Comparison of a U.S. and Zambian Ob/Gyn Residency Training Programme.

Introduction: The major objective of the study was to compare and contrast a U.S. and Zambian Ob/Gyn residency programme, using uniform metrics, as the basis for an initial exploration of perceived inequities in post-graduate medical education between low- and high-income countries. Methods: Measurements of the following procedures were used to indicate whether minimum standards had been met by trainees in their respective postgraduate programmes: vaginal deliveries; C-sections; abdominal, vaginal and laparoscopic hysterectomies; other laparoscopic surgeries; cancer cases; abortions; obstetrical ultrasounds; cystoscopies; incontinence and pelvic floor surgeries. Evaluations were also made with respect to the presence or absence of an official ultrasound rotation, subspeciality and off-service rotations, protected didactic time and exclusive time on obstetrics and gynaecologic clinical services. Comparisons were made relative to these various categories and the average procedural numbers at each level of training to determine differences in trends and degree of exposure. Results: Minimal procedural requirements were met by both the U.S. and Zambian programmes. For open surgical cases, the minimum standards were higher for the Zambian programme, whereas for procedures associated with the use of high-end technology, such as ultrasound and minimally invasive surgery, minimum standards were higher for the U.S. programme. Conclusion: There were no significant differences in the Zambian and U.S. Ob/Gyn post-graduate training programmes, relative to their respective metrics. A more extensive analysis is required to determine the actual competency levels that are produced by the respective training systems.

Disparities in the surgical staging of high-grade endometrial cancer in the United States.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) and the Society of Gynecologic Oncology (SGO) recommend lymph node sampling (LNS) as a key component in the surgical staging of high-grade endometrial cancer. Our goal was to examine surgical staging patterns for high-grade endometrial cancer in the United States. METHODS: The National Cancer Data Base (NCDB) was searched for patients who underwent surgery for serous, clear cell, or grade 3 endometrioid endometrial cancer. Outcomes were receipt of LNS and overall survival (OS). Multivariate logistic regression was used to examine receipt of LNS in Stage I-III disease based on race (White vs. Black), income, surgical volume, and distance traveled to care. Multivariate Cox proportional hazards regression modeling was used to assess OS based on stage, race, income, LNS, surgical volume, and distance traveled. RESULTS: Forty-two thousand nine hundred seventy-three patients were identified: 76% White, 53% insured by Medicare/Medicaid, 24% traveled >30 miles, and 33% stage III disease. LNS was similar among White and Black women (81% vs 82%). LNS was more common among >30 miles traveled (84% vs 81%, p < 0.001), higher surgical volume (83% vs 80%, p < 0.001), and academic centers (84% vs 80%, p < 0.001). In multivariate analysis, higher income, higher surgical volume, Charlson-Deyo score, and distance traveled were predictors of LNS. Stage III disease (HR 3.39, 95% CI 3.28-3.50), age (10-year increase; HR 1.63, 95% CI 1.61-1.66), lack of LNS (HR 1.64, 95% CI 1.56-1.69), and low income (HR 1.20, 95% CI 1.14-1.27) were predictors of lower survival. CONCLUSIONS: Surgical care for high-grade endometrial cancer in the United States is not uniform. Improved access to high quality care at high volume centers is needed to improve rates of recommended LNS.

Inherited determinants of ovarian cancer survival.

PURPOSE: Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer-related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence. EXPERIMENTAL DESIGN: Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1-8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNP). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HR) and 95% confidence intervals (CI), adjusting for known prognostic factors. RESULTS: Variation within angiogenesis was most strongly associated with survival time overall (P = 0.03) and among patients with serous cancer (P = 0.05), particularly for EIF2B5 rs4912474 (all patients HR, 0.69; 95% CI, 0.54-0.89; P = 0.004), VEGFC rs17697305 (serous subtype HR, 2.29; 95% CI, 1.34-3.92; P = 0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, P = 0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up. CONCLUSION: An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain.

Quality improvement in the surgical approach to advanced ovarian cancer: the Mayo Clinic experience.

BACKGROUND: After observing disparate rates of cytoreduction, we initiated efforts to improve outcomes through feedback and education, and we reassessed outcomes. STUDY DESIGN: Outcomes from group A (2006 and 2007, n=105) were compared with those from the cohort predating quality-improvement efforts (group B, 2000 to 2003, n=132). All stage IIIC ovarian cancer patients at our institution were evaluated for tumor dissemination, age, performance status, surgical complexity, residual disease (RD), morbidity, and mortality. A surgical complexity score previously described was used to categorize extent of operation. RESULTS: No significant differences in age, performance status, or extent of disease were observed between cohorts. Surgical complexity increased after initiation of quality improvement (mean surgical complexity score, 5.5 to 7.1; p < 0.001), rates of optimal RD (< 1 cm) improved from 77% to 85% (p=0.157), and rates of complete resection of all gross disease rose from 31% to 43% (p=0.188). In the subset of patients with carcinomatosis most likely to benefit from extended surgical resection, radical procedures were used more frequently (63% versus 79%; p=0.028), rates of optimal debulking (RD<1 cm) increased (64% to 79%), and the rate of RD=0 increased from 6% to 24% (p=0.006). When disease was noted on the diaphragm, procedures to remove the disease were more frequently used (38% to 64%; p=0.001). The rates of major perioperative morbidity (group B, 21% versus group A, 20%; p=0.819) and 3-month mortality (8% versus 6%; p=0.475) were not affected despite this more aggressive surgical approach. CONCLUSIONS: Analysis of outcomes with appropriate feedback and education is a powerful tool for quality improvement. We observed improvements in rates of cytoreduction and use of specific radical procedures, with no increase in morbidity as a result of this process.

Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging.

OBJECTIVE: To prospectively assess pelvic and para-aortic lymph node metastases in endometrial cancer with lymphatic dissemination, emphasizing the examination of para-aortic metastases relative to the inferior mesenteric artery (IMA). METHODS: Over 36 months, 422 consecutive patients were managed by predefined surgical guidelines differentiating low-risk patients from patients at risk for dissemination requiring systematic lymphadenectomy. Low risk was defined as grade 1 or 2 endometrioid type with myometrial invasion (MI) < or = 50% and primary tumor diameter (PTD) < or = 2 cm. Pelvic and para-aortic lymph nodes were submitted separately, with nodes identified from all 8 pelvic and 4 para-aortic node-bearing basins. Surgical quality assessments examined median node counts (primary surrogate for quality) and nodes harvested above and below the IMA and excised gonadal veins (secondary surrogates). RESULTS: Lymphadenectomy was not required in 27% of patients (all low risk) and in 33% (n=112) of endometrioid cases. However, 22 patients (20%) of this latter cohort had lymphadenectomy and all lymph nodes were negative. Sixty-three (22%) of 281 patients undergoing lymphadenectomy had lymph node metastases: both pelvic and para-aortic in 51%, only pelvic in 33%, and isolated to the para-aortic area in 16%. Therefore, 67% of patients with lymphatic dissemination had para-aortic lymph node metastases. Furthermore, 77% of patients with para-aortic node involvement had metastases above the IMA, whereas nodes in the ipsilateral para-aortic area below the IMA and ipsilateral common iliac basin were declared negative in 60% and 71%, respectively. Gonadal veins were excised in 25 patients with para-aortic node metastases; 7 patients (28%) had documented metastatic involvement of gonadal veins or surrounding soft tissue. CONCLUSIONS: The high rate of lymphatic metastasis above the IMA indicates the need for systematic pelvic and para-aortic lymphadenectomy (vs sampling) up to the renal vessels. The latter should include consideration of excision of the gonadal veins. Conversely, lymphadenectomy does not benefit patients with grade 1 and 2 endometrioid lesions with MI < or = 50% and PTD < or = 2 cm.

Patterns of inguinal groin metastases in squamous cell carcinoma of the vulva.

OBJECTIVES: Assess the pattern of groin node metastases in squamous cell carcinoma (SCC) of the vulva in relation to the site of the primary lesion. Assess whether the identified pattern of lymphatic spread supports the current surgical practice of assessing contralateral nodes for lateral lesions with ipsilateral nodal involvement. METHODS: A retrospective study of surgically staged patients with primary SCC of the vulva between 1955 and 1990 was conducted. This cohort of patients was divided in 4 subgroups by location of primary lesion: unilateral, bilateral, midline, and patients with mediolateral lesions. All clinical and pathological data were reviewed and updated to the 1988 TNM vulvar classification. RESULTS: 320 patients met the inclusion criteria, and almost all of them (>95%) underwent bilateral groin assessment. Of the 108 patients with positive groin lymph-node (LN) involvement, 77 presented with unilateral and 24 with bilateral inguinofemoral involvement. Of the 163 patients presenting with only unilateral vulvar lesions, 48 had inguinofemoral node involvement: 37 with ipsilateral-only nodal metastases, 8 with bilateral LN invasion, and only 3 (1.8%) had isolated contralateral nodal metastases. None of these patients with unilateral vulvar lesion that was either < or = 2 cm in biggest diameter or with invasion < or = 5 mm had bilateral groin LN involvement at diagnosis. CONCLUSIONS: Ipsilateral lymphadenectomy is suitable for patients with unilateral lesions, distant from the midline, and either negative ipsilateral nodes, or with positive ipsilateral LN with lesions smaller than 2 cm.

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells.

OBJECTIVE: To characterize the molecular pathways involved in apoptosis following administration of histone deacetylase inhibitors to Type I and II endometrial cancer cells. METHODS: Ark2, Ishikawa, and AN3 cell lines representing both Type I and II endometrial cancers were treated with various concentrations of oxamflatin and HDAC inhibitor-1. Cell apoptosis was determined by flow cytometry, nuclear staining, Western blotting, and mitochondrial membrane potential assays. RESULTS: Compared to controls, there was a 95% reduction in the growth of Ark2 cells following administration of histone deacetylase inhibitors and this response was dose-dependent. These agents also caused profound morphologic changes and loss of mitochondrial membrane potentials consistent with the induction of apoptosis. Cleavage of PARP, caspase-9, and caspase-8 was detected, confirming the activation of apoptotic cascades in endometrial carcinoma cells. This effect was present in both serous and endometrioid cell types. CONCLUSION: Our results suggest that oxamflatin and HDAC inhibitor-1 have potent cytotoxicity in endometrial cancer cells by inducing cell apoptosis. Histone deacetylase inhibitors are promising agents for the treatment of both Type I and II endometrial carcinoma.

