Emma L. Barber

Indications Contributing to the Increasing Cesarean Delivery Rate

OBJECTIVE: To examine physician-documented indications for cesarean delivery in order to investigate the specific factors contributing to the increasing cesarean delivery rate. METHODS: We analyzed rates of primary and repeat cesarean delivery, including indications for the procedure, among 32,443 live births at a major academic hospital between 2003 and 2009. Time trends for each indication were modeled to estimate the absolute and cumulative annualized relative risk of cesarean by indication over time and the relative contribution of each indication to the overall increase in primary cesarean delivery rate. RESULTS: The cesarean delivery rate increased from 26% to 36.5% between 2003 and 2009; 50.0% of the increase was attributable to an increase in primary cesarean delivery. Among the documented indications, nonreassuring fetal status, arrest of dilation, multiple gestation, preeclampsia, suspected macrosomia, and maternal request increased over time, whereas arrest of descent, malpresentation, maternal-fetal indications, and other obstetric indications (eg, cord prolapse, placenta previa) did not increase. The relative contributions of each indication to the total increase in primary cesarean rate were: nonreassuring fetal status (32%), labor arrest disorders (18%), multiple gestation (16%), suspected macrosomia (10%), preeclampsia (10%), maternal request (8%), maternal-fetal conditions (5%), and other obstetric conditions (1%). CONCLUSION: Primary cesarean births accounted for 50% of the increasing cesarean rate. Among primary cesarean deliveries, more subjective indications (nonreassuring fetal status and arrest of dilation) contributed larger proportions than more objective indications (malpresentation, maternal-fetal, and obstetric conditions). LEVEL OF EVIDENCE: III

Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging.

Objective To describe the incidence of low-volume ultrastage-detected metastases in sentinel lymph nodes (SLNs) identified at surgical staging for endometrial carcinoma and to correlate it with depth of myoinvasion and tumor grade. Methods We reviewed all patients who underwent primary surgery for endometrial carcinoma with successful mapping of at least one SLN at our institution from September 2005 to December 2011. All patients underwent a cervical injection for mapping. The SLN ultrastaging protocol involved cutting an additional 2 adjacent 5-μm sections at each of 2 levels, 50-μm apart, from each paraffin block lacking metastatic carcinoma on routine hematoxylin and eosin (H&E) staining. At each level, one slide was stained with H&E and with immunohistochemistry (IHC) using anticytokeratin AE1:AE3. Micrometastases (tumor deposits >0.2 mm and ≤2 mm) and isolated tumor cells (≤0.2 mm) were classified as low-volume ultrastage-detected metastases if pathologic ultrastaging was the only method allowing detection of such nodal disease. Results Of 508 patients with successful mapping, 413 patients (81.3%) had endometrioid carcinoma. Sixty-four (12.6%) of the 508 patients had positive nodes: routine H&E detected 35 patients (6.9%), ultrastaging detected an additional 23 patients (4.5%) who would have otherwise been missed (4 micrometastases and 19 isolated tumor cells), and 6 patients (1.2%) had metastatic disease in their non-SLNs. The incidence rates of low-volume ultrastage-detected nodal metastases in patients with grades 1, 2, and 3 tumors were 3.8%, 3.4%, and 6.9%, respectively. The frequency rates of low-volume ultrastage-detected metastases in patients with a depth of myoinvasion of 0, less than 50%, and 50% or more were 0.8%, 8.0%, and 7.4%, respectively. Lymphovascular invasion was present in 20 (87%) of the cases containing low-volume ultrastage-detected metastases in the lymph nodes. Conclusions Sentinel lymph node mapping with pathologic ultrastaging in endometrial carcinoma detects additional low-volume metastases (4.5%) that would otherwise go undetected with routine evaluations. Our data support the incorporation of pathologic ultrastaging of SLNs in endometrial carcinoma with any degree of myoinvasion. The oncologic significance of low-volume nodal metastases requires long-term follow-up.

