Margaux J. Kanis

Survival of women with Mullerian adenosarcoma: A National Cancer Data Base study

OBJECTIVE To determine overall survival (OS) and factors associated with OS of women with Mullerian adenosarcoma. METHODS Women with adenosarcoma of the uterus, cervix or ovary (n=2205) were identified from the 1998-2011 National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. A subset analysis of women with uterine adenosarcoma was also performed. Analyzed confounders included age, insurance status, income, race, surgical margin status, nodal and distant metastasis, surgical procedure type, and treatment with radiation and/or chemotherapy. RESULTS Primary sites were uterus (n=1884), cervix (n=229) and ovary (n=92), representing 0.43% of uterine, 0.16% of cervical, and 0.04% of ovarian cancers in the NCDB. Only 36/1176 (3.1%) and 2.5% (33/1,342) had nodal and/or distant metastasis, respectively, at diagnosis. Distant metastasis, positive surgical margin, increased age, higher composite comorbidity score and adjuvant radiotherapy were independently associated with decreased OS. Primary site, lymph node status, surgical procedure, chemotherapy use, race, insurance status and income quartiles were not significantly associated with OS. Each 1cm increase in tumor size was associated with increased hazard for death (HR (95% CI) 1.06 (1.01-1.12), p=0.018) among women with uterine adenosarcoma. CONCLUSION Complete surgical resection remains the only treatment with well-evidenced OS benefit among women with Mullerian adenosarcoma. Early surgical resection may increase survival of Mullerian adenosarcoma.

Receipt of vaginal brachytherapy is associated with improved survival in women with stage I endometrioid adenocarcinoma of the uterus: A National Cancer Data Base study.

Randomized controlled trials have consistently shown that the use of postoperative radiotherapy (RT) for stage I endometrial cancer leads to a reduction in the incidence of pelvic recurrences without a corresponding reduction in overall mortality. It was hypothesized that a reduction in mortality associated with the receipt of RT could be identified in a large data set with greater statistical power.

Is it necessary to perform routine appendectomy for mucinous ovarian neoplasms? A retrospective study and meta-analysis

OBJECTIVES To evaluate whether routine appendectomy is necessary in all patients with mucinous borderline ovarian tumor (mBOT) or mucinous ovarian cancer (MOC) who undergo gynecologic surgery. METHODS The database of Qilu Hospital was searched for women who underwent appendectomy in a primary surgery for an ovarian tumor between June 2005 and June 2015 and whose final diagnosis was mBOT, MOC or primary appendiceal tumor. A retrospective review was performed, as well as a meta-analysis of the literature to further validate the findings. RESULTS Seventy-one patients, 29 with mBOT and 42 with malignant mucinous tumors (including 40 with primary MOC and 2 with appendiceal mucinous adenocarcinoma), underwent appendectomy at the time of primary surgery. Among those with mBOT, two (6.9%) appendices were grossly abnormal and pathologically diagnosed with appendiceal implantation by mBOT. In the 42 patients with malignant disease, five (12%) appendices had a grossly abnormal appearance, one (2.4%) was diagnosed with an appendiceal metastasis from MOC and two (4.7%) were primary appendiceal adenocarcinoma. For grossly normal appendices, only one (2.4%) was confirmed to have microscopic metastasis from MOC. The meta-analysis included a total of 914 mBOT and MOC cases with appendectomies, including our current cases. The estimated rate of overall appendiceal pathology is 4.97%, and the pooled odds ratio (OR) showed statistical differences between MOC and mBOT (MOC vs. mBOT, OR=2.15, P<0.05). The estimated malignant pathology rate in macroscopically normal vs. abnormal appendices is 1.4% and 59%, respectively, with an estimated OR up to 97.5 (95% CI 28.1-338.5, P<0.05). CONCLUSION There is not sufficient evidence to support a routine appendectomy for patients with a grossly normal appendix in mBOT and MOC. A careful intra-operative exploration of the appendix is crucial, but appendectomy is only warranted when the appendix is abnormal.

