Risk-Reducing Salpingo-Oophorectomy and Breast Cancer Risk Reduction in the Gynecologic Oncology Group Protocol-0199 (GOG-0199).

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) has been associated with approximately 50% breast cancer risk reduction among women with a pathogenic variant in BRCA1 or BRCA2 (BRCA1/2), a finding that has recently been questioned. METHODS: We estimated incidence rates of breast cancer and all cancers combined during 5 years of follow-up among participants selecting RRSO or ovarian cancer screening (OCS) among women with a BRCA1/2 pathogenic variant or strong breast and/or ovarian cancer family history. Ovarian or fallopian tube or peritoneal cancer incidence rates were estimated for the OCS group. Breast cancer hazard ratios (HRs) for time-dependent RRSO were estimated using Cox regression with age time-scale (4943 and 4990 women-years in RRSO and OCS cohorts, respectively). All statistical tests were two-sided. RESULTS: The RRSO cohort included 925 participants, and 1453 participants were in the OCS cohort (381 underwent RRSO during follow-up), with 88 incident breast cancers diagnosed. Among BRCA1/2 pathogenic variant carriers, a non-statistically significant lower breast cancer incidence was observed in the RRSO compared with the OCS cohort (HR = 0.86, 95% confidence interval = 0.45 to 1.67; P = .67). No difference was observed in the overall population or among subgroups stratified by prior breast cancer history or menopausal status. Seven fallopian tube and four ovarian cancers were prospectively diagnosed in the OCS cohort, and one primary peritoneal carcinoma occurred in the RRSO cohort. CONCLUSIONS: These data suggest that RRSO might be associated with reduced breast cancer incidence among women with a BRCA1/2 pathogenic variant, although the effect, if present, is small. This evolving evidence warrants a thorough discussion regarding the impact of RRSO on breast cancer risk with women considering this intervention.

Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials.

Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL.Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.Results: Specificity for ultrasound referral was 92% versus 90% (P = 0.0001), and PPV was 4.6% versus 10% (P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years).Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation. Clin Cancer Res; 23(14); 3628-37. ©2017 AACR.

Factors associated with deciding between risk-reducing salpingo-oophorectomy and ovarian cancer screening among high-risk women enrolled in GOG-0199: An NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVES: Women at increased genetic risk of ovarian cancer (OC) are recommended to have risk-reducing salpingo-oophorectomy (RRSO) after completion of reproductive planning. Effective screening has not been established, and novel screening modalities are being evaluated. METHODS: Participants chose either RRSO or a novel OC screening regimen (OCS) as their risk management option, and provided demographic and other data on BRCA mutation status, cancer worry, perceived intervention risks/benefits, perceived cancer risk, and quality-of-life at enrollment. We performed univariate and multivariate analyses to evaluate factors influencing decision between RRSO and OCS. RESULTS: Of 2287 participants enrolled, 904 (40%) chose RRSO and 1383 (60%) chose OCS. Compared with participants choosing OCS, participants choosing RRSO were older (p<0.0001), more likely to carry deleterious BRCA1/2 mutations (p<0.0001), perceive RRSO as effective, be more concerned about surgical harms and OCS limitations, and report higher perceived OC risk and OC-related worry. OCS participants were more likely to perceive screening as effective, be more concerned about menopausal symptoms, infertility, and loss of femininity, and report better overall quality-of-life. Twenty-four percent of participants believed they would definitely develop OC, and half estimated their lifetime OC risk as >50%, both higher than objective risk estimates. CONCLUSIONS: Cancer worry, BRCA1/2 mutation status, and perceived intervention-related risks and benefits were associated with choosing between RRSO and OCS. Efforts to promote individualized, evidence-based, shared medical decision-making among high-risk women facing management choices should focus on conveying accurate OC risk estimates, clarifying the current understanding of intervention-related benefits and limitations, and addressing OC worry.

Pathologic findings at risk-reducing salpingo-oophorectomy: primary results from Gynecologic Oncology Group Trial GOG-0199.