Prosurvival function of the granulin-epithelin precursor is important in tumor progression and chemoresponse.

The granulin-epithelin precursor (GEP/PCDGF), a 68-88 kDa secreted glycoprotein, has been shown to be an important growth and survival factor for ovarian cancer cells. Furthermore, GEP expression is a predictor of patient survival in metastatic ovarian cancer cells. Up to this point, however, the molecular mechanisms and clinical relevance of a GEP-mediated prosurvival phenotype remain poorly characterized. We hypothesize that the prosurvival function of GEP is important in ovarian cancer tumor progression and chemoresponse. To explore this hypothesis, we examined the effects of GEP overexpression on migration, invasion and cisplatin (CDDP) chemosensitivity in the ovarian cancer cell line A2780. Full length GEP transfectants demonstrated an increased capacity to migrate and invade their substratum when compared to empty vector controls. In addition, GEP overexpression was associated with CDDP chemoresistance. Finally, GEP overexpression increased tumor formation and protected cells from tumor regression in response to CDDP treatment in vivo. Taken together, these data support a role for GEP in tumor progression and development of drug resistance.

Role of rectosigmoidectomy and stripping of pelvic peritoneum in outcomes of patients with advanced ovarian cancer.

BACKGROUND: The peritoneum of the cul-de-sac is frequently affected in advanced ovarian cancer patients. Stripping of the pelvic peritoneum (SoP) combined with rectosigmoidectomy (RS) in patients with confluent tumor are safe techniques that can eradicate macroscopic disease. We evaluated the therapeutic value of this maximal surgical effort in advanced ovarian cancer. STUDY DESIGN: Data from all consecutive patients with stages IIIC and IV epithelial ovarian cancer, primarily operated on from 1994 through 1998, were collected and analyzed using the chi-square test, Cox regression analysis, and Kaplan-Meier curves including log-rank test. RESULTS: Two hundred forty-four eligible patients were identified; 209 patients had tumor involving the peritoneum of the cul-de-sac. For this subgroup, those who were managed with stripping of the peritoneum (SoP, n=77) or rectosigmoidectomy (RS, N=57) had improved 5-year overall survivals relative to those who were not (n=75). (SoP=37% versus RS=39% versus neither=6%; p < 0.0001). In the subgroup of patients with cul-de-sac involvement optimally cytoreduced, we noted a survival benefit for those who were managed with a maximal pelvic surgical effort (5-year overall survival, 38% [SoP] versus 38% [RS] versus 15% [neither]; p=0.02). When evaluating patients with no macroscopic residual disease, a survival advantage for patients managed with RS compared with SoP was observed (5-year overall survival, 89% (RS) versus 50% (RS); p=0.04). CONCLUSIONS: Surgical resection of cul-de-sac disease by SoP and RS is associated with improved survival in ovarian cancer patients. Tumor resection with en bloc RS may be preferable to allowing microscopic or infiltrative residual tumor.

Aggressive surgical effort and improved survival in advanced-stage ovarian cancer.

OBJECTIVE: Residual disease after initial surgery for ovarian cancer is the strongest prognostic factor for survival. However, the extent of surgical resection required to achieve optimal cytoreduction is controversial. Our goal was to estimate the effect of aggressive surgical resection on ovarian cancer patient survival. METHODS: A retrospective cohort study of consecutive patients with International Federation of Gynecology and Obstetrics stage IIIC ovarian cancer undergoing primary surgery was conducted between January 1, 1994, and December 31, 1998. The main outcome measures were residual disease after cytoreduction, frequency of radical surgical resection, and 5-year disease-specific survival. RESULTS: The study comprised 194 patients, including 144 with carcinomatosis. The mean patient age and follow-up time were 64.4 and 3.5 years, respectively. After surgery, 131 (67.5%) of the 194 patients had less than 1 cm of residual disease (definition of optimal cytoreduction). Considering all patients, residual disease was the only independent predictor of survival; the need to perform radical procedures to achieve optimal cytoreduction was not associated with a decrease in survival. For the subgroup of patients with carcinomatosis, residual disease and the performance of radical surgical procedures were the only independent predictors. Disease-specific survival was markedly improved for patients with carcinomatosis operated on by surgeons who most frequently used radical procedures compared with those least likely to use radical procedures (44% versus 17%, P < .001). CONCLUSION: Overall, residual disease was the only independent predictor of survival. Minimizing residual disease through aggressive surgical resection was beneficial, especially in patients with carcinomatosis. LEVEL OF EVIDENCE: II-2.