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Purpose We sought to retrospectively examine clinical outcomes for three adjuvant vaginal high-dose-rate (HDR) brachytherapy regimens after hysterectomy for early-stage endometrial cancer. Methods Included were women of all ages from two independent hospital systems diagnosed with Stage I-II endometrial cancer of any grade between 2000 and 2016 who underwent hysterectomy followed by adjuvant vaginal cylinder HDR brachytherapy with either 7.0 Gy × 3 fractions prescribed to 0.5 cm vaginal depth, 6.5 Gy × 3 fractions prescribed to 0.5 cm vaginal depth, or 6.0 Gy × 5 fractions prescribed to the vaginal surface. Outcomes included vaginal recurrence (VR), pelvic recurrence, distant recurrence, locoregional recurrence, recurrence-free survival, and overall survival. Results Of the 348 women, 45 (13%) received 7.0 Gy × 3 fractions, 259 (74%) received 6.5 Gy × 3 fractions, and 44 (13%) received 6.0 Gy × 5 fractions. Women receiving 5-fraction brachytherapy were more likely to be younger with a higher performance status. At a median follow-up of 4.5 years, VR rates were 2.2%, 0.8%, and 4.5%, respectively. Multivariate analysis revealed no significant differences in the risks for VR among brachytherapy regimens. Risks for VR, pelvic recurrence, distant recurrence, locoregional recurrence, recurrence-free survival, and overall survival did not differ between propensity score–matched five- and 3-fraction brachytherapy cohorts. Conclusions VR rates after hysterectomy and adjuvant vaginal brachytherapy for early-stage endometrial cancer were low and not significantly different by HDR dose fractionation.

Objective We aimed to evaluate the relationship between hyperglycosylated human chorionic gonadotropin (hCG-H) and placenta accreta spectrum (PAS) in the second and third trimesters of pregnancy. Study Design This was a case–control study of PAS and controls. hCG-H was measured in the second and third trimesters of pregnancy in women with pathologically confirmed cases of PAS and in gestational age-matched controls without PAS. We compared serum hCG-H levels in cases and controls, calculated summary statistics for diagnostic accuracy, and used receiver operating characteristic (ROC) curves to define an optimal cut-point for diagnosis of PAS using hCG-H. Results Thirty case samples and 30 control samples were evaluated for hCG-H. Mean hCG-H was lower in the case compared with control group (7.8 ± 5.9 μg/L vs. 11.8 ± 8.8 μg/L, p = 0.03). At an optimal cut-point for hCG-H of ≤7.6 μg/L, the sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, and area under the ROC curve were 66.7%, 69.7%, 2.20%, 0.48%, and 0.68%, respectively. Conclusion Hyperglycosylated hCG levels in the second and third trimesters of pregnancy were lower in patients with PAS than in controls, but hCG-H showed only modest capability as a diagnostic test for PAS.

One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). Currently, there are no biomarkers available for predicting a woman’s likelihood of successful progestin therapy. Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy and were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach, a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of genes to reduce spurious results due to samples with outlier expression. Analysis of all samples identified 137 genes significantly associated with outcome. These 137 genes were largely increased in post-treatment samples from progestin responders and were highly enriched for progestogen and estrogen responsive genes, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success. Focusing solely on pre-treatment samples, we identified more variable expression differences across tumors, suggesting multiple reasons for progestin success/failure. We found that the combined expression of estrogen receptor alpha and progesterone receptor was predictive of progestin therapy success. In addition, non-responding tumors had increased expression of several immune-related genes that we are currently exploring. Overall, these results show that progestin therapy response could be predicted using gene expression signatures and that multiple factors may underlie progestin success/failure.

One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). This study aims to identify gene expression signatures indicative of the likelihood of successful progestin therapy. Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy. Samples were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach (Illumina), a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression (DE) analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of DE genes to reduce spurious results due to samples with outlier expression. Gene set enrichment was performed using ENRICHR. Analysis of all samples using DESeq2 identified 843 genes significantly associated with outcome, while Noiseq identified 318 genes, with an overlap between the two methods of 137. These 137 genes were largely increased in post-treatment samples from progestin responders and were enriched for the DSigDB terms “progesterone”, “medroxyprogesterone acetate”, and “estradiol”, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. Additionally, a small gene signature (61 genes) was specifically decreased in post-treatment responders compared to all other groups. This gene set is enriched for the GO molecular function “enhancer binding”, BioPlanet 2019 sets “BMP signaling pathway in stem cells” and “Signaling events mediated by the hedgehog family”. The genes in this set may be related to failure on progestin therapies and surprisingly include both ESR1 (estrogen receptor a) and PGR (progesterone receptor). Analysis of RNA-seq data from our cohort of CAH and EEC samples identified a 137 gene signature post-progestin treatment that indicate successful clinical response. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success. Citation Format: Craig M. Rush, Jeffery M. Vahrenkamp, Kathryn Szczotka, Mark K. Dodson, Elke A. Jarboe, Andrew P. Soisson, Jay Gertz. Identification of differentially expressed genes in primary samples of endometrial hyperplasia and endometrioid endometrial carcinoma responsive to progestin therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO019.

