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Ovarian cancer is highly curable when diagnosed early as localized disease. Most women come to medical attention, however, with metastatic disease. For these women, cure rates are quite low; only 30% of patients with late-stage high-grade serous ovarian cancer (HGSOC) will live more than 5 years. Although initially sensitive to platinum-based chemotherapy, in most cases, drug resistance develops and a progressive disease course ensues. Therefore, in order to improve prognosis and overall survival, there is an urgent need to understand the basis of drug resistance and to identify new therapeutic targets. Previous studies have stressed the significant role that tumor heterogeneity and microenvironment have in clinical outcome. It is our goal to understand the genomics of metastatic lesions as compared to primary lesions, to identify the genetic drivers of metastasis and drug resistance, which we can then functionally investigate in order to develop novel therapies. Corresponding primary and metastatic tumor tissue samples from women with HGSOC were analyzed by single-cell RNA-seq. Isolated cells from each paired tissue sample were processed for next-gen sequencing using the BioRad droplet digital SEQ Single Cell Isolator and the Illumina SureCell Whole Transcriptome Analysis 3’ library prep kit, Normalization of expression, clustering of cells and gene expression markers defining each cluster was done by using the Seurat package in R. To identify specific tumor cell subsets in intra- and inter-patient analyses, a graph-based clustering using the principal components of the most variable expressed genes and T-distributed stochastic neighbor embedding (tSNE) analyses was performed. Overall, we have found that while there is considerable heterogeneity among primary tumor cells from different patients, the expression profiles of metastatic lesions from different patients are remarkably similar, and are distinct from the primary lesions. As one example, by single-cell RNA-seq paired analysis of HGSOC primary tumor and corresponding metastatic lesions from 2 patients (primary fallopian and primary ovarian), we identified several cell clusters based on gene expression of common cellular markers. Further analysis identified significant expression of CD24, EPCAM, and KRT18 in epithelial cells of primary tumors while elevated CD44 expression was found in the T and B cell clusters of the metastatic lesions. Published studies have suggested elevated CD44 as a prognostic marker of poor overall survival. Whether elevated CD44 expression influences survival in our patients remains to be determined since clinical response data are not yet available. Additional analysis of gene expression profiles in other cell clusters is in progress. Our ability to study patient-derived primary tumor and corresponding metastatic lesions using high-throughput single-cell analysis represents an unprecedented unique opportunity to study ovarian cancer without a priori knowledge of tumor and stromal cell inter-relationships. The single-cell assessment of patient-derived samples can provide critical information needed to understand chemoresistance commonly observed in high-grade serous ovarian cancer. Citation Format: Andrew Shih, Andrew Menzin, Jill Whyte, John Lovecchio, Anthony Liew, Houman Khalili, Kenan Onel, Peter Gregersen, Annette Lee. Single-cell RNA-seq analysis of primary tumor and corresponding metastatic lesion in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A32.

An in vitro chemoresponse assay may aid effective therapy selection in epithelial ovarian cancer (EOC). This study explores changes in chemoresponse between paired primary and recurrent EOC tumors.RESULTS from metachronous tumors were examined in 242 patients. Changes in in vitro chemoresponse, measured by the area under the dose response curve (AUC) between paired tumors were assessed.A significant increase in AUC was identified in most first-line therapies over time. No significant difference was observed in most recurrent therapies. When the elapsed time between occurrences was17 months, no difference was observed for any recurrent therapies, and half of first-line therapies exhibited significant increases in AUC. When ≥17 months, all 7 therapies showed significant increases.These results suggest an increase in chemoresistance over time, which is more pronounced for first-line therapies. This is consistent with clinical observations and suggests the biologic concordance between assay results and response to chemotherapy.

