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Purpose:Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer.Patients and Methods:Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib.Results:A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9–9.9) vs. 7.3 months (5.6–8.2); HR 0.63 (95% CI, 0.38–1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%).Conclusions:Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

Supplementary Figure 3

Supplementary Figure 1

We implemented a low-cost education initiative to improve the rate of same-day discharge following hysterectomy performed for malignancy and assessed feasibility and impact on resource utilization.Development and implementation of faculty, patient, clinical, and perioperative staff education regarding the goal of same-day discharge for patients undergoing robotic hysterectomy and staging by gynecologic oncologists was started in July 2019. Chart review of 103 patients prior to the intervention and 112 patients after the start of the intervention was completed.The rate of same-day discharge increased from 5% to 32% following the low-cost process change initiative, and a total of approximately 682 inpatient care hours were saved per 31 patients.The rate of same-day discharges after hysterectomy and staging performed by gynecologic oncologists can be safely increased with a simple educational intervention, which can save significant patient care resources.

Completion of genetic testing is increasingly important for the complex care of patients with suspected hereditary breast and ovarian cancers (HBOC) and their at-risk family members. Identification of individuals with pathogenic variants has implications for targeted treatment recommendations, risk reduction strategies, increased surveillance recommendations, as well as the genetic testing of family members, known as cascade testing or screening. Due to advances in technology and decreasing costs, what was once single-gene genetic testing has evolved into large-scale multi-gene panel genomic testing. As germline genomic testing for HBOC becomes more and more available, it is important to identify the challenges that are associated with its use. In this manuscript, we review the current issues faced by germline genomic testing for HBOC which include effectively managing the marked increases in genetic referrals, interpreting the vast amount of information yielded by newer testing methods such as next generation sequencing (NGS), recognizing the need for better cascade screening strategies, potential exacerbation of health disparities and improving support for patients navigating the emotional impact related to positive, negative and indeterminate testing results.

Purpose: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer. Patients and Methods: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib. Results: A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9–9.9) vs. 7.3 months (5.6–8.2); HR 0.63 (95% CI, 0.38–1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%). Conclusions: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies. Although initial response to therapy is observed, recurrence and ultimately chemoresistance result in overall therapeutic failure. This pattern has been evident with platinum therapy since the 1980s. Significant excitement surrounded the approval of poly (ADP-ribose) polymerase inhibition (PARPi) as a novel therapeutic option, especially with the advent of personalized medicine, but resistance has similarly developed to these treatments. Novel agents are constantly being sought, but if the obstacle of chemoresistance remains, the durability of responses will remain tenuous. Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured. Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes.

ObjectiveTo identify factors that affect successful adaptation of sentinel lymph node mapping and those that lead to unintended adipose-only sentinel lymph node identification.MethodsSurgical and pathological data were prospectively collected on patients with endometrial cancer who underwent sentinel lymph node mapping with indocyanine green with or without pelvic and/or para-aortic lymph node dissection between November 2013 and April 2017. All mapping cases were performed with the robotic system. Adipose-only specimens were defined as a sentinel lymph node without a pathologically identified lymph node after ultrastaging.ResultsA total of 202 patients were included: 83% had endometrioid pathology, 12% serous, 3% carcinosarcoma, and 2% clear cell, with mixed pathology noted in 2%. The bilateral sentinel lymph node detection rate was 66%, and the rate of mapping at least a unilateral sentinel lymph node was 86%. Neither the bilateral nor the unilateral sentinel lymph node mapping rate changed with increased surgeon experience. The rate of adipose-only sentinel lymph node identification was more frequent when comparing the first 10 cases (37%), cases 11 – 30 (28%), and > 30 cases (9%) (P = 0.006). Body mass index > 30 kg/m2, uterine fibroids, The International Federation of Gynecology and Obstetrics (FIGO) grade, and histology were not found to have a statistically significant impact on either sentinel lymph node identification or adipose-only sentinel lymph node identification. Adipose-only sentinel lymph nodes were more likely with increased time from cervical injection to identification of the sentinel lymph node in the right hemipelvis. The median range was 28 min (14–73) for true sentinel lymph node identification vs 33 min (23–74) for adipose-only sentinel lymph node identification (P = 0.02).ConclusionPatient and surgeon factors did not impact the identification of sentinel lymph nodes over time. Adipose-only sentinel lymph nodes were more frequently identified in the initial cases and represent a potential complication to adapting sentinel lymph node biopsy without lymphadenectomy. The increase in adipose-only sentinel lymph node identification that was associated with time from cervical injection may represent delayed or disrupted uptake of indocyanine green.

