E.M. Hinchcliff

The value of re-exploration in patients with inadvertently morcellated uterine sarcoma

OBJECTIVE To describe the role of immediate re-exploration in patients with inadvertently morcellated uterine leiomyosarcoma (ULMS) and smooth muscle tumors of uncertain malignant potential (STUMP). METHODS All patients with ULMS/STUMP who were managed or referred to the participating institutions from January 2005 to January 2012 following minimally invasive gynecology surgery with morcellation were detected through the pathology database. The diagnosis was confirmed by gynecologic-pathologists following post-surgery pathology review. RESULTS Twenty-one patients with the diagnosis of ULMS (N = 15) and STUMP (N = 6) after morcellation were identified. The median age of occurrence was 46 years (range, 25-58 years). Median follow-up duration was 27 months (range, 1.8-93.1 months). None of the 21 patients had documented evidence of extra-uterine disease at the time of original surgery. Ultimately 12 patients were immediately re-explored to complete staging. The median time to the staging surgery was 33 days (range 15-118 days). Two (28.5%) out of seven patients with presumed stage I ULMS and one (25%) out of four patients with presumed stage I STUMP had significant findings of disseminated intraperitoneal disease detected at immediate surgical re-exploration. One of the 8 patients with confined early ULMS and STUMP at the second surgery had intraperitoneal recurrence, while the remaining 7 patients have had no recurrence and remain disease free. CONCLUSION Surgical re-exploration is likely to show findings of disseminated peritoneal sarcomatosis in a significant number of patients diagnosed with ULMS after a morcellation procedure. Findings from re-exploration can contribute to the knowledge of natural history of morcellated ULMS/STUMP and allow for accurate prognostication.

Trends in the use of neoadjuvant chemotherapy for advanced ovarian cancer in the United States.

OBJECTIVE Neoadjuvant chemotherapy and interval debulking surgery for the treatment of advanced ovarian cancer has remained controversial, despite the publication of two randomized trials comparing this modality with primary cytoreductive surgery. This study describes temporal trends in the utilization of neoadjuvant chemotherapy and interval debulking surgery in clinical practice in the United States. METHODS We completed a time trend analysis of the National Cancer Data Base. We identified women with stage IIIC and IV epithelial ovarian cancer diagnosed between 2004 and 2013. We categorized subjects as having undergone one of four treatment modalities: primary cytoreductive surgery followed by adjuvant chemotherapy, neoadjuvant chemotherapy followed by interval debulking surgery, surgery only, and chemotherapy only. Temporal trends in the frequency of treatment modalities were evaluated using Joinpoint regression, and χ2 tests. RESULTS We identified 40,694 women meeting inclusion criteria, of whom 27,032 (66.4%) underwent primary cytoreductive surgery and adjuvant chemotherapy, 5429 (13.3%) received neoadjuvant chemotherapy and interval surgery, 5844 (15.4%) had surgery only, and 2389 (5.9%) received chemotherapy only. The proportion of women receiving neoadjuvant chemotherapy and surgery increased from 8.6% to 22.6% between 2004 and 2013 (p<0.001), and adoption of this treatment modality occurred primarily after 2007 (95%CI 2006-2009; p=0.001). During this period, the proportion of women who received primary cytoreductive surgery and chemotherapy declined from 68.1% to 60.8% (p<0.001), and the proportion who underwent surgery only declined from 17.8% to 9.9% (p<0.001). CONCLUSION Between 2004 and 2013 the frequency of neoadjuvant chemotherapy and interval surgery increased significantly in the United States.

