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Supplementary Figure Legends 1-2 from Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors

Supplementary Table 1 from Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors

Supplementary Figure 1 from Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors

Supplementary Figure 2 from Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors

Supplementary Table 2 from Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors

The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals. Ovarian serous adenocarcinomas were disaggregated and subjected to growth conditions selective for self-renewing, nonadherent spheroids previously shown to derive from tissue stem cells. To affirm the existence of OCICs, xenoengraftment of as few as 100 dissociated spheroid cells allowed full recapitulation of the original tumor (grade 2/grade 3 serous adenocarcinoma), whereas >105 unselected cells remained nontumorigenic. Stemness properties of OCICs (under stem cell–selective conditions) were further established by cell proliferation assays and reverse transcription–PCR, demonstrating enhanced chemoresistance to the ovarian cancer chemotherapeutics cisplatin or paclitaxel and up-regulation of stem cell markers (Bmi-1, stem cell factor, Notch-1, Nanog, nestin, ABCG2, and Oct-4) compared with parental tumor cells or OCICs under differentiating conditions. To identify an OCIC cell surface phenotype, spheroid immunostaining showed significant up-regulation of the hyaluronate receptor CD44 and stem cell factor receptor CD117 (c-kit), a tyrosine kinase oncoprotein. Similar to sphere-forming OCICs, injection of only 100 CD44+CD117+ cells could also serially propagate their original tumors, whereas 105 CD44−CD117− cells remained nontumorigenic. Based on these findings, we assert that epithelial ovarian cancers derive from a subpopulation of CD44+CD117+ cells, thus representing a possible therapeutic target for this devastating disease. [Cancer Res 2008;68(11):4311–20]

Description, Tumor tissue collection and processing under physioxia allow highly relevant detection of signaling networks and drug sensitivity., Preclinical studies of primary cancer cells are typically done after tumors are removed from patients or animals at ambient atmospheric oxygen (O2, ~21%). However, O2 concentrations in organs are in the ~3 to 10% range, with most tumors in a hypoxic or 1 to 2% O2 environment in vivo. Although effects of O2 tension on tumor cell characteristics in vitro have been studied, these studies are done only after tumors are first collected and processed in ambient air. Similarly, sensitivity of primary cancer cells to anticancer agents is routinely examined at ambient O2. Here, we demonstrate that tumors collected, processed, and propagated at physiologic O2 compared to ambient air display distinct differences in key signaling networks including LGR5/WNT, YAP, and NRF2/KEAP1, nuclear reactive oxygen species, alternative splicing, and sensitivity to targeted therapies. Therefore, evaluating cancer cells under physioxia could more closely recapitulate their physiopathologic status in the in vivo microenvironment.

Cancer is the second leading cause of death in women of reproductive age and accounts for 16% of deaths among women between ages 20–44 years. The most common malignancies diagnosed during pregnancy vary in order of frequency depending on the country studied and inclusion criteria, but the most common pregnancy-associated malignancies consistently include breast cancer, cervical cancer, lymphoma and leukemia, melanoma, thyroid cancer, and colorectal cancer. The care of the patient with a malignancy during pregnancy requires a multidisciplinary approach.

The prevalence of cervical cancer has dropped significantly since introduction of the Papanicolaou (Pap) screen. The greatest risk factor for cervical cancer is inadequate screening. Altered pelvic anatomy can limit the ability to collect a Pap smear. In the presented case, a woman with a history of fibroids and bleeding presented for an exam under anesthesia. Traditional approaches for collecting a Pap smear failed. A GlideScope video laryngoscope was used to visualize the cervix, and a Pap smear was collected. The specimen was satisfactory, negative for intraepithelial lesion or malignancy, and HPV negative. A laryngoscope can be repurposed to visualize collection of a challenging Pap smear. Novel approaches for Pap smear collection and cervical cancer screening are needed and have the potential to save lives.

PURPOSE: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). PATIENTS AND METHODS: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1–3 prior regimens, performance status (PS) 0–2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. RESULTS: 150 patients were randomized to BV with (n=75) and without (n=75) EV. Arms were well-balanced for age (median 63: range 28–92), PS (0: 73%, 1–2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (= grade 2 toxicities with BV+EV were cytopenia, nausea, fatigue and rash. CONCLUSION: The combination regimen (BV+EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.

