Consecutive Infusions Research Articles

Inflammatory cytokines, cortisol, and anhedonia in patients with treatment-resistant depression after consecutive infusions of low-dose esketamine.

Anhedonia, defined as a significant loss of interest or pleasure, is one of the core symptoms of treatment- resistant depression (TRD) and is often associated with poor prognosis. This article primarily investigates the changes in anhedonia symptoms, inflammatory markers, and cortisol levels in TRD patients after low-dose esketamine treatments. A total of sixty patients with TRD were enrolled in the clinical study of esketamine. We primarily assessed the severity of depressive symptoms and anhedonia using the Hamilton Rating Scale for Depression (HAMD) and the Snaith-Hamilton Pleasure Scal(SHAPS), respectively, before esketamine treatment and within 24h after each treatment. Blood specimens were collected before the first treatment and within 1h after the sixth treatment, measuring the levels of cortisol, interleukin-6(IL-6), interleukin-4(IL-4), and tumor necrosis factor-alpha(TNF-α) in plasma. We found that after six consecutive infusions of low-dose esketamine, patients' depressive symptoms and anhedonia showed improvement. After six treatments, plasma levels of cortisol, IL-6, and TNF-α decreased in patients with TRD, while the anti-inflammatory cytokine IL-4 increased. Multiple linear regression analysis revealed that baseline cortisol levels were correlated with anhedonia, while inflammatory factors showed no significant correlation. Add-on esketamine appears to be a good choice for the treament of the anhedonia in TRD. It has also shown promising effects on altering inflammatory markers in patients with TRD. Moreover, elevated plasma cortisol levels may serve as a potential biomarker for anhedonia in patients with TRD.

A randomized controlled pilot study of daily intravenous ketamine over three days for treatment-resistant depression

BackgroundStudies have confirmed the rapid antidepressant action of ketamine in depressive episodes. Nevertheless, a standardized procedure for the delivery of ketamine infusion in individuals suffering from treatment-resistant depression, particularly in terms of infusion frequency and total dosage, remains undetermined. In addition, an efficacious ketamine regimen for persistent pain management involved a continuous 10-day infusion period with no notable adverse effects. Consequently, the primary objective of this study was to evaluate the antidepressant capacity of consecutive ketamine infusions spanning over three successive days, the duration of therapeutic response, and the overall safety profile of the treatment.MethodsIn this randomized controlled trial, participants aged 18–64 with treatment-resistant depression were randomized to receive either intravenous ketamine or midazolam (used as an active placebo) for 40 min daily over three consecutive days. Statistical analysis using repeated measures ANOVA was employed to assess the changes in the total score of the Montgomery–Åsberg Depression Rating Scale (MADRS) and the clinical global impression-Severity from the initial assessment to 10 and 31 days post-infusion. Additionally, the duration of response and remission was evaluated using Kaplan–Meier survival analysis.ResultsOut of 33 randomized participants, 20 underwent the treatment as planned. By day 10th, the ketamine group had a mean reduction in MADRS score of 12.55 (95% CI = 6.70–18.09), whereas the midazolam group had a decrease of 17.22 (95% CI = 11.09–23.36). This pattern continued to day 31, with ketamine showing a mean score decrease of 13.73 (95% CI = 7.54–19.91) and midazolam a fall of 12.44 (95% CI = 5.61–19.28). Both treatments were well tolerated, with dissociative symptoms in the ketamine group being temporary and ceasing by the end of each infusion.ConclusionIntravenous ketamine given for three consecutive days did not show a notable antidepressant advantage when compared to the active placebo midazolam, highlighting the need for further research into effective treatments schedules for treatment-resistant depression.Trial registrationNCT05026203, ClinicalTrials.gov, registered on 24/08/2021.