Oncologic and obstetrical outcomes with fertility-sparing treatment of cervical cancer: a systematic review and meta-analysis

OBJECTIVE The objectives of this study were to evaluate the rates of recurrence, survival and pregnancy, and characterize pregnancy outcomes of early-stage cervical cancer(eCC) treated with fertility-sparing methods such as cervical conization (CON) and radical trachelectomy(RT) with or without pelvic lymphadenectomy. STUDY DESIGN This was a meta-analysis of observational studies analyzed by a random-effects model and a meta-regression to assess heterogeneity. RESULTS Sixty observational studies encompassing 2,854 patients were included; 17 of which evaluated CON and 43 RT. Three hundred and seventy-five patients were included in the CON group: 176(46.9%) stage IA1 and 167(44.5%) stage IB1. In the RT group, 2479 cases were included: 143(6.0%) stage IA1, 299(12.1%) stage IA2, 1987(79.9%) stage IB1. CON was performed in 347(92.5%) cases, resulting in a recurrence rate of 0.4%(95%CI: 0.0%-1.4%), a death rate of 0%(0%-0%), a pregnancy rate of 36.1%(26.4%-46.2%), a spontaneous abortion rate of 14.8%(9.3%-21.2%) and a preterm delivery rate of 6.8%(1.5%-15.5%). For the RT group, 2273(91.7%) underwent successful surgeries with a recurrence rate of 2.3%(1.3%-3.4%),a death rate of 0.7%(0.3%-1.1%), a pregnancy rate of 20.5%(16.8%-24.5%), a spontaneous abortion rate of 24.0%(18.8%-29.6%) and a preterm delivery rate of 26.6%(19.6%-34.2%). From a subgroup analysis, the recurrence rates for stage IA tumors treated with CON and RT were 0.4%(0.0%-1.9%) and 0.7%(0.0%-2.3%), respectively; and for stage IB were 0.6%(0.0%-2.7%) and 2.3%(0.9%-4.1%). CONCLUSION Fertility-sparing treatment including CON or RT for eCC is feasible and carefully selected women can preserve fertility and achieve pregnancy resulting in live births. CON seems to result in better pregnancy outcomes than RT with similar rates of recurrence and mortality.

Role of adjuvant external beam radiotherapy and chemotherapy in one versus two or more node-positive vulvar cancer: A National Cancer Database study

BACKGROUND AND PURPOSE Inguinal lymph node involvement is considered the most important prognostic risk factor for survival in vulvar cancer. However, controversy exists concerning the optimal adjuvant therapy for node-positive disease. This study sought to identify the optimal adjuvant therapy for each subset of women with node-positive disease. MATERIAL AND METHODS The National Cancer Database (NCDB) was queried to identify women with inguinal node positive vulvar cancer. Survival analysis was performed using log-rank test, the Kaplan-Meier estimates, and Cox proportional hazards to both clarify prognosis and identify the benefit of each treatment modality in individual subsets of women. RESULTS A total of 2779 women with inguinal node positive vulvar cancer were identified. On multivariate Cox model hazard ratio, radiotherapy yielded a survival advantage for women with one positive node (HR 0.81, p = 0.027) and two or more positive nodes (HR = 0.59, p < 0.001). The addition of chemotherapy to radiotherapy yielded an incremental improvement in survival for women with 2 or more positive nodes (HR = 0.79, p = 0.022) but not women with 1 positive node (HR = 0.93, p = 0.605). CONCLUSIONS All patients with node positive disease benefited from radiotherapy. By contrast, only those with 2 or more positive nodes benefited from the addition of chemotherapy to radiotherapy.

