Search

Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin.In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 μg or 12 μg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response.Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 μg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups.In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.).

The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM).In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5 mg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively.After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (P 0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (P 0.0001), vaginal pH decreased by 0.66 pH unit over placebo (P 0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = 0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (P = 0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (P 0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants.The daily intravaginal administration of 0.50% (6.5 mg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women.

There are about 2,500 war and military service dogs in service, with about 700 serving at any given time overseas. Military Working Dogs (MWDs) are critical assets for military police, special operations units, and others operating in today's combat environment. The expectation, given the significant combat multiplier impact of these dogs and the intense bond between the handler and dog, is that injured working dogs will receive the same level of care as any injured U.S. military personnel. Veterinary care is available at multiple locations throughout theater, and the veterinary healthcare team is the MWD's primary provider. Yet, human healthcare providers (HCPs) may be the only medical personnel available to MWDs that are gravely ill or injured. As most HCPs are unfamiliar with medical care of dogs, the Joint Trauma System published a Clinical Practice Guideline (CPG), a set of detailed clinical guidelines for managing life-threatening problems of MWDs encountered in combat operations. The CPG is available at the JTS website. This article is covers the most common urgent MWD care challenges HCPs may face.

The Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) released a draft guidance (DG) on adaptive clinical tri...

A multiple testing procedure can be a single-step procedure such as Bonferroni's method or a stepwise procedure such as Hochberg's stepup method and Hommel's method. It can be an α-exhaustive or α-conservative approach. We develop a single α-exhaustive procedure that can improve power 2-5% over Hochberg's and Hommel's methods in common situations when the test statistics are mutually independent. The method can also be generalized to dependent test statistics. The idea behind our method is to construct the rejection rules using the product of marginal p-values and by controlling the upper bounds of the kth order terms so that α is controlled for any configuration of k null hypotheses. Such upper bounds or critical values are determined progressively from k = 1 towards k = K, the number of null hypotheses in the problem.

The objective of the study is to evaluate the acceptability of the intravaginal administration of ovules/suppositories of DHEA (dehydroepiandrosterone, prasterone) for the treatment of vulvovaginal atrophy (VVA) in women with moderate to severe dyspareunia who were administered daily for 12 weeks intravaginal 0.50% (6.5 mg) DHEA or placebo. There were a total of 373 women in the per-protocol population who responded to the questionnaire for both treatment groups. While it was planned that the applicator would be evaluated as suitable if at least 80% of participants have a global score ≤ 2 units, 99% and 100% of participants had a score ≤ 2 units in the placebo and DHEA groups, respectively, for the global score (mean of 5 questions). When asked about like and dislike the technique of drug administration, 284 comments were positive, while 114 women gave no comment. About 92-94% of women indicated that they were very confident to be able use the applicator successfully in the future. The survey shows a high degree of satisfaction and of confidence to use the applicator successfully in the future.

Introduction Previous data have shown that intravaginal dehydroepiandrosterone (DHEA, prasterone) improved all the domains of sexual function, an effect most likely related to the local formation of androgens from DHEA. Aims To confirm in a placebo-controlled, prospective, double-blind and randomized study the benefits of daily intravaginal DHEA for 12 weeks on sexual function using the Female Sexual Function Index (FSFI) questionnaire. Methods Placebo was administered daily to 157 women while 325 women received 0.50% (6.5 mg) DHEA daily for 12 weeks. All women were postmenopausal meeting the criteria of vulvovaginal atrophy (VVA), namely moderate to severe dyspareunia as their most bothersome symptom of VVA in addition to having ≤5% of vaginal superficial cells and vaginal pH > 5.0. The FSFI questionnaire was filled at baseline (screening and day 1), 6 weeks and 12 weeks. Comparison between DHEA and placebo of the changes from baseline to 12 weeks was made using the analysis of covariance test, with treatment group as the main factor and baseline value as the covariate. Main Outcome Measures The six domains and total score of the FSFI questionnaire were evaluated. Results The FSFI domain desire increased over placebo by 0.24 unit (+49.0%, P = 0.0105), arousal by 0.42 unit (+56.8%, P = 0.0022), lubrication by 0.57 unit (+36.1%, P = 0.0005), orgasm by 0.32 unit (+33.0%, P = 0.047), satisfaction by 0.44 unit (+48.3%, P = 0.0012), and pain at sexual activity by 0.62 unit (+39.2%, P = 0.001). The total FSFI score, on the other hand, has shown a superiority of 2.59 units in the DHEA group over placebo or a 41.3% greater change than placebo (P = 0.0006 over placebo). Conclusion The present data show that all the six domains of the FSFI are improved over placebo (from P = 0.047 to 0.0005), thus confirming the previously observed benefits of intravaginal DHEA on female sexual dysfunction by an action exerted exclusively at the level of the vagina, in the absence of biologically significant changes of serum steroids levels.