P.004 Real-world effectiveness of intravenous eptinezumab in patients with chronic migraine and previous subcutaneous preventive migraine treatment

Background: Since 2018, several CGRP-targeted therapies have entered the migraine market, including eptinezumab. Minimal evidence exists evaluating the real-world effectiveness of switching from a subcutaneous to an intravenous anti-CGRP mAb. Methods: An observational, multi-site (n=4), US-based study, REVIEW evaluated real-world experiences of patients with chronic migraine (CM) treated with eptinezumab using a chart review, patient survey, and physician interviews. Adults (≥18 years) with a diagnosis of CM who had completed ≥2 consecutive eptinezumab infusion cycles were eligible. Results: Enrolled patients were primarily female (83%, 78/94), had a mean age of 49 years and a mean migraine diagnosis duration of 15.4 years. All patients (94/94) self-reported prior preventive therapy with 89% (84/94) reporting prior subcutaneous anti-CGRP mAb use (i.e., fremanezumab, galcanezumab, or erenumab). Regardless of prior exposure to a CGRP ligand or receptor blocker, the number of “good” days/month more than doubled following eptinezumab. Patients experienced a similar mean change in the number of “good” days/month regardless of the number and type of previous subcutaneous anti-CGRP mAb used. Conclusions: This real-world, patient survey showed that patients with prior exposure to subcutaneous anti-CGRP mAbs had high overall satisfaction with the effectiveness of eptinezumab treatment regardless of the number and type of previous therapies used.

Real-world effectiveness and satisfaction with intravenous eptinezumab treatment in patients with chronic migraine: REVIEW, an observational, multi-site, US-based study

BackgroundDespite recent advancements in migraine treatment, some patients continue to endure significant disease burden. Due to the controlled nature of randomized trials in migraine prevention, many real-world patients with comorbidities or prior exposure to certain therapies are excluded. Capturing evidence of the effectiveness of treatment in real-world clinical settings can further shape treatment paradigms. The objective of this study was to develop a comprehensive understanding of both patients’ and physicians’ real-world experiences with eptinezumab for chronic migraine (CM).MethodsREVIEW (Real-world EVidence and Insights into Experiences With eptinezumab) is an observational, multi-site (n = 4), US-based study designed to evaluate real-world experiences of patients treated with eptinezumab and their treating physicians. Patients were ≥ 18 years of age, with a diagnosis of CM, who had completed ≥ 2 consecutive eptinezumab infusion cycles (≥ 6 months of exposure). The study included a retrospective chart review, a patient survey, and a semi-structured physician interview that assessed patient and/or physician satisfaction with elements of daily living / well-being, migraine symptomology, and perspectives of the eptinezumab infusion experience.ResultsOf the 94 patients enrolled, 83% (78/94) were female, the mean age was 49.2 years, and the mean time since migraine diagnosis was 15.4 years. Before eptinezumab treatment, patients experienced a mean of 8 self-reported “good” days/month, which increased to 18 after treatment. Most patients took, on average, ≥ 10 days/month of prescription and/or over-the-counter medication (81% [75/93] and 66% [61/93], respectively) to treat migraine attacks before eptinezumab treatment, which dropped to 26% (24/93) and 23% (21/93) following eptinezumab treatment. Prior to receiving eptinezumab, 62% (58/93) of patients indicated being at least slightly concerned about infusions; after eptinezumab infusion, this dropped to 14% (13/93). These patient survey findings were consistent with physician responses.ConclusionThis real-world evidence study demonstrated high overall satisfaction with the effectiveness of eptinezumab treatment for CM among most patients and their physicians.

Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report.

Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.

Renal safety of zoledronic acid in patients with osteoporosis: a retrospective study.