Racial disparities in survival in malignant germ cell tumors of the ovary

OBJECTIVE To investigate racial disparities with respect to adjuvant treatment and survival in patients presenting with malignant ovarian germ cell tumors (OGCT). METHODS The National Cancer Database (NCDB) was used to identify women diagnosed with OGCT. Demographic data were abstracted, including stratification by race and histology. Standard univariate and multivariate analyses using logistic regression were performed to describe predictors of adjuvant treatment. Kaplan-Meier and Cox proportional hazards survival methods were used to evaluate racial differences in survival between African American (AA) and white (W) women. RESULTS The study population included 2196 patients, with 1654 (75.3%) W and 328 (14.9%) AA women. Histologic distribution varied significantly by race (p<0.0001), but neither age nor stage at presentation showed racial differences (p=0.086 and p=0.209, respectively). AA received more chemotherapy than W (W: 54.6%, AA: 65.5%, p=0.008), but in multivariate analysis there was no statistically significant difference in any adjuvant treatment modality. Despite similar treatment, and independent of histology, survival varied significantly by race with 91% (CI 0.89-0.93) five year survival in W patients compared to 84% five year survival in AA (CI 0.8-0.89) (p=0.02). These disparities were most pronounced in advanced stage disease, with 5 year survival of 84% (CI 0.79-0.89) in W compared to 61% (CI 0.48-0.78) for AA in stage III (p=0.0002), and 54% (CI 0.42-0.68) compared to 14% (CI 0.03-0.71) for stage IV (p=0.05). CONCLUSIONS AA with OGCT have significantly worse 5 year survival when compared to W patients despite similar rates and modalities of adjuvant treatment.

Outcome of neoadjuvant chemotherapy in BRCA1/2 mutation positive women with advanced-stage Müllerian cancer

OBJECTIVES To investigate whether patients with germline BRCA1/2 mutations who received neoadjuvant chemotherapy (NAC) for advanced-stage Müllerian cancer (MC) have an improved outcome compared to patients who did not undergo genetic testing. METHODS Three hundred and two patients who received NAC for stage III-IV MC were identified from a multi-institutional study involving Cleveland Clinic and Brigham and Womens Hospital for 2000-2014 and 2010-2014 respectively. Patients were divided into 3 cohorts: patients with germline BRCA1/2 mutations (BRCA_mut+; N=30), patients with no genetic testing (BRCA_mut_unk; N=166) and patients with negative genetic testing (BRCA_mut-, N=106). RESULTS There were no differences in the clinical characteristics and rates of complete cytoreduction and bowel resection between the three groups. BRCA_mut+ had longer PFS compared to BRCA_mut_unk and BRCA_mut- (19.1 vs. 15.1 vs. 15.7months respectively. However, this difference was not statistically significant (p=0.48). Patients with BRCA2 mutation had non-significant trend toward longer PFS compared to patients with unknown BRCA or BRCA1 mutation (20.2 vs. 15.1 vs. 14.8months respectively, p=0.58). BRCA_mut+ and BRCA_mut- had longer overall survivals (OS) compared to BRCA_mut_unk patients (50.5 vs. 54.1 vs. 36.5months respectively, p=0.009). In multivariable analyses, controlling for age, stage and complete cytoreduction, BRCA_mut_unk was associated with worse PFS (HR 1.44, 95% CI 1.01-2.05, p=0.045) and OS (HR 2.67, 95% CI 1.33-5.36, p=0.006). CONCLUSIONS Patients with germline BRCA mutations had improved outcomes with NAC compared to patients with unknown BRCA status. These outcomes were more favorable compared to the outcome of NAC in prior studies.

Clinical characteristics and outcomes of patients with stage I epithelial ovarian cancer compared with fallopian tube cancer