Rationale: Interferon-γ release assays have significant advantages over tuberculin skin testing in many clinical situations. However, recent studies have called into question their reliability in serial testing of healthcare workers because of reportedly high rates of positivity and high conversion/reversion rates on retesting.Objectives: To define the performance characteristics of the T-SPOT.TB test, an interferon-γ release assay, during serial screening programs of healthcare workers at 19 U.S. hospitals.Methods: A total of 42,155 T-SPOT.TB test results from healthcare workers at 19 geographically diverse hospitals obtained for routine tuberculosis screening programs were analyzed to determine the rates of positivity, reversion, and conversion in serial testing data.Measurements and Main Results: In 19,630 evaluable serial pairs from 16,076 healthcare workers, the mean test positivity rate was 2.3% (range, 0.0–27.4%). The mean conversion rate was 0.8% (range, 0.0–2.5%), and the mean reversion rate was ...

Introduction We have previously observed that intravaginal prasterone (dehydroepiandrosterone, DHEA) improved all domains of female sexual dysfunction (FSD). Aim Investigate the influence of moderate/severe pain at sexual activity (dyspareunia) (MSD) at baseline on FSD following prasterone administration. Methods The effect of daily administration of prasterone (0, 3.25 mg, 6.5 mg or 13 mg) for 12 weeks on FSD in 215 postmenopausal women with or without MSD at baseline was evaluated in a prospective, randomized, double‐blind, and placebo‐controlled phase III clinical trial. Main Outcome Measures Differences were examined on desire, arousal and orgasm. Results Comparable benefits were observed in women not having MSD (n = 56) vs. those having MSD (n = 159). The benefits over placebo in prasterone‐treated women for desire, avoiding intimacy and vaginal dryness as well as for the total sexual domain of the MENQOL (Menopause Specific Quality of Life) questionnaire, ranged between 18.0% and 38.2% with P values of P = 0.01), 118% ( P = 0.001) and 31.1% ( P = 0.03) were observed over placebo, respectively, while similar differences (58.0%, 67.6% and 32.1%) did not reach statistical significance in the MSD− group having up to only 44 prasterone‐treated women compared with 119 in the MSD+ group. Conclusions No MSD at baseline does not apparently affect the effects of intravaginal prasterone on sexual dysfunction. Knowing the absence of significant effects of estrogens on FSD, the present data suggest that vulvovaginal atrophy (VVA) and vulvovaginal sexual dysfunction (VVSD) are two different consequences of sex steroid deficiency at menopause which can respond independently. In addition, the present data seriously question the justification of pain being part of FSD as well as the separation of FSD into separate domains. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez J‐L, Girard G, Baron M, Ayotte N, Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Gilbert L, Martel C, and Balser J. Lack of influence of dyspareunia on the beneficial effect of intravaginal prasterone (dehydroepiandrosterone, DHEA) on sexual dysfunction in postmenopausal women. J Sex Med 2014;11:1766–1785.