This study aimed to investigate the renal safety of Zoledronic Acid (ZOL) in patients with osteoporosis (OP). A total of 1379 patients (baseline estimated glomerular filtration rate, eGFR ≥ 60 mL/min/1.73 m2) with primary OP who received ZOL from January 2008 to October 2020 at our hospital were retrospectively analyzed. Baseline and the changes in renal function within 1 year following infusions were collected, the incidence of renal impairment (eGFR < 60 mL/min/1.73 m2 or a > 25% reduction in the eGFR from baseline) was noted and the risk factors were analyzed. Furthermore, the changes in renal function between a 3-year consecutive infusion and a single infusion of ZOL were compared. Renal impairment occurred in 8.05% of patients, who with a significantly higher age, Charlson Comorbidity Index (CCI), smoking history, combination of hypertension or diabetes mellitus and worse renal function indicators (all P < 0.05). Binary logistic regression analysis showed that higher CCI (≥5) or smoking history or the baseline eGFR <90 mL/min/1.73 m2 were the risk factors for renal impairment (all P < 0.05). Patients of 3-year continuous infusion group had a significantly greater drop in the eGFR levels than the single infusion group after 1 year of infusion(s) (P < 0.05). Attention should be given to possible potential renal impairment following ZOL infusion in clinical practice for the management of OP, particularly in patients with higher CCI (≥5) or smoking history or the baseline eGFR <90 mL/min/1.73 m2. Continuous infusion of ZOL exerts a significant impact on renal function when compared to single infusion and intensive monitoring of renal function is necessary.

Serial Fecal Microbiota Infusions via Colonoscopy for Active Ulcerative Colitis: A Feasibility, Safety, and Translational Monocentric Italian Study.

The effectiveness of fecal microbiota transplantation (FMT) in ulcerative colitis (UC) remains unclear. This study aimed to investigate the feasibility and effectiveness of serial fecal infusions via colonoscopy in patients with active UC. Subjects with mild-to-moderate UC received three consecutive fecal infusions via colonoscopy. A control population with the same baseline features receiving Infliximab treatment was enrolled. Adverse events and clinical, endoscopic, and microbial outcomes were investigated. Nineteen patients with mildly-to-moderately active UC were enrolled. Clinical response was obtained in six patients at week 2, in eight at week 6, and in nine at week 12. Clinical response was maintained in eight patients at week 24. Endoscopic remission at week 12 was reached in six patients. In the control population, 13/19 patients achieved clinical response at week 6, and 10/19 patients maintained clinical response after 6 months. Microbiota richness was higher in responders compared with the non-responders. Peptostreptococcus, Lactobacillus, and Veillonella were higher in non-responders, while Parabacteroides, Bacteroides, Faecalibacterium, and Akkermansia were higher in responders at all timepoints. Serial FMT infusions appear to be feasible, safe, and effective in UC patients, with a potential role in inducing and maintaining clinical response. Specific bacteria predict the response to FMT.

Using Deep Ocean Water in the Fermentation of Antrodia cinnamomea to Boost Magnesium Ion Bioabsorption and Anti-Inflammatory Effects in the Brain of an Alzheimer’s Disease Rat Model

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid β-peptide (Aβ) and subsequent oxidative inflammatory response, leading to brain damage and memory loss. This study explores the potential of Antrodia cinnamomea (AC), a Taiwan-native fungus known for its anti-inflammatory and antioxidant properties. The metabolites of AC, including dehydroeburicoic acid (DEA), 4-acetylantroquinonol B (4-AAQB), dehydrosulphurenic acid (DSA), and polysaccharides, were of particular interest. In the experiment, deep ocean water (DOW) was used to facilitate the solid-state fermentation of Antrodia cinnamomea NTTU 206 (D-AC), aiming to enhance its functional components. The impact of D-AC on the modulation of AD-related risk factors and the augmentation of cognitive abilities was subsequently evaluated in an AD rat model. This model was established via consecutive infusions of Aβ40 into the brain over a 28-day period. The administration of D-AC resulted in remarkable improvements in the rats’ reference memory, spatial probe test, and working memory. Notably, it restored the hippocampal magnesium levels by upregulating the expression of the magnesium transporter MAGT1. Concurrently, D-AC significantly downregulated the expressions of β-secretase 1 (BACE1) and the phosphorylated tau protein (p-tau), which were both implicated in AD progression. Additionally, it mitigated inflammatory responses, as suggested by the decreased levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the hippocampus and cerebral cortex. Ultimately, the ability of D-AC to restore the brain magnesium levels, attenuate inflammatory responses, and reduce hippocampal Aβ40 deposition led to significant improvements in the cognitive decline of AD rats. D-AC demonstrated a comparable efficacy with its counterpart, AC fruiting bodies (F-AC group), despite their componential differences. This study underscores the potential of D-AC, enriched through fermentation, as a novel dietary strategy for Alzheimer’s disease prevention.

