AE Rates Research Articles

Efficacy and safety of traditional Chinese medicine for the treatment of epilepsy: a meta-analysis of randomized controlled trials

Objective: To evaluate the efficacy and safety of traditional Chinese medicine (TCM) in the treatment of epilepsy. Methods: A comprehensive search of database in both Chinese and English was performed. Data from the selected studies was extracted and analyzed independently by two authors. Results: Twenty-two randomized controlled trials were included in the meta-analysis with a total of 1773 patients. Among them, three trials (n=166) focused on TCM monotherapy, while the other 19 trials (n=1607) assessed the benefit of TCM add-on therapy to antiepileptic drugs (AEDs). For the efficacy, meta-analysis found (1) TCM monotherapy had a higher effective rate compared with AEDs (OR=6.007, 95%CI: 2.570-14.037, Z=6.007, P<0.001); (2) the add-on of TCM increased the effective rate (OR=3.123, 95%CI: 2.356, 4.140), Z=7.916, P<0.001). In terms of safety, the add-on of TCM reduced the rate of total AEs (OR = 0.407, 95%CI: 0.274-0.605, P <0.0001) as well as AEs regarding the gastrointestinal and nervous system. Nineteen different TCM prescription was used in these RTCs. Among them, the five most frequently used herbs were Acorus tatarinowii (14 out of 19), Wolfiporia Cocos (10 out of 19), Pinellia Ternata (9 out of 19), Licorice Root (9 out of 19) and Rhizoma Gastrodiae (8 out of 19). Conclusion: TCM is an efficacy and safety strategy for the mono- or add-on treatment of epilepsy. However, as the small sample size, the diversified composition of TCM prescriptions, and the low quality of study design, further studies remain needed.

Semi-field life-table studies of Aedes albopictus (Diptera: Culicidae) in Guangzhou, China.

Aedes albopictus is a major vector for several tropical infectious diseases. Characterization of Ae. albopictus development under natural conditions is crucial for monitoring vector population expansion, dengue virus transmission, and disease outbreak preparedness. This study employed mosquito traits as a proxy to understanding life-table traits in mosquitoes using a semi-field study. Ae. albopictus larval and adult life-table experiments were conducted using microcosms under semi-field conditions in Guangzhou. Stage-specific development times and survivorship rates were determined and compared under semi-field conditions in different seasons from early summer (June) to winter (January), to determine the lower temperature limit for larval development and adult survivorship and reproductivity. The average egg- hatching rate was 60.1%, with the highest recorded in October (77.1%; mid-autumn). The larval development time was on average 13.2 days (range, 8.5-24.1 days), with the shortest time observed in September(8.7 days; early autumn) and longest in November (22.8 days). The pupation rates of Ae. albopictus larvae were on average 88.9% (range, 81.6-93.4%); they were stable from June to September but decreased from October to November. The adult emergence rates were on average 82.5% (range, 76.8-87.9%) and decreased from July to November. The median survival time of Ae. albopictus adults was on average 7.4 (range, 4.5-9.8), with the shortest time recorded in September. The average lifetime egg mass under semi-field conditions was 37.84 eggs/female. The larvae could develop into adults at temperatures as low as 12.3°C, and the adults could survive for 30.0 days at 16.3°C and still produce eggs. Overall, correlation analysis found that mean temperature and relative humidity were variables significantly affecting larval development and adult survivorship. Ae. albopictus larvae could develop and emerge and the adults could survive and produce eggs in early winter in Guangzhou. The major impact of changes in ambient temperature, relative humidity, and light intensity was on the egg hatching rates, adult survival time, and egg mass production, rather than on pupation or adult emergence rates.

Pooled analysis of bleeding profile, efficacy and safety of oral oestradiol valerate/dienogest in women aged 25 and under

Purpose: To evaluate differences in key outcomes between younger and older women receiving the oral contraceptive oestradiol valerate/dienogest (E2V/DNG).Methods: We conducted a pooled post hoc analysis of primary data from 12 studies of E2V/DNG, stratified by age (≤25 [n = 1309] and >25 [n = 2132] years). Outcomes included safety, efficacy, bleeding profile and hormone-withdrawal-associated symptoms (HWAS). Bleeding and HWAS analyses are also presented for women aged ≤20 years (n = 362). Discontinuations were considered a proxy for patient satisfaction.Results: Results were generally similar for younger and older women. The percentage of women aged ≤25 and >25 years experiencing intracyclic bleeding did not differ between groups (13.4% and 12.8% at cycle 12, respectively), with similar results in women aged ≤20 years (12.7%, cycle 12). Rates of withdrawal bleeding were very similar in women aged ≤25 and >25 years (78.5% and 78.9%, respectively, cycle 12). We also found a similar adjusted Pearl index in the two age groups (0.45 vs 0.57, respectively), similar rates of AEs and HWAS and no difference in discontinuations.Conclusions: Women aged ≤25 and >25 years have a similar experience with an E2V/DNV oral contraceptive, supporting this as an appropriate contraceptive option in younger and older women.

