Sentinel Lymph Node Ultra-staging as a Supplement for Endometrial Cancer Intraoperative Frozen Section Deficiencies.

For endometrial cancer (EC), most surgeons rely on intraoperative frozen section (IFS) to determine the risk of nodal metastasis and necessity of lymphadenectomy. IFS remains a weak link in this practice due to its susceptibility to diagnostic errors. As a less invasive alternative, sentinel lymph node (SLN) mapping and ultra-staging have gradually gained acceptance for EC. We aimed to establish the SLN success rate, negative predictive value, and whether SLNs provide useful information for cases misdiagnosed on IFS. From 2013 to 2017, 100 patients (63 low-risk and 37 high-risk EC) underwent hysterectomy, bilateral salpingo-oophorectomy, and SLN. Among them, 56 had additional pelvic lymphadenectomy. A total of 337 SLNs were obtained in 86 cases: 55 bilaterally and 31 unilaterally. The remaining 14 cases failed because of patient obesity or leiomyoma. Pathology ultra-staging detected 2 positive SLNs from 2 patients (1 with isolated tumor cells, 1 with micrometastases). One of 773 nonsentinel pelvic nodes was positive on the contralateral hemi-pelvis in a patient who was mapped unilaterally, resulting in negative predictive value of 100%. During IFS, tumor grade and/or depth of myometrial invasion was misdiagnosed in 22 cases (22%). These errors would have resulted in under-staging in 10 high-risk patients or over-staging in 4 low-risk patients. SLNs were mapped in these misestimated patients, with one revealing metastases. SLN provides invaluable information on nodal status while detecting occult metastases in cases misdiagnosed on IFS. Our findings justify the incorporation of SLN in initial surgery for EC as an offset to IFS diagnostic errors, minimizing their negative impact on patient care.

Interferon regulatory factor 1 is an independent predictor of platinum resistance and survival in high-grade serous ovarian carcinoma.

OBJECTIVE: High-grade serous ovarian cancer (HGSOC) that is resistant to platinum-based chemotherapy has a particularly poor prognosis. Response to platinum has both prognostic survival value and dictates secondary treatment strategies. Using transcriptome analysis, we sought to identify differentially expressed genes/pathways based on a tumor's platinum response for discovering novel predictive biomarkers. METHODS: Seven primary HGSOC tumor samples, representing two extremes of platinum sensitivity/timing of disease recurrence, were analyzed by RNA-Seq, Ingenuity Pathways Analysis (IPA) and Upstream Regulator Analysis (URA), and used to explore differentially expressed genes and prevalent molecular and cellular processes. Progression-free and overall survival (PFS, OS) was estimated using the Kaplan-Meier method in two different sample sets including GEO and TCGA data sets. RESULTS: IPA and URA highlighted an IRF1-driven transcriptional program (P=0.0017; z-score of 3.091) in the platinum sensitive improved PFS group. QRT-PCR analysis of 31 HGSOC samples demonstrated a significant difference in PFS between low and high IRF1 expression groups (P=0.048) and between groups that were platinum sensitive versus not (P=0.016). In a larger validation data set, increased levels of IRF1 were associated with both increased PFS (P=0.043) and OS (P=0.019) and the effect on OS was independent of debulking status (optimal debulking, P=0.025; suboptimal, P=0.041). CONCLUSION: Transcriptome analysis identifies IRF1, a transcription factor that functions both in immune regulation and as a tumor suppressor, as being associated with platinum sensitivity and an independent predictor of both PFS and OS in HGSOC.

Survival analysis of robotic versus traditional laparoscopic surgical staging for endometrial cancer.

