Previous Randomized Clinical Trials Research Articles

Protocol for the Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Studies.

In post hoc analyses of our previous phase 2b Bayesian randomized clinical trial (RCT), prophylaxis with enoxaparin reduced central venous catheter (CVC)-associated deep venous thrombosis (CADVT) in critically ill older children but not in infants. The goal of the Catheter-Related Early Thromboprophylaxis with Enoxaparin (CRETE) Studies is to investigate this newly identified age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against CADVT in critically ill children. Two parallel, multicenter Bayesian superiority explanatory RCTs, that is, phase 3 for older children and phase 2b for infants, and an exploratory mechanistic nested case-control study (Trial Registration ClinicalTrials.gov NCT04924322, June 7, 2021). At least 15 PICUs across the United States. Older children 1-17 years old ( n = 90) and infants older than 36 weeks corrected gestational age younger than 1 year old ( n = 168) admitted to the PICU with an untunneled CVC inserted in the prior 24 hours. Subjects with or at high risk of clinically relevant bleeding will be excluded. Prophylactic dose of enoxaparin starting at 0.5 mg/kg then adjusted to anti-Xa range of 0.2-0.5 international units (IU)/mL for older children and therapeutic dose of enoxaparin starting at 1.5 mg/kg then adjusted to anti-Xa range of greater than 0.5-1.0 IU/mL or 0.2-0.5 IU/mL for infants while CVC is in situ. Randomization is 2:1 to enoxaparin or usual care (no enoxaparin) for older children and 1:1:1 to either of 2 anti-Xa ranges of enoxaparin or usual care for infants. Ultrasonography will be performed after removal of CVC to assess for CADVT. Subjects will be monitored for bleeding. Platelet poor plasma will be analyzed for markers of thrombin generation. Samples from subjects with CADVT will be counter-matched 1:1 to subjects without CADVT from the opposite trial arm. Institutional Review Board approved the "CRETE Studies" on July 1, 2021. Enrollment is ongoing with planned completion in July 2025 for older children and July 2026 for infants.

CTIM-34. EFFECTS OF NEOADJUVANT IMMUNE CHECKPOINT INHIBITION ON PEDIATRIC AND ADULT HIGH-GRADE GLIOMAS

Abstract High-grade gliomas (HGG) are lethal tumors with few long-term survivors affecting adult and pediatric patients. Studies investigating immune checkpoint inhibition (ICI) suggest administration of neoadjuvant anti-PD1 blockade (neo-aPD1) enhances local and systemic anti-tumor responses. This data is supported by increased T cell density in the tumor and proportion of cytotoxic T cells in peripheral blood. In a previous randomized clinical trial, neo-aPD1 improved survival in adult with recurrent glioblastoma. In this study, we utilized multiplex immunofluorescence (mIF), and single-cell RNA sequencing (scRNA-seq) to investigate the effects of neoadjuvant ICI on the TME and compare between pediatric and adult populations. Tissue samples from adult patients with recurrent GBM treated with neo-aPD1 (n=22) or adjuvant only therapy (n=5) were obtained from our UCLA off-label neo-PD1 study. Tissue samples were also obtained from pediatric patients with recurrent/progressive HGG treated with neoadjuvant ICI from the ongoing Pediatric Neuro-Oncology Consortium study PNOC19. Samples included diagnostic tissue from two patients and on study surgery tissue from four patients. All tissue samples were subjected to mIF and underwent imaging analysis to assess immune cell infiltration by quantifying lymphoid and myeloid cell densities across the two treatment groups. Our preliminary findings elucidated a trend of higher T cell infiltration in adult neoadjuvant compared to adjuvant-only treated patients (median density 58.11 vs 15.15 T-cells/mm2). Compared to their adult counterparts, neoadjuvant ICI treated pediatric patients had even more robust total T cell infiltration (median density 268.10 vs 58.11 T-cell/mm2, pediatric vs adult respectively). scRNA-seq analysis revealed a greater enrichment of monocytic macrophages in the pediatric population compared to tissue resident microglia in the adults. This early data requires analysis of additional samples to better understand differences in the anti-tumor immune response between adult and pediatric recurrent/progressive HGG patients.

Heterogeneous effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular events among people with type 2 diabetes: an application of machine learning to target trial emulation

