Prespecified Time Points Research Articles

Effect of Anesthesia Induction on Cardiac Hemodynamics in Patients Undergoing Durable Left Ventricular Assist Device Implantation: The EACH-LVAD Study.

Right ventricular (RV) dysfunction is common after left ventricular assist device (LVAD) implantation leading to clinical right heart failure (RHF) associated with worsened survival and quality of life. It is likely that intraoperative events such as anesthesia induction play a role in the development or unmasking of RV dysfunction in addition to known effects from hemodynamic changes that occur after LVAD implantation. The EACH-LVAD Study is a prospective, single-center, single-arm, observational cohort study of adult patients with advanced heart failure undergoing durable LVAD implantation with standard anesthesia induction. Intraoperative RV hemodynamics via central venous pressure, mean pulmonary artery pressure, pulmonary artery pulsatility index, and vasoactive-inotropic score (a simple weighted summation of standardized drug doses) and echocardiographic parameters (RV fractional area change, RV area in diastole, RV basal diameter, septum position, RV function, tricuspid regurgitation) were measured and compared at prespecified timepoints, including postinduction. Postoperative clinical RHF was determined based on published definitions. Forty-two patients receiving a first-time LVAD were included between September 2017 and March 2019. Propofol-based induction was used in 31 patients and etomidate-based induction in eight patients. A significant increase in central venous pressure (CVP; p < 0.001), mean pulmonary artery pressure (mPAP; p < 0.001), and vasoactive inotropic score (VIS; p < 0.001) with associated decrease in pulmonary artery pulsatility index (PAPi; p < 0.001) was observed. Right ventricular function worsened throughout. Right heart failure occurred in 70% of patients. Propofol-based induction was not associated with a higher risk of RHF (relative risk [RR], 1.01 [95% confidence interval {CI}, 0.64-1.61]). The EACH-LVAD study demonstrates an effect of anesthesia induction on worsened RV hemodynamics and echocardiographic changes which may have an effect on the development of RHF.

Effect of Anterior Chamber Depth and Axial Length on Corneal Endothelial Cell Density After Phacoemulsificatio

Objective: To assess the average amount of corneal endothelial cell density reduction in patients with various anterior chamber depths and axial lengths after phacoemulsification.&#x0D; Study Design: Quasi-experimental study.&#x0D; Place and Duration of Study: Armed Forces Institute of Ophthalmology, Rawalpindi Pakistan, from Jul 2022 to Dec 2022.&#x0D; Methodology: Ninety-four patients with cataract who underwent uneventful phacoemulsification surgery with IOL Implantation were included in the study. Patients were divided into two groups on the basis of anterior chamber depth and axial length values. All patients underwent surgery, and corneal endothelial cell density was measured and compared pre and post-operatively at pre-specified time points.&#x0D; Results: A significant decrease in the number of corneal endothelial cells was found between both the groups at pre and postop measurements. The mean CED decreased to 2420.04±296.73 post-operatively from 2608.44±237.22 (p&lt;0.001) among patients belonging to group 1, while for group 2 the mean CED decreased to 2484.02±254.89 from 2646.19±205.52 (p&lt;0.001), post and pre-operatively respectively. There was no significant difference found between postoperative reduction in mean CED value between group 1 and 2.&#x0D; Conclusion: In current study we conclude that there is a reduction in endothelial cell density after phacoemulsification surgery for cataract, but we failed to support the fact that anterior chamber depth or axial length can be used as potential predictors to predict the loss of endothelial cells post-operatively.

COVID-19-associated Coagulopathy Characterization using Rotational Thromboelastometry in a Prospective, Observational Cohort Study: The HemoCoV Study

Introduction: COVID-19-associated coagulopathy includes systemic and endothelial inflammation with coagulation dysregulation related to immunothrombosis. The aim of this study was to characterize this complication of SARS-CoV-2 infection in patients with moderate to severe COVID-19. Methods: An open-label, prospective observational study conducted in patients with COVID-19 moderate to severe acute respiratory failure admitted to an intensive care unit (ICU). Coagulation testing, including thromboelastometry, biochemical analysis and clinical variables, were collected at prespecified time points during the 30 days of ICU stay.Results: The study included 145 patients, 73.8% male, with a median age of 68 years (interquartile range - IQR 55 - 74). The most prevalent comorbidities were arterial hypertension (63.4%), obesity (44.1%) and diabetes (22.1%). Simplified acute physiology score II (SAPS II) was on average 43.5 (11 - 105) and sequential organ failure assessment (SOFA) at admission was 7.5 (0 - 14). During ICU stay, 66.9% of patients underwent invasive mechanical ventilation and 18.4% extracorporeal membrane oxygenation support; thrombotic and hemorrhagic events occurred in 22.1% and 15.1% of the patients respectively; anticoagulation with heparin was present in 99.2% of patients since early ICU stay. Death occurred in 35% of patients. Longitudinal studies revealed changes in almost all coagulation tests during the ICU stay. SOFA score, lymphocyte counts, some biochemical, inflammatory and coagulation parameters, including hypercoagulability and hypofibrinolysis seen in thromboelastometry, differed significantly (p &lt; 0.05), between ICU admission and discharge. Hypercoagulability and hypofibrinolysis persisted throughout ICU hospitalization, showing higher incidence and severity in non-survivors.Conclusion: COVID-19-associated coagulopathy is characterized by hypercoagulability and hypofibrinolysis from ICU admission, and persisted throughout the clinical course in severe COVID-19. These changes were more pronounced in patients with higher disease burden and in non-survivors.