OBJECTIVE: The purpose of this study was to compare the survival of women with endometrial cancer managed by robotic- and laparoscopic-assisted surgery. STUDY DESIGN: This was a retrospective study conducted at 2 academic centers. Primary outcomes were overall survival, disease-free survival (DFS), and disease recurrence. RESULTS: From 2003 through 2010, 415 women met the study criteria. A total of 183 women had robotic and 232 women had laparoscopic-assisted surgery. Both groups were comparable in age, body mass index, comorbid conditions, histology, surgical stage, tumor grade, total nodes retrieved, and adjuvant therapy. With a median follow-up of 38 months (range, 4-61 months) for the robotic and 58 months (range, 4-118 months) for the traditional laparoscopic group, there were no significant differences in survival (3-year survival 93.3% and 93.6%), DFS (3-year DFS 83.3% and 88.4%), and tumor recurrence (14.8% and 12.1%) for robotic and laparoscopic groups, respectively. Univariate and multivariate analysis showed that surgery is not an independent prognostic factor of survival. CONCLUSION: Robotic-assisted surgery yields equivalent oncologic outcomes when compared to traditional laparoscopic surgery for endometrial adenocarcinoma.

The role of liver resection at the time of secondary cytoreduction in patients with recurrent ovarian cancer.

OBJECTIVE: The aim of this study is to determine the role of liver metastatectomy in the morbidity and survival of patients with recurrent ovarian carcinoma. METHODS: We retrospectively reviewed the records of all patients who had undergone hepatic resection for liver metastases from ovarian carcinoma at the time of cytoreductive surgery at our institution from 1988 to 2012. The Kaplan-Meier method was used for survival analysis. A total of 76 patients met the inclusion criteria and had undergone liver resection as part of cytoreductive surgery for ovarian carcinoma during the study period. Of these 76 patients, 27 underwent liver resection at the time of secondary cytoreduction, and these patients that are the focus of this analysis. RESULTS: Median overall survival for the study group from the time of diagnosis to the last follow-up or death was 56 months (range, 12-249 months). Twenty died of the disease with an overall median survival of 12 months from the time of the liver resection (2-190 months), and 7 patients were alive with the disease at the time of the last follow-up. Based on Kaplan-Meier survival analysis, the factors associated with the longest survival after the liver resection (2-190 months) were the interval from the primary surgery of less than 24 months versus more than 24 months (P = 0.044) and secondary cytoreduction to residual disease of less than 1 cm (P = 0.014). CONCLUSIONS: Based on our analysis of a single institution's series of ovarian cancer patients with hepatic metastasis, liver resection is feasible and safe and should be considered as an option in selected patients at the time of secondary cytoreduction.

Alterations in nuclear pore architecture allow cancer cell entry into or exit from drug-resistant dormancy.

Phenotypic diversity arises in tumors just as it does in developing organisms, and tumor recurrence frequently manifests from the selective survival of divergent drug-resistant cells. Although the expanding tumor cell population may be successfully targeted, drug-resistant cells may persist and sustain the tumor or enter dormancy before igniting a future relapse. Herein, we show that partial knockdown of nucleoporin p62 (NUP62) by small-interfering RNA confers cisplatin resistance to cultured high-grade ovarian carcinoma cells. Treatment with NUP62 small-interfering RNA and cisplatin leaves resistant cells in a state of dormancy; some dormant cells can be induced to proliferate by transient induction of NUP62 expression from an ectopic expression construct. In addition to suggesting functional links between nuclear pore complex architecture and cancer cell survival, the culture system provides a novel experimental window into the dynamics of tumor cell drug resistance and dormancy.

Does the type of surgery for early-stage endometrial cancer affect the rate of reported lymphovascular space invasion in final pathology specimens?