Background: An advanced bipolar (ABP) tissue sealer designed for division of major vessels in open procedures was evaluated in a prospective post-market study. The objective was to provide clinical data for assessment of vessel transection, hemostatic performance and ease of use of the ABP device duringopen colectomy, gynecologic, and thoracic operations.Materials and methods: The ABP test device was used in colectomy (n ¼ 36), gynecologic (n ¼ 44), and thoracic (n ¼ 21) procedure groups. Vessels transected with the ABP device were graded intraoperatively on a hemostasis scale of 1e4, defined as follows: Grade1, no bleeding; Grade 2, minor bleeding with no intervention; Grade 3, minor bleeding requiring touchup with the test device or monopolar cautery; and Grade 4, significant bleeding requiring intervention with any additional hemostatic product. The primaryperformance measure was the percentage of vessels that achieved hemostasis grades 3. The primary safety endpoint was the summarization of all ABP device-related adverse events (AEs).Results: For all three procedure groups together, 302 (96.2%) of 314 total vessel transections were scored as hemostasis grades 3, including 270 (86.0%) that were rated Grade 1. Twelve transections (3.8%) were Grade 4, which included 9 vessels transected in the gynecologic group and 3 in the thoracic group. Threesubjects experienced a total of 4 device-related AEs, consisting of hematoma, hypotension, procedural pain, and superficial thermal burn. All 4 device-related AEs were mild in severity.Conclusion: The advanced bipolar device exhibited effective hemostasis, an acceptable safety profile, and ease of use during colectomy, thoracic, and gynecologic procedures.Trial registry number: ClinicalTrials.gov, NCT034411.

Introduction Patients presenting with advanced, recurrent, or metastatic endometrial cancer have limited treatment options. On behalf of the Gynecologic Oncology Group, we conducted this phase II trial of nintedanib (BIBF 1120), a potent small molecule triple receptor tyrosine kinase inhibitor of PDGFR α and β, FGFR 1/3, and VEGFR 1–3, in this population. Objectives The primary objectives were to estimate event-free survival (EFS) at 6months and the proportion of patients who have an objective tumor response. In addition, we sought to determine the nature and degree of toxicity. Secondary objectives were to estimate progression-free and overall survival. Methods This was a two-stage, single-arm phase II study. Eligible patients were treated with single-agent nintedanib at a dose of 200mg twice daily. Results Of 37 patients enrolled, 32 were eligible. There were zero complete and three partial responses for an overall response rate of 9.4% (90% 2-sided CI=2.6–22.5%). Seven patients (21.9%; 90% 2-sided CI=10.7–37.2%) were EFS at 6months, with one patient continuing on study at the time of this writing. Serious toxicity included the following grade 3 events: gastrointestinal toxicity (5), neutropenia (1), edema (1), hypertension (1), and liver function abnormalities (5). Conclusions Nintedanib lacked sufficient activity as a single agent to warrant enrollment to second stage. However, preclinical data indicate it may be synergistic with paclitaxel in a population of patients enriched for specific p53 mutations that result in loss of function. Subsequent studies may evaluate this agent in combination with paclitaxel.

High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85⁻90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically—and genetically—cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality.

Purpose The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. Patients and Methods Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m2) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. Results The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. Conclusion On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.

Objective To determine whether clinicians at various levels of training can reproduce and apply the Morphology Index when compared to Ueland's Morphology Index data, and to determine intra-observer variability when applied by observers at various levels of training. Methods One hundred four transvaginal ultrasound images of adnexal masses obtained at Indiana University between 1991 and 2003 were identified which had correlating surgical pathology. The images were scored by four investigators at four different levels of training. Scoring was based upon the revised University of Kentucky Morphology Index by Ueland. Each mass received 0–5 points for its structure, and 0–5 points for tumor volume. Each total score was then correlated with the surgical pathology. Sensitivity, specificity, positive predictive value and negative predictive value for each investigator were determined. All images were reviewed independently by each investigator; each was blinded to scores given by the other investigators and to final pathology. Results Nine malignant and 95 benign masses were noted on final pathology. Ranges for statistical values were: positive predictive value (PPV) 15–18%, negative predictive value (NPV) 93–98%, sensitivity 44–89%, and specificity 52–76%. Conclusion The Morphology Index is a consistent and reliable tool for predicting benign disease demonstrating a high negative predictive value with little intra-observer variability. However, when predicting malignancy, the results showed more intra-observer variability and a positive predictive value half of that previously reported. This study confirms the clinical utility of the Morphology Index when utilized for its NPV and demonstrates its widespread application even among clinicians with minimal ultrasound training.

