Additional Endpoints Research Articles

Efficacy and safety of crisaborole ointment in Chinese and Japanese patients aged ≥2 years with mild-to-moderate atopic dermatitis.

Atopic dermatitis is a chronic inflammatory skin disease with a significant impact on the overall wellbeing of patients and their families. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild-to-moderate atopic dermatitis in multiple countries. However, in the key pivotal trials, a low proportion of the overall patient population was Asian, therefore the safety and efficacy of crisaborole in the Asian population with atopic dermatitis remains unclear. CrisADe CLEAR was a multicenter, randomized, double-blind, vehicle-controlled, phase 3 study (NCT04360187) to assess the efficacy and safety of crisaborole ointment in Chinese and Japanese patients aged ≥2 years with mild-to-moderate atopic dermatitis involving ≥5% treatable body surface area. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. The primary endpoint was percentage change from baseline in the Eczema Area and Severity Index total score at day 29. Additional endpoints were improvement and success per Investigator's Static Global Assessment score at day 29 and change from baseline on the Peak Pruritus Numerical Rating Scale at week 4. Safety was assessed using rates of treatment emergent adverse events, serious adverse events, and clinically significant changes in vital signs and clinical laboratory parameters. Crisaborole-treated patients showed a significantly greater reduction versus vehicle in percentage change from baseline in Eczema Area and Severity Index total score at day 29 (P = 0.0002). Response rates for achievement of Investigator's Static Global Assessment improvement and success at day 29 were significantly higher for patients treated with crisaborole versus vehicle (P = 0.0124 and P = 0.0078, respectively). Crisaborole-treated patients showed a significantly greater reduction versus vehicle in change from baseline on the Peak Pruritus Numerical Rating Scale at week 4 (P = 0.0009). No new safety signals were identified. Treatment with crisaborole was effective and well tolerated in Chinese and Japanese patients with mild-to-moderate atopic dermatitis.

Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 versus reference tocilizumab: a randomized, double-blind, single-dose phase I study

ABSTRACT Background CT-P47 is a candidate tocilizumab biosimilar. This study assessed the pharmacokinetic (PK) equivalence of CT-P47 and European Union-approved reference tocilizumab (EU-tocilizumab) in healthy Asian adults. Research design and methods This double-blind, multicenter, parallel-group trial randomized healthy adults (1:1) to receive a single (162 mg/0.9 mL) subcutaneous dose of CT-P47 or EU-tocilizumab. The primary endpoint (Part 2) was PK equivalence by area under the concentration – time curve (AUC) from time zero to last quantifiable concentration (AUC0–last), AUC from time zero to infinity (AUC0–inf), and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the 80–125% equivalence margin. Additional PK endpoints, immunogenicity, and safety were evaluated. Results In Part 2, 289 participants were randomized (146 CT-P47; 143 EU-tocilizumab); 284 received study drug. AUC0–last, AUC0–inf, and Cmax were equivalent between CT-P47 and EU-tocilizumab: 90% CIs for the ratios of gLSMs were within the 80–125% equivalence margin. Secondary PK endpoints, immunogenicity, and safety were comparable between groups. Conclusions CT-P47 demonstrated PK equivalence with EU-tocilizumab and was well tolerated, following a single dose in healthy adults. Clinical trial registration www.clinicaltrials.gov identifier is NCT05188378.

Coronary CTA for Acute Chest Pain in the Emergency Department: Comparison of 64-Detector-Row Single-Source and Third-Generation Dual-Source Scanners.