e17058 Background: Dose-dense chemotherapy is increasingly more utilized in the adjuvant treatment of patients (pts) with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (EOC), as compared to the conventional q3 week chemotherapy regimen. The safety and tolerability of the dose-dense regimen in pts ≥65 yrs old has not been well studied. We performed a retrospective analysis of pts with stage II-IV EOC treated at our institution with either regimen. Methods: We identified pts with stage II-IV EOC treated at Northwell Health from 2010-2015 who received adjuvant chemotherapy with the dose-dense (carboplatin q3 weeks/weekly paclitaxel) or the conventional (carboplatin and paclitaxel q3 weeks) regimen. Pts who received IP chemotherapy were excluded. Demographics, adverse events (AEs), dose delays/reductions and efficacy outcomes were evaluated. Results: 38 pts received conventional chemotherapy (median age 68 yrs) and 29 pts received dose-dense chemotherapy (median age 61 yrs). There were no differences in the frequency of grade ≥3 hematologic toxicities b/w the two arms. There were no differences in delayed or missed doses between the two arms but a higher proportion of dose reductions in the dose-dense arm ( P= 0.0472). Among pts treated in the dose-dense arm, 87.5% of women < 65 yrs old had at least one grade ≥3 AE when compared to 38.5% of women ≥ 65 yrs old ( P= 0.0161). There were no differences in dose delays, dose reductions, or missed doses when compared by age in the dose-dense arm. In the dose-dense arm, stage III-IV pts < 65 yrs old had a median time to progression (TTP) of 13.0 mo (95% CI, 6.7-13.8) and a median overall survival (OS) of 48.3 months (95% CI, 11.5-48.3). Pts ≥ 65 yrs old had a median TTP of 10.9 mo (95% CI, 8.7-12.7) and median OS of 35.9 mo (95% CI, 30.8-not reached). There was no difference in TTP ( P= 0.2154) or OS ( P= 0.9260) between the two cohorts. Conclusions: Our institutional experience of administering dose-dense adjuvant chemotherapy to women with EOC suggests that this regimen is likely safe in women ≥ 65 yrs old, with similar efficacy outcomes and should be considered for this population. Further study with larger sample sizes and in prospective trials is warranted.

Purpose : To determine if postoperative external pelvic radiation (EBRT), without vaginal brachytherapy, is sufficient to prevent vaginal cuff and pelvic recurrences in patients with surgical Stage I endometrial adenocarcinoma (ACA). Methods and Materials : The records of 122 patients with surgical Stage I endometrial cancer were reviewed. There were 87 patients with ACA who received EBRT alone and are the subject of this study. Their radiation records were reviewed. All patients underwent exploration, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH BSO), and pelvic and paraaortic lymph node sampling. They were staged according to the FIGO 1988 surgical staging system recommendations. Postoperatively, pelvic EBRT was administered by megavoltage equipment using four fields, to a total dose of 45 to 50.4 Gy. Actuarial survival and disease free survival were calculated according to Kaplan-Meier Method. Results : Twenty-seven patients with Stage IA Grade 1 or 2 ACA with less than one-third myometrial invasion, who did not receive EBRT, and eight patients with histology other than adenocarcinoma (i.e., serous papillary, mucinous, etc.) were not included in the study. For the remaining 87 patients who are in the study group, the median follow-up was 52 months (range : 12-82 months). The 5-year overall survival for these 87 patients was 92%, with a disease-free survival of 83%. There were no tumor recurrences in the upper vagina or in the pelvis. Two patients developed small bowel obstruction (no surgery required), and one patient developed chronic enteritis. Conclusion : Adjuvant external pelvic radiation, without vaginal brachytherapy, prevents pelvic and vaginal cuff recurrences in surgical Stage I endometrial ACA.

e17070Background: MicroRNAs (miRNA) have been established as key regulators of tumor gene expression as well as prime biomarker candidates for clinical phenotypes. We analyzed the regulatory structure of miRNAs and their colocalized gene targets in EOC tissue to construct a regulatory signature for clinical prognosis. Methods: FFPE blocks of primary EOC tumor tissue with > 80% tumor cells were selected for 20 patients (stage ≥ IIc) for whom follow up data was available. Expression levels of mRNA and miRNA were assayed separately. An integrated analysis was performed to identify miRNA/mRNA regulatory clusters. Gene set enrichment analysis (GSEA) was carried out on the coexpression of putative miRNA target genes, from the miRTarBase database, with their respective miRNAs, to identify enriched categories for each miRNA. MiRNAs with at least one significantly enriched category from the MSigDB C2 dataset at a false discovery rate of 0.05 were chosen. For each enriched category of each miRNA, a regulon was defi...