A small molecule inhibitor of the perinucleolar compartment, ML246, attenuates growth and spread of ovarian cancer

BackgroundOvarian cancer remains a major health problem for women as it is often diagnosed at a late stage with metastatic disease. There are limited therapeutic agents and survival rates remain poor. The perinucleolar compartment (PNC) has been shown to be associated with malignancy and is considered a surrogate phenotypic marker for metastatic cancer cells. A small molecule, ML246, was derived from a screen against PNCs. In this study, the effect of ML246 on ovarian cancer growth and spread was investigated.MethodsSKOV3 or OVCAR3 cells were treated with ML246 in vitro and PNC was visualized with immunofluorescent staining. Cell invasion was assessed using Matrigel-coated transwell systems. SKOV3 cells were xenografted orthotopically under the ovarian bursa of immunocompromised mice. Additionally, a patient derived ovarian cancer cell line was grafted subcutaneously. Mice were treated with ML246 and tumor growth and spread was assessed.ResultsPNCs were prevalent in the ovarian cancer cell lines OVCAR3 and SKOV3 with higher prevalence in OVCAR3 cells. Treatment with ML246 significantly reduced PNC prevalence in OVCAR3 and SKOV3 cells. Moreover, the invasive activity of both cell lines was significantly inhibited in vitro. Orthotopic implantation of SKOV3 cells resulted in growth of the tumor on the ovary as well as spread of tumor tissues outside of the primary site on organs into the abdominal cavity. Treatment with ML246 decreased the incidence of tumors outside of the ovary. In addition, a patient-derived xenograft (PDX) line was grafted subcutaneously to monitor tumor growth. ML246 significantly attenuated growth of tumors over a 5-week treatment period.ConclusionsPNC’s are present in ovarian cancer cells and treatment with ML246 decreases invasion in vitro and tumor growth and spread in vivo. Additional studies are warranted to determine the efficacy of ML246 as an inhibitor of metastatic disease in ovarian cancer and to determine its precise mechanism of action.

Comparison among fertility-sparing therapies for well differentiated early-stage endometrial carcinoma and complex atypical hyperplasia

Objective To compare fertility-sparing therapies including oral progestogens, hysteroscopic resection (HR), and the levonorgestrel- releasing intrauterine system (LNG-IUS) in achieving disease regression, recurrence and live birth rate in well differentiate early-stage endometrial carcinoma (eEC) and complex atypical hyperplasia(CAH). Study Design This was a meta-analysis of previous studies focus on the fertility-sparing therapy for well differentiate early-stage endometrial carcinoma (eEC) and complex atypical hyperplasia (CAH). Date Sources Medline, the Cochrane Library and Embase was searched with the terms and Synonyms: words similar to eEC and CAH with therapies associated with fertility-sparing. Main Outcome Measures The number of all patients accepted fertility sparing therapies, patients got regressed, relapsed and delivered were extracted from each study, and the regression, recurrence, and live birth rate of each study were calculated. The regression, recurrence and live birth rates between each two interventions were compared with the aid of meta-regression in packages of “meta” and ”meta for” written in R. Results Fifty-four studies reported fertility sparing therapies in young women with eEC and CAH were included. Meta-analysis showed that HR followed by progestogens achieved a higher pooled regression (98.06% vs 77.20% P < 0.0001) and live birth rate (52.57% vs 33.38%, P = 0.0944) and a lower recurrence rate compared with oral progestogens alone (4.79% vs 32.17% P = 0.0004). At the same time, the pooled live birth rate (52.57% vs 18.09% P =0.0399) of HR followed by progestogens are significantly higher than the LNG-IUS alone. Which no statistical difference in regression (98.06% vs 94.24%; P = 0.4098) and recurrence rates (4.79% vs 3.90% P = 0.8561) was seen. Conclusions Of the available fertility-sparing therapeutic options, HR followed by progestogens may be a more effective one.