BACKGROUND. When coronary CTA is performed in the emergency department (ED), the use of a contemporary scanner with improved temporal resolution may eliminate the need to administer β-blockers for heart rate (HR) control, thereby expediting workup. OBJECTIVE. The purpose of this study was to compare ED length of stay (LOS), image quality, frequency of nondiagnostic examinations, and other clinical outcomes between patients undergoing coronary CTA in the ED on a single-source CT (SSCT) scanner with HR control versus on a dual-source CT (DSCT) scanner without HR control. METHODS. This retrospective study included 509 patients (283 men, 226 women; mean age, 52.1 ± 15.1 [SD] years) at low to intermediate risk for acute coronary syndrome who underwent coronary CTA for acute chest pain during off-hours in a single ED from March 1, 2020, to April 25, 2022. A total of 205 patients initially underwent CTA using a 64-detector-row SSCT scanner with HR control (oral β-blocker administration if HR was > 65 beats/min); after scanner replacement on April 26, 2021, 304 patients underwent CTA using a third-generation DSCT without HR control. Groups were compared in terms of ED LOS and CT completion time (defined as time from ordering CTA to completion of acquisition) using propensity score matching and additional endpoints including image quality and nondiagnostic examinations based on radiology reports. RESULTS. The DSCT group, compared with the SSCT group, showed no significant difference in median ED LOS (505 vs 457 minutes, respectively; p = .37) but showed shorter median CT completion time (95 vs 117 minutes, p < .001); on the basis of a mediation analysis, 89% of the reduction in CT completion time for DSCT was attributed to the absence of HR control. The DSCT group, compared with the SSCT group, showed higher frequency of examinations with good or excellent image quality (87.8% vs 60.0%, p < .001) and lower frequency of nondiagnostic examinations (1.6% vs 6.3%, p = .01) but showed no significant difference in frequencies of emergent cardiology consultation, invasive angiography, ED disposition, or coronary revascularization (all p > .05). No patient in either group experienced 30-day all-cause mortality or a major adverse cardiovascular event. CONCLUSION. The use of a DSCT scanner for coronary CTA can eliminate the need for β-blocker administration for HR control while decreasing nondiagnostic examinations. CLINICAL IMPACT. A DSCT scanner can expedite clinical processes in the ED.

Effect of regional versus general anesthesia on thirty-day outcomes following carotid endarterectomy: a cohort study.

The effect of regional versus general anesthesia on carotid endarterectomy outcomes is debated. This study assesses the effect of anesthetic technique on major morbidity and mortality and additional secondary endpoints following carotid endarterectomy. This was a retrospective propensity-matched-cohort analysis investigating elective carotid endarterectomy patients in the 2015-2019 American College of Surgeons National Surgical Quality Improvement Program ( n =37204). The primary endpoint was 30-day mortality and major morbidity, defined as stroke, myocardial infarction, or death. Secondary endpoints included minor morbidity, bleeding events, healthcare resource utilization, and length of hospital stay. Univariate, multivariable, and survival analyses were applied. The 1:1 propensity-matched-cohort included 8304 patients (4152 in each group). Regional anesthesia was associated with similar incidences of major morbidity and mortality [odds ratio (OR), 0.81 (95% CI, 0.61-1.09); P = 0.162] and unplanned resource utilization [OR, 0.93 (95% CI, 0.78-1.11); P = 0.443], but lower incidences of minor morbidity [OR, 0.60 (95% CI, 0.44-0.81); P < 0.001] and bleeding events [OR, 0.49 (95% CI, 0.30-0.78); P = 0.002], and a shorter length of hospital stay [1.4 vs. 1.6 days; mean difference, -0.16 days (95% CI, -0.25 to -0.07); P < 0.001]. On multivariable analysis, regional anesthesia remained independently predictive of minor morbidity [adjusted odds ratio (AOR), 0.58 (95% CI, 0.42-0.79); P = 0.001] and bleeding events [AOR, 0.49 (95% CI, 0.30-0.77); P = 0.003]. Significance was maintained on survival analysis for these two endpoints. A mortality benefit was observed on univariate [OR, 0.50 (95% CI, 0.25-1.00); P = 0.045], multivariable [AOR, 0.49 (95% CI, 0.24-0.96); P = 0.043], and survival analysis ( P = 0.045). Carotid endarterectomy patients receiving regional anesthesia experience favorable outcomes compared to propensity-matched general anesthesia controls.

Feasibility of introducing a smartphone navigation application into the care of breast cancer patients (The FIONA Study)

PurposePatients with breast cancer (BC) face complex medical information and decisions. The Outcomes4Me mobile app provides evidence-based BC education, symptom management tracking and clinical trial matching. This study sought to evaluate the feasibility of introducing this app into routine BC care.MethodsIn this pilot study among BC patients undergoing therapy at an academic cancer center, patients were followed for 12 weeks with survey administration and electronic health record (EHR) abstraction at baseline and completion. Feasibility was defined as 40% of patients engaging with the app 3 or more times during the study. Additional endpoints included app usability (system usability scale), patient care experience, symptom evaluation, and clinical trial matching.ResultsThe study enrolled 107 patients from 6/01/2020 to 3/31/2021. Utilization of the app was deemed feasible with 60% of patients engaging with the app at least 3 times. SUS score of 70 indicated above average usability. New diagnosis and higher education level was associated with greater app engagement, with usability similar across all age groups. 41% of patients found the app helped track symptoms. Cognitive and sexual symptoms were infrequently reported, but were more frequently captured in the app than in the EHR. After using the app, 33% of patients reported increased interest in clinical trial enrollment.ConclusionIntroducing the Outcomes4Me patient navigation app into routine BC care is feasible and may improve the patient experience. These results support further evaluation of this mobile technology platform to improve BC education, symptom management, and decision making.Clinical trial registryClinicaltrials.gov registration #: NCT04262518