Objective To describe a technique for image-guided percutaneous insertion of peritoneal ports in patients without ascites who have undergone surgical debulking for stage III ovarian cancer. Materials and Methods Between 2006 and 2010, 29 intraperitoneal ports were placed percutaneously in 29 patients who presented after debulking surgery for stage III ovarian cancer. Ultrasound and fluoroscopy guidance were used to assist in the port placement. Results We demonstrated a technical success rate of 100% in 29 patients. The ports remained in place for an average of 186 days; and during that time, only 2 complications (6.9%) arose. One patient presented with kinking and looping of the catheter/port reservoir connection, and the redundant loop was removed. The other patient presented with a suspected wound infection over the port pocket, and the port was removed. Conclusions Placement of percutaneous intraperitoneal ports is feasible with an acceptably low complication rate of 6.9% in patients without abdominal ascites.

Radical therapy for locally advanced or recurrent gynecologic malignancies (LARGM) may include intestitial brachytherapy (IB) when intracavitary brachytherapy is impossible or inadequate and external beam teletherapy would be limited by surrounding normal tissue tolerance. Sixteen women received IB as all or part of their treatment at North Shore University Hospital for the treatment of locally advanced primary or recurrent tumors of gynecologic origin from May 1988 through September 1990. Primary sites included the vulva (3), vagina (2), cervix (7), and endometrium (4). Radiosensitizing chemotherapy was used in 8 patients. With a median follow-up of 23 months (range, 12–44 months), 11 patients (69%) have experienced continuous local control of their tumor and 4 patients (25%) have experienced severe complications. While significant risks may attend the use of IB, IB is an integral part of management for select patients with LARGM.

Struma ovarii are specialized teratomas consisting of thyroid tissue with various microscopic features, ranging from benign to malignant. We report a rare form of malignant struma ovarii, composed exclusively of a follicular variant of papillary thyroid carcinoma with capsular invasion, which occurred in a 65-yr-old woman.

The ageing of the population has resulted in a greater emphasis on cancer treatment effects in elderly patients. This population has often had arbitrary dose modification of chemotherapy owing to fear of excessive side-effects. A review was undertaken to evaluate cisplatin toxicity in patients of 70 years of age or older. Thirty-four patients were evaluated. Their mean age was 72.8 years and 85.3% were women. Fourteen of 34 (41%) patients completed the planned therapy. Treatment was terminated because of disease progression (35%), renal toxicity (9%) and non-renal toxicity (15%). Our conclusion is that cisplatin can safely be administered to elderly patients. Arbitrary dose modification or elimination of cisplatin from a treatment programme on the grounds of patient age alone is not justified.

Objective. The objective of this study was to review the current practice patterns regarding the surgical management of borderline ovarian tumors. Methods. A one-page survey was mailed to the members of the Society of Gynecologic Oncologists (SGO), using the directory of the Society. The survey addressed the demographics of the respondent and the recommended staging procedure for presumed early-stage disease. Results. Of the 660 surveys mailed, 274 (42%) were returned. Ninety-seven percent (267/274) of respondents advocate surgical staging. Of this group, 96% (257/267) perform peritoneal washings, 97% (259/267) sample the omentum, and 92% (245/267) submit random peritoneal biopsies. Eighty-eight percent (235/267) perform lymph node sampling: paraaortic biopsies by 89% (210/235) and pelvic biopsies by 97% (228/235). Of this latter group, 91% sample the external iliac chain, 82% submit hypogastric nodal tissue, and 70% remove obturator lymph nodes. Conclusion. Diversity exists in the surgical management of borderline ovarian tumors among members of the SGO who responded to this survey. Efforts to ensure a consistent approach to the management of borderline ovarian tumors are warranted.

Struma ovarii are specialized teratomas consisting of thyroid tissue. They may demonstrate all pathologic features seen in the thyroid gland. Malignant transformation of thyroid tissue in struma ovarii is uncommon and is rarely recurrent or metastatic. We report the diagnosis and treatment of a recurrent struma ovarii with malignant transformation, and intraperitoneal, retroperitoneal, and hepatic metastases.

