Magnetic resonance imaging of uterine leiomyosarcoma

Summary The magnetic resonance imaging (MRI) findings in a patient with uterine leiomyosarcoma are reported. MRI provides higher contrast resolution in soft tissues than ultrasonography or CT, and the MRI findings described in this case report suggest that MRI can be used to help differentiate between leiomyosarcoma from myoma.     

Array comparative genomic hybridization analysis of uterine leiomyosarcoma

PURPOSE: Using a genome-wide array-based comparative genomic hybridization (array-CGH), DNA copy number changes in uterine leiomyosarcoma were analyzed. MATERIALS AND METHODS: We analyzed 4 cases of uterine leiomyoma and 7 cases of uterine leiomyosarcoma. The paraffin-fixed tissue samples were microdissected under microscope and DNA was extracted. Array-based CGH and fluorescence in situ hybridization (FISH) were carried out with Genome database (Gene Ontology). RESULTS: Uterine leiomyoma showed no genetic alterations, while all of 7 cases of uterine leiomyosarcoma showed specific gains and losses. The percentage of average gains and losses were 4.86% and 15.1%, respectively. The regions of high level of gain were 7q36.3, 7q33-q35, 12q13-12q15, and 12q23.3. And the regions of homozygous loss were 1p21.1, 2p22.2, 6p11.2, 9p21.1, 9p21.3, 9p22.1, 14q32.33, and 14q32.33 qter. There were no recurrent regions of gain, but recurrent regions of loss were 1p21.1-p21.2, 1p22.3-p31.1, 9p21.2-p22.2, 10q25-q25.2, 11q24.2-q25, 13q12-q12.13, 14q31.1-q31.3, 14q32.32-q32.33, 15q11-q12, 15q13-q14, 18q12.1-q12.2, 18q22.1-q22.3, 20p12.1, and 21q22.12-q22.13. In the high level of gain regions, BAC clones encoded HMGIC, SAS, MDM2, TIM1 genes. Frequently gained BAC clone-encoded genes were TIM1, PDGFR-beta, REC Q4, VAV2, FGF4, KLK2, PNUTL1, GDNF, FLG, EXT1, WISP1, HER-2, and SOX18. The genes encoded by frequently lost BAC clones were LEU1, ERCC5, THBS1, DCC, MBD2, SCCA1, FVT1, CYB5, and ETS2/E2. A subset of cellular processes from each gene was clustered by Gene Ontology database. CONCLUSION: Using array-CGH, chromosomal aberrations related to uterine leiomyosarcoma were identified. The high resolution of array-CGH combined with human genome database would give a chance to find out possible target genes present in the gained or lost clones.     

Increased risk of secondary uterine leiomyosarcoma in hereditary retinoblastoma

Objective

In the US, second non-ocular malignancies are the primary cause of death in retinoblastoma survivors with the germline RB1 mutation. Soft tissue sarcomas are one of the most likely malignancies to pose a risk to these patients, with leiomyosarcoma (LMS) being the most common subtype. As our cohort is followed for a longer period, we discover new second malignancy risks for these patients.

Methods

We estimated the risk for uterine leiomyosarcoma (ULMS) in a cohort of 1854 patients with retinoblastoma who were diagnosed at two US institutions from 1914 through 1996. The standardized incidence ratio and excess absolute risk were calculated by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. The cumulative risk at 50 years of age was also calculated.

Results

Seven of 525 female hereditary retinoblastoma patients developed ULMS. Five of these patients were used in the risk analysis, resulting in an excess risk of 3.87 per 10,000 women. Among hereditary patients who developed ULMS the excess risk increases dramatically with age: to 20/10,000 for female hereditary retinoblastoma patients aged between 30 and 39 years, and to 27/10,000 for patients aged 40 + years.

Conclusion

There is a substantial excess risk of ULMS in female hereditary retinoblastoma patients. As more patients survive into their thirties, this number is likely to increase. These findings raise the question of early childbearing, screening and prophylactic measures in hereditary retinoblastoma patients: all issues that would benefit from confirmation from other retinoblastoma cohorts, to allow for better guided counsel of these patients.     