The selected biomarker analysis in 5 types of uterine smooth muscle tumors

Uterine smooth muscle tumors (USMTs) consist of a group of histologically heterogeneous and clinically diverse diseases ranging from malignant leiomyosarcoma (LMS) to benign leiomyoma (ULM). The genetic alterations in LMS are complex, with some genetic alterations present in both LMS and other atypical histologic variants of USMT. In this study, we reviewed 119 USMTs with a diagnosis of LMS, smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, and cellular leiomyoma, as well as 46 ULMs and 60 myometrial controls. We selected 17 biomarkers highly relevant to LMS in 4 tumorigenic pathways including steroid hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]), cell cycle/tumor suppressor genes, AKT pathway markers, and associated oncogenes. ER and PR expression was significantly lower in LMS than smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, cellular leiomyoma, and ULM (P < .01). Sixty-five percent of LMSs showed complete loss of ER, and 75% of LMSs showed complete loss of PR. All cell cycle genes were differentially expressed in different types of tumor, but significant overlap was noted. More than 75% of LMSs had Ki-67 index greater than 33%, and only 5% in all other types of USMT. Expression of the selected oncogenes varied widely among different types of USMT. PR positivity and p53 had a borderline association with progression-free survival (P = .055 for PR and P = .0847 for p53). Furthermore, high PR expression was significantly associated with a longer overall survival (P = .0163, hazard ratio 0.198). Cell proliferative indices (Ki-67) and sex steroid hormone receptors were the most valuable markers in differentiating LMS from other USMT variants.

Pulmonary resection in the management of high-risk gestational trophoblastic neoplasia

Objective The aim of this study was to evaluate the role of pulmonary resection in the management of high-risk gestational trophoblastic neoplasia (GTN). Methods Patients who underwent pulmonary resection as part of their treatment for chemotherapy-resistant high-risk GTN from 1986 and 2014 were retrospectively analyzed. All patients had received 1 or more multiagent chemotherapy regimens preoperatively. Patient and disease characteristics were evaluated with respect to outcome. Results Fifteen (26%) of 58 patients treated for high-risk GTN underwent pulmonary resection with curative intent. Mean age of patients was 29 years (range, 19–37 years). International Federation of Gynecology and Obstetrics stage was III in 12 and IV in 3. International Federation of Gynecology and Obstetrics scores ranged from 5 to 20 (mean, 10). Antecedent pregnancy was nonmolar in 11 patients (73%). Adjuvant surgical procedures other than pulmonary resection were performed in 8 patients (53%). Preoperative chemotherapy regimens ranged from 1 to 10 (median, 4) and courses numbered from 2 to 32 (median, 14). Preoperative human chorionic gonadotropin (hCG) levels ranged from 2 to 2786 mIU/mL (median, 177 mIU/mL). Pulmonary wedge resections or lobectomies were performed via video-assisted thoracoscopic surgery (11) or thoracotomy (4). Two patients underwent pulmonary resections on 2 separate occasions. No patient had complications as a result of these procedures. Eleven patients (73%) were cured. In these 11 patients, hCG levels decreased to less than 2 mIU/mL within 6 to 52 days (mean, 22 days) postoperatively. Conclusions Pulmonary resection of chemotherapy-resistant GTN was an important component of treatment in 26% of high-risk patients, 73% of whom were cured. Ideal candidates have disease isolated to the lungs and low hCG levels.

Abstract 5020: Associations of clinical, molecular and immunohistochemical parameters in five different types of uterine smooth muscle tumors

Objective: To evaluate clinical, molecular and pathologic factors associated with 5 types of uterine smooth muscle tumors. Materials and Methods: Seventy-nine patients with leiomyosarcoma [31 (39.2%) LMS], smooth muscle tumors of undetermined significance [10 (12.7%) STUMP], atypical leiomyoma [19 (24.1%) ALM], mitotically active leiomyoma [5 (6.3%) MALM], and cellular leiomyoma [14 (17.7%) CLM] treated from 1997-2015 were analyzed. Statistical analysis was performed using ANOVA, chi-square and logrank tests. Results: Mean age (years) differed across histologies: 54 (LMS), 36 (STUMP), 41 (ALM), and 47 (CLM/MALM) (p Of 6 gene markers examined by immunohistochemistry (IHC), ER and PR expression were significantly lower in LMS than in other types (p Conclusions: ER/PR and Ki67 IHC are valuable biomarkers in differentiating histology and predicting clinical recurrence in uterine smooth muscle tumors. Smoking cessation is key to decreasing recurrence. Citation Format: Margaux J. Kanis, Jennifer L. Bender, Anna E. Strohl, Denise Scholtens, Dachao Liu, John Lurain, Shohreh Shahabi, Jian-Jun Wei. Associations of clinical, molecular and immunohistochemical parameters in five different types of uterine smooth muscle tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5020.