Purpose Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Patients and Methods Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. Results Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Conclusion Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

Objective To examine the effect of intravaginal dehydroepiandrosterone (DHEA) on pain at sexual activity (dyspareunia) identified as the most bothersome symptom of vaginal atrophy in postmenopausal women at both screening and day 1. Methods This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of prasterone (DHEA) applied locally in the vagina on the severity of dyspareunia in 114 postmenopausal women who had identified dyspareunia as their most bothersome symptom of vaginal atrophy, while meeting the criteria for superficial cells � 5% and pH4 5.0 at both screening and day 1. Results At the standard duration of 12 weeks of treatment, increasing doses of 0.25%, 0.5% and 1.0% DHEA decreased the percentage of parabasal cells by 48.6+ 6.78%, 42.4+ 7.36% and 54.9+ 6.60% (p5 0.0001 vs. placebo for all) with no change with placebo (p ¼ 0.769). The effects on superficial cells and pH were also highly significant compared to placebo at all DHEA doses. The severity score of pain at sexual activity decreased by 0.5, 1.4, 1.6 and 1.4 units in the placebo and 0.25%, 0.5% and 1.0% DHEA groups, respectively, with the p value of differences from placebo ranging from 0.0017 to 5 0.0001. Conclusions Intravaginal DHEA, through local estrogen and androgen formation, causes a rapid and highly efficient effect on pain at sexual activity without systemic exposure of the other tissues, thus avoiding the recently reported systemic effects of estrogens.

Following the compelling data obtained in a pivotal phase III clinical trial performed in 218 postmenopausal women suffering from vaginal atrophy who received daily intravaginal 0.25, 0.5 or 1.0% DHEA (dehydroepiandrosterone) ovules for 12 weeks, we have performed analysis of the four co-primary objectives at each site of that multicentre U.S. and Canadian trial. Comparison was made of the change in percentage of parabasal and superficial cells, vaginal pH and severity of the most bothersome symptom. The site-by-site (seven sites) analysis has shown that 10-13 women per group are generally sufficient to obtain a significant or highly statistically significant decrease in vaginal pH and percentage of parabasal cells and increased percentage of superficial cells at p values ranging from 0.02 to

Objective: The objective of this study was to provide evidence that the transformation of DHEA into both androgens and/or estrogens locally in cells of the three layers of the vagina (epithelium, lamina propria, and muscularis) would have effects of greater impact, including effects on sexual function, than only effects on superficial epithelial cells as achieved with estrogens. Methods: This prospective, randomized, double-blind, and placebo-controlled phase III clinical trial has evaluated the effect of daily local intravaginal application of Prasterone (dehydroepiandrosterone; DHEA) for 12 weeks on the domains of sexual dysfunction, namely, desire/interest, arousal, orgasm, and pain at sexual activity, in 216 postmenopausal women with moderate to severe symptoms of vaginal atrophy. Results: A time- and dose-dependent improvement of the four domains of sexual function was observed. At the 12-week time interval, the 1.0% DHEA dose led, compared with placebo, to 49% (P = 0.0061) and 23% (P = 0.0257) improvements of the desire domains in the Menopause Specific Quality of Life and Abbreviated Sex Function questionnaires, respectively. Compared with placebo, the Abbreviated Sex Function arousal/sensation domain was improved by 68% (P = 0.006), the arousal/lubrication domain by 39% (P = 0.0014), orgasm by 75% (P = 0.047), and dryness during intercourse by 57% (P = 0.0001). Conclusions: By a local action in the vagina, DHEA applied daily at doses at which serum steroids remain well within normal postmenopausal values exerts relatively potent beneficial effects on all four aspects of sexual dysfunction. Such data indicate that combined androgenic/estrogenic stimulation in the three layers of the vagina exerts important beneficial effects on sexual function in women without systemic action on the brain and other extravaginal tissues.