Background The primary goal of this study was to determine the prevalence of pelvic floor symptoms in postoperative patients with endometrial cancer. The secondary goal was to assess the impact of these issues on patient quality of life. Methods This cross-sectional study looked at women (N = 25) returning for postoperative care at least 6 months after total abdominal hysterectomy for endometrial cancer. Demographic and clinical data were collected. Severity of pelvic floor symptoms was assessed using the short-form version of the Pelvic Floor Distress Inventory (PFDI-20). The impact of these symptoms on quality of life was assessed using the short-form version of the Pelvic Floor Impact Questionnaire (PFIQ-7). Demographic data and PFDI-20 and PFIQ-7 scores were summarized using descriptive statistics. Results Pelvic symptoms were reported at a much higher rate than seen in the general public. Symptom prevalence was reported by 21/25 (84%) patients on the PFDI-20 questionnaire, with a mean score of 52.5 ± 64.8. Patients reported prevalence of symptoms in the following order: urinary symptoms (19/25 [76%]) > colorectal-anal symptoms (17/25 [68%]) > pelvic organ prolapse symptoms (11/25 [44%]). Slightly fewer than half (11/24) of the study participants reported quality of life issues associated with their pelvic symptoms, with a mean score in the mild range: 26.4 ± 64.5. The reported prevalence of the effect of pelvic symptoms on quality of life was urinary (10/25 [40%]) > colorectal-anal (8/24 [33%]) > pelvic organ prolapse (4/24 [17%]). Conclusion This study has shown that there was a high prevalence of symptoms of PFDs in our population after abdominal hysterectomy for endometrial cancer.

Introduction Patient recall is often used by clinicians to create a history of care leading to consultation with a gynecologic oncologist. Although patient recall may be an efficient method to explore the context of the patient's concerns, the accuracy of recall and its potential impact on care are unknown. This study sought to explore the consistency of patient recall compared with data found in health care records. Patients and Methods This study enrolled 105 eligible patients who were referred to a gynecologic oncologist for suspected ovarian cancer. Ninety-one of these patients were interviewed regarding symptoms, health care events, and the dates leading to diagnosis. The medical records of these patients from all previous providers were obtained and data were abstracted. The intraclass correlation coefficient (intraclass correlation coefficient, ICC[3,1]) was used to examine correspondence between recall and medical record data. Results There was low correspondence between patient recall and the medical record for time to diagnosis (ICC = 0.12; 95% confidence interval [CI] = −0.09 to 0.33; P = .12) and health care events (0.15; 95% CI, −0.05 to 0.348; P = .008). Conclusions There should be limited confidence in information obtained from patient recall given the inconsistency between recall and actual dates and events.

Preclinical studies have shown that hypomethylating agents reverse platinum resistance in ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining study, we tested the clinical and biologic activity of low-dose decitabine administered before carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate (RR) and progression-free survival (PFS) of 10.2 months, with nine patients (53%) free of progression at 6 months. Global and gene-specific DNA demethylation was achieved in peripheral blood mononuclear cells and tumors. The number of demethylated genes was greater (P < 0.05) in tumor biopsies from patients with PFS more than 6 versus less than 6 months (311 vs. 244 genes). Pathways enriched at baseline in tumors from patients with PFS more than 6 months included cytokine–cytokine receptor interactions, drug transporters, and mitogen-activated protein kinase, toll-like receptor and Jak-STAT signaling pathways, whereas those enriched in demethylated genes after decitabine treatment included pathways involved in cancer, Wnt signaling, and apoptosis (P < 0.01). Demethylation of MLH1, RASSF1A, HOXA10, and HOXA11 in tumors positively correlated with PFS (P < 0.05). Together, the results of this study suggest that low-dose decitabine altered DNA methylation of genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resulting in a high RR and prolonged PFS. Cancer Res; 72(9); 2197–205. ©2012 AACR.

Tissue transglutaminase (TG2), an enzyme involved in cell proliferation, differentiation and apoptosis is overexpressed in ovarian carcinomas, where it modulates epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Its regulation in ovarian cancer (OC) remains unexplored. Here, we show that transforming growth factor (TGF)-β, a cytokine involved in tumor dissemination is abundantly secreted in the OC microenvironment and induces TG2 expression and enzymatic activity. This is mediated at transcriptional level by SMADs and by TGF-β-activated kinase 1-mediated activation of the nuclear factor-κB complex. TGF-β-stimulated OC cells aggregate as spheroids, which enable peritoneal dissemination. We show that TGF-β-induced TG2 regulates EMT, formation of spheroids and OC metastasis. TG2 knock-down in OC cells decreases the number of cells harboring a cancer stem cell phenotype (CD44+/CD117+). Furthermore, CD44+/CD117+ cells isolated from human ovarian tumors express high levels of TG2. In summary, TGF-β-induced TG2 enhances ovarian tumor metastasis by inducing EMT and a cancer stem cell phenotype.