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are widely used to reduce cardiovascular risk in patients with type 2 diabetes. However, certain patient subgroups, including younger individuals or those with lower body mass index (BMI), have been underrepresented in previous randomized clinical trials. Therefore, the consistency of the effectiveness of SGLT2i has not been thoroughly investigated. Purpose This research aims to investigate the individual benefit of SGLT2i on cardiovascular risk reduction across the diverse patient population with type 2 diabetes Methods We investigated the effectiveness of SGLT2i versus active comparators (dipeptidyl peptidase 4 inhibitors [DPP4i]) using a target trial emulation framework, prevalent new-user design, and a nationwide insurer-based database covering more than 30 million working-age citizens in Japan. Participants were identified using data from April 2015 to March 2022 and were followed until March 2023. The primary endpoint was the composite of all-cause death, myocardial infarction, stroke, or heart failure. We then applied the machine learning causal forest algorithm to the emulated trial cohort to predict the individualized benefit of SGLT2i in reducing cardiovascular outcomes. After describing the characteristics of patients with predicted benefits above the median (high-benefit group) and those with predicted benefits below the median (low-benefit group), we compared the long-term survival outcomes between the high-benefit group and the low-benefit group using adjusted Cox proportional hazard models. Results The study included 274,886 participants (SGLT2i, n=137,443; DPP4i, n=137,443) with a mean age of 55.7 years, 17.3% (n=47,517) female, and a mean BMI of 27.3kg/m2. Over a median follow-up of 36 months, 3.6% (n=9,896) experienced the primary outcome. SGLT2i were associated with a reduced incidence of the primary endpoint in the entire cohort (hazard ratio [HR] = 0.94 [95% confidence interval (95%CI): 0.90–0.97]). The causal forest model showed that the effects of SGLT2i were heterogeneous across individuals. Patients in the low-benefit group were characterized by older age, female gender, lower BMI, lower blood pressure, worse kidney function, and milder diabetes status than those in the high-benefit group. While we found the preventive effect of SGLT2i on long-term cardiovascular outcomes in the high-benefit group (HR [95%CI] = 0.86 [0.82–0.90]), the effect was not observed in the low-benefit group (HR [95%CI] = 1.05 [1.00–1.11]; p-for-interaction < 0.001). Conclusion By applying a machine-learning causal forest to a target trial emulation cohort in the general population, we found heterogeneity in the effect of SGLT2i on cardiovascular outcomes, and identified characteristics of patients who are less likely to benefit from SGLT2i. The findings suggest personalized treatment strategies for cardiovascular risk reduction in patients with type 2 diabetes.Graphical summary

Clinical Outcomes and Tendon Structure at 3- to 4-Year Follow-up After Exercise-Based Treatment of Patellar Tendinopathy: A Prospective Study.

The long-term recovery (in years) of patellar tendinopathy treated with loading-based rehabilitation remains largely unknown. To examine the clinical outcome and tendon structure years after exercise-based treatment of chronic patellar tendinopathy. Case series; Level of evidence, 4. This was a 3- to 4-year follow-up evaluation of participants (N = 28) from a previous randomized clinical trial by the author group. All participants received loading-based rehabilitation for 12 weeks with either moderate-slow resistance (55% of 1 repetition maximum) or heavy-slow resistance (up to 90% of 1 repetition maximum). Both groups showed similar improvements after 3 and 12 months and were therefore collapsed in the present analysis. Function and symptoms (the Victorian Institute of Sport Assessment-Patella [VISA-P] questionnaire), tendon pain (numeric rating scale [NRS] during activity and during a single-leg decline squat test), and tendon structure (tendon vascularization and thickness on ultrasound) were assessed. The mean follow-up was 3.6 ± 0.4 years after the baseline assessment in the original clinical trial. The VISA-P score was 83.9 ± 11.9 (95% CI, 79.3-88.5) at the latest follow-up and did not differ from the 1-year follow-up score (P = .54). Similarly, NRS score during preferred sport (1.6 ± 1.7; 95% CI, 0.9-2.2) and single-leg decline squat (1.0 ± 1.8; 95% CI, 0.3-1.7) did not differ from the 1-year values and remained elevated. Power Doppler area and tendon thickness decreased significantly from 1 year to latest follow-up (P < .0001 and P = .02, respectively), but power Doppler area >1 mm2 was still present in 43% of the participants after 3 to 4 years, and the tendon thickness was still mildly elevated (6.4 ± 1.8 mm; 95% CI, 5.7-7.1 mm). Sports participation after 3 to 4 years (3.9 ± 2.7 h/wk; 95% CI, 2.9-7.1 h/wk) was significantly lower compared with preinjury levels (P < .0001). Clinical symptoms remained even years after loading-based treatment for patellar tendinopathy, whereas some but not all tendon structures normalized in this longer term follow-up.

Efficacy and safety of TOMAC for treatment of medication-naïve and medication-refractory restless legs syndrome: A randomized clinical trial and meta-analysis

