Dental abnormalities in individuals with pathogenic germline variation in DICER1.

Pathogenic germline variation in the microRNA processing gene DICER1 gives rise to an autosomal dominant, tumor-predisposition disorder. Conditional deletion of Dicer1 in murine dental epithelium shows that it controls tooth patterning, size, number, and shape. The human dental phenotype of people with germline pathogenic variation in DICER1 is unknown. DICER1-carriers (n = 57) and family controls (n = 55) were evaluated at the NIH Clinical Center dental clinic as part of a comprehensive medical evaluation. Digital panoramic radiographs, bite-wing radiographs, and oral photographs were collected. A single observer, blind to DICER1 status, reviewed the dental records and determined the presence or absence of 11 dental characteristics as described in the clinic notes, radiographs, or oral photographs. Subjective phenotypes were reviewed on radiographs by two examiners (blind to DICER1 status) for the presence or absence of the dental characteristics to reduce inconsistencies. By simple association, bulbous crown, periodontitis, and taurodontism were all significant (p < .05). Logistic regression with chi-square maximum likelihood estimates showed that bulbous crown and periodontitis remained significant. Recognition of these phenotypes may aid identification of individuals and families at risk for DICER1-associated neoplasms. These findings may also guide dental care for individuals with germline DICER1 pathogenic variation.

Residency Interview Experiences in Oral and Maxillofacial Surgery Differ by Gender and Affect Residency Ranking.

PURPOSE: Resident interview experiences are crucial for applicants when ranking programs. The purpose of the present study was to evaluate the interview experience among current oral and maxillofacial surgery (OMS) residents to determine the factors that influenced their selection and ranking of training programs and whether these experiences differed between women and men. MATERIALS AND METHODS: We conducted a cross-sectional survey of OMS residents in 2018. The 12-question survey included demographics, reasons for selecting an interview and ranking programs, and positive and negative experiences during the interviews. Logistic regression models were constructed to evaluate the predictors of unprofessional or negative experiences. RESULTS: A total of 1134 surveys were emailed, with 165 completed questionnaires (14.6%) returned by 35 women (21.2%) and 130 men (78.8%). Their average age was 30.8 years (range, 25 to 42). The racial/ethnic distribution was as follows: white, 75.8%; Asian, 15.8%; and other, 8.4%. Of the 165 respondents, 52% were in MD and 48% in non-MD programs. The top factors in selecting an institution at which to interview were clinical scope and volume, and the reason for ranking a program high was resident friendliness, which was similar among the female and male respondents. Unprofessional behavior or negative experiences were reported by 62 respondents (38%) and occurred by both faculty and residents and during both interviews and social events. Demeaning behavior toward the applicant, residents, and colleagues was the most common negative experience overall, with the women experiencing more gender-specific inappropriate behavior. Female respondents and those who were in dual-degree programs were 2.4 and 2.1 times more likely to experience unprofessional conduct than their peers, respectively (P = .03). CONCLUSIONS: Female and male residents were influenced by the same factors when selecting interviews and ranking residency programs. Unprofessional and inappropriate conduct was reported by 38% of the respondents. Women and dual-degree respondents were 2.4 and 2.1 times more likely to experience unprofessionalism during interviews, respectively. This might have contributed to the low number of current female OMS residents.

Age-Related Changes and Effects of Bisphosphonates on Bone Turnover and Disease Progression in Fibrous Dysplasia of Bone.

