Citations

Objective To evaluate onset of effect of galcanezumab in patients with episodic migraine. Background Galcanezumab is a monoclonal antibody that binds to calcitonin gene‐related peptide and is indicated for preventive treatment of migraine. Design/Methods Data on the primary outcome measure were analyzed from 2 previously published double‐blind, Phase 3 studies (EVOLVE‐1 [N = 858] and EVOLVE‐2 [N = 915]) wherein adult patients with episodic migraine were randomized to receive monthly subcutaneous injections of galcanezumab 120 mg (with 240‐mg loading dose) or 240 mg or placebo for up to 6 months. Monthly onset of effect was defined as the earliest month at which galcanezumab achieved and subsequently maintained statistical superiority to placebo on the mean change from baseline in the number of monthly migraine headache days (MHDs). If onset occurred in Month 1, weekly onset was evaluated and defined as the earliest week at which galcanezumab statistically separated from placebo and maintained statistical separation for remaining weeks in that month. Day of onset of effect was also analyzed, as were monthly and weekly onset, for occurrence of ≥50% reduction from baseline in number of MHDs. Results For both studies, change from baseline in monthly MHDs showed a statistically significant separation of galcanezumab from placebo at Month 1 and each subsequent month (each P < .001). Analysis of the first month for both studies indicated onset of effect in the first week, with galcanezumab‐treated patients having significantly higher odds of having fewer MHDs in the first week (odds ratio [95% confidence interval] for EVOLVE‐1, 2.71 [2.00, 3.66], and for EVOLVE‐2, 2.88 [2.16, 3.86]; both P < .001) and each subsequent week compared with placebo‐treated patients ( P ≤ .004). Daily analysis showed onset of effect at Day 1 (first day after injection day). Galcanezumab also demonstrated superiority to placebo on occurrence of ≥50% reduction in MHDs starting at Week 1 (percentage of patients with 50% response in galcanezumab group vs placebo group for EVOLVE‐1, 54.3% vs 32.4% [ P < .001], and for EVOLVE‐2, 59.4% vs 38.0% [ P < .001]). Conclusion Rapid onset of preventive effect on the first day after injection of galcanezumab was confirmed in both studies of episodic migraine.

AbstractBackgroundPatients with acute myeloid leukemia (AML) are surviving longer. There are no data on changes in myocardial mechanics from standard of care low‐dose anthracycline‐based induction chemotherapy in older patients with AML. The aim of this study was to demonstrate the potential utility of strain imaging in detecting early changes in left ventricular function in this patient population after induction chemotherapy.MethodsThirty two patients enrolled in the ECOG‐ACRIN E2906 study (cytarabine and daunorubicin vs clofarabine [Genzyme/Sanofi]) from 2011 to 2014 were evaluated retrospectively. Two‐dimensional transthoracic echocardiography (TTE) imaging with Doppler and two‐dimensional speckle‐tracking echocardiography (2DSTE) using EchoInsight software (Epsilon imaging) were performed before and after induction chemotherapy.ResultsEighteen patients received cytarabine and daunorubicin (7 + 3) and 14 received clofarabine. The clofarabine group was older than the 7 + 3 cohort (67.8 ± 4.0 vs 63.7 ± 3.8, P = .007). There were no other significant differences in cardiac risk factors between groups. The 7 + 3 group had a decrease in average peak systolic global longitudinal (−19.1 ± 2.8 to −17.2 ± 3.0, P = .01) and circumferential strain (−29.4 ± 6.3 to −23.9 ± 4.3, P = .011). These changes were not demonstrated in the clofarabine group and were not associated with a decline in left ventricular ejection fraction (LVEF).ConclusionsIn older AML patients, standard cytarabine and daunorubicin chemotherapy causes early changes in global longitudinal and circumferential strain not seen with clofarabine therapy. These findings demonstrate subclinical left ventricular dysfunction after exposure to low cumulative doses of anthracycline‐based induction chemotherapy and may help us better identify those patients at risk for adverse long‐term cardiovascular outcomes.

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) and spindle cell lipoma are lipomatous tumors with distinct clinical, molecular, and prognostic features. Although histological and immunophenotypic features can overlap between ALT/WDL and spindle cell lipoma, the oncogenesis and clinical behavior are markedly different. In borderline cases, molecular analysis for MDM2 or CDK4 amplification can aid in distinguishing ALT/WDL from spindle cell lipoma. Although dedifferentiated liposarcoma has been reported to harbor both MDM2 amplification and loss of the RB1 region, we are not aware of a reported RB1 loss in well-differentiated ALT/WDL. In this article, we present a 69-year-old woman with a lipomatous tumor in the gluteal region that histologically, immunohistochemically, and molecularly mimicked spindle cell lipoma (with positive immunohistochemical staining for CD34 and loss of the RB1 gene region), yet harbored amplification of MDM2 and CDK4 confirmed by fluorescence in situ hybridization, supporting classification as ALT/WDL. This case strengthens the argument that in atypical clinical contexts, molecular studies for MDM2/CDK4 should be considered in tumors resembling spindle cell lipoma.