Objective/backgroundThere is a significant unmet need for safe and effective nonpharmacological therapies for restless legs syndrome (RLS). The objective was to evaluate the efficacy and safety of tonic motor activation (TOMAC) in patients with RLS. Patients/methodsA multicenter, randomized, participant-blinded, sham-controlled trial enrolled 45 adults with primary moderate-to-severe RLS who were either medication-naïve (n = 20) or medication-refractory (n = 25). Participants were 1:1 randomized to TOMAC (n = 22) or sham (n = 23) for two weeks and instructed to self-administer 30-min TOMAC sessions when they experienced RLS symptoms. The primary outcome was mean change in International RLS Study Group Rating Scale (IRLS) total score. A subsequent meta-analysis included the present trial and a previous randomized clinical trial that enrolled medication-naïve RLS patients. ResultsIRLS reduction was significantly greater for TOMAC than sham (TOMAC -6.59 vs. sham −2.17; mean difference (MD) = −4.42; 95 % confidence interval [CI] −1.57 to −7.26; p = 0.0040). Subgroup analysis showed similar IRLS mean difference for medication-refractory (MD = −4.50; p = 0.02) and medication-naïve (MD = −4.40; p = 0.08) cohorts, which was significantly different from sham only for the medication-refractory cohort. Meta-analysis of combined data from 33 medication-naïve RLS patients showed a significant reduction in mean IRLS score after two weeks for TOMAC compared to sham (MD = −4.30; 95 % CI -1.36 to −7.24; p = 0.004). ConclusionsThe present trial confirmed previous reports documenting efficacy and safety of TOMAC in refractory RLS and indicated similar effect sizes in refractory versus naïve subgroups. The meta-analysis demonstrated that TOMAC significantly improves RLS symptoms in naïve participants.

Prognostic factors of second-line nivolumab monotherapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study for 184 cases.

The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated. This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors. Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1months and overall survival was 14months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7months. Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding.

Long-Term Outcomes of Self-Fit vs Audiologist-Fit Hearing Aids

With rising interest in over-the-counter (OTC) hearing aids as an alternative to traditional audiologist-fit devices, understanding their long-term efficacy is crucial. However, given the novelty of the US Food and Drug Administration category of OTC hearing aids, minimal evidence currently supports their long-term efficacy. To compare the long-term self-reported outcomes at 8 months of self-fit OTC hearing aids to the same hearing aids fit by audiologists. Building on a previous randomized clinical trial, this follow-up comparative effectiveness research study reassessed a number of the original participants that were not lost to follow-up. Participants were initially divided into those with self-fit OTC hearing aids and those with audiologist-fit devices. Approximately 8 months after fitting, participants completed self-reported questionnaires. Missing data were addressed through multiple imputation. The original noninferiority trial was conducted at the University of Pretoria in South Africa from April 2022 to August 2022. The current analysis took place between July 7, 2023, to November 20, 2023. In the original trial, participants in the self-fit device group received a pair of OTC hearing aids and independently fit them with remote support as needed. The audiologist-fit device group received the same hearing aids fit by a certified audiologist using best practices. The main outcomes were self-reported hearing aid benefit, measured using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the International Outcome Inventory for Hearing Aids (IOI-HA). Of 64 participants in the trial, 44 participants were included in the extension study (21 [47.7%] in the audiologist-fit group; 23 [52.3%] in the self-fit group). The mean (SD) age of these participants was 63.0 (13.2) years, and 21 (47.7%) were male. At the long-term follow-up, self-fit and audiologist-fit groups showed no significant differences in the APHAB global score (mean difference, 0.02 [95% CI, -7.1 to 7.1]; Cohen d, 0.01 [95% CI, -0.5 to 0.5]) or the IOI-HA total score (mean difference, 1.5 [95% CI, -1.4 to 4.4]; Cohen d, 0.3 [95% CI, -0.2 to 0.8]). From 6 weeks to 8 months, no clinically meaningful group-time interaction was found between groups for the APHAB global score (Cohen d, 0.1 [95% CI, -0.2 to 0.3]), but a significant interaction for the IOI-HA total score was found (Cohen d, -0.6 [95% CI, -0.8 to -0.3]), with the self-fit group generally performing better. This comparative effectiveness research study demonstrated that self-fit OTC hearing aids can offer comparable long-term benefits to audiologist-fit hearing aids for individuals with mild to moderate hearing loss.

Probiotics plus vitamin D in irritable bowel syndrome: a prospective multicentric non-interventional study.

Patients with irritable bowel syndrome (IBS) experience recurrent symptoms and anxiety disorders that significantly impact their quality of life (QoL). The aim of the study was to assess in daily practice the benefit of the combination of three probiotic strains (Lactobacillus plantarum CETC 7484 and CETC 7485; Pediococcus acidilactici CECT 7483) plus vitamin D in patients with diarrhea-predominant IBS (IBS-D) or IBS with mixed bowel movements (IBS-M). This was a prospective, multicenter, non-interventional study in adult patients with IBS-D or IBS-M (Rome IV criteria) followed by private-practice gastroenterologists. Patients received daily one sachet of a combination of probiotics (3×109 CFU) and vitamin D (10 μg) for 42 days. The primary endpoint was the responder rate at D42 (≥50% and/or ≥100-point decrease of IBS-Severity Scoring System; IBS-SSS). Gut-related anxiety was measured with the Visceral Sensitivity Index (VSI). The full analysis set population included 246 patients (mean age, 51.2±15.4 years; women, 73.2%; IBS-D, 56.1%; IBS-M, 43.9%). At D42, among the 89 patients with evaluable data, the responder rate was 62.9% with a mean decrease of IBS-SSS of 146.6±125.9 (P<0.0001). Changes of IBS-SSS were significantly correlated with changes of IBS-QoL (r=-0.78; P<0.0001), HAD-anxiety (r=0.46; P<0.0001), HAD-depression (r=0.61; P<0.001) and VSI (r=0.74; P<0.0001). These real-life results are in line with a previous randomized clinical trial demonstrating the benefits of this combination in IBS-D and IBS-M. Symptom relief was associated with improvement of IBS-QoL, anxiety, depression and specifically gut-related anxiety.