PURPOSE: Risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study. PARTICIPANTS AND METHODS: This analysis included asymptomatic high-risk women age ≥ 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression. RESULTS: Invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign. CONCLUSION: Clinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer.

Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers.

Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.

Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study.

PURPOSE: The primary objective was to establish noninferiority of laparoscopy compared with laparotomy for recurrence after surgical staging of uterine cancer. PATIENTS AND METHODS: Patients with clinical stages I to IIA disease were randomly allocated (two to one) to laparoscopy (n = 1,696) versus laparotomy (n = 920) for hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and para-aortic lymphadenectomy. The primary study end point was noninferiority of recurrence-free interval defined as no more than a 40% increase in the risk of recurrence with laparoscopy compared with laparotomy. RESULTS: With a median follow-up time of 59 months for 2,181 patients still alive, there were 309 recurrences (210 laparoscopy; 99 laparotomy) and 350 deaths (229 laparoscopy; 121 laparotomy). The estimated hazard ratio for laparoscopy relative to laparotomy was 1.14 (90% lower bound, 0.92; 95% upper bound, 1.46), falling short of the protocol-specified definition of noninferiority. However, the actual recurrence rates were substantially lower than anticipated, resulting in an estimated 3-year recurrence rate of 11.4% with laparoscopy and 10.2% with laparotomy, or a difference of 1.14% (90% lower bound, -1.28; 95% upper bound, 4.0). The estimated 5-year overall survival was almost identical in both arms at 89.8%. CONCLUSION: This study previously reported that laparoscopic surgical management of uterine cancer is superior for short-term safety and length-of-stay end points. The potential for increased risk of cancer recurrence with laparoscopy versus laparotomy was quantified and found to be small, providing accurate information for decision making for women with uterine cancer.

Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status.

Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, whereas the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols. Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the National Cancer Institute-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this preplanned analysis. Because of the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points on the basis of 98th percentile. The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL, while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL. To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (50 for premenopausal women, 40 for premenopausal on OC, and 35 for postmenopausal women).

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2.

PURPOSE: The objective was to compare laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer. PATIENTS AND METHODS: Patients with clinical stage I to IIA uterine cancer were randomly assigned to laparoscopy (n = 1,696) or open laparotomy (n = 920), including hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and para-aortic lymphadenectomy. The main study end points were 6-week morbidity and mortality, hospital length of stay, conversion from laparoscopy to laparotomy, recurrence-free survival, site of recurrence, and patient-reported quality-of-life outcomes. RESULTS: Laparoscopy was initiated in 1,682 patients and completed without conversion in 1,248 patients (74.2%). Conversion from laparoscopy to laparotomy was secondary to poor visibility in 246 patients (14.6%), metastatic cancer in 69 patients (4.1%), bleeding in 49 patients (2.9%), and other cause in 70 patients (4.2%). Laparoscopy had fewer moderate to severe postoperative adverse events than laparotomy (14% v 21%, respectively; P < .0001) but similar rates of intraoperative complications, despite having a significantly longer operative time (median, 204 v 130 minutes, respectively; P < .001). Hospitalization of more than 2 days was significantly lower in laparoscopy versus laparotomy patients (52% v 94%, respectively; P < .0001). Pelvic and para-aortic nodes were not removed in 8% of laparoscopy patients and 4% of laparotomy patients (P < .0001). No difference in overall detection of advanced stage (stage IIIA, IIIC, or IVB) was seen (17% of laparoscopy patients v 17% of laparotomy patients; P = .841). CONCLUSION: Laparoscopic surgical staging for uterine cancer is feasible and safe in terms of short-term outcomes and results in fewer complications and shorter hospital stay. Follow-up of these patients will determine whether surgical technique impacts pattern of recurrence or disease-free survival.

A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: design and baseline characteristics: a Gynecologic Oncology Group study.