Abstract GS6-01: Oral paclitaxel with encequidar: The first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: A phase III clinical study in metastatic breast cancer

Abstract Intravenous paclitaxel (IV Pac) is an efficacious chemotherapeutic agent against multiple cancers including metastatic breast cancer (mBC). We hypothesized that the high peak concentration with IV Pac may be responsible for peripheral neuropathy. We have developed an orally administered Pac made bioavailable through the combination with the minimally absorbed P-glycoprotein pump inhibitor encequidar (Pac+E). The pharmacokinetic exposure (AUC) matches that of IV Pac 80 mg/m2 with peak concentrations that are approximately 1/10 of IV Pac.Objective: To determine the efficacy and safety profile of oral Pac+E vs IV Pac in patients with mBC.Patients/Methods: This is a pivotal, Phase 3, open-label, randomized study of oral 205mg/m2 Pac+E for 3 days/week vs IV Pac at the labeled dose of 175mg/m2 q3weeks (NCT02594371). Subjects were randomized 2:1 to Pac+E vs IV Pac. The primary endpoint is radiologically confirmed tumor response rate (CR and PR) at two consecutive timepoints, 3-6 weeks apart, by study Day 160 using RECIST v1.1 criteria, as assessed by the blinded, independent central radiology company (Intrinsic Imaging). Progression-free survival (PFS) and overall survival (OS) were secondary endpoints.Results: A total of 402 mBC patients were enrolled (Pac+E 265 vs IV Pac 137); demographics were balanced. A similar percentage of subjects in each treatment group received prior taxane therapy (Pac+E, 28%; IV Pac, 31%). For the ITT population, final analysis of the primary endpoint of confirmed tumor response demonstrated a statistically significant difference between treatments; Pac+E 35.8% vs IV Pac 23.4%, a difference of 12.4%, p=0.011, favoring Pac+E. For the protocol defined mITT population (baseline evaluable scans and received at least 75% of the first cycle of dosing) the confirmed response rates were 40.4% for Pac+E vs 25.6% for IV Pac (p=0.005). For the population with evaluable post-baseline scan, the confirmed response rates were 50.3% for Pac+E vs 29.6% for IV Pac (p=0.0005). Tumor response in all clinically important subgroups was consistent with the overall confirmed response profiles. Responses were durable. Ongoing analysis of duration of confirmed response showed the median durations were39.0 weeks for Pac+E vs 30.1 weeks for IV Pac. Ongoing analysis of OS in the prespecified mITT population favors Pac+E (p=0.035) with a median of 27.9 months vs 16.9 months for Pac+E and IV Pac, respectively. Ongoing analysis of PFS in the prespecified mITT population shows a strong trend favoring Pac+E (p=0.077) with a median of 9.3 months vs 8.3 months. The Pac+E group had a lower incidence of alopecia and a lower incidence and severity of neuropathic AEs compared to IV Pac (17% versus 57% respectively to Week 23), with Grade 3 neuropathic symptoms observed in 1% for Pac+E vs 8% for IV Pac. The toxicity profile of Pac+E was generally similar to IV Pac. However higher rates of neutropenia, infection and gastrointestinal AEs were observed in Pac+E group. The risk of serious AEs on both treatments was highest among subjects with pre-treatment evidence of hepatic impairment and the protocol was amended to address this issue. Conclusion: Oral paclitaxel + encequidar is the first orally administered paclitaxel shown to be superior to IV paclitaxel for confirmed response, progression-free survival, and overall survival, with minimal clinically meaningful neuropathy. Citation Format: Gerardo Umanzor, David L Cutler, Francisco J Barrios, Rosa H Vassallo, Marco A Chivalan, Suyapa A Bejarano, Julio R Ramirez, Luis Fein, E Douglas Kramer, Rubio D Kowalyszyn, Hui Wang, John Goldfinch, Taryn Moore, Rudolf MF Kwan. Oral paclitaxel with encequidar: The first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: A phase III clinical study in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS6-01.

