Median Percent Change Research Articles

Glucose Variability as Measured by Inter-measurement Percentage Change is Predictive of In-patient Mortality in Aneurysmal Subarachnoid Hemorrhage.

Critically ill aneurysmal subarachnoid hemorrhage (aSAH) patients suffer from systemic complications at a high rate. Hyperglycemia is a common intensive care unit (ICU) complication and has become a focus after aggressive glucose management was associated with improved ICU outcomes. Subsequent research has suggested that glucose variability, not a specific blood glucose range, may be a more appropriate clinical target. Glucose variability is highly correlated to poor outcomes in a wide spectrum of critically ill patients. Here, we investigate the changes between subsequent glucose values termed "inter-measurement difference," as an indicator of glucose variability and its association with outcomes in patients with aSAH. All SAH admissions to a single, tertiary referral center between 2002 and 2016 were screened. All aneurysmal cases who had more than 2 glucose measurements were included (n = 2451). We calculated several measures of variability, including simple variance, the average consecutive absolute change, average absolute change by time difference, within subject variance, median absolute deviation, and average or median consecutive absolute percentage change. Predictor variables also included admission Hunt and Hess grade, age, gender, cardiovascular risk factors, and surgical treatment. In-patient mortality was the main outcome measure. In a multiple regression analysis, nearly all forms of glucose variability calculations were found to be correlated with in-patient mortality. The consecutive absolute percentage change, however, was most predictive: OR 5.2 [1.4-19.8, CI 95%] for percentage change and 8.8 [1.8-43.6] for median change, when controlling for the defined predictors. Survival to ICU discharge was associated with lower glucose variability (consecutive absolute percentage change 17% ± 9%) compared with the group that did not survive to discharge (20% ± 15%, p < 0.01). Interestingly, this finding was not significant in patients with pre-admission poorly controlled diabetes as indicated by HbA1c (OR 0.45 [0.04-7.18], by percentage change). The effect is driven mostly by non-diabetic patients or those with well-controlled diabetes. Reduced glucose variability is highly correlated with in-patient survival and long-term mortality in aSAH patients. This finding was observed in the non-diabetic and well-controlled diabetic patients, suggesting a possible benefit for personalized glucose targets based on baseline HbA1c and minimizing variability. The inter-measure percentage change as an indicator of glucose variability is not only predictive of outcome, but is an easy-to-use tool that could be implemented in future clinical trials.

Estimating the Impact of Food and Drug Administration's Unapproved Drug Initiative on Drug Prices and Sales.

The 2006 FDA's Unapproved Drug Initiative (UDI) aimed to improve safety and public health by decreasing the availability of drug products that never obtained FDA approval (unapproved drug products) in the market and incentivizing manufacturers to emphasize that these products must obtain FDA approval. The objective of this study was to measure changes in the prices, sales, and quantities sold of drug products approved under the FDA-UDI. Drug products that obtained voluntary approval under FDA-UDI from 2006 to 2015 were identified and trends in prices, sales, and units sold were analyzed using the IQVIA National Sales Perspective database. Eleven drug products were included in the final analysis. Relative to baseline levels 2 years before approval, a steep increase in price and sales was observed 2 years postapproval for all except 2 of the drug categories-with median percent change of 245% (range: -37% to 9618%) for price and 238% (range: -4% to 6707%) for sales. Substantial variance was observed in the changes in units sold. A marked increase was seen in postapproval prices and sales for the vast majority of drug products approved in the FDA-UDI with mixed results in changes in units sold. In addition to increased information on safety, the policy's impact on postapproval drug prices and associated effects on units sold should be considered in assessing the policy, especially when substantial price increases and decreases in units sold may negatively impact health.

Off‐clamp tumor excision using soft coagulation in laparoscopic and robotic partial nephrectomy

The aim of this study was to assess the perioperative outcomes of off-clamp tumor excision using soft coagulation in laparoscopic and robotic partial nephrectomy. We retrospectively analyzed the data from 78 patients who underwent minimally invasive partial nephrectomy, using soft coagulation, at the Shiga University of Medical Science, between September 2013 and April 2017. Tumor excision and hemostasis without renal arterial clamping was performed using soft coagulation. Collecting system repair and renorrhaphy with arterial clamping were carried out only if the collecting system had been opened. Forty-three of the 78 patients underwent laparoscopic partial nephrectomy using soft coagulation and the other 35 patients underwent robotic partial nephrectomy using soft coagulation. The median estimated total blood loss was 73 (0-1140) mL and no patient needed a blood transfusion. No cases featured postoperative hemorrhagic events. Six patients with urinary fistula needed prolonged ureteral stenting. The median percentage change of the estimated glomerular filtration rate was -7.2 at one to 3 months after surgery. The off-clamp soft coagulation technique in laparoscopic partial nephrectomy and robotic partial nephrectomy is a safe and feasible approach to excise kidney tumors. This procedure may reduce the incidence of perioperative hemorrhagic complications.