Fibrous dysplasia (FD) is a mosaic disease in which bone is replaced with fibro-osseous tissue. Lesions expand during childhood, reaching final burden by age 15 years. In vitro data suggest that disease activity decreases in adulthood; however, there is no clinical data to support this concept. Bone turnover markers (BTMs) have been used as markers of disease activity in FD; however, the natural history of BTM changes, the effects of antiresorptive treatment, and their association to clinical outcomes have not been described. The goals of this study are to describe 1) the natural history of FD disease activity and its association with pain; 2) the impact of bisphosphonates on the natural history of BTMs; and 3) the effect of bisphosphonates on progression of FD burden during childhood. Disease burden scores and alkaline phosphatase, osteocalcin, NTx, FGF23, and RANKL levels from 178 subjects in an FD/MAS natural history study were reviewed, including 73 subjects treated with bisphosphonates. BTMs, RANKL, and FGF23 demonstrated a sustained reduction with age. Bisphosphonate treatment did not significantly impact this age-dependent decrease in BTMs. Pain was more prevalent and severe in adults compared with children and was not associated with BTMs. In children, the progression of disease burden was not affected by bisphosphonates. In conclusion, FD is associated with an age-dependent decline in bone turnover and other markers of disease activity. Pain, in contrast, is more frequent and severe in adults with FD and is not related to bone turnover. Bisphosphonate treatment does not significantly impact the age-dependent decrease in bone turnover, nor does it prevent the progression of FD disease burden in children. These findings, in association with the established adverse effects of antiresorptives, should be considered when evaluating use and response to bisphosphonates in patients being treated for FD and in any study using BTMs as surrogate endpoints. © 2019 American Society for Bone and Mineral Research.

Combined Analysis of Mifepristone for Psychotic Depression: Plasma Levels Associated With Clinical Response.

BACKGROUND: Patients with psychotic depression exhibit elevated cortisol levels. Competitively antagonizing cortisol at the glucocorticoid receptor with mifepristone demonstrated therapeutic benefit in early studies of patients with psychotic depression. We present a combined analysis of all controlled phase 2 and 3 studies to report antipsychotic differences between treatment with mifepristone or placebo and to evaluate the relative contributions to response of attaining an a priori-defined, high mifepristone plasma level and markers of glucocorticoid receptor antagonism (increases in adrenocorticotropin hormone and cortisol) with treatment. METHODS: Data from five similarly designed double-blind phase 2 or 3 studies evaluating the efficacy and safety of 7-day treatment with mifepristone for the psychotic symptoms of psychotic depression were pooled for analysis (mifepristone n = 833; placebo n = 627). Clinical assessments were performed at baseline and on days 7, 14, 28, 42, and 56. Mifepristone, adrenocorticotropin hormone, and cortisol samples were collected at baseline and day 7. RESULTS: Combined results demonstrated meaningful efficacy (p < .004) for mifepristone in reducing psychotic symptoms with wide safety margins. Patients in the a priori-defined, high mifepristone plasma level group (≥1637 ng/mL) demonstrated a more significant treatment effect over placebo (p = .0004). A number needed to treat of 7 and 48 was observed in the high and low mifepristone plasma level groups, respectively. Adverse events were similar in mifepristone- and placebo-treated patients. CONCLUSIONS: A high mifepristone plasma level carried the strongest association with response, followed by changes in adrenocorticotropin hormone and cortisol. Therapeutic plasma levels of mifepristone were most likely to be achieved with the 1200 mg/day dose.

Mifepristone Plasma Level and Glucocorticoid Receptor Antagonism Associated With Response in Patients With Psychotic Depression.