Abstract P1-19-17: Dose escalation and expansion study of lerociclib (G1T38), an oral CDK4/6 inhibitor, dosed with no drug holiday in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer

Abstract Approved CDK4/6 inhibitors have demonstrated significant improvements in progression free survival when combined with fulvestrant in patients with HR+/HER2- advanced breast cancer, though limited by neutropenia and gastrointestinal side effects. Lerociclib is a potent selective CDK4/6 inhibitor with a differentiated PK/PD profile from currently approved CDK4/6 inhibitors that has demonstrated clinical proof-of-concept (Phase 1b data ASCO 2018). This Phase 1b/2a study assesses lerociclib dose escalation in combination with 500 mg fulvestrant using a 3+3 design followed by dose expansion in patients with metastatic or locally advanced HR+/HER2- breast cancer that had progressed following endocrine therapy. Up to two prior chemotherapies in Phase 1b and one prior in Phase 2a in the advanced setting are allowed. Prior fulvestrant was excluded for all patients; prior CDK4/6 inhibitors were excluded in Phase 2a only. Lerociclib is administered daily without a drug holiday. The objectives are to evaluate DLTs, safety, tolerability, PK, and tumor response and to determine the recommended dose and schedule (QD or BID) of lerociclib administered with fulvestrant for randomized trials. The BID dosing regimen demonstrated optimal safety, tolerability, and antitumor activity. To date, 35 patients (6 patients @ 100 mg BID, 9 patients @ 150 mg BID, 17 patients @ 200 mg BID, and 3 patients @ 250 mg BID) with mean age of 54 years, ECOG of 0 (86%) or 1 (14%), and a median of two prior anticancer therapies in the advanced setting have received lerociclib + fulvestrant for up to 804 days. A dose proportional increase in drug exposure has been observed. The most common lerociclib-related adverse events were neutropenia (63%), leukopenia (57%), nausea (37%), anemia (29%), diarrhea (20%), and thrombocytopenia (20%). The rates of lerociclib-related Grade 3 and Grade 4 neutropenia were 29% and 9%, respectively. Following an initial decline, ANC plateaued beginning at week 4. There were no reports of Grade 3 or greater nausea, vomiting, or diarrhea. One DLT of dose interruption due to Grade 2 fatigue and nausea was observed at 200 mg BID. There have been no reports of venous thromboembolism, QT prolongation or drug-induced liver injury. Twenty patients were evaluable for tumor response based on RECIST v1.1. Five patients (25%) had a confirmed PR; 8 patients (40 %) had stable disease; 6 patients (30 %) had PD. The CBR (CR + PR + SD ≥ 24 weeks) was 67% (12 of 18 patients either had SD at the week 24 tumor assessments or achieved an objective response). A population PK/PD/efficacy model was developed, and simulation data are concordant with existing clinical results. Additional patients are being enrolled at 150 mg BID and 200 mg BID, and updated data will be presented. Lerociclib, dosed BID with no drug holiday, has a favorable safety profile with low rates of gastrointestinal AEs and Grade 3/4 neutropenia, as well as encouraging antitumor activity in patients with HR+/HER2- advanced breast cancer. Phase 2b is ongoing to confirm the BID dose (150 mg or 200 mg) for randomized clinical trials. Clinical trial information: NCT02983071. Citation Format: Iurie Bulat, Marina Maglakelidze, Carmen Murias, Boris Krastev, Richard D Baird, Andrew M Wardley, Rebecca Roylance, Adrian Crijanovschi, Maia Gogiladze, Yili Pritchett, Amy McCullough, Chao Li, Jessica A Sorrentino, Rajesh Malik, Andrew P Beelen. Dose escalation and expansion study of lerociclib (G1T38), an oral CDK4/6 inhibitor, dosed with no drug holiday in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-17.

Quantification of dose dependence and frequency of checkpoint inhibitor immune-mediated adverse events: A Bayesian model-based meta-analysis.

83 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse events (imAEs). The objective of this study was to use a Bayesian model-based meta-analysis to quantify dose dependence and compare imAE frequencies for PD-1, PD-L1 and CTLA-4 inhibitor monotherapies and their combinations. Methods: We searched PubMed, TrialTrove, ASCO and ESMO databases and retrieved relevant ICI safety data. In order to quantitatively compare safety across doses and drugs against a given target, we converted the various dose regimens used into drug exposures derived from pharmacokinetic models; we also normalized exposures by the corresponding drug potency. We performed a Bayesian meta-analysis for Grades 3&4 of treatment related (trAE) and immune-mediated (imAE) adverse events. Results: A total of 149 articles were identified, covering 35,559 patients in 197 dosing cohorts treated with ICI therapies. For PD-1 and PD-L1 inhibitor monotherapies, no dose dependence of AEs was found; Grades 3&4 trAE rates for anti PD-L1 vs. anti PD-1 were, respectively, 12% and 15%. The AE rates for the different ICI drugs and organ classes were estimated. Dose dependence was found for anti CTLA-4 monotherapies, for total trAEs of Grades 3/4, gastrointestinal and hepatic imAEs. Dose dependence was found and quantified for anti CTLA-4 in combination with anti PD-1 with respect to total trAEs of Grades 3/4 trAEs and imAEs per gastrointestinal and hepatic organ groups. We found that combination of anti PD-L1 agents with anti CTLA-4 exhibited lower AE rates, as compared to anti PD-1 combined with anti CTLA-4. Conclusions: We introduced a novel meta-analysis methodology and used it to quantify and compare AE rates across ICI agents. Significant AE rate dose dependencies were observed for CTLA-4 inhibitors, either as monotherapy or used in combinations. Patients naive to anti-cancer therapies exhibited higher AE rates vs. previously treated patients. AE rates for CTLA-4 + PD-1 inhibitor combination regimens were supra-additive vs. the respective monotherapies. AE rates for anti PD-L1 agents were lower vs. anti PD-1, both in monotherapy and combinations with CTLA-4.