5510 Background: Patients with metastatic recurrent endometrial cancer have limited effective therapies. Single agent pembrolizumab is utilized in mismatch repair deficient (MMRd) patients, while the combination of lenvatinib and pembrolizumab is now more commonly used in MMR intact patients who have progressed after chemotherapy combinations. This trial investigated a novel three drug regimen. Methods: Patients with recurrent endometrial cancer not amenable to curative intent surgery or radiation after one or two lines of therapy were eligible regardless of histology. This study is a multicenter, open-label, nonrandomized phase II trial. All subjects initially received the three-drug combination of rucaparib, bevacizumab, and atezolizumab. The primary goal of this trial was to estimate the overall response rate in these patients, and secondarily to estimate the progression-free and overall survival of patients treated with this triplet combination. Total enrollment was 30, with the first six subjects participated in a safety lead-in. Treatments until progression, toxicity, or clinician choice. Subjects could continue past progression if, in the estimate of the treating clinician and subject, clinical benefit was being provided. Subjects were eligible for analysis if they received at least one cycle and had one post-dose tumor assessment. The ORR assumption was 27% with a lower bound of 14%. Results: 30 subjects were enrolled between 07/2019 and 06/2021. Of these 26 were evaluable. Median follow up at cut off was 14.9 months. 23 subjects had clinical benefit, with 1 (4%) with CR, 9 (39%) with PR, and 13 (57%) with stable disease as best response. Overall median event-free (progression or death) was 5.3 (95% CI 2.7-7.9) months and overall survival 13.3 (95% CI NA) months at cut off. Median duration of therapy was 4.4 months (IQR 1.7-7.3), with 4 subjects remaining on study directed therapy at data cut off. Histology distribution was 50% serous, 20% endometrioid, and 13% carcinosarcoma. 19 pts were White, 8 African American, 2 identified as Asian, 1 unknown. In the MMR deficient patients, event-free probability was 11.9 months. Grade 3 or 4 treatment related adverse events occurred in 50% patients. Conclusions: To our knowledge, this trial represents the first use of a non-chemotherapy-based triplet therapy for recurrent endometrial cancer. The combination of rucaparib, bevacizumab, and atezolizumab may safely be used to treat recurrent/persistent endometrial cancer. This combination demonstrates clinically meaningful improvement in response, with acceptable toxicity. Enhanced response to therapy was seen in MMR deficient subjects. Clinical trial information: NCT03694262.

Objectives: Enhanced Recovery After Surgery (ERAS) protocols have been developed for several surgical fields based off the available evidence to improve patient surgical outcomes with shortened recovery to return of baseline function. The ERAS® Society 2019 preoperative guidelines for gynecologic oncology give a “strong” recommendation for written and verbal preoperative patient education with “moderate” data to support this; however, the recommendation remains vague as to how this should be implemented. We hypothesized patient satisfaction related to their disease state, treatment plan, and hospital course would be improved after implementation of a standardized written preoperative education protocol in addition to traditional oral education for patients undergoing laparotomy with the gynecology oncology faculty at the Medical College of Wisconsin. Secondarily, we hypothesized that enhanced patient education preoperatively could positivelyimpact patient length of stay, emergency department admissions, nursing calls, and readmission rates following surgery. Methods: Based on the ERAS Society recommendations, our practice initiated a pilot program to improve our perioperative patient education. In collaboration with our clinic nurses, providers and inpatient nursing staff we revised all of our patient perioperative instructions which address the surgical procedure, expectations prior to surgery, expectations during hospital admission and post- operative instructions including activity limitations, pain management, bowel management and issues of concern during recovery from surgery. We obtained Institutional Review Board (IRB) approval. We compared two groups of patients undergoing laparotomy. The Standard Group received the standard patient education: the current oral and written education that had been utilized in the clinic. The Enhanced Group received the enhanced patient education material after all providers and staff had undergone education regarding the changed process. The enhanced patient education process provided consistent written instructions in addition to the oral instructions communicated by the team. In addition, at the time of discharge standardized post-operative instructions were printed and provided to the patient. During July 2019-Dec 2019, 15 patients who underwent standard preoperative instructions were included in the pilot initiative and comprised the Standard Group. During Jan 2020 - June 2020, 17 patients were included in the pilot as the Enhanced Group. All patients included in the pilot completed the EORTC QLQ-INFO 25 validated survey at the time of discharge or at their post-operative visit. Results: Patient satisfaction scores, as quantified by items 31-55 of the EORTC QLQ-INFO 25 survey, showed improvement in patient satisfaction with the possible causes of their disease after protocol implementation (p=0.03). There was also a reduction in the number of patient nursing calls following surgery (p=0.035). There was no difference between groups regarding length of stay, emergency department visits or readmission rates. Conclusions: Consistent printed and oral perioperative patient education is an effective measure that can positively impact patient satisfaction as well as staff satisfaction (personal communication). Additional ERAS measures may need to be implemented to impact perioperative patient emergency room visits, length of stay and readmission rates.

Introduction STRO-002 is a novel FRα-targeting ADC that delivers SC209, a potent tubulin-targeting hemiasterlin cytotoxin-warhead. Methods All patients in the ongoing dose escalation study (NCT03748186) had platinum resistant/refractory OC without selection for FRα expression. STRO-002 is given IV on Day 1 of each 21-day cycle. Results 38 patients have been dosed at 9 dose levels (0.5 to 6.4 mg/kg). Median number of cycles given is 3 (1–18). Median age is 61 (48–79). Median prior therapies - 5 (2–10). Clinically active doses (≥ 2.9 mg/kg) have been administered to 33 patients. 21/33 (64%) remain on treatment. Partial response was seen in 5 of 29 evaluable patients (17%) with 2 confirmed on second scan. 9 pts have confirmed SD for a clinical benefit rate of 48% (14/29). CA125 reduction of >50% was seen in 14/22 (64%) evaluable patients per GCIG. Clinical activity appears to be durable with 36% and 24% on study >16 and >24 weeks, respectively. 88% of AEs are grade 1 or 2. Grade 3–4 neutropenia, an expected and reversible effect of STRO-002 occurred in 15/38 (39%). DLTs reported – grade 3 neuropathy (6.0 mg/kg) and grade 3 bone pain (6.4 mg/kg). Conclusions STRO-002 is a novel FRα-targeting ADC with a promising emerging safety and efficacy profile and preliminary clinical benefit/disease control rate of 48% in patients with relapsed/refractory OC treated at ≥ 2.9 mg/kg. No ocular toxicity signals have been observed, suggesting potential differentiation from other FRα-targeting investigational therapies. Expansion cohorts in less heavily pre-treated patients are planned for 4Q20.

Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizesFollowing safety run-in, this double-blind phase II trial (NCT01357161) randomized women withA total of 121 patients were randomized to adavosertib (A+C;Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

Objectives: To determine impact and cost savings of a quality intervention involving enhanced patient, provider, and staff education focused on same day discharge after robotic assisted total hysterectomy, and/or bilateral salpingo-oophorectomy with sentinel and/or additional lymph node dissection. Methods: A quality project was undertaken at our institution to improve the rate of same day discharge after robotic assisted hysterectomy and to assess the resource utilization savings of such an intervention. Literature supports feasibility and safety of same day discharge for robotic assisted hysterectomies alone or with other procedures for benign and malignant indications. Complex robotic assisted hysterectomies include bilateral salpingo-oophorectomy plus sentinel or additional lymph node resection. We collected historical data via chart review for the 12 months of 2018 (Group A) to determine our baseline same day discharge rate for complex robotic hysterectomies. Faculty, outpatient clinic and perioperative clinic staff were provided with education regarding the same day discharge goal for complex robotic assisted hysterectomies for patients from a single institution in our gynecologic oncology practice. We then prospectively collected the outcome data on patients undergoing complex robotic hysterectomies for the subsequent 12 months in 2019 (Group B). We compared demographic, clinical factors, and factors of resource utilization such as time in surgery and recovery and length of admission. Descriptive statistics and t-test were utilized to compare the groups. Results: One hundred three patients underwent complex robotic assisted hysterectomy in 2018, and 5% (5 patients) were discharged home on the day of surgery (Group A). One hundred twelve patients underwent complex robotic assisted hysterectomy in 2019 (Group B), and 32% (36 patients) were discharged home on the day of surgery. There was no significant difference between mean age (62 vs 64) or BMI (37 vs 36) in the two cohorts, respectively. Median length of stay was 21 hours for patients that were not discharged on day of surgery and 3.5 hours for patients discharged day of surgery. Of the 41 total patients undergoing same day discharge (Group A + Group B), there was one urgent care visit, one ER visit and and no readmissions in 30 days post procedure. A savings of approximately $1975 per case when patient discharged day of surgery. By promoting same day discharge after robotic assisted hysterectomy, 648 in-patient care hours were saved during the 12 months post intervention. Conclusions: A low cost patient and provider education initiative to increase same day discharge after robotic hysterectomy in gynecologic oncology patients positively impacted cost and resource utilization without negatively impacting readmission rates and ER utilization. In 12 months, the same day discharge rate in one facility was increased from 5% to 32% of robotic hysterectomy cases.

Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as nonadherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis, and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent and nonadherent conditions in vitro and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in adherent and nonadherent cells. EGFR or ERBB2 upregulated ZEB1 in nonadherent cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of integrin β1, integrin-α V, and integrin-α 5 for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1, and caused the transition of adherent cells to nonadherent cells. Strikingly, the combinatorial treatment with lapatinib [dual kinase inhibitor of EGFR (ERBB1) and ERBB2] and thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single-agent treatment in vivo. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells. Significance: This study describes the mechanism exhibited by ovarian cancer cells required for adherent cell transition to nonadherent form during peritoneal spread and metastasis.

Objective: To report a patient with the hyperparathyroidism-jaw tumor syndrome (HPT-JT) who was found to have a rare ovarian tumor (granulosa cell tumor &lsqb;GCT]). HPT-JT is caused by pathogenic variants in the CDC73 gene and results in primary hyperparathyroidism (PHPT), benign fibro-osseous jaw tumors, benign or malignant renal tumors and cysts, and benign or malignant uterine tumors. We believe this is the first reported case of HPT-JT and GCT.Methods: The patient was a 31-year-old woman with abdominal pain who was found to have adult GCT. Her history was significant for a single gland parathyroidectomy at age 23 for PHPT. Her mother also had PHPT with 1-gland removal, as well as a history of renal cysts. Because of the personal and familial history of PHPT, she underwent germline sequencing of genes associated with PHPT including CASR, CDC73, CDKN1B, MEN1 and RET.Results: Genetic testing revealed a CDC73 gene pathogenic variant (c.687_688dupAG) which creates a premature translational stop signal causing loss-of-function.Conclusion: We report a case of ovarian GCT in a young patient with primary hyperparathyroidism and a CDC73 gene mutation. Ovarian granulosa cell tumor may be another CDC73-related tumor.Abbreviations: GCT = granulosa cell tumor HPT-JT = hyperparathyroidism-jaw tumor syndrome IHC = immunohistochemistry PHPT = primary hyperparathyroidism

