Alexander Melamed

Effects of the levonorgestrel-releasing intrauterine system on cervical mucus quality and sperm penetrability ☆

BACKGROUND In levonorgestrel intrauterine system (LNG-IUS) users, the prevention of sperm penetration through cervical mucus has not been demonstrated. STUDY DESIGN Subjects were enrolled in an investigator-blinded study to compare quality and sperm penetrability of mid-cycle cervical mucus between LNG-IUS users and hormone-free controls. Cervical mucus was microscopically examined using World Health Organization (WHO) cervical mucus analysis (CMA). CMA score ≥10 of 15 points indicated cervical mucus favoring sperm penetration. Mucus was incubated with sperm using the WHO simplified slide test (SST) and Kremer sperm cervical mucus penetration test (SCMPT). RESULTS Data from 14 LNG-IUS users and 16 controls showed 14% of LNG-IUS users had CMA score ≥10% vs. 69% of controls (p=.004). SST showed no sperm penetration for LNG-IUS users, significantly less than controls (0% vs. 64.3%, p<.001). SCMPT demonstrated no sperm mucus penetration for LNG-IUS users at 2 and 6 h (0% vs. 85% in controls with 2-h score ≥6, p<.001; 6 h 0% vs. 79% in controls, p<.001). CONCLUSIONS Mid-cycle cervical mucus of LNG-IUS users is poor quality and prevents endocervical sperm transport in vitro.

Overall Survival Following Neoadjuvant Chemotherapy vs Primary Cytoreductive Surgery in Women With Epithelial Ovarian Cancer: Analysis of the National Cancer Database

Importance Uncertainty remains about the relative benefits of primary cytoreductive surgery (PCS) vs neoadjuvant chemotherapy (NACT) for advanced-stage epithelial ovarian cancer (EOC). Objective To compare overall survival of PCS vs NACT in a large national population of women with advanced-stage EOC. Design, Setting, and Participants Retrospective cohort study of women with stage IIIC and IV EOC diagnosed between 2003 and 2011 treated at hospitals across the United States reporting to the National Cancer Data Base. We focused on patients 70 years or younger with a Charlson comorbidity index of 0 who were likely candidates for either treatment. Exposures Initial treatment approach of PCS vs NACT, examined using an intent-to-treat analysis. Main Outcomes and Measures Overall survival, defined as months from cancer diagnosis to death or date of the last contact. We used propensity score matching to compare similar women who underwent PCS and NACT. The association of treatment approach with overall survival was assessed using the Kaplan-Meier method and the log-rank test. We assessed whether the findings were influenced by differences in the prevalence of an unobserved confounder, such as limited performance status (Eastern Cooperative Oncology Group 1-2), preoperative disease burden, and BRCA status. Results Among 22 962 patients (mean [SD] age, 56.12 [9.38] years), 19 836 (86.4%) received PCS and 3126 (13.6%) underwent NACT. We matched 2935 patients treated with NACT with similar patients who received PCS. The median follow-up was 56.5 (95% CI, 54.5-59.2) months in the PCS group and 56.3 (95% CI, 54.5-59.8) months in the NACT group in the propensity-matched cohort. Among propensity score–matched groups, the median overall survival was 37.3 (95% CI, 35.2-38.7) months in the PCS group and 32.1 (95% CI, 30.8-34.1) months in the NACT group (P < .001). However, if the NACT group had a higher proportion of women with performance statuses of 1 to 2 compared with those who underwent PCS (60% vs 50%), the association of PCS and improved survival would not be statistically significant. Conclusions and Relevance Primary cytoreductive surgery was associated with improved survival compared with NACT in otherwise healthy women with advanced-stage epithelial ovarian cancer aged 70 years or younger. The lower survival in women who received NACT could be explained by a higher prevalence of limited performance status in women undergoing NACT.

Infection and extramural delivery with use of digoxin as a feticidal agent

BACKGROUND Many abortion providers use digoxin to induce fetal demise prior to dilation and evacuation (D&E). Our primary objective was to examine the frequency of infection and extramural delivery following digoxin use. STUDY DESIGN We conducted a retrospective single-cohort study. Inclusion criteria were all women between 18 and 24 weeks of estimated gestational age who received digoxin in preparation for D&E at our outpatient facility. We queried two electronic databases to collect data on the frequency of extramural delivery and the rate of perioperative infection. RESULTS From January 1, 2000, to December 31, 2008, 4906 abortions were performed between 18 and 24 weeks of estimated gestation with digoxin injection administered as feticidal agent 1 day prior to D&E. Extramural delivery frequency was 0.30%, and infection frequency was 0.04%. There were no significant differences in the frequency of extramural deliveries across procedure year (p = .2), estimated gestational age (p = .3), race/ethnicity (p = .2) or maternal age (p = .3). CONCLUSION Rates of extramural delivery and infection are acceptably low following digoxin use prior to scheduled D&E.

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.

