Does the number of nodes removed impact survival in vulvar cancer patients with node-negative disease? Gynecol Oncol. 2010 Feb 12. [Epub ahead of print]

Objective: To determine if the extent of lymphadenectomy as determined by lymph node count from an inguinal-femoral lymph node dissection for vulvar cancer impacts overall survival (OS) and disease-specific survival (DSS) in patients with node-negative disease.

Methods: Patients with stage I, II and III squamous cell carcinoma of the vulva who underwent primary inguinal-femoral nodal dissection were identified from the Surveillance, Epidemiology and End Results Program between 1988 and 2003. Patients were divided into 2 groups, those with ≤10 nodes and those with >10 nodes removed, and analyzed according to stage. All patients with histologically positive nodes were excluded. Log-rank test was done for univariate analysis. Cox regression method was used for multivariate analysis.

Results: Squamous cell vulvar cancer was identified in 1030 patients. Statistically significant differences were seen on univariate analysis of OS between stage II and III patients with ≤10 and >10 nodes removed. The difference in 5-year DSS survival was statistically significant only for patients with stage III disease. On multivariate analysis age, stage and number of lymph nodes removed were all found to be significant variables affecting OS and DSS.

Conclusion: The removal of greater than 10 lymph nodes was associated with a significant improvement in DSS in patients with stage III vulvar carcinoma. This improvement in survival may be due to removal of micrometastatic disease in the inguinal lymph nodes. These data suggest that a thorough inguinal-femoral lymph node dissection should be performed in patients with advanced-stage node-negative vulvar carcinoma. Copyright © 2009 Elsevier Inc. All rights reserved.

Impact of Human Papillomavirus (HPV)-6/11/6/18 Vaccine on All HPV-Associated Genital Diseases in Young Women. J Natl Cancer Inst. 2010;102:325-339. Epub 2010 Feb 5.

Background: The impact of the prophylactic vaccine against human papillomavirus (HPV) types 6, 11, 16, and 18 (HPV6/11/16/18) on all HPV-associated genital disease was investigated in a population that approximates sexually naive women in that they were "negative to 14 HPV types" and in a mixed population of HPV-exposed and -unexposed women (intention-to-treat group).

Methods: This analysis studied 17 622 women aged 15-26 years who were enrolled in one of two randomized, placebo-controlled, efficacy trials for the HPV6/11/16/18 vaccine (first patient on December 28, 2001, and studies completed July 31, 2007). Vaccine or placebo was given at day 1, month 2, and month 6. All women underwent cervicovaginal sampling and Papanicolaou (Pap) testing at day 1 and every 6-12 months thereafter. Outcomes were any cervical intraepithelial neoplasia; any external anogenital and vaginal lesions; Pap test abnormalities; and procedures such as colposcopy and definitive therapy. Absolute rates are expressed as women with endpoint per 100 person-years at risk.

Results: The average follow-up was 3.6 years (maximum of 4.9 years). In the population that was negative to 14 HPV types, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and of HPV6/11-related genital warts. In the intention-to-treat group, vaccination also statistically significantly reduced the risk of any high-grade cervical lesions (19.0% reduction; rate vaccine = 1.43, rate placebo = 1.76, difference = 0.33, 95% confidence interval [CI] = 0.13 to 0.54), vulvar and vaginal lesions (50.7% reduction; rate vaccine = 0.10, rate placebo = 0.20, difference = 0.10, 95% CI = 0.04 to 0.16), genital warts (62.0% reduction; rate vaccine = 0.44, rate placebo = 1.17, difference = 0.72, 95% CI = 0.58 to 0.87), Pap abnormalities (11.3% reduction; rate vaccine = 10.36, rate placebo = 11.68, difference = 1.32, 95% CI = 0.74 to 1.90), and cervical definitive therapy (23.0% reduction; rate vaccine = 1.97, rate placebo = 2.56, difference = 0.59, 95% CI = 0.35 to 0.83), irrespective of causal HPV type.

Conclusions: High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures. In the longer term, substantial reductions in the rates of cervical, vulvar, and vaginal cancers may follow.

Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: A population based cohort study. BMJ. 2010 Feb 8;340:c693. doi: 10.1136/bmj.c693.

Objective: To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen's effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6).

Design: Population based cohort study.

Participants: Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI.

Main Outcome Measures: Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed.

Results: Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (p < 0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater.

Conclusion: Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.

Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear? A randomized trial. Ann Intern Med. 2010;152:211-217.

Background: Estrogen plus progestin therapy increases the risk for coronary heart disease (CHD) in postmenopausal women. However, this increased risk might be limited to the first years of use and to women who start therapy late in menopause.

Objective: To estimate the effect of continuous estrogen plus progestin therapy on CHD risk over time and stratified by years since menopause.

Design: Women's Health Initiative randomized, double-blinded, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00000611)

Setting: 40 U.S. clinical centers.

Patients: 16 608 postmenopausal women with an intact uterus at baseline from 1993 to 1998.

Intervention: Conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo.

Measurements: Adherence-adjusted hazard ratios and CHD-free survival curves estimated through inverse probability weighting.

Results: Compared with no use of hormone therapy, the hazard ratio for continuous use of estrogen plus progestin therapy was 2.36 (95% CI, 1.55 to 3.62) for the first 2 years and 1.69 (CI, 0.98 to 2.89) for the first 8 years. For women within 10 years after menopause, the hazard ratios were 1.29 (CI, 0.52 to 3.18) for the first 2 years and 0.64 (CI, 0.21 to 1.99) for the first 8 years, and the CHD-free survival curves for continuous use and no use of estrogen plus progestin crossed at about 6 years (CI, 2 years to 10 years).

Limitation: The analysis may not have fully adjusted for joint determinants of adherence and CHD risk. Sample sizes for some subgroup analyses were small.

Conclusion: No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use, including in women who initiated therapy within 10 years after menopause. A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use.

Primary Funding Source: National Heart, Lung, and Blood Institute.

Effects of Teriparatide, Alendronate, or Both in Women with Postmenopausal Osteoporosis. J Clin Endocrinol Metab. 2010 Feb 17. [Epub ahead of print]

Context: Teriparatide increases both bone formation and bone resorption.

Objective: We sought to determine whether combining teriparatide with an antiresorptive agent would alter its anabolic action.

Design and Setting: This was a randomized controlled trial conducted in a single university hospital.

Patients and Intervention: We randomized 93 postmenopausal women with low bone mineral density (BMD) to alendronate 10 mg daily (group 1), teriparatide 40 mg sc daily (group 2), or both (group 3) for 30 months. Teriparatide was begun at month 6.

Main Outcome Measures: BMD of the lumbar spine, proximal femur, proximal radius, and total body was measured by dual-energy x-ray absorptiometry (DXA) every 6 months. Lumbar spine trabecular BMD was measured at baseline and month 30 by quantitative computed tomography. Serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide levels were assessed frequently. Women who had at least one repeat DXA scan on therapy were included in the analyses (n = 69).

Results: DXA spine BMD increased more in women treated with teriparatide alone than with alendronate alone (18 +/- 11 vs. 7 +/- 4%; p < 0.001) or both (18 +/-11 vs. 12 +/- 9%; p = 0.045). Similarly, femoral neck BMD increased more in women treated with teriparatide alone than with alendronate alone (11 +/- 5 vs. 4 +/- 4%; p < 0.001) or both (11 +/- 5 vs. 3 +/- 5%; p < 0.001). Quantitative computed tomography spine BMD increased 1 +/- 7, 61 +/- 31, and 24 +/- 24% in groups 1, 2, and 3 (p < 0.001 for all comparisons). Serum osteocalcin, N-terminal propeptide of type 1 collagen, and cross-linked N-telopeptides of type I collagen increased more with teriparatide alone than with both (p < 0.001 for each marker).

Conclusion: Alendronate reduces the ability of teriparatide to increase BMD and bone turnover in women.