Antidepressant-placebo differences for specific adverse events in major depressive disorder: A systematic review

BackgroundAdverse events (AEs) are known to occur while patients are treated with placebos, part of the so-called nocebo effect. Yet evidence is limited regarding the likelihood that specific AEs occurring with antidepressant treatment are or are not due to nocebo effects. MethodsThis study identified 56 placebo-controlled, randomized controlled trials (RCTs) of antidepressant monotherapy for adults with major depressive disorder that reported AE rates in sufficient detail for comparison. Poisson regression analyses compared rates of AEs according to antidepressant class weighted by study population to determine which separated from placebo. A “nocebo index” was also calculated (with 0 defined as the lowest rate and 1 or higher indicating the same or greater rate of an AE in the placebo group). ResultsNumerous AEs did not differ statistically between antidepressant classes and placebo including worsening psychiatric symptoms, all forms of pain, weight gain and respiratory symptoms. Nevertheless, a number of AEs were significantly more common in antidepressants than placebos across multiple antidepressant classes. These were predominantly neurological, sexual and anticholinergic effects. Several AEs that separated statistically between antidepressants and placebos nevertheless had moderate nocebo indices (≥0.5). For example, dizziness in SSRIs separated significantly from placebo (OR 1.50, 95%CI 1.13–1.99) but had a nocebo index of 0.67. LimitationsThis study relied on multiple RCTs with subtle design differences. ConclusionsThis study identified several AEs that are likely the physiological result of antidepressants and many that likely represent nocebo effects. These results should inform clinical decision making and discussions with patients.

Endoscopic papillectomy for neoplastic ampullary lesions: A systematic review with pooled analysis.

Endoscopic papillectomy (EP) is a viable therapy in ampullary lesions (AL). Many series have reported low morbidity and acceptable outcomes. We performed a systematic review with pooled analysis to assess the safety and efficacy of EP for AL. Electronic databases (Medline, Scopus and EMBASE) were searched up to September 2018. Studies that included patients with endoscopically resected AL were eligible. The rate of adverse events (AEs; primary outcome) and the rates of both technical and clinical efficacy outcomes were pooled by means of a random- or fixed-effects model to obtain a proportion with a 95% confidence interval (CI). Twenty-nine studies were included (1751 patients). The overall AE rate was 24.9%. The post-procedural pancreatitis rate was 11.9%, with the only factor affecting this outcome being prophylactic pancreatic stenting. The complete resection rate was 94.2%, with a rate of oncologically curative resection of 87.1%. The recurrence rate was 11.8% (follow-up: 9.6-84.5 months). EP is a relatively safe and effective option for AL. Our study might definitively suggest the protective role of prophylactic pancreatic stenting against post-procedural pancreatitis.

Long-term safety and efficacy studies of epinephrine HFA metered-dose inhaler (Primatene® Mist): a two-stage randomized controlled trial

Objective: A new epinephrine hydrofluoroalkane (HFA) asthma metered-dose inhaler (MDI) was reformulated to replace the previously marketed epinephrine chlorofluorocarbon (CFC) MDI. In addition to the HFA propellant change, several enhanced modifications (i.e. changed from solution to suspension, 43% dose reduction, etc.) were made to the formulation of epinephrine HFA MDI. This study evaluates the 6-month long-term safety and efficacy profile of the new epinephrine HFA MDI.Method: The long-term safety study consists of two 3-month, multi-center, double- or evaluator-blinded, parallel-group, placebo, and active controlled stages. In each stage, subjects aged ≥12 years with intermittent or mild-to-moderate persistent asthma were randomized to receive epinephrine HFA (2 × 125 mcg/inhalation), placebo HFA, or epinephrine CFC (2 × 220 mcg/inhalation). Bronchodilator efficacy was assessed in Stage 1 and was determined primarily by the change in the forced expiratory volume in 1 s (ΔFEV1) at Week 12, relative to the same day baseline.Results: The primary efficacy endpoint (AUC0-6hrs of %ΔFEV1 at Week 12) for epinephrine HFA (47.3 ± 54.2) closely paralleled those for the active control, epinephrine CFC (41.0 ± 43.4). Both groups were found to be overall comparable in bronchodilator efficacy. Both also showed low incidence rates of AEs with tremor being most commonly reported for epinephrine HFA. All AEs found were non-serious and non-significant. The observed changes in vital signs, ECG, serum glucose, and potassium were minimal and not clinically relevant.Conclusion: This study demonstrated that the new epinephrine HFA is overall comparable, in both safety and efficacy, to the previous epinephrine CFC.