A case of myxoid sarcoma of the Bartholin gland occurring during pregnancy is reported. This neoplasm possessed pathologic features consistent with a high-grade malignancy. The patient underwent a wide reexcision of the clinically negative operative site 8 weeks post partum, and no residual evidence of sarcoma was identified. In spite of this, a local recurrence occurred 10 months later. This was reexcised, and localized electron beam teletherapy was administered.

A unique case of a 50-year-old woman is reported who presented with a suburethral mass in the anterior vaginal wall. The resected tumor was an adenoid cystic carcinoma arising from Skene's glands. Tumor was not involving Bartholin's glands. In addition to the typical glands and areas with cysts containing periodic acid-Schiff positive intraluminal material, less well-differentiated areas with neoplastic cells growing in a trabecular or solid pattern were also seen. Prominent perineural invasion was noted throughout the tumor. Immunostaining revealed positive reactions for cytokeratins, carcinoembryonic antigen, and focally for S-100 protein. Ultrastructural studies showed epithelial cells with well-formed basal lamina and prominent microvilli. This case illustrates an uncommon site, the Skene's glands for adenoid cystic carcinoma in the female genitourinary tract.

5056 Background: To determine if an age group exists for which interval cytoreductive surgery (ICS) in patients with suboptimal residual disease at primary surgery influences progression free survival (PFS) and overall survival (OS) among women with advanced ovarian cancer treated on GOG 182. Methods: GOG 182 was a prospective, randomized trial of first-line chemotherapy in patients with advanced ovarian cancer. Patients with both optimal and suboptimal residual disease were included, and those with suboptimal residual were considered for ICS, with intent registered and stratified prior to randomization. Patients were randomized to one of five chemotherapy arms, employing combinations of either two or three agents delivered intravenously, with a control arm of paclitaxel and carboplatin. A retrospective analysis was approved by the GOG Ancillary Study Committee to investigate the influence of age on treatment and outcomes. In that analysis, Cox regression was used to identify independent prognostic factors and estimate their covariate effects on the adjusted PFS and OS of patients with suboptimal residual disease. Statistical significance was set at p 1 cm) and 109 of these patients elected to undergo ICS. Hazard ratios (HR) were determined for patients undergoing ICS with reference to patients with suboptimal disease not undergoing ICS. Based on the most current follow-up data, the HR for progression or death was not statistically different between the groups, but the HR of death alone was significant at 0.72 (95% CI: 0.57–0.92, p=0.008). There was no significant association of age with ICS in either the PFS or the OS model. Conclusions: In this trial, a patient’s age did not influence the effect of ICS on PFS or OS. There is no demonstrable benefit in PFS associated with ICS, but there was a statistically significant improvement in OS. To elucidate this finding, further study is warranted, likely in the form of a meta-analysis incorporating data from other prospective trials.

5057 Background: To determine if an age group exists for which the interval from surgery to the initiation of chemotherapy influences progression free survival (PFS) and overall survival (OS) among women with advanced ovarian cancer treated on GOG 182. Methods: GOG 182 was a prospective, randomized trial of first-line chemotherapy in patients with advanced ovarian cancer, including those with optimal and suboptimal residual disease. Patients were randomized to one of five chemotherapy arms, employing combinations of either two or three agents delivered intravenously, with a control arm of paclitaxel and carboplatin. Chemotherapy was to be initiated within 12 weeks of primary surgery. A retrospective analysis was approved by the GOG Ancillary Study Committee to investigate the influence of age on treatment and outcomes. In that analysis, Cox regression was used to identify independent prognostic factors and estimate their covariate effects on the adjusted PFS and OS of the study population. Statistical significance was set at p

5030 Background: GOG182 proved that the incorporation of a third cytotoxic agent to carboplatin and paclitaxel (C+P) did not improve overall survival (OS) or progression-free survival (PFS) for pat...