Body mass index does not influence the outcome of anti-incontinence surgery among women whereas menopausal status and ageing do: A randomised trial. Int Urogynecol J Pelvic Floor Dysfunct. 2010 Feb 24. [Epub ahead of print]

Introduction and Hypothesis: A few series comparing the clinical efficacy of midurethral slings in obese and postmenopausal patients are available. The aim of the study was to assess clinical efficacy of suburethral tape operations for the surgical treatment of female stress urinary incontinence (SUI) stratified by obesity, menopause and ageing.

Methods: Five hundred thirty-seven patients underwent either retropubic or transobturator sling procedure. Patients were randomly allocated into two study groups in a ratio of 1:1. After 18 months, 398 women were available for a follow-up efficacy evaluation.

Results: The clinical effectiveness of surgical SUI treatment did not depend on patients' body mass index (BMI) and type of midurethral sling, but menopausal status and ageing significantly influenced the outcome of the surgery.

Conclusion: We found that BMI does not influence the clinical effectiveness of SUI treatment, whereas both menopause and ageing had a detrimental influence on the final outcome of the surgery.

Population-Based Study of Contralateral Prophylactic Mastectomy and Survival Outcomes of Breast Cancer Patients. J Natl Cancer Inst. 2010 Feb 25. [Epub ahead of print]

Background: Despite increased demand for contralateral prophylactic mastectomy (CPM), the survival benefit of this procedure remains uncertain.

Methods: We used the Surveillance, Epidemiology, and End Results database to identify 107 106 women with breast cancer who had undergone mastectomy for treatment between 1998 and 2003 and a subset of 8902 women who also underwent CPM during the same period. Associations between predictor variables and the likelihood of undergoing CPM were evaluated by use of chi(2) analyses. Risk-stratified (estrogen receptor [ER] status, stage, and age) adjusted survival analyses were performed by using Cox regression. Statistical tests were two-sided.

Results: In a univariate analysis, CPM was associated with improved disease-specific survival (hazard ratio [HR] of death = 0.63, 95% confidence interval [CI] = 0.57 to 0.69; p < .001). Risk-stratified analysis showed that this association was because of a reduction in breast cancer-specific mortality in women aged 18-49 years with stages I-II ER-negative cancer (HR of death = 0.68, 95% CI = 0.53 to 0.88; p = .004). Five year-adjusted breast cancer survival for this group was improved with CPM vs without (88.5% vs 83.7%, difference = 4.8%). Although rates of contralateral breast cancer among young women with stages I-II disease undergoing CPM were independent of ER status, women with ER-positive tumors in the absence of prophylactic mastectomy also had a lower overall risk for contralateral breast cancer than women with ER-negative tumors (0.46% vs 0.90%, difference = 0.44%; p < .001).

Conclusions: CPM is associated with a small improvement in 5-year breast cancer-specific survival mainly in young women with early-stage ER-negative breast cancer. This effect is related to a higher baseline risk of contralateral breast cancer.

Sex differences in presentation, severity, and management of stroke in a population-based study. Neurology. 2010 Feb 24. [Epub ahead of print]

Objectives: Women may have poorer outcomes after stroke than men because of differences in their acute management. We examined sex differences in presentation, severity, in-hospital treatment, and early mortality in a cohort of first-ever-in-a-lifetime stroke patients.

Methods: Data were collected from May 1, 1996, to April 30, 1999, in the North East Melbourne Stroke Incidence Study. Stroke symptoms, prestroke medical history, in-hospital investigations, admission and discharge medications, initial stroke severity, and 28-day mortality were recorded. Multivariable regression was used to estimate sex differences in treatment, investigations, and 28-day mortality.

Results: A total of 1,316 patients were included. Women were older (mean age 76 +/- 0.6 vs 72 +/- 0.6, p < 0.01), had more severe strokes (median NIH Stroke Scale score 6 vs 5, p < 0.01), and more likely to experience loss of consciousness (31% vs 23%, p = 0.003) and incontinence (22% vs 11%, p = 0.01) than men. Women were less often on lipid-lowering therapy on admission. Echocardiography and carotid investigations were less frequently performed in women due to greater age and stroke severity. Women had greater 28-day mortality (32% vs 21%, p < 0.001) and stroke severity (44% vs 36%, p = 0.01) than men, but adjustment for age, comorbidities, and stroke severity (for mortality only) completely attenuated these associations.