BACKGROUND: Psychotic depression has no Food and Drug Administration-approved treatment. Patients demonstrate significant dysregulation of the hypothalamic-pituitary-adrenal axis providing a biologically targeted treatment opportunity. The purpose of this study was to explore the clinical and biological effects of short-duration (7-day) glucocorticoid receptor antagonism with mifepristone and the role of mifepristone plasma levels in patients with psychotic depression. METHODS: This double-blind, randomized study took place at 34 US clinical research centers and included patients with a diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder, severe, with psychotic features. Patients underwent daily, observed, in-clinic administration of oral study drug (mifepristone 1200 mg or placebo) for days 1 to 7 of the 56-day trial, followed by treatment with a single Food and Drug Administration-approved antidepressant on days 8 to 56. The following scales were administered on days 0, 7, 14, 28, 42, and 56: Brief Psychiatric Rating Scale (BPRS), BPRS Positive Symptom Subscale, Hamilton Rating Scale for Depression, and Columbia-Suicide Severity Rating Scale. The primary end point was a categorical analysis evaluating the proportion of patients with 50% or greater reduction from baseline in BPRS Positive Symptom Subscale score on both days 7 and 56, demonstrating early and durable response. Cortisol and adrenocorticotropic hormone were measured on days 0, 7, 28, and 56. Mifepristone plasma levels were assessed on days 0 and 7. RESULTS: An interim analysis indicated that the primary efficacy end point was unlikely to be met, and the study was stopped early with 292 of the planned 450 patients enrolled. Although the primary end point was not met, in a secondary prespecified analysis, patients who attained a mifepristone plasma level of 1637 ng/mL or greater (defined a priori and termed the high plasma level; 66.7% of patients) demonstrated statistically significant reductions in psychotic symptoms compared with patients who received placebo starting on day 28. This group also showed nonsignificant, numeric superiority on Hamilton Rating Scale for Depression improvement. No significant improvements were observed in the low-mifepristone group (<1637 ng/mL) versus the placebo group. There were no significant differences in Columbia-Suicide Severity Rating Scale suicidality ratings between groups. CONCLUSIONS: Mifepristone 1200 mg daily for 7 days was safe and well tolerated, allowing most treated patients to achieve the a priori defined therapeutic plasma level of 1637 ng/mL, the mifepristone level associated with biological effect and clinical benefit.

Androgen Treatment Effects on Motor Function, Cognition, and Behavior in Boys with Klinefelter Syndrome.

OBJECTIVES: To examine the effects of early low-dose androgen on motor, cognitive, and behavioral function in prepubertal boys with Klinefelter syndrome (47,XXY). STUDY DESIGN: Double-blind trial of 84 boys, ages 4-12 years, randomized to oxandrolone (Ox; 0.06?mg/kg daily; n?=?43) or placebo (Pl; n?=?41) for 24 months. Standardized assessments were performed at baseline and every 12 months for 24 months evaluating motor, cognitive, and behavioral function. RESULTS: The 24-month outcomes were better in the Ox vs. Pl group on 1 of 5 primary endpoints (motor function/strength): Bruininks Visual-Motor scale (P?=?.005), without significant differences between the 2 groups for the other 4 components. Secondary analyses suggested improvement in the Ox vs. Pl group in the anxiety/depression (P?=?.03) and social problems (P?=?.01) scales on the Child Behavior Checklist, anxiety (P?=?.04) on the Piers Harris Self Concept Scale, and interpersonal problems (P?=?.02) on the Children's Depression Inventory, without significant differences in hyperactive or aggressive behaviors. CONCLUSIONS: This double-blind, randomized trial demonstrates that 24 months of childhood low-dose androgen treatment in boys with Klinefelter syndrome benefited 1 of 5 primary endpoints (visual-motor function). Secondary analyses demonstrated positive effects of androgen on aspects of psychosocial function (anxiety, depression, social problems), without significant effects on cognitive function, or hyperactive or aggressive behaviors. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00348946.

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency. METHODS: We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group. RESULTS: No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group. CONCLUSIONS: In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

Patient acceptability and satisfaction with a low-dose solubilized vaginal estradiol softgel capsule, TX-004HR.