Open‐label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (4 to &lt;12 years) with inadequately controlled focal seizures or generalized tonic‐clonic seizures

ObjectiveStudy 311 (NCT02849626) was a global, multicenter, open‐label, single‐arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once‐daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic‐clonic seizures [FBTCS]) or generalized tonic‐clonic seizures (GTCS).MethodsIn the 311 Core Study, a 4‐week Pre‐treatment Period (Screening/Baseline) preceded a 23‐week Treatment Period (11‐week Titration; 12‐week Maintenance) and 4‐week Follow‐up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure‐freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme‐inducing anti‐seizure drug (EIASD) use.ResultsOne hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment‐emergent AEs (TEAEs; 89%) was similar between patients with FS (with/without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs. Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure‐freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; and GTCS, 64% and 55%, respectively. Improvements in response/seizure frequency from Baseline were seen regardless of age or concomitant EIASD use.SignificanceResults from the 311 Core Study suggest that daily oral doses of adjunctive perampanel are generally safe, well tolerated, and efficacious in children age 4 to <12 years with FS (with/without FBTCS) or GTCS.

Safety and Efficacy of Lemborexant in Patients With Irregular Sleep-Wake Rhythm Disorder and Alzheimer\u2019s Disease Dementia: Results From a Phase 2 Randomized Clinical Trial

BACKGROUNDIrregular sleep-wake rhythm disorder (ISWRD) is a common sleep disorder in individuals with Alzheimer’s disease dementia (AD-D).OBJECTIVESThis exploratory phase 2 proof-of-concept and dose-finding clinical trial evaluated the effects of lemborexant compared with placebo on circadian rhythm parameters, nighttime sleep, daytime wakefulness and other clinical measures of ISWRD in individuals with ISWRD and mild to moderate AD-D.DESIGNMulticenter, randomized, double-blind, placebo-controlled, parallel-group study.SETTINGSites in the United States, Japan and the United Kingdom.PARTICIPANTSMen and women 60 to 90 years of age with documentation of diagnosis with AD-D and Mini-Mental State Exam (MMSE) score 10 to 26.INTERVENTIONSubjects were randomized to placebo or one of four lemborexant treatment arms (2.5 mg, 5 mg, 10 mg or 15 mg) once nightly at bedtime for 4 weeks.MEASUREMENTSAn actigraph was used to collect subject rest-activity data, which were used to calculate sleep-related, wake-related and circadian rhythm-related parameters. These parameters included least active 5 hours (L5), relative amplitude of the rest-activity rhythm (RA) and mean duration of sleep bouts (MDSB) during the daytime. The MMSE and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used to assess for changes in cognitive function.RESULTSSixty-two subjects were randomized and provided data for circadian, daytime and nighttime parameters (placebo, n = 12; lemborexant 2.5 mg [LEM2.5], n = 12; lemborexant 5 mg [LEM5], n = 13, lemborexant 10 mg [LEM10], n = 13 and lemborexant 15 mg [LEM15], n = 12). Mean L5 showed a decrease from baseline to week 4 for LEM2.5, LEM5 and LEM15 that was significantly greater than with placebo (all p > 0.05), suggesting a reduction in restlessness. For RA, LS mean change from baseline to week 4 versus placebo indicated greater distinction between night and day with all dose levels of lemborexant, with significant improvements seen with LEM5 and LEM15 compared with placebo (both p > 0.05). The median percentage change from baseline to week 4 in MDSB during the daytime indicated a numerical decrease in duration for LEM5, LEM10 and LEM15, which was significantly different from placebo for LEM5 and LEM15 (p > 0.01 and p = 0.002, respectively).There were no serious treatment-emergent adverse events or worsening of cognitive function, as assessed by the MMSE and ADAS-Cog. Lemborexant was well tolerated. No subjects discontinued treatment.CONCLUSIONSThis study provides preliminary evidence of the potential utility of lemborexant as a treatment to address both nighttime and daytime symptoms in patients with ISWRD and AD-D.

A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11β-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.

Interpreting Anion Gap Values in Adult and Pediatric Patients: Examining the Reference Interval.