Introduction: Young women with endometrial intraepithelial hyperplasia or low-grade endometrial carcinoma are potential candidates for conservative fertility sparing therapy utilizing progesterone rather than hysterectomy. High-dose progesterone treatment is associated with 55–80% initial response but high relapse rates. Using aromatase inhibitors in conjunction with high-dose progesterone has largely been unstudied. Case descriptions: Three obese premenopausal women with endometrial cancer failed to respond to oral or intrauterine progesterone as first line therapy. Due to their desire to continue to pursue fertility sparing treatment options, an aromatase inhibitor was added to their treatment regimen. This resulted in resolution of their malignancy in each case. Discussion: In obese premenopausal women, the mechanism of malignant transformation in endometrial carcinoma is considered to be an association with relatively high levels of serum estrogen from peripheral conversion of androgens to estrone in adipose tissue with a deficiency in progesterone exposure due to chronic anovulation. Using aromatase inhibitors seems reasonable as an adjunct to progesterone given the high likelihood that this population has a significant proportion of their estrogen production coming from peripheral conversion in adipose tissue. This case series is unique in that each woman initially failed to respond to progesterone but had resolution when an aromatase inhibitor was added to their treatment regimen. This would suggest that obese women with low grade malignancy or hyperplasia who have no radiographic evidence of deep myometrial invasion, ovarian or retroperitoneal metastases and who wish to retain their fertility may be treated with intrauterine progesterone and an aromatase inhibitor., Highlights • Nearly 1/5 women with Endometrial Cancer are of reproductive age. • Progesterone is reasonable treatment for women desiring fertility preservation. • Aromatase inhibitors added to progesterone therapy can result in EC resolution.

To analyze our institutional experience and oncologic outcomes for salvage treatment for the recurrence of early-stage endometrial cancer patients.We included women of all ages diagnosed with FIGO stage I-II, any grade endometrial cancer from 2000 to 2016 at our institutions who were treated with at least a hysterectomy. Recurrences in the pelvis and/or vagina were considered locoregional recurrences (LRR). Overall survival (OS) was assessed using Kaplan-Meier survival analysis. Univariate (UV) and multivariate (MV) Cox proportional hazards modeling was also used.A total of 2691 women were analyzed. The majority had endometrioid histology (91%), stage IA disease (61%), and were grade 1 (57%). With a median follow-up of 6.1 years, the overall rate of recurrence was 7.2%, and the rate of LRR was 3.7%. Women with vaginal-only recurrences had a longer median OS after recurrence (14.0 years) compared to both pelvic (1.2 years) and distant (1.0 year) failures. For women with vaginal-only recurrences, salvage radiotherapy (RT) was the only factor associated with improved OS on MVA (HR 0.1, p = .04). For women with pelvic recurrences, salvage surgery (HR 0.3, p = .01), salvage RT (HR 0.3, p .01), and salvage chemotherapy (HR 0.4, p = .03) were associated with improved OS.Failure rates for women with early-stage endometrial cancer are low. Women with vaginal-only recurrences have improved OS compared to pelvic or distant recurrences. Salvage RT appears to be an important factor for treatment of women with vaginal-only recurrences. Aggressive multimodality treatment may be beneficial for women with pelvic recurrences.

Objectives To explore patterns of communication among families with a Lynch syndrome diagnosis and understand what resources could facilitate family communication. Methods 127 probands (i.e., first person in family with identified mutation) and family members participated in semi-structured interviews about: how they learned about the Lynch syndrome diagnosis, with whom they shared genetic test results, confidence in sharing results with other family members, and helpfulness of educational resources. Results Both probands and family members were most likely to share genetic test results with parents and siblings, and least likely to share results with aunts, uncles, and cousins. Most participants felt very confident sharing their test results with family members, but reported that certain topics such as cancer risk were challenging to convey. Probands reported the most helpful resources to be access to a specialty clinic or website, while family members described general printed materials as most helpful. Conclusions Families affected by Lynch syndrome may experience barriers to communication with more distant relatives, and may benefit from receiving specific resources (e.g., websites about Lynch syndrome, print materials) to facilitate family communication. Practice implications Providers could emphasize the need to share information with more distant family members and provide appropriate supportive resources.