BACKGROUND: Women who are genetically predisposed to ovarian cancer are at very high risk of developing this disease. Although risk-reducing salpingo-oophorectomy (RRSO) and various screening regimens are currently recommended to reduce ovarian cancer risk, the optimal management strategy has not been established nor have multiple additional issues been adequately addressed. We developed a collaboration among the Clinical Genetics Branch (National Cancer Institute's Intramural Research Program), the Gynecologic Oncology Group (GOG), and the Cancer Genetics Network to address these issues. METHODS: This is a prospective, international, two-cohort, nonrandomized study of women at genetic risk of ovarian cancer, who chose either to undergo RRSO or screening, at study enrollment. Primary study objectives include quantifying and comparing ovarian and breast cancer incidence in the two study groups, assessing feasibility and selected performance characteristics of a novel ovarian cancer screening strategy (the Risk of Ovarian Cancer Algorithm), evaluating various aspects of quality of life and nononcologic morbidity related to various interventions in at-risk women, and creating a biospecimen repository for subsequent translational research. RESULTS: Study accrual is complete as of November 2006; 2,605 participants enrolled: 1,030 (40%) into the surgical cohort and 1,575 (60%) into the screening cohort. Five years of prospective follow-up ends in November 2011. Verification of BRCA mutation carrier status is under way, either through patient-provided reports from clinical genetic testing done before enrollment or through research-based genetic testing being conducted as part of the protocol. Patient eligibility is currently under evaluation and baseline, surgical, pathology, and outcome data are still being collected. The study design and selected baseline characteristics of cohort members are summarized. CONCLUSION: This National Cancer Institute intramural/extramural collaboration will provide invaluable prospectively collected observational data on women at high familial ovarian cancer risk, including substantial numbers of women carrying BRCA1/2 mutations. These data will aid in elucidating the effect of RRSO on breast/ovarian cancer risk and the effects of two management strategies, on quality of life and other issues that may influence patient care, as well as providing preliminary estimates of test specificity and positive predictive value of a novel ovarian cancer screening strategy.

A phase III randomized trial of postoperative pelvic irradiation in Stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study.

PURPOSE: To investigate, in a phase III randomized trial, whether postoperative external-beam irradiation to the standard pelvic field improves the recurrence-free interval and overall survival (OS) in women with Stage IB cervical cancers with negative lymph nodes and certain poor prognostic features treated by radical hysterectomy and pelvic lymphadenectomy. METHODS AND MATERIALS: Eligible patients had Stage IB cervical cancer with negative lymph nodes but with 2 or more of the following features: more than one third (deep) stromal invasion, capillary lymphatic space involvement, and tumor diameter of 4 cm or more. The study group included 277 patients: 137 randomized to pelvic irradiation (RT) and 140 randomized to observation (OBS). The planned pelvic dose was from 46 Gy in 23 fractions to 50.4 Gy in 28 fractions. RESULTS: Of the 67 recurrences, 24 were in the RT arm and 43 were in the OBS arm. The RT arm showed a statistically significant (46%) reduction in risk of recurrence (hazard ratio [HR] = 0.54, 90% confidence interval [CI] = 0.35 to 0.81, p = 0.007) and a statistically significant reduction in risk of progression or death (HR = 0.58, 90% CI = 0.40 to 0.85, p = 0.009). With RT, 8.8% of patients (3 of 34) with adenosquamous or adenocarcinoma tumors recurred vs. 44.0% (11 of 25) in OBS. Fewer recurrences were seen with RT in patients with adenocarcinoma or adenosquamous histologies relative to others (HR for RT by histology interaction = 0.23, 90% CI = 0.07 to 0.74, p = 0.019). After an extensive follow-up period, 67 deaths have occurred: 27 RT patients and 40 OBS patients. The improvement in overall survival (HR = 0.70, 90% CI = 0.45 to 1.05, p = 0.074) with RT did not reach statistical significance. CONCLUSIONS: Pelvic radiotherapy after radical surgery significantly reduces the risk of recurrence and prolongs progression-free survival in women with Stage IB cervical cancer. RT appears to be particularly beneficial for patients with adenocarcinoma or adenosquamous histologies. Circumstances that may have influenced the overall survival differences are considered.