Hyaluronic acid as a pulpotomy material in primary molars: an up to 30 months retrospective study

BackgroundThe aim of this retrospective study was to determine the long-term clinical and radiographic success of our previous randomized clinical trial and to compare the success of hyaluronic acid, with the widely used formocresol and ferric sulphate agents.MethodsThis retrospective study is the extension of the 1-year survey of our randomized clinical trial that had compared the effectiveness of a hyaluronic acid pulpotomy over formocresol and ferric sulphate pulpotomies and included clinical and radiographic evaluations with a follow-up period of over 24 months for 44 children who applied to our clinic between May 2019 and September 2019. Long-term clinical and radiographic data were obtained from the periodic files of our department, wherein each tooth’s file was examined to identify any clinical and radiographic findings. Descriptive statistics and Pearson’s chi-square tests were used to evaluate the data. Statistical significance was considered as p < 0.05.ResultsThe clinical and radiographic success rates of the hyaluronic acid, formocresol, and ferric sulphate groups were not statistically different at > 24 months. None of the teeth in the hyaluronic acid group showed any clinical findings at > 24 months.ConclusionsHyaluronic acid pulpotomies exhibited comparable success rates to formocresol and ferric sulphate materials spanning over 24 months examinations. Because of convenient accessibility and applicability of hyaluronic acid, it may be recommended as a promising alternative medicament for pulpotomy treatments of primary molars. However, further long-term follow-up human studies are needed to better understand the effect of hyaluronic acid on the dental pulp of human primary molars.

Atrioventricular Interval Modulation (AVIM) therapy for ambulatory systolic blood pressure (aSBP) reduction with a dual chamber pacemaker: comparison of conduction system vs. right ventricular pacing

Abstract Background AVIM is a pacing algorithm incorporated into dual-chamber pacemakers to treat hypertension. AVIM delivers repeating sequences of short and longer atrioventricular delays leading to reduced preload and afterload. The therapy lowers blood pressure while simultaneously modulating the autonomic nervous system. The marked blood pressure reducing capability of AVIM has been already confirmed by a previous randomized clinical trial using conventional right ventricular (RV) pacing. Nevertheless, whether a similar blood pressure reduction could be also achieved by AVIM when conduction system pacing (CSP) is applied instead of RV pacing has not been investigated yet. Considering the facts that CSP using Left Bundle Branch Area Pacing (LBBAP) has been found to elicit more synchronous ventricular contraction and improved hemodynamics compared to RV pacing and AVIM is associated with a signficant burden of ventricular pacing, it is tempting to hypothesize that AVIM with CSP could be particularly beneficial. Purpose To compare the effects of AVIM therapy when delivered via an LBBAP location with the effects when delivered using a traditional RV lead location. Methods This single-center study evaluated subjects indicated for a dual chamber pacemaker who also had uncontrolled hypertension despite a stable dose of ³ 1 antihypertensive drug. Leads were placed in the RV or the LBBAP position. Subjects entered a run-in period of 4 weeks in which baseline office (oSBP)and 24-hour aSBP were measured. Subjects with baseline aSBP &amp;gt;130 mmHg and oSBP&amp;gt;140 mmHg at week 4 were included in the study. AVIM therapy was activated and a 24-hour aSBP was performed immediately after activation. Results Using a dedicated CSP pacemaker lab setup, CSP was performed in 5 patients with the Select Secure electrode (model 3830-69 cm) delivered via a fixed curve sheath (C315HIS). During the run in phase, in 3 out of the 5 CSP-AVIM patients, high blood pressure did not reach the level of inclusion and therefore these patients were not used for further analysis. In the remaining two patients, AVIM was activated. These two patients had a V6 stimulus-peak time of 69 ms and 61 ms, while V1 stimulus peak time was: 121ms and 109ms respectively. The effect of AVIM on 24-hour aSBP in the activated CSP-AVIM patients was compared to the average effect seen in patients from the same center enrolled in the prior randomized study with leads in the RV. Table 1 shows individual aSBP values for the two patient groups. Results suggest that delivery of AVIM therapy through leads in either position generates a significant reduction in blood pressure: -24.1 mmHg vs. -15.4 mmHg when the lead is placed in LBBAP or RV positions respectively. Conclusion These results demonstrate a significant reduction in aSBP in both lead locations. Additional studies evaluating larger sample sizes are required to assess if specific lead positions are preferable.Table 1

Parallel Cerebrospinal Fluid and Serum Temporal Profile Assessment of Axonal Injury Biomarkers Neurofilament-Light Chain and Phosphorylated Neurofilament-Heavy Chain: Associations With Patient Outcome in Moderate-Severe Traumatic Brain Injury.