OBJECTIVE Stage II endometrial cancer is relatively uncommon. There is no consensus for appropriate adjuvant therapy in endometrial cancer patients with cervical stromal involvement (International Federation of Gynecology and Obstetrics [FIGO] stage II). This study investigates how adjuvant treatments and tumor characteristics influence overall survival (OS) and disease-free survival (DFS) in stage II patients in order to establish better treatment guidelines. METHODS This multi-institution, Institutional Review Board approved, study is a retrospective review of 40 endometrial cancer patients with cervical stromal involvement treated from 1993 to 2009. Kaplan-Meier estimates were used to evaluate OS and DFS. RESULTS OS was 85% at three years and 67% at five years. There were no significant differences in age, histology, depth of invasion, comorbid conditions, surgical staging or recurrence between patients who received radiation therapy (RT) and those who did not. However, patients with FIGO grade 1 cancers were less likely to receive RT (p=0.007). Patients treated with RT had a similar 5 year OS (n=33, 69%) to those treated with surgery only (n=7, 60%, p=0.746). There were no OS differences when evaluating by grade, histology, or depth of invasion between patients who did and did not receive RT. Four patients recurred: three were locoregional failures only, and one failed locally and distant. CONCLUSION Patients receiving RT had higher grade tumors. Despite this, OS was comparable between the RT and the no RT cohorts. Local failure was the predominant pattern of failure. Endometrial cancer patients with cervical stromal involvement likely receive better locoregional control with the addition of adjuvant RT and we continue to advocate for RT in most cases.

UNLABELLED Approximately 15% of patients with endometrial cancer are premenopausal. Previous studies largely support the conservative treatment of endometrial cancer in women desiring future fertility. From these studies, 75% to 80% of patients demonstrate a complete response to progestin therapy and the average recurrence rate is 30% to 35%. Conservative therapy should be reserved for women with International Federation of Gynecology and Obstetrics grade I tumors. Before conservative management, patients should be informed of the elevated risk (11%-29%) of concurrent ovarian cancer in cases of premenopausal endometrial cancer, and screening and ongoing surveillance during the treatment period is mandatory. A suggestion of myometrial invasion or metastatic disease is a contraindication to conservative management. Individuals meeting criteria for Lynch syndrome testing should be referred to genetic counseling. Fertility treatment should be individualized, and close surveillance is required during treatment. Staging hysterectomy is recommended after the completion of the childbearing period. TARGET AUDIENCE Obstetricians & Gynecologists, Family Physicians Learning Objectives: After participating in this activity, physicians should be better able to select appropriate candidates with endometrial cancer for fertility-sparing treatment. Educate patients with endometrial cancer regarding the risks and benefits of standard of care therapy and conservative therapy and screen appropriate patients for Lynch syndrome.

Purpose To examine the risk of subsequent primary malignancies (SPMs) in women diagnosed with endometrial cancer. Methods and Materials The National Cancer Institute's Survival, Epidemiology, and End Results database was used to determine the risk of SPM after endometrial cancer in 69,739 women diagnosed between 1973 and 2005. Standardized incidence ratios were calculated (observed/expected [O/E]) for SPM sites. Results Median follow-up was 11.2 years, representing 757,567 person-years of follow-up. The risk of SPM was significantly increased for small intestine (O/E = 1.48; 99% confidence interval [CI], 1.03–2.05), colon (O/E = 1.16; CI, 1.09–1.24), vagina (O/E = 2.71; CI, 1.86–3.8), and urinary bladder (O/E = 1.41; CI, 1.25–1.59) SPMs and decreased for oral cavity and pharynx (O/E = 0.75; CI, 0.6–0.93), lung and bronchus (O/E = 0.78; CI, 0.72–0.84), and esophagus (O/E = 0.58; CI, 0.37–0.86) SPMs. Patients receiving external-beam radiotherapy for endometrial cancer had an increased risk of colon ( p p p = 0.04), and soft-tissue ( p = 0.014) SPMs. Patients treated with brachytherapy had an increased risk of bladder SPM ( p = 0.006). A positive bidirectional association with endometrial cancer was observed for colorectal cancer, with a negative bidirectional association for oropharyngeal and lung cancers. Conclusions Genetic, environmental, and treatment-related factors influence SPM risk. Genetic factors may contribute to the increased risk of colorectal cancer. Smoking's negative effect on endometrial cancer risk factors might explain the decreased risk of lung and oropharyngeal cancer. Patients treated with radiotherapy likely have a small but significantly increased risk of bladder, vagina, colon, and soft-tissue SPM.

To compare the efficacy of electrocautery with that of the suture method for achieving hemostasis of the cervical cone bed.We performed a retrospective chart review of all patients who underwent cold-knife conization of the cervix over a 5-year period. Patients were categorized into two groups: the cautery group, in which the cone bed was electrocauterized with a hand-held electrocoagulation device; and the suture group, in which hemostasis was achieved by a continuous locking suture placed circumferentially around the cone bed. Outcome measures evaluated include estimated blood loss, operative time, and incidence of complications, including secondary hemorrhage, cervicitis, and cervical stenosis. Data were analyzed by Student t test, chi(2) test, linear regression, and multiple logistic regression where appropriate.There were 156 women in the cautery group and 35 in the suture group. The cautery group had significantly lower estimated blood loss (27 mL versus 101 mL; P.01) and shorter operative time (34 versus 43 minutes; P.01) than the suture group. The procedure-related complication rate was 6.4% in the cautery group, compared with 14.3% in the suture group (P = nonsignificant). A higher use of lateral sutures, vasopressors, and thrombotic agents was seen in the cautery group. However, even after adjusting for these variables, mean estimated blood loss (33 mL, P.01) and mean operative time (34 minutes, P.01) were significantly less in the cautery group than in the suture group.Cauterization of the cone bed is superior to suture as a method of achieving hemostasis, with significantly less blood loss and shorter operative time.

