Outcomes and toxicity after salvage radiotherapy for vaginal relapse of endometrial cancer.

OBJECTIVES: Studies of salvage radiotherapy in locally recurrent endometrial cancer remain limited. The aim of this study was to evaluate the efficacy of salvage radiotherapy for vaginal relapse of endometrial cancer and to explore prognostic factors associated with outcomes. METHODS: We evaluated 30 patients treated with salvage external-beam radiotherapy and/or vaginal brachytherapy for vaginal relapses of endometrial cancer between 2009 and 2018. The inclusion criteria were: pathologically-confirmed recurrence; loco-regional relapse (in absence of distant metastases); and salvage treatment including external-beam radiotherapy and/or vaginal brachytherapy. Outcomes were evaluated via Kaplan-Meier, with the log-rank test employed to compare differences among various groups and identify prognostic factors. RESULTS: 30 patients developed vaginal recurrence at a median time of 20.6 months (range 2-219) post-hysterectomy. The most common site of recurrence was the vaginal apex (60%), followed by the distal vagina (10%). Salvage radiotherapy entailed combination external-beam radiotherapy and vaginal brachytherapy (n=24) or single modality treatment (n=6), along with concurrent chemotherapy in 20 cases. At a median follow-up of 4.4 years (range 0.1-130) post-radiotherapy, the 5 year rates of local control, regional control, metastasis-free interval, disease-free interval, and overall survival were 89%, 91.5%, 75.5%, 69%, and 83%, respectively. Factors associated with improved disease-free interval included: endometrioid histology (p=0.03), isolated vaginal relapse (p=0.003), late recurrence (>9 months) (p=0.007), and combined modality radiotherapy (p=0.001). The only factor associated with overall survival was isolated vaginal relapse (in the absence of other recurrent disease) (p=0.02). Regarding toxicity, 18% of patients experienced acute grade ≥3 events (most commonly gastrointestinal). The 5 year rates of rectal bleeding, small bowel obstruction, and pelvic fracture were 31%, 18%, and 13%, respectively. CONCLUSIONS: Salvage radiotherapy imparts excellent loco-regional control for vaginal relapses of endometrial cancer and should entail combination external-beam radiotherapy and vaginal brachytherapy. Patients should be closely monitored for late gastrointestinal toxicity following salvage radiotherapy.

Influence of Comorbidity on the Risk of Death: A Single Institution Study of 1132 Women With Early-stage Uterine Cancer.

PURPOSE/OBJECTIVE(S): The impact of competing medical comorbidity on survival endpoints in women with early stage endometrial carcinoma (EC) is not well studied. The study goal was to utilize a validated comorbidity scoring system to determine its impact on all-cause mortality as well as on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with early-stage EC. MATERIALS AND METHODS: For this IRB-approved study, we reviewed our prospectively maintained uterine cancer database of 1720 patients. We identified 1132 patients with EC FIGO stages I-II who underwent hysterectomy from 1984 to 2011. Age-adjusted Charlson Comorbidity Index (AACCI) at time of hysterectomy was retrospectively calculated by physician chart review. The cause of death (uterine cancer-related and unrelated) was correlated with AACCI. Univariate and multivariate modeling with Cox regression analysis was used to determine significant predictors of OS, DSS, and RFS. The Kaplan-Meier and the log-rank test methods were used to evaluate survival outcomes. RESULTS: After a median follow-up of 51 months, 262 deaths were recorded (42 from EC [16%], and 220 [84%] from other causes). Median AACCI score for the study cohort was 3 (range, 0 to 15). On the basis of AACCI, patients were grouped as follows: 0 to 2 (group 1, n=379), 3 to 4 (group 2, n=532), and ≥5 (group 3, n=221). By AACCI grouping, the 5-year RFS, DSS, and OS were 95%, 98%, and 97% for group 1, 89%, 95%, and 87% for group 2, and 86%, 95% and 72% for group 3 (P<0.0001). The cause of death in the first 10 years after hysterectomy in our study was mainly non-uterine cancer-related (78% vs. 22% for uterine cancer-related) causes. On multivariate analyses, higher AACCI, lymphovascular space invasion (LVSI), higher tumor grade, age, and involvement of the lower uterine segment were significant predictors of shorter OS. On multivariate analysis for DSS and RFS, only high tumor grade and LVSI were significant predictors. CONCLUSIONS: The cause of death for women with early stage EC is mainly nonuterine cancer-related. Comorbidity score is a significant predictor of OS in our study cohort. Comorbidity scores may be useful as a stratification factor in any prospective clinical trial for women with early-stage EC.