5550 Background: STRO-002-GM1 is a Phase 1, open-label study in patients (pts) with advanced, platinum resistant or refractory EOC. STRO-002 is a novel FRα-targeting ADC with a precise DAR of 4 using site-specific conjugation technology to circumvent limitations of current ADCs. STRO-002 induces immunogenic cell death and contains the tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is a weak substrate for P-gp. Methods: STRO-002 is given IV on Day 1 of each 21-day cycle until disease progression. Ocular exams are performed at baseline and every other cycle. Prophylactic corticosteroid eyedrops are not administered. FRα expression was not required for eligibility and retrospective analysis of FRα expression in archival tumor tissue is ongoing. Results: Enrollment has been completed with 39 pts treated at 9 dose levels (0.5 to 6.4 mg/kg). Data cut-off is Jan 30, 2021. Median age was 61 years (range 48-79). Median number of prior systemic therapies was 6 (range 2-11). 86% of treatment emergent adverse events (AEs) were Grade 1-2. The most common treatment related Grade 3 and 4 AEs were reversible neutrophil count decreased (36%) and neutropenia (33%), Grade 3 arthralgia (12.8%) and neuropathy (7.7%). Two pts developed neutropenic fever that resolved with antibiotic therapy. 34 pts were treated at clinically active doses (≥ 2.9 mg/kg) and 31/34 are evaluable for RECIST 1.1 response. Objective responses were seen in 10/31 pts - 1 CR, 4 confirmed PR, and 5 unconfirmed PR (imaging studies under review in 1 pt with uPR). Disease control rate (CR+PR+SD) is 74% at ≥ 12 weeks and 61% at ≥ 16 weeks. 5 pts remain on treatment with 3 ongoing at > 74 weeks. FRα-expression results are available in 14 pts treated at ≥ 2.9 mg/kg with 50% low, 21% medium and 29% high FRα-expressing tumors per PS2+ scoring algorithm. 12/13 pts with H-scores of ≥ 105 achieved disease control with PR or SD. Maximum plasma concentrations of STRO-002 were achieved at the end of the 1 hour infusion and exposure increased in an apparent dose proportionate/linear manner. Conclusions: STRO-002 is a novel FRα-targeting ADC with an encouraging emerging safety and efficacy profile in heavily pretreated relapsed/refractory EOC. No ocular toxicity signals have been observed. Durable responses and anti-tumor activity have been demonstrated across a broad range of FRα expression levels in evaluable pts treated at ≥ 2.9 mg/kg. 48% (15/31) of pts were on treatment without disease progression for ≥ 24 weeks and 13% (4/31) remain on treatment for over a year, suggesting that STRO-002 is well tolerated in long-term responding patients. A randomized expansion cohort comparing STRO-002 at 4.3 mg/kg vs 5.2 mg/kg dose levels in less heavily pretreated EOC pts is ongoing. Clinical trial information: NCT03748186.

Objective Endometrial cancer is the most common gynecologic cancer and yet much is still unknown about this disease. Our goal was to identify unique biomarkers of disease by performing a comprehensive proteomic analysis of early stage, low-grade endometrial cancer through analysis of serum collected from patients pre- and post-definitive surgery. Methods We used mass spectrometry (MS)-based proteomics to identify serum proteins from these patients. Serum samples from women undergoing hysterectomy with bilateral salpingo-oophorectomy for benign reasons served as control samples for the correlative studies. We then correlated our findings with The Cancer Genome Atlas (TCGA) database for additional confirmation. Results The Ingenuity Pathway Analysis of proteins that were differentially expressed in endometrial cancer showed increased cell survival and decreased organismal death, the most common hallmarks of cancer. We identified over expression of FAM83D (family with sequence similarity 83, member D) in the serum of patients with early stage low-grade endometrial cancer and verified the same in the endometrial cancer cell lines and patient tumors. We also confirmed our hypothesis that FAM83D may serve as a biomarker for endometrial cancer in a cohort of patients with endometrial cancer from The Cancer Genome Atlas (TCGA) project. Conclusion Comprehensive proteomic analysis is a feasible strategy for potential biomarker identification. Using this technique, FAM83D was identified as a candidate biomarker in early endometrial cancer in our patient samples and was not present in benign control samples. FAM83D has been associated with poor clinical outcomes in several human malignancies. Significance Our manuscript describes an alternative approach to comprehensive protein analysis in a model pre and post tumor removal for a sample of patients with early endometrial cancer. The model is innovative and the findings of over expression FAM83D in this population of early cancer may be useful in the study of a disease where there are few biomarkers or targetable therapies.

To determine the incidence of lower-extremity lymphedema after surgical therapy including lymphadenectomy in endometrial cancer patients using standardized leg measurements. Also, to determine additional risk factors for the development of lymphedema and to study the effect of lymphedema on one's quality of life. In this prospective cohort study, patients with the diagnosis of endometrial cancer who were to undergo definitive surgical management were evaluated pre-operatively and followed post-operatively over the course of two years. Standardized leg measurements were performed by the same individuals at six time-points. Subjects also completed a standardized quality-of-life survey at each time-point. The incidence of lymphedema in 39 women with endometrial cancer using a standardized leg measurement protocol was 12.8% with lymphedema defined as a 20% increase in post-operative leg measurements. There was no significant association between the development of lymphedema and the number of pelvic or para-aortic lymph nodes removed, medical comorbidities, or surgical approach (p > 0.05). Of the five patients who met criteria for lymphedema, only one had worsening quality-of-life concerns post-operatively on the FACT-En, version 4, survey. This is the first prospective study using standardized leg measurements to calculate the incidence of post-operative lymphedema in endometrial cancer. Medical comorbidities, surgical approach, number of lymph nodes removed, and location of lymph nodes removed did not appear to affect the development of lymphedema in this cohort. A prospective, multicenter trial is needed to confirm these findings and to further assess the impact of lymphedema on one's quality of life., Highlights • We found the incidence of lymphedema in endometrial cancer to be 12.8%. • This is the first prospective study using standardized leg measurements to do so. • Medical comorbidities, surgical approach did not affect development of lymphedema. • The number/type of lymph nodes removed did not affect the development of lymphedema.