Longitudinal transcriptome profiling of localized hormone-sensitive tumors in treatment-naïve ENACT patients with prostate cancer with and without enzalutamide (ENZA).

5026 Background: The ENACT trial (NCT02799745) randomized men with low- or intermediate-risk prostate cancer to 12 months of ENZA monotherapy followed by active surveillance (AS) for 12 months or to AS alone. Men were followed longitudinally, including by serial genome-wide expression profiling. Of 258 genomic signatures evaluated from baseline samples, increased Decipher genomic classifier score was prognostic for progression on AS; androgen receptor activity (AR-A) and PAM50 subtypes were associated with clinical benefit from ENZA, as previously reported. Here we present transcriptomic changes over time for men undergoing AS and those treated transiently with ENZA. Methods: Gene-expression profiling was performed via the Decipher GRID platform (Veracyte, Inc.) on 131 ENACT patient samples (ENZA, n=57; AS, n=74) collected at prespecified time points (screening, 12 months, and 24 months). Predefined GRID signatures were assessed for correlation with biological and clinical characteristics, including immune activity, treatment sensitivity, metastatic risk, and molecular subtypes. Statistical analysis was conducted by Cox proportional hazards models and logistic/linear regression; longitudinal changes were assessed by linear mixed-effects models. Results: Analysis of 12-month longitudinal samples showed significant transcriptomic changes in patients treated with ENZA, including markers of AR-A downregulation, decreased regulatory T-cell suppression, and increased immune activation. Many of the transcriptomic signature changes that occurred during ENZA treatment, including immune marker changes, were transient and returned to baseline values by 24 months following ENZA treatment discontinuation at 12 months. Conclusions: This exploratory biomarker analysis provides valuable data on transcriptomic changes in patients undergoing AS and those exposed to ENZA followed by cessation of treatment. Longitudinal analysis data provided insights into progression of early disease in the AS arm and possible strategies for extending ENZA activity beyond progression. Immune modulation with ENZA treatment may provide further insights for exploration of immunotherapy strategies. Clinical trial information: NCT02799745 .

Abstract 798: SeroNet Pooling Project of immunocompromised populations

Abstract Introduction: COVID-19 vaccination substantially reduces morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe illness. However, despite effective COVID-19 vaccines many questions remain about the efficacy of vaccines and the durability and robustness of immune responses, especially in immunocompromised persons. The NCI-funded Serological Sciences Network (SeroNet) is a coordinated effort including 11 sites to advance research on the immune response to SARS-CoV-2 infection and COVID-19 vaccination among diverse and vulnerable populations. The goals of the Pooling Project are: (1) to conduct real-world data (RWD) analyses using electronic medical records (EMR) data from four health care systems (Kaiser Permanente Northern California, Northwell Health, Veterans Affairs-Case Western, and Cedars-Sinai) to determine vaccine effectiveness in (a) cancer patients; (b) autoimmune diseases and (c) solid organ transplant recipients (SOTR); (2) to conduct meta-analyses of prospective cohort studies from eight SeroNet institutions (Cedars-Sinai, Johns Hopkins, Northwell Health, Emory University, University of Minnesota, Mount Sinai, Yale University) to determine post-vaccine immune responses in (a) lung cancer patients; (b) hematologic cancers/hematopoietic stem cell transplant (HSCT) recipients; (c) SOTR; (d) lupus. Methods: For our RWD analyses, data is extracted from EMR using standardized algorithms using ICD-10 codes to identify immunocompromised persons (hematologic and solid organ malignancy; SOTR; autoimmune disease, including inflammatory bowel disease, rheumatoid arthritis, and SLE). We use common case definitions to extract data on demographic, laboratory values, clinical co-morbidity, COVID-19 vaccination, SARS-CoV-2 infection and severe COVID-19, and disease-specific variables. In addition, we pool individual-level data from prospective cohorts enrolling patients with cancer and other immunosuppressed conditions from across network. Surveys and biospecimens from serology and immune profiling are collected at pre-specified timepoints across longitudinal cohorts. Results: Currently, we have EMR data extracted from 4 health systems including &amp;gt;715,000 cancer patients, &amp;gt;9,500 SOTR and &amp;gt;180,000 with autoimmune conditions. Prospective cohorts across the network have longitudinal data on &amp;gt;450 patients with lung cancer, &amp;gt;1,200 patients with hematologic malignancies, &amp;gt;400 SOTR and &amp;gt;400 patients with lupus. We will report results examining vaccine effectiveness for prevention of SARS-CoV-2 infection, severe COVID-19 and post-acute sequelae of COVID-19 (PAS-C or long COVID) in cancer patients compared to other immunocompromised conditions. Conclusion: Our goal is to inform public health guidelines on COVID-19 vaccine and boosters to reduce SARS-CoV-2 infection and severe illness in immunocompromised populations. Citation Format: Elham Kazemain, Jane Figueiredo, Jacek Skarbinski, Russell McBride, Viviana Simon, Amy B. Karger, F. Eun-Hyung Lee, Fred R. Hirsch, Andrea Cox, Sabra Klein, Rong Fan, Stephanie Halene, David A. Zidar, James M. Crawford, Bharat Thyagarajan, Charles Gleason, Alex Mathson, Komal Srivastava, Puleng Moshele, Toby Amoss, Martin Runnstrom, Susanne Linderman, Ananda M. Rodilla, Philip C. Mack, Yu Shyr, Anna Yin, Patrick Shea, Jennifer VanOudenhove, Hinnah Siddiqui, Brigid M. Wilson, Eric P. Elkin, Crystal A. Hsiao, Yonah Ziemba, Cheryl B. Schleicher, Sharon Fox, Lawrence H. Kushi, Karen Reckamp, Akil Merchant, Noah Merin. SeroNet Pooling Project of immunocompromised populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 798.