No Increase in Symptoms Toward the End of the Ocrelizumab Infusion Cycle in Patients With Multiple Sclerosis: Symptom Burden on Ocrelizumab: A Longitudinal Study (SymBOLS).

Some patients with multiple sclerosis (MS) receiving ocrelizumab (OCR) report worsening symptoms toward the end of the 6-month infusion cycle ('wearing off'). The objective of our study was to comprehensively assess changes in symptom burden across 2 consecutive OCR infusion cycles. SYMptom Burden on Ocrelizumab, a Longitudinal Study (SymBOLS; NCT04855617) was an investigator-initiated, 2-center study of patients with MS starting or receiving OCR. Patients' symptoms were assessed with NeuroQoL short forms, SymptoMScreen, and Work Productivity and Activity Impairment Questionnaire at the start-cycle, mid-cycle, and end-cycle time points in each of the 2 infusion cycles. Symptom scores at the 3 time points within each cycle were compared with repeated-measures ANOVA or the Friedman rank-sum test for non-normal variables. The proportions of patients with a meaningful symptomatic change from the start to the end of each infusion cycle were calculated, and patients whose symptoms improved, worsened, and stayed the same from the start to the end of the cycle were compared with respect to demographic and clinical characteristics. One hundred three patients with MS provided longitudinal data for analyses (mean age [SD]: 46.7 [12.2] years, 68% female, 33% non-White, disease duration: 15.5 [5] years, 41% with the Extended Disability Status Scale score >3). On a group level, NeuroQoL and SymptoMScreen scores mostly remained stable or even improved slightly toward the end of each cycle. On an individual level, symptoms remained unchanged across either cycle for most patients, and meaningful symptom worsening from the start to the end of the cycle was no more common than improvement. Meaningful change in symptoms in both cycles was very rare and generally in the direction of improvement toward the end cycle. Despite the lack of evidence for symptom worsening with a longer time from infusion, 54% of patients endorsed feeling of "wearing off" at least sometimes, most commonly as an increase in fatigue. Our prospective study failed to uncover evidence for the worsening of symptoms with a longer time from OCR infusion. These findings cast doubt on the existence of wearing off as a physiologic phenomenon in OCR-treated patients with MS. The perception of wearing off is likely the result of natural fluctuations in MS symptoms and attribution bias.

Home-Based Infusion of Alglucosidase Alfa Can Safely be Implemented in Adults with Late-Onset Pompe Disease: Lessons Learned from 18,380 Infusions.

Enzyme replacement therapy (ERT) with alglucosidase alfa is the treatment for patients with Pompe disease, a hereditary metabolic myopathy. Home-based ERT is unavailable in many countries because of the boxed warning alglucosidase alfa received due to the risk of infusion-associated reactions (IARs). Since 2008, home infusions have been provided in The Netherlands. This study aimed to provide an overview of our experience with home-based infusions with alglucosidase alfa in adult Pompe patients, focusing on safety, including management of IARs. We analysed infusion data and IARs from adult patients starting ERT between 1999 and 2018. ERT was initially given in the hospital during the first year. Patients were eligible for home treatment if they were without IARs for multiple consecutive infusions and if a trained home nurse, with on-call back-up by a doctor, was available. The healthcare providers graded IARs. We analysed data on 18,380 infusions with alglucosidase alfa in 121 adult patients; 4961 infusions (27.0%) were given in hospital and 13,419 (73.0%) were given at home. IARs occurred in 144 (2.9%) hospital infusions and 113 (0.8%) home infusions; 115 (79.9% of 144) IARs in hospital and 104 (92.0% of 113) IARs at home were mild, 25 IARs (17.4%) in hospital and 8 IARs (7.1%) at home were moderate, and very few severe IARs occurred (4 IARs in hospital [2.8%] and 1 IAR at home [0.9%]). Only one IAR in the home situation required immediate clinical evaluation in the hospital. Given the small numbers of IARs that occurred with the home infusions, of which only one was severe, we conclude that alglucosidase alfa can be administered safely in the home situation, provided the appropriate infrastructure is present.

