Erratum: Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro.

[This corrects the article on p. 2478 in vol. 7, PMID: 29312801.].

Prior breast cancer and tamoxifen exposure does not influence outcomes in women with uterine papillary serous carcinoma.

OBJECTIVES: To evaluate progression-free survival (PFS) and overall survival (OS) outcomes in women diagnosed with uterine papillary serous carcinoma (UPSC) who have had (UPSCBR+) or have not had (UPSCBR-) an antecedent history of breast cancer and to correlate their outcomes to prior tamoxifen exposure. METHODS: Data were collected for women diagnosed with UPSC at two academic institutions between January 1997 and July 2012. Patient demographics, tumor histology, stage, and treatments were recorded. Patients were divided into two groups: those with and without a personal history of breast cancer. Within the UPSCBR+ cohort, we identified those with a history of tamoxifen use. Cox regression modeling was used to explore associations between selected covariates of interest and the time-to-event outcomes of PFS and OS. RESULTS: Of 323 patients with UPSC, 46 (14%) were UPSCBR+. Of these, 15 (33%) had a history of tamoxifen use. UPSCBR+ patients were older than UPSCBR- (median years, 72 vs. 68, p=0.004). UPSCBR+ women showed no significant difference in PFS or OS compared to UPSCBR- (p=0.64 and p=0.73 respectively), even after controlling for age (p=0.15 and p=0.48 respectively). Within the UPSCBR+ cohort, there was no difference in PFS or OS with or without tamoxifen exposure (p=0.98 and p=0.94 respectively). CONCLUSIONS: There was no difference in PFS or OS between the UPSCBR+ and UPSCBR- cohorts. We did not demonstrate significant OS or PFS differences in women who took tamoxifen prior to their endometrial cancer diagnosis. These findings have implications for counseling, and should be encouraging to women who are facing their second cancer diagnosis.

Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro.

Ovarian cancer is the 8th most common cancer in women, and the 5th leading cause of cancer-related deaths among women in the United States. Statins have been shown to have promising anti-tumorigenic activity in many types of cancers. We sought to determine the effects of atorvastatin (ATO) on cell proliferation in ovarian cancer and identify the mechanisms by which ATO inhibits cell growth in this disease. ATO inhibited cell proliferation of both the Hey and SKOV3 ovarian cancer cells in a dose-dependent manner. The anti-proliferative activity of ATO in the ovarian cancer cell lines was associated with induction of apoptosis, autophagy, cellular stress and cell cycle G1 arrest via inhibition of AKT/mTOR and activation of the MAPK pathways. Moreover, ATO inhibited cell adhesion and invasion as well as decreased expression of VEGF and MMP9. c-Myc was downregulated in ovarian cancer cells exposed to ATO. Inhibition of c-Myc by JQ1 synergistically increased the sensitivity of ovarian cancer cells to ATO. This data suggests that ATO may have a therapeutic role in the treatment of ovarian cancer and warrant further exploration in clinical trials.

The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer.

Ovarian cancer is the 5th leading cause of cancer death among women in the United States. The mevalonate pathway is thought to be a potential oncogenic pathway in the pathogenesis of ovarian cancer. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitor, is a widely used drug for inhibiting the synthesis of cholesterol and may also have anti-tumorigenic activity. Our goal was to evaluate the effects of simvastatin on ovarian cancer cell lines, primary cultures of ovarian cancer cells and in an orthotopic ovarian cancer mouse model. Simvastatin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, and caused cellular stress via reduction in the enzymatic activity of HMGCR and inhibition of the MAPK and mTOR pathways in ovarian cancer cells. Furthermore, simvastatin induced DNA damage and reduced cell adhesion and invasion. Simvastatin also exerted anti-proliferative effects on primary cell cultures of ovarian cancer. Treatment with simvastatin in an orthotopic mouse model reduced ovarian tumor growth, coincident with decreased Ki-67, HMGCR, phosphorylated-Akt and phosphorylated-p42/44 protein expression. Our findings demonstrate that simvastatin may have therapeutic benefit for ovarian cancer treatment and be worthy of further exploration in clinical trials.

Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway.

Glutamine is one of the main nutrients used by tumor cells for biosynthesis. Therefore, targeted inhibition of glutamine metabolism may have anti-tumorigenic implications. In the present study, we aimed to evaluate the effects of glutamine on ovarian cancer cell growth. Three ovarian cancer cell lines, HEY, SKOV3, and IGROV-1, were assayed for glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis, cell stress, and glucose/glutamine metabolism. Our results revealed that administration of glutamine increased cell proliferation in all three ovarian cancer cell lines in a dose dependent manner. Depletion of glutamine induced reactive oxygen species and expression of endoplasmic reticulum stress proteins. In addition, glutamine increased the activity of glutaminase (GLS) and glutamate dehydrogenase (GDH) by modulating the mTOR/S6 and MAPK pathways. Inhibition of mTOR activity by rapamycin or blocking S6 expression by siRNA inhibited GDH and GLS activity, leading to a decrease in glutamine-induced cell proliferation. These studies suggest that targeting glutamine metabolism may be a promising therapeutic strategy in the treatment of ovarian cancer.

Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells.

High rates of aerobic glycolysis represent a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. The present study was aimed at evaluating the potential of a novel lactate dehydrogenase (LDH) inhibitor, Galloflavin, as a therapeutic agent for endometrial cancer. Our results revealed that Galloflavin effectively inhibited cell growth in endometrial cancer cell lines and primary cultures of human endometrial cancer through its involvement in multiple signaling pathways that regulate metabolism, cell cycle, apoptosis, cell stress and metastasis.

Metformin and gynecologic cancers.

IMPORTANCE: The obese population in the United States is reaching epic proportions, and obesity is linked to an increased risk for several cancers including gynecologic cancers. Obesity is not only a risk factor but also a marker of poor prognosis. It is crucial to develop novel treatment strategies to target this population. Metformin is a biguanide drug, typically used for diabetes treatment, currently being studied to evaluate its role in the treatment and prevention of gynecologic cancers. OBJECTIVE: The aim of this study was to review the underlying biologic mechanisms of metformin's antitumorigenic effects. We assessed the epidemiologic and preclinical data that support the use of metformin in patients with endometrial and ovarian cancer. Finally, we reviewed current clinical trials that incorporate metformin as a prevention or treatment strategy for gynecologic cancers. EVIDENCE ACQUISITION: A thorough search of PubMed for all current literature was performed. All preclinical, clinical, and epidemiologic reviews were evaluated across all cancers, with a focus on gynecologic cancer. RESULTS: The preclinical, epidemiologic, and clinical data evaluated in this review are strongly supportive of the use of metformin for the prevention and treatment of gynecologic cancer. On the basis of these data, centers are currently enrolling for clinical trials using metformin in patients diagnosed with gynecologic malignancies. CONCLUSIONS AND RELEVANCE: The data supporting the use of metformin in the prevention and treatment of cancers are building, including that of endometrial and ovarian cancer. The association between obesity, insulin resistance, as well as increased risk and poor outcomes in endometrial and ovarian cancer patients makes metformin an attractive agent for the prevention and treatment of these diseases.

Uterine morcellation at the time of hysterectomy: techniques, risks, and recommendations.

IMPORTANCE: Uterine leiomyomata or fibroids are the most common pelvic tumor experienced in women. A minimally invasive approach to hysterectomy has proven benefits of cosmesis, lower blood loss, less pain, decreased hospital stay, and faster recovery. The incidence of uterine morcellation, the process of making a uterine specimen smaller for purposes of removal via a minimally invasive approach, has increased for this reason. OBJECTIVE: We review the history, techniques, and direct and indirect risks described in the literature, recommendations for appropriate use, and how to counsel patients regarding this procedure. EVIDENCE ACQUISITION: A thorough search of PubMed for all current literature was performed. Techniques for morcellation were reviewed. We included studies that addressed the type and incidence of morcellator-associated risks including those addressing the incidence of leiomyosarcoma in patients with presumed uterine fibroids. RESULTS: We have summarized several techniques to aid the practitioner in performing morcellation procedures and the risks involved. We have summarized all of the current consensus statements regarding the recommendations for use of morcellation and the approach to proper counseling. CONCLUSIONS AND RELEVANCE: Morcellation is an effective method of specimen removal that can decrease the need for laparotomy in both benign and malignant conditions. Upon analysis of current data and consensus statements, when possible, morcellation should be performed within a contained environment to minimize any potential tumor spread in the event of an undiagnosed malignancy. Patients should be adequately counseled to make an informed decision regarding undergoing a morcellation procedure. Future methods for enclosed specimen extraction will hopefully change the future of morcellation.

A comprehensive review of diagnostic and treatment options for granulosa cell tumors of the ovary.

Granulosa cell tumors are rare and comprise approximately 2% to 8% of all ovarian malignancies. Research dedicated to these tumors is rare given the low incidence. These tumors are more difficult to diagnose than epithelial ovarian tumors, and understanding how they present may aid in appropriate referral to a gynecologic oncologist. The aim of this review was to summarize the epidemiology, risk factors, and clinical presentation of granulosa cell tumors to aid in provider recognition. We will also explore current diagnostic and treatment modalities with examination of newer, novel treatments. At the end of this review, the reader should understand how to appropriately diagnose and treat these rare malignancies.

Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer.