Introduction: FRα is overexpressed in 80% of OC and endometrial carcinoma (EC), with minimal expression in normal tissues. STRO-002 is a novel FRα-targeting ADC designed to circumvent limitations of current ADCs. STRO-002 was generated with Sutro’s cell-free antibody production system (XpressCF™) and site-specific conjugation (XpressCF+™) platform, which uses the non-natural amino acid pAMF. STRO-002 has a drug-antibody ratio (DAR) of 4 and contains the proprietary tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is rapidly cleared and a weak substrate for efflux pumps. STRO-002 demonstrated potent cytotoxic activity in multiple FRα-positive tumor cell lines and significant therapeutic efficacy in OC xenograft models. Toxicology studies demonstrate dose-dependent and reversible neutropenia when STRO-002 is administered to cynomolgus monkeys. No ocular toxicity was observed. Herein we report additional preclinical efficacy in PDX models and preliminary safety experience of STRO-002 in patients (pts) with OC. PDX model methods: FRα expression was evaluated in EC PDX models by IHC. Single agent efficacy of 10 mg/kg STRO-002 was assessed in models with negative, low (+), medium (++) and high (+++) FRα expression. Phase 1 trial methods: STRO-002-GM1 is a first-in-human Phase I, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) in pts with advanced, relapsed or refractory OC and EC. STRO-002 is given IV over an hour on Day 1 of each 21-day cycle until disease progression. Results: Statistically significant efficacy was observed in 60% of the FRα-positive PDX models tested, with STRO-002 response appearing to positively correlate with FRα expression levels. Though high FRα PDX models showed the highest response rates, some models with low and medium FRα also exhibited good responses. 5 pts with OC have completed at least one cycle (21 days) of STRO-002 at 3 dose levels: 0.5, 1.0, and 1.8 mg/kg and are evaluable for safety and toxicity. Median age is 63 (r, 52-64). Median ECOG performance status is 0 (r, 0-1). Median # of prior therapies is 6 (r, 2-8). Four pts have received PARP inhibitors. Median number of STRO-002 doses administered is 2 (r, 1-5). 3 additional pts have been treated at the 2.9 mg/kg dose level and continue in the first cycle. No grade ≥ 3 treatment-related adverse events (TRAEs) have been observed. 93% of AEs are grade 1 or 2. The most common TRAEs in ≥20 % of pts includes nausea, vomiting, abdominal pain, fatigue and insomnia. Four grade 3 events occurred in 2 pts after completion of the first cycle and were related to disease progression, including small intestine obstruction, gross hematuria, dehydration and vomiting. 2 pts have discontinued due to disease progression. 6 pts remain on treatment and dose escalation is ongoing. Conclusions: STRO-002 is the first ADC generated with cell-free protein synthesis technology and site-specific conjugation of a novel hemiasterlin linker-warhead to be tested in pts with solid tumors. The potent anti-tumor activity of STRO-002 in PDX models further supports the clinical development of this agent. The preliminary safety profile in 5 OC pts treated with STRO-002 is encouraging. MTD has not been reached, no DLTs have been observed and dose escalation is continuing. Updated results will be presented. This study is registered with clinicaltrials.gov identifier NCT03748186. Citation Format: Denise Uyar, Russell J Schilder, R Wendel Naumann, Fadi S Braiteh, Erika Hamilton, Sami Diab, John Moroney, Richard T Penson, Jennifer Smith, Cristina Abrahams, Michael Palumbo, Venita DeAlmeida, Shannon Matheny, Arturo Molina. Antitumor activity of STRO-002, a novel anti-folate receptor-α (FRα) antibody drug conjugate (ADC), in patient-derived xenograft (PDX) models and preliminary phase I dose escalation safety outcomes in patients with ovarian carcinoma (OC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C095. doi:10.1158/1535-7163.TARG-19-C095

Objective To evaluate the efficacy and tolerability of cabozantinib in recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer. Methods Patients with recurrent ovarian, fallopian or primary peritoneal tumors with at least 50% clear cell histomorphology, measurable disease, one or two prior regimens and ECOG performance status 0–2 received cabozantinib 60 mg orally once daily continuously, in 4-week cycles until disease progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) at six months and complete or partial tumor response (as assessed by RECIST 1.1). Secondary endpoints included toxicity, PFS, and overall survival (OS). Results Over 19 months, 13 patients were accrued. Fifty-four percent of patients were ≥60 years of age. Performance statuses of 0 and 1 comprised 8 and 5 patients. No objective tumor responses were seen. Three (23% [95% CI: 5%, 54%]) of 13 patients had PFS ≥6 months, including one patient who received cabozantinib for 23 cycles and was still on treatment as of the data cut-off date. Median PFS and OS were 3.6 and 8.1 months, respectively. There was one patient with a grade 5 event: a thromboembolic event considered possibly related to study therapy; patient's cause of death was determined to be due to disease and protocol treatment. Four other patients had thromboembolic events (two grade 3 and one each grade 1 and grade 2). Other grade 3 or higher events reported in two or more patients were nausea, vomiting, fatigue, dyspnea, and dehydration. Conclusions Cabozantinib demonstrated minimal activity in the second- and third-line treatments of clear cell ovarian, fallopian tube or primary peritoneal carcinoma.

Objective The National Comprehensive Cancer Network recommends all women with ovarian cancer be offered genetic testing. Despite a decade of endorsement, many oncology practitioners have yet to make this a part of routine practice. Referral to genetic counseling and completion of genetic testing among patients at substantial risk of germline mutations are significantly lacking, adversely affecting patient care and squandering an opportunity to maximize cancer prevention efforts. This project determined the impact and feasibility of implementing a basic model for universal referral to genetic counseling and completion of genetic testing in women with a diagnosis of ovarian cancer in an academic gynecology oncology practice with access to electronic health records (EHRs). Methods Patients diagnosed with ovarian cancer from January 2008 to November 2013 were retrospectively reviewed to determine the baseline referral rate for genetic counseling and testing completion in our practice. Implementation of a process change model combining provider training , patient education , enhanced electronic health record documentation and improved patient appointment scheduling strategies were implemented. We then prospectively collected data on all newly diagnosed ovarian cancer patients that had not already undergone genetic testing presenting from December 1, 2013 to November 30, 2016. Results Genetic referral rates, genetic counseling and testing completion rates were markedly improved. Pre-implementation our genetic testing rate was 27% and post implementation our testing rate was 82% (p-value≤0.001). Conclusions Low cost interventions that target education of both providers and patients regarding the importance of genetic testing along with utilization of the EHR and streamlined patient appointment services can significantly increase rates of genetic testing completion.