Neurofilament-light chain (NF-L) and phosphorylated neurofilament-heavy chain (pNF-H) are axonal proteins that have been reported as potential diagnostic and prognostic biomarkers in traumatic brain injury (TBI). However, detailed temporal profiles for these proteins in blood, and interrelationships in the acute and chronic time periods post-TBI have not been established. Our objectives were: 1) to characterize acute-to-chronic serum NF-L and pNF-H profiles after moderate-severe TBI, as well as acute cerebrospinal fluid (CSF) levels; 2) to evaluate CSF and serum NF-L and pNF-H associations with each other; and 3) to assess biomarker associations with global patient outcome using both the Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). In this multi-cohort study, we measured serum and CSF NF-L and pNF-H levels in samples collected from two clinical cohorts (University of Pittsburgh [UPITT] and Baylor College of Medicine [BCM]) of individuals with moderate-severe TBI. The UPITT cohort includes 279 subjects from an observational cohort study; we obtained serum (n = 277 unique subjects) and CSF (n = 95 unique subjects) daily for 1 week, and serum every 2 weeks for 6 months. The BCM cohort included 103 subjects from a previous randomized clinical trial of erythropoietin and blood transfusion threshold after severe TBI, which showed no effect on neurological outcome between treatment arms; serum (n = 99 unique subjects) and CSF (n = 54 unique subjects) NF-L and pNF-H levels were measured at least daily during Days (D) 0-10 post-injury. GOS-E and DRS were assessed at 6 months (both cohorts) and 12 months (UPITT cohort only). Results show serum NF-L and pNF-H gradually rise during the first 10 days and peak at D20-30 post-injury. In the UPITT cohort, acute (D0-6) NF-L and pNF-H levels correlate within CSF and serum (Spearman r = 0.44-0.48; p < 0.05). In the UPITT cohort, acute NF-L CSF and serum levels, as well as chronic (Months [M]2-6) serum NF-L levels, were higher among individuals with unfavorable GOS-E and worse DRS at 12 months (p < 0.05, all comparisons). In the BCM cohort, higher acute serum NF-L levels were also associated with unfavorable GOS-E. Higher pNF-H serum concentrations (D0-6 and M2-6), but not CSF pNF-H, were associated with unfavorable GOS-E and worse DRS (p < 0.05, all comparisons) in the UPITT cohort. Relationships between biomarker levels and favorable outcome persisted after controlling for age, sex, and Glasgow Coma Scale. This study shows for the first time that serum levels of NF-L and pNF-H peak at D20-30 post-TBI. Serum NF-L levels, and to a lesser extent pNF-H levels, are robustly associated with global patient outcomes and disability after moderate-severe TBI. Further studies on clinical utility as prognosis and treatment-response indicators are needed.

Effect of lidocaine on intraoperative blood pressure variability in patients undergoing major vascular surgery

BackgroundDynamic fluctuations of arterial blood pressure known as blood pressure variability (BPV) may have short and long-term undesirable consequences. During surgical procedures blood pressure is usually measured in equal intervals allowing to assess its intraoperative variability, which significance for peri and post-operative period is still under debate. Lidocaine has positive cardiovascular effects, which may go beyond its antiarrhythmic activity. The aim of the study was to verify whether the use of intravenous lidocaine may affect intraoperative BPV in patients undergoing major vascular procedures.MethodsWe performed a post-hoc analysis of the data collected during the previous randomized clinical trial by Gajniak et al. In the original study patients undergoing elective abdominal aorta and/or iliac arteries open surgery were randomized into two groups to receive intravenous infusion of 1% lidocaine or placebo at the same infusion rate based on ideal body weight, in concomitance with general anesthesia. We analyzed systolic (SBP), diastolic (DBP) and mean arterial blood (MAP) pressure recorded in 5-minute intervals (from the first measurement before induction of general anaesthesia until the last after emergence from anaesthesia). Blood pressure variability was then calculated for SBP and MAP, and expressed as: standard deviation (SD), coefficient of variation (CV), average real variability (ARV) and coefficient of hemodynamic stability (C10%), and compared between both groups.ResultsAll calculated indexes were comparable between groups. In the lidocaine and placebo groups systolic blood pressure SD, CV, AVR and C10% were 20.17 vs. 19.28, 16.40 vs. 15.64, 14.74 vs. 14.08 and 0.45 vs. 0.45 respectively. No differences were observed regarding type of surgery, operating and anaesthetic time, administration of vasoactive agents and intravenous fluids, including blood products.ConclusionIn high-risk vascular surgery performed under general anesthesia, lidocaine infusion had no effect on arterial blood pressure variability.Trial registrationClinicalTrials.gov; NCT04691726 post-hoc analysis; date of registration 31/12/2020.

