Summary Background Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less ...proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Methods In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3–125 mg/m2 in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov , number NCT01261312. Findings Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 41% of 93 patients), pneumonia (27 29% of 93 patients), thrombocytopenia (23 25% of 93 patients), anaemia (23 25% of 93 patients), and sepsis (16 17% of 93 patients). The most common serious adverse events were febrile neutropenia (29 31% of 93 patients), pneumonia (26 28% of 93 patients), and sepsis (16 17% of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m2 daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m2 daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m2 (designated as the biologically effective dose). Interpretation Guadecitabine given subcutaneously at 60 mg/m2 daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m2 daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Funding Astex Pharmaceuticals, Stand Up To Cancer.
Objective To describe surgical complications in 597 women over a 24-month period after randomization to retropubic or transobturator midurethral slings. Study Design During the Trial of Midurethral ...Slings study, the Data Safety Monitoring Board regularly reviewed summary reports of all adverse events using the Dindo Surgical Complication Scale. Logistic regression models were created to explore associations between clinicodemographic factors and surgical complications. Results A total of 383 adverse events were observed among 253 of the 597 women (42%). Seventy-five adverse events (20%) were classified as serious (serious adverse events); occurring in 70 women. Intraoperative bladder perforation (15 events) occurred exclusively in the retropubic group. Neurologic adverse events were more common in the transobturator group than in retropubic (32 events vs 20 events, respectively). Twenty-three (4%) women experienced mesh complications, including delayed presentations, in both groups. Conclusion Adverse events vary by procedure, but are common after midurethral sling. Most events resolve without significant sequelae.
Background Perineal lacerations are common at the time of vaginal delivery and may predispose patients to long-term pelvic floor disorders, such as urinary incontinence and pelvic organ prolapse. ...Obstetric anal sphincter injuries, which are the most severe form of perineal lacerations, result in disruption of the anal sphincter and, in some cases, the rectal mucosa during vaginal delivery. Long-term morbidity, including pain, pelvic floor disorders, fecal incontinence, and predisposition to recurrent injury at subsequent delivery may result. Despite several studies that have reported risk factors for obstetric anal sphincter injuries, no accurate risk prediction models have been developed. Objective The purpose of this study was to identify risk factors and develop prediction models for perineal lacerations and obstetric anal sphincter injuries. Study Design This was a nested case control study within a retrospective cohort of consecutive term vaginal deliveries at 1 tertiary care facility from 2004-2008. Cases were patients with any perineal laceration that had been sustained during vaginal delivery; control subjects had no lacerations of any severity. Secondary analyses investigated obstetric anal sphincter injury (3rd- to 4th -degree laceration) vs no obstetric anal sphincter injury (0 to 2nd -degree laceration). Baseline characteristics were compared between groups with the use of the chi-square and Student t test. Adjusted odds ratios and 95% confidence intervals were calculated with the use of multivariable logistic regression. Prediction models were created and model performance was estimated with receiver-operator characteristic curve analysis. Receiver-operator characteristic curves were validated internally with the use of the bootstrap method to correct for bias within the model. Results Of the 5569 term vaginal deliveries that were recorded during the study period, complete laceration data were available in 5524 deliveries. There were 3382 perineal lacerations and 249 (4.5%) obstetric anal sphincter injuries. After adjusted analysis, significant predictors for laceration included nulliparity, non-black race, longer second stage, nonsmoking status, higher infant birthweight, and operative delivery. Private health insurance, labor induction, pushing duration, and regional anesthesia were not statistically significant in adjusted analyses. Significant risk factors for obstetric anal sphincter injury were similar to predictors for any laceration; nulliparity and operative vaginal delivery had the highest predictive value. Area under the curve for the predictive ability of the models was 0.70 for overall perineal laceration, and 0.83 for obstetric anal sphincter injury. When limited to primiparous patients, 1996 term vaginal deliveries were recorded. One hundred ninety-two women sustained an obstetric anal sphincter injury; 1796 women did not. After adjusted analysis, significant predictors for laceration included non-black race, age, obesity, and nonsmoking status. In secondary analyses, significant predictors for obstetric anal sphincter injury included non-black race, nonsmoking status, longer duration of pushing, operative vaginal delivery, and infant birthweight. Area under the curve for the predictive ability of the models was 0.60 for any laceration and 0.77 for obstetric anal sphincter injury. Conclusions Significant risk factors for sustaining any laceration and obstetric anal sphincter injury during vaginal deliveries were identified. These results will help identify clinically at-risk patients and assist providers in counseling patients about modifications to decrease these risks.