Protocol for a bandit-based response adaptive trial to evaluate the effectiveness of brief self-guided digital interventions for reducing psychological distress in university students: the Vibe Up study

IntroductionMeta-analytical evidence confirms a range of interventions, including mindfulness, physical activity and sleep hygiene, can reduce psychological distress in university students. However, it is unclear which intervention is most effective....

LBA02-03 FIRST RESULTS FROM SunRISE-1 IN PATIENTS WITH BCG UNRESPONSIVE HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER RECEIVING TAR-200 IN COMBINATION WITH CETRELIMAB, TAR-200, OR CETRELIMAB ALONE

LBA02-03 FIRST RESULTS FROM SunRISE-1 IN PATIENTS WITH BCG UNRESPONSIVE HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER RECEIVING TAR-200 IN COMBINATION WITH CETRELIMAB, TAR-200, OR CETRELIMAB ALONE

A Phase 1, Randomized, Double-Blinded, Placebo-Controlled and Dose-Escalation Study to Evaluate the Safety and Immunogenicity of the Intranasal DelNS1-nCoV-RBD LAIV for COVID-19 in Healthy Adults.

An intranasal COVID-19 vaccine, DelNS1-based RBD vaccines composed of H1N1 subtype (DelNS1-nCoV-RBD LAIV) was developed to evaluate the safety and immunogenicity in healthy adults. We conducted a phase 1 randomized, double-blinded, placebo-controlled study on healthy participants, age 18-55 and COVID-19 vaccines naïve, between March and September 2021. Participants were enrolled and randomly assigned (2:2:1) into the low and high dose DelNS1-nCoV-RBD LAIV manufactured in chicken embryonated eggs or placebo groups. The low and high-dose vaccine were composed of 1 × 107 EID50/ dose and 1 × 107.7 EID50/ dose in 0.2 mL respectively. The placebo vaccine was composed of inert excipients/dose in 0.2 mL. Recruited participants were administered the vaccine intranasally on day 0 and day 28. The primary end-point was the safety of the vaccine. The secondary endpoints included cellular, humoral, and mucosal immune responses post-vaccination at pre-specified time-points. The cellular response was measured by the T-cell ELISpot assay. The humoral response was measured by the serum anti-RBD IgG and live-virus neutralizing antibody against SARS-CoV-2. The saliva total Ig antibody responses in mucosal secretion against SARS-CoV-2 RBD was also assessed. Twenty-nine healthy Chinese participants were vaccinated (low-dose: 11; high-dose: 12 and placebo: 6). The median age was 26 years. Twenty participants (69%) were male. No participant was discontinued due to an adverse event or COVID-19 infection during the clinical trial. There was no significant difference in the incidence of adverse events (p = 0.620). For the T-cell response elicited after full vaccination, the positive PBMC in the high-dose group increased to 12.5 SFU/106 PMBC (day 42) from 0 (baseline), while it increased to 5 SFU/106 PBMC (day 42) from 2.5 SFU/106 PBMC (baseline) in the placebo group. The high-dose group showed a slightly higher level of mucosal Ig than the control group after receiving two doses of the vaccine (day 31, 0.24 vs. 0.21, p = 0.046; day 56 0.31 vs. 0.15, p = 0.45). There was no difference in the T-cell and saliva Ig response between the low-dose and placebo groups. The serum anti-RBD IgG and live virus neutralizing antibody against SARS-CoV-2 were undetectable in all samples. The high-dose intranasal DelNS1-nCoV-RBD LAIV is safe with moderate mucosal immunogenicity. A phase-2 booster trial with a two-dose regimen of the high-dose intranasal DelNS1-nCoV-RBD LAIV is warranted.