Trends in the utilization of adjuvant vaginal brachytherapy in women with early-stage endometrial carcinoma: Results of an updated period analysis of SEER data.

PURPOSE: Adjuvant vaginal brachytherapy (VB) is a well-established and effective radiation treatment modality in women with early-stage endometrial carcinoma. We sought to evaluate and update published trends in the utilization of VB vs. other radiation therapy modalities (pelvic external beam radiation therapy (EBRT) or the combination of VB and pelvic EBRT using the National Cancer Institute's Surveillance, Epidemiology, and End Results database. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was queried for adult females with histologically confirmed International Federation of Gynecology and Obstetrics 1988 Stage I-II endometrial carcinoma diagnosed from 1995 to 2012 and treated definitively with hysterectomy and adjuvant radiation therapy. Chi-square tests were used to assess differences by radiation type (VB, EBRT, and VB + EBRT) and various demographic and clinical variables. RESULTS: We identified 15,201 patients that met inclusion criteria. There was a significant overall increase in the use of VB was observed from 17.1% in 1995-2000 compared to 57.1% in 2007-2012 (p < 0.0001). Similarly, there was a proportional decrease in the use of EBRT from 54.0% to 25.5% (p < 0.0001) as well as in the use of VB + EBRT from 28.9% to 17.4% during the same period (p < 0.0001). The observed increase in utilization of VB was not limited to any variables (age, race, histological type, International Federation of Gynecology and Obstetrics stage, and the status of lymph node dissection [yes or no]) or the number of dissected lymph nodes. CONCLUSIONS: In this large national database set, there continues to be an increasing trend for the use of VB in the adjuvant setting in women with early-stage endometrial carcinoma.

Predictive Capacity of 3 Comorbidity Indices in Estimating Survival Endpoints in Women With Early-Stage Endometrial Carcinoma.

OBJECTIVE: The negative impact of comorbidity on survival in women with endometrial carcinoma (EC) is well-known. Few validated comorbidity indices are available for clinical use, such as the Charlson Comorbidity Index (CCI), the Age-Adjusted CCI (AACCI), and the Adult Comorbidity Evaluation-27 (ACE-27). The aim of the study is to determine which index best correlates with survival endpoints in women with EC. MATERIALS AND METHODS: We identified 1132 women with early-stage EC treated at an academic center. Three scores were calculated for each patient using CCI, AACCI, and ACE-27 at the time of hysterectomy. Univariate and multivariable modeling was used to determine predictors of survival. RESULTS: For each of the studied comorbidity indices, the highest scores were significantly correlated with poorer overall survival. The hazard ratio of death from any cause was 3.92 for AACCI, 2.25 for CCI, and 1.57 for ACE-27. All 3 indices were independent predictors of overall survival with a P value of less than 0.001 on multivariate analysis. In addition, lymphovascular space invasion, lower uterine segment involvement, and tumor grade were predictors of overall survival. Lymphovascular space invasion, grade (P < 0.001), and high AACCI score were the only significant predictors of recurrence-free survival (RFS). Lymphovascular space invasion and tumor grade were the only 2 predictors of disease-specific survival. CONCLUSIONS: Although all 3 studied comorbidity indices were significant predictors of overall survival in women with early-stage EC, AACCI showed a stronger association. It should be considered for evaluating comorbidity in women with early-stage EC.

Recurrent Omental Hemangiopericytoma: A Therapeutic Challenge.

Hemangiopericytomas are vascular tumors with a susceptibility to arise anywhere in the human body. We present a case of a 68-year-old female with primary omental hemangiopericytoma and a two-time recurrence managed with surgery and close follow-up. The first recurrence was at 52 months and the second at 37 months following the prior presentation. No adjuvant chemotherapy or radiation therapy was administered. Given the widespread nature of the cell of origin, routine follow-up postoperatively with interval imaging in order to detect recurrences is imperative. Pathologic tumor characteristics may determine potential for recurrence and may also assist in determining whether adjuvant treatment modalities should be included in the management plan. Review of the English literature reveals a total of 24 cases of omental hemangiopericytomas inclusive of the current report.