Objective: Because the secretion of dehydroepiandrosterone (DHEA), the exclusive source of sex steroids in postmenopausal women, is already decreased by 60% and continues to decline at the time of menopause, the objective of this study was to examine the effect of intravaginal DHEA on the symptoms and signs of vaginal atrophy. Methods: This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of Prasterone (DHEA) applied locally in the vagina on the signs and symptoms of vaginal atrophy in 216 postmenopausal women. Results: All three doses (0.25%, 0.5%, and 1.0%) of DHEA ovules applied daily intravaginally induced a highly significant beneficial change in the percentage of vaginal parabasal and superficial cells and pH as well as in the most bothersome symptom at 2 weeks. At the standard 12-week time interval, 0.5% DHEA caused a 45.9 T 5.31 (P G 0.0001 vs placebo) decrease in the percentage of parabasal cells, a 6.8 T 1.29% (P G 0.0001) increase in superficial cells, a 1.3 T 0.13 unit (P G 0.0001) decrease in vaginal pH, and a 1.5 T 0.14 score unit (P G 0.0001) decrease in the severity of the most bothersome symptom. Similar changes were seen on vaginal secretions, color, epithelial surface thickness, and epithelial integrity. Comparable effects were observed at the 0.25% and 1.0% DHEA doses. Conclusions: Local Prasterone, through local androgen and estrogen formation, causes a rapid and efficient reversal of all the symptoms and signs of vaginal atrophy with no or minimal changes in serum steroids, which remain well within the normal postmenopausal range. This approach avoids the fear of systemic effects common to all presently available estrogen formulations and adds a novel physiological androgenic component to therapy.

Intravaginal DHEA (dehydroepiandrosterone, prasterone), the exclusive precursor of androgens and estrogens in postmenopausal women, has previously been shown to improve all the domains of sexual function by a strictly local action in the vagina. The well recognized female sexual function index (FSFI) questionnaire was used in the present study.The long-term effect of 52-week treatment with daily intravaginal 0.50% (6.5 mg) DHEA was evaluated on the various domains of female sexual function using the FSFI questionnaire at baseline, Week 26 and Week 52.One hundred and fifty-four postmenopausal women with at least one mild to severe symptom of vulvovaginal atrophy (VVA) and who have completed the FSFI questionnaire at baseline and at least one post-baseline timepoint were included in the analysis.The FSFI domains desire, arousal, lubrication, orgasm, satisfaction and pain were increased by 28%, 49%, 115%, 51%, 41% and 108%, respectively (pAs the serum levels of DHEA and all its metabolites, including estradiol and testosterone, show no meaningful change, the present clinical data indicate a stimulatory effect of intravaginal DHEA through a strictly local action in agreement with the preclinical data showing that the androgens made locally from DHEA in the vagina induce an increase in local nerve density.

This study aims to confirm the local effects of intravaginal prasterone on moderate to severe dyspareunia, a symptom of vulvovaginal atrophy (VVA) associated with menopause.In a prospective, randomized, double-blind, placebo-controlled phase III clinical trial, we examined the effects of daily intravaginal prasterone (6.5 mg) on four co-primary objectives, namely, percentage of vaginal parabasal cells, percentage of vaginal superficial cells, vaginal pH, and moderate to severe dyspareunia identified by women as the most bothersome VVA symptom.After daily intravaginal prasterone administration for 12 weeks, the percentage of parabasal cells decreased by 45.8% compared with placebo (P 0.0001), the percentage of superficial cells increased by 4.7% over placebo (P 0.0001), and vaginal pH decreased by 0.83 pH units compared with placebo (P 0.0001). The severity of most bothersome dyspareunia decreased by 46% over placebo (P = 0.013) at 12 weeks, whereas moderate to severe vaginal dryness decreased by 0.43 severity score units (or 42%) compared with placebo (P = 0.013). On gynecologic evaluation, a 14.4% to 21.1% improvement in vaginal secretions, epithelial integrity, epithelial surface thickness, and color over placebo (P = 0.0002 to P 0.0001) was observed. Serum steroids, in agreement with the physiology of intracrinology and menopause, remained well within reference postmenopausal concentrations. All endometrial biopsies at 12 weeks have shown atrophy.Daily intravaginal prasterone (0.50%; 6.5 mg) treatment has clinically and statistically significant beneficial effects on the four co-primary objectives of VVA, according to US Food and Drug Administration guidelines. No significant drug-related adverse effect in line with the strictly local action of treatment has been reported, thus providing a high benefit-to-risk ratio for intravaginal prasterone.