Risk factors for cognitive impairment in radically treated stage III NSCLC: Secondary findings of the NVALT-11 study

AimTo identify risk factors for self-reported cognitive impairment in radically treated stage III non-small cell lung cancer (NSCLC). MethodsCognitive functioning was assessed using the EORTC-QLQ-C30 at seven pre-specified time points in the phase III NVALT-11 trial (observation versus prophylactic cranial irradiation [PCI] in stage III NSCLC treated with chemo-radiotherapy ± surgery). Cognition was analyzed as binary (impairment or not) and continuous outcome, respectively, using generalized estimating equation (GEE) before and after multiple imputation. A score < 75 was defined as cognitive impairment. A mean difference by < 10, 10-<20, ≥ 20 points was regarded as of no, moderate, and large clinical effect, respectively. We categorized the cognitive impairment into four types based on changes over time: sustained, reversible, recurring, and alternating. ResultsIn the no-PCI arm, 43/84 [51.2%] reported cognitive impairment at least once, of which 31.4% were sustained, 25.7% reversible, 28.6% recurring, and 14.3% alternating. Results were similar in the PCI arm. Cognitive functioning at baseline was comparable in two arms and a score < 75 was a significant risk factor with large effect for subsequent cognitive impairment (no-PCI: β = –23.30, p < 0.001; PCI arm: β = –22.34, p < 0.001; All: β = –23.47, p < 0.001). Younger age (≤60y), squamous histology, and PCI were risk factors without clinical relevance (β > -10, p < 0.05). Cognitive functioning declined over time (β = -0.26, p = 0.001) except for patients with cognitive impairment at baseline (β = 0.141, p = 0.33). ConclusionCognitive impairment is dynamic over time with four types. Baseline cognitive impairment (score < 75) is the most important risk factor for subsequent cognitive impairment in stage III NSCLC.Note: This work has been partly reported as an oral presentation at the ESTRO 2021 meeting (OC-0176).

Longitudinal Ultrasound Evaluation of Dilapan-S During Cervical Ripening.

To assess the diameter change of hygroscopic rod dilation during 12hours of cervical ripening. This was an observational, prospective study of term women undergoing labor induction with a bishop score ≤ 6. Women were allocated into two groups (soaked gauze or no gauze) stratified by parity. Using transvaginal ultrasound, maximal rod diameters were obtained in a longitudinal plane. Measurements were taken at four pre-specified time points (3, 6, 8, and 12hours). All rods were removed at 12hours from insertion. Patient satisfaction scores between the groups were assessed. To evaluate if measures were significantly different among the four time points, a generalized linear model was used. Independent t-tests were used to compare mean rod diameter values and pain measures between the two groups. Fisher Exact tests were used to evaluate categorical satisfaction measures. Forty-four women were recruited with a total of 178 hygroscopic rods placed. Mean rod diameters (mm) were significantly different among the four time periods (3 hour: 7.9 mm [SD 0.9]; 6 hour: 9.4 mm [SD 0.9]; 8 hour: 10.0 mm [SD 0.9]; 12hour: 10.9 mm [SD 0.8]; P-value <.001). After stratifying by the use of gauze, there was no difference in rod diameters at 3, 6, 8, and 12hours respectively. There was no difference in patient satisfaction scores between the two groups. The majority of hygroscopic rod dilation occurs within the first 8 hours of cervical ripening. Placement of saturated gauze does not accelerate rod dilation.

Abstract TP158: Hemiparesis May Predict The Development Of Epilepsy In Children With Perinatal Stroke

Objective: While we know that perinatal stroke is often comorbid with hemiparesis and epilepsy, less known are the timing and potential predictors of these outcomes. With a moderate size cohort and the longest follow-up to date, we aimed to better characterize these outcomes. Methods: We identified a retrospective cohort of 78 children with perinatal strokes. Motor outcomes from neurologic examinations and other comorbidities were identified at prespecified timepoints across the subjects' lifespans. Results: With a mean follow-up of 9.5 years, 36 (46%) of our cohort developed hemiparesis. In these patients, strokes involving combined cortical and subcortical structures (basal ganglia, thalamus, deep or periventricular white matter), as well as isolated periventricular white matter made up 91% of cases (69% and 22%, respectively). However, not all children with similar lesions developed hemiparesis. 20 children who may have carried risk for hemiparesis based on their lesions (19 combined cortical and subcortical; 1 periventricular white matter) did not develop hemiparesis. Among patients who developed hemiparesis, epilepsy had a high incidence. 20 (56%) patients with hemiparesis also had epilepsy, representing 83% of all children with epilepsy in our cohort. Conversely, in non-hemiplegic children who may have been at risk for hemiparesis, only 2 (10%) developed epilepsy. Hemiparesis manifested early in life; 78% of patients by their first follow-up (mean 10 mos) and 100% of patients by ages 2-4 (mean 2.7 yrs) had overt motor deficits. Epilepsy presentations were more delayed; 7 (35%) were diagnosed by ages 2-4 (mean 3 yrs) and 11 (45%) by ages 5-7 (mean 5.9 yrs). Interpretation: Survivors of perinatal stroke were vulnerable to developing hemiparesis. Those who developed hemiparesis were also more likely to develop epilepsy. This may be the result of more extensive strokes, particularly from lesions to both cortical and subcortical structures. Importantly, these patients can be identified in infancy and be more closely monitored for the development of epilepsy.

