Z. Al-Wahab

Role of 12-lipoxygenase in regulation of ovarian cancer cell proliferation and survival

PurposeEicosanoid-related enzymes have been implicated in the pathogenesis of various cancers. Little is known about the relevance of lipoxygenase pathway to ovarian cancer growth. In this study, we examined the role of 12-lipoxygenase (12-LOX), the main human 12-HETE generating enzyme, in the regulation of proliferation and survival in epithelial ovarian cancer.MethodsImmunohistological analysis of 12-LOX expression in high-grade serous ovarian carcinoma and normal ovarian epithelium tissues was performed. The presence of 12-LOX-12-HETE system was confirmed in two epithelial ovarian cancer (EOC) cell lines, OVCAR-3 and SK-OV-3, using RT–PCR, Western blot and LC/MS analysis. The effects of N-benzyl-N-hydroxy-5-phenyl-pentanamide (BMD-122), a specific 12-LOX inhibitor, on cell growth, survival, apoptosis, and cell signaling were determined.ResultsWe found that a significantly higher level of 12-LOX expression in high-grade serous ovarian carcinoma compared to normal ovarian epithelium. OVCAR-3 and SK-OV-3 were found to express high level of 12-LOX mRNA and protein. Both EOC increased their 12-HETE production when incubated with arachidonic acid. BMD-122 inhibited the EOC growth in a dose-dependent fashion. Purified 12-HETE significantly reversed such inhibitory effects of BMD-122. In addition, BMD-122 blocked the MAPK signaling pathway by inhibiting the phosphorylation of ERK and induced a ~20–30% increase in the EOC apoptosis. Down-regulation of the 12-LOX expression using 12-LOX siRNA also resulted in markedly reduction in cell growth.ConclusionsThese data suggest that 12-LOX is involved in the regulation of ovarian cancer cell growth and survival and is a potential new therapeutic target.

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.

The prognostic significance of histologic type in early stage cervical cancer – A multi-institutional study

BACKGROUND Cervical adenocarcinomas (ADC) have been viewed as more aggressive than squamous cell carcinoma (SCC). We analyzed an international cohort of early stage cervical cancer to determine the impact of histologic type. METHODS Retrospective analysis of patients with SCC (148 patients) and ADC (130 patients) stages IA1-IB2 who underwent surgery at our three institutions (two from Detroit, one from Mexico) from 2000-2010 was performed for: age, stage, tumor size, lymphovascular invasion (LVI), invasion depth, lymph node status (LN), recurrence and survival. Pathologic review proceeded inclusion. RESULTS In the Latino population, ADCs tended to be higher grade (p=0.01), while SCCs were larger with deeper invasion (p<0.001). LVI and LN were not significantly different. Recurrence rate (RR) was 8% (8/101) in ADC and 11.8% (9/76) in SCCs. 5 year survival (OS) was equivalent (98.2% and 95.2% for ADC and SCC respectively, p=0.369). In the Detroit cohort, we noted no difference in size, grade, depth of invasion, LVI, LN. RR was 8/72 (13.7%) for SCC and 4/29 (13.7%) but not statistically different between the tumor types (p=0.5). 5 year survival was 91% and 92% for ADC and SCC, respectively. In this population 33% of the patients with SCC and 34% of the patients with ADC received adjuvant chemo-radiation (p=0.4). Histologic type demonstrated no significant outcome difference for any type of adjuvant therapy. CONCLUSION Comparing early stage disease cervical ADC and SCC suggests equivalent recurrence and survival. Therefore, the paradigm of more aggressive management of early stage cervical ADC warrants further investigation.

Recurrence patterns and survival endpoints in women with stage II uterine endometrioid carcinoma: A multi-institution study

OBJECTIVE There is paucity of data in regard to prognostic factors and outcome of women with 2009 FIGO stage II disease. The objective of this study was to investigate prognostic factors, recurrence patterns and survival endpoints in this group of patients. METHODS Data from four academic institutions were analyzed. 130 women were identified with 2009 FIGO stage II. All patients underwent hysterectomy, oophorectomy and lymph node evaluation with or without pelvic and paraaortic lymph node dissections and peritoneal cytology. The Kaplan-Meier approach and Cox regression analysis were used to estimate recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). RESULTS Median follow-up was 44months. 120 patients (92%) underwent simple hysterectomy, 78% had lymph node dissection and 95% had peritoneal cytology examination. 99 patients (76%) received adjuvant radiation treatment (RT). 5-year RFS, DSS and OS were 77%, 90%, and 72%, respectively. On multivariate analysis of RFS, adjuvant RT, the presence of lymphovascular space invasion (LVSI) and high tumor grades were significant predictors. For DSS, LVSI and high tumor grades were significant predictors while older age and high tumor grade were the only predictors of OS. CONCLUSIONS In this multi-institutional study, disease-specific survival for women with FIGO stage II uterine endometrioid carcinoma is excellent. High tumor grade, lymphovascular space invasion, adjuvant radiation treatment and old age are important prognostic factors. There was no significant difference in the outcome between patients who received vaginal cuff brachytherapy compared to those who received pelvic external beam radiation treatment.