Epithelioid leiomyosarcoma of the uterine cervix: a case report and review of the literature

BACKGROUND: Epithelioid leiomyosarcomas arising from the uterine cervix are extremely rare neoplasms, with only three cases reported in the English literature. CASE: A 53-year-old Japanese woman was admitted to our university hospital due to massive vaginal bleeding from a cervical tumor. A total hysterectomy with bilateral salpingo-oophorectomy was performed. Histological findings, including immunohistochemical study using desmin, SMA, cytokeratin, S-100, HMB-45, vimentin, melan-A, and CD68, led to a diagnosis of epithelioid leiomyosarcoma of the uterine cervix. The patient underwent adjuvant chemotherapy and has been disease-free for over 20 months. CONCLUSION: Immunohistochemical studies may be needed to differentiate among the alternative diagnoses of malignant melanoma, metastatic carcinoma, and epithelioid sarcoma. Additional cases are needed to develop optimal management strategies and to predict prognosis.     

The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma

Objective.

Uterine leiomyosarcoma (LMS) is usually diagnosed after surgery for leiomyoma; thus tumor morcellation frequently occurs. We evaluated the impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine LMS.

Methods.

Outcomes were retrospectively compared between patients who underwent total abdominal hysterectomy without tumor morcellation and those who underwent surgery that included abdominal, vaginal or laparoscopic tumor morcellation.

Results.

We assessed 56 consecutive patients with stage I and II uterine LMS between 1989 and 2010, 25 with and 31 without tumor morcellation. There were no significant between group differences in age, parity, menopausal status, body mass index, stage, mitotic count, tumor grade, lymph node dissection, adjuvant therapy, and follow-up duration. However, tumor size was significantly smaller (9.8 cm vs. 7.3 cm, P = 0.022) and ovarian tissue was more frequently preserved (38.7% vs. 72%, P = 0.013) in patients with tumor morcellation. In univariate analysis, only tumor morcellation was significantly associated with poorer disease-free survival (DFS) (odds ratio [OR], 2.59; 95% confidence interval [CI], 1.03-6.50; P = 0.043), and higher stage (I vs. II; (OR, 19.12; 95% CI, 1.19-307.11; P = 0.037)) and tumor morcellation (OR, 3.07; 95% CI, 1.05-8.93; P = 0.040) were significantly associated with poorer overall survival (OS). In multivariate analysis, higher stage (OR, 20.34; 95% CI, 1.27-325.58; P = 0.033) and tumor morcellation (OR, 3.11; 95% CI, 1.07-9.06; P = 0.038) were significantly associated with poorer OS. The percentage of patients with abdomino-pelvic dissemination, as shown by peritoneal sarcomatosis or vaginal apex recurrence, was significantly greater in patients with than without tumor morcellation (44% vs. 12.9%, P = 0.032).

Conclusion.

Tumor morcellation during surgery increased the rate of abdomino-pelvic dissemination and adversely affected DFS and OS in patients with apparently early uterine LMS.     

Surgical cytoreduction in patients with metastatic uterine leiomyosarcoma at the time of initial diagnosis

Objective

To determine whether cytoreduction is associated with improved outcome in patients newly diagnosed with metastatic uterine leiomyosarcoma (LMS).

Methods

We retrospectively identified all patients treated at our institution for high-grade uterine LMS with extrauterine disease at the time of initial diagnosis from 7/1/82 to 7/31/07. Pattern of disease spread was classified as intraperitoneal (IP) or extraperitoneal (EP). Progression-free survival (PFS) and overall survival (OS) were determined from date of initial surgery using Kaplan-Meier estimates.

Results

We identified 96 cases. Median age was 54 years (range, 23-81). IP disease was seen in 48 (50%) and EP in 48 (50%). A complete gross resection of all tumor was achieved in 41/84 (49%). Recurrence or progression was noted in 93 (97%); 81 (84%) have died. Median PFS and OS for the entire cohort was 9.7 months (range, 6.7-10.9) and 20.2 months (range, 15.5-24.8), respectively. All 8 non-surgical cases died within 30 months of diagnosis. Median PFS was 14.2 months (range, 11.4-16.9) for those with a complete gross resection versus 6.8 months (range, 4.1-9.5) for those with any residual disease (P = 0.002). Median OS was 31.9 months (range, 3.3-60.4) versus 20.2 months (range, 11.8-28.6), respectively (P = 0.04). On multivariate analysis, no residual disease was independently associated with PFS when adjusting for disease distribution (IP vs EP) and the use of chemotherapy but not OS.