The appearance of endometrial cancer in adolescence is uncommon and warrants investigation for an hereditary cancer syndrome. Cowden syndrome is an autosomal dominant cancer syndrome associated with a germline PTEN mutation and increased risk of breast, thyroid, endometrial and colon cancer. In this report we present a case of a 14-year-old nulligravid female diagnosed with grade 1 endometrial adenocarcinoma. She subsequently developed fibrocystic breast disease and colon polyps and was diagnosed with Cowden syndrome at age 20. We therefore recommend formal evaluation for Cowden syndrome to be considered when endometrial cancer is diagnosed in adolescence.

Objective: The objective of this study was to determine if the surgeon can accurately predict the depth of myometrial tumor invasion in women with endometrial cancer, and if tumor invasion will correlate with node metastases. Methods: We identified 1,943 women with endometrial carcinoma who underwent hysterectomy. Of these, 295 underwent comprehensive surgical staging including lymph node analysis. All subjects also underwent gross examination of the uterine specimen by their surgeon where the depth of myometrial invasion was recorded. Patients with grade III tumors or papillary serous and clear cell histology were excluded. The presence or absence of myometrial invasion was then correlated with the incidence of nodal involvement to determine if this system can be used to predict tumor spread at the time of hysterectomy. Results: The ability of the surgeon to accurately predict the depth of myometrial invasion was 82%, sensitivity was 57%, specificity 89%, positive predictive value 62% and the negative predictive value was 88%. If this system was used as the indication for nodal evaluation the authors would have missed 3% of women with nodal metastases who had less than 50% myometrial invasion. Conclusions: Gross evaluation of the hysterectomy specimen can accurately predict depth of myometrial invasion. However, in our analysis 3% of women with less than 50% invasion had node involvement. If the surgeon had used the absence of myometrial invasion to omit nodal assessment, these lesions would have been missed. Therefore, we feel that nodal assessment should be considered in the majority of cases.

Endometrial cancer patients with positive serosa and/or adnexae (FIGO stage IIIA) have a variable prognosis and are at a significant risk for recurrence. We investigated how tumor characteristics and adjuvant treatments influence the overall survival (OS) and recurrence patterns in these patients and patients with positive cytology alone (previously classified as stage IIIA before 2009).This multi-institution retrospective study reviewed 55 patients with positive serosa and/or adnexae and 18 patients with positive cytology only, surgically staged from 1990 to 2010. The study cohort was evaluated using the Kaplan-Meier estimates of OS and Cox proportional hazards modeling.The 5-year OS for all IIIA patients was 55%. Administration of adjuvant therapy was associated with improved OS when compared with surgery alone (P=0.0018). The 5-year OS was 20% for patients treated with surgery alone (n=10), 55% with surgery and radiation therapy (n=26), 75% with surgery and chemotherapy (n=7), and 79% with surgery followed by both radiation therapy and chemotherapy (n=12; P=0.005). The tumor characteristics showed that nonendometrioid histology (P=0.0143) and lymph vascular space invasion (P=0.0483) had a poorer OS. Recurrence occurred in 29% of IIIA patients, with 9% locoregional failures and 20% distant failures. Patients with positive cytology only had a similar OS to patients with positive serosa and/or adnexae (76% vs. 55%; P=0.104) and recurrence rate (22% vs. 29%; P=0.4101).This retrospective study suggests benefit from the use of adjuvant radiotherapy and chemotherapy for stage IIIA patients. We recommend further investigation of adjuvant therapies for IIIA patients in prospective studies and randomized clinical trials.

Objective : Ureteral injury is a complication of gynecologic surgery in approximately 1 % of all cases. The anatomic site of the injury determines the type of operative repair. When an end-to-end ureteral anastomosis is required, interrupted sutures are usually used. A prospective, randomized animal study was performed to determine the efficacy of a new microvascular anastomotic device, the Unilink system, in repairing transected ureters. Study Design : Nineteen pigs underwent randomized anastomosis with the Unilink system on one side and traditional anastomosis with suture on the contralateral side. A postoperative intravenous pyelogram was performed immediately and 2 weeks later, before the anastomotic site at a second laparotomy was harvested. Patency rates for each type of anastomosis were compared microscopically, and the degree of hydronephrosis was compared grossly and radiographically. Results and Conclusion : The anastomotic repair with the Unilink system did not significantly differ structurally or functionally from traditional suture repair.