Prognostic impact of lymphadenectomy in uterine serous cancer.

Objective  To estimate the survival impact of lymphadenectomy in women diagnosed with uterine serous cancer.

Outcomes of patients with uterine serous carcinoma using the revised FIGO staging system.

Objective Our aim was to evaluate the prognostic significance of the revised 2009 International Federation of Gynecology and Obstetrics (FIGO) staging criteria in patients with uterine serous carcinoma (USC). Materials and Methods We retrieved clinical and histopathologic data on women with USC from 2 large academic centers. Age, race, stage, myometrial invasion, angiolymphatic invasion, and adjuvant therapy were analyzed using Kaplan-Meier and Cox regression models. Results A total of 168 patients were included. Three-year survival rate was 81% for revised stage I, 52% for stage II, 46% for stage III, and 19% for stage IV. Survival was not significantly different when comparing overall 1988 FIGO stage I or II to 2009 FIGO stage I or II. The 3-year survival rate for 1988 stage IA (93%), IB (75%), and IC (60%) significantly differed (P = 0.02). When patients were restaged using the 2009 staging system, the 3-year overall survival of 2009 stage IA dropped to 83.4% and 68.8% for stage IB. New FIGO stage, myometrial invasion, angiolymphatic invasion, and administration of chemotherapy all remained independent predictors of survival on multivariate analysis (P < 0.05). Of note, extrauterine disease was observed in 22% of patients without myometrial invasion. Age and race were not prognostic factors for either classification. Conclusions The streamlined 2009 FIGO criteria do not adequately delineate survival for USC in early-stage disease. The 1988 FIGO classification correctly identified 3 subgroups of stage I USC patients with significantly different survival that is lost with the elimination of the most favorable 1988 stage IA subgroup. Because evaluation for adjuvant therapy and patient planning may change based on survival information, further evaluation of more appropriate USC staging is warranted. Caution should be taken when evaluating therapeutic response and comparing studies using these revised criteria in the future.

The impact of race on survival in uterine serous carcinoma: A hospital-based study

OBJECTIVE Although less common than endometrioid carcinoma, uterine serous carcinoma (USC) accounts for a disproportionate number of endometrial cancer-related deaths. It is relatively more common in black compared to white women. The aim of our study is to analyze the impact of race on survival in USC. METHODS We conducted a retrospective review in women with USC managed at two large urban medical centers. Clinical and histopathologic parameters were retrieved. Recurrence and survival data were obtained from medical records and the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in overall survival between African American and Caucasian women were compared using Kaplan-Meier curves and log rank test for univariate analysis. Cox regression models for multivariate analyses were built to evaluate the relative impact of the various prognostic factors. RESULTS One hundred seventy-two women with USC were included in this study, including 65 Caucasian women and 107 African American women. Both groups were similar with respect to age, stage at diagnosis, angiolymphatic invasion (p=0.79), and the depth of myometrial invasion (p=0.36). There was no statistical difference in overall survival between African American and Caucasian patients in univariate analysis (p=0.14). In multivariate analysis, stage at diagnosis, angiolymphatic invasion, and depth of myometrial invasion, but not race, were significantly associated with overall survival. CONCLUSION In this study, African American women with USC had a similar survival to Caucasian women. This suggests that the racial differences seen in USC at a larger population level may be diminished in hospital-based studies, where women are managed in a uniform way.