Symptom stability throughout Ocrelizumab infusion cycle in patients with Multiple Sclerosis: final results of SYMptom Burden on Ocrelizumab, a Longitudinal Study (SYMBOLS) (P7-3.017)

<h3>Objective:</h3> To determine whether symptom burden in Ocrelizumab (OCR)-treated MS patients varies over the 6-month infusion cycle. <h3>Background:</h3> OCR is a humanized anti-CD20 antibody therapy for multiple sclerosis (MS) given at 6-month intervals. Some patients report an increase in symptoms toward the end of the infusion cycle (“wearing off”). <h3>Design/Methods:</h3> One-year, prospective, observational, two-center study (NCT04855617) enrolled MS patients aged 18–80 with EDSS scores between 0–7 who were treated with OCR for ≥ 1 year or were initiated on OCR. All patients were followed at NYU MS Care Center (NYU), New York, NY, and the Elliot Lewis MS Center (ELC), Wellesley, MA. Patients completed NeuroQol short forms, SymptoMScreen, work productivity (WPAI:MS), and medical screening questionnaires at 4-, 12-, and 24-weeks post-infusion for two consecutive infusion cycles as well as a post-study completion questionnaire. <h3>Results:</h3> 115 participants were included in the study (n=53 NYU/n=62 ELC); 64% were female; 36% - non-White; baseline age - 46.2±12.5 years; disease duration −15.3±10.7 years; OCR treatment duration - 2.54 ±1.04 years; median (IQR) EDSS - 3.0 (1.5, 5.3); EDSS was &gt;= 4 in 48 patients (42%). Paired Wilcoxon nonparametric tests used to evaluate the changes in outcome scores from pre- to post-infusion showed no significant changes on any NeuroQol and SymptoMScreen scales. Scores on two WPAI-MS subscales (“impairment while working due to health” and “overall work impairment”) increased by 10% during the 2^nd cycle (p-values=0.02 and 0.001) but not the 1^st cycle. On the post-completion questionnaire, the percentage of patients who reported ‘wearing off’ always was 4%, usually - 33%, sometimes - 45%, and never - 17%. <h3>Conclusions:</h3> Although symptom burden remained stable throughout two OCR infusion cycles on multiple scales, most patients reported “wearing off” at least sometimes. We will discuss possible explanations for this discrepancy. <b>Disclosure:</b> Dr. Kister has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech-Roche. The institution of Dr. Kister has received research support from Genentech. Dr. Kister has received publishing royalties from a publication relating to health care. Prof. Oh has nothing to disclose. Ms. Douglas has nothing to disclose. Ms. O’Shea has nothing to disclose. An immediate family member of Tamar Bacon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. The institution of an immediate family member of Tamar Bacon has received research support from Gentech. An immediate family member of Tamar Bacon has received publishing royalties from a publication relating to health care. Dr. Bouley has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Banner Life Sciences. Dr. Bouley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Bouley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Bouley has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Genentech. Dr. Bouley has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Bouley has received research support from Novartis. Dr. Lathi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. The institution of Dr. Katz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Theraputics. The institution of Dr. Katz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jansen Pharmaceuticals. The institution of Dr. Katz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viela Bio. The institution of Dr. Katz has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Katz has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Novartis. The institution of Dr. Katz has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Sanofi-Genzyme. The institution of Dr. Katz has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Genentech. The institution of Dr. Katz has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD-Serono.