Background Recognition and assessment of apical vaginal support defects remains a significant challenge in the evaluation and management of prolapse. There are several reasons that this is likely: ...(1) Although the Pelvic Organ Prolapse-Quantification examination is the standard prolapse staging system used in the Female Pelvic Medicine and Reconstructive Surgery field for reporting outcomes, this assessment is not used commonly in clinical care outside the subspecialty; (2) no clinically useful and accepted definition of apical support loss exists, and (3) no consensus or guidelines address the degree of apical support loss at which an apical support procedure should be performed routinely. Objective The purpose of this study was to identify a simple screening measure for significant loss of apical vaginal support. Study Design This was an analysis of women with Pelvic Organ Prolapse-Quantification stage 0-IV prolapse. Women with total vaginal length of ≥7 cm were included to define a population with “normal” vaginal length. Univariable and linear regression analyses were used to identify Pelvic Organ Prolapse-Quantification points that were associated with 3 definitions of apical support loss: the International Consultation on Incontinence, the Pelvic Floor Disorders Network revised eCARE, and a Pelvic Organ Prolapse-Quantification point C cut-point developed by Dietz et al. Linear and logistic regression models were created to assess predictors of overall apical support loss according to these definitions. Receiver operator characteristic curves were generated to determine test characteristics of the predictor variables and the areas under the curves were calculated. Results Of 469 women, 453 women met the inclusion criterion. The median Pelvic Organ Prolapse-Quantification stage was III, and the median leading edge of prolapse was +2 cm (range, –3 to 12 cm). By stage of prolapse (0-IV), mean genital hiatus size (genital hiatus; mid urethra to posterior fourchette) increased: 2.0 ± 0.5, 3.0 ± 0.5, 4.0 ± 1.0, 5.0 ± 1.0, and 6.5 ± 1.5 cm, respectively ( P < .01). Pelvic Organ Prolapse-Quantification points B anterior, B posterior, and genital hiatus had moderate-to-strong associations with overall apical support loss and all definitions of apical support loss. Linear regression models that predict overall apical support loss and logistic regression models predict apical support loss as defined by International Continence Society, eCARE, and the point C; cut-point definitions were fit with points B anterior, B posterior, and genital hiatus; these 3 points explained more than one-half of the model variance. Receiver operator characteristic analysis for all definitions of apical support loss found that genital hiatus >3.75 cm was highly predictive of apical support loss (area under the curve, >0.8 in all models). Conclusions Increasing genital hiatus size is associated highly with and predictive of apical vaginal support loss. Specifically, the Pelvic Organ Prolapse-Quantification measurement genital hiatus of ≥3.75 cm is highly predictive of apical support loss by all study definitions. This simple measurement can be used to screen for apical support loss and the need for further evaluation of apical vaginal support before planning a hysterectomy or prolapse surgery.
This study was designed to determine the feasibility of anterior segment optical coherence tomography (AS-OCT) to objectively image and quantify the degree of AC inflammation.
Prospective evaluation ...of a diagnostic test.
Patients with anterior segment involving uveitis.
Observational case series of patients with uveitis. Single-line and 3-dimensional (3D) volume AS-OCT scans were manually graded to evaluate for the presence or absence of cells in the AC. Clinical grading scores were correlated to the number of cells seen in each line scan. An automated algorithm was developed to measure the number of cells seen in the 3D volume scan and compared with manual measurements and clinical grading scores.
Degree of anterior segment inflammation.
A total of 114 eyes from 76 patients were imaged, 83 eyes with line scans and 31 eyes with volume scans. The average number of cells on line scans was 0.13 for grade 0, 1.2 for grade 1/2+, 2.6 for grade 1+, 5.7 for grade 2+, 15.5 for grade 3+, and 41.2 for grade 4+. Spearman correlation coefficient comparing clinical grade with the individual AS-OCT line scans was 0.967 (P < 0.0001). The range of cells in the automated cell count of 3D volume scans was 13.60 to 1222; the range for manual cell counts was from 9.2 to 2245. The Spearman correlation coefficients were r = 0.7765 (P < 0.0001) and r = 0.7484 (P < 0.0001) comparing the manual and automated cell counts with the clinical grade, respectively. Spearman correlation coefficient comparing the automatic cell counts with manual cell count in the 3D volume scan was 0.997 (P < 0.0001).
Anterior segment OCT can be used to image and grade the degree of AC inflammation. Clinical grading strongly correlates with the number of cells on AS-OCT line scans and volume scans. The automated algorithm to measure cell count had a high correlation to manual measurement of cells in the 3D volume scans. This modality could be used to objectively grade response to treatment.
