixed Mullerian tumors comprised of neoplastic glands with the benign appearance and sarcomatous stroma. The epithelium most...
Uterine adenosarcoma is a rare variant of mixed Mullerian tumors comprised of neoplastic glands with the benign appearance and sarcomatous stroma. The epithelium most often consists of endometrium- like cells, while the sarcomatous component usually shows low-grade homologous uterine sarcoma. These tumors present as a pelvic mass or an enlarged uterus with abnormal vaginal bleeding. Here, we present a case of 61 years old postmenopausal female patient with chief complaints of excessive vaginal bleeding and urine retention.
Topics: Adenosarcoma; Female; Humans; Middle Aged; Mixed Tumor, Mullerian; Uterine Hemorrhage; Uterine Neoplasms
PubMed: 34506473
DOI: 10.31729/jnma.5373 -
Medicine Nov 2019Uterine adenosarcoma (UA) with sarcomatous overgrowth (ASSO) is a rare and aggressive disease. Herein, wereported the case of a young patient with advanced uterine ASSO.
RATIONALE
Uterine adenosarcoma (UA) with sarcomatous overgrowth (ASSO) is a rare and aggressive disease. Herein, wereported the case of a young patient with advanced uterine ASSO.
PATIENTS CONCERNS
A 29-year-old woman with the diagnoses of endometrial polyp and adenomyosis underwent hysteroscopic endometrial polypectomy for the giant endometrial polyp. Postoperative regular ultrasound scan indicated thickened endometriumand an ill-defined mass with continuous enlargement in the myometrium of the posterior wall of the uterus, which was considered as an adenomyoma. Two years after hysteroscopy, she was re-admitted due to lower abdominal distension and large pelvic mass. At that time, she had taken oral short-acting contraceptives for 2.5 years.
DIAGNOSES
Magnetic resonance imaging (MRI) of the pelvis revealed an irregular mass with the size of 12*56*107 mm in the right annex area, without distinct border with the rectum, moreover, an uneven intrauterine echo that has no obvious boundary with uterine wall. Right ovarian cancer and adenomyoma were initially considered.
INTERVENTIONS
The patient received transperitoneal retroperitoneal pelvic combined with total viscera resection, including uterus, bilateral appendages and rectum, omentectomy, appendectomy, lymphadenectomy, and ileostomy. Postoperative pathology confirmed ASSO in the uterine cavity and muscular layer, the whole cervical duct and the right adnexal. She underwent 2 systemic chemotherapy sessions after the surgery. The chemotherapy regimen was ifosfamide 2.5 g day 1 to 3, with liposomal doxorubicin 40 mg day 1.
OUTCOMES
The final diagnosis was uterine ASSO, International Federation of Gynecology and Obstetrics stage IVa. The patient has been following-up so far, with no progression.
LESSONS
Review of the case indicated that history of long-term oral short-acting contraceptives and giant endometrial polyps may be the high-risk factors for UA. For patients with high-risk factors, the follow-up ultrasound scan should be more frequently conducted. Moreover, 3D-ultrasound, MRI and outpatient hysteroscopy are recommended for routine screening. Placement of levonorgestrel-releasing intra-uterine system after hysteroscopy may be an effective intervention for patients with a high risk of giant polyps. Cluster of Differentiation 10, Estrogen receptor, Progesterone receptor, and nuclear antigen may be predictors for prognosis and selection of individualized treatment program.
Topics: Adenosarcoma; Adult; Female; Humans; Neoplasm Invasiveness; Sarcoma; Uterine Neoplasms
PubMed: 31764852
DOI: 10.1097/MD.0000000000018119 -
Archives of Gynecology and Obstetrics Nov 2019Uterine adenosarcomas (UAs) account for 5-8% of cases of uterine sarcomas. Treatment includes total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy...
PURPOSE
Uterine adenosarcomas (UAs) account for 5-8% of cases of uterine sarcomas. Treatment includes total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). Fertility preservation is an emerging concept in gynaecology oncology and is particularly relevant in UA, where cases are diagnosed as young as 15-year-old. This manuscript demonstrates a case of UA which was treated conservatively, achieved successful livebirths and underwent completion hysterectomy after two decades of follow-up.
METHOD
This was a retrospective case note review.
