Kevin Schuler

Non-endometrioid adenocarcinoma of the uterine corpus: a review of selected histological subtypes.

BACKGROUND Understanding the etiology, presentation, evaluation, and management of selected non-endometrioid endometrial adenocarcinomas of the uterine corpus is needed to define optimal treatment regimens. METHODS The pathology and treatment of selected non-endometrioid endometrial adenocarcinomas of the uterus are reviewed and summarized. RESULTS The most common non-endometrioid histology is papillary serous (10%), followed by clear cell (2% to 4%), mucinous (0.6% to 5%), and squamous cell (0.1% to 0.5%). Some non-endometrioid endometrial carcinomas behave more aggressively than the endometrioid cancers such that even women with clinical stage I disease often have extrauterine metastasis at the time of surgical evaluation. Therefore, when technically and medically feasible, comprehensive surgical staging is helpful for women with non-endometrioid endometrial cancer histology. Comprehensive surgical staging includes hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cytological evaluation of the abdominal cavity. While whole abdominal radiotherapy has a limited role in early-stage uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC), there may be a role for postoperative chemotherapy and volume-directed radiotherapy in both early-stage UPSC and CC. In the setting of optimally debulked advanced-stage disease, a combination of radiation and chemotherapy may be indicated. In the setting of recurrent disease or in women with residual disease after surgery, a platinum-based regimen or enrollment in a clinical trial is recommended. CONCLUSIONS UPSC and CC are managed similarly since sufficient data to separate treatment recommendations are lacking. Because both histologies are associated with a high rate of recurrence, adjuvant therapy is recommended even in women with early-stage disease. The remaining cell types should be treated similar to endometrioid or other low-grade histologies.

A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study

BACKGROUND Sentinel-lymph-node mapping has been advocated as an alternative staging technique for endometrial cancer. The aim of this study was to measure the sensitivity and negative predictive value of sentinel-lymph-node mapping compared with the gold standard of complete lymphadenectomy in detecting metastatic disease for endometrial cancer. METHODS In the FIRES multicentre, prospective, cohort study patients with clinical stage 1 endometrial cancer of all histologies and grades undergoing robotic staging were eligible for study inclusion. Patients received a standardised cervical injection of indocyanine green and sentinel-lymph-node mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. 18 surgeons from ten centres (tertiary academic and community non-academic) in the USA participated in the trial. Negative sentinel lymph nodes (by haematoxylin and eosin staining on sections) were ultra-staged with immunohistochemistry for cytokeratin. The primary endpoint, sensitivity of the sentinel-lymph-node-based detection of metastatic disease, was defined as the proportion of patients with node-positive disease with successful sentinel-lymph-node mapping who had metastatic disease correctly identified in the sentinel lymph node. Patients who had mapping of at least one sentinel lymph node were included in the primary analysis (per protocol). All patients who received study intervention (injection of dye), regardless of mapping result, were included as part of the assessment of mapping and in the safety analysis in an intention-to-treat manner. The trial was registered with ClinicalTrials.gov, number NCT01673022 and is completed and closed. FINDINGS Between Aug 1, 2012, and Oct 20, 2015, 385 patients were enrolled. Sentinel-lymph-node mapping with complete pelvic lymphadenectomy was done in 340 patients and para-aortic lymphadenectomy was done in 196 (58%) of these patients. 293 (86%) patients had successful mapping of at least one sentinel lymph node. 41 (12%) patients had positive nodes, 36 of whom had at least one mapped sentinel lymph node. Nodal metastases were identified in the sentinel lymph nodes of 35 (97%) of these 36 patients, yielding a sensitivity to detect node-positive disease of 97·2% (95% CI 85·0-100), and a negative predictive value of 99·6% (97·9-100). The most common grade 3-4 adverse events or serious adverse events were postoperative neurological disorders (4 patients) and postoperative respiratory distress or failure (4 patients). 22 patients had serious adverse events, with one related to the study intervention: a ureteral injury incurred during sentinel-lymph-node dissection. INTERPRETATION Sentinel lymph nodes identified with indocyanine green have a high degree of diagnostic accuracy in detecting endometrial cancer metastases and can safely replace lymphadenectomy in the staging of endometrial cancer. Sentinel lymph node biopsy will not identify metastases in 3% of patients with node-positive disease, but has the potential to expose fewer patients to the morbidity of a complete lymphadenectomy. FUNDING Indiana University Health, Indiana University Health Simon Cancer Center, and the Indiana University Department of Obstetrics and Gynecology.

Discussion: ‘Ovarian epithelial carcinoma with pelvic endometriosis,’ by Wang et al

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Wang S, Qui L, Lang JH, et al. Clinical analysis of ovarian epithelial carcinoma with coexisting pelvic endometriosis.