OBJECTIVE: TX-004HR is an investigational, muco-adhesive, vaginal, softgel capsule containing low-dose, solubilized, 17ß-estradiol designed to treat postmenopausal vulvar and vaginal atrophy (VVA) and improve user experience without an applicator and less mess. METHODS: As part of the 12-week, placebo-controlled, double-blind, phase 3 REJOICE trial evaluating the efficacy/safety of 4-, 10-, and 25-µg TX-004HR in 764 postmenopausal women with VVA, a five-question product survey was administered. Pearson correlation coefficients were used to evaluate correlations between clinical endpoints (vaginal physiology, dyspareunia, and vaginal dryness) and patient acceptability and satisfaction. RESULTS: Majority of the women receiving TX-004HR or placebo reported that the product was easy to use (85.4%-92.1%) and rated ease of capsule insertion as "good" to "excellent" (75.0%-82.6%). A significantly greater percentage of women reported being "very satisfied" or "satisfied" with TX-004HR (68.6%-76.3%) than with placebo (56.8%, P < 0.05 for all). A greater percentage of women "somewhat" or "very much" preferred TX-004HR over their previous treatment versus those taking placebo (P < 0.05). Significantly more women receiving TX-004HR (72.8%-80.5%) versus placebo (62.5%, P < 0.05) would "probably" or "definitely" consider using the product again. Dyspareunia and vaginal dryness reductions were correlated with higher product satisfaction and the percentage of women who would consider re-using TX-004HR. CONCLUSIONS: TX-004HR had a high level of product acceptability, and more women were satisfied with TX-004HR, preferred it over their previous treatment, and would consider using it again versus placebo. Women may find TX-004HR to be a more acceptable product than current options to treat their dyspareunia associated with postmenopausal VVA.

Pharmacokinetics of Lidocaine and Its Metabolites Following Vaginal Administration of Lidocaine Gel to Healthy Female Subjects.

Lidocaine vaginal bioadhesive gel is being developed as a local anesthetic for use in minimally invasive outpatient gynecological procedures and was investigated in single-dose and multiple-dose studies in healthy young adult women. Lidocaine doses of 2.5%, 5%, and 10% (w/w) were administered, and parent drug and metabolites monoethylglycinexylidide and glycinexylidide were measured in plasma. Lidocaine was absorbed through vaginal tissue and into the systemic circulation in a dose-proportional manner, and there was little systemic accumulation. Plasma concentrations were 10- to 20-fold lower than concentrations obtained after administration of intravenous lidocaine used to treat arrhythmic activity, thus demonstrating a wide safety margin for a vaginal lidocaine product.

The REJOICE trial: a phase 3 randomized, controlled trial evaluating the safety and efficacy of a novel vaginal estradiol soft-gel capsule for symptomatic vulvar and vaginal atrophy.

OBJECTIVE: To evaluate the safety and efficacy of TX-004HR vaginal estradiol soft-gel capsules for moderate-to-severe dyspareunia associated with postmenopausal vulvar and vaginal atrophy. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 study, postmenopausal women with a self-identified most bothersome symptom of dyspareunia received 4, 10, or 25 µg TX-004HR or placebo for 12 weeks. Four co-primary efficacy endpoints were change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH, and severity of dyspareunia. Secondary endpoints included severity of vaginal dryness and vulvar and/or vaginal itching or irritation. Endometrial histology and adverse events (AEs) were included in the safety endpoints. RESULTS: In all, 764 women were randomized (modified intent-to-treat population, n = 747; mean age 59 y). Compared with placebo, all three doses of TX-004HR significantly improved the four co-primary endpoints (P < 0.0001 for all, except dyspareunia with 4 µg, P = 0.0149). Changes in cytology, pH, and dyspareunia were also significant at weeks 2, 6, and 8. Vaginal dryness and vaginal itching/irritation improved. Sex hormone binding globulin concentrations did not change with treatment. TX-004HR was well-tolerated, with no clinically meaningful differences in treatment-emergent AEs versus placebo, and no treatment-related serious AEs or deaths. CONCLUSIONS: TX-004HR (4, 10, and 25 µg) was safe, well-tolerated, and effective for treating moderate-to-severe dyspareunia within 2 weeks with minimal systemic estrogen exposure. This novel product may be a potential new treatment option for women experiencing postmenopausal vulvar and vaginal atrophy.

TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol.