P187 Safety and efficacy of ixekizumab treatment in patients with axial spondyloarthritis: 3-year results from the COAST programme

Abstract Background/Aims Ixekizumab (IXE) has demonstrated efficacy at week (wk) 16 which was maintained through 2 years (yrs) and was associated with a consistent safety profile in patients (pts) with r- and nr-axSpA, who are bDMARD-naïve and TNFi-experienced. We aimed to report safety and efficacy from the COAST programme at 3 yrs: 1 yr of the originating studies (COAST-V/W/X) and 2 yrs of COAST-Y. Methods COAST-Y (NCT03129100) is the phase 3, long-term extension study of the 3 originating studies COAST-V/W/X. Pts continued with the dose received at the end of the originating trial at week (wk) 52, either with 80 mg IXE every 4 wks (Q4W) or every 2 wks (Q2W). Pts assigned to adalimumab (ADA) or placebo (PBO) were re-randomised to IXE Q4W or Q2W at wk 16 in COAST-V and -W. Pts who received PBO for 52 wks in COAST-X were switched to IXE Q4W to continue in COAST-Y. Starting at wk 116 (wk 64 of COAST-Y), pts receiving IXE Q4W could have their dose escalated to Q2W based on investigator's opinion. This analysis focused on pts receiving ≥1 dose of IXE Q4W, observed data while on IXE Q2W dose escalation are excluded. Continuous data are summarised as observed. Safety data while on IXE were analysed for pts who received ≥1 dose of IXE; observed data while on PBO or ADA are excluded. Results A total of 932 pts received ≥1 dose of IXE, 414 received ≥1 dose of IXE Q4W, and 562/932 (60%) pts completed 3 yrs of follow-up (PBO→IXE Q4W, 63/119 (53%); ADA→IXE Q4W, 29/44 (66%); and IXE Q4W→IXE Q4W, 114/251(45%)). Through 3 yrs, the most frequently reported treatment-emergent adverse events were infections [incidence rate (IR) 25.7/100 patient years (PY)] and injection site reactions [IR 7.4/100 PY], the majority of which were mild/moderate in severity. Serious adverse events were reported at an IR of 4.8/100 PY, of which osteoarthritis was the most frequent at 0.4/100 PY. A total of 3 deaths were reported among all pts who received ≥1 dose of IXE [IR 0.1/100 PY]. For all patients, baseline disease activity (Ankylosing Spondylitis Disease Activity Score; ASDAS) was high. A similar improvement in disease activity through 3 yrs was confirmed across additional efficacy endpoints. Conclusion This analysis in COAST-Y demonstrated that the safety profile is consistent with the established safety profile, with no new safety signals observed. Patients on IXE Q4W had sustained improvement through 3 years. Disclosure A. Deodhar: Consultancies; A. Deodhar has served as a speaker and/or consultant for: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos NV, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB Pharma. D. Poddubnyy: Shareholder/stock ownership; D. Poddubnyy has served as a speaker and/or consultant for: AbbVie, BIOCAD, Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, Samsung Bioepis, and UCB Pharma. Grants/research support; D.P. has received grant and/or research support from: AbbVie, Eli Lilly and Company, Merck Sharp &amp; Dohme, Novartis, and Pfizer. P. Rahman: Consultancies; P. Rahman has served as a speaker for: Abbott, AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, and Pfizer. Grants/research support; P.R. has received grant and/or research support from: Janssen and Novartis. R. Bolce: Shareholder/stock ownership; R. Bolce is an employee and shareholder of: Eli Lilly and Company. S. Liu Leage: Shareholder/stock ownership; S. Liu-Leage is an employee and shareholder of: Eli Lilly and Company. A. Kronbergs: Shareholder/stock ownership; A. Kronbergs is an employee and shareholder of: Eli Lilly and Company. C. Johnson: Shareholder/stock ownership; C. Johnson is an employee and shareholder of: Eli Lilly and Company. A. Leung: Corporate appointments; A. Leung is an employee of: Syneos Health; and a contractor for: Eli Lilly and Company. D. van der Heijde: Consultancies; D. van der Heijde has served as a consultant for: AbbVie, Bayer Pharmaceuticals, Bristol Myers Squibb, Cyxone, Eisai, Eli Lilly and Company, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB Pharma. Other; D. van der Heijde is the director of: Imaging Rheumatology BV. A. Kiprianos (Non-author Presenter): Shareholder/stock ownership; A. Kiprianos is an employee and shareholder in Lilly.