Salvage Versus Adjuvant Radiation Treatment for Women With Early-Stage Endometrial Carcinoma: A Matched Analysis.

OBJECTIVES: Adjuvant radiation treatment (ART) has been shown to reduce local recurrences in early-stage endometrial carcinoma (EC); however, this has not translated into improved overall survival (OS) benefit. As a result, some physicians forgo ART, citing successful salvage rates in cases of recurrence. Survival end points were compared between women treated with salvage RT (SRT) for locoregional recurrence and similarly matched women treated upfront with ART. MATERIALS AND METHODS: We identified 40 patients with stage I to II type 1 EC who underwent hysterectomy and received no adjuvant RT but later developed locoregional recurrence and subsequently received SRT. An additional 374 patients who underwent hysterectomy followed by ART during the same period were identified. Patients in the SRT group were matched to those in the ART group based on FIGO (International Federation of Gynecology and Obstetrics) stage and tumor grade in a 1:3 ratio. Disease-specific survival (DSS) and OS were calculated. RESULTS: A total of 156 women were matched (39:117). Median follow-up was 56 months. The 2 groups were generally well balanced. With regard to the site of tumor recurrence, it was commonly vaginal in the SRT group (74.3% vs 28.6%, P = 0.01). More SRT patients received a combination of pelvic external-beam RT with vaginal brachytherapy (94.8% vs 35%, P < 0.001). The ART group had significantly better 5-year DSS (95% vs 77%, P < 0.001) and 5-year OS (79% vs 72%, P = 0.005) compared with those of the SRT group. CONCLUSIONS: Our study suggests that women who receive SRT for their locoregional recurrence have worse DSS and OS compared with those matched patients who received ART. Further studies are warranted to develop a high-quality cost-effectiveness analysis as well as accurate predictive models of tumor recurrence. Until then, ART should at least be considered in the management of early-stage EC patients with adverse prognostic factors.

Solitary ovarian plasmacytoma. A case report and review of literature.

•A patient with rare solitary ovarian plasmacytoma is reported•Diagnostic work-up is mandatory to rule out ovarian involvement as part of multiple myeloma.•After complete surgical resection, the prognosis appears to be very favorable.

A phase II trial of paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma (EMCA).

OBJECTIVE: To evaluate the effect of adding bevacizumab to adjuvant paclitaxel and carboplatin and as maintenance on progression-free survival (PFS) in advanced or recurrent endometrial carcinoma (EMCA). METHODS: A phase II trial was conducted in patients with measurable disease. Paclitaxel (175mg/m(2)/3h), carboplatin (AUC 5) and bevacizumab (15mg/kg) were administered q 21 days. Patients with a complete response after 6-8cycles received maintenance therapy with bevacizumab 15mg/kg q 21 days for 16cycles. Based on GOG 177 which had a 6-month PFS rate of 59%, an increase in 6-month PFS to 72% with the treatment regimen was considered of clinical interest. RESULTS: 15 patients were enrolled on protocol when accrual to the study was discontinued due to the initiation of a national randomized phase II trial. A total of 127 courses (median 8, range 1-20) of carboplatin, paclitaxel, and bevacizumab combination therapy were administered. One patient suffered a bowel perforation after her first course of therapy and was inevaluable for response. Fourteen of the 15 patients (93%, 95% CI: 82-100) were progression free at 6months. The median follow-up was 36months (7-58+). The median PFS was 18months (CI: 11-25). Five complete responses and 6 partial responses were seen for an overall response rate of 73% (CI: 45-91). The median overall survival was 58months (CI: 48-68). CONCLUSIONS: The bevacizumab, paclitaxel, and carboplatin regimen is active and tolerable in advanced and recurrent EMCA. Its impact awaits results of the recently completed randomized phase II trial.

The impact of tumor grade on survival end points and patterns of recurrence of 949 patients with early-stage endometrioid carcinoma: a single institution study.