The Quality of Preoperative Glycemic Control Predicts Insulin Sensitivity During Major Upper Abdominal Surgery: A Case-Control Study.

To examine the association of the quality of preoperative glycemic control and insulin sensitivity during major upper abdominal surgery. In cardiac surgery, glycated hemoglobin A1c (HbA1c), an indicator of glycemic control during the preceding 3 months, correlated with intraoperative insulin sensitivity. Furthermore, insulin resistance showed a significant association with adverse clinical outcomes. This study is a post hoc exploratory analysis of a randomized controlled trial in patients undergoing elective hepatectomy and receiving the hyperinsulinemic-normoglycemic clamp (HNC) as a potential intervention to reduce surgical site infections (ClinicalTrials.gov NCT01528189). Immediately before skin incision, the HNC was initiated by infusing insulin at the rate of 2 mU/kg/min. Dextrose was administered at rates titrated to maintain normoglycemia (4.0-6.0 mmol/L). The average of 3 consecutive dextrose infusion rates during steady state was used as a measure of insulin sensitivity. Primary outcome was the relationship between preoperative HbA1c and insulin sensitivity during surgery. Secondary outcomes were the associations of insulin sensitivity with the patient's body mass index (BMI) and postoperative morbidity. Thirty-four patients were studied. HbA1c (Y = -0.52X + 4.8, P < 0.001, R2 = 0.29), BMI (Y = -0.12X + 5.0, P < 0.001, R2 = 0.43) showed negative correlations with insulin sensitivity. The odds ratio of postoperative complications within 30 days of surgery for every increase in insulin sensitivity by 1 mg/kg/min was 0.22 (95% confidential interval, 0.06-0.59; P = 0.009). We demonstrate significant associations of the quality of preoperative glycemic control and body mass index with insulin sensitivity during hepatectomy. The degree of insulin resistance correlated with postoperative morbidity.

Two-pore channel protein TPC1 is a determining factor for the adaptation of proximal tubular phosphate handling.

Two-pore channels (TPCs) constitute a small family of cation channels expressed in endo-lysosomal compartments. TPCs have been characterized as critical elements controlling Ca2+ -mediated vesicular membrane fusion and thereby regulating endo-lysosomal vesicle trafficking. Exo- and endocytotic trafficking and lysosomal degradation are major mechanisms of adaption of epithelial transport. A prime example of highly regulated epithelial transport is the tubular system of the kidney. We therefore studied the localization of TPC protein 1 (TPC1) in the kidney and its functional role in the dynamic regulation of tubular transport. Immunohistochemistry in combination with tubular markers were used to investigate TPC1 expression in proximal and distal tubules. The excretion of phosphate and ammonium, as well as urine volume and pH were studied in vivo, in response to dynamic challenges induced by bolus injection of parathyroid hormone or acid-base transitions via consecutive infusion of NaCl, Na2 CO3 , and NH4 Cl. In TPC1-deficient mice, the PTH-induced rise in phosphate excretion was prolonged and exaggerated, and its recovery delayed in comparison with wildtype littermates. In the acid-base transition experiment, TPC1-deficient mice showed an identical rise in phosphate excretion in response to Na2 CO3 compared with wildtypes, but a delayed NH4Cl-induced recovery. Ammonium-excretion decreased with Na2 CO3 , and increased with NH4 Cl, but without differences between genotypes. We conclude that TPC1 is expressed subapically in the proximal but not distal tubule and plays an important role in the dynamic adaptation of proximal tubular phosphate reabsorption towards enhanced, but not reduced absorption.