OBJECTIVE: Laparoscopically assisted vaginal hysterectomy (LAVH), which usually involves the use of an intrauterine manipulator for optimal surgical control, has been shown to be as effective and safe as conventional total abdominal hysterectomy (TAH) for the staging of endometrial carcinoma. The purpose of this study was to determine whether the use of an intrauterine manipulator was associated with an increase in the pathologic reporting of lymphovascular space invasion (LVSI), which is an important determinant in choosing adjuvant therapy. We hypothesized that intracavitary manipulation and an increase of the intrauterine pressure could cause pseudolymphovascular invasion. STUDY DESIGN: We performed a retrospective chart review of endometrial cancer patients treated at our institution from January 1996 through January 2006. Records were reviewed for patient's age, preoperative diagnosis, procedure type, final surgical staging, and final pathology report. Using the 2009 International Federation of Gynecology and Obstetrics staging, we included all patients having stage IA or IB endometrioid-type endometrial cancer who had undergone either a TAH or LAVH with or without pelvic and paraaortic lymph node dissection. The χ2 and Fisher exact tests were used to measure the association between risk of positive lymphovascular invasion and surgical groups. RESULTS: Of 568 women identified as having endometrioid-type endometrial cancer, 486 (85.6%) met criteria for stage IA-IB endometrioid histology, grade 1, 2, or 3. LVSI was reported in 553/568 cases, with LVSI positivity in 16.9% (n = 96/568). The mean ages of the LAVH and TAH groups were significantly different (59.4 vs 62.4 years, respectively, P = .0050). Also, mean estimated blood loss and uterine weight significantly varied between TAH and LAVH groups (P = .0001 and .008, respectively). For stage IA, 17/220 (7.7%) who had been treated with LAVH had positive LVSI compared with 20/199 (10.1%) of patients receiving TAH (P = .73). For stage IB, 11/25 (44.0%) of patients treated with LAVH had positive LVSI compared with 10/31 (32.3%) of patients receiving TAH (P = .53). The stage I cancer patients were further subdivided into histological grades 1, 2, and 3, and LVSI was not significantly different between TAH and LAVH groups per grade of cancer. We found no differences between TAH and LAVH in early-stage endometrial cancer (stage IA and IB), with respect to the presence of positive peritoneal washings. CONCLUSION: In early-stage endometrial cancer (stage IA and IB), there were no differences between TAH and LAVH in the final pathologic report of LVSI. The use of an intrauterine manipulator for LAVH was not associated with an increased detection of LVSI.

Role of FDG PET/CT in staging of recurrent ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer death among women in the United States and has a high likelihood of recurrence despite aggressive treatment strategies. Detection and exact localization of recurrent lesions are critical for guiding management and determining the proper therapeutic approach, which may prolong survival. Because of its high sensitivity and specificity compared with those of conventional techniques such as computed tomography (CT) and magnetic resonance (MR) imaging, fluorine 18 fluorodeoxyglucose positron emission tomography (PET) combined with CT is useful for detection of recurrent or residual ovarian cancer and for monitoring response to therapy. However, PET/CT may yield false-negative results in patients with small, necrotic, mucinous, cystic, or low-grade tumors. In addition, in the posttherapy setting, inflammatory and infectious processes may lead to false-positive PET/CT results. Despite these drawbacks, PET/CT is superior to CT and MR imaging for depiction of recurrent disease.

PET/CT evaluation of cervical cancer: spectrum of disease.

The prognosis of invasive cervical cancer is based on the stage, size, and histologic grade of the primary tumor and the status of the lymph nodes. Assessment of disease stage is essential in determining proper management in individual cases. In the posttherapy setting, the timely detection of recurrence is essential for guiding management and may lead to increased survival. However, the official clinical staging system of the International Federation of Gynecology and Obstetrics has inherent flaws that may lead to inaccurate staging and improper management. Combined positron emission tomography (PET)/computed tomography (CT) represents a major technologic advance, consisting of two integrated complementary modalities whose combined strength tends to overcome their respective weaknesses. PET/CT has higher sensitivity and specificity than do conventional anatomic modalities and is valuable in determining the extent of disease and detecting recurrent or residual tumor. The combination of 2-[fluorine-18]fluoro-2-deoxy-d-glucose PET with intravenous contrast material-enhanced high-resolution CT has proved useful for avoiding the interpretative weaknesses associated with either modality alone and in increasing the accuracy of staging or restaging. Nonetheless, accurate PET/CT interpretation requires a knowledge of the characteristics of disease spread or recurrence and an awareness of various imaging pitfalls if false interpretations are to be avoided.

Laparoscopic management of early ovarian and fallopian tube cancers: surgical and survival outcome.