Purpose Low-dose-rate (LDR) brachytherapy is an integral treatment modality in radiation oncology. Clinical efficacy is based on experience with manual source loading and continuous dose delivery. With remote afterloading technology, sources may be loaded and unloaded during the treatment course to prevent radiation exposure to nursing staff members and visitors. The aim of this study was to investigate treatment interruptions in terms of frequency and duration as well as extension of the overall treatment time period. The potential clinical impact of treatment interruptions was also considered. Materials and Methods The treatment records of 20 patients who underwent brachytherapy in the Indiana University Department of Radiation Oncology administered with a Selectron LDR remote afterloader were reviewed. Results were tabulated and analysis performed with respect to 1) the number of interruptions, 2) delay time, 3) delay time ( T d ) as a function of total implant time ( T ), 4) the time of day that each interruption occurred, and 5) the time in minutes of each individual interruption. Results The mean number of interruptions was 44.9 per patient, (range, 24-76), with a mean prescription implantation duration of 45.7 hours and a mean actual treatment time of 51.2 hours resulting in a mean interruption time of 6.4 minutes per treatment hour. The number of interruptions was standardized and divided by the number of prescribed dose in grays, translating to 1.2 to 3.7 interruptions per gray delivered, with a mean of 1.6, resulting in an average T d of 11.21% (range, 7.35%-17.12%). Conclusion Significant interruptions are frequent using remote afterloading LDR techniques, reducing the effective dose rate. Careful monitoring of such interruptions is warranted.

No research has investigated patients' representations of the vaginal symptoms commonly experienced after cervical cancer treatment. Leventhal's Self-regulation or Common Sense Model was used to explore these representations and their relationships with quality of life after cervical cancer. Women posttreatment for cervical cancer (n = 26) from a Midwest cancer center provided information on symptom representations for their 3 most bothersome symptoms and also completed a quality-of-life scale. Women perceived vaginal symptoms as mild to moderate overall but rated approximately one-third of 11 different symptoms as severe. Symptoms identified most frequently as the most bothersome were painful intercourse (23%), decrease in sexual desire (15%), and vaginal dryness (12%). On average, symptoms were mildly distressing and acute, had a minimal effect on life, and were associated with an indeterminate degree of perceived control. Cause was attributed equally to treatment and to the cancer. Quality of life was below normed data, to a degree consistent with a minimally important difference for total well-being scores and physical, emotional, and functional well-being. Emotional and consequence representations were significantly related to quality of life. Understanding and altering symptom representations may improve quality of life for women treated for cervical cancer.

The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals. Ovarian serous adenocarcinomas were disaggregated and subjected to growth conditions selective for self-renewing, nonadherent spheroids previously shown to derive from tissue stem cells. To affirm the existence of OCICs, xenoengraftment of as few as 100 dissociated spheroid cells allowed full recapitulation of the original tumor (grade 2/grade 3 serous adenocarcinoma), whereas >105 unselected cells remained nontumorigenic. Stemness properties of OCICs (under stem cell–selective conditions) were further established by cell proliferation assays and reverse transcription–PCR, demonstrating enhanced chemoresistance to the ovarian cancer chemotherapeutics cisplatin or paclitaxel and up-regulation of stem cell markers (Bmi-1, stem cell factor, Notch-1, Nanog, nestin, ABCG2, and Oct-4) compared with parental tumor cells or OCICs under differentiating conditions. To identify an OCIC cell surface phenotype, spheroid immunostaining showed significant up-regulation of the hyaluronate receptor CD44 and stem cell factor receptor CD117 (c-kit), a tyrosine kinase oncoprotein. Similar to sphere-forming OCICs, injection of only 100 CD44+CD117+ cells could also serially propagate their original tumors, whereas 105 CD44−CD117− cells remained nontumorigenic. Based on these findings, we assert that epithelial ovarian cancers derive from a subpopulation of CD44+CD117+ cells, thus representing a possible therapeutic target for this devastating disease. [Cancer Res 2008;68(11):4311–20]

The prognosis for patients who develop a recurrence after fertility-sparing surgery for epithelial ovarian cancer (EOC) remains unclear. This is the first study to evaluate survival in patients who have developed a recurrence in this context. The outcomes of relapsed patients reported in the literature in the four main series of fertility-sparing surgery for EOC were reviewed and updated (where feasible). Twenty-three of the 166 patients in the series were reported to have recurrent disease. The site of the recurrence was the peritoneum (+/- remaining ovary) in 17 patients, and distant in six patients. Twelve patients died of recurrent disease, two are still alive with persistent disease, eight are disease-free, and one is alive but her exact status is not known. Among eight patients (34%) with an isolated recurrence on the remaining ovary, two died and one was lost to follow-up. In this carefully monitored population, including systematic radiological examinations, the rate of isolated recurrences on the spared ovary is low. Recurrence in these patients carries a poor prognosis. Such results suggest that initial selection of candidates for fertility-sparing surgery should be carefully defined to reduce the rate of recurrences that carry a poor prognosis.