Comparison of the Pharmacokinetics, Bioequivalence and Safety of Aqueous Progesterone Formulation Administered as either Intramuscular or Subcutaneous Injection versus Oil-based Progesterone Formulation Administered as Intramuscular Injection: A Randomised Study

Introduction: Progesterone is the treatment of choice for support of the luteal phase of controlled ovarian stimulation cycles in women undergoing an Assisted Reproductive Technology (ART) treatment. Available progesterone preparations include oral, vaginal and oil-based Intramuscular (i.m.) formulations. Oral formulation has poor bioavailability whereas vaginal formulations cause side-effects such as vaginal discharge and/ or local irritation. Oil-based progesterone formulations for i.m. use are associated with discomfort and pain at the injection site. Hence, a novel aqueous-based progesterone formulation for i.m./Subcutaneous (s.c.) was developed to avoid the local tolerability issues of the existing parenteral formulations. Aim: To assess single-dose Pharmacokinetics (PK) and relative bioavailability of i.m. (test-1; T1) or s.c. (test-2; T2) administration of novel aqueous progesterone formulation with i.m. (reference; R) administration of oil-based progesterone formulation. Materials and Methods: In this open-label, three-sequence, three-period, single-dose, cross-over study, 51 healthy human postmenopausal female subjects between 45 to 65 years of age were included. The study was conducted at Lambda Therapeutic Research Limited, Ahmedabad, Gujarat, India, between 21 May 2018 to 06 July 2018. Subjects were randomised to a single 25 mg dose of T1, T2 or R in three-periods (Period-I: T1, R, T2; Period-II: T2, T1, R; Period-III: R, T2, T1) with ≥18 days washout period. Blood samples were collected at prespecified time points in each period and analysed using validated liquid chromatography with tandem mass spectrometry. PK parameters {maximum plasma concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration vs. time curve (AUC0-t), AUC from time 0 to ∞ (AUC0-∞), plasma half-life (t1/2)} were calculated from the plasma concentration vs. time profile by non compartmental model. The total study duration was about 47 days (11 hours prior to the drug administration in Period-I until the last ambulatory sample in Period-III). All patients provided written informed consent form and an approval from the Conscience-Independent Ethics Committee (CIEC) was taken. Descriptive statistics were calculated and reported for PK parameters for baseline corrected and uncorrected data. Results: Of 72 screened patients, 51 patients were included for the PK and statistical analysis. The mean±SD age of the patients was 55.1±4.67 years. The baseline corrected PK data shows that in T1, T2 and R arms, mean (range) Tmax were 1.00 (0.50– 1.75), 1.00 (0.75–1.75) and 8.00 hours (1.00–12.00), mean±SD t ½ (h) were 15.43±5.81, 15.27±6.68 and 19.80±6.35; mean±SD Cmax (ng/mL) were 101.91±73.07, 51.67±14.81 and 18.89±7.89, and mean±SD AUC0-t (ng/mL) were 385.10±89.29, 349.63±64.41 and 371.50±56.25, respectively. Similarly, the AUC0-∞ was also comparable in all three arms. The baseline uncorrected data were also in line with baseline corrected data. For AUC0-t and AUC0-∞, 90% CIs were 98.44-107.06% and 97.96-106.15%, respectively, for T1/R ratio, and 90.01-97.90 and 89.90-97.42, respectively, for T2/R ratio. Six Adverse Events (AEs) in four subjects were reported. All AEs were mild in nature and there were no deaths, significant or serious AEs reported. Overall, all the treatments were well-tolerated without any new safety concerns. Conclusion: Novel aqueous progesterone formulation i.m./s.c was bioequivalent with oil-based progesterone formulation i.m. with respect to AUC. The s.c. administration of aqueous progesterone formulation could offer a convenient alternative to the i.m. oil-based progesterone formulation for luteal phase support to patients undergoing ART treatments

Comparison of adjuvant therapy with midazolam, paracetamol, tramadol, or magnesium sulfate during intravenous regional anesthesia with ropivacaine: A randomized clinical trial.