Telehealth: Navigating the COVID-19 Pandemic and Beyond: The Sickle Cell Unit Experience.

Introduction: To examine the use of telehealth for delivery of health care in persons with sickle cell disease in a resource-constrained country during the COVID-19 pandemic. Methods: This study was a retrospective review of patient encounters at the Sickle Cell Unit (SCU), Jamaica during a 3-year period, March 10, 2019 to March 9, 2022 and a comparison of endpoints between 1 year before and 2 years during the pandemic. Primary endpoints of registration numbers, day-care admissions, and study visits were obtained from logbooks and the electronic medical records. Additional endpoints included well visits, hydroxyurea (HU) visits, and bone pain crisis. Results: Patients registered at the clinic on 17,295 occasions, with 7,820 in the pre-pandemic year decreasing by 43.8% and 35% in the 2 subsequent pandemic years. Overall, study visits increased by 4.9% and 1.3% in the pandemic years. They increased in adults by 13.1% and 8.9% but fell by 3.2% and 6.2% in children. Fewer people were seen in the pandemic years, with children showing a 20.7% decline in numbers. Tele-visits accounted for 31.4% of all study visits during the pandemic years and increased by 23.6% between the pandemic years. There were more well-visits and HU visits, but fewer pain visits and day-care admissions in the pandemic years. Conclusions: The SCU maintained health care delivery for a high-risk population during the pandemic, with tele-visits mitigating the short-fall from in-person visits. Tele-visits may be more acceptable to adults with a chronic illness and may be a suitable alternative for delivering health care.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study

Pegbelfermin is a polyethylene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) with compensated cirrhosis. FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study. Eligible adults had biopsy-confirmed NASH and stage 4 fibrosis. Pegbelfermin (10, 20, or 40 mg) or placebo was injected subcutaneously once weekly. The primary endpoint was 1 or more stages of improvement in the NASH Clinical Research Network fibrosis score without NASH worsening at week 48; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α= .05). Additional endpoints included histologic and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. Overall, 155 patients were randomized, and 154 patients received treatment. At week 48, 24% to 28% of the pegbelfermin arms had primary endpoint responses vs 31% of the placebo arm (P= .361). Nonalcoholic fatty liver disease activity score improvements were more frequent with pegbelfermin vs placebo and were driven primarily by reduced lobular inflammation. Numerically higher proportions of the pegbelfermin arms had liver stiffness (magnetic resonance elastography) and steatosis (magnetic resonance imaging-proton density fat fraction) improvements vs placebo; these differences were not statistically significant. Mean N-terminal type III collagen propeptide, alanine aminotransferase, and aspartate aminotransferase values were numerically lower in the 20- and/or 40-mg pegbelfermin arms compared with placebo. Serious adverse events were more frequent with pegbelfermin vs placebo, although none were treatment related. One patient (40-mg pegbelfermin) discontinued treatment because of a treatment-emergent adverse event (worsening ascites). FALCON 2 did not meet its primary endpoint of 1 or more stages of improvement in the NASH Clinical Research Network fibrosis without NASH worsening assessed via biopsy. Pegbelfermin generally was well tolerated in this advanced NASH population.

Abstract CT060: ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma

Abstract Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating dordaviprone in patients with H3 K27M-mutant disease. Methods: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023. Citation Format: Isabel Arrillaga-Romany, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E. Allen, Allen S. Melemed, Rohinton S. Tarapore, Dewen Yang, Patrick Wen, Timothy Cloughsey. ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT060.

Efficacy and safety of upadacitinib in patients with active psoriatic arthritis and axial involvement: results from two phase 3 studies