Only 2 of 125 patients with FIGO stage IB invasive squamous or adenocarcinoma of the cervix 3 cm or less in diameter who underwent exploration for radical hysterectomy, bilateral pelvic lymphadenectomy, and para-aortic node sampling had metastases to the para-aortic nodes. No patient had gross para-aortic nodal involvement, and both patients with microscopic para-aortic nodal metastases had grossly positive pelvic nodal involvement. Para-aortic node sampling in patients with small stage IB cervical cancers undergoing radical hysterectomy may be restricted to patients with suspicious pelvic or para-aortic nodes.

MRI of 54 patients with endometrial and cervical carcinoma was performed on a 0.6-T superconducting magnet. In 18 of 24 cases of surgically proved endometrial carcinoma, MRI accurately showed the depth of myometrial invasion. MRI was superior to CT scan for defining the primary site and extent of the tumor in 14 of 24 cases. Of 25 patients with cervical carcinoma studied, MRI was superior to CT scan in 15 of 19 cases with CT correlation for localizing the primary site. MRI showed parametrial extension and invasion of surrounding structures but is probably less reliable than CT scan for detection of adenopathy because of false positive findings from volume averaging with bowel.

A detailed study of salicylate binding to human serum albumin was undertaken because of the widespread use of the drug, its deleterious effect on fetal development (in the laboratory animal) and its well-documented adverse effects on neonatal well-being. Serum was obtained from 82 patients during each trimester of pregnancy, labor, 4 days and 6 weeks post partum. Equilibrium dialysis at 4 degrees C was carried out utilizing therapeutic levels of C-labeled sodium salicylate. Scatchard plots were employed to translate the data into association constants (k') which characterized the binding affinity between salicylate and albumin. At the primary binding site, the mean k' values were: controls (nonpregnant females) 40, first trimester 32, second trimester 28, third trimester 26, labor 15.5, 4 days post partum 18.4, and 6 weeks post partum 37.6 X 10 M. These results demonstrate a decrease in the binding affinity between salicylate and serum albumin as pregnancy proceeds to the puerperium, at which time the binding affinity increases to near control values at 6 weeks post partum. The transplacental concentration of free (unbound) salicylate would be readily available for transplacental transport to exert an effect upon fetal receptors. The changes found may be attributable to competitive or allosteric binding of endogenous compounds such as hormones, characteristic of the normal physiology of pregnancy.

MRI of the perirectal region is facilitated by the superb soft tissue contrast, multiplanar imaging capability, lack of respiratory motion artifact and absence of clip artifact which can hamper visualization by CT scan. MRI provides distinct advantages over CT scanning without the need for ionizing radiation or the injection of intravenous contrast material. This study reviews the findings in 18 consecutive patients with a variety of perirectal pathologies including rectal carcinoma (3), gynecologic neoplasm (8), sacral lesions (2), pelvic arteriovenous malformations (2), inflammatory bowel disease (2), and a pelvic kidney (1). In the perirectal region, MR was useful to show normal tissue planes, benign processes which can mimic neoplasm, intrapelvic extension of malignancy and adenopathy.

From 1969 to 1981 thirty-six patients with stage IB and IIA cervical carcinoma were identified at pretherapy surgical staging laparotomy with histologically documented metastatic disease to the periaortic lymph nodes. All patients underwent a periaortic node dissection and all patients completed a course of extendedfield radiotherapy in a postoperative setting. No major radiotherapeutic complications were encountered. The 5-year actuarial survival rate was 50%, with a median survival time of 29 months. The median time to recurrence was 10 months, while the median duration of survival following a recurrence was 7 months. Seventy-five percent of all recurrences occurred at distant sites. These data demonstrate that survival may be favorably influenced by employing extended-field radiotherapy in those patients with early-clinical-stage cervical cancer and periaortic nodal metastases. The subsequent development of distant metastases after such a treatment regimen emphasizes the need for adjuvant cytotoxic chemotherapy to enhance overall survival.

Four cases are described of acute peripheral arterial occlusion associated with surgery for gynecologic cancer during the 5 years 1979 to 1983 at the University of Miami, Jackson Memorial Hospital Center. No such cases were recorded during the preceding 5 years. The probable underlying etiologic factors are discussed and recommendations made regarding the evaluation and management of such patients.