Intravenous (IV) regional anesthesia is an easy, safe, reliable, and efficient option for inducing anesthesia during surgeries but with tourniquet-related pain. This study aimed to evaluate midazolam, paracetamol, tramadol, and magnesium sulfate administration as adjuvants with ropivacaine on pain relief and hemodynamic changes in IV regional anesthesia. A randomized, double-blind, placebo-controlled trial was conducted in subjects undergoing forearm surgery with IV regional anesthesia. The block randomization method was used to assign eligible participants to each of five study groups. Hemodynamic parameters were assessed before applying the tourniquet, at prespecified time points (5, 10, 15, and 20 min), then and every subsequent 10 min until surgery completion. A Visual Analog Scale was used to assess pain severity at baseline followed by every 15 min until completion of the surgery, and after tourniquet deflation every 30 min to 2 h, and at 6, 12, and 24 h postoperative. Data were analyzed using Chi-square and analysis of variance with repeated data testing. The shortest onset and the longest duration of sensory block were observed in the tramadol group and the shortest onset of motor block in the midazolam group (P < 0.001). Pain score was estimated to be significantly lower in the tramadol group at the time of tourniquet application and release, and 15 min to 12 h after tourniquet release (P < 0.05). In addition, the lowest dose of pethidine consumption was observed in the tramadol group (P < 0.001). Tramadol appeared to be able to effectively relieve pain, shorten the onset of sensory block, prolong the duration of sensory block, and achieve the lowest consumption of pethidine.

Sex-stratified differences in early antithrombotic treatment response in patients presenting with ST-segment elevation myocardial infarction

The mechanisms underlying the increased risk of bleeding that female patients with ST-segment Elevation Myocardial Infarction (STEMI) exhibit, remains unclear. The present report assessed sex-related differences in response to pre-hospital dual antiplatelet therapy (DAPT) initiation in patients with STEMI. The COMPARE CRUSH trial randomized patients presenting with STEMI to receive a pre-hospital loading dose of crushed or integral prasugrel tablets in the ambulance. In this substudy, we compared platelet reactivity levels and the occurrence of high platelet reactivity (HPR; defined as platelet reactivity ≥208) between sexes at 4 prespecified time points after DAPT initiation, and evaluated post-PCI bleeding between groups. Out of 633 STEMI patients, 147 (23%) were female. Females compared with males presented with significantly higher levels of platelet reactivity and higher HPR rates at baseline (232 [IQR, 209-256] vs 195 [IQR, 171-220], P < .01, and 76% vs 41%, OR 4.58 [95%CI, 2.52-8.32], P < .01, respectively). Moreover, female sex was identified as the sole independent predictor of HPR at baseline (OR 5.67 [95%CI, 2.56-12.53], P < .01). Following DAPT initiation, levels of platelet reactivity and the incidence of HPR were similar between sexes. Post-PCI bleeding occurred more frequently in females compared with males (10% vs 2%, OR 6.02 [95%CI, 2.61-11.87], P < .01). Female sex was an independent predictor of post-PCI bleeding (OR 3.25 [95%CI, 1.09-9.72], P=.04). In this contemporary STEMI cohort, female STEMI patients remain at risk of bleeding complications after primary PCI. However, this is not explained by sex-specific differences in the pharmacodynamic response to pre-hospital DAPT initiation.

18-Month effect of tafamidis on the progression of cardiac amyloidosis evaluated according to a multiparametric expert consensus tool

Background: A recently published expert consensus document recommended a multiparametric tool to monitor cardiac disease progression in patients with transthyretin cardiac amyloidosis (ATTR-CA). We aimed to evaluate the effect of the transthyretin stabiliser drug, tafamidis, by applying this integrative tool. Methods: We retrospectively applied a multiparametric tool in a group of ATTR-CA patients who were given tafamidis between the years 2019–2021 and were followed in a dedicated clinic. We used three pre-specified follow-up timepoints: at 6, 12 and 18 months. Results: We included 16 ATTR-CA patients (wild-type (n = 14) and mutant (n = 2)). The median age at the initiation of tafamidis was 76 (IQR 70, 84) years and 75% of study patients were classified as NYHA functional class 2 or 3. All patients had elevated levels of high-sensitive troponin T (median 92 (IQR 63, 115) ng/L) and NT-proBNP (median 3784 (2290, 8773) pg/mL). At the end of 18-month follow-up, two patients have suffered from high-grade atrioventricular block and required permanent pacing, and one patient had heart-failure-related admission. Twenty-five percent and 50% of patients were classified as NYHA Class 1 at the initiation of tafamidis and at 18-months treatment, respectively. No patient was defined with disease progression at 6- or 12-month follow up; however, one patient (14%) was defined with a deteriorated disease status at 18-month follow-up. Conclusions: Based on a multiparametric tool, the use of tafamidis promoted disease stabilisation in the majority of patients at 18-month follow-up. Further study should focus on monitoring disease improvement in patients with ATTR-CA.