The combination of intravenous bevacizumab and metronomic oral cyclophosphamide is an effective regimen for platinum-resistant recurrent ovarian cancer

Objective To determine the efficacy, progression-free survival (PFS) and overall survival (OS) for the combination of intravenous bevacizumab and oral cyclophosphamide in heavily pretreated patients with recurrent ovarian carcinoma. Methods A retrospective review was performed for all patients with recurrent ovarian carcinoma treated with intravenous bevacizumab 10 mg/kg every 14 days and oral cyclophosphamide 50 mg daily between January 2006 and December 2010. Response to treatment was determined by Response Evaluation Criteria in Solid Tumors criteria and/or CA-125 levels. Results Sixty-six eligible patients were identified. Median age was 53 years. Fifty-five patients (83%) had undergone optimal cytoreduction. All patients were primarily or secondarily platinum resistant at the time of administration of bevacizumab and cyclophosphamide. The median number of prior chemotherapy treatments was 6.5 (range, 3 to 16). Eight patients (12.1%) had side effects which required discontinuation of bevacizumab and cyclophosphamide. There was one bowel perforation (1.5%). Overall response rate was 42.4%, including, complete response in 7 patients (10.6%), and partial response in 21 patients (31.8%), while 15 patients (22.7%) had stable disease and 23 patients (34.8%) had disease progression. Median PFS for responders was 5 months (range, 2 to 14 months). Median OS from initiation of bevacizumab and cyclophosphamide was 20 months (range, 2 to 56 months) for responders and 9 months (range, 2 to 51 months) for non-responders (p=0.004). Conclusion Bevacizumab and cyclophosphamide is an effective, well-tolerated chemotherapy regimen in heavily pretreated patients with recurrent ovarian carcinoma. This combination significantly improved PFS and OS in responders. Response rates were similar and favorable to the rates reported for similar patients receiving other commonly used second-line chemotherapeutic agents.

Sentinel lymph node mapping with pathologic ultrastaging: A valuable tool for assessing nodal metastasis in low-grade endometrial cancer with superficial myoinvasion

OBJECTIVE To report the incidence of nodal metastases in patients presenting with presumed low-grade endometrioid adenocarcinomas using a sentinel lymph node (SLN) mapping protocol including pathologic ultrastaging. METHODS All patients from 9/2005 to 12/2011 who underwent endometrial cancer staging surgery with attempted SLN mapping for preoperative grade 1 (G1) or grade 2 (G2) tumors with <50% invasion on final pathology, were included. All lymph nodes were examined with hematoxylin and eosin (H&E). Negative SLNs were further examined using an ultrastaging protocol to detect micrometastases and isolated tumor cells. RESULTS Of 425 patients, lymph node metastasis was found in 25 patients (5.9%) on final pathology-13 cases on routine H&E, 12 cases after ultrastaging. Patients whose tumors had a DMI <50% were more likely to have positive SLNs on routine H&E (p<0.005) or after ultrastaging (p=0.01) compared to those without myoinvasion. CONCLUSIONS Applying a standardized SLN mapping algorithm with ultrastaging allows for the detection of nodal disease in a presumably low-risk group of patients who in some practices may not undergo any nodal evaluation. Ultrastaging of SLNs can likely be eliminated in endometrioid adenocarcinoma with no myoinvasion. The long-term clinical significance of ultrastage-detected nodal disease requires further investigation as recurrences were noted in some of these cases.

Duration of Intrapartum Prophylaxis and Concentration of Penicillin G in Fetal Serum at Delivery

OBJECTIVE: Intrapartum penicillin G prophylaxis aims to prevent early-onset group B streptococci (GBS) sepsis by interrupting vertical transmission. We examined the relationship between duration of prophylaxis and fetal serum penicillin G levels among fetuses exposed to fewer than 4 hours of prophylaxis compared with longer durations. METHODS: In this prospective cohort study, 98 laboring GBS-positive women carrying singleton gestations at 37 weeks or greater were administered 5 million units of intravenous penicillin G followed by 2.5 million units every 4 hours until delivery. Umbilical cord blood samples were collected at delivery, and penicillin G levels were measured by high-performance liquid chromatography. Intraassay and interassay coefficients of variation were less than 3%. RESULTS: Fetuses exposed to fewer than 4 hours of prophylaxis had higher penicillin G levels than those exposed to greater than 4 hours (P=.003). In multivariable linear regression analysis, fetal penicillin G levels were determined by duration of exposure, time since last dose, dosage, and number of doses, but not maternal body mass index. Penicillin G levels increased linearly until 1 hour (R2=.40) and then decreased rapidly according to a power-decay model (R2=.67). All subgroups analyzed were above the minimal inhibitory concentration (MIC) for GBS (0.1 micrograms/mL)(P<.002). Individual samples were 10–179-fold above the MIC. In patients receiving maintenance dosing, penicillin G did not accumulate in the cord blood and returned to baseline after each 4-hour interval. CONCLUSION: Short durations of prophylaxis achieved levels significantly above the MIC, suggesting a benefit even in precipitous labors. The designation of infants exposed to fewer than 4 hours of prophylaxis as particularly at risk for GBS sepsis may be pharmacokinetically inaccurate. LEVEL OF EVIDENCE: II