OBJECTIVE: To evaluate the role of laparoscopy for staging of early ovarian cancers. STUDY DESIGN: Case series conducted at the University Hospital with 36 patients who had presumed early-stage adnexal cancers. Laparoscopic staging/restaging was performed. RESULTS: Cases included 20 invasive epithelial tumors, 11 borderline tumors, and 5 nonepithelial tumors. Mean number of peritoneal biopsies, paraaortic nodes, and pelvic nodes were 6, 12.23, and 14.84, respectively. Eighty-three percent of the patients had laparoscopic omentectomy. On final pathology, 7 patients were upstaged. Postoperative complications included 1 small bowel obstruction, 2 pelvic lymphoceles, and 1 lymphocele cyst. Mean duration of follow-up is 55.9 months. Three patients had recurrences. All patients are alive without evidence of the disease. CONCLUSION: This represents 1 of the largest series and longest follow-ups of laparoscopic staging for early-stage adnexal tumors. Laparoscopic staging of these cancers appears to be feasible and comprehensive without compromising survival when performed by gynecologic oncologists experienced with advanced laparoscopy.

Abdominal cocoon: an unexpected cause of ascites in a healthy patient.

Abdominal cocoon is the idiopathic fibrotic encasement of abdominal organs. It classically presents as small bowel obstruction in young women. In this case report, we present a rare example of a patient presenting solely with massive ascites of presumed gynecologic origin, who upon surgical exploration was found to have abdominal cocoon. We discuss the patient's unique disease presentation, unrevealing work-up and the treatment strategy pursued, and provide a review of the literature.

Patient clinical factors influencing use of hysterectomy in New York, 2001-2005.

OBJECTIVE: To determine the effect of patient clinical factors on the utilization of hysterectomy and alternatives of hysterectomy. STUDY DESIGN: The database of Empire Blue Cross Blue Shield was abstracted for all claims relating to a hysterectomy procedure or a hysterectomy-associated diagnosis during the 48 consecutive months of May 2001-April 2005. Two hundred ninety-five thousand one hundred forty-eight claim lines were abstracted and analyzed by CPT and diagnostic grouping codes. RESULTS: One thousand nine hundred seventy-two hysterectomies were performed during the time analyzed, and 5,077 hysterectomy alternatives. The mean age of all patients encountered was 39.1 years. Patients undergoing a hysterectomy alternative or hysterectomy had mean ages of 46.0 and 49.7 years, respectively. Abnormal bleeding was associated with the most encounters, while leiomyomata was associated with the most hysterectomies performed. CONCLUSION: Patients who undergo hysterectomy are, on average, older than those undergoing office management or hysterectomy alternatives. Procedures are most commonly associated with diagnosis of bleeding, leiomyomata, or cancer. Bleeding typically results in a hysterectomy alternative, while leiomyomata has the highest association with hysterectomy.

Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations.

PURPOSE: The aims of this study were to determine the incidence of BRCA mutations among Ashkenazi Jewish patients with fallopian tube carcinoma (FTC) or primary peritoneal carcinoma (PPC), to study the clinicopathologic features of these cancers, and to estimate the risks of these cancers in association with a BRCA mutation. PATIENTS AND METHODS: A retrospective review at two institutions identified 29 Jewish patients with FTC and 22 Jewish patients with PPC. These patients were genotyped for the three Ashkenazi Jewish BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). Surgical and pathologic information, family history, and survival data were obtained from hospital records. All statistical tests were two sided. RESULTS: Germline BRCA mutations were identified in five of 29 patients with FTC (17%) and nine of 22 patients with PPC (41%). Mutation carriers had a younger mean age at diagnosis than patients without a mutation (60 v 70 years; P =.002). The overall median survival was 148 months for mutation carriers and 41 months for patients without a mutation (P =.04). For BRCA mutation carriers, the lifetime risks of FTC and PPC were 0.6% and 1.3%, respectively. CONCLUSION: Substantial proportions of Ashkenazi Jewish patients with FTC or PPC are BRCA mutation carriers. Patients with BRCA-associated FTC or PPC are younger at diagnosis and have improved survival compared with patients without a BRCA mutation. Although the lifetime risks of FTC or PPC for patients with BRCA heterozygotes are greater than those for the general population, the absolute risks seem relatively low.

Minimally invasive management of an advanced abdominal pregnancy.