BackgroundThe objective of this post-hoc analysis was to assess the efficacy and safety of upadacitinib in psoriatic arthritis (PsA) patients with axial involvement.MethodsPost-hoc analysis of SELECT-PsA 1 and SELECT-PsA 2 in patients randomized to upadacitinib 15 mg (UPA15), placebo (switched to UPA15 at week 24), or adalimumab 40 mg (ADA; SELECT-PsA 1 only). Axial involvement was determined by investigator judgement (yes or no; based on the totality of available clinical information, such as duration and characteristics of back pain, age of onset, and previous lab investigations and imaging, if available) alone, or investigator judgement and patient-reported outcome (PRO)-based criteria (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] ≥ 4 and BASDAI Q2 ≥ 4). Efficacy outcomes that describe axial disease activity, including BASDAI endpoints, such as change from baseline in the overall BASDAI score or proportion of patients achieving BASDAI50 (≥ 50% improvement from baseline), as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) endpoints, such as mean change from baseline in overall ASDAS or proportion of patients achieving ASDAS inactive disease or low disease activity, were evaluated at weeks 12, 24, and 56, with nominal P-values shown. Treatment-emergent adverse events (TEAEs) are summarized through week 56.Results30.9% of patients in SELECT-PsA 1 and 35.7% in SELECT-PsA 2 had axial involvement by investigator judgement alone; 22.6% (SELECT-PsA 1) and 28.6% (SELECT-PsA 2) had axial involvement by investigator judgement and PRO-based criteria. Greater proportions of patients achieved BASDAI50 with UPA15 versus placebo using either criterion, and versus ADA using investigator judgement alone, at week 24 in SELECT-PsA 1 (investigator alone: UPA15, 59.0%, placebo, 26.9%, P < 0.0001, ADA, 44.1%, P = 0.015; investigator and PRO-based: UPA15, 60.4%, placebo, 29.3%, P < 0.0001, ADA, 47.1%, P = 0.074), with comparable findings in SELECT-PsA 2. Similar results were observed with UPA15 for additional BASDAI and ASDAS endpoints at weeks 12 and 24, with improvements maintained at week 56. Rates of TEAEs were generally similar across sub-groups irrespective of axial involvement status.ConclusionsPsA patients with axial involvement determined by predefined criteria showed greater BASDAI and ASDAS responses with UPA15 versus placebo, and numerically similar/greater responses versus ADA. Safety results were generally comparable between patients with or without axial involvement.Trial registrationClinicalTrials.gov: SELECT-PsA 1, NCT03104400; SELECT-PsA 2, NCT0310437.

Focal Cortex Stimulation With a Novel Implantable Device and Antiseizure Outcomes in 2 Prospective Multicenter Single-Arm Trials

For the large population of people with drug-refractory epilepsy, alternative treatment approaches are needed. Clinical trial outcomes of a novel stimulation device, which is newly available in Europe for the treatment of patients with a predominant seizure focus, are reported for the first time. To perform a pooled analysis of the results of 2 prospective, multicenter, single-arm trials, A Pilot Study to Assess the Feasibility of Neurostimulation With the EASEE System to Treat Medically Refractory Focal Epilepsy (EASEE II) and A Pilot Study to Assess the Feasibility of Patient-Controlled Neurostimulation With the EASEE System to Treat Medically Refractory Focal Epilepsy (PIMIDES I), assessing the safety and efficacy of epicranial focal cortex stimulation (FCS) with a novel implantable device (EASEE [Precisis]) as adjunctive treatment for adult patients with drug-refractory focal epilepsy. This study was a pooled analysis of 2 nonrandomized uncontrolled trials, EASEE II and PIMIDES I, which began on January 15, 2019, and January 14, 2020, respectively, and ended on July 28, 2021. EASEE II and PIMIDES I were the first in-human, prospective, single-arm trials with an 8-month evaluation period. Patients were recruited at 7 European epilepsy centers. Consecutive participants with drug-refractory focal epilepsy were enrolled. Study data were analyzed from September 29, 2021, to February 2, 2022. After a 1-month prospective baseline period, patients were implanted with the neurostimulation device. After a 1-month postimplantation recovery period, unblinded FCS was activated using both high-frequency and direct current (DC)-like components performed via electrode arrays placed epicranially above the individual epileptic focus region. Efficacy was prospectively assessed by the responder rate in the sixth month of stimulation compared with baseline; safety and additional end points were assessed after device implantation and during the stimulation period. Of the 34 adult patients enrolled at 6 German and 1 Belgian investigational site, 33 (mean [SD] age, 34.6 [13.5] years; 18 male patients [54.5%]) received the neurostimulation device implant. A total of 32 patients underwent combined high-frequency direct current-like stimulation at least until the 8-month postimplant follow-up visit. After 6 months of stimulation, 17 of 32 patients (53.1%) were responders to treatment with at least a 50% reduction in seizure frequency compared with baseline, corresponding to a significant median seizure reduction by 52% (95% CI, 0.37%-0.76%; P < .001). No device- or procedure-related serious adverse events were reported (0; 95% CI, 0%-10.58%). There were no significant alterations in cognition, mood, or overall quality of life. Results of this pooled analysis of 2 nonrandomized uncontrolled trials suggest that FCS with a novel neurostimulation device was associated with an effective reduction in seizure frequency in patients with drug-refractory focal epilepsy and may offer a promising treatment option for patients with a predominant epileptic focus. German Clinical Trials Register: DRKS00015918 and DRKS00017833, respectively, and jointly under PROSPERO: CRD42021266440.