International audience; BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), the value of (18)fluoro-deoxyglucose positron emission tomography (FDG-PET) scans for assessing prognosis and response to treatment remains unclear. The utility of FDG-PET, in addition to conventional radiology, was examined as a planned exploratory end point in the pivotal phase 2 trial of romidepsin for the treatment of relapsed/refractory PTCL.PATIENTS AND METHODS: Patients received romidepsin at a dose of 14 mg/m(2) on days 1, 8, and 15 of 28-day cycles. The primary end point was the rate of confirmed/unconfirmed complete response (CR/CRu) as assessed by International Workshop Criteria (IWC) using conventional radiology. For the exploratory PET end point, patients with at least baseline FDG-PET scans were assessed by IWC + PET criteria.RESULTS: Of 130 patients, 110 had baseline FDG-PET scans, and 105 were PET positive at baseline. The use of IWC + PET criteria increased the objective response rate to 30% compared with 26% by conventional radiology. Durations of response were well differentiated by both conventional radiology response criteria [CR/CRu versus partial response (PR), P = 0.0001] and PET status (negative versus positive, P < 0.0001). Patients who achieved CR/CRu had prolonged progression-free survival (PFS, median 25.9 months) compared with other response groups (P = 0.0007). Patients who achieved PR or stable disease (SD) had similar PFS (median 7.2 and 6.3 months, respectively, P = 0.6427). When grouping PR and SD patients by PET status, patients with PET-negative versus PET-positive disease had a median PFS of 18.2 versus 7.1 months (P = 0.0923).CONCLUSIONS: Routine use of FDG-PET does not obviate conventional staging, but may aid in determining prognosis and refine response assessments for patients with PTCL, particularly for those who do not achieve CR/CRu by conventional staging. The optimal way to incorporate FDG-PET scans for patients with PTCL remains to be determined.TRIAL REGISTRATION: NCT00426764.

An objective was to analyze the time course of efficacy of daily intravaginal administration of 0.5% (6.5mg) DHEA (prasterone) for 52 weeks on the moderate to severe (MS) symptoms and signs of vulvovaginal atrophy (VVA).Five hundred twenty-one postmenopausal women were enrolled and received daily intravaginal administration of 0.5% DHEA in an open-label phase III study. The severity of the VVA symptoms examined in detail in the different groups.A parallel improvement of pain at sexual activity was observed in women who had moderate to severe (MS) dyspareunia as their most bothersome symptom (MBS) (n=183) or not MBS (n=240) and MS without being MBS (n=57) with a 1.70 severity unit change in the MBS group for a decrease of 66.1% from baseline (p0.0001 versus baseline) over 52 weeks. A further improvement of dyspareunia, namely 0.33 severity unit (19.4%), was observed with continuing treatment from 12 weeks to 52 weeks. Similar results were observed on vaginal dryness and irritation/itching. Highly significant beneficial effects (p0.0001 versus baseline for all) were observed at gynecological examination on vaginal secretions, color, epithelial integrity and epithelial surface thickness.The present study shows, in addition to the parallel benefits on the three symptoms of VVA, that the choice of any of the MS symptoms as being or not being MBS by women has no influence on the observed therapeutic effect (NCT01256671).

TPS5606Background: Niraparib is a highly selective PARP1/2 inhibitor that induces synthetic lethality in tumor cells with homologous recombination DNA repair deficiencies (HRD). Niraparib is admini...