RESULTS
An 18-year-old nulliparous woman presented with abnormal vaginal bleeding. Ultrasound identified an endometrial polyp, which was histologically diagnosed as low-grade adenosarcoma. She was advised to undergo TAH and BSO, but instead decided to preserve her fertility and opted for conservative management. She was monitored with pelvic ultrasound, hysteroscopy and endometrial biopsy bi-annually, with annual pelvic magnetic resonance imaging for 10 years which was uneventful. 11 years post-operatively she conceived following in-vitro fertilization (IVF) but suffered a miscarriage at 16 weeks likely due to cervical incompetence. She subsequently conceived with twins. She delivered spontaneously preterm at 28 weeks. Both children are alive and well. After 20 years of follow-up, she underwent a laparoscopic hysterectomy with no evidence of recurrence. She remains disease free.
CONCLUSION
Whilst radical completion surgery should be advised in UA, this case, in addition to all published conservatively managed cases of UA, demonstrates that conservative management is possible in appropriately selected women. Intensive monitoring post-operatively is essential owing to the risk of recurrence; however, this may pose deleterious side effects which require consideration.
Topics: Adenosarcoma; Adolescent; Conservative Treatment; Female; Follow-Up Studies; Humans; Retrospective Studies; Time Factors; Uterine Neoplasms
PubMed: 31584132
DOI: 10.1007/s00404-019-05306-6 -
Gynecologic Oncology Reports May 2020•Cervical Mullerian adenosarcoma is a tumor that affects reproductively aged women.•Hysterectomy had been the standard of care for these premenopausal women.•This...
Management and survival of patients with Mullerian adenosarcoma of the cervix without sarcomatous overgrowth desiring fertility preservation, a case report and review of the literature.
•Cervical Mullerian adenosarcoma is a tumor that affects reproductively aged women.•Hysterectomy had been the standard of care for these premenopausal women.•This case reports the most minimally invasive approach with no recurrence.•Accurate pathology interpretation is essential to diagnose and treat patients.•This is a rare tumor that if misdiagnosed or mischaracterized could be lethal.
PubMed: 32181315
DOI: 10.1016/j.gore.2019.100525 -
Cancer Science Mar 2021We have previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a direct transcriptional target of TTF-1/NKX2-1, a lineage-survival oncogene in...
We have previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a direct transcriptional target of TTF-1/NKX2-1, a lineage-survival oncogene in lung adenocarcinoma. ROR1 sustains prosurvival signaling from multiple receptor tyrosine kinases including epidermal growth factor receptor, MET, and insulin-like growth factor 1 receptor in part by maintaining the caveolae structure as a scaffold protein of cavin-1 and caveolin-1. In this study, a high throughput screening of the natural product library containing 2560 compounds was undertaken using a cell-based FluoPPI assay detecting ROR1-cavin-1 interaction. As a result, geldanamycin (GA), a known inhibitor of heat shock protein 90 (HSP90), was identified as a potential inhibitor of ROR1. Geldanamycin, as well as two GA derivatives tested in the clinic, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), decreased ROR1 protein expression. We found that ROR1 physically interacted with HSP90α, but not with other HSP90 paralogs, HSP90β or GRP94. Geldanamycin in turn destabilized and degraded ROR1 protein in a dose- and time-dependent manner through the ubiquitin/proteasome pathway, resulting in a significant suppression of cell proliferation in lung adenocarcinoma cell lines, for which the kinase domain of ROR1, but not its kinase activity or N-glycosylation, was required. Our findings indicate that HSP90 is required to sustain expression of ROR1 crucial for lung adenosarcoma survival, suggesting that inhibition of HSP90 could be a promising therapeutic strategy in ROR1-positive lung adenocarcinoma.
Topics: Adenocarcinoma of Lung; Antibiotics, Antineoplastic; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Gene Knockdown Techniques; HSP90 Heat-Shock Proteins; High-Throughput Screening Assays; Humans; Lactams, Macrocyclic; Lung Neoplasms; Proteasome Endopeptidase Complex; Proteolysis; RNA-Binding Proteins; Receptor Tyrosine Kinase-like Orphan Receptors
PubMed: 33370472
DOI: 10.1111/cas.14786