Michel Prefontaine

Combination of AKT inhibition with autophagy blockade effectively reduces ascites-derived ovarian cancer cell viability.

Recent genomics analysis of the high-grade serous subtype of epithelial ovarian cancer (EOC) show aberrations in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway that result in upregulated signaling activity. Thus, the PI3K/AKT pathway represents a potential therapeutic target for aggressive high-grade EOC. We previously demonstrated that treatment of malignant ascites-derived primary human EOC cells and ovarian cancer cell lines with the allosteric AKT inhibitor Akti-1/2 induces a dormancy-like cytostatic response but does not reduce cell viability. In this report, we show that allosteric AKT inhibition in these cells induces cytoprotective autophagy. Inhibition of autophagy using chloroquine (CQ) alone or in combination with Akti-1/2 leads to a significant decrease in viable cell number. In fact, Akti-1/2 sensitizes EOC cells to CQ-induced cell death by exhibiting markedly reduced EC50 values in combination-treated cells compared with CQ alone. In addition, we evaluated the effects of the novel specific and potent autophagy inhibitor-1 (Spautin-1) and demonstrate that Spautin-1 inhibits autophagy in a Beclin-1-independent manner in primary EOC cells and cell lines. Multicellular EOC spheroids are highly sensitive to Akti-1/2 and CQ/Spautin-1 cotreatments, but resistant to each agent alone. Indeed, combination index analysis revealed strong synergy between Akti-1/2 and Spautin-1 when both agents were used to affect cell viability; Akti-1/2 and CQ cotreatment also displayed synergy in most samples. Taken together, we propose that combination AKT inhibition and autophagy blockade would prove efficacious to reduce residual EOC cells for supplying ovarian cancer recurrence.

Epidemiology and investigations for suspected endometrial cancer.

OBJECTIVE To review the evidence relating to the epidemiology of endometrial cancer and its diagnostic workups. OPTIONS Women with possible endometrial cancer can undergo an endometrial evaluation by office biopsy, hysteroscopy, or dilatation and curettage. To assist in treatment planning, pelvic ultrasound, CT scan, or MRI may be considered. OUTCOMES The identification of optimal diagnostic tests to evaluate patients with possible endometrial cancer. EVIDENCE Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS This document is intended to guide the development of a standardized cost-effective investigation of patients with suspected endometrial cancer. VALIDATION The guideline was reviewed for accuracy by experts in pathology, radiation oncology, and medical oncology. Guideline content was also compared with relevant documents from the American Congress of Obstetricians and Gynecologists.

TGFβ signaling regulates epithelial–mesenchymal plasticity in ovarian cancer ascites-derived spheroids

Epithelial-mesenchymal transition (EMT) serves as a key mechanism driving tumor cell migration, invasion, and metastasis in many carcinomas. Transforming growth factor-beta (TGFβ) signaling is implicated in several steps during cancer pathogenesis and acts as a classical inducer of EMT. Since epithelial ovarian cancer (EOC) cells have the potential to switch between epithelial and mesenchymal states during metastasis, we predicted that modulation of TGFβ signaling would significantly impact EMT and the malignant potential of EOC spheroid cells. Ovarian cancer patient ascites-derived cells naturally underwent an EMT response when aggregating into spheroids, and this was reversed upon spheroid re-attachment to a substratum. CDH1/E-cadherin expression was markedly reduced in spheroids compared with adherent cells, in concert with an up-regulation of several transcriptional repressors, i.e., SNAI1/Snail, TWIST1/2, and ZEB2. Treatment of EOC spheroids with the TGFβ type I receptor inhibitor, SB-431542, potently blocked the endogenous activation of EMT in spheroids. Furthermore, treatment of spheroids with SB-431542 upon re-attachment enhanced the epithelial phenotype of dispersing cells and significantly decreased cell motility and Transwell migration. Spheroid formation was significantly compromised by exposure to SB-431542 that correlated with a reduction in cell viability particularly in combination with carboplatin treatment. Thus, our findings are the first to demonstrate that intact TGFβ signaling is required to control EMT in EOC ascites-derived cell spheroids, and it promotes the malignant characteristics of these structures. As such, we show the therapeutic potential for targeted inhibition of this pathway in ovarian cancer patients with late-stage disease.

The role of surgery in endometrial cancer.

OBJECTIVE To review current practice and make recommendations for the management and treatment of endometrial cancer. OUTCOMES This guideline makes recommendations with respect to extended surgical staging, which provides important prognostic information and aids in determining the need for adjuvant treatments. EVIDENCE Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts BENEFITS, HARMS, AND COSTS This guideline reviews the benefit of extended surgical staging compared with the potential harm of a limited surgery in grade 2 and 3 disease. VALUES The quality of evidence is rated and recommendations are made using the criteria described by the Canadian Task Force on Preventive Health Care (Table).

The Role of Adjuvant Therapy in Endometrial Cancer

OBJECTIVE To review the evidence relating to the use of adjuvant therapy after surgical treatment for endometrial cancer. OPTIONS Women with endometrial cancer can be given the option of receiving adjuvant radiotherapy and/or chemotherapy according to pathologic findings at time of surgery. OUTCOMES The outcomes measured are postoperative progression-free and overall survival in endometrial cancer patients. EVIDENCE Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS This guideline is intended to help standardize postoperative treatment of endometrial cancer and minimize undertreatment and overtreatment. VALIDATION The guideline was reviewed for accuracy by content experts in pathology, radiation oncology, and medical oncology. Guideline content was also compared with relevant documents from the American Congress of Obstetricians and Gynecologists.