OBJECTIVE: To evaluate the pharmacokinetics of TX-004HR vaginal estradiol softgel capsules when used for treating moderate-to-severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy. METHODS: A substudy of the REJOICE trial (multicenter, double-blind, placebo-controlled, phase 3) evaluated the pharmacokinetics of 4, 10, and 25-µg TX-004HR doses once/d for 2 weeks, followed by twice/wk for 10 weeks. Serum samples obtained at 2, 4, 6, 10, and 24 hours postdose on days 1 and 14, and once on day 84, were analyzed for area under the serum concentration-time curve, tmax, Cmin, Cavg, and Cmax for estradiol, estrone, and estrone conjugates. RESULTS: Seventy-two women (mean 59 y) participated. TX-004HR 4 µg showed no statistical differences from placebo in estradiol pharmacokinetic (PK) parameters. At 10 µg, estradiol Cmax was statistically higher than placebo on day 1, but was not different from placebo on day 14. With 25 µg, estradiol PK parameters were statistically higher than placebo. Estradiol Cavg values for 25 µg were 9.1 pg/mL on day 1 and 7.1 pg/mL on day 14. Estrone and estrone conjugate PK parameters with TX-004HR were lower than or similar to placebo across all doses. No drug accumulation was observed. CONCLUSIONS: Vaginal TX-004HR resulted in negligible to very low systemic absorption of estradiol. No statistical differences in estradiol PK parameters were observed on day 14 with 4 and 10 µg, and only minor increases were observed with 25 µg (within the normal postmenopausal range). This PK substudy, in conjunction with the primary efficacy results, demonstrated that TX-004HR provided local benefits of estradiol with limited systemic exposure.

Bone-Grafting in Polyostotic Fibrous Dysplasia.

BACKGROUND: Polyostotic fibrous dysplasia is a skeletal disease that results from somatic activating mutations in the gene GNAS in skeletal stem cells, leading to proliferation of immature osteogenic cells with replacement of normal marrow and bone with fibro-osseous tissue. Lesions may cause bone deformity or fracture. In the surgical care of polyostotic fibrous dysplasia, the role of grafting and the optimal grafting material are not clear. The purpose of this study was to evaluate the long-term survival of bone-grafting procedures in subjects with polyostotic fibrous dysplasia over time. METHODS: The operative reports and radiographs of a cohort of subjects with polyostotic fibrous dysplasia followed in a natural history study were reviewed. Twenty-three subjects (mean age at the time of enrollment, thirteen years [range, two to forty years]) with fifty-two bone-grafting procedures had a mean follow-up time of 19.6 years (range, twenty-nine months to forty-seven years). Kaplan-Meier life table estimates, Cox proportional hazard models, and t tests comparing means were performed to assess various aspects of graft survival. RESULTS: Kaplan-Meier curves showed a 50% estimate of survival of 14.5 years. Cox proportional hazards models showed no advantage comparing allograft with autograft or structural with nonstructural graft materials. The mean age of the patients was significantly greater (p < 0.001) in the subgroup of subjects in whom grafts were maintained over time (20.9 years) compared with the subgroup of patients whose grafts were resorbed over time (9.8 years). CONCLUSIONS: Bone-grafting, including both allograft and autograft, is of limited value in ablating the lesions of fibrous dysplasia. The expectations of patients and surgeons should include the high probability of graft resorption over time with return of bone characteristics of fibrous dysplasia, particularly in younger patients. This suggests the maintenance of normal bone mechanics with implant support should be the priority of any surgical intervention.

Correlation of Airway Volume With Orthognathic Surgical Movement Using Cone-Beam Computed Tomography.