Objectives. To determine a recommended dose level (RDL) of paclitaxel, cisplatin and topotecan in women with previously untreated epithelial ovarian or peritoneal cancer as a possible experimental arm in a future Gynecologic Oncology Group phase III study. Methods. Patients with newly diagnosed stage III or IV disease were treated with paclitaxel 175 mg/m 2 /3 h, followed 2 h later by cisplatin 50 mg/m 2 on day 1. Topotecan was administered on consecutive days as a 30-minute infusion, beginning after cisplatin on day 1, receiving either 5 days beginning at 0.3 mg/m 2 (cohort 1), or 3 days beginning at 0.5 mg/m 2 (cohort 2). Treatment was given every 21 days for a maximum of 8 cycles. Results. Forty-five evaluable patients were enrolled in the two cohorts. Thrombocytopenia and prolonged neutropenia were the major dose-limiting toxicities. Dose-limiting neutropenia was seen at the first dose level, thus all subsequent dose escalations included Filgrastim. The RDL of cohort 1 was paclitaxel 175 mg/m 2 /3 h, cisplatin 50 mg/m 2 and topotecan 0.5 mg/m 2 daily×5 with Filgrastim. The RDL of cohort 2 was paclitaxel 175 mg/m 2 /3 h, cisplatin 50 mg/m 2 and topotecan 0.75 mg/m 2 daily×3 with Filgrastim. Conclusion. In women with previously untreated epithelial ovarian or peritoneal cancer the combination of paclitaxel, cisplatin and topotecan is feasible. However, this treatment requires the use of Filgrastim and attenuated dosing of topotecan in both a 5-day and 3-day topotecan infusion schedule.

Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer.Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]).Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD.Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.

The objective of this study was to evaluate the ability of a preoperative serum CA125 to predict whether optimal debulking (OD) could be achieved for patients with stage III and IV epithelial ovarian cancer (EOC). The records of consecutive patients who underwent primary surgery for EOC at Indiana University Hospital between January 1997 and January 2003 were reviewed. Eligibility criteria included FIGO stage III/IV disease, surgery by gynecologic oncology faculty, preoperative CA125, and an operative note clearly defining volume of residual disease. The Medcalc software statistical package was used to generate a receiver-operating characteristic (ROC) curve. Two hundred and eighty-nine cases of stage III/IV EOC were identified, of which 164 met the eligibility criteria. Serum CA125/=400 was associated with OD/=75% of the time. Conversely, OD was achieved in/=40% of patients with CA125/=4500. The area under the ROC curve for CA125 was .670. The OD rate for those with and without ascites was 49% and 79%, respectively (P0.001). In a multivariate analysis using CA125, age, and ascites, the area under the curve was 0.686. We conclude that preoperative serum CA125 did not reliably predict OD in patients with stage III-IV EOC.

Objective To estimate the antitumor activity of 9-aminocamptothecin (9-AC) in patients with recurrent platinum-"resistant" ovarian cancer; and to determine the nature and degree of toxicity of 9-AC in this cohort of patients. Methods A multicenter phase II study was conducted by the Gynecologic Oncology Group (GOG). Patients were to receive 9-AC (colloidal dispersion) 25 μg/m 2 /h (600 μg/m 2 /day) IV over 120 h (5 days) beginning days 1 and 8. Dose adjustment was permitted for toxicity. This schedule was repeated every 21 days until disease progression or unacceptable adverse events. Hematopoietic growth factor support was used as necessary. Results From January 1999 to December 2000, 29 member institutions of the GOG enrolled 58 patients. Two patients received no therapy; thus, 56 (97%) were evaluable. Median age was 61 (range: 33–81) years. A median of four (range: 1–32) courses of 9-AC was administered. The most frequent grade 3 or 4 toxicities were neutropenia in 46%, leukopenia in 37%, gastrointestinal in 29%, anemia in 25%, and thrombocytopenia in 21%. There was one possible treatment-related death. There were four (7%) complete and four (7%) partial responses, for an overall response rate of 14%. Eighteen (32%) patients had stable disease, 22 (39%) progressed, and response could not be assessed in 8 (14%). Conclusion The 9-AC at this dose and schedule showed limited activity comparable to that seen with other agents in platinum-resistant ovarian or primary peritoneal cancer.

Early-stage cervical cancer is unique among malignancies in that two radically different yet equally efficacious treatments can be offered to most patients with the disease. The choice between surgery and radiation therapy depends on the patient's age and comorbidities, tumor factors, physician bias, and discussion of the risks and benefits of each modality. A thorough discussion between the physician and patient is necessary to determine the optimal management for each individual. This review discusses the major factors that influence physician and patient management choices.

Bladder injuries occur in approximately 1.6% of all laparoscopic procedures. Most often, these injuries are recognized intraoperatively or immediately postoperatively because of gross hematuria. We report two cases of bladder injury related to placement of suprapubic laparoscopic trocars that were not recognized at the time of surgery and in which no gross hematuria was evident. In each case, the patient had a history of abdominal surgery, and the diagnosis was difficult to make. The treatment was prolonged catheterization in one patient and laparotomy through a midline incision in the other. Strategies are discussed for minimizing the risk of bladder injury during laparoscopic trocar placement and for diagnosing and treating injuries.