Abstract PO5-18-12: Can we cure de novo oligometastatic stage IV HER2+ breast cancer with multimodality therapy? (CHLOE)

Abstract Background: The current standard of care is to treat all patients with metastatic breast cancer with palliative intent, regardless of extent of disease. However, in real world practice patients with oligometastatic disease are sometimes treated with surgery and/or radiation/ablation in combination with systemic therapy to render them as having no evidence of disease. Previous randomized clinical trials have not shown a benefit to adding surgery or radiation in metastatic breast cancer, however, these trials had a small number of HER2+ patients. HER2+ patients are uniquely responsive to combination of chemotherapy and targeted HER2 therapy and therefore may have different outcomes with a multimodality approach. The goal of this project is to use a novel, user friendly, on-line clinical study platform that registers patients and enables follow-up data collection to test the hypothesis that de novo stage IV oligometastatic HER2+ patients treated with multimodality therapy may result in improved long-term distant metastasis free survival and overall survival. Trial design: This is a prospective, nationwide registry study that will enroll newly diagnosed (de novo) oligometastatic (operationally defined by local tumor boards as disease where all metastatic lesions can be ablated) HER2+ breast cancer. A secure online portal has been created by the Yale IT team in accordance with HIPPA and cybersecurity guidelines. Data will be directly entered into the online portal by participating investigators and information regarding what treatment the patient received, if they completed treatment, and survival data will be collected. All treatment decisions will be at the discretion of the treating provider. Eligibility criteria: Patients with de novo oligometastatic HER2+ breast cancer in whom local treatment of all metastatic sites by either surgery, radiation, or ablative techniques is feasible as determined by multidisciplinary discussion or local tumor board. Specific aims: Primary: To estimate the 3 year distant metastasis free survival in patients with de novo oligometastatic HER2+ breast cancer treated with a multi-modality treatment plan. Secondary: To estimate 3 year overall survival and to monitor QOL. Statistical methods: The major analysis will occur after at least 3 years following the last subject’s enrollment in a cohort, to ensure that the objective of distant metastasis free survival at 3 years will be analyzed. It will include: tabulation of all cases entered, number and location of metastases, if treatment plan was implemented, compliance rate of treatment delivery, observed results with respect to the primary endpoint. Kaplan-Meier estimates will be presented for the analysis of survival endpoints together with a summary of associated statistics (median survival time if reached, landmark survival rate estimates and estimates for every 6 months thereafter if applicable), including the corresponding two-sided 95% confidence intervals. The 95% exact Clopper Pearson confidence intervals will be presented for binary endpoints. Paired t-test or Wilcoxon signed rank test will be used to assess the difference of continuous variables measured at different time points. The secondary clinical outcome is overall survival at 3 years, defined as the percentage of patients without an event at the 3-year follow-up time point measured from the study registration date. An event is considered death from any cause. OS time will be measured from the date of randomization to the date of first OS failure or last follow-up. OS will be estimated by the Kaplan-Meier method with OS failure defined as: death from any cause. Present accrual and target accrual: 4/42 patients Contact information for people with a specific interest in the trial: Mariya.Rozenblit@yale.edu https://chloe.yalepathaws.org Citation Format: Mariya Rozenblit, Nathalie Wiesendanger, Kelly Shanahan, Christine Hodgdon, Peter Gershkovich, Mehra Golshan, Meena Moran, Maryam Lustberg, Lajos Pusztai. Can we cure de novo oligometastatic stage IV HER2+ breast cancer with multimodality therapy? (CHLOE) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-12.

Abstract PO5-01-03: Neoadjuvant HER2-targeted regimens with or without anthracyclines for HER2-positive inflammatory breast cancer (IBC): a multicenter retrospective study