Background: Folate receptor alpha (FolRα) is overexpressed in 80% of epithelial ovarian cancer (EOC) and endometrial adenocarcinoma (EC), with minimal expression on normal tissues and is thus a relevant target for cancer therapy using antibody drug conjugates (ADCs). STRO-002 is a novel, site-specific FolRα-targeting ADC that was generated using Sutro’s XpressCF+™ cell free protein synthesis platform. STRO-002 has highly specific cytotoxic activity on cells expressing FolRα. STRO-002 demonstrated reproducible and significant therapeutic efficacy in multiple preclinical models in vivo. STRO-002 activity was evaluated in EC patient-derived xenograft (PDX) models with a range of FolRα expression. Statistically significant efficacy was observed in 60% of the FolRα-positive PDX models tested, with response appearing to positively correlate with FolRα expression levels. Toxicology studies in cynomolgus monkeys demonstrate dose-dependent and reversible neutropenia when STRO-002 is administered at up to 9 mg/kg, with no evidence of ocular toxicity (Solis et al. AACR 2019). Methods: This study is a first-in-human Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), recommended phase 2 doses (RP2D) and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-002 in adults with ovarian cancer and endometrial cancer who are refractory to, or intolerant of, therapies known to provide clinical benefit. STRO-002 is given to all patients on study via intravenous infusion on Day 1of each 21-day cycle until disease progression. Dose limiting toxicities will be assessed in the first cycle (Days 1-21) of dose escalation. Part 1 will enroll about 30 ovarian cancer patients to determine the MTD and RP2D for expansion while Part 2 will enroll 2 cohorts based on disease subtypes (ovarian or endometrial). Efficacy will be evaluated per RECIST 1.1 criteria. Key inclusion criteria include relapsed and or progressive disease, adequate bone marrow and renal function, and ability to comply with treatment, testing and pharmacokinetic (PK) schedules. Key exclusion criteria include clear cell, mucinous or sarcomatous ovarian carcinoma, prior treatment with a FolRα-targeting ADC, need for ongoing immunotherapy including systemic corticosteroids and a history of CNS involvement. Samples will be collected to assess FolRα expression levels, PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US with the ClinicalTrials.gov Identifier: NCT03748186.: Citation Format: Robert Wendel Naumann, Denise S. Uyar, Russell J. Schilder, Michael A. Palumbo, Venita DeAlmeida, Shannon L. Matheny, Arturo Molina. A Phase I, open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-002, an anti-folate receptor alpha (FolRα) antibody drug conjugate (ADC), in patients with advanced epithelial ovarian cancer (including fallopian tube or primary peritoneal cancers) and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT160.

Elderly patients are less likely to receive surgery and platinum-based combination chemotherapy than younger patients. We evaluated multi-institutional management of ovarian cancer in the elderly.Charts of women with ovarian, primary peritoneal or fallopian tube cancer from 1/1996-6/2004, ageor =70 years were reviewed. Age, stage, medical co-morbidities, surgery, chemotherapy, treatment modification, toxicity and survival were analyzed. Chi-square, logistic regression and survival analysis were used.Of 131 patients, 90 were ages 70-79 (group 1 = G1) and 41 were80 years of age (group 2 = G2). Surgery was performed in 80 patients in G1; 25 patients in G2 (P = 0.001). Among patients who underwent surgery, optimal debulking and post-operative complications did not differ between groups. Ninety-five percent of patients received platinum-based therapy and 83% received combination platinum/paclitaxel in G1, compared to 90% and 41%, respectively, in G2 (P0.001). Of those receiving platinum therapy, 36% in G1 and 41% in G2 required dose reductions or termination of therapy. Forty percent of G1 and 50% of G2 required a delay of therapy; the majority occurring in patients receiving combination therapy. Hematological toxicity increased with use of combination therapy, but not with advancing age or Charlson score. Successful debulking surgery significantly impacted survival, and when controlling for this factor, age was not a significant variable.The extreme elderly had a decreased likelihood of receiving surgery and combination chemotherapy despite equivalent co-morbidities. In this analysis, optimal surgical cytoreduction had the greatest impact on survival.

OBJECTIVE: To examine conventional and liquid-based cervical smears falsely diagnosed as malignant at our institution and to investigate, through cytologic-histologic correlation, factors influence ing false positive diagnoses. STUDY DESIGN: Cervical cytologic diagnoses of malignancy from May 1, 1995, to April 30, 2001, were retrieved through a computer search. A retrospective review of hospital records and pathology reports was performed. Cases identified as false positives were reviewed and correlated with histologic follow-up specimens. RESULTS: A group of 68 patients with malignancy reported on cervical smears and with histologic follow-up was identified. Conventional smears numbered 32 (47%); the remaining 36 (53%) were liquid-based samples. Of the total, 7 false positive cases (10.3%) were identified in 4 conventional and 3 liquid-based preparations. Cytologic diagnosis in these cases was squamous cell carcinoma in 5 and adenocarcinoma in 2. On histologic follow-up, all 7 patients were ultimately found to have high grade squamous intraepithelial lesions (HSILs) without invasion. Review of the original slides confirmed most, or all, of the ' following features in all cases: major cellular pleomorphism, extensive cytoplasmic keratinization, intense nuclear pyknosis, background necrosis and severe atrophy. CONCLUSION: There was no significant difference in rates of false positive diagnoses between conventional (12.5%) and liquid-based (8.3%) samples. The chief reason for overdiagnosis in this series was the capacity of HSIL to exfoliate cells mimicking invasive malignancy, particularly when keratinized and especially in an atrophic milieu. The other cause of false positivity was superimposition of inflammation and atypical reparative change on a background of HSIL, which then suggested invasion.