Changing presentation of complete hydatidiform mole at the New England Trophoblastic Disease Center over the past three decades: Does early diagnosis alter risk for gestational trophoblastic neoplasia?

OBJECTIVE To compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among recent (1994-2013) and historical (1988-1993) cases of complete hydatidiform mole (CHM). METHODS This study included two non-concurrent cohorts (1988-1993 versus 1994-2013) of patients from the New England Trophoblastic Disease Center (NETDC). Clinical and pathologic reports of patients diagnosed with CHM between 1994 and 2013 were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin (hCG) levels, and the rate of progression to GTN were compared. RESULTS In the current cohort (1994 to 2013) the median gestational age at diagnosis continued to decline compared to our prior cohort (1988-1993) (9weeks versus 12weeks). Patients from the current cohort were significantly more likely to be diagnosed prior to the 11th week of gestation (56 versus 41%, p=0.04). Patients in the current cohort were also significantly less likely to present with vaginal bleeding (46 versus 84%, p<0.001). Earlier diagnosis of complete mole did not result in a decrease in the rate of postmolar GTN. The frequencies of postmolar GTN in the current (1994-2013) and prior (1988-1993) cohorts were 19 and 23%, respectively. In the current cohort, even diagnosis prior to ten weeks gestation did not decrease the risk of developing GTN. CONCLUSIONS This study indicates that complete mole continues to be diagnosed progressively earlier resulting in a further decrease in some classical presenting symptoms. However, despite earlier detection, the risk of development of postmolar GTN has not been affected.

Temporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system.

BACKGROUND The major contraceptive action of the levonorgestrel-releasing intrauterine system (LNG-IUS) is cervical mucus (CM) thickening, which prevents sperm penetration. No study to date has examined the temporal relationship between the insertion of the LNG-IUS and changes in CM quality and sperm penetration. STUDY DESIGN Participants were enrolled in a clinically descriptive study to compare the quality of CM and three parameters of sperm penetration prior to insertion of the LNG-IUS and on Days 1, 3 and 5 after insertion. Measurements of estradiol, progesterone and levonorgestrel (LNG) in serum and LNG in CM were also carried out at these times. CM was analyzed using the World Health Organization CM grading criteria. Sperm penetration was determined using an in vitro sperm-CM penetration test. RESULTS All 10 participants underwent LNG-IUS insertion during midcycle when CM quality was good and sperm penetration was excellent. On Day 1 after LNG-IUS insertion, the majority of participants demonstrated poor CM quality and poor sperm penetration. On Day 3, all participants had poor CM quality, and all but one subject had poor sperm penetration. By Day 5, all participants had poor CM quality and poor sperm penetration. LNG levels in CM peaked on the day after LNG-IUS insertion. CONCLUSION Significant changes in quality of CM and sperm penetration were observed shortly after LNG-IUS insertion; however, CM can remain penetrable for up to 5 days when the LNG-IUS is inserted midcycle.

Ovarian Conservation and Overall Survival in Young Women With Early-Stage Low-Grade Endometrial Cancer.

OBJECTIVE: To characterize contributing factors for ovarian conservation during surgical treatment for endometrial cancer and to examine the association of ovarian conservation on survival of young women with early-stage, low-grade tumors. METHODS: This was a population-based study using the Surveillance, Epidemiology, and End Results program to identify surgically treated stage I type I (grade 1–2 endometrioid histology) endometrial cancer cases diagnosed between 1983 and 2012 (N=86,005). Multivariable models were used to identify independent factors for ovarian conservation. Survival outcomes and cause of death were examined for women aged younger than 50 with stage I type I endometrial cancer who underwent ovarian conservation (1,242 among 12,860 women [9.7%]). RESULTS: On multivariable analysis, age younger than 50 years, grade 1 endometrioid histology, and tumor size 2.0 cm or less were noted to be independent factors for ovarian conservation (all, P<.001). For 9,110 women aged younger than 50 years with stage I grade 1 tumors, cause-specific survival was similar between ovarian conservation and oophorectomy cases (20-year rates 98.9% compared with 97.7%, P=.31), whereas overall survival was significantly higher in ovarian conservation cases than oophorectomy cases (88.8% compared with 82.0%, P=.011). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.73, 95% confidence interval [CI] 0.54–0.98, P=.036) and was independently associated with a lower cumulative risk of death resulting from cardiovascular disease compared with oophorectomy (20-year rates, 2.3% compared with 3.7%, adjusted hazard ratio 0.40, 95% CI 0.17–0.91, P=.029). Contrary, cause-specific survival (20-year rates 94.6% compared with 96.1%, P=.68) and overall survival (81.0% compared with 80.6%, P=.91) were similar between ovarian conservation and oophorectomy among 3,750 women aged younger than 50 years with stage I grade 2 tumors. CONCLUSION: Ovarian conservation is performed in less than 10% of young women with stage I type I endometrial cancer. Ovarian conservation is associated with decreased mortality in young women with stage I grade 1 tumors.