The role of flumazenil in generalised anxiety disorder: a pilot naturalistic open-label study with a focus on treatment resistance

Anxiety disorders are highly prevalent and chronic disorders with treatment resistance to current pharmacotherapies occurring in approximately one in three patients. It has been postulated that flumazenil (FMZ) is efficacious in the management of anxiety disorders via the removal of α4β2δ gamma-aminobutyric acid A receptors. To assess the safety and feasibility of continuous low-dose FMZ infusions for the management of generalised anxiety disorder (GAD) and collect preliminary efficacy data. Uncontrolled, open-label pilot study. Participants had a primary diagnosis of generalised anxiety disorder (GAD) and received two consecutive subcutaneous continuous low-dose FMZ infusions. Each infusion contained 16 mg of FMZ and was delivered over 96 ± 19.2 h. The total dose of FMZ delivered was 32 mg over approximately 8 days. Sodium valproate was given to participants at risk of seizure. The primary outcome was the change in stress and anxiety subscale scores on the Depression Anxiety Stress Scale-21 between baseline, day 8, and day 28. Nine participants with a primary diagnosis of GAD were treated with subcutaneous continuous low-dose FMZ infusions; seven participants met the criteria for treatment resistance. There was a significant decrease in anxiety and stress between baseline and day 8 and baseline and day 28. There was also a significant improvement in subjective sleep quality from baseline to day 28 measured by the Jenkins Sleep Scale. No serious adverse events occurred. This study presents preliminary results for subcutaneous continuous low-dose FMZ's effectiveness and safety in GAD. The findings suggest that it is a safe, well-tolerated, and feasible treatment option in this group of patients. Future randomised control trials are needed in this field to determine the efficacy of this treatment.

Early Results of MT-401 (Zedenoleucel) in Post-Transplant MRD+ aml Patients

Background: Measurable residual disease (MRD) testing has become more prevalent in AML. MRD positivity is associated with increased relapse risk and shorter survival in AML, and currently, there no approved therapies for these patients. Zedenoleucel (also known as MT-401) is a non-genetically modified allogeneic multi-tumor associated antigen (mTAA)-specific T cell therapy with selectivity to multiple tumor antigens, specifically preferentially expressed antigen in melanoma (PRAME), Wilms' tumor 1 (WT1), New York esophageal 1 (NY-ESO-1) and Survivin. An ongoing Phase 1 dose-escalation study (ADSPAM) conducted by Baylor College of Medicine (BCM) shows acceptable safety and tolerability at doses up to 200 x 106 cells administered post-HSCT in the adjuvant, as well as relapsed/refractory setting. There are promising preliminary clinical results with mTAA-specific T cell therapy targeting these same tumor antigens (Lulla et al., 2021). Objective: To determine whether MRD+ patients post-allogeneic transplant can be treated safely and effectively with multiTAA-specific T cells (MT-401/zedenoleucel) Methods: A multicenter Phase 2 study (ARTEMIS) evaluating the safety, tolerability and efficacy of zedenoleucel in patients with AML, including MRD+ patients, post-HSCT is ongoing. The study explores this therapy in patients with no active disease [in complete remission (CR) and MRD-] or in patients with active disease (frank relapse or MRD+). Patients may receive up to 3 consecutive infusions of zedenoleucel as a monotherapy (50-200 × 106 cells every 2 weeks) at weeks 0, 2 and 4 during the Intervention Period, and enter Follow-up at Week 8. Primary endpoints include various safety measurements. Efficacy evaluations occur at weeks 8, 12, 18, 24, 48 and yearly for 4 years using ELN recommendations for standard AML response criteria. MRD testing was done by flow cytometry or molecular testing (e.g. RT-PCR). Results: No concerning safety signals arose, including any dose-limiting toxicities in safety lead-in patients. The MRD+ patients had a variety of genetic mutations/abnormalities. One patient with NPM1 mutation converted from MRD+ to MRD- at week 8 evaluation. Another patient with RUNX1 genetic abnormality showed a decrease in MRD by PCR from a starting baseline of 0.8093% to resolution via peripheral blood at approximately 32 weeks post-treatment with MT-401. T cell composition of the product consisted of 71% CD4+ and 24% CD8+ T cells. T cell receptor (TCR) analysis identified 3,117 antigen-specific clones (881 Survivin, 783 NY-ESO-1, 750 PRAME, 709 WT1). Immune monitoring of this patient using biomarker analysis showed T cell specificity not only for the targeted antigens but also for non-targeted antigens over time, thereby demonstrating epitope spreading. Interestingly, the tumor antigen composition by RNASeq identified an antigen expression profile that changes over time and inversely correlates with the presence of antigen-specific T cells, demonstrating the interplay of tumor cell immunogenicity and antigen-specific T cells. Conclusions: The preliminary ARTEMIS results showed that administration of MT-401 converted MRD+ patients to MRD- indicating that early intervention with MT-401 administration at MRD+ stage in post-transplant AML can be beneficial.