Objectives The predictive value of cervical Papanicolaou (Pap) smears reported as "positive for malignancy," especially those obtained by the liquid-based method, has not been adequately assessed. The objectives of this study are to determine the positive predictive value of Papanicolaou smears with features of malignancy, to compare the accuracy of Papanicolaou smears obtained by the liquid-based method to those obtained by the conventional technique in this setting, and to study the factors influencing a false-positive cytologic diagnosis of malignancy. Materials and methods Pap smears significant for malignant cytology were identified at Fletcher Allen Health Care Hospital in Burlington, VT, from May 1, 1995, to April 30, 2001. A retrospective review of the hospital records and pathology reports was performed documenting patient characteristics, the collection technique, and the final histology. An independent review of the cytology and histology was performed. The positive predictive value and false-positive rate of malignant cytology were calculated for the liquid-based and conventional Pap smear techniques. Results A total of 472,743 Pap smears were performed during the period specified. One hundred four Pap smears were reported as positive for malignancy, yielding a prevalence rate of 0.02%. A total of 68 patients had paired cytology and histology specimens. Malignant cytology was identified in 36 smears obtained by the liquid-based technique and 32 smears obtained by the conventional technique. A true-positive result, meaning malignant cytology confirmed by the presence of invasive carcinoma on histology, was obtained in 61 of 68 (89.7%) patients. A false-positive result, meaning malignant cytology not confirmed by histology, was obtained in 7 of the 68 (10.3%) patients. The false-positive rate of malignant cytology was 8.4% for the liquid-based technique and 12.5% for the conventional technique. All 7 false-positive smears were diagnosed with high-grade dysplasia by histology. Three of the 7 patients with high-grade dysplasia had previous treatment for dysplasia, one of whom was also pregnant at the time of the smear. Conclusions Malignant cervical Papanicolaou smear cytology has a high positive predictive value in the setting of gynecologic and nongynecologic malignancies. Previous treatment for cervical dysplasia or pregnancy may influence the false-positive rate of malignant cytology.

Aberrant expression of SOX4 in endometrial cancer has been identified and partially was contributed to hypermethylation of miR-129-2. Other miRNAs are suspected to influence SOX 4 as well. The current study seeks to identify other hypermethylated miRNAs that regulate SOX4 in endometrial carcinomas.Methylation levels of miRNA promoter regions were measured by combined bisulfite restriction analysis (COBRA) and pyrosequencing assays. Gene expression was determined by RT-qPCR. Methylation level of a miRNA locus was corrected with clinicopathologic factors for 252 gynecological specimens.In silico analysis identified 13 miRNA loci bound on the 3'-UTR of SOX4. Using COBRA assays, increased methylation of miR-203, miR-219-2, miR-596, and miR-618 was detected in endometrial cancer cells relative to those seen in a normal cell line and in normal endometrium. Transfection of a miR-203 mimic decreased SOX4 gene expression. Hypermethylation of miR-203 was detected in 52% of type I endometrioid endometrial carcinomas (n=131) but was not seen in any of 10 uninvolved normal endometria (P0.001). Methylation status of miR-203 was significantly associated with microsatellite instability and MLH1 methylation in endometrial tumors (P0.001). Furthermore, hypermethylation of miR-203 was found in endometrioid and clear endometrial subtype tumors, but not in cervical squamous cell and ovarian carcinomas.Hypermethylation of miR-203 is a frequent event in endometrial carcinomas and is strongly associated with microsatellite instability and MLH1 methylation status. Thus, miR-203 methylation level might represent a marker for patients with endometrioid and clear endometrial sub-cancers.

Cervical cancer represents one of the most common malignancies in women worldwide and predominantly affects women of poor socioeconomic status. Persistent infection with high-risk human papillomavirus (HPV)3 is an essential factor for development of cervical cancer. HPV infection is also associated with cancers of the vulva, vagina, anus, and oropharynx. Globally, an estimated 610 000 (4.8%) of the 12.7 million new cancer cases that occurred in 2008 could be attributed to HPV infection, and >500 000 of those cases represent cancers of the cervix alone (1). Within the last 2 decades, research has culminated in major advances in techniques for cervical cancer screening using HPV DNA and has led to a vaccine to prevent HPV infection. Yet, our strategies for the care and treatment of today's patients already infected with HPV need urgent attention. Women diagnosed with invasive and metastatic cervical cancer are in critical need of more-sophisticated prognostic markers, targeted therapeutic options, and more-accurate surveillance strategies. There are about 120 HPV types, and types 16 and 18 are associated with 70% of the cases of cervical cancer worldwide. Many studies have shown that HPV-18–associated cervical cancer is a strong independent prognostic factor for poorer disease-free survival for women undergoing surgery or radiation for early-stage invasive cervical cancer (2). The biology behind the poorer outcomes is unknown, but studies have suggested that sequence variation in HPV genes produces differences in their oncogenic potential. For example, HPV-18 E6 4 (E6 transforming protein) oncogene variants differentially regulate members of the Akt/P13K pathway and show increased expression of genes involved in cancer cell extravasation and metastasis (3, 4). HPV integration into the host genome is a critical step in cervical carcinogenesis and is found in almost all invasive cervical cancers. Integration frequently disrupts HPV E2 (E2 regulatory protein) gene expression, …