To compare maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team with similar cases managed by standard obstetric care.This was a retrospective cohort study of all cases of placenta accreta identified in the State of Utah from 1996 to 2008. Cases of placenta accreta were identified using International Classification of Diseases (ICD-9) codes for placenta accreta, placenta previa, and cesarean hysterectomy. Maternal morbidity was compared for cases managed by a multidisciplinary care team in two tertiary care centers and similar cases managed at 26 other hospitals using multivariable logistic regression analysis.One-hundred forty-one cases of placenta accreta were identified including 79 managed by a multidisciplinary care team and 62 cases managed by standard obstetric care. Women managed by a multidisciplinary care team were less likely to require large-volume blood transfusion (4 or more units of packed red blood cells) (43% compared with 61%, P=.031) and reoperation within 7 days of delivery for bleeding complications (3% compared with 36%, P.001) compared with women managed by standard obstetric care. Women with suspected placenta accreta managed by a multidisciplinary team were less likely to experience composite early morbidity (prolonged maternal admission to the intensive care unit, large-volume blood transfusion, coagulopathy, ureteral injury, or early reoperation) than women managed by standard obstetric care (47% compared with 74%, P=.026). The odds ratio of composite early morbidity in women managed by a multidisciplinary team was 0.22, (95% confidence interval, 0.07- 0.70) in the multivariable model.Maternal morbidity is reduced in women with placenta accreta who deliver in a tertiary care hospital with a multidisciplinary care team.II

Objective Using a genealogical database, we examined risk of endometrial cancer among family members of individuals with endometrial cancer. Methods We identified endometrial cancer cases in the Utah Population Database (UPDB), a computerized archive of genealogy data linked to the Utah Cancer Registry. We tested for excess relatedness and estimated relative risks (RR) among first-, second-, and third-degree relatives of endometrial cancer cases and stratified analyses by tumor histology and body mass index (BMI). Results We identified 3911 cases; 3546 were Type I cancers and 365 Type II cancers. The RR for all endometrial cancer cases and for cases with type I histology was significantly increased for first-, second-, and third-degree relatives. An almost three-fold risk was observed among first-degree relatives of individuals with Type I cancers and a 2.24-fold risk among second-degree relatives of Type I morbidly obese cases. The magnitude of endometrial cancer risk among relatives appeared to increase with case BMI. Conclusions The elevated risks for endometrial cancer among first-, second-, and third-degree relatives support a genetic contribution to predisposition to endometrial cancer. The increased risk appears to be limited to Type I endometrial cancer. We observed increased risks for endometrial cancer among relatives of obese and morbidly obese Type I cases, which may be indicative of a synergistic relationship between underlying genetic propensity and shared environment. This study quantifies risk of developing cancer among relatives of patients with disease and provides the basis for further analysis of high risk pedigrees and gene identification for genetic etiologies of endometrial cancer.

Neuroendocrine small cell carcinoma is a lethal, but rare, tumor that arises most frequently in the lung. Small cell cancer also rarely may occur in the female genital tract, usually in the cervix. This article concerns the fourth reported case of neuroendocrine small cell carcinoma of the vulva. Previously, small cell carcinoma of the vulva has been treated with regional therapy including surgery and radiation. Survival has been poor, however, due to the propensity of these tumors to metastasize early in the course of the disease. Recently, the median survival of patients with small cell carcinoma of the lung has been improved with the use of chemotherapy. The authors review the literature on the treatment of small cell carcinoma of the vulva and report on a patient who was treated successfully with vulvectomy and inguinal lymphadenectomy followed by adjuvant chemotherapy.

Endometrial carcinoma is the fourth most common cancer among women in the United States. Surgical pathologic staging has been the standard of care since 1988, which consists of analysis of collected peritoneal fluid, hysterectomy/oophorectomy, and pelvic and para-aortic lymphadenectomy. In 2005, it was further recommended that essentially all women with endometrial cancer who choose to undergo surgery have pelvic and para-aortic lymph node analysis. Despite this recommendation, there still remains controversy as to whether all patients with endometrial cancer should undergo full lymph node dissection. In this review, we assess the evidence surrounding this controversy and conclude that women with endometrial cancer should undergo complete lymphadenectomy at the time of surgery. Furthermore, we evaluate the evidence regarding laparoscopic surgical staging as a safe and effective alternative to the more invasive traditional laparotomy. Finally, for those patients who a gynecologic oncologist is not readily available to perform a complete lymph node dissection, we evaluate the various imaging studies and their utility as preoperative triage modalities.