Conclusions

Surgical cytoreduction of metastatic uterine LMS was independently associated with PFS but not OS in cases selected for surgery. The improvement in PFS must be weighed against the morbidity of surgery.     

Immunohistochemical expression of estrogen and progesterone receptors and outcomes in patients with newly diagnosed uterine leiomyosarcoma

Objective

We assessed the IHC expression of ER and PR and their prognostic significance in uterine leiomyosarcoma (LMS).

Methods

We identified 43 “high-grade” uterine LMS cases from 7/82-7/07 for whom ER/PR IHC analysis was performed at initial diagnosis at our institution.

Results

Disease was confined to the uterine body in 20/43 (47%). Eighteen (42%) of 43 were ER(+); 17/42 (41%) were PR(+). At last follow-up, 33 (77%) had recurred or progressed, and 23 (54%) had died. PR expression was associated with improved progression-free survival (PFS; P = 0.002) and overall survival (OS; P = 0.03) overall; ER expression was not. After adjusting for stage, ER expression was associated with PFS (P = 0.01), not OS (P = 0.3), and PR expression maintained a significant association with PFS (P = 0.002) and approached a significant association with OS (P = 0.05). Neither ER nor PR expression was associated with outcome in cases with disease outside the uterine body. In cases with confined disease, median PFS for ER(+) or PR(+) cases was not reached compared to 16.9 months for ER(−) cases (95% CI: 8.1-25.7; P = 0.03) and 13.5 months for PR(−) cases (95% CI: 5.9-21.1; P = 0.001). Only 1/10 PR(+) cases recurred and died; 9/10 PR(−) cases recurred, and 5 died. Two of 9 ER(+) cases recurred and died; 8/11 ER(−) cases recurred, and 4 died.

Conclusion

ER/PR expression is associated with survival outcomes in patients with high-grade uterine LMS confined to the uterine body. PR expression seems capable of identifying cases confined to the uterine body, which have better outcomes.     

A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D

Objective

This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS).

表皮生长因子对子宫肌瘤细胞MAPK信号通路的活化作用

目的：研究表皮生长因子（EGF）对子宫肌细胞（HM-SMCs）和子宫肌瘤细胞（HL．SMCs）中有丝分裂原激活的蛋白激酶（MAPK）信号转导通路的活化作用。方法：收集30例子宫肌瘤患者的子宫肌瘤组织和正常子宫肌组织进行原代细胞培养。采用激光扫描细胞法（LSC法）检测BrdU渗入率;Western blot法检测p44／42MAPK及其磷酸化水平和p44／42MAPK特异性底物ELK-1的表达,MAPK特异性抑制剂PD98059和EGFR受体抑制剂AG1478对p44／42MAPK表达的抑制作用,以及p44／42MAPK的时间依赖性表达以及细胞周期相关蛋白p27的表达。结果：EGF诱导p-p44／42MAPK和ELK-1水平显著上调,HM．SMCs中的表达量显著高于HL-SMCs。AG1478和PD98059可抑制EGF对MAPK的诱导作用。HM-SMCs中p44／42MAPK对EGF的刺激呈持续平稳的激活,伴随着p27的显著上调;HL．SMCs中则呈快速短暂的激活,伴随着p27低水平上调。结论：EGF通过活化MAPK信号通路促进细胞增殖可能是子宫肌瘤发病的-个重要的机制,为肌瘤的非手术治疗提供了可能。     

mTOR信号通路在人子宫肌和子宫肌瘤组织中的活性研究

目的:检测哺乳动物雷帕霉素靶分子(m TOR)信号通路中相关蛋白在人子宫肌和子宫肌瘤组织中的表达。方法:收集22例子宫肌和与之配对的子宫肌瘤组织,采用Western blot法和Real-time PCR法检测tuberin、hamartin、p-S6K、p-4EBP1和p-Akt表达。结果:与子宫肌比较,子宫肌瘤中tuberin、S6K和4EBP1呈高表达,hamartin表达不升高,p-S6K和p-4EBP1表达降低,Akt和p-Akt表达无显著变化。结论:Tuberin在子宫肌瘤中高表达;m TOR信号通路在子宫肌瘤中受到抑制。     

Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway

Objectives

To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines.