The anion gap is primarily used in the diagnosis of acid-base disorders. We conducted a study to determine the anion gap reference interval in our patient population, investigated the workup of abnormal vs normal anion gaps, and examined the anion gap variation upon repeated testing. A retrospective review was performed on 17137 adult and pediatric patients who presented to Yale-New Haven Hospital outpatient clinics, emergency department, or intensive care units between 2012 and 2017. We derived a new reference interval of 7 to 18 mmol/L with a median of 13 mmol/L in healthy adults with no significant differences owing to partitioning by sex or age. Based on the new reference interval, 5%, 23%, and 18% of healthy, emergency department, and intensive care unit adult patients, respectively, were misclassified as having high values with the previous interval of 6 to 16 mmol/L. However, there were no significant differences in the number of tests ordered in patients with anion gaps above and below the upper limit of the previous reference interval. The majority of increased anion gaps that were repeated normalized by 12 h. In a subgroup of healthy adult patients with annual testing, the median percent change in each patient's anion gap from 2015 to 2016 was approximately 13%. The anion gap should be used with an appropriate reference interval to avoid misclassification. There may be a moderate degree of individuality that argues for comparing the anion gap with its baseline value in the same patient pending further studies that formally derive its biological variation.

Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial

More than a third of patients with epilepsy are treatment resistant, and thus new, more effective therapies to achieve seizure freedom are needed. Cenobamate (YKP3089), an investigational antiepileptic drug, has shown broad-spectrum anticonvulsant activity in preclinical studies and seizure models. We aimed to evaluate the safety, efficacy, and tolerability of adjunctive cenobamate in patients with uncontrolled focal (partial)-onset epilepsy. We did a multicentre, double-blind, randomised, placebo-controlled, dose-response study at 107 epilepsy and neurology centres in 16 countries. Adult patients (aged 18-70 years) with focal seizures despite treatment with 1-3 antiepileptic drugs were randomly assigned (1:1:1:1) via an interactive web response system, by block sizes of 4 within each country, to adjuvant once daily oral cenobamate at dose groups of 100 mg, 200 mg, or 400 mg, or placebo following an 8-week baseline assessment. Patients, investigators, and study personnel were masked to treatment assignment. The study included a 6-week titration phase and 12-week maintenance phase. The primary efficacy outcomes were percentage change in 28-day focal seizure frequency (focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizures) from baseline analysed in the modified intention-to-treat population (≥1 dose and any post-baseline seizure data) and responder rates (≥50% reduction) analysed in the maintenance phase population (≥1 dose in the maintenance phase and any maintenance phase seizure data). The primary efficacy outcomes were analysed using a hierarchal step-down procedure comparing 200 mg versus placebo, 400 mg versus placebo, then 100 mg versus placebo. Safety and tolerability were compared descriptively across treatment groups for all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01866111. Between July 31, 2013, and June 22, 2015, 437 patients were randomly assigned to either placebo (n=108) or cenobamate 100 mg (n=108), 200 mg (n=110), or 400 mg (n=111). Of these patients, 434 (106 [98%] in placebo group, 108 [100%] in 100 mg group, 109 [99%] in 200 mg group, and 111 [100%] in 400 mg group) were included in the modified intention-to-treat population, and 397 (102 [94%] in placebo group, 102 [94%] in 100 mg group, 98 [89%] in 200 mg group, and 95 [86%] in 400 mg group) were included in the modified intention-to-treat maintenance phase population. Median percentage changes in seizure frequency were -24·0% (IQR -45·0 to -7·0%) for the placebo group compared with -35·5% (-62·5 to -15·0%; p=0·0071) for the 100 mg dose group, -55·0% (-73·0 to -23·0%; p<0·0001) for the 200 mg dose group, and -55·0% (-85·0 to -28·0%; p<0·0001) for the 400 mg dose group. Responder rates during the maintenance phase were 25% (26 of 102 patients) for the placebo group compared with 40% (41 of 102; odds ratio 1·97, 95% CI 1·08-3·56; p=0·0365) for the 100 mg dose group, 56% (55 of 98; 3·74, 2·06-6·80; p<0·0001) for the 200 mg dose group, and 64% (61 of 95; 5·24, 2·84-9·67; p<0·0001) for the 400 mg dose group. Treatment-emergent adverse events occurred in 76 (70%) of 108 patients in the placebo group, 70 (65%) of 108 in the 100 mg group, 84 (76%) of 110 in the 200 mg group, and 100 (90%) of 111 in the 400 mg group. Treatment-emergent adverse events led to discontinuation in five (5%) patients in the placebo group, 11 (10%) in the 100 mg dose group, 15 (14%) in the 200 mg dose group, and 22 (20%) in the 400 mg dose group. One serious case of drug reaction with eosinophilia and systemic symptoms occurred in the 200 mg cenobamate group. No deaths were reported. Adjunctive cenobamate reduced focal (partial)-onset seizure frequency, in a dose-related fashion. Treatment-emergent adverse events were most frequent in the highest dose group. Cenobamate appears to be an effective treatment option in patients with uncontrolled focal seizures. SK Life Science.