From 1971 through 1984, 320 women underwent radical hysterectomy as primary therapy of stage IB and IIA cervical cancer. Two hundred forty-eight patients (78%) were treated with surgery alone and 72 patients (22%) received adjuvant postoperative external-beam radiotherapy. Presence of lymph node metastasis, large lesion (greater than 4 cm in diameter), histologic grade, race (noncaucasian), and age (greater than 40 years) were significant poor prognostic factors for the entire group of patients. Patients treated with surgery alone had a better disease-free survival than those who received combination therapy (P less than 0.001). However, patients receiving adjuvant radiation therapy had a higher incidence of lymphatic metastases, tumor involvement of the surgical margin, and large cervical lesions. Adjuvant pelvic radiation therapy did not improve the survival of patients with unilateral nodal metastases or those who had a large cervical lesion with free surgical margins and the absence of nodal involvement. Radiation therapy appears to reduce the incidence of pelvic recurrences. Unfortunately, 84% of patients who developed recurrent tumor after combination therapy had a component of distant failure. The incidence of severe gastrointestinal or genitourinary tract complications was not different in the two treatment groups. However, the incidence of lymphedema was increased in patients who received adjuvant radiation therapy. Although adjuvant radiation therapy appears to be tolerated without a significant increase in serious complications, the extent to which it may improve local control rates and survival in high-risk patients appears to be limited. In view of the high incidence of distant metastases in high-risk patients, consideration should be given to adjuvant systemic chemotherapy in addition to radiation therapy.

Attempted surgical removal of advanced stage peritoneal cancers is mostly insufficient and often fails in areas affected by disseminated disease. But the successful elimination of peritoneal surface spread is known to have a significant impact on patient survival. However, standard therapies such as surgical cytoreduction and systemic chemotherapy combined with radiation have only shown limited-efficacy, accessibility, and nonspecific toxicity as well as frequent development of multidrug resistance (MDR). To overcome those limitations, we previously reported about the development of a mucoadhesive, chitosan-hybrid gel (CS(BCDDP)) embedded with cisplatin (CDDP) containing alginate beads for intraperitoneal administration (# 1948, AACR 2012). Here we report additional results illustrating CDDP release from CS(BCDDP) at different pH in vitro, CDDP accumulation to genomic DNA (gDNA) isolated from tissues as well as toxicity data in vivo. To determine the amount of CDDP released from CS (BCDDP) in vitro, B50μgCDDP, CDDP-chitosan (CS50μgCDDP) and CS (B50μgCDDP) pellets (8 mm ø, 1.5 mm thickness) were prepared and placed into a 6 well plate containing 2 ml/well PBS (pH 6, 7, 7.4 and 8). Multiple samples were collected during the 24 h incubation (37°C, 100rpm) period. The majority (75%) of CDDP was successfully released from CS(BCDDP) within the first 2 h at pH 7.4 showing the rate of drug release to be inversely correlated with pH yielding a more rapid release under acidic pH conditions. To assess CDDP accumulation to gDNA, inductively coupled plasma mass spectrometry (ICP-MS) was performed with tissue samples obtained from the left peritoneal sidewall of female nu/nu mice 24 hours after treatment with CS50μgCDDP, CS(B50μgCDDP), intravenously (i.v.) CDDP(IV50μgCDDP) and intraperitoneal (i.p) CDDP (IP50μgCDDP), respectively. The results demonstrated a greater than three-time enhancement of CDDP-accumulation to the gDNA from CS(B50μgCDDP) when compared to CS50μgCDDP and IV50μgCDDP administration. In addition, CS(B50μgCDDP) showed similar levels of CDDP adduction compared to direct IP50μgCDDP administration. Moreover, assessment of CDDP accumulation in kidneys and blood 24 h following treatment with either IP50μgCDDP or CS(B50μgCDDP), demonstrated significantly decreased kidney toxicity from CS(B50μgCDDP) when compared to IP50μgCDDP. Our results, therefore strongly suggest that administration of this hybrid gel directly to mucosal surfaces such as the peritoneal cavity is feasible making it an advantageous, safe and non-toxic intraperitoneal drug delivery system for the treatment of disseminated peritoneal cancers such as advanced or recurrent ovarian cancer. Currently ongoing experiments are evaluating the efficacy and safety of our hybrid gel/CDDP in an orthotopic peritoneal cancer animal model. Citation Format: Sungpil Cho, Yongen Sun, Elke A. Jarboe, Andrew P. Soisson, Mark K. Dodson, David K. Gaffney, C.Mattew Peterson, Margit M. Janat-Amsbury. Tissue accumulation and toxicity of platinum released from a novel chitosan hybrid gel for intraperitoneal drug delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5402. doi:10.1158/1538-7445.AM2014-5402