Vanishing Endometrial Cancer in Hysterectomy Specimens A Myth or a Fact

The incidence of endometrial cancers diagnosed on biopsy that have no residual cancer identified at hysterectomy is not well studied. The aim of our study was to determine the incidence and long-term follow-up of this “vanishing cancer” phenomenon. All slides from the initial biopsy/curettage and hysterectomy specimens were reviewed and the diagnosis confirmed by a gynecologic pathologist. The entire endometrium was serially sectioned and submitted for histologic examination. Clinical and pathologic variables were analyzed, including patient demographics, tumor histologic type and grade, stage, biopsy method, adjuvant therapy, surgical procedure, recurrence, and disease-specific survival. We identified 23 biopsy-proven cases of endometrial cancer with no residual disease on hysterectomy specimen. Of the 23 patients, 15 (65.2%) were diagnosed as endometrioid, 6 (26%) serous, 1 clear cell (4.3%), and 1 (4.3%) serous intraepithelial carcinoma. Seventeen underwent dilatation and curettage, and 6 had endometrial biopsy as the primary procedure. The median follow-up was 8.8 years (range, 1.2 to 17 y). Only 2 cases with serous carcinoma underwent adjuvant chemotherapy, and none received radiation therapy. Only 1 patient died of disease after 27 months and was diagnosed as FIGO grade II endometrioid carcinoma on dilatation and curettage. The inability to identify cancer in a hysterectomy specimen for biopsy-confirmed carcinoma does not indicate technical failure. Although there is no specific standard treatment for patients with “vanishing endometrial cancer,” the prognosis is excellent; however, close follow-up is suggested.

Significance of lymphovascular space invasion in uterine serous carcinoma: what matters more; extent or presence?

To analyze the clinical significance of the extent of lymphovascular space invasion (LVI) in patients with uterine serous carcinoma. After IRB approval, 232 patients with uterine serous carcinoma from the pathology databases of 4 large academic institutions were included. Patients were divided into 3 groups based on extent of LVI. Extensive LVI (E-LVI) was defined as ≥3 vessel involvement; low LVI (L-LVI) was defined <3 vessel involvement; and the third group consisted of tumors with no LVI (A-LVI). The association between LVI and myometrial invasion, cervical involvement, lower uterine segment involvement, positive peritoneal washings, lymph node involvement, stage, and survival were analyzed. Of 232 patients, 47 had E-LVI (20.3%), 83 had L-LVI (35.8%), and 102 had A-LVI (44%). A total of 9.8% of the patients with A-LVI had lymph node involvement as compared with 18.1% in the L-LVI group and 55.4% in the E-LVI group (P<0.0001). Fifty-nine percent of the patients in A-LVI, 85% in L-LVI, and 100% in the E-LVI group demonstrated myometrial invasion (P<0.0001). Cervical involvement was noted in 23%, 43%, 66% (P<0.0001) and lower uterine segment involvement involvement in 31%, 43%, and 42% of A-LVI, L-LVI, and E-LVI (P<0.0001), respectively. Stage III and IV disease were seen in 29%, 38%, and 79% of the patients with A-LVI, L-LVI, and E-LVI, respectively (P<0.0001). The median overall survival was 172, 95, and 39 mo for the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). The racial distribution was significant with African American patients demonstrating significantly more L-LVI (27.8%) and E-LVI (40.4%) when compared with A-LVI (19.6%) (P=0.040). In a subgroup analysis including patients with Stage I and II (n=123) revealed median survivals of 172, 169, and 38 mo in the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). Fifty percent of these patients with E-LVI, 20% in L-LVI group, and 15% in A-LVI group had disease recurrence (P=0.040). The extent of LVI was associated with multiple pathologic factors and was found to be a negative prognostic factor for overall survival and disease recurrence.

Racial disparities in uterine clear cell carcinoma: a multi-institution study.

Objective The aim of this study was to evaluate the impact of race on the overall survival (OS) and progression-free survival (PFS) of white and African-American patients with uterine clear cell carcinoma (UCCC). Methods A retrospective review was conducted of all primary UCCC cases treated at 1 of 4 major gynecologic cancer centers between 1982 and 2012. Patients and tumor characteristics were retrieved from the cancer databases of the respective institutions and based on a retrospective review of the medical records. Differences in the OS and PFS between African-American and white women were compared using the Kaplan-Meier curves and log-rank test for univariate analysis. Cox regression models for the multivariate analyses were built to evaluate the relative impact of the various prognostic factors. Results One hundred seventy women with UCCC were included in the study, including 118 white and 52 African-American women. Both groups were comparable with respect to age (P = 0.9), stage at diagnosis (P = 0.34), angiolymphatic invasion (P = 0.3), and depth of myometrial invasion (P = 0.84). In the multivariate analyses for known prognostic factors, OS and PFS were significantly different between white and African-American patients in the early-stage disease (hazard ratio [HR], 5.4; 95% confidence interval [CI], 1.2–23.2; P = 0.023 and HR, 3.5; 95% CI, 1.60–7.77; P = 0.0016, respectively) but not in the advanced-stage disease (HR, 0.83; 95% CI, 0.40–1.67; P = 0.61 and HR, 1.5; 95% CI, 0.84–2.78; P = 0.15, respectively). Conclusions In the current study, African-American patients have a prognosis worse than that of white patients in early-stage UCCC. We could not prove the same difference in advanced-stage disease.