1288. Bone Safety Outcomes with F/TAF vs. F/TDF for PrEP in the DISCOVER Trial

BackgroundIn the DISCOVER PrEP trial, emtricitabine/tenofovir alafenamide (F/TAF) was noninferior to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV prevention. Here we report the bone safety outcomes of F/TAF and F/TDF.MethodsMen who have sex with men (MSM) and transgender women (TGW) at risk of HIV were randomized 1:1 to receive blinded F/TDF or F/TAF, taken once daily. Those on PrEP with F/TDF were eligible to enroll. Bone densitometry (DXA) of the hip and spine were performed in a subset of participants (BMD subset). Fracture events were compared in all study participants. Week 48 data are presented.Results5387 participants were enrolled in the main study, with 383 included in the BMD subset. In the BMD subset, the median age was 37 (IQR 29, 46); 0.8% were TGW, 9.4% were black, and 20.6% were Hispanic or Latinx. Fifty-three BMD subset participants were on baseline F/TDF PrEP at enrollment, 26 of whom were randomized to F/TAF. F/TAF was associated with more favorable changes in hip and spine BMD compared with F/TDF (Table 1); these differences were similar when participants on baseline PrEP were excluded. Participants age <35 on F/TAF gained BMD, whereas those on F/TDF lost BMD (Table 1). BMD decreases of ≥3% were less frequent in the F/TAF group than the F/TDF group at the hip (3.8% vs. 18.4%, P < 0.001) and spine (10.1% vs. 26.9%, P < 0.001). Osteopenia was more frequently diagnosed in the spine in participants on F/TDF compared with F/TAF (Figure 1, P = 0.007); but not in the hip. Fracture event frequency was the same (53 [2.0%] per group, P = 1.00). One pathological fracture was reported in the F/TAF group compared with two in the F/TDF group (P = 0.57). In participants on baseline F/TDF PrEP, those randomized to F/TAF had significantly improved hip BMD compared with baseline (median percent change 1.13 [IQR −0.86, 3.47], P = 0.027), while spine BMD was unchanged.ConclusionThrough 48 weeks, DXA subset participants taking F/TAF for PrEP had significantly less change in BMD than those taking F/TDF, and were less likely to develop spine osteopenia. The incidence of fracture was similar, and pathological fractures were rare. F/TAF for PrEP is effective and has a superior bone safety profile compared with F/TDF. Disclosures All authors: No reported disclosures.

Clinical Prediction Models for Valvular Heart Disease.

BackgroundWhile many clinical prediction models (CPMs) exist to guide valvular heart disease treatment decisions, the relative performance of these CPMs is largely unknown. We systematically describe the CPMs available for patients with valvular heart disease with specific attention to performance in external validations.Methods and ResultsA systematic review identified 49 CPMs for patients with valvular heart disease treated with surgery (n=34), percutaneous interventions (n=12), or no intervention (n=3). There were 204 external validations of these CPMs. Only 35 (71%) CPMs have been externally validated. Sixty‐five percent (n=133) of the external validations were performed on distantly related populations. There was substantial heterogeneity in model performance and a median percentage change in discrimination of −27.1% (interquartile range, −49.4%–−5.7%). Nearly two‐thirds of validations (n=129) demonstrate at least a 10% relative decline in discrimination. Discriminatory performance of EuroSCORE II and Society of Thoracic Surgeons (2009) models (accounting for 73% of external validations) varied widely: EuroSCORE II validation c‐statistic range 0.50 to 0.95; Society of Thoracic Surgeons (2009) Models validation c‐statistic range 0.50 to 0.86. These models performed well when tested on related populations (median related validation c‐statistics: EuroSCORE II, 0.82 [0.76, 0.85]; Society of Thoracic Surgeons [2009], 0.72 [0.67, 0.79]). There remain few (n=9) external validations of transcatheter aortic valve replacement CPMs.ConclusionsMany CPMs for patients with valvular heart disease have never been externally validated and isolated external validations appear insufficient to assess the trustworthiness of predictions. For surgical valve interventions, there are existing predictive models that perform reasonably well on related populations. For transcatheter aortic valve replacement (CPMs additional external validations are needed to broadly understand the trustworthiness of predictions.