A preoperative personalized risk assessment calculator for elderly ovarian cancer patients undergoing primary cytoreductive surgery

OBJECTIVE Cytoreductive surgery for ovarian cancer has higher rates of postoperative complication than neoadjuvant chemotherapy followed by surgery. If patients at high risk of postoperative complication were identified preoperatively, primary therapy could be tailored. Our objective was to develop a predictive model to estimate the risk of major postoperative complication after primary cytoreductive surgery among elderly ovarian cancer patients. METHODS Patients who underwent primary surgery for ovarian cancer between 2005 and 2013 were identified from the National Surgical Quality Improvement Project. Patients were selected using primary procedure CPT codes. Major complications were defined as grade 3 or higher complications on the validated Claviden-Dindo scale. Using logistic regression, we identified demographic and clinical characteristics predictive of postoperative complication. RESULTS We identified 2101 ovarian cancer patients of whom 35.9% were older than 65. Among women older than 65, the rate of major postoperative complication was 16.4%. Complications were directly associated with preoperative laboratory values (serum creatinine, platelets, white blood cell count, hematocrit), ascites, white race, and smoking status, and indirectly associated with albumin. Our predictive model had an area under receiver operating characteristic curve of 0.725. In order to not deny patients necessary surgery, we chose a 50% population rate of postoperative complication which produced model sensitivity of 9.8% and specificity of 98%. DISCUSSION Our predictive model uses easily and routinely obtained objective preoperative factors to estimate the risk of postoperative complication among elderly ovarian cancer patients. This information can be used to assess risk, manage postoperative expectations, and make decisions regarding initial treatment.

Type of attending obstetrician call schedule and changes in labor management and outcome

OBJECTIVE: To estimate whether a night-float call schedule for attending obstetricians is associated with different labor management or obstetric outcomes compared with a traditional call schedule. METHODS: A chart review was performed for all women admitted for labor and delivery during two 3-month periods. One period occurred immediately before a single group of generalist obstetricians changed from a traditional call schedule to a night-float call schedule, whereas the second 3-month period occurred immediately after this change. A control group of women who were managed during the same 6-month time period by a group of generalist obstetricians at the same institution who did not alter their traditional call schedule was also identified. Data on labor management and perinatal outcomes were collected. RESULTS: Change to a night-float call schedule was associated with a decreased use of induction of labor (30% to 16.7%, P=.02). Physicians also were more likely to use oxytocin augmentation (57.5% to 75.0%, P=.01) and less likely to manually extract the placenta (5.0% to 0%, P=.02) or perform an episiotomy (10.1% to 2.6%, P=.04). There were fewer observed third-degree and fourth-degree lacerations (10.3% to 3.3%, P=.045) and fewer neonates born with an umbilical artery pH less than 7.10 (9.3% to 2.2%, P=.03). CONCLUSION: A night-float call schedule was associated with both a reduction in obstetric interventions, such as labor induction and episiotomy, and improvement of particular obstetric outcomes, such as the frequency of perineal lacerations. LEVEL OF EVIDENCE: II

Association between obstetrician forceps volume and maternal and neonatal outcomes.