Genetic Signatures of Acute Asthma Exacerbation Related With Ineffective Response to Corticosteroid.

PurposeAcute exacerbation (AE) is an important domain of asthma management and may be related with ineffective response to corticosteroid. This study aimed to find mechanisms of AE using genome-wide gene expression profiles of blood cells from asthmatics and its perturbation by in vitro dexamethasone (Dex)-treatment.MethodsWe utilized lymphoblastoid B cells from 107 childhood asthmatics and peripheral blood mononuclear cells from 29 adult asthmatics who were treated with inhaled corticosteroids. We searched for a preserved co-expression gene module significantly associated with the AE rate in both cohorts and measured expression changes of genes belong to this module after Dex-treatment.ResultsWe identified a preserved module composed of 77 genes. Among them, expressions of 2 genes (EIF2AK2 and NOL11) decreased significantly after Dex-treatment in both cohorts. EIF2AK2, a key gene acting antiviral defense mechanism, showed significantly higher expressions in asthmatics with AE. The protein repair pathway was enriched significantly in 64 genes which belong to the preserved module but showed no expression differences after Dex-treatment in both cohorts. Among them, MSRA and MSRB2 may play key roles by controlling oxidative stress.ConclusionsMany genes belong to the AE rate-associated and preserved module identified in blood cells from childhood and adults asthmatics showed no expression changes after in vitro Dex-treatment. These findings suggest that we may need alternative treatment options to corticosteroids to prevent AE. EIF2AK2, MSRA and MSRB2 expressions on blood cells may help us select AE-susceptible asthmatics and adjust treatments to prevent AE.

Increased temperatures reduce the vectorial capacity of Aedes mosquitoes for Zika virus

ABSTRACT Rapid and significant range expansion of both Zika virus (ZIKV) and its Aedes vector species has resulted in ZIKV being declared a global health threat. Mean temperatures are projected to increase globally, likely resulting in alterations of the transmission potential of mosquito-borne pathogens. To understand the effect of diurnal temperature range on the vectorial capacity of Ae. aegypti and Ae. albopictus for ZIKV, longevity, blood-feeding and vector competence were assessed at two temperature regimes following feeding on infectious blood meals. Higher temperatures resulted in decreased longevity of Ae. aegypti [Log-rank test, χ2, df 35.66, 5, P < 0.001] and a decrease in blood-feeding rates of Ae. albopictus [Fisher's exact test, P < 0.001]. Temperature had a population and species-specific impact on ZIKV infection rates. Overall, Ae. albopictus reared at the lowest temperature regime demonstrated the highest vectorial capacity (0.53) and the highest transmission efficiency (57%). Increased temperature decreased vectorial capacity across groups yet more significant effects were measured with Ae. aegypti relative to Ae. albopictus. The results of this study suggest that future increases in temperature in the Americas could significantly impact vector competence, blood-feeding and longevity, and potentially decrease the overall vectorial capacity of Aedes mosquitoes in the Americas.

Aedes aegypti vector resistance status on malation and activity of non specific esteration enzymes in Tembalang district, Semarang city

Background: Controlling of dengue vectors around dengue haemorrhagic fever cases is often conducted by using insecticides, including a malathion insecticide in the city of Semarang. A research on susceptibility status of Ae. aegypti to insecticides, used for fogging and based on a high number of hemorrhagic fever cases in Tembalang district, Semarang city, needs to be observed. Objective: This study aimed to determine resistance status of Ae. aegypti mosquitoes based on bioassay and biochemical tests of esterase non-specific enzyme activity in the Tembalang District. Methods: This study used a cross sectional design, it was conducted in June-September 2018 in a population of Aedes sp. from Tembalang District, Semarang City. Samples of F2 generations of female Ae. aegypti were obtained by ovitraps in the Tembalang District consisting of 12 urban villages, and their resistance status were tested by impregnated paper bioassay with malathion at a diagnostic dose of 0.8%. Esterase enzyme activity in the Ae. aegypti mosquito body of this population was tested biochemically to prove an increase in a non-specific esterase enzyme on the a-naphthyl acetate substrate. Results: The bioassay results showed that mortality rates of Ae. aegypti at the 12 villages in Tembalang district after 24 hourtest by impregnated paper indicated a range of 0-62%. Mechanism of resistance indicating an increase of non-specific enzyme esterase activity on a-naphthyl acetate at Rowosari, Kedungmundu, Sambiroto, and Meteseh could not be seen, It began to be seen in a low percentage (15%) at Sendang Mulyo, Tandang, Sendangguwo and Bubusan, and in a moderate percentage (45-75%) in Tembalang, Jangli and Mangunharjo. The mechanism of high esterase enzyme activity could be seen in the Ae. aegypti population at Kramas with AV=0,700-0,900 by a percentage of 20%, and AV=0,900 by a percentage of 80%. Conclusion: This study provided information about some Ae. aegypti mosquitoes from Tembalang District that showed resistance to the malathion insecticide with an elevation of non-specific esterase enzyme activity ona-naphthyl acetate substrate in several villages except Kelurahan Rowosari, Kedungmundu, Sambiroto, and Meteseh.

