R.T. Morris

Inhibition of paclitaxel-induced apoptosis by the specific COX-2 inhibitor, NS398, in epithelial ovarian cancer cells

OBJECTIVE In vitro studies have revealed that treatment of various human cancer cell lines with specific cyclo-oxygenase 2 (COX-2) inhibitors induces apoptotic cell death. It is currently proposed that the combination of COX-2 inhibitors with chemotherapeutic agents improves the efficacy of cancer treatment. MATERIALS AND METHODS In this study we sought to determine the effects of combining paclitaxel and the COX-2 inhibitor NS398 on apoptosis of epithelial ovarian cancer (EOC) cells. Two EOC cell lines, SKOV3 and MDAH2774, were exposed to increasing concentrations of paclitaxel (0.1, 10, and 100 microM) and NS398 (10, 100 microM) as well as a combination of both drugs. Apoptosis was evaluated by the Tunel assay. The fluorescein-labeled DNA was visualized directly by fluorescence microscopy and quantitated by flow cytometry. RESULTS While NS398 did not significantly alter apoptosis of either EOC cell lines after 24 h of continuous exposure, treatment of both cell lines with paclitaxel resulted in a significant increase in the rate of apoptosis (60-70%). Concomitant treatment of both SKOV3 and MDAH2774 cells with paclitaxel and NS398 resulted in marked impairment of paclitaxel-induced apoptosis. Similarly, sequential treatment during which both cell lines were treated with NS398 for 4 h, triple-washed, and then exposed to paclitaxel for 24 h resulted in a significant inhibition of paclitaxel-induced apoptosis. Similar inhibition was seen when NS398 was replaced by aspirin. CONCLUSIONS Combining COX-2 inhibitors and paclitaxel does not have an additive or synergistic tumoricidal effect. On the contrary, NS398 treatment markedly inhibited the apoptotic effects of paclitaxel in each of these two EOC cell lines.

Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary

Background:The aim of this study was to determine the impact of lymphadenectomy and nodal metastasis on survival in clinical stage I malignant ovarian germ cell tumour (OGCT).Methods:Data were obtained from the National Cancer Institute registry from 1988 to 2006. Analyses were performed using Students t-test, Kaplan–Meier and Cox proportional hazard methods.Results:In all, 1083 patients with OGCT who have undergone surgical treatment and deemed at time of the surgery to have disease clinically confined to the ovary were included 590 (54.48%) had no lymphadenectomy (LND−1) and 493 (45.52%) had lymphadenectomy. Of the 493 patients who had lymphadenectomy, 441 (89.5%) were FIGO surgical stage I (LND+1) and 52 (10.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND+3C). The 5-year survival was 96.9% for LND−1, 97.7% for LND+1 and 93.4% for LND+3C (P=0.5). On multivariate analysis, lymphadenectomy was not an independent predictor of survival when controlling for age, histology and race (HR: 1.26, 95% CI: 0.62–2.58, P=0.5). Moreover, the presence of lymph node metastasis had no significant effect on survival (HR: 2.7, 95% CI: 0.67–10.96, P=0.16).Conclusion:Neither lymphadenectomy nor lymph node metastasis was an independent predictor of survival in patients with OGCT confined to the ovary. This probably reflects the highly chemosensitive nature of these tumours.

Stage IA vs. IB endometrial stromal sarcoma: Does the new staging system predict survival?