Pharmacologic stimulation of a G protein–coupled receptor preferentially expressed on fibroblasts reverses experimental lung and liver fibrosis.

Abstract Background CDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomycin; VAN). SER-262 is an oral investigational microbiome drug rationally designed to reduce rCDI by restoring colonization resistance. Methods SERES-262-001 was a Phase 1b randomized placebo (PBO)-controlled single and multidose study. Subjects with primary CDI (n = 96) were enrolled in 8 cohorts (SER-262: PBO, 5:1). Subjects were dosed after MET (n = 57) or VAN (n = 39) per investigator discretion. Engraftment of SER-262 strains was evaluated using strain-specific molecular probes in fecal samples; microbial diversity was measured via whole metagenomic shotgun sequencing. Endpoints included safety and rCDI rates up to 8 weeks posttreatment and strain engraftment at 1, 4, 8, 12, and 24 weeks. Results SER-262 safety was comparable to PBO. Although overall rCDI rates were similar in SER-262 (n = 80) and PBO (n = 16) subjects (18.8% vs. 12.5%, respectively), in a post-hoc analysis we observed reduced rates of rCDI in the VAN+SER-262 arm compared with MET+SER-262 (6.3 vs. 27.1%, respectively, P = 0.02, Figure 1). Overall, 8 of 12 SER-262 strains showed significant engraftment relative to PBO. However, greater SER-262 strain engraftment was observed in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 2). To better understand the impact of dysbiosis on engraftment, we evaluated baseline microbial diversity by prior antibiotic received and observed that the diversity of Bacteroidetes and Firmicute species was lower in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 3). Conclusion In this first phase 1b study of a fermented microbiome drug in subjects with primary CDI, SER-262 was safe and well-tolerated. The higher efficacy rates of SER-262 in reducing rCDI among VAN-treated subjects may be due to low baseline microbial diversity, which creates an ecologic niche for greater engraftment of dose species. Treatment of C. difficile with VAN, followed by restoration of colonization resistance with SER-262, is a promising 2-pronged therapeutic paradigm to reduce rCDI. Disclosures All authors: No reported disclosures.

Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation affecting over 1,000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. In order to identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multi-species drug repurposing screen using a first-ever worm model of PMM2-CDG followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 are plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains range from 30% to 400% over baseline depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.

Abstract Context Central and peripheral administration of peptide YY (PYY) has potent anorectic effects, and PYY analogs are under development as antiobesity treatments. Recent animal data suggest PYY may also influence the reproductive axis; however the effects of PYY on the human reproductive system are unknown. Objective To investigate the effects of PYY administration on the reproductive axis in healthy young men. Design Single-blind, randomized, placebo-controlled crossover study. Setting Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean age 24.1 ± 0.9 years, mean body mass index 22.2 ± 0.4 kg/m2). Intervention Eight-hour intravenous infusion of 0.4 pmol/kg/min PYY3-36 or rate-matched vehicle infusion. Main Outcome Measures Number of luteinizing hormone (LH) pulses, LH, follicle stimulating hormone (FSH), and testosterone levels. Results The number of LH pulses (mean number of LH pulses/8 hours: PYY 4.4 ± 0.3 vs vehicle 4.4 ± 0.4, P &gt; .99), LH area under the curve (AUC) (PYY 1503 ± 79 IU.min/L vs vehicle 1574 ± 86 IU.min/L, P = .36), FSH AUC (PYY 1158 ± 513 IU.min/L vs vehicle 1199 ± 476 IU.min/L, P = .49) and testosterone AUC (PYY 10 485 ± 684 IU.min/L vs vehicle 11 133 ± 803 IU.min/L, P = .24) were similar during PYY and vehicle infusions. Conclusions Acute intravenous infusion of 0.4 pmol/kg/min PYY does not affect the reproductive axis in healthy men.

AbstractIntroductionUlcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is a rare phenotype. We aimed to assess patients with UC-PSC or UC alone and describe differences in clinical and phenotypic characteristics, antitumor necrosis factor (TNF) therapy, and long-term clinical outcomes.MethodsThis retrospective multicenter cohort study included patients who received a diagnosis of UC from 1962 through 2015. We evaluated clinical factors associated with UC-PSC vs UC alone and assessed associations by using multivariable logistic regression models.ResultsAmong 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P &lt; 0.001). In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar. Fewer patients with UC-PSC received corticosteroids (OR, 0.24; adjusted P = 0.005) or rectal 5-aminosalicyte acid (OR, 0.26; adjusted P &lt; 0.001). Other differences were identified that were not statistically significant in a multivariable model: patients with UC-PSC more commonly were male, had lower rates of smoking, and had higher rates of colorectal cancer and colectomy.DiscussionThis study identified a unique phenotype of UC with concurrent PSC, which had different clinical behavior compared with UC only. These phenotypic characteristics can help identify high-risk patients with UC before PSC is diagnosed and guide different management and monitoring strategies.