Ovarian cancer is the second most frequent invasive malignancy of the female genital tract and the most common cause of death among women with gynecologic malignancies. Although epithelial ovarian cancer (EOC) accounts for over 90% of all ovarian malignancies, the lack of proper animal models that mimic the development and consequences of human EOC limits the ability of current preclinical ovarian cancer models to predict treatment response. The orthotopic development of syngeneic EOC within its relevant tumor microenvironment is an experimental ideal. Here, we demonstrate the development and characterization of a syngeneic EOC mouse model in immunecompetent C57BL/6 mice by orthotopic implantation of ID 8 mouse ovarian cancer cells. Using conventional and ultrasound-based techniques to compare tumor weight, volume and vascularity we followed the development of primary tumors, metastases and ascites over 16 weeks. ID 8 cells were implanted directly underneath the left ovarian bursa. Normal saline was injected to the contralateral ovary as control. Ovarian tumors grew consistently throughout the study period; ovarian weight and volume increased twelve and seven fold, respectively, compared to the contralateral, non-cancerous ovary. Ultrasound measurements of primary tumors and surrounding tumor tissue correlated with the actual size after surgical tumor harvest. Abdominal ascites were first observed at 12 weeks post orthotopic ID8 implantation with volume changes correlating with changes in abdominal circumference. Metastatic lesions were identified by ultrasound at 12 weeks after orthotopic ID8 implantation; sites included peritoneum, liver, and intestine. Histopathological analysis of tumors and metastases indicated similarities between orthotopic ID8 ovarian tumors and human ovarian tumors, except a significantly lower formation of angiogenic vasculature within the ID8 tumors. This study confirms the successful development of a mouse model that closely replicates characteristics seen in human ovarian cancer patients. It shows the feasibility of using ultrasound to assess tumor formation, progression and vascularization. Furthermore, we demonstrate potential shortcomings, which could significantly limit the use of current animal models predicting therapeutic efficacy of novel agents, especially anti-angiogenic therapeutics, impacting the translation of preclinical information to actual clinical outcomes. Citation Format: Sungpil Cho, Yongen Sun, Andrew P. Soisson, Mark K. Dodson, C. Matthew Peterson, Elke A. Jarboe, Anne M. Kennedy, Margit M. Janat-Amsbury. Characterization and evaluation of a mouse ovarian cancer model for its preclinical suitability. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 325. doi:10.1158/1538-7445.AM2013-325

Gynecological malignancies such as cervical, endometrial and ovarian cancer still are the leading causes of death for women worldwide. However, standard therapies such as surgical cytoreduction and systemic chemotherapy combined with radiation have shown limited-efficacy by accessibility as well as nonspecific toxicity. To overcome those limitations, we previously reported about the development of a muco-adhesive, chitosan-hybrid gel (CS(BCDDP)) embedded with alginate beads containing cisplatin (CDDP) for a local, intraperitoneal application (# 3232, AACR 2011). Here we report the results of CDDP release from the (CS(BCDDP)), its cellular activity in vitro and CDDP accumulation to genomic DNA (gDNA) of tissues in vivo. To determine the amount of CDDP released from (CS(BCDDP)) in vitro, we used a colorimetric SnCl2 assay following the incubation in 0.9% NaCl solution for 24 hrs. (CS(BCDDP)) demonstrated successful release of 90% CDDP within 2 hrs and consistent CDDP-release could be maintained for up to 24 hrs. To test activity of CDDP released from (CS(BCDDP)), clonogenic assay was performed with Hela (human cervical adenocarcinoma) cells. Cells treated with (CS(BCDDP)) demonstrated a significantly low number of colonies, generating 9 (± 6) colonies per 500 cells seeded compared with 233 (± 10) colonies per 500 cells treated with an empty, no drug containing control gel (CS). To further assess CDDP accumulation to gDNA of tissues in vivo, inductively coupled plasma mass spectrometry (ICP-MS) was performed with tissue samples obtained from the left peritoneal sidewall of female nude mice following treatment with a control gel mixed with CDDP (CSCDDP), (CS(BCDDP)), and intravenously (i.v.) CDDP(CDDPIV). The results demonstrated a greater than three-time enhancement of CDDP-accumulation to the gDNA from (CS(BCDDP)) when compared to CDDPIV. Moreover, (CS(BCDDP)) also demonstrated higher accumulation of CDDP to gDNA when compared with CSCDDP. Relative values were 3.2 (±0.9) for (CS(BCDDP)) and 1.3 (± 0.4) for CSCDDP compared to values obtained from CDDPIV. Our in vitro and in vivo results, strongly suggest the feasibility of applying this hybrid gel locally to mucosal surfaces of the female reproductive tract and its advantage for intraperitoneal drug accumulation. Currently ongoing experiments are evaluating the efficacy and safety of our hybrid gel/CDDP in orthotopic endometrial, ovarian and cervical cancer animal models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1948. doi:1538-7445.AM2012-1948

The objective of this prospective study was to determine the efficacy of subcutaneous retention sutures in the prevention of superficial wound separation in obese women undergoing gynecologic surgery. From 1985 to 1990, 80 women with subcutaneous tissue of 5 cm or greater undergoing laparotomy were randomly assigned to either standard wound closure (37 patients) or closure including subcutaneous retention sutures (43 patients). We examined the relationship of the following factors to the development of superficial wound dehiscence: malnutrition (total protein6.0 mg/dl, albumin3.0 mg/dl), minidose heparin (5000 U subcutaneously every 8 hr for 5 days), diabetes mellitus, prolonged operative time (180 min), intraoperative spillage of enteral contents, and subcutaneous retention sutures. In a univariate analysis, malnutrition (P = 0.02), the use of heparin (P = 0.03), and the absence of retention sutures (P = 0.02) were associated with an increased risk of separation. In a multivariate analysis, malnutrition (P = 0.02), low-dose heparin (P = 0.03), and the absence of retention sutures (P = 0.04) retained their independent association with superficial wound separation. This study suggests that the use of subcutaneous retention sutures reduces the incidence of superficial wound separation in obese women undergoing gynecologic surgery.