P5326Effect of evolocumab on lipoprotein(a) levels: results across 15 studies

Abstract Background/Introduction Elevated levels of lipoprotein(a) (Lp[a]) have been associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Elevated Lp(a) is relatively refractory to lifestyle change and pharmacologic intervention. Purpose To examine the effect of evolocumab on Lp(a) in a range of clinical trial populations, including hypercholesterolaemia/mixed dyslipidaemia, statin-intolerance, diabetes mellitus, and heterozygous familial hypercholesterolaemia (HeFH) at different timepoints up to 5 years. Methods Fifteen phase 2 and phase 3 double-blind and open-label extension studies, with a minimum 12 weeks duration that used approved doses of evolocumab (140 mg every 2 weeks [Q2W] or 420 mg once monthly [QM]) were included in this analysis. Studies were pooled on the basis of patient population, duration, and comparator groups (of which the MENDEL-1, -2, GAUSS-1, -2, and LAPLACE-2 atorvastatin cohort studies employed ezetimibe comparators). The effect of evolocumab on percent change from baseline in Lp(a) was examined. Results In short-term studies, evolocumab led to a median percent change in Lp(a) from baseline to week 12 of −21.2% to −33.3% overall (Table). Results were similar for both evolocumab doses with median percent change ranging from −22.0% to −38.2% for 140 mg Q2W and −20.0% to −33.3% for 420 mg QM. In long-term studies (1 to 5 years), percent change in Lp(a) ranged from −23.8% to −33.3%. Patient populations Percent change from baseline in Lp(a), median (Q1, Q3), % Ezetimibe comparator trials Placebo comparator trials Evolocumab Ezetimibe Evolocumab Placebo 12-week studies Hypercholesterolaemia/mixed dyslipidaemia (YUKAWA-1, -2, LAPLACE-TIMI-57, LAPLACE-2, MENDEL-1, -2) −22.0 (−39.4, 0.0), n=760 0.0 (−11.8, 14.6), n=387 −26.3 (−44.7, −5.0), n=1838 0.0 (−10.4, 15.4), n=1179 Statin intolerance (GAUSS-1, -2) −23.1 (−42.0, −3.3), n=223 0.0 (−16.7, 3.6), n=126 – – HeFH (RUTHERFORD-1, -2) – – −21.2 (−38.1, −7.0), n=263 0.0 (−4.2, 15.3), n=150 Type 2 diabetes (BANTING, BERSON) – – −33.3 (−55.6, −16.7), n=833 0.0 (−16.2, 16.7), n=425 Long-term studies 1-Year (DESCARTES) – – −28.4 (−49.2, −6.0), n=535 −5.5 (−20.5, 0.9), n=272 2-Year (OSLER-2)†‡ −23.8 (−44.4, 0.0), n=3077 – – – 5-Year (OSLER-1)† −33.3 (−51.3, −11.1), n=941 – – – †All patients received evolocumab in the OSLER studies. ‡OSLER-2 was a 3-year study; however, only 2-year data were available for Lp(a). Conclusion Evolocumab reduces Lp(a) in a variety of patient populations at 12 weeks with sustained lowering over 5 years. Acknowledgement/Funding Amgen Inc.

Antitumor activity of TAK-788 in NSCLC With EGFR exon 20 insertions

Abstract Background We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor. Methods Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (3.6 mo on treatment; 3.8 treatment cycles [medians]); 24 pts remain on treatment. At data cutoff, best response (by RECIST v1.1) among 26 pts with ≥1 disease assessment was PR, n = 14; SD, n = 9; and PD, n = 1; 2 pts were not evaluable. 7/14 objective responses (all PR) were confirmed, with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/26 pts achieved disease control. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Most common TEAEs (≥20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr ≥ 3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, and stomatitis (7% each). Among pts treated with 160 mg qd, median dose intensity was 93%, and the rate of treatment discontinuation due to AEs was 10.7%. There is no clear trend that response to TAK-788 is enriched in any single EGFR exon 20 insertion variant. Conclusions In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs.

Changes in cardiac Aquaporin expression during aortic valve replacement surgery with cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) use is an essential strategy for many cardiovascular surgeries. However, its use and duration have been associated with a higher rate of postoperative complications, such as low cardiac output syndrome due to myocardial oedema and dysfunction. Though Aquaporin water channels have been implicated in myocardial water balance, their specific role in this clinical scenario has not been established. In a consecutive study of 17 patients with severe aortic stenosis undergoing aortic valve replacement surgery, 2 myocardial biopsies of the left ventricle were taken: 1 before and 1 after CPB use. Sociodemographic, clinical and laboratory data were collected. Western blot and immunohistochemistry studies were performed. After CPB use, there was a mean increase of ∼62% in Aquaporin 1 protein levels (P = 0.001) and a mean reduction of ∼38% in Aquaporin 4 protein levels (P = 0.030). In immunohistochemistry assays, Aquaporin 1 was found lining small blood vessels, while Aquaporin 4 formed a circular label in cardiomyocytes. There were no changes in the localization of either protein following CPB use. During the observed on-pump time interval, there was a 1.7%/min mean increase in Aquaporin 1 (P = 0.021) and a 2.5%/min mean decrease in Aquaporin 4 (P = 0.018). Myocardial interstitial oedema increased by 42% (95% confidence interval 31-54%) after CPB use. Patients who developed low cardiac output syndrome were in the upper half of the median percentage change of Aquaporin expression. Time-dependent changes in cardiac Aquaporin expression may be associated with myocardial oedema and dysfunction related to CPB use.