OBJECTIVE The purpose of this study was to compare clinical characteristics and survival between patients with stage I epithelial ovarian cancer and fallopian tube cancer. STUDY DESIGN We identified women with stage I epithelial ovarian cancer and fallopian tube cancer who underwent treatment from 2000-2010. Correlation between categoric variables was assessed with χ2 test. The Kaplan-Meier survival analysis was used to generate overall survival data. Factors predictive of outcome were compared with the use of the log-rank test and Cox proportional hazards model. RESULTS The study group consisted of 385 women with epithelial ovarian cancer and 43 women with fallopian tube cancer. Patients with fallopian tube cancer had a higher rate of stage IA disease (65% vs 48%; P=.02) and grade 3 tumors (60.4% vs 30.9%; P<.001). Patients with fallopian tube cancer had a significantly higher rate of breast cancer (25.6% vs 5.7%; P<.001) and BRCA 1 mutations (45.8% vs 9.1%; P<.001). There was no difference in the rates of platinum-based and paclitaxel chemotherapy between the groups. Women with fallopian tube cancer were more likely to have received ≥6 cycles of chemotherapy (58.1% vs 44.1%; P=.02). The 5-year disease-free survival rates were 100% in women with fallopian tube cancer and 93% in patients with epithelial ovarian cancer (P=.04). The 5-year overall survival rates were 100% and 95% for fallopian tube cancer and epithelial ovarian cancer, respectively (P=.7). CONCLUSION We found a higher rate of stage IA, grade 3, and serous carcinoma in fallopian tube cancer. Women with fallopian tube cancer had a higher rate of breast cancer. There was no difference in overall survival between the groups.

Laparoscopic Hysterectomy for Uterine Fibroids: Is it Safe?

As more complex cases and larger uterine specimens are able to be managed with minimally invasive surgery, the limitations of tissue retrieval with these methods are of increasing concern. Risks of morcellator-related injury, tissue dissemination, or fragmentation must be weighed against increased morbidity of abdominal approach to hysterectomy. In an effort to mitigate the risks of tissue morcellation, containment system use must be considered when fragmenting a specimen, either with power morcellation or a manual technique via the vagina or minilaparotomy.

Intensive care admissions among ovarian cancer patients treated with primary debulking surgery and neoadjuvant chemotherapy-interval debulking surgery

OBJECTIVE Admissions to intensive care units (ICU) are costly, but are necessary for some patients undergoing radical cancer surgery. When compared to primary debulking surgery (PDS), neoadjuvant chemotherapy (NACT) with interval debulking surgery, is associated with less peri-operative morbidity. In this study, we compare rates, indications and lengths of ICU stays among ovarian cancer patients admitted to the ICU within 30days of cytoreduction, either primary or interval. METHODS A retrospective chart review was performed of patients with stage III-IV ovarian cancer who underwent surgical cytoreduction at two large academic medical centers between 2010 and 2014. Chi square tests, Student t-tests, and Mann-U Whitney tests were used. RESULTS A total of 635 patients were included in the study. There were 43 ICU admissions, 7% of patients. Compared to NACT, a higher percentage of PDS patients required ICU admission, 9.4% vs 3.9% of patients (P=0.004). ICU admission indications did not vary between PDS and NACT patients. NACT patients admitted to the ICU had comparable mean surgical complexity scores to those PDS patients admitted to the ICU, 6.2 (95%CI 5.3-7.1) vs 4.5 (95%CI 3.1-6.0) (P=0.006). Length of ICU admission did not vary between groups, PDS 2.7days (95%CI 2.3-3.2) vs 3.5days (95%CI 1.5-5.6) for NACT (P=0.936). CONCLUSIONS The rate of ICU admissions among patients undergoing PDS is higher than for NACT. Among patients admitted to the ICU, indications for admission, length of stay and surgical complexity were similar between patients treated with NACT and PDS.

Clinical outcomes of women with recurrent or persistent uterine leiomyosarcoma.

Objectives This study aimed to identify prognostic factors influencing the outcome of recurrent or persistent uterine leiomyosarcoma (ULMS). Methods All patients with recurrent or persistent ULMS who underwent treatment at the participating institutions between January 2000 and December 2010 were identified from the tumor registry. The Kaplan-Meier method was used to generate overall survival data. Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. Results One hundred fifteen (68.8%) patients who had recurrent/persistent disease were identified, 40 (34.8%) had persistent disease, and 75 (65.2%) had a recurrence. Median follow-up time was 24.9 months. The 5-year postrelapse survival rate was 15% and was not significantly different between women with recurrent or persistent disease (16% vs 13%; P = 0.1). Variables identified affecting the 5-year postrelapse survival rate included low number of mitosis at the time of diagnosis (<25, 25% vs 5%; P = 0.002), time to relapse from original diagnosis (≤6 vs >6 months, 8% vs 22%; P = 0.003)), and surgical treatment (17% vs 12%; P = 0.01). Age, stage, chemotherapy at time of original diagnosis or at the time of relapse, site of recurrence, and single versus multiple sites of recurrence were not associated with survival. In a multivariate Cox regression model, only low number of mitosis (hazard ratio, 0.5; 95% confidence interval, 0.3–0.8, P = 0.02) was identified as a predictor of overall survival. Conclusions The prognosis of patients with recurrent/persistent ULMS is, in general, poor. Women who have low number of mitosis at the time of diagnosis seemed to have better postrelapse survival.