PURPOSE: Orthognathic surgery can induce changes in airway volume. The aim of this study was to determine whether there is a correlation of surgical movement of the maxilla or mandible to airway volume changes. MATERIALS AND METHODS: This was a prospective cohort study and the sample was composed of patients undergoing single-jaw orthognathic procedures from 2004 through 2007. Cone-beam computed tomograms were obtained before surgery (T0), immediately after surgery (T1), and at least 6 months after surgery (T2). The airway was segmented from 3-dimensional images and identified as the whole airway, consisting of the naso-, oro-, and hypopharynx. The volumetric percentage of change of the airway between time points was compared and correlated to the surgical movements using paired t test and cubic regression analysis. The level of statistical significance was set at a P value less than or equal to .05. RESULTS: The sample was composed of 33 patients. Sixteen patients underwent maxillary advancement with mean advancement of 5.4 mm (3 to 8 mm), 13 underwent mandibular advancement with mean advancement of 8.0 mm (5 to 15 mm), and 4 underwent mandibular setback of 4.0 mm. For maxillary advancement at T1, volume percentages of change for the whole airway and the naso-, oro-, and hypopharynx were 18.4 (P ≤ .05), 53.8 (P ≤ .05), 26.3, and 5.5%, respectively, and at T2, the changes were 10.0, 46.7 (P ≤ .05), 6.8, and 1.0%, respectively. For mandibular advancement at T1, volume percentages of change were 34.6 (P ≤ .05), 26.1, 54.1 (P ≤ .05), and 17.4%, respectively, and at T2, the changes were 15.0 (P ≤ .05), -3.7, 23.5 (P ≤ .05), and 12.1%, respectively. There were no meaningful long-term airway changes with mandibular setback. CONCLUSION: The study results suggest that there might be an anatomic limit to pharyngeal airway expansion associated with single-jaw orthognathic surgery.

Sustained weight loss in patients treated with mifepristone for Cushing's syndrome: a follow-up analysis of the SEISMIC study and long-term extension.

BACKGROUND: Overweight and obesity are common among patients with Cushing's syndrome (CS) and may persist in some patients even after ostensibly curative surgery, contributing to cardiometabolic dysfunction and increased cardiovascular risk. Mifepristone, a selective glucocorticoid receptor antagonist, was effective in controlling hyperglycemia in a 24-week trial of adults (N = 50) with endogenous CS and associated type 2 diabetes mellitus/impaired glucose tolerance or hypertension who had failed or were not candidates for surgery (SEISMIC, Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome). This analysis examines long-term weight change among patients who received mifepristone in SEISMIC and enrolled in a long-term safety extension (LTE) study. METHODS: Patients completing the 24-week SEISMIC study and subsequent 6-week off-drug safety evaluation were invited to enroll in the LTE study. Mifepristone doses at the end of SEISMIC were the LTE starting doses. Body weight measures were reviewed at baseline and week 24 of SEISMIC and at LTE month 6, 12, 18, 24, and final visit (last observation collected during the LTE study). RESULTS: Of the 30 patients enrolled in the LTE, evaluable weight data were available for 29 (20/29 female; mean age of 44.7 ± 11.2 years). These patients received mifepristone for a median of 29.2 months (range 8.4-41.9). Mean ± SD weight from SEISMIC baseline to LTE final visit decreased by 10.3 ± 16.3 kg (mean 105.4 ± 34.3 kg to 95.1 ± 32.9 kg), a 9.3 % decrease from baseline weight (P = 0.0008). Of the 29 LTE patients, 18 (62.1 %) lost ≥ 5 % of body weight by the end of the initial 24-week treatment period; this ≥5 % weight loss persisted in 83.3 % (15/18) at LTE final visit. Ten patients (34.5 %) lost ≥ 10 % of initial body weight by week 24 of SEISMIC, which persisted in 80 % at LTE final visit. No new safety signals were detected with long-term mifepristone use. CONCLUSION: Clinically meaningful weight loss achieved during a 24-week study of mifepristone for CS persisted for two additional years in patients who remained on therapy. Long-term treatment with mifepristone appears to have a beneficial effect on weight in patients with endogenous CS. TRIAL REGISTRATION: NCT00569582 (SEISMIC); NCT00936741 (Long-Term Extension).

ASSOCIATION BETWEEN MIFEPRISTONE DOSE, EFFICACY, AND TOLERABILITY IN PATIENTS WITH CUSHING SYNDROME.