Achievement of glycaemic control is associated with improvements in lipid profile with iGlarLixi versus iGlar: A post hoc analysis of the LixiLan-L trial.

Diabetic dyslipidaemia is a major risk factor for accelerated atherosclerosis. Glycaemic treatments that improve dyslipidaemia may help reduce the burden of atherosclerosis. This analysis investigated the effect of iGlarLixi [insulin glargine U100 (iGlar) and lixisenatide] versus iGlar on lipid profiles in patients with type 2 diabetes uncontrolled on basal insulin. Data from LixiLan‐L were used to estimate changes in fasting lipid levels from baseline to week 30, overall and in patients stratified by achievement of glycaemic targets {2‐hour postprandial glucose [≤10, >10 mmoL/L], fasting plasma glucose [≤6.1, >6.1 mmoL/L], HbA1c [≤7, >7% (≤53, >53 mmol/mol)]}. At week 30, median percentage change in triglycerides remained nearly unchanged (0.3% increase) with iGlarLixi versus a 6.5% increase with iGlar (P = 0.035; overall); similarly, trends towards better total and LDL cholesterol levels were observed with iGlarLixi versus iGlar. In patient subgroups achieving glycaemic targets, all lipid variables except for HDL cholesterol improved with iGlarLixi but not with iGlar. In summary, patients with type 2 diabetes uncontrolled on basal insulin showed improved fasting lipid profiles with iGlarLixi compared with iGlar, particularly when achieving glycaemic targets.

Increased expansion and decreased contraction of embryos corresponds to increased clinical pregnancy rates in single FET cycles

Objective To investigate the possible association between expansion or contraction of blastocoeles after thawing with ongoing clinical pregnancy rates in frozen embryo transfer (FET) cycles. We hypothesize a greater change in blastocele size between thaw and transfer will correspond with an increase in pregnancy rate. Design Retrospective Study Materials and Methods A total of 257 single FET cycles from November 2017 to January 2019 were included. Patient ages ranged from 24 to 48 years. Programmed FET priming was performed with exogenous estrogen and progesterone. 67 embryos that underwent PGT-A (Preimplantation-Genetic Testing for aneuploidy) and 9 donor egg cycles were included. All blastocysts were cultured in trigas incubators ranging from 20 minutes to 4 hours 42 minutes. Pictures of each blastocyst were taken utilizing the Hamilton Thorne Zilos laser software (Beverly, MA) immediately after thaw and before transfer. The longest portion of the embryo was measured in µm using the ruler tool on the laser by one of two laboratory technicians. Pregnancy was defined by a positive HCG 9 days after embryo transfer and ongoing clinical pregnancy was defined by the presence of fetal cardiac activity at 6 ½ weeks. Wilcoxon rank sum tests were used to access differences in change parameters. Results Using the two measurements and their time difference we analyzed the amount of expansion and contraction and the rate of expansion and contraction. The 186 women that had embryos that expanded between thaw and transfer were more likely to have ongoing pregnancies than those whose embryos did not expand (median expansion 27.0µm vs. 19.6µm, p=0.036). The median percent change of expansion was also significantly different between groups (p=0.028) (Table 1). Among the 70 embryos that contracted, there was a trend between more distance contracted and lower ongoing pregnancy (p=0.075) and percent change of contraction and ongoing pregnancy (p=0.058), but neither reached significant. Conclusions We found a significant increase in ongoing pregnancy rates from embryos with greater expansion rates and percent changes in expansion. We also found a trend between increased pregnancy rates and smaller amounts of embryo contraction and percent change of contraction, however, neither reached significance. According to this study, a larger degree of embryo expansion post thaw has a better chance of ongoing pregnancy. Additional studies are needed to determine if smaller degrees of contraction is suggestive of ongoing pregnancy outcome. Disclosures None. Funding None.