OBJECTIVE To determine the correlation of the new FIGO staging system with survival in stage I patients with low-grade and high-grade endometrial stromal sarcomas. METHODS Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Kaplan-Meier log rank and Cox proportional hazards models were used for survival analysis and to identify possible predictors for survival. RESULTS The identified cohort included 464 women, 310 (67%) low-grade endometrial stromal sarcoma, 96 (21%) high-grade endometrial stromal sarcoma, and 58 (12%) unclassified endometrial stromal sarcoma. Among low-grade and high-grade endometrial stromal sarcomas, there was no significant demographic or clinico-pathologic difference between stages IA and IB. The 5-year overall survival was worse in high-grade endometrial stromal sarcoma than low-grade endometrial stromal sarcoma (45.4% vs. 97.2%, p<0.001). The difference in 5-year overall survival among women with low-grade endometrial stromal sarcoma between stages IA and IB was significant (100% vs. 93.5%, p=0.003), but not among women with high-grade endometrial stromal sarcoma (51.4% vs. 43.5%, p=0.27). Although age (p=0.001), race (p=0.005), and stage (p=0.004) were all significant prognostic factors in low-grade endometrial stromal sarcoma, only cervical involvement (p=0.02) was a significant predictor in high-grade endometrial stromal sarcoma. CONCLUSION The new staging system is appropriate for risk stratification in low-grade endometrial stromal sarcoma. The prognosis in high-grade endometrial stromal sarcoma seems to be most influenced by the presence of cervical involvement and not by tumor size as the staging criteria would suggest.

Risk of postoperative venous thromboembolism after minimally invasive surgery for endometrial and cervical cancer is low: A multi-institutional study

OBJECTIVE To determine the 30-day prevalence of venous thromboembolism (VTE) after minimally invasive surgery (MIS) for endometrial (EC) and cervical cancers (CC). METHODS A retrospective cohort study at two large tertiary care centers between 2006 and 2011. Patients having MIS for EC or CC were included. Cases converted to laparotomy were excluded. The primary outcome measure was clinically diagnosed VTE within 30 days of operation. RESULTS Of the 558 patients, 90% had EC and 10% had CC. Modalities of hysterectomy included robotic (88%), vaginal (9%), and laparoscopic (3%). A total of 66% had pelvic and 35% had paraaortic lymphadenectomy. The VTE prophylaxes were sequential compression devices (100%) and heparin (39%). There were no VTE events during hospital stay (95% CI, 0.0%-0.7%). The 30-day prevalence of VTE was (0.5%; 95% CI, 0.1%-1.6%). The hitherto recommended risk criteria for giving extended 30-day thromboprophylaxis by the American College of Obstetrics and Gynecologists (ACOG) or by the American Society of Clinical Oncology (ASCO) did not predict risk of VTE in our population. CONCLUSIONS The prevalence of VTE in EC and CC undergoing MIS is very low. The existing 30-day risk prediction models proposed by the ACOG and ASCO stem from open surgery patients and do not appear to apply to MIS patients. Certainly, we found no evidence supporting the use of extended prophylactic heparin in this setting. Further research is urgently needed to define the role of any duration of thromboprophylaxis in MIS patients with endometrial or cervix cancer.

Impact of adjuvant chemotherapy and pelvic radiation on pattern of recurrence and outcome in stage I non-invasive uterine papillary serous carcinoma. A multi-institution study

OBJECTIVES To determine the impact of adjuvant chemotherapy or pelvic radiation on risk of recurrence and outcome in stage IA non-invasive uterine papillary serous carcinoma (UPSC). METHODS This is a multi-institutional retrospective study for 115 patients with stage IA non-invasive UPSC (confined to endometrium) treated between 2000 and 2012. Kaplan-Meier and multivariable Cox proportional hazards regression modeling were used. RESULTS Staging lymphadenectomy and omentectomy were performed in 84% and 57% respectively. Recurrence was seen in 26% (30/115). Sites of recurrences were vaginal in 7.8% (9/115), pelvic in 3.5% (4/115) and extra-pelvic in 14.7% (17/115). Adjuvant chemotherapy did not impact risk of recurrence (25.5% vs. 26.9%, p=0.85) even in subset of patients who underwent lymphadenectomy (20% vs. 23.5%, p=0.80). These findings were consistent for pattern of recurrence. Among those who underwent lymphadenectomy, adjuvant chemotherapy did not impact progression-free survival (p=0.34) and overall survival (p=0.12). However among patients who did not have lymphadenectomy, adjuvant chemotherapy or pelvic radiation was associated with longer progression-free survival (p=0.04) and overall survival (p=0.025). In multivariable analysis, only staging lymphadenectomy was associated with improved progression-free survival (HR 0.34, 95% CI 0.12-0.95, p=0.04) and overall survival (HR 0.35, 95% CI 0.12-1.0, p=0.05). Neither adjuvant chemotherapy nor pelvic radiation were predictors of progression-free or overall survivals. CONCLUSION In stage IA non-invasive UPSC, staging lymphadenectomy was significantly associated with recurrence and outcome and therefore, should be performed in all patients. Adjuvant chemotherapy or pelvic radiation had no impact on outcome in surgically staged patients but was associated with improved outcome in unstaged patients.