OBJECTIVES: This study aimed to determine the impact of tumor grade on patterns of recurrence and survival end points in patients with endometrioid carcinoma 2009 International Federation of Gynecology and Obstetrics stages I-II. METHODS: We identified 949 patients who underwent hysterectomy between 1988 and 2011. Patients were divided into 3 groups based on tumor grade. Kaplan-Meier plots were generated for each group for recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: Median follow-up was 52 months. Median age was 60 years. All patients underwent total abdominal hysterectomy and salpingo-oophorectomy. Eighty percent of patients underwent lymph node dissection, 83% had peritoneal cytology. There were 76 (8%) patients who developed tumor recurrence. Tumor recurrence rates were significantly higher in patients with grade 3 tumors compared to grade 1 (P = 0.006). Additionally, patients with grade 3 tumors developed significantly more frequent distant metastases compared to patients with grade 1 (P = 0.002). Five-year RFS for the patients with grade 1, 2, and 3 were 95%, 82%, and 68%, respectively (P = <0.001). Five-year DSS was 99%, 93%, and 79%, respectively (P = <0.001). Five-year OS was 89%, 84%, and 63%, respectively (P = <0.001). Lymphovascular space involvement and grade were significant independent predictors of RFS and DSS. For OS age, lymphovascular space involvement, grade, and body mass index were significant predictors. CONCLUSIONS: International Federation of Gynecology and Obstetrics grade is a strong predictor of clinical survival end points in women with early-stage endometrioid carcinoma. The pattern of recurrence in patients with grade 3 tumors is mainly distant rather than locoregional. Further studies incorporating systemic therapy in the adjuvant settings in these patients are warranted.

Adjuvant radiation therapy for patients with type II endometrial carcinoma: impact on tumor recurrence and survival.

PURPOSE/OBJECTIVE: The optimal adjuvant treatment of type II endometrial carcinoma after hysterectomy remains controversial. The objective of this study was to determine the effect of adjuvant radiation therapy (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival in patients with early-stage type II endometrial carcinoma. MATERIALS AND METHODS: In this institutional review board-approved study, our database of 1450 patients with endometrial cancer was reviewed. Seventy-nine surgically staged patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stages I and II serous and clear cell carcinoma were treated from 1991 to 2010. These patients were then divided into 2 groups; one group received adjuvant RT, and the other group included patients who did not receive adjuvant RT. RESULTS: The median age of the study cohort is 65 years, and the median follow-up is 47 months. Thirty-nine patients (49%) received adjuvant RT, and 40 patients did not. The 5-year RFS was significantly improved in patients who received RT (84% vs 58%; P = 0.002). Similarly, 5-year DSS was significantly improved in patients who received RT (87% vs 58%; P = 0.023) with a trend toward improved 5-year overall survival (74% vs 58%; P = 0.088). On multivariate analysis, lack of angiolymphatic invasion (P < 0.001 and P < 0.001), adjuvant RT (P < 0.001 and P = 0.004), and lack of lower uterine segment involvement (P = 0.007 and P = 0.009) were independent predictors of improved RFS and DSS, respectively. CONCLUSIONS: In the current study of surgically staged patients with type II endometrial carcinoma International Federation of Gynecology and Obstetrics stages I and II, adjuvant radiation therapy with or without chemotherapy resulted in a significant improvement in recurrence-free and disease-specific survival.

Cervical epithelial brightness by optical coherence tomography can determine histological grades of cervical neoplasia.

OBJECTIVE: The study aimed to determine if the difference in cervical epithelium brightness, as measured by optical coherence tomography (OCT), has potential as a distinguishing characteristic of normal, low-grade, high-grade (cervical intraepithelial neoplasia 2+), and cancer histological findings. MATERIALS AND METHODS: Information from 476 women was available for analysis. Demographic information was collected through in-person interview. All participants were human papillomavirus positive and/or had abnormal cytological finding and underwent colposcopy or unaided visual inspection and examination by OCT by quadrant. All women had a minimum of 4 OCT-matched cervical biopsies and endocervical curettage. Two sample t tests were used to measure differences in OCT image brightness by histological grades. RESULTS: Mean OCT image brightness differed significantly between each preinvasive histological grade and invasive cancer (p < .01 for all comparisons). Brightness as measured by OCT was also able to differentiate between squamous metaplasia and cervical intraepithelial neoplasia 3/cancer; p values were .004 and .003, respectively. CONCLUSIONS: Epithelial brightness is an important component of cervical epithelium diagnosis by OCT, and we plan to add it to our diagnostic mathematical algorithm in all future versions of OCT software.