OBJECTIVE: To estimate the association between obstetric forceps volume and severe perineal lacerations or adverse neonatal outcomes. METHODS: This is a retrospective cohort of forceps deliveries performed at a tertiary care hospital. Obstetricians were grouped by quartile of forceps volume over the study time period. Severe (third- or fourth-degree) perineal lacerations and adverse neonatal outcomes were compared across quartiles. Individual patient characteristics were controlled for using multilevel multivariable analysis. This study had 90% power to detect a twofold difference in severe perineal lacerations between the first and fourth quartiles. Additional analyses were performed using physician years in practice or year of residency of the involved resident physicians. RESULTS: One hundred eighteen attending physicians (2,369 forceps deliveries) were included. The median (interquartile range) annual number of forceps per quartile was 1.3 (1.0–1.8), 3.8 (3.0–4.3), 6.3 (5.5–6.8), and 11.5 (9.8–17.3). The frequency of severe perineal lacerations from lowest to highest quartile was 29.9%, 27.5%, 33.3%, and 36.9% (P=.013). After adjusting for confounders, the relationship between volume quartile and severe perineal lacerations became nonsignificant. Although not powered to this outcome, the frequency of composite adverse neonatal outcome was not associated with volume quartile in either bivariate or multivariable analysis. Similarly, neither physician years of practice nor resident year was associated with severe perineal laceration. However, more experience as a resident was associated with a reduced odds of composite adverse neonatal outcomes. CONCLUSIONS: After controlling for patient factors, neither attending forceps volume nor physician years in practice was associated with severe perineal lacerations or composite neonatal injury. LEVEL OF EVIDENCE: II

The significance of perineural invasion in early-stage cervical cancer

INTRODUCTION Cervical cancer spreads directly and through lymphatic and vascular channels. Perineural invasion is an alternative method of spread. Several risk factors portend poor prognosis and inform management decisions regarding adjuvant therapy. OBJECTIVE To evaluate the incidence and significance of PNI in early cervical cancer. METHODS Retrospective chart review of early-stage cervical cancer patients (IA-IIA) from 1994 to 2009. RESULTS One hundred ninety two patients were included, 24 with perineural invasion in the cervical stroma (cases) and 168 without (controls). The mean age of the cases was 53 years, versus 45.9 in the controls (P=0.01). PNI was associated with more adjuvant therapy (P=0.0001), a higher stage (P=0.005), a larger tumor size (≥ 4 cm) (P<0.0001), lymphovascular space invasion (P=0.002), parametrial invasion (P<0.0001) and more tumor extension to the uterus (P=0.015). On multivariate analysis using an adjusted hazard ratio, risk factors for recurrence included grade (HR, 95% CI; 3.61, 1.38-9.41) and histopathology (HR, 95% CI; 2.85, 100-8.09). Similarly, risk factors for death included grade (HR, 95% CI; 3.43, 1.24-9.49) and histopathology (HR, 95% CI; 3.71, 1.03-13.33). Perineural invasion was not identified as an independent risk factor for either recurrence or death. The mean follow up time was 56 months. There was no significant difference in recurrence (P=0.601) or over-all survival (P=0.529) between cases and controls. CONCLUSION While perineural invasion was found to be associated with multiple high-risk factors, it was not found to be associated with a worse prognosis in early cervical cancer.

Venous Thromboembolism in Minimally Invasive Compared With Open Hysterectomy for Endometrial Cancer.

OBJECTIVE: To evaluate whether minimally invasive surgery for endometrial cancer is independently associated with a decreased odds of venous thromboembolism compared with open surgery. METHODS: We performed a secondary analysis cohort study of prospectively collected quality improvement data and examined patients undergoing hysterectomy for endometrial cancer from 2008 to 2013 recorded in the National Surgical Quality Improvement Program database. Patients undergoing minimally invasive (laparoscopic or robotic) surgery were compared with those undergoing open surgery with respect to 30-day postoperative venous thromboembolism. Demographic and procedure variables were examined as potential confounders. Data regarding receipt of perioperative venous thromboembolism prophylaxis were not available. Bivariable tests and logistic regression were used for analysis. RESULTS: Of 9,948 patients who underwent hysterectomy for the treatment of endometrial cancer, 61.9% underwent minimally invasive surgery and 38.1% underwent open surgery. Patients undergoing minimally invasive surgery had a lower venous thromboembolism incidence (0.7%, n=47) than patients undergoing open surgery (2.2%, n=80) (P<.001). In a multivariate model adjusting for age, body mass index, race, operative time, Charlson comorbidity score, and surgical complexity, minimally invasive surgery remained associated with decreased odds of venous thromboembolism (adjusted odds ratio 0.36, 95% confidence interval 0.24–0.53) compared with open surgery. CONCLUSION: Minimally invasive surgery for the treatment of endometrial cancer is independently associated with decreased odds of venous thromboembolism compared with open surgery.