Volume change in amygdala enlargement as a prognostic factor in patients with temporal lobe epilepsy: A longitudinal study

Considering the clinical heterogeneity of temporal lobe epilepsy with amygdala enlargement (TLE-AE), identifying distinct prognostic subgroups of TLE-AE has clinical implications. Until now, baseline volume of the enlarged amygdala (EAV) has consistently failed to predict prognosis in TLE-AE. Based on studies suggesting that patients responsive to antiepileptic drugs (AEDs) exhibit remission of AE on follow-up imaging, we investigated whether reduction rate of EAV is predictive of long-term prognosis in TLE-AE. Sixty-one consecutive patients with two separate magnetic resonance imaging (MRI) scans were enrolled. To utilize longitudinally measured biomarkers in prediction, the period beyond the first MRI acquisition was split into two periods: the "observation window" (period between the two MRIs) and "prediction window" (follow-up period beyond the second MRI). Patients were classified according to their AED responsiveness during the observation window, and AED-responsive patients were further subdivided by initial seizure frequency: (a) AED-responsive patients presenting with low-frequency seizures (<5 seizures/3mo; Group A, n=25), (b) high-frequency seizures (≥5 seizures/3mo; Group B, n=23), and (c) patients with poor initial treatment response (Group C, n=13). Multivariate logistic regression models were constructed for identification of prognostic factors. Along with factors obtained at baseline, factors derived from the observation window (annual percentage change of EAV [APCEAV] and initial AED responsiveness) were also considered as potential predictors. Favorable initial treatment response and faster volume reduction rate (APCEAV ≤ -5.0%/y) were identified as factors predictive of achieving overall seizure freedom. Among the AED-responsive patients, Group A (low-frequency seizures) showed slower remission of AE and higher rate of seizure recurrence, whereas Group B (high-frequency seizures) exhibited faster remission of AE and lower rate of seizure recurrence. Faster recuperation of AE in patients with initial high-frequency seizures may be indicative of seizure-induced changes. As volume reduction rate serves as a prognostic marker in TLE-AE, short-term MRI follow-up may be useful in prognostication.

The Efficacy and Safety of Epicutaneous Immunotherapy for Allergic Diseases: A Systematic Review and Meta-Analysis

Objectives: To systematically review the effect and safety of epicutaneous immunotherapy (EPIT) for allergic diseases. Methods: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, CQ VIP Database, Wanfang Data, and international trial register from their inception to July 29, 2019, without language restrictions, for randomized controlled trials (RCTs) that compared EPIT versus no EPIT for allergen-triggered allergic reactions. We assessed certainty of evidence by the GRADE approach. Results: Ten RCTs with 1,085 participants (aged from 10 months to 65 years) comparing EPIT with placebo for peanut, cow milk, or grass-pollen allergy met the eligibility criteria. A substantial benefit in terms of desensitization in EPIT group was more likely for peanut or cow milk protein allergy (risk ratio [RR] 2.34, 95% CI 1.69–3.23; I² = 0%; high certainty evidence). EPIT increased local-treatment-related adverse events (L-TRAE; RR 1.56, 95% CI 1.03–2.36; I² = 82%; moderate certainty evidence). But there were no significantly increased risk of any TRAEs (low certainty evidence) or systemic-TRAEs (S-TRAEs; very low certainty evidence) in EPIT group. The incidence rate of serious AEs, the use of rescue medications, and anaphylactic reactions stratified by organ systems including skin and mucosa, eyes and upper respiratory, lower respiratory, and gastrointestinal system in EPIT group were similar to placebo group. In subgroup analysis, desensitization of EPIT was significantly effective in peanut allergy (RR 2.29, 95% CI 1.64–3.21; I² = 0%) and children <12 years (RR 2.85, 95% CI 1.92–4.24; I² = 0%) with high certainty evidence. Only epicutaneous grass-pollen immunotherapy significantly increased the risk of S-TRAE (RR 4.65, 95% CI 1.10–19.64; I² = 0%). Conclusion: The systematic review suggests that EPIT might induce desensitization in peanut allergy and an increased risk of local AEs. These findings should be interpreted with caution owing to the limited study and heterogeneity. More data in the older (children ≥12 years and adults) and other allergic diseases are needed.