Purpose To report the techniques and initial clinical outcomes for MRI-based adaptive brachytherapy (MRIB-ABT) using 3-T MRI. Methods and Materials All patients who underwent MRIB-ABT between January 2008 and June 2012 for cervical cancer using 3-T MRI for at least three fractions were retrospectively reviewed. The institutional standard for initiation of brachytherapy planning was 100% of dose at point A and 160% at the vaginal surface with five fractions of 500–550 cGy at Point A. The dose distribution was modified to enhance coverage of the high-risk clinical target volume (HR-CTV) and to spare the organs at risk (OAR) by altering dose specification distances around the tandem and the percentage of the Point A dose around the ring or ovoids. Results Eighteen patients (FIGO stages IB = 4, II = 12, III = 1, and IVA = 1) underwent eighty-two 3-T MRI-based insertions. All patients received 3D conformal, external beam radiation (45–50.4 Gy). The median gross tumor volume pretreatment was 38 cm 3 (2–165 cm 3 ) compared with 4.8 cm 3 (1–9 cm 3 ) at the first high–dose rate fraction with a median volume reduction of 88%. Dose specification at the level of Point A was altered in 51% of 3-T MRI fractions from the standard 20 mm (range, 14–18 mm) and in 8% at the ring surface to optimally cover the HR-CTV and spare the OAR. The 2-year local control, disease-specific survival, and overall survival are 100%, 100%, and 93%, respectively. Conclusions MRIB-ABT using 3-T MRI for treatment of cervix cancer allows for customized alterations in dose specification that minimize dose to the OAR and maximize coverage of the HR-CTV.

Smooth muscle tumors of the vulva are rare entities with variable morphologic features and clinical behavior. Our report summarizes the case of a multifocal vulvar smooth muscle tumor of undetermined malignant potential with an unusual intravascular growth pattern and subsequent local recurrence in a 10-year-old girl, the youngest case reported to date, and reviews the specific pathologic findings of that category. Vulvar smooth muscle tumors of undetermined malignant potential represent a diagnostic, prognostic, and therapeutic challenge. The histologic features of this case were predictive of local recurrence, although the significance of the intravascular growth pattern is still uncertain. The relationship of this multifocal, recurrent tumor to the clinical entity, vulvar leiomyomatosis, is unknown at this time.

5506 Background: Data suggest synthetic lethality when TP53-deficient cells are exposed to genotoxic drugs plus the Wee1 inhibitor AZD1775 (MK-1775). AZD1775 plus C was well tolerated in patients (...

Objective . Pegylated liposomal doxorubicin (PLD) is currently utilized in the management of several solid tumors. While PLD has been shown to be less cardiotoxic than doxorubicin, the safety of prolonged administration (e.g., ≥6 cycles) of the agent remains undefined. Methods . A retrospective chart review was performed of the Cleveland Clinic experience from 1997 to 2003 with the prolonged (≥6 cycles) use of PLD in individuals with gynecologic malignancies. PLD was administered at doses ranging from 20 to 40 mg/m 2 (infused over 1–2 h) with treatment repeated every 4–6 weeks. While on therapy, patients underwent routine evaluation for toxicity, including the performance of multigated acquisition (MUGA) scans for determination of left ventricular ejection fraction (LVEF). Results . Twenty-two patients (18 ovarian cancer; 3 primary peritoneal cancer, 1 endometrial cancer) met the criteria for inclusion in this analysis. This population had received a median of 4 (range 1–8) chemotherapy regimens before initiation of PLD. No patient had previously received doxorubicin. The median number of PLD cycles and cumulative dose of LD delivered were 8 (range 6–26) and 483 mg/m 2 (256–1699 mg/m 2 ), respectively. One or more MUGA scans were obtained in 14 (64%) patients. No patient experienced clinical evidence (physical findings, symptoms) of heart failure. There were no dose reductions due to cardiac dysfunction, and no patient experienced a decline in LVEF to Conclusions . Prolonged therapy with PLD is possible in appropriately selected patients with advanced gynecologic malignancies. In this clinical setting, cardiac dysfunction does not appear to be a toxicity, which limits the duration of treatment. The development of evidence-based guidelines for monitoring cardiac function in this patient population would be quite useful.

Genes on human chromosome 18 are associated with familial glucocorticoid deficiency (MC2R), pemphigus vulgaris (DSG3) and foliaceus (DSG1), familial amyloidosis (TTR), colorectal carcinoma (DCC), erythropoietic protoporphyria (FECH), follicular lymphoma (BCL2, FVT1), and congenital methemoglobinemia (CYB5). As the resolution of human genetic maps improves, linkage between other diseases and specific regions of chromosome 18 will occur. A physical map of human chromosome 18 will prove useful in identifying candidate genes that are associated with these disorders. Using various physical and genetic mapping techniques, over 35 genes and 19 expressed sequence tags (ESTs) are assigned to human chromosome 18. Most of these genes and several of the ESTs were sublocalized using a well-defined panel of somatic cell hybrids that contain different segments of human chromosome 18. Despite recent efforts, progress in mapping human chromosome 18 has lagged behind that achieved for other chromosomes. Thus, the purpose of this study was to integrate 9 new transcriptional tags [8 brain ESTs (8) and the melanocortin 4 receptor (MC4R) (3)] and 19 simple sequence repeats (SSRs) into the physical map of human chromosome 18. The SSRs were isolated by screening genomic DNA libraries constructed in M13mp18 vectors with oligonucleotide probes that detected dinucleotide d(CA)- andmore » tetranucleotide-repeat motifs. DNA sequences of clones that contained microsatellite repeats were obtained by thermal-cycle sequencing, and STSs were developed from clones that contained numerous repeats. STSs that identified highly polymorphic loci in eight unrelated CEPH parents were used for genotyping. Results of linkage analyses and estimates of heterozygosity for these markers will be reported. 9 refs., 1 fig., 1 tab.« less