Abstract Background Previous randomized clinical trials have shown no significant benefit with the addition of anthracyclines to neoadjuvant treatment for HER2-positive breast cancer. However, these studies did not focus on inflammatory breast cancer (IBC), or a small minority of patients on these trials. The study aims to compare pathologic complete response rates with and without anthracyclines in HER2-positive IBC. Methods We reviewed patients diagnosed with Stage III HER2-positive IBC who underwent neoadjuvant therapy and modified radical mastectomy at MD Anderson Cancer Center and Dana-Farber Cancer Institute between 2014 and 2021. Patients received either docetaxel/trastuzumab/pertuzumab-doxorubicin/cyclophosphamide (THP-AC) or docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP). The primary outcome was pathologic complete response (pCR) rate, defined as ypTisT0/N0. Secondary outcomes included 2-year event-free survival (EFS) and overall survival (OS). Univariate and multivariable analyses were performed with adjustments for clinically relevant covariates. Results Ninety-nine patients were included in the analysis. Thirty-nine patients received TCHP and 60 received THP-AC. The median follow-up time was 3.02 years. Three patients had disease progression during neoadjuvant therapy. pCR rates did not differ between the two regimens (48.7% TCHP vs. 51.7% THP-AC; p = 0.774). Patient’s baseline characteristics did not significantly affect the pCR rate, except for age. A multivariable logistic regression model adjusted for age and estrogen receptor (ER) status did not show a significant association between pCR and regimen (odds ratio 1.232, 95% CI 0.537–2.829 for THP-AC vs. TCHP, p = 0.623). The 2-year EFS rates for TCHP and THP-AC were 57% and 74%, respectively. In univariate analysis, patients who received THP-AC had better EFS than patients who received TCHP (hazard ratio [HR] 0.423, 95% CI 0.214–0.835, p = 0.013). The EFS benefit of THP-AC remained statistically significant after adjusting for age and type of adjuvant therapy in the final reduced multivariable Cox model (HR 0.441, 95% CI 0.220–0.882, p = 0.021). Univariate analysis did not show a significant association between EFS and other baseline covariates (body mass index, race, N and M category, nuclear grade, ER status, and HER2-targeted therapy). OS did not differ between the THP-AC and TCHP groups (HR 0.419, 95% CI 0.122–1.440, p = 0.167). Conclusions The present analysis revealed that a non–anthracycline-containing regimen in HER2-positive IBC patients had no significant difference in pCR rates but was associated with lower 2-year EFS when compared to an anthracycline-containing regimen. However, OS was similar. Limitations of the study include a small sample size, lack of temporal analysis, and retrospective design with its possible selection bias. Further investigation of the optimal neoadjuvant regimen for patients with HER2-positive IBC is warranted. Citation Format: Toshiaki Iwase, Sridhar Nithya, Megumi Kai, Jie Willey, Wenli Dong, Yu Shen, Savitri Krishnamurthy, Anthony Lucci, H. T. Carisa Le-Petross, Azadeh Nasrazadani, Sadia Saleem, Rachel Layman, Vicente Valero, Debu Tripathy, Wendy Woodward, Yee Chung Cheng, Faina Nakhlis, Jennifer Bellon, Filipa Lynce, Naoto Ueno. Neoadjuvant HER2-targeted regimens with or without anthracyclines for HER2-positive inflammatory breast cancer (IBC): a multicenter retrospective study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-03.

Endoscopic transoral outlet reduction induces enterohormonal changes in patients with weight regain after Roux-en-Y gastric bypass

Abstract Background and study aims Transoral outlet reduction (TORe) has long been employed in treating weight regain after Roux-en-Y gastric bypass. However, its impact on gut hormones and their relationship with weight loss remains unknown. Patients and methods This was a substudy of a previous randomized clinical trial. Adults with significant weight regain and dilated gastrojejunostomy underwent TORe with argon plasma coagulation (APC) alone or APC plus endoscopic suturing (APC-suture). Serum levels of ghrelin, GLP-1, and PYY were assessed at fasting, 30, 60, 90, and 120 minutes after a standardized liquid meal. Results were compared according to allocation group, clinical success, and history of cholecystectomy. Results Thirty-six patients (19 APC vs. 17 APC-suture) were enrolled. There were no significant baseline differences between groups. In all analyses, the typical postprandial decrease in ghrelin levels was delayed by 30 minutes, but no other changes were noted. GLP-1 levels significantly decreased at 12 months in both allocation groups. Similar findings were noted after dividing groups according to the history of cholecystectomy and clinical success. The APC cohort presented an increase in PYY levels at 90 minutes, while the APC-suture group did not. Naïve patients had significantly lower PYY levels at baseline (P = 0.01) compared with cholecystectomized individuals. This latter group experienced a significant increase in area under the curve (AUC) for PYY levels, while naïve patients did not, leading to a higher AUC at 12 months (P = 0.0001). Conclusions TORe interferes with the dynamics of gut hormones. APC triggers a more pronounced enteroendocrine response than APC-suture, especially in cholecystectomized patients.

The real-world data of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study.

The real-world efficacy, feasibility, and prognostic factors of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer are not fully established. This multi-institutional retrospective cohort study evaluated 71 consecutive patients treated with immune-checkpoint inhibitor combination therapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, safety, and long-term survival. In patients with measurable lesions, the response rate was 58%, and the disease control rate for all enrolled patients was 80%. Five patients (7.0%) underwent successful conversion surgery. Grade 3 or higher immune-related adverse events occurred in 13% of patients, and one patient (1.4%) died due to cholangitis. Median progression-free survival was 9.7 (95% confidence interval: 6.5-not reached). C-reactive protein levels and performance status were identified as significant predictors of progression-free survival through Cox proportional hazards analysis. Immune-checkpoint inhibitor combination therapy for esophageal cancer demonstrated comparable tumor response, safety, and long-term survival to previous randomized clinical trials. Patients with good performance status and low C-reactive protein levels may be suitable candidates for this treatment.

Safety profile of rivaroxaban in first-time users treated for venous thromboembolism in four European countries.