BACKGROUND: Advanced abdominal pregnancy is a rare, life-threatening condition that presents a number of challenges. CASE: A 29-year-old primigravida with 10 years of secondary infertility and a previous tuboplasty had a 21-week abdominal pregnancy treated with preoperative arterial embolization before laparoscopically assisted fetal delivery. Postoperatively, 4 cycles of methotrexate were administered at 50 mg/m2 intramuscularly every 3 weeks for the retained abdominal placenta. Subsequent spontaneous conception occurred, and a live, full-term infant was delivered by cesarean delivery 17 months later. No adverse sequelae were found during long-term follow-up. CONCLUSION: This report demonstrates successful minimally invasive management of an advanced abdominal pregnancy with a multimodal approach that included preoperative arterial embolization, laparoscopically assisted delivery, and judicious use of postoperative methotrexate.

Vacuum-assisted closure in the treatment of complex gynecologic wound failures.

BACKGROUND: Complex wound failures are a source of significant morbidity and mortality. They are costly and time consuming to treat, and may evolve into chronic, debilitating conditions. Vacuum-assisted closure is a novel wound healing technique applying subatmospheric pressure to wounds to expedite healing. CASES: We report the successful use of vacuum-assisted closure therapy on three patients on a gynecologic oncology service with complex wound failures of various chronicity. In all cases, vacuum-assisted closure therapy was well tolerated and demonstrated efficacy within 48 hours of initiation. CONCLUSION: We conclude that vacuum-assisted closure therapy should be included in the armamentarium of the gynecologist addressing complex wound failures.

The incidence of port-site metastases in gynecologic cancers.

OBJECTIVES: To determine the incidence of port-site metastases in patients undergoing laparoscopic procedures for gynecologic cancers. METHODS: The charts of patients treated by laparoscopy for diagnosis, treatment, or staging of gynecologic cancers by the academic faculty attending physicians were studied from July 1, 1997 to June 30, 2001. No patient without a histological or cytological diagnosis of cancer from the index procedure were included. Fisher's exact test was used for statistical analysis. RESULTS: Eighty-three patients were identified accounting for 87 procedures. Types of cancer treated included endometrial (39), ovarian (29), and cervical (14). Twenty procedures were performed for recurrence of ovarian or peritoneal cancer, and ascites was present in 10 cases. Port-site metastases occurred in 2 patients accounting for 8 sites. Five sites were diagnosed in a single patient 13 days after a second-look laparoscopy for stage IIIB ovarian cancer, and 3 sites were diagnosed in a patient 46 days after an interval laparoscopy for stage IIIC primary peritoneal cancer. Ascites was present in both patients. The overall incidences of port-site metastases per procedure and per port placed were 2.3% (2/87) and 2.4% (8/330), respectively. In patients with a recurrence of ovarian or peritoneal cancer, no port-site metastases (0/16) occurred in the absence of ascites, whereas 50% (2/4) of patients with ascites developed port-site metastases (P < .035). CONCLUSIONS: The overall incidence of port-site metastases in gynecologic cancers in our study was 2.3%. The risk of port-site metastases is highest (5%) in patients with recurrence of ovarian or primary peritoneal malignancies undergoing procedures in the presence of ascites.

microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition.

Ovarian cancer is a leading cause of cancer deaths among women. Effective targets to treat advanced epithelial ovarian cancer (EOC) and biomarkers to predict treatment response are still lacking because of the complexity of pathways involved in ovarian cancer progression. Here we show that miR-181a promotes TGF-ß-mediated epithelial-to-mesenchymal transition via repression of its functional target, Smad7. miR-181a and phosphorylated Smad2 are enriched in recurrent compared with matched-primary ovarian tumours and their expression is associated with shorter time to recurrence and poor outcome in patients with EOC. Furthermore, ectopic expression of miR-181a results in increased cellular survival, migration, invasion, drug resistance and in vivo tumour burden and dissemination. In contrast, miR-181a inhibition via decoy vector suppression and Smad7 re-expression results in significant reversion of these phenotypes. Combined, our findings highlight an unappreciated role for miR-181a, Smad7, and the TGF-ß signalling pathway in high-grade serous ovarian cancer.