Safety and efficacy of the tumor-selective adenovirus enadenotucirev, in combination with nivolumab, in patients with advanced/metastatic epithelial cancer: a phase I clinical trial (SPICE)

BackgroundNovel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in...

Euglycemic diabetic ketoacidosis (EDKA) after pancreaticoduodenectomy: An under-recognized metabolic abnormality with outcome implications

Euglycemic diabetic ketoacidosis is a metabolic condition characterized by relative euglycemia, ketonemia, and metabolic acidosis that occurs through mechanisms resembling starvation. Pancreaticoduodenectomy is a complex abdominal operation that subjects patients to a prolonged fasting and an inflammatory state. This study examined the incidence of euglycemic diabetic ketoacidosis and potential opportunities for early diagnosis and management in patients undergoing pancreaticoduodenectomy. A single-institution retrospective review of 350 patients who underwent pancreaticoduodenectomy between 2017 and 2020 was performed. Primary endpoints were peak beta-hydroxybutyrate levels, peak lactate levels, lowest pH, peak base deficits, and urinary output within the first 24 hours, postoperatively. Additional endpoints included incidence of postoperative pancreatic fistula, delayed gastric emptying, total complications, postoperative hospital length of stay, readmission rates, and changes in insulin regimen at discharge. Of the 350 cases reviewed, 39 (11.1%) patients developed euglycemic diabetic ketoacidosis. Male sex and pancreatic cancer were associated with a risk for euglycemic diabetic ketoacidosis (P < .05). Patients with euglycemic diabetic ketoacidosis had significantly higher peak beta-hydroxybutyrate levels than patients without euglycemic diabetic ketoacidosis (mean difference= 19.8 mg/dL, 95% confidence interval= 14.7-24.9, P < .001), and were nearly four times more likely to require insulin at discharge (odds ratio 3.8, 95% confidence interval= 1.1-13.0, P < .05). This is the first large descriptive study that investigates euglycemic diabetic ketoacidosis after pancreaticoduodenectomy. Euglycemic diabetic ketoacidosis after pancreaticoduodenectomy is associated with significantly higher beta-hydroxybutyrate levels and new or increased insulin requirement at discharge. Our study demonstrates potential markers for euglycemic diabetic ketoacidosis after pancreaticoduodenectomy, offering an opportunity to identify and successfully treat this disease in a timely manner.

The dependence of particle size on cell toxicity for modern mining dust

Progressive massive pulmonary fibrosis among coal miners has unexpectedly increased. It would likely due to the greater generation of smaller rock and coal particles produced by powerful equipment used in modern mines. There is limited understanding of the relationship between micro- or nanoparticles with pulmonary toxicity. This study aims to determine whether the size and chemical characteristics of typical coal-mining dust contribute to cellular toxicity. Size range, surface features, morphology, and elemental composition of coal and rock dust from modern mines were characterized. Human macrophages and bronchial tracheal epithelial cells were exposed to mining dust of three sub- micrometer and micrometer size ranges at varying concentrations, then assessed for cell viability and inflammatory cytokine expression. Coal had smaller hydrodynamic size (180–3000 nm) compared to rock (495–2160 nm) in their separated size fractions, more hydrophobicity, less surface charge, and consisted of more known toxic trace elements (Si, Pt, Fe, Al, Co). Larger particle size had a negative association with in-vitro toxicity in macrophages (p < 0.05). Fine particle fraction, approximately 200 nm for coal and 500 nm for rock particles, explicitly induced stronger inflammatory reactions than their coarser counterparts. Future work will study additional toxicity endpoints to further elucidate the molecular mechanism causing pulmonary toxicity and determine a dose–response curve.