Every gynecologist must have a thorough understanding of the gastrointestinal (GI) tract. Problems of the GI tract will often present as gynecologic complaints. In addition, many gynecologic problems have related GI symptoms. Finally, the GI tract must be considered in the pre-, intra-, and postoperative management of most gynecologic operations. Many ofthe intraoperative and postoperative complications of gynecologic operations involve the GI tract. Awareness ofthe relationship ofthe bowel to gynecologic disorders and procedures, appropriate preoperative evaluation in order to establish the differential diagnosis, and diagnosis and management of complications involving the GI tract are crucial to the pelvic surgeon.

To establish the location of the transverse colon in relationship to the umbilicus, and determine if it varies as a function of patient height or weight.Retrospective review of computed tomograms (CT) of the abdomen (Canadian Task Force classification II-2).University hospital.Sixty-seven women with normal abdominal anatomy.Review of abdominal CT scans.The relative relationships of the transverse colon and umbilicus were compared with age, height, weight, and body mass index (BMI = kg/m2) using multiple regression analysis. Average location of the superior margin of the transverse colon was 4.6 cm (95% CI 3.5-5.7 cm) above the umbilicus. In nine (13%) women it was below the umbilicus. The colon was below the umbilicus in 25% of nonobese women (BMI25 kg/m2).Because the transverse colon lies below the umbilicus in more than 10% of women, injury to it may be an uncommon yet unavoidable complication of laparoscopy.

Objective. The objective was to determine whether, when compared with traditional dietary advancement, early oral intake following major gynecologic surgery leads to a reduction in the length of hospitalization. Methods. Patients undergoing major abdominal gynecologic surgery were invited to participate in this study. After informed consent was obtained, they were randomized to one of two groups. The control group (group 1) was treated traditionally. Oral intake was initiated only after documentation of bowel function, which was defined by two of the following three criteria: (1) bowel sounds; (2) flatus or bowel movement; and (3) subjective hunger. Those assigned to the study group (group 2) were given a clear liquid diet on postoperative day 1. Once 500 cc was tolerated, a regular diet was given. Patients were evaluated on a daily basis for bowel sounds, flatus, bowel movement, hunger, nausea, vomiting, and need for nasogastric tube decompression. The groups were compared with regard to length of hospital stay, length of postoperative ileus, and incidence of adverse effects including nausea, vomiting, and postoperative complications. Statistical analyses were performed with the Student t and χ 2 tests. Results. The demographic characteristics of the control ( N = 47) and study groups ( N = 49) were similar, with no significant differences in underlying medical conditions, prior abdominal surgery, or diagnosis of a malignancy. The groups did not vary statistically in the number of subjects who required postoperative antiemetics or postoperative biscodyl suppository. There was a statistically significant reduction in the length of hospitalization for those patients on the early feeding regimen. The average length of stay for group 1 was 4.02 days ± 0.30 (SEM), while that for group 2 was 3.12 days ± 0.16 ( P = 0.008). While there was a significantly higher incidence of emesis in the study population, this was not associated with any untoward outcome, and this group actually tolerated a solid diet nearly one full day earlier (2.72 days ± 0.14 vs 1.88 days ± 0.14, P Conclusions. Early postoperative oral intake results in a decreased length of hospitalization and is well tolerated when compared with traditional dietary management in patients undergoing abdominal surgery on a university gynecologic oncology service.

Objective This two-stage phase II study was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma (EMC). Methods Eligible patients had persistent or recurrent EMC after receiving 1–2 prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status≤2. Treatment consisted of bevacizumab 10mg/kg every other week and temsirolimus 25mg IV weekly until disease progression or prohibitory toxicity. Primary end points were progression-free survival (PFS) at six months and overall response rate using RECIST criteria. Results Fifty-three patients were enrolled. Forty-nine patients were eligible and evaluable. Median age was 63years, and prior treatment consisted of one or two regimens in 40 (82%) and 9 (18%), respectively. Twenty (41%) received prior radiation. Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment. Two gastrointestinal–vaginal fistulas, one grade 3 epistaxis, two intestinal perforations and 1 grade 4 thrombosis/embolism were seen. Three patient deaths were possibly treatment related. Twelve patients (24.5%) experienced clinical responses (one complete and 11 partial responses), and 23 patients (46.9%) survived progression free for at least six months. Median progression-free survival (PFS) and overall survival (OS) were 5.6 and 16.9months, respectively. Conclusion Combination of temsirolimus and bevacizumab is deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC. However, this treatment regimen was associated with significant toxicity in this pretreated group. Future study will be guided by strategies to decrease toxicity and increase response rates.