Is time to recurrence after hysterectomy predictive of survival in patients with early stage endometrial carcinoma?

PURPOSE/OBJECTIVE(S): To determine the prognostic significance of time to recurrence (TTR) on overall survival (OS) and disease-specific survival (DSS) following recurrence in patients with stage I-II uterine endometrioid carcinoma. MATERIALS/METHODS: After IRB approval, we retrospectively identified 57 patients with recurrent endometrioid carcinoma who were initially treated for FIGO 1988 stages I-II between 1987 and 2009. The Kaplan-Meier approach and Cox regression analysis were used to estimate OS and DSS following recurrence and identify factors impacting outcomes. RESULTS: Median follow-up times were 54.8 months from hysterectomy and 19.8 months after recurrence. Median time to recurrence was 20.2 months. Twenty-eight (47%) patients had a recurrence<18 months after hysterectomy and 29 (53%) had a recurrence≥18 months. Both groups were evenly matched regarding initial pathological features and adjuvant treatments. The median OS and DSS in patients with TTR<18 months was shorter than those with TTR≥18 months, but not statistically significant (p=0.216). TTR did not impact outcomes after loco-regional recurrence, but for extrapelvic recurrence, a shorter TTR resulted in worse OS and DSS (p=0.03). On multivariate analysis, isolated loco-regional recurrence (HR 0.28, p=0.001) and salvage radiation therapy (HR 0.47, p=0.045) were statistically significant independent predictors of longer OS following recurrence. TTR as a continuous variable or dichotomized was not predictive of OS or DSS. CONCLUSIONS: In our study, the prognostic impact of time to recurrence was less important than the site of recurrence. While not prognostic for the entire cohort or for patients with loco-regional recurrence, TTR<18 months was associated with shorter OS and DSS after extrapelvic recurrence.

Endometrial stromal sarcoma invading the abdominal aorta treated with aortic replacement.

Endometrial stromal sarcomas are extremely rare tumors with few reports describing invasion of major blood vessels. Tumors that primarily involve the abdominal aorta or invade the vessel secondarily are uncommon. Outcomes from radical tumor resection and aortic reconstruction are thus poorly understood. We present a rare case of a symptomatic recurrent endometrial stromal sarcoma with encasement of the infrarenal abdominal aorta requiring en bloc tumor resection and in situ aortic replacement.

Single-port laparoscopic pelvic and para-aortic lymph node sampling or lymphadenectomy: development of a technique and instrumentation.

BACKGROUND AND OBJECTIVES: Innovations in minimally invasive surgery have allowed surgeons to perform increasingly complex surgeries through smaller incisions. We describe the feasibility and the technique of single-port laparoscopic pelvic and para-aortic lymph node sampling or lymphadenectomy in gynecologic malignancies. METHODS: The study was approved by the institutional review board at the Cleveland Clinic (Cleveland, Ohio). Inclusion criterion was patients with apparent early-stage gynecologic malignancies who required pelvic and/or para-aortic lymph node sampling or lymphadenectomy and were candidates for single-port laparoscopy. Procedures were performed through a single 2.0- to 3.0-cm umbilical incision using a single-port device, deflecting-tip laparoscope, and multifunctional instrumentation. RESULTS: Twenty-one patients underwent single-port surgery/staging performed during the study period. The median patient age was 58 years (range, 17-80 years), and the median patient body mass index was 30 mg/kg² (range, 19-46 mg/kg²). Median overall operating time was 120 minutes (range, 60-185 minutes). Median pelvic and para-aortic node counts were 14 (range, 7-19) and 6 (range, 2-14), respectively. CONCLUSIONS: In this preliminary report, the technique was feasible, and no morbidity was noted. Further studies are needed to better define the ideal gynecologic oncology procedures for single-site surgery and to assess the relative benefits of this new technique compared with more conventional minimally invasive approaches.

CCL2 expression in primary ovarian carcinoma is correlated with chemotherapy response and survival outcomes.