The GIANT trial (ECOG-ACRIN EA2186) methods paper: A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer - defining a new treatment option for older vulnerable patients

IntroductionPancreatic cancer is the fourth leading cause of cancer-related death in the US with an increasing incidence in older adults (OA) over age 70. There are currently no treatment guidelines for OA with metastatic pancreatic cancer (mPCA) and selecting a chemotherapy regimen for these patients is subjective, based largely on chronologic age and performance status (PS). Geriatric screening tools provide a more objective and accurate evaluation of a patient's overall health but have not yet been validated in patient selection for mPCA treatment. This study aims to elucidate the optimal chemotherapy treatment of vulnerable OA with mPCA and understand the geriatric factors that affect outcomes in this population. Methods/DesignThe GIANT (ECOG-ACRIN EA2186) study is multicenter, randomized phase II trial enrolling patients over age 70 with newly diagnosed mPCA. This study utilizes a screening geriatric assessment (GA) which characterizes patients as fit, vulnerable, or frail. Patients with mild abnormalities in functional status and/or cognition, moderate comorbidities, or over age 80 are considered vulnerable. Enrolled patients are randomized to one of two dose-reduced treatment regimens (gemcitabine/nab-paclitaxel every other week, or dose-reduced 5-fluoruracil (5FU)/ liposomal irinotecan (nal-IRI) every other week). GA and quality of life (QoL) evaluations are completed prior to treatment initiation and at each disease evaluation. Overall survival (OS) is the primary endpoint, with secondary endpoints including progression free survival (PFS) and objective response rate (ORR). Enrolled patients will be stratified by age (70–74 vs ≥75) and ECOG PS (0–1 vs 2). Additional endpoints of interest for OA include evaluation of risk factors identified through GA, QoL evaluation, and toxicities of interest for older adults. Correlative studies include assessment of pro-inflammatory biomarkers of aging in the blood (IL-6, CRP) and imaging evaluation of sarcopenia as predictors of treatment tolerance. DiscussionThe GIANT study is the first randomized, prospective national trial evaluating vulnerable OA with mPCA aimed at developing a tailored treatment approach for this patient population. This trial has the potential to establish a new way of objectively selecting vulnerable OA with mPCA for modified treatment and to establish a new standard of care in this growing patient population.Trial Registration: This trial is registered with ClinicalTrial.gov Identifier NCT04233866.

From bench to behaviour: The role of lifestyle factors on intraocular pressure, neuroprotection, and disease progression in glaucoma.

Current glaucoma management centres on intraocular pressure (IOP) reduction through pharmacological and surgical therapy. Despite broad interest in active management of glaucoma through lifestyle modifications, such recommendations have yet to be incorporated into standards of treatment. In this review, noteworthy preclinical studies and their translations in clinical populations are discussed to evaluate the roles of lifestyle factors in lowering IOP, offering neuroprotection, and/or slowing disease progression in those with open-angle glaucoma. Current literature suggests that aerobic exercise may be associated with neuroprotection and decreased disease progression. Mindfulness is associated with IOP reductions and neuroprotection. Caffeine is associated with mild, transient IOP elevations of uncertain significance. Nicotinamide supplementation is associated with neuroprotection and short-term visual function improvement. This review also highlights knowledge gaps regarding these factors and opportunities to strengthen our understanding of their role in glaucoma, including future preclinical studies that elucidate underlying mechanisms and clinical studies with additional functional endpoints and longer follow-up.

Prospective Pilot Study of 18F-Fluoroestradiol PET/CT in Patients With Invasive Lobular Carcinomas.

BACKGROUND. PET/CT with 18F-fluoroestradiol (FES) (FDA-approved in 2020) depicts tissues expressing estrogen receptor (ER). Invasive lobular carcinoma (ILC) is commonly ER positive. OBJECTIVE. The primary aim of this study was to assess the frequency with which sites of histologically proven ILC have abnormal uptake on FES PET/CT. METHODS. This prospective single-center pilot study, conducted from December 2020 to August 2021, enrolled patients with histologically confirmed ILC to undergo FES PET/CT; patients optionally underwent FDG PET/CT. Two nuclear radiologists assessed FES PET/CT and FDG PET/CT studies for abnormal uptake corresponding to known ILC sites at enrollment and for additional sites of abnormal uptake, resolving differences by consensus. The primary endpoint was percentage of known ILC sites showing abnormal FES uptake. The alternative to the null hypothesis was that more than 60% of sites would have abnormal FES uptake, exceeding the percentage of ILC with abnormal FDG uptake described in prior literature. A sample size of 24 biopsied lesions was preselected to provide 81% power for the alternative hypothesis (one-sided α = .10). Findings on FES PET/CT and FDG PET/CT were summarized for additional secondary endpoints. RESULTS. The final analysis included 17 patients (mean age, 59.1 ± 13.2 years) with 25 sites of histologically confirmed ILC at enrollment (22 breast lesions, two axillary lymph nodes, one distant metastasis). FES PET/CT showed abnormal uptake in 22 of 25 (88%) lesions, sufficient to reject the null hypothesis (p = .002). Thirteen patients underwent FDG PET/CT. Four of 23 (17%) sites of histologically confirmed ILC, including additional sites detected and confirmed after enrollment, were identified with FES PET/CT only, and 1 of 23 (4%) was identified only with FDG PET/CT (p = .18). FES PET/CT depicted additional lesions not detected with standard-of-care evaluation in 4 of 17 (24%) patients (two contralateral breast cancers and two metastatic axillary lymph nodes, all with subsequent histologic confirmation). Use of FES PET/CT resulted in changes in clinical stage with respect to standard-of-care evaluation in 3 of 17 (18%) patients. CONCLUSION. The primary endpoint of the trial was met. The frequency of abnormal FES uptake among sites of histologically known ILC was found to be to be significantly greater than 60%. CLINICAL IMPACT. This pilot study shows a potential role of FES PET/CT in evaluation of patients with ILC. TRIAL REGISTRATION. ClinicalTrials.gov NCT04252859.