Because the exclusive source of sex steroids (at least estrogens) after menopause is recognized to be dehydroepiandrosterone (DHEA), this study examines the interindividual variability of serum DHEA and its metabolites as well as the contribution of the ovary to global sex steroid physiology in postmenopausal women.Serum levels of DHEA and 11 of its metabolites were measured by gas or liquid chromatography/mass spectrometry in 442 intact and 71 ovariectomized postmenopausal women aged 42 to 74 years.With a mean ± SD concentration of 2.03 ± 1.33 ng/mL, serum DHEA in intact postmenopausal women is highly variable with 5th and 95th centiles at 0.55 and 4.34 ng/mL, respectively, for a 7.9-fold difference. A comparable variability is observed for the 11 metabolites of DHEA. The 22.3% higher serum DHEA in intact compared with ovariectomized women is accompanied by parallel differences for all the other steroids, thus indicating that all sex steroids originate from circulating DHEA in postmenopausal women with no direct secretion of active estrogens or androgens by the postmenopausal ovary.The 7.9-fold difference between low and high serum DHEA levels provides an explanation for the lack of signs of hormone deficiency in some women, whereas most of them have symptoms or signs. The approximately 20% contribution of the ovary to the total pool of DHEA with no direct secretion of estrogens or androgens in the circulation could possibly explain the reported negative effect of oophorectomy on longevity, especially from coronary heart disease events.

Background Seasonal influenza imposes a substantial personal morbidity and societal cost burden. Vaccination is the major strategy for influenza prevention; however, because antigenically drifted influenza A and B viruses circulate annually, influenza vaccines must be updated to provide protection against the predicted prevalent strains for the next influenza season. The aim of this study was to assess the efficacy, safety, reactogenicity, and immunogenicity of a trivalent inactivated split virion influenza vaccine (TIV) in healthy adults over two influenza seasons in the US. Methods The primary endpoint of this double-blind, randomized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched, culture-confirmed influenza (VMCCI) across the 2005-2006 and 2006-2007 influenza seasons. Secondary endpoints included the prevention of laboratory-confirmed (defined by culture and/or serology) influenza, as well as safety, reactogenicity, immunogenicity, and consistency between three consecutive vaccine lots. Participants were assessed actively during both influenza seasons, and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness. Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season's surveillance period. Results Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2% (97.5% confidence interval [CI] lower bound of 48.2%), the point estimate for the primary endpoint, efficacy of TIV against VMCCI across both influenza seasons, was 46.3% with a 97.5% CI lower bound of 9.8%. This did not satisfy the pre-specified success criterion of a one-sided 97.5% CI lower bound of >35% for vaccine efficacy. The VMCCI attack rates were very low overall at 0.6% and 1.2% in the TIV and placebo groups, respectively. Apart from a mismatch for influenza B virus lineage in 2005-2006, there was a good match between TIV and the circulating strains. TIV was highly immunogenic, and immune responses were consistent between three different TIV lots. The most common reactogenicity events and spontaneous adverse events were associated with the injection site, and were mild in severity. Conclusions Despite a good immune response, and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2%, the pre-specified target (lower one-sided 97.5% confidence bound for efficacy > 35%) for the primary efficacy endpoint, the prevention of VMCCI, was not met. However, the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005-2006 and 2006-2007, which corresponded to relatively mild influenza seasons in the US. Overall, the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk. Trial registration NCT00216242

Objective Because a previous 1-week study has shown no or minimal changes in the serum levels of dehydroepiandrosterone (DHEA) and its metabolites after up to daily 1.8% (23.4 mg) intravaginal DHEA, the objective of the present study was to investigate the serum steroid levels during a 12-week daily intravaginal administration of 0%, 0.25%, 0.5%, and 1.0% DHEA (Prasterone) 1.3 mL ovules. Methods In a double-blind, placebo-controlled phase III study, 218 postmenopausal women (age range, 42-74 y) were randomized to receive daily one of four DHEA concentrations intravaginally. Serum steroids were measured by a Good Laboratory Practice-validated mass spectrometry technology in samples obtained at time of visit. Results The serum levels of DHEA and 11 of its metabolites measured at screening, day 1, and weeks 2, 4, 8, and 12 in women showed no or minimal changes during the whole observation period, with all values remaining well within the limits of normal postmenopausal women. No accumulation of the steroid metabolites nor change in DHEA bioavailability was detected. Conclusions The present data show that local daily intravaginal DHEA administration at DHEA doses of 3.25-13 mg was able to rapidly and efficiently achieve correction of all the signs and symptoms of vaginal atrophy and improve sexual function and caused no or minimal changes in serum sex steroid levels, which all remain within the normal postmenopausal range, thus avoiding the risks of all estrogen formulations.