Methods

ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed after exposure to paclitaxel and metformin. Cell cycle progression was assessed by flow cytometry. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the effect of metformin/paclitaxel on the mTOR pathway.

Results

Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC₅₀ values of 1-5 nM and 5-10 nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5 mM) resulted in a significant synergistic anti-proliferative effect in both cell lines (Combination Index < 1). Metformin induced G1 arrest in both cell lines. Paclitaxel alone or in combination with metformin resulted in predominantly G2 arrest. Metformin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Metformin stimulated AMPK phosphorylation and decreased phosphorylation of the S6 protein. In contrast, paclitaxel inhibited AMPK phosphorylation in the ECC-1 cell line and induced phosphorylation of S6 in both cell lines. Treatment with metformin and paclitaxel resulted in decreased phosphorylation of S6 in both cell lines but only had an additive effect on AMPK phosphorylation in the ECC-1 cell line.

Conclusions

Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. This combination may be a promising targeted therapy for endometrial cancer.     

The role of the phosphatidylinositol 3-kinase (PI3K) pathway in the development and treatment of uterine cancer

Objective

Uterine cancer is the most common gynecologic malignancy in the United States. Although surgery is often curative for women diagnosed in the early stages, prognosis for patients with advanced disease is poor. Alterations in the phosphatidylinositol 3-kinase (PI3K) pathway are known to play a significant role in the development of uterine cancer and provide a possible target for new therapies.

Methods

PubMed was searched for articles of relevance to uterine cancer and the PI3K pathway. In addition, abstracts from key oncology congresses were scanned for data on novel therapeutic agents targeting the PI3K pathway.

Results

The PI3K pathway is an important promoter of cellular growth, metabolism, differentiation, proliferation, survival, and angiogenesis. It is often upregulated in uterine cancer, with the most frequent genetic alterations occurring in phosphatase and tensin homolog (PTEN), PIK3CA, and KRAS. Deregulation of the pathway has been associated with resistance to hormonal therapy and chemotherapy. Inhibitors of the PI3K pathway are in clinical testing in patients with solid tumors, including uterine cancer. Results with monotherapy demonstrate some clinical responses, but mainly as prolonged stable disease. PI3K pathway inhibitors are currently being evaluated in patients with tumors in which the PI3K pathway is deregulated. Another strategy being evaluated is the ability of PI3K pathway inhibitors to restore sensitivity to standard therapy.

Conclusions

Investigational PI3K pathway inhibitors represent a promising new therapeutic strategy in uterine cancer. Exploration of effective drug combinations and their applicability to individual tumors will be important in the future clinical development of these agents.     

Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer

Objective

Activation of the mammalian target of rapamycin (mTOR) pathway enhances cell survival and growth by regulating the efficiency of protein translation. This study was conducted to evaluate the association of activated mTOR signaling molecules with the clinicopathologic characteristics in epithelial ovarian cancer.

Methods

Immunohistochemical staining with antibodies against p-4EBP1, p-mTOR, and p-p70S6K were performed on specimens of 103 patients with ovarian cancer. Tumors were classified as chemoresistant in cases where time to recurrence after the end of chemotherapy was shorter than 6 months.

Results

Expressions of p-mTOR, p-4EBP1, and p-p70S6K were detected in 47.6%, 85.4%, and 64.1% of all patients, respectively. p-4EBP1 overexpression was associated with advanced stage (p = 0.04), histologic grade (p < 0.01), residual mass (p < 0.01), shorter disease-free survival rate (p = 0.01) and chemoresistance (p = 0.02). p-p70S6K was associated with residual mass with marginal significance (p = 0.06). p-4EBP1 expression was correlated with p-p70S6K expression (r = 0.42, p < 0.01), whereas p-mTOR was not associated with expression of its downstream effectors or prognostic factors.

Conclusions

Our findings suggest that p-4EBP1 expression was associated with poor prognostic factors of ovarian cancer and that p-4EBP1 overexpression may be a prognostic biomarker of ovarian cancer.