Use of pharmacodynamic end points in the evaluation of gatifloxacin for the treatment of acute maxillary sinusitis.

The relationship between drug exposure and the time course of antimicrobial effect at the primary infection site for acute maxillary sinusitis has not previously been explored. This single-center, open-label study quantified the time course of sinus sterilization, described gatifloxacin exposure at the infection site, and posed the hypothesis that the use of continuous and quantitative time-related end points may allow for better characterization of drug effect with fewer patients than traditional clinical trial approaches. Of the 12 enrolled patients, 10 were clinically evaluable, from whom 7 pathogens were isolated: 4 Streptococcus pneumoniae, 2 staphylococci, and 1 Enterobacter aerogenes. The median predicted 24-h area under the curve (AUC) in sinus aspirates and plasma samples was 54.7 mg x h/L and 30.1 mg x h/L, respectively. The median 24-h AUC ratio for sinus aspirates and plasma samples was 1.51 (range, 0.88-2.23). For patients infected with pneumococci, the median time to sinus sterilization was 50 h. The use of quantitative time-related end points may be useful in evaluating the efficacy of antimicrobial agents with fewer patients.

Gatifloxacin and the elderly: pharmacokinetic-pharmacodynamic rationale for a potential age-related dose reduction.

OBJECTIVES: Recently, anecdotal reports via the FDA's MedWatch reporting system have documented rare but serious hyperglycaemia in elderly patients receiving gatifloxacin. One possible factor contributing to these events may be gatifloxacin overexposure, resulting from age-related decreases in renal function in elderly patients predisposed to glycaemic alterations. These analyses examine gatifloxacin exposure in 10 patients with severe hyperglycaemia, provide a pharmacokinetic-pharmacodynamic (PK-PD) rationale for a potential age-related dose reduction to avoid high exposures, and evaluate the likely impact of such a dose reduction on clinical efficacy in this specific patient population. METHODS: First, a previously derived population pharmacokinetic model, with patient demographics, was used to estimate gatifloxacin AUC0-24 following a dosage regimen of 400 mg/24 h in 10 index patients with severe hyperglycaemia. Second, the population pharmacokinetic model and patient demographic data from 2696 patients aged > or =65 years from two New Drug Application (NDA) databases were used to estimate AUC0-24 following dosage regimens for gatifloxacin of 200 and 400 mg/24 h. Finally, Monte Carlo simulation was utilized to assess the probability of achieving PK-PD target exposures against Streptococcus pneumoniae in elderly patients using these regimens. RESULTS: The mean estimated AUC0-24 among severe hyperglycaemia cases was 74 mg.h/L (range 57-100). Gatifloxacin AUC0-24 exposures for the 400 mg regimen were predicted to be higher in patients aged > or =65 years and similar to the severe hyperglycaemia cases. The probability of AUC0-24 > or =60 and > or =70 in patients aged > or =65 years for the 200 mg regimen was 0.03 and <0.01, respectively, versus 0.51 and 0.35 for the 400 mg regimen, respectively. The probability of achieving PK-PD target exposures against S. pneumoniae in patients aged > or =65 years receiving the 200 mg regimen was 0.99. CONCLUSIONS: The probability of a patient aged > or =65 years having an AUC0-24 > or =60-70 mg.h/L is markedly lower following a 200 mg regimen relative to a 400 mg regimen, suggesting a decreased risk of severe hyperglycaemia in a predisposed patient. Moreover, a dose reduction does not appear to significantly modify the likelihood of achieving the PK-PD target of gatifloxacin against S. pneumoniae.

ARF after open-heart surgery: Influence of gender and race.