Ascites in epithelial ovarian cancer (EOC) promotes tumor development by mechanisms that are incompletely understood. Lysophosphatidic acid (LPA), a major tumor-promoting factor in EOC ascites, is an enzymatic product of autotaxin (ATX) and phospholipase A2 (PLA2)enzymes. The contribution of PLA2 activities to ovarian tumorigenesis was investigated. The quantitative measurement of PLA2 activities in ascites and tissues, as well as assay conditions selective for PLA2 subtypes, were optimized and validated. PLA2 activities correlated with tumor-promoting activates in cell-based and in vivo assays. High activities consistent with both cytosolic and calcium-independent PLA2 were found in human EOC ascites for the first time. Elevated PLA2 and ATX activities were also observed in EOC compared to benign tumors and normal tissues. Cell-free and vesicle-free (S4) human EOC ascites potently promoted proliferation, migration, and invasion of human EOC cells in a PLA2-dependent manner. LPA mediated a significant part of the cell-stimulating effects of ascites. S4 ascites stimulated tumorigenesis/metastasis in vivo, and methyl arachidonyl fluorophosphonate was highly effective in inhibiting EOC metastasis in mouse xenograft models. PLA2 activity was found in conditioned media from both EOC cells and macrophages. Collectively, our work implies that PLA2 activity is a potential marker and therapeutic target in EOC.— Cai, Q., Zhao, Z., Antalis, C., Yan, L., Del Priore, G., Hamed, A. H., Stehman, F. B., Schilder, J. M., Xu, Y. Elevated and secreted phospholipase A2 activities as new potential therapeutic targets in human epithelial ovarian cancer.

Objectives There is a lack of knowledge about the health care events experienced by individual patients that lead to a definitive diagnosis of ovarian cancer (OC). The goal of this study was to describe the various pathways and to identify an optimal path to accurate diagnosis. Methods Women who were referred to gynecologic oncology for a suspected OC were enrolled to this study. Medical records (MRs) from all health care providers were obtained from the time the patient recalled first suspecting a health issue through the time of diagnosis to build a decision tree model. A Monte Carlo simulation was conducted of 83,000 patients to identify the optimal pathway to reach diagnosis. Results In the Monte Carlo simulation, gynecologic oncologists and gynecologists accounted for the most efficient diagnosis in over 37.9% and 29.2% of suspected OC cases, respectively, in terms of the least amount of time to reach diagnosis. Gynecologic oncologists were further associated with the fewest health care visits needed to reach diagnosis in 37% of the simulation cases; however, 23% of trials were indifferent to any specific provider. Conclusions The decision tree provides a more comprehensive view of the complexity in reaching an accurate diagnosis of OC. This analysis was able to identify the health care utilization patterns that underlie the events that occur to reach an accurate diagnosis in the setting of a suspected OC, and was able to identify the most efficient pathways that utilize the fewest health care resources in the least amount of time.

This trial determined the efficacy and tolerability of sorafenib and weekly topotecan in patients with platinum-resistant ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC).Primary endpoints were maximum tolerated dose of sorafenib with weekly topotecan (phase I) and response rate (phase II). Secondary endpoints were progression free survival (PFS), overall survival (OS), toxicity, and rate of clinical benefit. Eligibility included recurrent platinum-resistant OC or PPC,3 prior regimens, normal end-organ function. 3+3 dose escalation was used for phase I, sorafenib being tested at 400mg and 800 mg orally daily. Topotecan dose was reduced from 4 mg/m(2) to 3.5mg/m(2) IV weekly. The phase II regimen was sorafenib 400mg daily and topotecan 3.5mg/m(2) weekly on days 1, 8, 15 of a 28 days cycle.16 patients were enrolled in phase I and 14 patients in phase II. Median age was 52.5 years (range 35-79), 27 patients had OC, and 3 PPC. Median number of cycles administered was 2.5 (0-15). There were 5 partial responses (PR) (16.7%), and 14 patients (46.7%) with stable disease (SD). Four PRs were recorded during phase I and 1 during phase II. One of those PRs occurred in a patient with platinum-sensitive disease. Grade 3/4 toxicities included leukopenia/neutropenia (23%), thrombocytopenia (17%), anemia (10%), fatigue, nausea, vomiting (7% each). One case of grade 3 hand-foot syndrome was recorded.The combination of sorafenib and topotecan causes significant toxicity, precluding administration of full doses and resulting in modest clinical efficacy in platinum resistant OC or PPC.