OBJECTIVE: To examine the relationship between dose, clinical response (based on independent evaluation of metabolic, physical, neurologic, and social assessments), and safety of mifepristone treatment in patients with endogenous Cushing syndrome (CS). METHODS: This post hoc analysis included 40 clinical responders and 50 participants who received a dose of mifepristone (safety population) in the 24-week phase 3 SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial. The dose of mifepristone at the initial clinical response was analyzed, and the rate of serious adverse events (SAEs) and AEs reported in ≥20% of patients were compared to average mifepristone doses over time. RESULTS: Among the clinical responders, 85% and 35% had their initial clinical responses at mifepristone doses ≥600 and ≥900 mg/day, respectively. The SAE rate did not increase with a higher dose over time. The AE rates for fatigue, headache, nausea, and peripheral edema declined significantly at weeks 16 to 24 (all P<.05 vs. weeks 1-2) as the study progressed and mifepristone doses were increased. Other AEs such as hypokalemia, vomiting, and decreased appetite did not significantly increase from weeks 1 to 2 as mifepristone doses were increased. CONCLUSIONS: The majority of clinical responders in the SEISMIC trial received mifepristone doses ≥600 mg/day suggesting that higher doses were required to achieve optimal clinical benefit in patients with endogenous CS. Notably, mifepristone dose escalations did not result in any significant or concordant increase in the rates of SAEs and common AEs.

Cone-beam computed tomographic comparison of surgically assisted rapid palatal expansion and multipiece Le Fort I osteotomy.

PURPOSE: To examine and compare the skeletal and dental effects of surgically assisted rapid palatal expansion (SARPE) and multipiece Le Fort osteotomy using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: This was a prospective cohort study. Patients underwent SARPE or multipiece Le Fort I osteotomy to address maxillary transverse deficiency. CBCT scans were taken preoperatively, immediately postoperatively or after retention, and at least 6 months postoperatively. Four landmark measurements and ratios of dental-to-skeletal change were used to follow skeletal and dental widths in the posterior and anterior maxillary regions. Wilcoxon signed-rank test and Wilcoxon 2-sample rank-sum test were used to compare the landmark measurements and the ratio of dental-to-skeletal change for the 2 surgeries. A P value less than .05 was statistically significant. RESULTS: Thirteen patients (mean, 28.3 yr old; 7 women) were enrolled: 9 were treated by multipiece Le Fort I osteotomy and 4 were treated by SARPE. The ratios of dental-to-skeletal expansion in the posterior maxilla for the Le Fort procedure and SARPE were 0.70 ± 0.41 and 25.20 ± 15.8, respectively, and the dental-to-skeletal relapses were 1.17 ± 0.80 and -3.63 ± 3.70, respectively. The ratios of dental-to-skeletal expansion in the anterior maxilla for the Le Fort procedure and SARPE were 0.58 ± 0.38 and 31.80 ± 59.4, respectively, and the dental-to-skeletal relapses were 2.25 ± 3.41 and 4.86 ± 8.10, respectively. CONCLUSION: There was greater correlation between dental and skeletal changes in the multipiece Le Fort procedure, indicating bodily separation of the segments, whereas the SARPE showed noteworthy dental and skeletal tipping. Dental relapse was greater than skeletal relapse for these 2 procedures.

A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone.

CONTEXT: Fibrous dysplasia (FD) is a rare skeletal disorder, resulting in deformity, fracture, functional impairment, and pain. Bisphosphonates have been advocated as a potential treatment. OBJECTIVE: To determine the efficacy of alendronate for treatment of FD. DESIGN: Two-year randomized, double-blind, placebo-controlled trial. SETTING: Clinical research center. PATIENTS: Forty subjects with polyostotic FD (24 adults, 16 children). Subjects were randomized and stratified by age. INTERVENTIONS: Study drug was administered over a 24 month period in 6 month cycles (6 months on, 6 months off). Alendronate dosing was stratified: 40 mg daily for subjects >50 kg, 20 mg for 30-50 kg, 10 mg for 20-30 kg. MAIN OUTCOME MEASURES: Primary endpoints were bone turnover markers, including serum osteocalcin, and urinary NTX-telopeptides. Secondary endpoints included areal bone mineral density (aBMD), pain, skeletal disease burden score, and functional parameters including the 9-min walk test and manual muscle testing. RESULTS: Clinical data was collected on 35 subjects who completed the study. There was a decline in NTX-telopeptides in the alendronate group (P = .006), but no significant difference in osteocalcin between groups. The alendronate group had an increase in areal BMD in normal bone at the lumbar spine (P = .006), and in predetermined regions of FD (P < .001). There were no significant differences in pain scores, skeletal disease burden scores, or functional parameters between the groups. CONCLUSIONS: Alendronate treatment led to a reduction in the bone resorption marker NTX-telopeptides, and improvement in aBMD, but no significant effect on serum osteocalcin, pain, or functional parameters.