Conclusion: Sex differences seen in this study were mostly explained by women's older age, greater comorbidity, and stroke severity. The reasons for differences according to age may need further examination.

The effects of drug and behavior therapy on urgency and voiding frequency. Int Urogynecol J Pelvic Floor Dysfunct. 2010 Feb 9. [Epub ahead of print]

Introduction and Hypothesis: The objective of this study was to examine the effects of drug therapy alone and combined with behavioral therapy on urgency and 24-h voiding frequency in women with urge-predominant incontinence and to identify predictors of change.

Methods: A planned analysis of data from a multi-site, randomized, controlled trial (N = 307). Bladder diaries were used to document voids, incontinence, and urgency severity.

Results: Urgency scores decreased significantly within both treatment groups, but changes did not differ between groups (p = 0.30). Improvement in urgency was associated with greater baseline urgency (p < 0.0001) and black ethnicity (p = 0.03). Voiding frequency increased with drug alone and decreased slightly with combined therapy (p = 0.009), and improvement was associated with combined treatment (p < 0.0001), higher baseline frequency (p < 0.0001), and lower baseline incontinence episode frequency (p = 0.001).

Conclusions: Although combined drug and behavioral therapy does not appear to improve urgency more than drug alone, it resulted in better outcomes on voiding frequency.

Trends in delivery and neonatal outcome after in vitro fertilization in Sweden: Data for 25 years. Hum Reprod. 2010 Feb 5. [Epub ahead of print]

Background: Marked changes have occurred in in vitro fertilization (IVF) methodology during the past 25 years but also in characteristics of couples undergoing treatment.

Methods: This study was based on 27 386 women undergoing IVF treatment from 1982 to 2006 and giving birth to 31 850 infants. Outcomes of deliveries were studied using Swedish health registers. Comparisons were made with all deliveries in the population (n = 2 603 601). Adjusted odds ratios were calculated when important changes in background rates had occurred.

Results: There was a substantial increase in the use of intracytoplasmatic sperm injection (ICSI) and the transfer of cryopreserved embryos. Among all ICSI cases, the proportion using epididymal or testicular sperm varied between 5 and 10%. Maternal characteristics changed during the observation period but the median age remained relatively constant in spite of the increasing maternal age in the population. There was a decline in the rate of some maternal pregnancy diagnoses (notably pre-eclampsia, premature rupture of membranes) and some neonatal diagnoses (notably preterm births, low birthweight, cerebral hemorrhage, respiratory diagnoses, use of continuous positive airway pressure and mechanical ventilation, sepsis/pneumonia). Up till 1992, the twinning rate increased to a maximum of about 30% and then declined to 5% towards the end of the period whereas higher order multiples nearly disappeared. The total rate of infants with congenital malformations changed only little.

Conclusions: The decrease in unwanted outcomes can, to a large extent, be explained by the reduced rate of multiple births but was seen also among singletons. Other explanations can be sought in changes in the characteristics of patients undergoing IVF.

A prospective study of body size during childhood and early adulthood and the incidence of endometriosis. Hum Reprod. 2010 Feb 19. [Epub ahead of print]

Background: An inverse association between adult body mass index (BMI) and risk of endometriosis has frequently been reported. However, the association between body size during childhood and early adulthood and endometriosis is not as well documented.

Methods: Using data collected from the Nurses' Health Study II, a prospective cohort study of premenopausal US nurses, that began in 1989, we have attempted to clarify this relationship. Data are updated every 2 years with follow-up for these analyses through 2001. In 1989 women recalled their body size at ages 5, 10 and 20 years using a validated 9-level figure drawing.