Objective This study was performed to assess the effect of pregnancy, route of delivery, and parity on the risk of primary and subsequent anal sphincter laceration in women at first vaginal delivery ...(1st VD), vaginal birth after cesarean delivery (VBAC), or second vaginal delivery (2nd VD). Methods This retrospective cohort study used data from a perinatal database that included all deliveries at Magee-Womens Hospital from 1995 to 2002. Anal sphincter laceration was the primary outcome, defined as third- and fourth-degree perineal lacerations. The adjusted odds ratio (OR) for primary and subsequent anal sphincter laceration at delivery by risk group was estimated using logistic regression models and reported with 95% confidence intervals (CIs). Results We assessed 20,674 live, singleton, term deliveries at Magee-Womens Hospital from 1995 to 2002, including 13,183 with 1st VD, 6068 with 2nd VD, and 1423 with VBAC. Anal sphincter laceration occurred in 16% of women with 1st VD, 18% with VBAC, and 3% with 2nd VD. Multivariable logistic regression modeling for primary anal sphincter laceration showed that 1st VD had OR of 5.1 and 95% CI 4.4, 5.9, and VBAC had OR of 5.1, 95% CI 4.2, 6.2 when compared with the reference group with 2nd VD. Shown in order for 1st VD, VBAC, and 2nd VD, the following factors, adjusted for the other listed factors, were significantly related to anal sphincter laceration except as noted: forceps, ORs of 3.0, 2.6, 5.5; midline episiotomy, ORs of 2.7, 2.9, 2.9; infant birth weight 3500 g or more, ORs of 1.9, 1.9, 1.1, not significantly different from OR of 1.0; vacuum delivery, ORs of 1.7, 1.8, 1.5, not significantly different from OR of 1.0, and 2nd stage of labor 2 hours or longer, ORs of 1.8, 0.9, 0.9, last 2 not significantly different from OR of 1.0. Of women who had anal sphincter laceration in their first vaginal delivery, 7.2% (76 of 1054 women who had 2 pregnancies) had recurrent laceration in their second vaginal delivery, compared with 2.3% (123 of 5147) of women who had a primary anal sphincter laceration in their second vaginal delivery. Multivariable logistic regression modeling for recurrent anal sphincter laceration yielded the following significant factors: episiotomy, OR 8.5, 95% CI 4.1, 17.7; vertex malpresentation (primarily occiput posterior), OR 4.3, 95% CI 1.4, 12.6; shoulder dystocia, OR 2.7, 95% CI 1.2, 5.8; and infant birth weight 3500 g or greater, OR 1.7, 95% CI 1.1, 2.7. Conclusion At this institution, women undergoing VBAC are at similarly high risk of anal sphincter laceration, compared with nulliparous women. Women with prior anal sphincter laceration are at 3 times increased risk for subsequent sphincter laceration, compared with women with prior vaginal delivery without sphincter laceration. Pregnancy by itself does not appear to be an important factor in decreasing the risk of anal sphincter laceration in subsequent deliveries.
Objective To describe perceptions of prolapse-specific body image in women with symptomatic prolapse. Study Design Women with symptomatic pelvic organ prolapse quantification stage ≥ II prolapse ...participated in semistructured focus groups or self-report questionnaire. Transcripts were independently reviewed and body image themes were identified and confirmed by consensus. Results Twenty-five women participated in focus groups and 27 in online questionnaires. Transcript analysis revealed 3 central themes and 25 body-image related subthemes. Women living with prolapse were more likely to feel self-conscious, isolated, “different,” less feminine, and less attractive. Women often changed sexual intimacy practices because of embarrassment or discomfort, and many avoided intimacy all together. Prolapse greatly affected women's personal and professional activities causing some women to adjust routines or stop activities. Women reported loss of interest in activities, distraction while performing daily/work-related tasks, and embarrassment when asking for help with activities. Conclusion Themes identified in this qualitative study demonstrate the profound effect of prolapse on a woman's body image.
Objective We sought to describe national trends for inpatient procedures for pelvic organ prolapse from 1979–2006. Study Design The National Hospital Discharge Survey was analyzed for patient and ...hospital demographics, as were International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic and procedures codes from 1979–2006. Age-adjusted rates (AARs) per 1000 women were calculated using the 1990 US Census data. Results There was a significantly decreasing trend in the AARs for inpatient prolapse procedures, from 2.93–1.52 per 1000 women from 1979–2006. AARs for hysterectomy decreased from 8.39–4.55 per 1000 women from 1979–2006. Over the study period, AARs remained at about the 1979 level among the women ≥52 years old (2.73–2.86; P = .075). In women <52 years old, AARs declined to less than one-third of the 1979 rate (3.03–0.84; P < .001). Conclusion AARs for inpatient procedures for prolapse in the United States remained stable for women aged ≥52 years from 1979–2006; rates declined by two-thirds for women aged <52 years.