Mylox-1: An Open-Label, Phase IIa Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral LOXL2 Inhibitor, GB2064, in Myelofibrosis

Background: GB2064 is a high-affinity, selective, pseudo-irreversible, small-molecule inhibitor of LOXL2, a secreted glycoprotein that crosslinks extracellular matrix collagens and elastin which contributes to stiffness and loss of function of fibrotic organs. GB2064 is being developed as an oral treatment for myelofibrosis (MF), a rare myeloproliferative disease with high morbidity and mortality. Janus kinase (JAK) inhibitor therapy has brought significant advancements in the treatment of MF, but a significant proportion of patients would eventually discontinue treatment, predominantly due to the development of cytopenias (Kyukendall et al.,Ann Hematol. 2018). Thus, a substantial unmet need to develop well-tolerated disease-modifying treatments that reduce bone marrow fibrosis to improve haematological parameters, splenomegaly, symptom burden and quality of life remains. Aims: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical effects of oral GB2064 (1000 mg twice daily [BID]), which was administered to participants with primary or secondary myelofibrosis (PMF/SMF) for 9 months. Methods: Open-label study in 16 adult participants diagnosed with PMF or SMF in accordance with World Health Organization diagnostic criteria (Barbui et al., Blood Cancer 2018; Cruz et al.,Expert Rev Hematol. 2020), who are not taking a JAK inhibitor and therefore are likely to be refractory, intolerant or ineligible for such inhibitors; participants had Eastern Cooperative Oncology Group performance status 0-2, and the clinical laboratory parameters were within appropriate limits per protocol. Primary endpoint is safety and tolerability. Safety and tolerability, PK, PD and appropriate MF-specific assessments will take place at all visits except Day 7, Day 15 and Month 4 when only safety and tolerability will be assessed (Fig A). Bone marrow biopsies, magnetic resonance imaging of spleen and quality of life measures, MPN-10 and EQ-5D-5L are performed at prespecified timepoints within the protocol. Exploratory endpoints include LOXL2 binding assay in the circulation, relationships between PK plasma exposure, PD markers, and markers of clinical activity, fibrosis and inflammation biomarkers (YKL-40, PAI-1, PDGF, CCN2, collagen formation and degradation neoepitopes). The study is not formally powered. Participants who derive benefit may continue therapy for an additional 3 years (Fig B). Results: At least half of the intended participants have been enrolled and are on GB2064 treatment as of June 2022. One participant successfully completed the study in May 2022 and moved to the extension phase. GB2064 was detected in bone marrow biopsies at concentrations close to those in the plasma and demonstrated LOXL2 target engagement in the systemic compartment using a LOXL2 binding assay in plasma. No significant safety concerns were observed at a dose of 1000 mg BID to date. Conclusions: MYLOX-1 is designed to explore the safety and clinical effects of GB2064, a novel small-molecule LOXL-2 inhibitor, addressing bone marrow fibrosis as a main element of MF, with the aim to decrease extramedullary haematopoiesis and improve haematological parameters, symptom burden and the quality of life for patients with MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CTIM-20. PROSPECTIVE RANDOMIZED PHASE II PLACEBO-CONTROLLED TRIAL OF SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA (SURVIVE)

Abstract BACKGROUND Newly diagnosed glioblastoma (nGBM) has a dismal prognosis with survival of 15-18 months. Tumor associated “survivin” protein is expressed in &amp;gt;95% of nGBM and is targetable with the use of SurVaxM, shown to be effective at generating cytotoxic T lymphocytes. METHODS nGBM patients are being enrolled in this randomized placebo-controlled trial phase II study. Eligibility Criteria includes age ≥ 18, KPS ≥ 70, IHC confirmed survivin-expression, and residual contrast enhancement of ≤1 cm3 by MRI, within 72 hours of surgical resection. Patients are randomized 3:2 into two arms A:B to treatment with SurVaxM in emulsion with Montanide plus sargramostim (local injection) and standard-of-care TMZ (Arm A), or placebo (saline in emulsion with Montanide) plus saline (local injection) and standard-of-care TMZ (Arm B). There are three active treatment phases in the study with vaccine priming (VP) phase; adjuvant TMZ phase; and Vaccine Maintenance (VM) phase. A total of four (4) priming doses of SurVaxM in Montanide plus sargramostim (“SurVaxM/sargramostim”) or placebo in Montanide/saline (“Placebo/Placebo”) will be administered every two weeks ( ± 3 days) during the priming phase, with subsequent dosing every 8 weeks ( ± 1 week) during the vaccine maintenance phase. After priming doses, SurVaxM/sargramostim or Placebo/Placebo will be administered every 8 weeks ( ± 1 week) until tumor progression or for a maximum of 24 months. The total sample size is of 265 patients, with 159 patients in the SurVaxM arm and 106 patients in the control arm. The primary objective is to determine the overall survival (OS), and the secondary objectives include progression-free survival (PFS), OS at pre-specified time points (OS-15, OS-18 and OS-24), PFS at pre-specified time points (PFS-3, PFS-6 and PFS-12) and evaluation of toxicities. Study duration is expected at 36 months, with enrollment ongoing at several centers and planned for total of 20 participating centers.