Recent advances in the surgical management of cervical cancer.

Recent advances in the surgical management of early cervical cancer, including abdominal, laparoscopic, vaginal, and robotic approaches to radical hysterectomy as well as fertility-sparing radical trachelectomy, are reviewed. The nerve-sparing abdominal radical hysterectomy technique allows for a significant reduction in postoperative bladder morbidity. Radical vaginal hysterectomy with laparoscopic lymph node dissection is a well-recognized technique that offers excellent cure rates without abdominal entry as well as reduced postoperative febrile and gastrointestinal morbidity. Total laparoscopic radical hysterectomy is a minimally invasive alternative to the traditional abdominal radical hysterectomy approach and yields a comparable safety profile with a significant reduction in blood loss and hospital stay. Robotic surgery is becoming more widely accepted in the management of gynecologic cancers, including radical hysterectomy for early cervical cancer. Young women desiring to bear children in the future may be candidates for fertility preservation options, and the radical trachelectomy operation has been described and performed with abdominal, vaginal, laparoscopic, and robotic techniques. There are a number of surgical options for the treatment of women with early cervical cancer. The feasibility and safety of some of these techniques have been well established, whereas for others, the oncological outcome data are only preliminary. The decision to use newer techniques should be directed by patient variables as well as the surgeon's training and competence with laparoscopy, robotics, or vaginal surgery.

Chemotherapy for gynecologic cancers.

This review highlights significant recent developments and trends in chemotherapy for major gynecologic malignancies, i.e., ovarian cancer, endometrial cancer, uterine sarcomas, gestational trophoblastic neoplasia, and cervical cancer. In ovarian cancer, chemotherapeutic options for early, advanced and recurrent disease are in the adjuvant setting as well as in the neoadjuvant setting are explored. For uterine cancer, adjuvant chemotherapy is employed for high risk epithelial subtypes with early disease, such as uterine papillary serous carcinomas, uterine carcinosarcomas and leiomyosarcomas, advanced stage cases, as well as recurrent disease. The review then proceeds to further discuss the appropriate treatment based on the International Federation of Gynecology and Obstetrics prognostic scoring system for gestational trophoblastic neoplasia. Finally, chemotherapy is utilized in cervical cancer as neo-adjuvant therapy prior to surgery or radiation, as a sensitizer concomitantly with radiation therapy or for the treatment of advanced and recurrent disease.

Analysis of survival after laparoscopic management of endometrial cancer.

STUDY OBJECTIVE: To assess the effect of laparoscopic surgery on the survival of women with early-stage endometrial cancer and to analyze the factors that affect survival. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary teaching hospital. PATIENTS: Women with clinical stage I and II endometrial cancer (International Federation of Gynecology and Obstetrics staging, 1971) from January 1993 through June 2003. INTERVENTION: Demographic, surgical, perioperative, and pathologic characteristics of women treated with laparoscopy or laparotomy were compared by use of Fisher's exact test or the Student t test. Recurrence-free and overall survival was calculated by use of the Kaplan-Meier method. Stratified analyses were performed with the log-rank test for factors affecting survival (surgical stage, histologic study, and grade). MEASUREMENTS AND MAIN RESULTS: Sixty-seven and 127 women were treated with laparoscopy and laparotomy, respectively. Median follow-up was 36.3 months for the laparoscopy group and 29.6 months for the laparotomy group. The complication rates in the 2 groups were comparable. Women undergoing laparoscopy had shorter hospital stay and less morbidity related to infection. The 2- and 5-year estimated recurrence-free survival rates for the laparoscopy and laparotomy groups (93 % vs 91.7% and 88.5% vs 85%, respectively), as well as the overall 2- and 5-year survival rates (100% vs 99.2% and 100% vs 97%, respectively) were similar. CONCLUSIONS: Laparoscopic surgery in women with early-stage endometrial carcinoma resulted in survival rates similar to laparotomy, although a small sample size precludes definitive conclusions. A larger randomized comparison of the 2 techniques is needed to validate these findings.