Positioning of enhanced monofocal intraocular lenses between conventional monofocal and extended depth of focus lenses: a scoping review

BackgroundNew intraocular lenses (IOLs) have emerged since the originally coined monofocal and multifocal IOLs. The extended depth of focus (EDoF) and enhanced monofocal IOLs (mono-EDoF) that have appeared in the last decade have caused some confusion in their classification. The aim of this review was to summarize the outcomes provided by mono-EDOF IOLs and to determine which of the endpoints, described by the American National Standard (ANSI) for EDoF IOLs, are fulfilled.MethodsThe MEDLINE, EMBASE, and WEB OF SCIENCE databases were searched. Two independent reviewers screened the studies for inclusion and data extraction. The search strategy was limited to studies published between 2020 and 2022, but not by language. The results are presented as a narrative summary accompanied by tables, in alignment with the objectives of this scoping review. Compliance with the endpoints for clinical outcomes described in the American National Standard Z80.35–2018 (ANSI) for EDoF lenses was checked and additional endpoints were defined.ResultsTwo systematic reviews, 13 laboratory, 21 clinical, and two mixed studies were included. Tecnis Eyhance was the mono-EDOF with the highest volume of evidence to date. Although laboratory studies included other IOLs, clinical evidence for them is still scarce, with only one study of IsoPure compared to a standard monofocal IOL. Evidence in comparison to EDoF lenses is also scarce, even for Tecnis Eyhance, with only three studies including this lens in comparison to an EDoF lens. After evaluation of the ANSI criteria, agreement was found in the failure for the increase in depth of field equal to or greater than 0.5 D for a visual acuity (VA) level of 0.2 logMAR and none of the studies supported that the median monocular VA at intermediate distance was at least 0.2 logMAR.ConclusionsAdditional clinical evidence is required for other mono-EDOF IOLs beyond Tecnis Eyhance. Until the arrival of a standard classification, mono-EDOF should be better still classified as monofocal because the ANSI standards were not fully met.

Consensus of the Brazilian Association of Nutrology on diagnosis, prophylaxis, and treatment of vitamin B12 deficiency

Introduction: Vitamin B12 deficiency is quite prevalent in all age groups and all regions of the country, however, there is a need for standardization of clinical management recommendations. Objective: It was to achieve a consensus on the diagnosis, prophylaxis, and treatment of vitamin B12 deficiency. Methods: An integrative review of the scientific literature was carried out in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases and on governmental and regulatory websites. Results: According to the literary search carried out by the authors of this study, 84 scientific works were selected. Based on these findings, in the timeline from 1999 to 2022, randomized controlled clinical studies represented the majority, and prospective and retrospective studies with significant sample sizes were elucidated in this consensus on the vitamin B12 administration for all patient populations. The basis of this scientific evidence was determined by appropriate clinical trials, with additional endpoints including patient clinical symptoms and biochemical parameters in addition to serum and marginal B12 level. Conclusions: Based on the scientific literature, the recommendations of the Brazilian Association of Nutrology for diagnosis, prophylaxis, and treatment of vitamin B12 deficiency were presented.

Abstract OT2-01-09: ABEMACARE: Abemaciclib in Combination with Endocrine Therapy as First Line Therapy in Metastatic Breast Cancer Patients with Symptomatic Visceral Metastases or High Tumor Burden – A prospective multicenter observational study

Abstract OT2-01-09: ABEMACARE: Abemaciclib in Combination with Endocrine Therapy as First Line Therapy in Metastatic Breast Cancer Patients with Symptomatic Visceral Metastases or High Tumor Burden – A prospective multicenter observational study