The European rivaroxaban post-authorization safety study evaluated bleeding risk among patients initiated on rivaroxaban or vitamin K antagonists for the treatment and secondary prevention of venous thromboembolism in routine clinical practice. Cohorts were created using electronic healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients with a first prescription of rivaroxaban or vitamin K antagonist during the period from December 2011 (in the UK, January 2012) to December 2017 (in Germany, December 2016) for venous thromboembolism indication, with no record of atrial fibrillation or recent cancer history, were observed until the occurrence of each safety outcome (hospitalization for intracranial, gastrointestinal, urogenital or other bleeding), death or study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed. Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled, mean age, 59.9-63.8 years. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher incidence rates for gastrointestinal bleeding in rivaroxaban users than in vitamin K antagonist users. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. This study provides further data from routine clinical practice that broadly support safety profile of rivaroxaban for VTE indication and complement findings from previous randomized clinical trials.

The effect of oral supplementation of Paricalcitol on C-reactive protein levels in chronic kidney disease patients: GRADE-assessed systematic review and dose-response meta-analysis of data from randomized controlled trials

BackgroundPrevious studies investigating the effect of oral supplementation of paricalcitol on reactive protein levels in chronic kidney disease (CKD) patients reported inconsistent findings. In this systematic review and meta-analysis, we have analyzed and interpreted the results obtained from previous randomized clinical trials on the effect of paricalcitol on C-reactive protein in CKD patients in the literature.MethodsMEDLINE, SciVerse Scopus, and Clarivate Analytics Web of Science databases were searched until January 2023 and related articles were obtained through a careful screening process allowing extraction of required data from selected articles. The effect size was calculated using a random effect model and weighted mean differences (WMD) and 95% confidence intervals (CI). Heterogeneity among studies was evaluated using Cochran’s Q test and I2.ResultsAmongst the 182 articles obtained from the initial search, 4 studies (6 arms) were finally included in the meta-analysis. Pooled analysis shows that C-reactive protein levels significantly decrease after oral supplementation with paricalcitol (WMD: -2.55 mg/L, 95% CI (-4.99 to -0.11; P = 0.04). The studies used in this meta-analysis showed significant heterogeneity (I2 = 66.3% and P = 0.01).ConclusionOral paricalcitol supplementation in CKD patients can significantly reduce C-reactive protein levels, which may prevent CKD progression.

Microbiota and mucosal gene expression of fecal microbiota transplantation or placebo treated patients with chronic pouchitis

ABSTRACT Altered microbiota and impaired host immune function have been linked to the pathogenesis of pouchitis. We used 16S rRNA gene sequencing and RNA sequencing data from a previous randomized clinical trial (RCT) on fecal microbiota transplantation (FMT) therapy in 26 chronic pouchitis patients with one-year follow-up. We analyzed changes in both luminal and mucosal microbiota composition, as well as in host mucosal gene expression to gain insights into the host–microbiota interactions possibly underlying clinical outcomes of the patients. Antibiotic type and pattern of use were significant drivers of the luminal microbiota at baseline. Differential gene expression analysis indicated transition from ileal to colonic gene expression in the pouch, and upregulation in inflammation- and immune system-related pathways in the pouch. At 4 weeks, the non-relapsed FMT patients had a lower microbiota dissimilarity to the donor than the non-relapsed placebo patients (p = .02). While two FMT-treated patients showed a shift toward the donor’s microbiota during the one-year follow-up, the overall FMT microbiota modulation effect was low. Patient’s luminal and mucosal microbiota profiles were unstable in both FMT and placebo groups. Expression of the chemokine receptor CXCR4 was downregulated at 52 weeks compared to the baseline in the non-relapsed patients in both FMT and placebo groups. Microbiota modulation by FMT seems to be low in this patient group. The microbiota composition or alterations did not explain the relapse status of the patients. Some evidence for remission-related host gene expression pattern was found; specifically, CXCR4 expression may have a role in sustained remission.

Developmental Disturbance in Premolars After Intraligamental Anesthesia Using Computer-Controlled Local Anesthesia Delivery System: An-Eight-Years Follow-Up Study in Children.

Aim This study aimed to evaluate the prevalence of developmental disturbances in permanent second premolars in which their tooth buds were exposed to mandibular intraligamental anesthesia (ILA) using a computer-controlled local anesthetic delivery system (CCLAD). Materials and methods This was a longitudinal follow-up study conducted in a previous randomized clinical trial (RCT). In the previous RCT, a total of 91 children were included (61 control and 30 cases). A structured form was created that contained details about the date of birth, age, and sex at which the participants received local anesthesiaand the type of local anesthesia administered (ILA using CCLADS, traditional inferior alveolar nerve block [IANB], and IANB using CCLADS). A history of post-treatment abscess, retreatment, and post-treatmentextraction was documented in both groups.Descriptive statistics, including frequency and percentage, and additionally, the chi-square test and Fisher's exact test were used to compare ILA and IANB. Results Forty of the 91 children attended follow-up visits. Only two children had developmental defects: one child who received traditional IANB had a demarcated white opacity (this patient had a history of dental abscess), and another who received ILA using CCLADS showed hypoplasia on his permanent premolar. No significant association was found between the type of anesthesia and the presence of developmental defects. Conclusion The slow administration of ILA delivered by CCLADS in the primary teeth does not increase the chances of developmental disturbances or damage to the corresponding permanent tooth bud.