Objectives The aim of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of whole abdomen radiation as a chemosensitizer of weekly docetaxel for women with recurrent epithelial ovarian fallopian tube, or peritoneal cancers. Patients and methods Women were enrolled on one of three dose levels of docetaxel (20, 25, or 30mg/m 2 ) administered weekly with concurrent low-dose whole abdominal radiation given as 60cGy bid 2days weekly for a total of 6weeks. Results Thirteen women were enrolled and received 70 weekly treatments of docetaxel in combination with radiation therapy. At the first dose level, docetaxel 25mg/m 2 , grade 3 fatigue and thrombocytopenia were observed. At the next dose level, docetaxel 30mg/m 2 , grade 3 febrile neutropenia, grade 4 thrombocytopenia with epistaxis, and grade 3 diarrhea were observed. Given these dose-limiting toxicities, a lower dose of docetaxel 20mg/m 2 was administered and found to be tolerable. No objective responses were observed among the 10 patients with measurable disease; however, the median progression-free survival (PFS) in all patients was 3.3months, and 3 of the patients with measurable disease were free of tumor progression after 6months (30%; 90% confidence interval 8.7–61%). Conclusions Twice weekly low-dose whole abdomen radiation during weekly docetaxel 20mg/m 2 was well-tolerated. Given the PFS demonstrated in these women with resistant ovarian cancer, further study of whole abdominal radiation and concurrent chemotherapy may be warranted.

BACKGROUND: Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of low-dose decitabine combined with carboplatin in patients with recurrent, platinum-resistant ovarian cancer. METHODS: Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28-day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m2 (7 patients) or 20 mg/m2 (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE-1 repetitive element) and gene-specific DNA methylation. RESULTS: Dose-limiting toxicity (DLT) at the 20-mg/m2 dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m2. The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1-2. One complete response was observed, and 3 additional patients had stable disease for ≥6 months. LINE-1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer-associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15. CONCLUSIONS: Repetitive low-dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA-hypomethylating) activity, justifying further testing for clinical efficacy. Cancer 2010. © 2010 American Cancer Society.

Purpose: To review our institutional experience in the treatment of primary vaginal cancer and identify predictors for outcome, in particular, recurrence rate. Materials and Methods: We retrospectively reviewed the charts of 45 patients identified as having primary squamous cell cancer and adenocarcinoma of the vagina and recorded information regarding both patient and tumor characteristics and treatment modalities. Treatment modalities included surgery and radiation with or without chemotherapy (6 patients), radiation alone (30 patients), and chemoradiation (9 patients). Then, univariate and multivariate analyses were used to identify factors, which predicted for recurrence. Kaplan-Meier survival curves were also generated. Results: The median follow-up time for all surviving patients was 5.8 years (range, 9-146 months). The mean and the median minimum tumor doses were 7300 cGy. The 5-year overall survival rate was 71%, and the 5-year progression-free survival rate was 77%. The 5-year overall survival rates by stage were carcinoma in situ with microinvasion and stage I, 92%; stage II, 82%; and stages III and IVA, 20% (P = 0.0005). The 5-year progression-free survival rates by stage were carcinoma in situ and stage I, 92%; stage II, 88%; and stages III and IVA, 30% (P = 0.00049). Of the factors analyzed, only stage predicted for a statistically significant increased risk for recurrence (P = 2.23E-0.05). Conclusions: Early-stage vaginal cancer can be successfully managed with radiation therapy with excellent rates of local control and survival. Patients with stages III and IV disease have a very poor outcome, and more aggressive therapies need to be investigated. Given the limited number of patients treated with chemotherapy and radiation, no definitive conclusions can be made regarding the impact of combined therapy in the management of this disease.

Purpose To estimate antitumor activity and toxicity of weekly topotecan hydrochloride in patients with persistent or recurrent cervical carcinoma who failed prior treatment. Patients and methods Women entered on study had or failed one prior chemotherapy regimen in addition to radiosensitizing chemotherapy, performance status less than 3, and adequate hematologic, renal, hepatic, and neurological function. Topotecan was infused at 3.0 mg/m 2 on days 1, 8, and 15 every 28 days. Results Twenty-seven patients were enrolled onto this study with 25 evaluable. Twenty-two patients had received radiation and chemotherapy prior to study. A median of two and mean of three courses of chemotherapy was given (range, one to eight courses). The most frequently severe adverse events were grade 3 anemia (28%) and grade 4 (4%) along with grade 3 neutropenia (8%) and grade 4 (8%). Two patients had grade 4 thrombocytopenia. There were no complete or partial responders. Ten patients (40%) had stable disease, twelve (48%) had increasing disease, and response could not be assessed in three (12%). The median progression-free survival was 2.4 months for the patients with increasing disease and 6.2 months (3.5–8.8 months) for those with stable disease. Disease location was equally divided within and outside the irradiated field. The 12 patients with increasing disease were more likely to have disease outside the pelvic radiation field. Conclusion There were no complete or partial responders to weekly topotecan among the 25 patients in this study.