Real-world evidence on siponimod treatment in patients with secondary progressive multiple sclerosis

BackgroundTherapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing–remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape.MethodsWe conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions.ResultsUnder siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy.ConclusionTreatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE.

HEALTH-RELATED QUALITY OF LIFE IN CHILDREN AND CAREGIVER PROXIES FROM TRIALS OF PEANUT ORAL IMMUNOTHERAPY

<h3>Introduction</h3> We assessed health-related quality of life (HRQoL) of pediatric participants across phase 3 and follow-on trials for peanut (<i>Arachis hypogaea</i>) allergen powder-dnfp (PTAH). <h3>Methods</h3> HRQoL data were analyzed from PALISADE (ARC003), ARC004 (PALISADE follow-on; daily dosing cohorts), ARTEMIS (ARC010), RAMSES (ARC007), and ARC011 (RAMSES follow-on) using the Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM). Assessments were completed by caregiver proxies of participants aged 4-17 years and participants aged 8-17 years at prespecified time points. Scores were summarized descriptively, and mean changes were reported for between groups (PTAH vs placebo) and within groups (PTAH only) from the screening to exit visit. <h3>Results</h3> Baseline FAQLQ and FAIM mean total scores appeared comparable between placebo- and PTAH-treated participants. Self- and caregiver proxy-reported total scores on the FAQLQ and FAIM for PTAH-treated participants generally improved over time from baseline to exit throughout all trials (<b>Table</b>). PTAH was generally favored in PALISADE and ARTEMIS versus placebo. PTAH-treated participants reported statistically significant changes in scores for self-reported responses (mean change) versus placebo for domains relating to allergy avoidance and dietary restrictions (-1.46 for ages 8-12, ARTEMIS) and risk of accidental exposure (-1.44 for ages 8-12, ARTEMIS) on the FAQLQ, and death (-0.91 for ages 8-12, PALISADE; -1.29 for ages 13-17; ARTEMIS) and severe reaction (-0.77 for ages 8-12, RAMSES; -1.57 for ages 13-17, ARTEMIS) on the FAIM. <h3>Conclusion</h3> PTAH for peanut allergy management appeared to be associated with an improvement in reported HRQoL in children.

The Use of Breast Cup Immobilization in Radiation Therapy and Patient Reported Outcomes on Cosmesis and Pain

<h3>Purpose/Objective(s)</h3> Breast cosmesis and pain are among the most reported outcomes in patients undergoing breast irradiation. There is variability in the degree of adverse reactions based on different patient specific characteristics. It has been found that women with large body habitus, African American race, and larger breast size tend to have an increased chance of experiencing worse toxicity from treatment. Attempts to improve cosmesis and pain have been highly explored. We explore here whether the use of a breast cup for treatment leads to worse cosmesis and pain when compared to those treated without a breast cup. This is an important topic as it is felt that the use of a breast cup would provide a significant dosimetric advantage (i.e., organ at risk dosing) during treatment. We now explore this treatment option through a retrospective analysis of patient reported outcomes experienced during and after completing post-operative radiation therapy to the breast. <h3>Materials/Methods</h3> 645 patients undergoing adjuvant breast irradiation were evaluated from 2011 through 2019. 79 patients were treated using a breast cup. Mean heart dose was analyzed and compared between the two treatment groups and was found to be comparable in each arm. Additionally, patient reported outcomes among the entire cohort were collected via survey documentation forms during treatment, at 1 month post treatment, and at 1 year after treatment. These results were collected using the Michigan Radiation Oncology Quality Consortium (MROQC) database as each patient was consented to enroll in MROQC prior to starting treatment. The outcomes of skin changes, lymphedema, and breast pain among the two treatment groups were then compared for statistically significant differences via a logistic regression analysis. <h3>Results</h3> Patients were evaluated at 3 time points; during treatment, 1-month post-treatment and at 1 year after treatment. Of the 79 patients treated with a breast cup, when compared to the no cup patients, grade 2 pruritus and grade 1 alteration in skin texture were not significantly different at any time point (p > 0.05). With regards to lymphedema, no statistically significant difference was seen between the two groups of patients outside of the 1 month after treatment survey time point; all p values greater than 0.05 except for the 1-month mark (p value 0.03). Lastly, breast pain survey remarks at the pre-specified time points failed to show a significant difference in the symptom between the two analyzed treatment groups (p> 0.05). <h3>Conclusion</h3> From our patient's perspective, the use of a breast cup during radiation therapy did not negatively impact breast cosmesis or pain when compared to patients treated without a cup. Breast cup use was also found to produce similar dosimetric coverage to the heart as non-cup patients, even in left sided breast cancers.