We evaluated 109 women with endometrial carcinoma to determine the accuracy of preoperative tumor-associated antigen levels (CA 125, CA 72, CA 15-3) for prediction of extrauterine disease and whether TAG 72, CA 15-3, or both would improve the predictive value of CA 125 alone. Eleven (12%) of 80 patients with disease confined to the uterus or positive cytologic findings had CA 125 values greater than 35 U/ml versus 12 (65%) of 20 patients with extrauterine metastasis. Therefore CA 125 values had sensitivity of 65% and specificity of 88%. The TAG 72 level was elevated (greater than 6 U/ml) in 4% of patients with localized disease and 30% with metastasis. CA 15-3 was elevated (greater than 30 U/ml) in 17% and 65% in these categories, respectively. TAG 72 or CA 15-3 levels did not improve the combination of sensitivity and specificity of CA 125 alone. In addition, only one of 10 patients with microscopic metastasis (three cases) or positive peritoneal cytology (seven) had elevation of any of these tumor-associated antigen levels. Failure to detect occult metastasis and a high false-positive rate limit the role of these tumor-associated antigen assays in the preoperative evaluation of patients with endometrial carcinoma.

Unusual complications of warfarin therapy include cutaneous necrosis and the "purple toe syndrome." The latter is more common in men and is not associated with vascular compromise; it usually occurs 3 to 8 weeks after warfarin therapy is begun and may persist for many months after the medication is discontinued. The following is a case of a 63-year-old woman who received warfarin therapy in conjunction with heparin for treatment of a left leg deep vein thrombosis. Approximately 8 hours after receiving her first dose of warfarin (15 mg), she developed acute pain, edema, and discoloration of the entire left leg to the mid-thigh, most prominent in the left great toe. After discontinuation of warfarin therapy, her symptoms completely resolved within 48 hours. This may be a report of a new cutaneous lesion associated with anticoagulant therapy.

Summary Immunohistochemical techniques were used to evaluate the expression of six antigens (CA 125, TAG 72, CA 19-9, 0VTL3, DF3, and transferrin receptor) in frozen sections from the primary tumor and metastases of 20 patients with epithelial ovarian cancer. Heterogeneous expression of most antigens was observed within a given tumor nodule, but in each patient the proportion of cells expressing an antigen was similar in the primary tumor and metastases. To explore the stability of the antigenic phenotype of individual cells, we studied CA 125 expression in an ovarian cancer cell line. Cells were separated into CA 125-positive and -negative groups using fluorescence-activated cell sorting. After the two groups of cells were recultured separately, only 38% of cells originally sorted as CA 125 positive still expressed CA 125, whereas 27% of cells sorted as CA 125 negative expressed CA 125. That cells may gain or lose CA 125 expression in culture suggests that expression of CA 125 by ovarian cancer cells is not a stable trait. (Am J Obstet Gynecol 1990;162:883-8.)

To evaluate our surveillance program for recurrent cervical carcinoma, we reviewed patients who underwent radical hysterectomy for International Federation of Gynecology and Obstetrics (FIGO) stages IB and IIA cervical cancer. The study group consisted of 203 women followed at Duke University Medical Center exclusively who had at least 2 years of regular surveillance. Thirty-one (15%) developed recurrence. For the detection of recurrent tumor, vaginal cytology had a sensitivity and specificity of 13 and 100%, pelvic or general physical examination 58 and 96%, and the presence of suspicious symptoms 71 and 95%, respectively. Ninety-four percent of all patients with recurrent tumor had at least one abnormal surveillance index. Three of 31 patients (10%) with recurrent tumor were treated successfully with secondary therapy. Two recurrences were detected by vaginal cytology exclusively. Even though vaginal cytology is not sensitive and may not be cost-effective, we conclude that it is the technique most likely to detect recurrent tumor while it is localized and potentially curable.

TAG-72 is a tumor-associated antigen that is expressed by secretory endometrium and most endometrial adenocarcinomas. We used immunohistochemical techniques to quantitate expression of TAG-72, estrogen receptor, and progesterone receptor in 21 normal endometria and 44 endometrial adenocarcinomas. In normal cycling endometrial glands, TAG-72 expression was related inversely to expression of receptors for estrogen and progesterone. This suggests that TAG-72 expression in normal endometrium may be hormonally regulated. Ninety-one percent of endometrial adenocarcinomas expressed immunohistochemically detectable TAG-72. The magnitude of TAG-72 expression did not correlate with other known prognostic factors in endometrial cancer such as histologic grade, depth of myometrial invasion, surgical stage, or steroid receptor status. The production of TAG-72 by most endometrial adenocarcinomas may represent nonspecific expression by cells that have dedifferentiated.