OBJECTIVE: Our goal was to evaluate the effects of simvastatin on endometrial cancer cell lines and primary cultures of endometrial cancer cells. METHODS: Cell proliferation in the ECC-1 and Ishikawa endometrial cancer cell lines and primary cultures of endometrial cancer cells was assessed by MTT assay. Apoptosis and cell cycle were detected by Annexin V assay and propidium iodide staining, respectively. Reactive oxygen species and cell adhesion were assessed using ELISA assays. Invasion was analyzed using a transwell invasion assay. Mitochondrial DNA damage was confirmed using qPCR. The effects of simvastatin on the AKT/mTOR and MAPK pathways were determined by Western blotting. RESULTS: Simvastatin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines and 5/8 primary cultures of endometrial cancer cells. Simvastatin treatment resulted in G1 cell cycle arrest, a reduction in the enzymatic activity of HMG-CoA, induction of apoptosis as well as DNA damage and cellular stress. Treatment with simvastatin resulted in inhibition of the MAPK pathway and exhibited differential effects on the AKT/mTOR pathway in the ECC-1 and Ishikawa cells. Minimal change in AKT phosphorylation was seen in both cell lines. An increase in phosphorylated S6 was seen in ECC-1 and a decrease was seen in Ishikawa. Treatment with simvastatin reduced cell adhesion and invasion (p<0.01) in both cell lines. CONCLUSION: Simvastatin had significant anti-proliferative and anti-metastatic effects in endometrial cancer cells, possibly through modulation of the MAPK and AKT/mTOR pathways, suggesting that statins may be a promising treatment strategy for endometrial cancer.

Pre-operative imaging with CA125 is a poor predictor for granulosa cell tumors.

OBJECTIVE: To determine the radiographic characteristics of ovarian granulosa cell tumors (GCTs) and to evaluate the use of CA125 levels >35 in combination with imaging as an algorithm for preoperative diagnosis. METHODS: A retrospective analysis of women from two academic medical centers who were diagnosed with ovarian GCT between January 1998 and August 2012 was conducted. Clinical data included tumor appearance on pre-operative imaging and CA125 levels. Ovarian cysts were defined as complex if imaging exhibited multicystic areas, hemorrhagic, solid, or cystic and solid components. A CA125 level >35 was abnormal. RESULTS: One hundred and fifteen women were diagnosed with GCTs, of whom 63 underwent pre-operative imaging. Median age at surgery was 46 years (12-87). Forty women had preoperative ultrasounds, 43 had CT scans and 20 underwent both modalities. GCTs were almost exclusively classified as complex cysts in 62 (98%) cases. The most common morphology was solid and cystic (n=44 (70%)). Forty-four (70%) patients had tumors >10 cm. Forty-two patients had a pre-operative CA125 performed. Eighteen (43%) patients had complex masses and CA125 >35. Twenty-three (55%) had CA125 <35 with a complex mass, and one (2%) had a unilocular cyst with a CA125 >35. CONCLUSIONS: In this study, there was a near equal distribution of patients with complex masses and CA125 levels > or <35. If established strategies to predict malignancy are applied to GCTs, we will frequently fail to make the diagnosis pre-operatively. Additional research is necessary to generate an appropriate algorithm to guide pre-operative referral to a gynecologic oncologist.

Outpatient end of life discussions shorten hospital admissions in gynecologic oncology patients.

OBJECTIVE: The study goal was to determine whether prior outpatient exposure to hospice discussion altered the inpatient course and end-of-life (EOL) care among patients ultimately discharged to hospice. METHODS: Medical records from January 2009 to June 2012 were reviewed and data were abstracted under an IRB-approved protocol. Hospice discussions were identified in the last outpatient clinical encounter prior to admission. Kaplan-Meier was used to estimate overall survival (OS) and the log-rank test was used to test for differences. RESULTS: There were 89 hospitalizations resulting in discharge to hospice care: 41 women with ovarian (46%), 23 with uterine (29%), 19 with cervical (21.3%), and with 6 vulvar/vaginal (6.7%) cancers. 83 patients (93%) had outpatient clinical encounters prior to admission;18% (15/83) were exposed to a hospice discussion (HD) and 82% (68/83) were not (NHD). Median time from last outpatient encounter was 18 days (range 0-371). NHD patients had longer inpatient length of stay (median 7 days vs. 4 days, p=0.008) and were less likely to receive palliative care consults than the HD patients (65% vs. 93%, p=0.03). Median OS for HD patients was 33 days (95% CI 22d-61 d) vs. 60 days (95% CI 49 d-84 d) for NHD patients (p=0.01). There were no differences detected based on race, ethnicity, or insurance status. CONCLUSIONS: HD patients had significantly shorter OS suggesting that providers were accurate in identifying patients nearing the EOL. Patients exposed to outpatient hospice discussions had a shorter length of stay and increased utilization of palliative care resources.