Objective We sought to identify and summarize definitions of apical support loss utilized for inclusion, success, and failure in surgical trials for treatment of apical vaginal prolapse. Background ...Pelvic organ prolapse is a common condition affecting more than 3 million women in the US, and the prevalence is increasing. Prolapse may occur in the anterior compartment, posterior compartment or at the apex. Apical support is considered paramount to overall female pelvic organ support, yet apical support loss is often under recognized and there are no guidelines for when an apical support procedure should be performed and/or incorporated into a procedure designed to address prolapse. Study Design A systematic literature search was performed in 8 search engines: PubMed 1946-, Embase 1947-, Cochrane Database of Systematic Reviews, Cochrane Database of Abstracts of Review Effects, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov , Proquest Dissertations and Theses, and FirstSearch Proceedings, using key words for apical pelvic organ prolapse and apical suspension procedures through April 2016. Searches were limited to human beings using human filters and articles published in English. Study authors (M.R.L.M., J.L.L.) independently reviewed publications for inclusion based on predefined variables. Articles were eligible for inclusion if they satisfied any of the following criteria: (1) apical support loss was an inclusion criterion in the original study, (2) apical support loss was a surgical indication, or (3) an apical support procedure was performed as part of the primary surgery. Results A total of 4469 publications were identified. After review, 35 articles were included in the analysis. Prolapse-related inclusion criteria were: (1) apical prolapse (n = 20, 57.1%); (2) overall prolapse (n = 8, 22.8%); or (3) both (n = 6, 17.1%). Definitions of apical prolapse (relative to the hymen) included: (1) apical prolapse >–1 cm (n = 13, 50.0%); (2) apical prolapse >+1 cm (n = 7, 26.9%); (3) apical prolapse >50% of total vaginal length (–total vaginal length/2) (n = 4, 15.4%); and (4) cervix/apex >0 cm (n = 2, 7.7%). Sixteen of the 35 studies (45.7%) required the presence of symptoms for inclusion. A measurement of the apical compartment (relative to the hymen) was used as a measure of surgical success or failure in 17 (48.6%) studies. Definitions for surgical success included: (1) prolapse stage >2 in each compartment (n = 5, 29.4%); (2) prolapse >–total vaginal length/2 (n = 2, 11.8%); (3) apical support >–total vaginal length/3 (n = 1, 5.9%); (4) absence of prolapse beyond the hymen (n = 1, 5.9%); and (5) point C at ≥–5 cm (n = 2, 11.8%). Surgical failure was defined as: (1) apical prolapse ≥0 cm (n = 2, 11.8%); (2) apical prolapse ≥–1 cm (n = 2, 11.8%); (3) apical prolapse >–total vaginal length/2 (n = 3, 17.6%); and (4) recurrent apical prolapse surgery (n = 1, 5.9%). Ten (28.6%) of the 35 studies also included symptomatic outcomes in the definition of success or failure. Conclusion Among randomized, controlled surgical trials designed to address apical vaginal support loss, definitions of clinically significant apical prolapse for study inclusion and surgical success or failure are either highly variable or absent. These findings provide limited evidence of consensus and little insight into current expert opinion.
Abstract The eye is a common site for complications of human immunodeficiency virus (HIV) infection. Although cytomegalovirus retinitis remains the most prevalent of the blinding ocular disorders ...that can occur in individuals with the acquired immunodeficiency syndrome (AIDS), several important HIV-associated disorders may involve the anterior segment, ocular surface, and adnexae. Some of these entities, such as Kaposi sarcoma, were well described, but uncommon, before the HIV epidemic. Others, like microsporidial keratoconjunctivitis, have presentations that differ between affected individuals with HIV disease and those from the general population who are immunocompetent. The treatment of many of these diseases is challenging because of host immunodeficiency. Survival after the diagnosis of AIDS has increased among individuals with HIV disease because of more effective antiretroviral therapies and improved prophylaxis against, and treatment of, opportunistic infections. This longer survival may lead to an increased prevalence of anterior segment and external ocular disorders. In addition, the evaluation and management of disorders such as blepharitis and dry eye, which were previously overshadowed by more severe, blinding disorders, may demand increased attention, as the general health of this population improves. Not all individuals infected with HIV receive potent antiretroviral therapy, however, because of socioeconomic or other factors, and others will be intolerant of these drugs or experience drug failure. Ophthalmologists must, therefore, still be aware of the ocular findings that develop in the setting of severe immunosuppression. This article reviews the spectrum of HIV-associated anterior segment and external ocular disorders, with recommendations for their evaluation and management.
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