Active dispersal of Aedes albopictus: a mark-release-recapture study using self-marking units

BackgroundUnderstanding the dispersal dynamics of invasive mosquito species is fundamental to improve vector surveillance and to target control efforts. Aedes albopictus has been deemed a poor flyer as its range of active dispersal is generally assumed to be limited to a few hundred metres, while laboratory studies suggest this mosquito could actually fly several kilometres. The discrepancy may be due to differences in the local environment or to the methodological approach. In Switzerland, Ae. albopictus has been present since 2003 and has since then expanded its range. While passive dispersal is a key driver, it remains unclear how far this mosquito spreads through active flight and what the age structure and size of the local population are, all important parameters for vector surveillance and control.MethodWe investigated the active dispersal, daily survival rate and population size of Ae. albopictus in mark-release-recapture studies in Coldrerio and Lugano, two areas of intensive control in Switzerland. To mark mosquitoes emerging from breeding sites, we used self-marking units with fluorescent pigment that have minimal impact on mosquito survival and behaviour. We recaptured the adult mosquitoes with BG-Sentinel traps within a radius of 1 km from the marking units over 22 consecutive days.ResultsWe found that 77.5% of the recaptured Ae. albopictus individuals flew further than 250 m, the limit that is usually deemed sufficient for vector containment. The average age of females and males was 8.6 days and 7.8 days in Coldrerio and Lugano, respectively, while the estimated mosquito population densities were 134 mosquitoes/ha in Coldrerio and 767 mosquitoes/ha in Lugano.ConclusionsSelf-marking units are an effective tool to mark wild mosquitoes. Using this approach, we found that mosquitoes survive long enough to potentially transmit arboviral disease in our study area and that host-seeking Ae. albopictus females may travel further than previously assumed for European mosquito populations. This finding has direct implications for vector control as emergency treatments around positive cases, as well as surveillance and control around detections of new infestations, might need to be extended beyond the usual recommended range of just a few hundred metres.

LBA2 First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC: Safety, pharmacokinetics (PK) and immunogenicity in CASPIAN

LBA2 First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC: Safety, pharmacokinetics (PK) and immunogenicity in CASPIAN

Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure.

IntroductionLong-term safety data are critical for evaluating therapies for psoriasis. Ixekizumab has demonstrated efficacy and is well tolerated for the treatment of moderate-to-severe plaque psoriasis. We examined the safety and tolerability of up to 5 years of ixekizumab therapy in patients with psoriasis.MethodsIntegrated safety data were analyzed from 13 ixekizumab clinical studies. Rates of treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and AEs of special interest were analyzed for the 12-week induction period in the combined pivotal studies, and for all pooled studies by year(s) of therapy and overall, reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (p-y) and/or frequencies.ResultsTotal ixekizumab exposure was 17,003.4 p-y (N = 5898); 2749 patients had ≥ 4 years of exposure. When compared across years of exposure, rates for AEs remained largely stable or declined, including TEAEs leading to discontinuation (3.8/100 p-y in year 1, declining to 2.0/100 p-y in year 5); SAEs (range 6.2–7.0/100 p-y); serious infections (range 1.3–1.7/100 p-y); nonmelanoma skin cancer (ranging from 0.5/100 p-y in year 1 to 0.2/100 p-y in years 4–5); other malignancies (range 0.4–0.6/100 p-y); inflammatory bowel disease including ulcerative colitis and Crohn’s disease (IR 0.2/100 p-y); and major adverse cardiovascular events (MACE) (range 0.3–0.7/100 p-y). Candidiasis was reported in 327 patients (IR 1.9/100 p-y), with the majority identified as mucocutaneous. The rate of injection site reactions was 15.5/100 p-y during year 1 and 2.0–2.3/100 p-y by years 3–5.ConclusionsThe decrease in rates of TEAEs and the stable rates of SAEs, other malignancies and MACE during up to 5 years of ixekizumab dosing are consistent with previous reports describing a favorable safety profile of ixekizumab following shorter durations of exposure.FundingEli Lilly and Company.