Analysis of efficacy and safety of treatment with collagenase Clostridium histolyticum among subgroups of patients with Dupuytren contracture.

Collagenase Clostridium histolyticum (CCH) injection is a nonoperative treatment of hand contractures from Dupuytren disease. This study assessed the efficacy and safety of CCH in several subgroups of patients with increased surgical risk.Data were pooled from 3 randomized, placebo-controlled, double-blind trials. This analysis included 271 patients with metacarpophalangeal (n = 167) or proximal interphalangeal (n = 104) joint contractures greater than or equal to 20 degrees treated with CCH (0.58 mg collagenase per injection). Subgroups included age, sex, and diabetes status. End points included rate of clinical success (reduction in contracture to 0-5 degrees of normal) and percentage of adverse events.There was no significant difference in clinical success by age, diabetes status, or sex with 63% reaching the end point. There was no difference in adverse events among the subgroups, with peripheral edema, contusion, and injection-site hemorrhage being most common.High-risk subgroups do not demonstrate differences in efficacy or safety with CCH treatment of Dupuytren-related contractures.

12-month observation of testosterone replacement effectiveness in a general population of men.

BACKGROUND: Testosterone decline becomes more prevalent as men age and symptomatic testosterone deficiency is associated with potentially serious comorbidities. Despite limitations, registries can provide an opportunity to accumulate data regarding disease management in a typical patient population, including diagnosis, treatment, and outcomes. MATERIALS AND METHODS: The Testim Registry in the United States (TRiUS) was a prospective, 12-month, observational cohort registry of men prescribed Testim® (1% testosterone gel; Auxilium Pharmaceuticals, Inc.) for the first time; patients previously on other forms of testosterone replacement therapy (TRT) were eligible to participate in the study as well. The registry recorded total testosterone (TT) and free testosterone (FT) levels, prostate-specific antigen (PSA), sexual function, mood/depression, and cardiometabolic and anthropometric criteria before and after TRT. Changes over time were analyzed by analysis of variance, and linear regression and Pearson product-moment correlation coefficients were used to examine relationships between variables. RESULTS: At baseline, 849 patients from 72 sites were enrolled, with 743 of 849 started on 5 g gel/day (50 mg testosterone/day) and 106 of 849 started on 10 g gel/day (100 mg testosterone/day). Mean TT and FT levels increased significantly after 3 months of TRT (TT level, 16.8 ± 9.87 nmol/L [485 ± 284 ng/dL], P < 0.001; FT level, 286.3 ± 224.9 pmol/L [82.5 ± 64.8 pg/mL], P < 0.001) and were maintained at eugonadal levels. Mean PSA levels increased significantly (P = 0.004) from 1.12 ± 1.11 µg/L (1.12 ± 1.11 ng/mL) at baseline to 1.26 ± 1.22 µg/L (1.26 ± 1.22 ng/mL) after 12 months of TRT, although changes were well within guidelines (< 1.4 µg/L/year increase). Significant improvements were seen in sexual function and mood/depression at 3 months and in metabolic parameters at 12 months. CONCLUSION: Testosterone deficiency symptoms improved with TRT use in men; sexual function and mood/depression improvements were seen before metabolic improvements. Prostate-specific antigen levels increased, although increases were within guideline-determined safety limits.