Pharmacokinetics of vaginal progesterone in pregnancy

Characterization of pharmacokinetics is lacking for vaginal progesterone in pregnancy. Dosing of vaginal progesterone for preterm birth prevention has been empirical. Owing to pregnancy-related changes in vaginal and uterine blood flow, hepatic metabolism, renal clearance, and endogenously elevated serum progesterone, studies outside of pregnancy may not be applicable. The lack of the pharmacokinetics profile of vaginally administered progesterone in pregnancy limits the ability to define the exposure-response relationship needed to optimize dosing, which has implications for its use in research and clinical care regarding management of short cervix, prevention of recurrent preterm birth, and prevention of recurrent miscarriage. This was a study to establish the feasibility of using serum progesterone to establish basic pharmacokinetic parameters of vaginal progesterone in pregnancy for preterm birth prevention. This is a prospective study of 6 low-risk singletons at 18 0/7 to 23 6/7 weeks' gestation with body mass index 20-40. Exclusion criteria were current vaginitis, abnormal Pap smear, prescription medication use, cervical length ≤25 mm, prior preterm birth, and contraindication to progesterone. Participants received a single dose of 200 mg micronized vaginal progesterone and serum progesterone levels were evaluated every 2 hours from 0 to 12 hours and then 24 hours postdose. Primary outcome was concentration/time profile of serum progesterone. Median (range) maternal age was 27 (21.5-33.3) years, median body mass index was 26.5 (23.3-29.0) kg/m2, and median gestational age was 22.9 (21.0-23.4) weeks. Median baseline serum progesterone was 47 (40-52) ng/mL, median peak concentration was 54 (48-68) ng/mL, and median time to peak was 12 (4-15) hours. There was a trend in rising serum progesterone over baseline with a median change in peak concentration of 11 ng/mL and interquartile range of 2-22. Median percent change from baseline was an increase by 24% (interquartile range, 4%-53%). However, there was no clear elimination phase and the median area under the curve was 112 ng*h/mL with an interquartile range of -43 to239. Unlike in nonpregnant individuals, administration of vaginal progesterone in pregnant individuals only minimally impacts systemic exposure. There is a limited trend of rising serum progesterone over baseline levels, with significant inter-individual variability. Serum progesterone is unlikely to be a good candidate for establishing pharmacokinetics or dosing of vaginal progesterone in pregnancy for preterm birth prevention.

Liquid buccal mucosa graft endoscopic urethroplasty: a validation animal study.

To validate a novel method of urethral stricture treatment using liquid buccal mucosal grafts (LBMG) to augment direct vision internal urethrotomy (DVIU) in an animal model. A rabbit stricture model was used to test this method. Strictures were induced in 26 rabbits using electroresection of urethral epithelium. The animals were randomized into two groups: Group-1, treated with DVIU and LBMG in fibrin glue, and Group-2, DVIU with fibrin glue only. LBMG was prepared by suspension of mechanically minced buccal mucosa micrografts in fibrin glue. This LBMG-fibrin glue mixture was later injected into the urethrotomies of Group-1 animals. All animals were killed at 24weeks after repeat retrograde urethrogram (RUG) and urethroscopy by surgeon blinded to the treatment arm. Radiographic images and histological specimens were reviewed by a radiologist and a pathologist, respectively, blinded to the treatment arm. Stricture treatment was considered a success if a diameter measured on RUG increased by ≥ 50% compared to pre-treatment RUG diameter. Histological specimens were assessed for the presence of BMG engraftment. In Group-1, 8/12(67%) animals demonstrated engraftment of LBMG, compared to none in Group-2 (p = 0.0005). 7/12(58%) in Group-1 showed radiographic resolution/improvement of strictures compared to 5/13 Group-2 rabbits (38%, p = 0.145). The median percent change for the Group-1 was 59%, compared to 41.6% for Group-2 (p = 0.29). This proof-of-concept study demonstrates feasibility of LBMG for endoscopic urethral stricture repairs. Further studies are needed to establish the role of this novel concept in treatment of urethral strictures.

The PRINTO evidence-based proposal for glucocorticoids tapering/discontinuation in new onset juvenile dermatomyositis patients

