[Show abstract][Hide abstract] ABSTRACT: High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA) represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Our aim was to assess current surgical practices and use of adjuvant therapy in the treatment of FIGO (International Federation of Gynecology and Obstetrics) stage I endometrioid endometrial cancer.
A 19-question survey was developed and sent to all Society of Gynecologic Oncologist members by e-mail. Data were collected anonymously using Internet-based survey software. Respondents were asked questions regarding preoperative evaluation, surgical approach, lymph node dissection (LND), and adjuvant therapy.
A total of 1399 surveys were distributed, 320 (23%) members completed the survey. Ninety-seven percent of respondents were gynecologic oncologists or fellows, and 87% treat 30 or more endometrial cancer patients yearly. Respondents were more likely to order preoperative tests such as computed tomography abdomen/pelvis and CA-125 for biopsy-proven grade 3 disease versus grade 1 (82% vs 29%). Robot-assisted laparoscopy was the preferred surgical approach (66%), followed by conventional laparoscopy (21%). Twenty-six percent of respondents perform LND in all cases. Forty-eight percent describe their LND as complete, to the level of the inferior mesenteric artery. Adjuvant therapy was recommended more often with increasing myometrial invasion, tumor grade, and lymphovascular space invasion. Vaginal brachytherapy was the most commonly recommended adjuvant therapy for stage IA. For stage IB, grade 3, positive lymphovascular space invasion disease, respondents were more likely to combine vaginal brachytherapy with external beam radiotherapy and/or chemotherapy. Older patients were more likely to have adjuvant therapy in earlier stages of disease than younger patients.
Our findings demonstrate that respondents are individualizing care based on preoperative, intraoperative, and pathologic findings. As expected, adjuvant treatment is recommended for patients with higher stage and grade disease. Robot-assisted hysterectomy and chemotherapy are now commonly used in the management of this disease. We anticipate that new trends will continue to emerge as results from additional studies become available.
[Show abstract][Hide abstract] ABSTRACT: Objective:
High-grade serous ovarian cancer (HGSOC) that is resistant to platinum-based chemotherapy has a particularly poor prognosis. Response to platinum has both prognostic survival value and dictates secondary treatment strategies. Using transcriptome analysis, we sought to identify differentially expressed genes/pathways based on a tumor's platinum response for discovering novel predictive biomarkers.
Seven primary HGSOC tumor samples, representing two extremes of platinum sensitivity/timing of disease recurrence, were analyzed by RNA-Seq, Ingenuity Pathways Analysis (IPA) and Upstream Regulator Analysis (URA), and used to explore differentially expressed genes and prevalent molecular and cellular processes. Progression-free and overall survival (PFS, OS) was estimated using the Kaplan-Meier method in two different sample sets including GEO and TCGA data sets.
IPA and URA highlighted an IRF1-driven transcriptional program (P=0.0017; z-score of 3.091) in the platinum sensitive improved PFS group. QRT-PCR analysis of 31 HGSOC samples demonstrated a significant difference in PFS between low and high IRF1 expression groups (P=0.048) and between groups that were platinum sensitive versus not (P=0.016). In a larger validation data set, increased levels of IRF1 were associated with both increased PFS (P=0.043) and OS (P=0.019) and the effect on OS was independent of debulking status (optimal debulking, P=0.025; suboptimal, P=0.041).
Transcriptome analysis identifies IRF1, a transcription factor that functions both in immune regulation and as a tumor suppressor, as being associated with platinum sensitivity and an independent predictor of both PFS and OS in HGSOC.
No preview · Article · Jul 2014 · Gynecologic Oncology
[Show abstract][Hide abstract] ABSTRACT: Retrospective studies have demonstrated that nearly 50% of patients with ovarian cancer with normal cancer antigen 125 (CA125) levels have persistent disease; however, prospectively distinguishing between patients is currently impossible. Here, we demonstrate that for one patient, with the first reported fibroblast growth factor receptor 2 (FGFR2) fusion transcript in ovarian cancer, circulating tumor DNA (ctDNA) is a more sensitive and specific biomarker than CA125, and it can also inform on a candidate therapeutic. For a 4-year period, during which the patient underwent primary debulking surgery and chemotherapy, tumor recurrences, and multiple chemotherapeutic regimens, blood samples were longitudinally collected and stored. Whereas postsurgical CA125 levels were elevated only three times for 28 measurements, the FGFR2 fusion ctDNA biomarker was readily detectable by quantitative real-time reverse transcription-polymerase chain reaction (PCR) in all of these same blood samples and in the tumor recurrences. Given the persistence of the FGFR2 fusion, we treated tumor cells derived from this patient and others with the FGFR2 inhibitor BGJ398. Only tumor cells derived from this patient were sensitive to FGFR2 inhibitor treatment. Using the same methodologic approach, we demonstrate in a second patient with a different fusion that PCR and agarose gel electrophoresis can also be used to identify tumor-specific DNA in the circulation. Taken together, we demonstrate that a relatively inexpensive, PCR-based ctDNA surveillance assay can outperform CA125 in identifying occult disease.
Full-text · Article · Jan 2014 · Neoplasia (New York, N.Y.)
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to determine the role of liver metastatectomy in the morbidity and survival of patients with recurrent ovarian carcinoma.
We retrospectively reviewed the records of all patients who had undergone hepatic resection for liver metastases from ovarian carcinoma at the time of cytoreductive surgery at our institution from 1988 to 2012. The Kaplan-Meier method was used for survival analysis. A total of 76 patients met the inclusion criteria and had undergone liver resection as part of cytoreductive surgery for ovarian carcinoma during the study period. Of these 76 patients, 27 underwent liver resection at the time of secondary cytoreduction, and these patients that are the focus of this analysis.
Median overall survival for the study group from the time of diagnosis to the last follow-up or death was 56 months (range, 12-249 months). Twenty died of the disease with an overall median survival of 12 months from the time of the liver resection (2-190 months), and 7 patients were alive with the disease at the time of the last follow-up. Based on Kaplan-Meier survival analysis, the factors associated with the longest survival after the liver resection (2-190 months) were the interval from the primary surgery of less than 24 months versus more than 24 months (P = 0.044) and secondary cytoreduction to residual disease of less than 1 cm (P = 0.014).
Based on our analysis of a single institution's series of ovarian cancer patients with hepatic metastasis, liver resection is feasible and safe and should be considered as an option in selected patients at the time of secondary cytoreduction.
No preview · Article · Jan 2014 · International Journal of Gynecological Cancer
[Show abstract][Hide abstract] ABSTRACT: The shape of nuclei in many adherent cultured cells approximates an oblate ellipsoid, with contralateral flattened surfaces facing the culture plate or the medium. Observations of cultured cell nuclei from orthogonal perspectives revealed that nucleoporin p62 (NUP62) and nucleoporin 214 (NUP214) are differentially distributed between nuclear pore complexes on the flattened surfaces and peripheral rim of the nucleus. High resolution stimulated emission depletion (STED) immunofluorescence microscopy resolved individual NPCs, and suggested both heterogeneity and microheterogeneity in NUP62 and NUP214 immunolabeling among in NPC populations. Similar to nuclear domains and interphase chromosome territories, architectural diversity and spatial patterning of NPCs may be an intrinsic property of the nucleus that is linked to the functions and organization of underlying chromatin.