GSK3-mediated instability of tubulin polymers is responsible for the failure of immature CD4+CD8+ thymocytes to polarize their MTOC in response to TCR stimulation.

Although mature T cells divide and differentiate when they receive strong TCR stimulation, most immature CD4+CD8+ thymocytes die. The molecular basis for this marked difference in response is not known. Observations that TCR-stimulated CD4+CD8+ thymocytes fail to polarize their microtubule-organizing center (MTOC), one of the first events that occurs upon antigen activation of mature T cells, suggests that TCR signaling routes in immature and mature T cells diverge early and upstream of MTOC polarization. To better understand the source of the divergence, we examined the molecular basis for the difference in TCR-mediated MTOC polarization. We show that unstable microtubules are a feature of immature murine CD4+CD8+ thymocytes, which also exhibit higher levels of glycogen synthase kinase 3 (GSK3) activity, a known inhibitor of microtubule stability. Importantly, CD4+CD8+ thymocytes gained the ability to polarize their MTOC in response to TCR signals when GSK3 activity was inhibited. GSK3 inhibition also abrogated TCR-mediated apoptosis of immature thymocytes. Together, our results suggest that a developmentally regulated difference in GSK3 activity has a major influence on immature CD4+CD8+ thymocyte versus mature T-cell responses to TCR stimulation.

Visuospatial Aptitude Testing Differentially Predicts Simulated Surgical Skill

OBJECTIVE To determine whether visuospatial perception (VSP) testing is correlated to simulated or intraoperative surgical performance as rated by the American College of Graduate Medical Education (ACGME) milestones. DESIGN (Canadian Task Force classification II-2). SETTING Two academic training institutions. PARTICIPANTS Forty-one residents, including 19 from Brigham and Womens Hospital and 22 from the Mayo Clinic, from 3 different specialties: obstetrics and gynecology, general surgery, and urology. INTERVENTION Participants underwent 3 different tests: visuospatial perception testing (VSP), Fundamentals of Laparoscopic Surgery (FLS) peg transfer, and da Vinci robotic simulation peg transfer. Surgical grading from the ACGME milestones tool was obtained for each participant. Demographic and background information was also collected, including specialty, year of training, previous experience with simulated skills, and surgical interest. Standard statistical analyses were performed using Students t test, and correlations were determined using adjusted linear regression models. MEASUREMENTS AND MAIN RESULTS In univariate analysis, Brigham and Womens Hospital and Mayo Clinic training programs differed in times and overall scores for both the FLS peg transfer and da Vinci robotic simulation peg transfer tests (p < .05 for all). In addition, type of residency training affected time and overall score on the robotic peg transfer test. Familiarity with tasks correlated with higher score and faster task completion (p = .05 for all except VSP score). There were no differences in VSP scores by program, specialty, or year of training. In adjusted linear regression modeling, VSP testing was correlated only to robotic peg transfer skills (average time, p = .006; overall score, p = .001). Milestones did not correlate to either VSP or surgical simulation testing. CONCLUSION VSP score was correlated with robotic simulation skills, but not with FLS skills or ACGME milestones. This suggests that the ability of VSP score to predict competence differs between tasks. Therefore, further investigation of aptitude testing is needed, especially before its integration as an entry examination into a surgical subspecialty.