CCL2, a chemokine, is expressed in normal human ovarian epithelium but down-regulated in ovarian adenocarcinomas. The association of CCL2 expression with chemotherapy response, invasion and survival outcomes was studied in patients with primary ovarian cancer (OC) and in ovarian cancer cell lines (OCCLs). Tumor specimens (>80% tumor) from patients with primary, advanced serous OC obtained at the time of cytoreductive surgery was used to isolate total RNA. The CCL2 gene expression evaluated by RT-PCR was investigated in relation to chemo-response/clinical outcomes in the OC patients and to sensitivity to cisplatin/paclitaxel in the OCCLs. In vitro invasion was measured by matrigel invasion and matrixmetallo-proteinase-9 (MMP-9) zymogram assays. Thirty-seven patients were included. In multivariable analyses that adjusted for the impact of debulking status, the CCL2 mRNA expression was correlated with objective complete response (p = 0.01), chemosensitivity (p = 0.04), and progression-free survival (PFS; p = 0.006). These findings were corroborated in vitro in the OCCLs. The cells expressing higher levels of CCL2 were more sensitive to paclitaxel and cisplatin as compared to those lines expressing lower levels of this chemokine. Up-regulation of CCL2 in the PAT-7 cell line further enhanced the response of these cells to paclitaxel (p = 0.0001) and led to decreased invasion (p = 0.0009). Increased ovarian tumoral expression of CCL2 is associated with improved chemoresponse and survival outcomes, and higher levels of CCL2 in ovarian cancer cell lines are associated with increased chemosensitivity and decreased invasion in vitro.

Fertility-preserving surgical procedures for patients with gynecologic malignancies.

Gynecologic malignancies often affect young women who are at the peak of their reproductive potential. The treatment for gynecologic malignancies often consists of removal of the ovaries or uterus, affecting the future fertility of these patients. Advances in surgical management have allowed patients to undergo more conservative treatment with preservation of their fertility. This review summarizes fertility-sparing surgical procedures for patients with gynecologic malignancies evaluating the role of radical trachelectomy and ovarian transposition in cervical cancer, hormonal therapy and hysteroscopic resection in endometrial cancer, and conservative surgery in ovarian cancer.

Study of the diagnostic efficacy of real-time optical coherence tomography as an adjunct to unaided visual inspection with acetic acid for the diagnosis of preinvasive and invasive neoplasia of the uterine cervix.

OBJECTIVES: To determine the sensitivity and specificity of optical coherence tomography (OCT) as an adjunct to unaided visual inspection using acetic acid (VIA) in the detection of cervical intraepithelial neoplasia 2 (CIN 2) in a real-time clinical evaluation. BACKGROUND: This clinical study was a prospective cross-sectional comparative trial that screened 1000 patients (aged 30-50 years) in a low-resource setting. Women with abnormal cervical cytology or positive human papillomavirus (HPV) tests were referred for further evaluation including VIA, OCT imaging, colposcopy, and cervical biopsies. METHODS: The VIA diagnoses were coded by quadrant. The OCT was then performed in all VIA-positive areas and at the squamocolumnar junction in all 4 quadrants. All patients were colposcoped; assessed by quadrant with biopsies at 2, 4, 8, and 10 o'clock; all abnormal areas were biopsied; and endocervical curettage was performed. Data were analyzed using generalized estimating equations and logistic regression. RESULTS: Of the 1000 patients, 175 (17.5%) were HPV positive, 93 (9.3%) had abnormal cervical cytology greater than or equal to atypical squamous cells of undetermined significance, and 211 (21.1%) were either HPV positive or had abnormal cytology. The VIA, OCT, colposcopy, and biopsies were completed on 183 (86.7%) of 211 women. For VIA alone, the sensitivity and specificity in detecting lesions greater than or equal to CIN 2 was 43% and 96%. With the addition of OCT, the sensitivity increases to 62% with a specificity of 80%. CONCLUSIONS: With the addition of OCT, the sensitivity of VIA increased in all analyses for the detection of greater than or equal to CIN II, with a loss in specificity. We hope that the potential of this technology will be realized when a computer algorithm is generated to aid in image interpretation.

Secretory leukocyte protease inhibitor antagonizes paclitaxel in ovarian cancer cells.