Ovarian Conservation and Overall Survival in Young Women With Early-stage Cervical Cancer

OBJECTIVE To identify predictors of ovarian conservation at hysterectomy and to examine the association of ovarian conservation and survival of young women with early-stage cervical cancer. METHODS This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results Program to identify hysterectomy-based surgically treated patients with stage I cervical cancer diagnosed between 1983 and 2012 (N=16,511). Multivariable models were used to identify independent factors associated with ovarian conservation. Among the subgroup of 9,419 women younger than 50 years of age with stage I disease, survival outcomes and causes of death were examined for 3,908 (41.5%) women who underwent ovarian conservation at hysterectomy without radiotherapy. RESULTS On multivariable analysis, age younger than 50 years, stage IA disease, and squamous histology were independent factors associated with ovarian conservation (all, P<.001). Among 5,526 women younger than 50 years of age with stage IA disease who underwent hysterectomy without radiotherapy, overall survival was significantly higher in patients undergoing ovarian conservation than in those undergoing oophorectomy (20-year rate, 93.5% compared with 86.8%, P<.001); cervical cancer-specific survival was similar between the patients who underwent ovarian conservation and those who underwent oophorectomy (98.8% compared with 97.8%, P=.12). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.63, 95% confidence interval [CI] 0.49-0.82, P=.001) and was independently associated with lower cumulative risks of death resulting from cardiovascular disease (20-year cumulative rate, 1.2% compared with 3.3%, adjusted hazard ratio 0.47, 95% CI 0.26-0.86, P=.014) and other chronic disease (0.5% compared with 1.4%, adjusted hazard ratio 0.24, 95% CI 0.09-0.65, P=.005) compared with oophorectomy. Both cervical cancer-specific survival (20-year rate, 93.1% compared with 92.0%, P=.37) and overall survival (86.7% compared with 84.6%, P=.12) were similar between ovarian conservation and oophorectomy among 3,893 women younger than 50 years of age with stage IB disease who underwent hysterectomy without radiotherapy. CONCLUSION Among young women with stage IA cervical cancer, ovarian conservation at hysterectomy is associated with decreased all-cause mortality including death resulting from cardiovascular disease and other chronic diseases.

BMD Reference Standards Among South Asians in the United States

The relationship between bone mineral density (BMD) and fracture risk is not well established for non-white populations. There is no established BMD reference standard for South Asians. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD at total hip and lumbar spine in 150 US-based South-Asian Indians. For each subject, T-scores were calculated using BMD reference values based on US white, North Indian, and South Indian populations, and the resulting WHO BMD category assignments were compared. Reference standards derived from Indian populations classified a larger proportion of US-based Indians as normal than did US white-based standards. The percentage of individuals reclassified when changing between reference standards varied by skeletal site and reference population origin, ranging from 13% (95% confidence interval [CI]: 7-18%), when switching from US white- to North Indian-based standard for total hip, to 40% (95% CI: 32-48%), when switching from US white to South Indian reference values for lumbar spine. These findings illustrate that choice of reference standard has a significant effect on the diagnosis of osteoporosis in South Asians, and underscore the importance of future research to quantify the relationship between BMD and fracture risk in this population.

Outcomes of Women With High-grade and Low-grade Advanced-stage Serous Epithelial Ovarian Cancer

OBJECTIVE To compare outcomes of women with advanced-stage low-grade serous ovarian cancer and high-grade serous ovarian cancer and identify factors associated with survival among patients with advanced-stage low-grade serous ovarian cancer. METHODS A retrospective study of patients diagnosed with grade 1 or 3, advanced-stage (stage IIIC and IV) serous ovarian cancer between 2003 and 2011 was undertaken using the National Cancer Database, a large administrative database. The effect of grade on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. Among women with low-grade serous ovarian cancer, propensity score matching was used to compare all-cause mortality among similar women who underwent chemotherapy and lymph node dissection and those who did not. RESULTS A total of 16,854 (95.7%) patients with high-grade serous ovarian cancer and 755 (4.3%) patients with low-grade serous ovarian cancer were identified. Median overall survival was 40.7 months among high-grade patients and 90.8 months among women with low-grade tumors (P<.001). Among patients with low-grade serous ovarian cancer in the propensity score-matched cohort, the median overall survival was 88.2 months among the 140 patients who received chemotherapy and 95.9 months among the 140 who did not receive chemotherapy (P=.7). Conversely, in the lymph node dissection propensity-matched cohort, median overall survival was 106.5 months among the 202 patients who underwent lymph node dissection and 58 months among the 202 who did not (P<.001). CONCLUSION When compared with high-grade serous ovarian cancer, low-grade serous ovarian cancer is associated with improved survival. In patients with advanced-stage low-grade serous ovarian cancer, lymphadenectomy but not adjuvant chemotherapy was associated with improved survival.