Cystic struma ovarii (with macrocystic change)

In this article, a case of cystic struma ovarii with macrocystic change is presented. Cysts derived from struma ovarii may mimic a mucinous or serous cystadenoma. A careful examination for any thyroid microfollicles within fibrous septa or areas of solid stroma is key. In problematic cases, immunohistochemical staining with thyroglobulin and thyroid transcription factor-1 may be required to establish the diagnosis.

Role of Adjuvant Therapy for Stage IA Serous and Clear Cell Uterine Cancer: Is Observation a Valid Strategy?

Objectives The adjuvant treatment of early stage IA serous and clear cell carcinomas of the uterus is controversial. The aims of the study were to report on a single institution experience treating these high-risk early uterine cancers and to identify women who may be suitable for observation alone. Methods and Materials A retrospective review of patients presenting from 2003 to 2013 with pathologic stage IA (International Federation of Gynecology and Obstetrics 2009) serous or clear cell uterine carcinoma was performed. Patient and disease characteristics, surgical staging, treatment details, and recurrence data were collected. Recurrence rates and 5-year actuarial estimates of recurrence free survival (RFS) were the primary outcomes of interest. Results A total of 77 patients with stage IA were identified. Median (range) follow-up was 34 (1–108) months. Staging lymphadenectomy was performed in 83%. Adjuvant treatment was given to 27 patients, whereas 50 underwent observation. There were 12 recurrences total, with the 5-year RFS 79% for the cohort, with no statistically significant difference between observation and adjuvant treatment. Only 4 patients received adjuvant chemotherapy and none recurred. In the observation cohort, the presence versus absence of myometrial invasion showed a trend to poorer 5-year RFS (75% vs 93%, P = 0.06). Conclusions Observation seems to be a valid strategy in those patients with stage IA serous and clear cell carcinoma without myometrial invasion. The presence of any myometrial invasion may confer a higher risk of recurrence, although further studies are needed to determine the optimal adjuvant treatment regimen.

Choriocarcinoma in an AIDS patient – relapsing but not fatal

Summary Choriocarcinoma is associated with high mortality in immunocompromised patients, in contrast to a good prognosis in immunocompetent individuals. Respiratory failure due to metatstatic choriocarcinoma is associated with high mortality in any patient. We report a case of a woman with AIDS that survived metastatic choriocarcinoma and respiratory failure. We also observed that in contrast to some in vitro studies, the markedly elevated levels of β-subunit of human chorionic gonadotropin in this patient did not have any apparent inhibitory effect on viral replication.

Abstract A47: The LKB1-AMPK pathway mediates the metabolic stress response of dormant ovarian cancer spheroids

Metastatic epithelial ovarian cancer (EOC) cells can form multicellular spheroids while in suspension and disperse throughout the peritoneum via ascites to seed secondary lesions. We hypothesize that EOC spheroids are key mediators of metastasis, which use specific signaling pathways to alter cell metabolism for increased survival. Our lab discovered that AKT signaling is reduced during spheroid formation leading to cellular quiescence and autophagy. Given the induction of quiescence and autophagy in EOC spheroids, we are studying the 5′-AMP-activated protein kinase (AMPK) pathway as a master controller of the metabolic stress response and dormant phenotype of EOC spheroids. We demonstrate AMPK activity and its upstream kinase LKB1 are increased in quiescent EOC spheroids compared with proliferating adherent EOC cells. We also show elevated AMPK activity in spheroids isolated directly from patient ascites. Targeted knockdown of STK11 , encoding LKB1, reduces cell viability in ovarian cancer cell line spheroids; PRKAA1 (AMPKα1) knockdown has little to no effect on EOC cell or spheroid viability. Combination of STK11 knockdown with carboplatin treatment leads to a synergistic enhancement in EOC spheroid cell death. In contrast, AICAR treatment of proliferating adherent ovarian cancer cell lines and primary EOC cells induces AMPK activity and causes either cytostasis or cell death. In addition, AICAR treatment of spheroids during reattachment decreases the dispersion capacity of migrating EOC cells. These results offer a glimpse of the potential important contributions of LKB1-AMPK pathway in stress signaling related to EOC cell survival during metastasis. In addition, downstream effectors of upregulated LKB1-AMPK signalling may provide additional mechanisms by which EOC evades chemotherapy. It is foreseeable that these findings will allow us to identify new therapeutic targets within this pathway critical to EOC progression for ultimate translation to the clinic. Citation Format: Teresa Peart, Elena Fazio, Yudith Ramos-Valdes, Monique Bertrand, Jacob McGee, Michel Prefontaine, Akira Sugimoto, Gabriel E. DiMattia, Trevor G. Shepherd. The LKB1-AMPK pathway mediates the metabolic stress response of dormant ovarian cancer spheroids. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A47.

Inversion utérine complète chez une patiente présentant un cancer de l’endomètre

U femme de 71 ans presentait des saignements postmenopausiques et le tomodensitogramme revelait la presence d’une carcinomatose abdominale. La biopsie endometriale indiquait la presence d’un carcinome endometrial faiblement differencie. Le jour de la chirurgie, la patiente s’est plainte de difficultes mictionnelles et de la presence d’une masse ayant fait saillie a partir du vagin pendant une semaine (Figure 1). Au moment de la laparotomie, elle presentait des signes d’une inversion uterine complete (Figure 2). La patiente a subi une hysterectomie abdominale totale, une salpingo-ovariectomie bilaterale et une intervention de reduction tumorale. L’inversion uterine est une complication obstetricale peu courante qui peut etre associee a l’application d’une traction excessive sur le cordon ombilical. Les cas non puerperaux sont tres rares. Aucun autre cas d’inversion uterine associee a la presence d’un adenocarcinome de l’endometre n’a ete signale auparavant.