Abstract 4663: The cyclooxygenase-2 inhibitor, celecoxib, suppresses proliferation and induces apoptosis in endometrial cancer cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL INTRODUCTION: Obesity is associated with increased risk and worse outcomes for women with endometrial cancer. Inflammation may play a critical role in obesity-driven cancers; thus, the anti-inflammatory effects of COX-2 inhibitors may be a novel treatment strategy that is particularly beneficial in endometrial cancer patients. As a result, our objective was to evaluate the effect of COX-2 inhibitors on proliferation and apoptosis in endometrial cancer cell lines. METHODS: Two endometrial cancer cell lines (ECC-1 and Ishikawa) were used in these studies. Cell proliferation was assessed by MTT assay after exposure to the COX-2 inhibitor, celecoxib. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by ELISA for caspase-3. hTERT mRNA expression was assessed by real-time PCR. Western immunoblotting was performed to determine the effect of celecoxib on COX-2 expression in the endometrial cancer cell lines. RESULTS: Celecoxib significantly inhibited proliferation in a dose-dependent manner in both endometrial cancer cell lines (IC50 5-10 μM for ECC-1, 10-20 μM for Ishikawa; p<0.005 for each). Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis and inhibition of hTERT mRNA expression. Western immunoblot analysis demonstrated that celecoxib treatment suppresses COX-2 expression in both endometrial cancer cell lines. CONCLUSION: Celecoxib potently inhibits cell growth via G1 arrest, decreases telomerase activity and increases apoptotic cell death in endometrial cancer cells. This work suggests that celecoxib may be a novel chemotherapeutic agent for endometrial cancer prevention and treatment, especially given the interplay between obesity, inflammation and cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4663. doi:1538-7445.AM2012-4663

Abstract 504: Metformin potently inhibits cell proliferation, adhesion and invasion in ovarian cancer cells

ABSTRACT Objectives: Metformin is an anti-diabetic drug that has been shown to have anti-tumorgenic effects by behaving as a novel mTOR inhibitor. Metformin has been shown to suppress cancer cell growth, but little is known of its potential to halt metastatic spread. Thus, our goal was to assess the effect of metformin on proliferation, adhesion and invasion in ovarian cancer cell lines. Methods: Four ovarian cancer cell lines, SKOV3, CAOV3, OVCAR3 and IGROV1 were used. Cell proliferation was assessed by MTT assay after exposure to metformin. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by Annexin V-FITC assay. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of metformin, including AMPK and the ribosomal protein S6. Inhibition of adhesion and invasion by metformin was assessed by in vitro adhesion assay and ChemoTx® invasion assay. Results: Metformin potently inhibited growth in a dose-dependent manner in all four ovarian cancer cell lines (IC 50 of 0.1-1 mM) (p=0.00001-0.0121). Treatment with metformin resulted in G1 arrest, induction of apoptosis and decreased hTERT expression. Western immunoblot analysis demonstrated that metformin induced phosphorylation of AMPK, its immediate downstream mediator, and decreased phosphorylation of the S6 protein, a key target of the mTOR pathway, within 24 hours of exposure. Metformin inhibited cellular adhesion in the ovarian cancer cell lines by 10-23% at 1 mM (p=0.04-0.00001) and 25-35% at 10 mM (p=0.05-0.00001). In addition, metformin decreased invasion by 7-21% at 1 mM (p=0.03-0.0009) and 29-42% at 10 mM (p=0.03-0.0012). Conclusions: We report that metformin is a potent inhibitor of cell proliferation and exhibits anti-metastatic effects in ovarian cancer cells. Thus, metformin may have potential as a targeted chemotherapeutic agent in the treatment of ovarian cancer. More work is needed to determine if metformin will be universally beneficial in all ovarian cancer patients versus selectively efficacious in a subset of ovarian cancer patients, such as those women who are obese and/or diabetic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 504. doi:1538-7445.AM2012-504

Discussion: 'Surgical staging in early ovarian carcinoma' by Garcia-Soto et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research.

Abstract 5175: Predictors of metastatic spread and progression free survival in uterine papillary serous carcinoma: A pilot study

Background: Uterine Papillary Serous Carcinoma (UPSC) comprises 5-10% of all endometrial cancers but is responsible for nearly 40% of all endometrial cancer-related deaths. Progression-free survival (PFS) controlled for stage is also markedly shorter in UPSC compared to Type 1 endometrial cancers. Unlike endometrioid carcinoma, in which depth of myometrial invasion, grade, and lymphovascular space invasion (LVSI) are risk factors for extrauterine spread, UPSC often metastasizes in those with no myometrial invasion. Objective: The objective of this study is to identify markers that may predict metastatic disease in women with non-invasive UPSC or portend a shorter progression free survival. Materials: A retrospective chart review was performed on women diagnosed with Stage IA or Stage III/IV UPSC without myometrial invasion from 1995-2008. Examined factors include age, parity, race, weight, LVSI, CA125 levels, and tumor location within the endometrium. Tissue microarrays (TMAs) were constructed using paraffin blocked specimens and stained for ER, PR, p53, VEGF, Claudin 3, Claudin 4, Her-2/neu, Her-3, Synuclein gamma, and Maspin. Chi-square analysis, Student9s t-test, and Fisher9s Exact analysis were used where appropriate to detect statistically significant differences in these 2 groups with Kaplan-Meyer analysis used to determine PFS. Significance was represented at p Results: Thirty-two patients were identified to have UPSC without myometrial invasion, 24 (75%) comprising Stage IA and 8 (25%) having Stage III/IV disease. Pathology blocks were available for 21 patients (14 Stage I and 7 Stage III/IV). CA125 was the only factor to achieve significance (p=0.04) in predicting metastatic spread; biomarkers, either alone or in combination, were not predictive of metastatic disease. In Stage I disease, positive ER status was associated with a significantly longer PFS (p Conclusions: In addition to traditional risk factors not being predictive of metastatic disease, molecular markers that have been associated with metastatic disease and a worsening prognosis do not appear to be predictive in UPSC. However, the contribution of ER status and Her-3 needs to be further evaluated as this may offer new insight into therapeutic options for treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5175. doi:10.1158/1538-7445.AM2011-5175