Adjuvant vaginal brachytherapy decreases the risk of vaginal recurrence in patients with stage I non-invasive uterine papillary serous carcinoma. A multi-institutional study

OBJECTIVES To investigate the impact of adjuvant vaginal brachytherapy on vaginal recurrence in stage I non-invasive uterine papillary serous carcinoma (UPSC). METHODS This is a retrospective multi-institutional study from 2000-2012. 103 patients who underwent surgical treatment with non-invasive stage IA UPSC were included. RESULTS 85% and 55% underwent staging lymphadenectomy and omentectomy respectively. 28.2% (29/103) developed recurrence. Vaginal, pelvic and extra-pelvic recurrences developed in 7.8% (8/103), 3.9% (4/103) and 16.5% (17/103) respectively. Among patients who were observed or received only chemotherapy, the rate of vaginal recurrence was 10.9% (7/64) compared to 2.6% (1/39) among those who received vaginal brachytherapy +/- chemotherapy (p=0.035). The rate of vaginal recurrence was not different between those who were observed and those who received only chemotherapy (9.3% vs. 14.3%, p=0.27). The 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 88.3% and 90.6%. Patients who underwent surgical staging had longer PFS (p=0.001) and OS (p=0.0005) compared to those who did not. In multivariable analysis controlling for age, histology, chemotherapy, brachytherapy, and staging lymphadenectomy, only lymphadenectomy was an independent predictor of PFS (HR 0.28, 95% CI 0.11-0.71, p=0.0037) and OS (HR 0.27, 95% CI 0.10-0.71, p=0.0035). Neither chemotherapy nor brachytherapy were predictors of PFS or OS. CONCLUSIONS This is the largest study reported in stage I non-invasive UPSC. The majority of recurrences were extra-pelvic. Vaginal brachytherapy has a significant role in reducing the risk of vaginal recurrence and surgical staging was the only predictor of outcome. Therefore, both should be considered in these patients.

Endometrial cancer in morbidly obese women: do racial disparities affect surgical or survival outcomes?

OBJECTIVE Endometrial cancer mortality disproportionately affects black women and whether greater prevalence of obesity plays a role in this disparity is unknown. We examine the effect of race on post-surgical complications, length of stay, and mortality specifically in a morbidly obese population. METHODS Black and white women with endometrial cancer diagnosed from 1996 to 2012 were identified from the University Pathology Group database in Detroit, Michigan, and records were retrospectively reviewed to obtain clinicopathological, demographic, and surgical information. Analysis was limited to those with a body mass index of 40kg/m(2) or greater. Differences in the distribution of variables by race were assessed by chi-squared tests and t-tests. Kaplan-Meier and Cox regression analyses were performed to examine factors associated with mortality. RESULTS 97 white and 89 black morbidly obese women were included in this analysis. Black women were more likely to have type II tumors (33.7% versus 15.5% of white women, p-value=0.003). Hypertension was more prevalent in black women (76.4% versus 58.8%, p-value=0.009), and they had longer hospital stays after surgery despite similar rates of open vs minimally invasive procedures and lymph node dissection (mean days=5.4) compared to whites (mean days=3.5, p-value=0.036). Wound infection was the most common complication (16.5% in whites and 14.4% in blacks, p-value=0.888). Blacks were more likely to suffer other complications, but overall the proportions did not differ by race. In univariate analyses, black women had higher risk of endometrial cancer-related death (p-value=0.090). No racial differences were noted in adjusted survival analyses. CONCLUSION A more complete investigation, incorporating socio-demographic factors, is warranted to understand the effects of morbid obesity and race on endometrial cancer.