BACKGROUND: Both acute renal failure (ARF) and female sex are strongly associated with mortality after open-heart surgery. This study analyzes the effect of sex and race on the incidence of ARF after open-heart surgery and its influence on mortality. METHODS: A total of 24,660 patients underwent open-heart surgery at the Cleveland Clinic Foundation (Cleveland, OH) from 1993 to 2000. The primary outcome was ARF defined as ARF requiring dialysis, 50% or greater decline in glomerular filtration rate (GFR) not requiring dialysis, or 50% or greater decline in GFR relative to baseline or requirement of dialysis. The secondary outcome was all-cause hospital mortality. RESULTS: The overall frequency of ARF requiring dialysis after open-heart surgery was 1.82%. The frequency was greater in women (2.36%) than men (1.60%; P < 0.0001) and blacks (2.94%) than nonblacks (1.70%; P < 0.0001) by univariate analysis. By multivariate analysis, risk for ARF requiring dialysis in women was 1.61 (confidence interval [CI], 1.27 to 2.05; P < 0.0001), but race was not a risk factor. The overall postoperative mortality rate was 2.2%, and for patients with ARF requiring dialysis, it was 61.2% (women, 68.6% versus men, 56.5%; P = 0.01) with an odds ratio of 49.29, whereas in patients with ARF not requiring dialysis, it was 14.1% (women, 13.3% versus men 14.6%; P = 0.63) with an odds ratio of 7.18. CONCLUSION: Female sex is an independent risk factor for developing ARF after open-heart surgery. The influence of race on risk for ARF is less clear. Regardless of its definition, ARF is strikingly associated with a high risk for mortality.

Outcomes of primary repair of anorectal and rectovaginal fistulas using the endorectal advancement flap.

PURPOSE: The endorectal advancement flap is a surgical procedure used in the treatment of anorectal and rectovaginal fistulas. There is a wide range of success rates published in the literature. This study was undertaken to examine the success rate of primary endorectal advancement flap in our own institution. We attempted to identify factors that influence the rate of healing. METHODS: A retrospective review was performed on 105 patients (43 males) who underwent their first endorectal advancement flap at our institution between January 1, 1994, and June 30, 1999. Ninety-nine patients were available for follow-up. Sixty-two patients had anorectal and 37 had rectovaginal fistulas. The causes of fistula included cryptoglandular (48 patients), Crohn's disease (44), obstetric injury (5), trauma (1), and other (1). RESULTS: The median follow-up was 17.1 (range, 0.4-66.9) months. The median age was 42 (range, 16-78) years. Recurrence was seen in 36 patients (36.4 percent); thus, the primary rate of healing was 63.6 percent. Factors that were associated with higher rates of success were increased age (P = 0.011), greater body surface area (P = 0.012), history of incision and drainage of a perianal abscess preceding advancement flap (P = 0.010), previous placement of a seton drain (P = 0.025), and short duration of fistula (P = 0.003). Factors that negatively influenced the healing rate of the flap were the diagnoses of Crohn's disease (P = 0.027) and rectovaginal fistula (P = 0.002). Length of hospitalization, discharge on oral antibiotics, and the presence of a diverting stoma did not influence the rate of healing. Prednisone was associated with a distinct trend toward failure, with none of the patients on high-dose prednisone (greater than 20 mg/day) having achieved long-term healing. No fistulas recurred after a period of 15 months. CONCLUSION: The endorectal advancement flap is an effective method of repair for both anorectal and rectovaginal fistulas, even though the success rate may not be as optimistic as in some other published studies. Patient selection is imperative, realizing that a higher rate of failure may be present in Crohn's disease and rectovaginal fistulas. Control of sepsis before endorectal advancement flap with drainage of a perianal abscess and/or seton placement, whenever possible, is indicated.

Failed extubation after cardiac surgery in young children: Prevalence, pathogenesis, and risk factors.

Background: Most children who undergo congenital heart surgery require postoperative mechanical ventilation. Failed extubation (FE) may result in physiologic instability, delay, or set back of the weaning process. FE is statistically associated with prolonged mechanical ventilation. Purpose: We sought to identify frequency, pathogenesis, and risk factors for FE after congenital heart surgery in young children. SETTING: Pediatric intensive care unit. PATIENTS: Children