TPS5609 Background: Niraparib is a potent, orally active PARP-1 and -2 inhibitor in development for the treatment of tumors that exhibit defects in the PARP-mediated homologous recombination DNA re...

Abstract 591FN2 Background: Romidepsin is a potent class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for treatment of patients with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy and patients with peripheral T-cell lymphoma (PTCL) who have received at least 1 prior therapy. Approval for use in patients with PTCL was based in part on results from the phase 2, single-arm, open-label registration study GPI-06-0002, which demonstrated clinical benefit and tolerability of romidepsin in patients with recurrent or refractory PTCL. The aim of this subanalysis was to evaluate the efficacy and safety of romidepsin on GPI-06-0002 in the three major subtypes of PTCL: PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic lymphoma kinase-1–negative anaplastic large cell lymphoma (ALK-1–negative ALCL). Methods: Patients with histologically confirmed PTCL who failed or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for patients achieving stable disease (SD) or better. The primary efficacy endpoint was rate of confirmed/unconfirmed complete response (CR/CRu); secondary endpoints were objective response rate (ORR: CR/CRu + partial response [PR]) and duration of response (DOR). Because of the aggressive nature of PTCL, prolonged disease stabilization can provide patient benefit, thus ORR + SD ≥ 90 days was used as an overall measure of disease control. Efficacy assessments were made by an Independent Review Committee (IRC) and consisted of an initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters. Results: Of the 131 enrolled patients, 130 patients had histologically confirmed PTCL by central review, with a median of 2 (range 1–8) prior systemic therapies for PTCL. The majority of patients (117/130) had PTCL-NOS (n = 69), AITL (n = 27), or ALK-1–negative ALCL (n = 21). Responses assessed by the IRC and the most common grade ≥ 3 adverse events (AEs) for the 3 major subtypes are noted in the table. ORR was similar across subtypes, including 30% in patients with AITL, with 19% CR/CRu. With a median duration of follow-up of 10.9 months, the median DOR for all responders was 17 months for patients with PTCL-NOS and 12 months for patients with ALK-1–negative ALCL. Median DOR was not yet evaluable for patients with AITL, who had the longest DOR ongoing at 34 months. Overall, 66% of patients experienced at least 1 grade ≥ 3 AE; 78% in patients with AITL, 67% in patients with PTCL-NOS, and 48% in patients with ALK-1–negative AITL. Eighteen of 117 patients (15%) experienced grade ≥ 3 infection; however infections led to discontinuation in only 4 of 117 patients (3%), 1 with PTCL-NOS and 3 with ALK-1–negative ALCL. Infection rates were higher in patients whose disease had bone marrow involvement or who had received prior monoclonal antibody therapy. Conclusions: Similar CR/CRu rates were observed across the 3 major PTCL subtypes (PTCL-NOS, AITL, and ALK-1–negative ALCL). Romidepsin induced durable responses in patients with the major subtypes of PTCL, with nearly half (46%) of these patients experiencing disease control. These data support the use of single-agent romidepsin to treat relapsed or refractory PTCL-NOS, AITL, and ALK-1–negative ALCL as well as the development of romidepsin-based combination regimens and front-line therapies in these histologies Disclosures: Coiffier: Celgene: Consultancy; Gloucester: Consultancy. Pro:Celgene: Consultancy, Honoraria. Prince:Celgene: Honoraria, Research Funding. Foss:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy. Sokol:Celgene: Consultancy, Speakers Bureau; Gloucester: Research Funding. Caballero:Celgene: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau; Pfizer: Speakers Bureau. Morschhauser:Bayer: Honoraria; Roche: Consultancy, Honoraria. Pinter-Brown:Celgene: Consultancy; Allos: Consultancy; Merck: Consultancy; Spectrum: Honoraria; Genetech: Speakers Bureau. Padmanabhan:Celgene: Consultancy, Honoraria. Shustov:Celgene: Research Funding, Speakers Bureau. Nichols:Celgene: Employment, Equity Ownership. Carroll:Celgene: Employment, Equity Ownership. Balser:Celgene: Contracted Consultancy. Horwitz:Celgene: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Merck: Honoraria; Millennium: Consultancy; Genzyme: Research Funding.