PURPOSE: Ovarian cancer recurrence with the development of paclitaxel resistance is an obstacle to long-term survival. We showed that secretory leukocyte protease inhibitor (SLPI) is a survival factor for ovarian cancer. We hypothesize that SLPI may antagonize paclitaxel injury. EXPERIMENTAL DESIGN: Differential SLPI induction in response to paclitaxel and in response to stable forced expression of SLPI was shown in A2780-1A9 cells and their paclitaxel-resistant sublines, PTX10 and PTX22, and confirmed with HEY-A8 cells. SLPI-mediated survival was reduced by the MAP/extracellular signal-regulated kinase (ERK) kinase inhibitor, U0126, and a humanized neutralizing monoclonal anti-SLPI antibody, CR012. OVCAR3 xenographs tested the role of CR012 in vivo. RESULTS: SLPI expression was lower in A2780-1A9 ovarian cancer cells than in PTX10 and PTX22, and SLPI was induced by paclitaxel exposure. Stable SLPI expression yielded a proliferation advantage (P = 0.01); expression of and response to SLPI in OVCAR3 cells were abrogated by exposure to CR012. SLPI reduced the paclitaxel susceptibility of 1A9 and HEY-A8 cells (P

Stage I, grade 3 endometrioid adenocarcinoma of the endometrium: an analysis of clinical outcomes and patterns of recurrence.

OBJECTIVE: To study patterns of recurrence and survival outcomes in patients with surgical stage I, grade 3 endometrioid adenocarcinoma of the endometrium (EA) treated with various treatment modalities. METHODS: A retrospective multi-institutional study of surgical stage I, grade 3 EA patients diagnosed between 1988 and 2006 was performed. Demographic, clinicopathologic, treatment and outcome data were collected. After surgery, patients were treated with either observation or radiotherapy (vaginal brachytherapy, whole pelvic or both). RESULTS: One hundred seventy-six patients were collected with a median age of 68 years. Twenty-six (15%) were stage IA, 96 (54%) IB and 54 (31%) IC. Sixty-one patients (35%) had lymphovascular space invasion (LVSI) and a mean of 18.9 lymph nodes (LNs) was removed. Seventy-eight patients (44%) were observed while 98 (56%) were treated with radiotherapy, the majority (n=51) receiving brachytherapy. After a median follow-up of 58 months, 20 recurrences (11%) were noted. Ninety percent of recurrences occurred in Stage IB/IC patients. The median time to recurrence was 22.5 months (5-74.5) and 80% of recurrences were extra-pelvic. There was no significant difference in recurrence based upon treatment modality or LVSI. Majority of recurrences were not salvaged as 75% (12/16) died of their disease with a median time of recurrence to death of 8 months. CONCLUSIONS: Patients with stage IB/IC, grade 3 endometrioid adenocarcinoma have a significant risk for extra-pelvic recurrence. Most patients will not be salvaged and will succumb to their disease, suggesting that current loco-regional adjuvant treatment strategies are not optimal and evaluation of more systemic therapies is warranted.

Overexpression of protease inhibitor-dead secretory leukocyte protease inhibitor causes more aggressive ovarian cancer in vitro and in vivo.

The alarm anti-protease secretory leukocyte protease inhibitor (SLPI) is frequently overexpressed in ovarian cancer cells and has been proposed for inclusion in biomarker panels but function remains unclear. We hypothesized that SLPI overexpression promotes ovarian cancer growth and survival. Low SLPI-expressing Hey-A8 ovarian cancer cells were engineered to produce functional (WT) or protease inhibitor-null (PI-) mutant SLPI; lack of PI activity was confirmed by enzymatic assay. WT/SLPI and PI- mutants stimulated significant proliferation and survival of Hey-A8 ovarian cancer cells under basal culture conditions (P < or = 0.02), in soft agar colony number and size (P < or = 0.05), and in anoikis resistance (P < or = 0.005). SLPI protected the ovarian cancer survival factor, progranulin (PRGN), and HEY-A8 cells from degradation and apoptosis due to neutrophil elastase. PI-/SLPI cells had greater protective activity than WT/SLPI cells. HEY-A8 murine xenografts revealed enhanced solid tumor formation, dissemination, and invasion in WT/SLPI and PI-/SLPI mutants. Increased proliferation was demonstrated by Ki-67 staining (P < or = 0.02). Increased secreted PRGN was seen in culture and was also observed by immunohistochemistry in the SLPI transfectant xenografts. This study describes a PI-independent function for SLPI in ovarian cancer growth and dissemination.