Results: During 831 910 person-years of follow-up, 1817 cases of self-reported laparoscopically-confirmed endometriosis were observed among women with no past infertility. After adjusting for age, birthweight, age at menarche, parity, oral contraceptive use and adult BMI, we observed a significant reduction in the incidence of endometriosis with increasing body size for all time periods. The relative risks (RRs) comparing the smallest and largest figure sizes to the middle category during childhood (ages 5-10) were 1.18 (95% confidence interval 1.02-1.36) and 0.82 (0.66-1.02), p-trend = 0.0002. At age 20, the RRs for the same comparisons were 1.32 (1.06-1.65) and 0.87 (0.74-1.03), p-trend = 0.04. Additional adjustment by menstrual cycle length and regularity yielded similar associations. The associations were stronger among nulliparous women than among parous women, although not all differences were statistically significant.

Conclusion: In this large cohort of premenopausal women, there was evidence of a persistent inverse association between childhood and early adulthood body size and incidence of laparoscopically confirmed endometriosis, independent of adult BMI and menstrual cycle characteristics.

In vitro fertilization and preterm delivery, low birth weight, and admission to the neonatal intensive care unit: A prospective follow-up study. Fertil Steril. 2010 Feb 24. [Epub ahead of print]

Objective: To compare the risk of preterm delivery, low birth weight, and admission of the newborn to a neonatal intensive care unit (NICU) in women pregnant after fertility treatment and subfertile women with the risk in fertile women.

Design: Prospective follow-up study.

Setting: Aarhus University Hospital, Skejby, Denmark, 1989-2006.

Patient(s): A total of 20,080 liveborn singletons.

Intervention(s): None.

Main Outcome Measure(s): Preterm delivery, low birth weight, and admission of the newborn to a NICU.

Result(s): After adjustment we found a statistically significantly increased risk of preterm delivery and very preterm delivery in women who conceived after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) compared with fertile women. Compared with fertile women, the risk of preterm delivery and very preterm delivery was not statistically significantly different in women pregnant after non-IVF assisted reproductive treatment (non-IVF ART) or subfertile women. We found no association between IVF/ICSI and the risk of low birth weight at term or admittance to the NICU.

Conclusion(s): The increased risk of preterm delivery after IVF/ICSI may be due to the fertility treatment or unknown characteristics in the couples who undergo IVF/ICSI. Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

The effect of hysterectomy or levonorgestrel-releasing intrauterine system on lower urinary tract symptoms: A 10-year follow-up study of a randomised trial. BJOG. 2010 Feb 15. [Epub ahead of print]

Objective: To evaluate the effect of hysterectomy and levonorgestrel-releasing intrauterine system (LNG-IUS) on lower urinary tract symptoms (LUTS) among women treated for menorrhagia.

Design: Randomised controlled trial analysed by actual treatment.

Setting: Five university hospitals in Finland. Sample A cohort of 236 women, aged 35-49 years, referred for menorrhagia between 1994 and 1997.

Methods: Women were randomly assigned to treatment by hysterectomy (n = 117) or LNG-IUS (n = 119).

Main outcome measures: Lower urinary tract symptoms were evaluated by questionnaires at baseline, and after 6, 12 months, 5, and 10 years. Medications and operations for urinary incontinence were confirmed from medical records and national registries.

Results: Overall, 221 (94%) women took part in the 10-year follow-up evaluation. As 55 (46%) women originally randomised to the LNG-IUS group underwent hysterectomy, the results were analysed by actual treatment. Women treated by hysterectomy used more medication for urinary incontinence than LNG-IUS users (12% versus 1%) (OR 9.45, 95% CI 1.24-71.87, p = 0.006). Three hysterectomised women and one LNG-IUS user underwent surgery for stress urinary incontinence (SUI). Women treated by hysterectomy had more urinary tract infections (UTIs) than LNG-IUS users (OR 3.20, 95% CI 1.47-6.96, p = 0.002). Feeling of incomplete emptying (OR 3.00, 95% CI 1.00-9.05, p = 0.04) and SUI (OR 1.83, 95% CI 1.01-3.32, p = 0.04) were more common among women treated by hysterectomy. No differences between the study arms were noted in urge urinary incontinence or by the Urinary Incontinence Severity Score. A multivariate model showed that UTIs were associated with hysterectomy (p = 0.004).

Conclusions: Hysterectomy increases the risks for incomplete emptying, lower UTIs and SUI.