8033 Background: Potent histone deacetylase inhibitor, romidepsin, has shown durable clinical benefit and tolerability in patients (pts) with R/R PTCL with objective response rates of 38% (17/45, N...

Abstract 114 Background: Romidepsin is a potent HDAC inhibitor approved by the FDA for patients (pts) with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. Durable clinical benefit and tolerability of romidepsin in pts with recurrent or refractory PTCL have been previously observed in a phase 2 trial conducted by the National Cancer Institute. The aim of this phase 2, single-arm, open-label registration study was to evaluate the activity of romidepsin in a larger number of pts with progressive or relapsed PTCL. Methods: Pts with histologically confirmed PTCL (PTCL NOS, angioimmunoblastic T-cell lymphoma, ALCL [ALK-1 negative], other subtypes) who failed or were refractory to ≥ 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Exclusions included inadequate bone marrow or other organ function and significant cardiovascular abnormalities. Pts received romidepsin 14 mg/m2 as a 4-h IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for stable disease (SD) or response. The primary endpoint was rate of complete response (CR + CRu) as evaluated by a central Independent Review Committee (IRC) using International Working Criteria for non-Hodgkin's lymphoma. IRC assessment consisted of a 2-step process, with initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters. Secondary endpoints included objective response rate (ORR): CR + CRu + partial response (PR), investigator-assessed responses, duration of response, time to response, and safety. Results: 131 pts from 48 US, European, and Australian sites were enrolled and received at least 1 dose of romidepsin (as-treated population); 130 patients had histologically confirmed PTCL by central review. Mean age of all pts was 59.4 y (range, 20–83) and median time since diagnosis was 1.25 y (range, 0–17). Median number of prior systemic therapies was 2 (range, 1–8). 21 pts (16%) had failed a prior stem cell transplant. Responses assessed by the IRC are noted in the table below. Longest duration of response is 26+ mo and 16 (94%) of the 17 pts with a CR had not progressed as of the data cutoff (March 31, 2010). Investigator-assessed responses included 21 pts (16%) with CR + CRu, 18 pts (14%) with PR for an ORR of 30%. Currently, 13 pts continue to receive treatment (range, 10–36 cycles). Adverse events (AEs) were reported in 126 of 131 pts (96%). AEs reported in ≥ 20% of pts were nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). AEs ≥ grade 3 were reported for 86 pts (66%), with the most common (≥ 5%) being pneumonia (5%), pyrexia (5%), sepsis (5%), and vomiting (5%). 60 pts (46%) had at least 1 serious AE: the most frequently reported (≥ 5%) were pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). 22 pts (17%) withdrew due to AEs. 8 pts (6%) died within 30 days of the last dose of romidepsin; 1 death, due to sepsis, was assessed as possibly related to treatment. Conclusions: Complete and durable responses were observed with single agent romidepsin in pts with relapsed PTCL. These data support the therapeutic potential for romidepsin in relapsed PTCL and suggest that romidepsin is a strong candidate for inclusion in future novel regimens for these diseases. As of the data cutoff (March 31, 2010), the median duration of follow-up for CR is 8.2 mo. Disclosures: Coiffier: Gloucester: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is not currently approved for the treatment of peripheral T-cell lymphoma (PTCL). Pro:Celgene: Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding. Foss:Celgene: Consultancy; Eisai: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Allos: Consultancy, Speakers Bureau; Cephalon: Speakers Bureau. Sokol:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche: Consultancy, Honoraria; Bayer: Honoraria. Padmanabhan:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shustov:Celgene: Research Funding. Nichols:Celgene: Employment. Carroll:Celgene: Employment. Balser:Gloucester Pharmaceutical: Consultancy. Horwitz:Celgene: Consultancy, Honoraria.