Advancements in Treatment for Newly Diagnosed Frail and Elderly Myeloma Patients: A Systematic Review

Introduction: About 60% newly diagnosed multiple myeloma (NDMM) cases are above age of 60 years. The paucity of studies exclusively targeting management of frail patients has led to persistence of therapeutic uncertainties. With data on more than ten thousand patients, purpose of this review is to summarize the available therapeutic options with emphasis on recent advances for treatment of frail and elderly, transplant ineligible NDMM patients. Methods: We performed a comprehensive literature search on June 1st, 2019 on PubMed, Cochrane Library and ClinicalTrials.gov. We used the MeSH terms: 'Multiple Myeloma' and 'Frail Elderly', with associated entry words. Search yielded 71 studies regarding our topic of interest. Following PRISMA guidelines and subsequent screening by two reviewers, we shortlisted 19 ongoing/completed studies (n=10297) and included data from these studies in our systematic review. Results: Two/Three Drug regimens: Among the two drug regimens [Table 1], Lenalidomide (R) and Dexamethasone (D) (RD) combination has been most widely studied (n=1445). RD yielded objective response rate (ORR) of 81.3%, complete response (CR) or above of 24.9% and progression free survival (PFS) of 31.9 months in a phase III trial (Usmani, 2019) (n=369). Facon et al. (2019) [n=368] used Daratumumab (Dara)+R+D (DaraRD) which exhibited the best response overall with an ORR of 92.9%, CR of 47.6%, VGPR of 31.8% while the PFS was not reached till study end point. However, &gt;grade 3 neutropenia developed in 50% patients. Three-drug regimen of Bortezomib(V)+Melphalan(M)+Prednisolone(P) (VMP) has been the most widely studied regimen (n=1059) in four phase II/III clinical trials. In a phase II trial (Kizaki, 2016) (n=87), VMP yielded a PFS of 36 months and CR of 25%. In a Phase II trial by Larocca et al (2016, n=148), 3 cohorts (VP, V+ Cyclophosphamide (C) +P and VMP respectively) were studied. Best response was achieved by VMP with ORR of 86%, PFS of 17.1 months and CR of 14%, compared with VCP (ORR=67%, PFS=15.2 months and CR=2%) and VP (ORR=64%, PFS=14 months, CR=8%). However, the discontinuation rate (DR) due to AEs for VMP was relatively high (20%). A phase III trial (San-Miguel, 2018) (n=955) compared Carfilzomib(K)+M+P (KMP) against VMP. Median PFS was found to be 22.3 months with KMP Vs 22.1 months with VMP. Grade ≥3 AE rates were 74.7% for KMP and 76.2% for VMP. Thus, the results showed no significant difference between both regimens. Thalidomide (T) has also been used in three drug combinations in two phase II/III trials (n=667). Ixazomib(I)+T+D (ITD) in a phase II trial (Abildgaard, 2017) (n=120) revealed an ORR of 75% compared to ORR of 62% in a phase III trial (Benboubker et al, 2014) (n=547) using MPT. Notable &gt;grade 3 AEs with ITD were infections (15%) and cardiac abnormalities (10%) while with MPT were &gt;grade 3 neutropenia (45%) and infections (17%). A retrospective analysis by Facon et al. (2015, n=1517) comparing RD Vs MPT demonstrated that RD reduced the risk of progression or death by 21% compared to MPT in frail patients. 2. Four Drug Regimens: Four drug regimens have also been used in transplant-ineligible patients in two phase II/III trials (n=583). Mateos et al. (2015, n=233) conducted a phase II trial in which patients were treated with VMP+RD (VMPRD). 49 frail patients based on Age &gt;80 years (IMWG criteria) had ORR of 68%, PFS of 25 months and CR of 10%, with a DR of 63% due to toxicity or informed consent withdrawal. However, in the ALCYONE trial (San-Miguel, 2017) (n=350), use of Dara+VMP (DaraVMP) resulted in ORR of 90.9%, ≥CR of 42.6%, VGPR of 28.6% and PFS was not reached till study end point. Furthermore, the DR due to AEs for DaraVMP was also lesser (4.9%). Various trials [Table 2] are being conducted to establish correlation of frailty scores with parameters of efficacy. Conclusion: Management of frail and elderly NDMM patients is challenging as there is need to individualize therapy for this group. Novel agents such as lenalidomide, bortezomib and daratumumab have shown promising efficacy when used as combination therapies with other conventional agents. Intensity of treatment and efficacy goals should be tailored to the functional capacity and tolerance of each individual patient. There is need for focused clinical trials for this group in terms of greater recruitment into clinical trials to establish better correlation between frailty status and efficacy, and consolidating evidence for improved patient care. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Updated Analysis of Bellini, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Updated Analysis of Bellini, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

ME-401-003 (TIDAL): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Two-Arm, Phase 2 Study of ME-401 Investigating Continuous and Intermittent Dosing Schedules in Patients with Relapsed/Refractory Follicular Lymphoma

ME-401-003 (TIDAL): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Two-Arm, Phase 2 Study of ME-401 Investigating Continuous and Intermittent Dosing Schedules in Patients with Relapsed/Refractory Follicular Lymphoma