BackgroundPrednisone (PDN) in juvenile dermatomyositis (JDM), alone or in association with other immunosuppressive drugs, namely methotrexate (MTX) and cyclosporine (CSA), represents the first-line treatment option for new onset JDM patients. No clear evidence based guidelines are actually available to standardize the tapering and discontinuation of glucocorticoids (GC) in JDM. Aim of our study was to provide an evidence-based proposal for GC tapering/discontinuation in new onset juvenile dermatomyositis (JDM), and to identify predictors of clinical remission and GC discontinuation.MethodsNew onset JDM children were randomized to receive either PDN alone or in combination with methotrexate (MTX) or cyclosporine (CSA). In order to derive steroid tapering indications, PRINTO/ACR/EULAR JDM core set measures (CSM) and their median absolute and relative percent changes over time were compared in 3 groups. Group 1 included those in clinical remission who discontinued PDN, with no major therapeutic changes (MTC) (reference group) and was compared with those who did not achieve clinical remission, without or with MTC (Group 2 and 3, respectively). A logistic regression model identified predictors of clinical remission with PDN discontinuation.ResultsBased on the median change in the CSM of 30/139 children in Group 1, after 3 pulses of methyl-prednisolone, GC could be tapered from 2 to 1 mg/kg/day in the first two months from onset if any of the CSM decreased by 50–94%, and from 1 to 0.2 mg/kg/day in the following 4 months if any CSM further decreased by 8–68%, followed by discontinuation in the ensuing 18 months. The achievement of PRINTO JDM 50–70-90 response after 2 months of treatment (ORs range 4.5–6.9), an age at onset > 9 years (OR 4.6) and the combination therapy PDN + MTX (OR 3.6) increase the probability of achieving clinical remission (p < 0.05).ConclusionsThis is the first evidence-based proposal for glucocorticoid tapering/discontinuation based on the change in JDM CSM of disease activity.Trial registrationTrial full title: Five-Year Single-Blind, Phase III Effectiveness Randomized Actively Controlled Clinical Trial in New Onset Juvenile Dermatomyositis: Prednisone versus Prednisone plus Cyclosporine A versus Prednisone plus Methotrexate. EUDRACT registration number: 2005–003956-37. Clinical Trial.gov is NCT00323960. Registered on 17 August 2005.

Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.

9007 Background: TAK-788 is an oral investigational EGFR/HER2 inhibitor under evaluation in NSCLC patients (pts) with EGFR exon 20 insertions. We report results of a phase 1/2 open-label, multicenter study (NCT02716116). Methods: Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results: As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (median 3.6 mo on treatment; median 3.8 treatment cycles); 24 pts remain on treatment. Antitumor activity in pts with EGFR exon 20 insertions is shown in Table. At data cutoff, 7/14 responses were confirmed with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Rate of treatment discontinuation due to AEs was 10.7% in pts treated at 160 mg. Most common TEAEs (≥20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr ≥3 TEAEs (≥5%) were diarrhea (26%) and hypokalemia, nausea, and stomatitis (7% each). Median dose intensity for pts treated with 160 mg qd was 93%. There is no clear trend that response to TAK-788 is enriched in particular EGFR exon 20 insertion variants. Conclusions: In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs. Clinical trial information: NCT02716116. [Table: see text]

Testosterone Levels and Sexual Quality of Life After Stereotactic Body Radiation Therapy for Prostate Cancer: A Multi-Institutional Analysis of Prospective Trials

The impact of higher scatter doses per fraction on testicular function and quality of life after prostate stereotactic body radiation therapy (SBRT) is poorly studied. Six hundred thirty-six patients treated with SBRT for low- to intermediate-risk prostate cancer from 2009 to 2014 were included. Changes in testosterone and in sexual and hormonal domain scores on the Expanded Prostate Cancer Index Composite-26 (EPIC) questionnaire over a 24-month period were evaluated via a 1-sided t test. EPIC score changes were evaluated in comparison with a distribution-based minimal clinically important difference threshold, wherein changes of greater than one half or greater than one third of the standard deviation in each domain were considered as medium-sized or small-sized effects, respectively. Median and mean percent changes in testosterone at the 3- to 6-month, 7- to 12-month, 13- to 18-month, and 19- to 24-month time periods were -13.41% and -4.49% (P = .02); -12.23% and -2.77% (P = .13); -11.20% and -0.29% (P = .47); -5.00% and + 1.20% (P = .65). When analyzed after dividing the cohort into 3 groups based on baseline testosterone values using tertiles, testosterone tended to increase in patients in the first group and decrease in patients in the third group. Overall, the decline in EPIC hormonal domain scores never exceeded the threshold for a small-sized effect, though the decline in EPIC sexual domain scores did pass this threshold at the 19- to 24-month time period (mean 10.90 point decline). This decline was not present when groups were examined individually. In this large cohort of prospectively followed patients, there was a transient decline in testosterone shortly after SBRT that normalized by 24 months posttreatment. There was no significant change in EPIC hormonal domain scores. A significant decline in EPIC sexual domain scores, consistent with a small-sized clinically detectable difference, manifested between 19 and 24 months of follow-up. These results are consistent with testosterone decline patterns and sexual function changes seen after other forms of photon-based radiation therapy.