Modern possibilities of correction of postcovid disorders in the fetoplacental complex

The objective: to determine the peculiarities of hormonal support, liver enzymatic function and the state of the fetal-placental complex (FPC) in unvaccinated women with fetal growth retardation (FGR) and placental dysfunction (PD) who was ill with the coronavirus disease during the current pregnancy, on the background of the proposed correction scheme of the disorders and evaluation of its effectiveness.Materials and methods. The study included 22 pregnant women with FGR and PD who were being treated and delivered in the Department of Pregnancy and Childbirth Pathology of the State Institution «Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova National Academy of Sciences of Ukraine» in 2021–2022 and suffered a coronavirus disease during the current pregnancy. All pregnant women had a general clinical examination and the following parameters were additionally determined: the level of placental lactogen (PL) in blood serum, indicators of liver enzyme activity (alanine aminotransferase – ALT, aspartate aminotransferase – AST, gamma-glutamyl transpeptidase – GHTP), the level of estriol in urine (after the 22d week of pregnancy). The examination was carried out before the start of treatment and preventive measures and 12–14 days after a 10-day course of therapy with simultaneous ultrasound (US) monitoring of the condition of the FPC. In the case of diagnosis of FGR and PD, a course of therapy was carried out, which included daily consecutive intravenous infusions of a balanced crystalloid infusion preparation with lactate and sorbitol in the amount of 200 ml and a solution of levocarnitine and arginine hydrochloride in the amount of 100 ml for 10 days, followed by ultrasound control of the condition of the fetus and FPC. The evaluation of the effectiveness of the treatment was carried out based on a combination of clinical, laboratory and instrumental indicators after 10 days of therapy. Results. All pregnant women had a moderate or mild course of the coronavirus disease at different terms of the current pregnancy. There were 9 (40.9 %) women who were infected with SARS-CoV-2 in the early terms of pregnancy (up to 12 weeks), and they were diagnosed the 2nd and 2nd-3rd degrees of FGR.The majority of pregnant women had gestational complications. Before treatment, 10 (45.5 %) women had oligohydramnios. FGR was diagnosed in 14 (63.6 %) pregnant women, among them: in 3 (13.6 %) persons – fetal growth retardation of the 2nd-3rd degree, in 6 (27.3 %) – of the 2nd degree, in 5 (22.7 %) – 1st degree. The analysis of laboratory indicators demonstrated the increase in the levels of ALT, AST and GHTP, and a decrease in the levels of estriol in urine. After the proposed course of treatment, oligohydramnios was found only in 2 (9.1 %) women. The average amniotic index before treatment was 10.1, after treatment – 15.3. 4 (18.2 %) women were diagnosed FGR after the treatment. As a result of the treatment, the improvement of all determined laboratory parameters and perinatal consequences were determined. Conclusions. The proposed scheme for correcting the identified disorders with the inclusion of balanced crystalloid infusion preparation with lactate and sorbitol and balanced crystalloid infusion preparation with lactate and sorbitol drugs made possible to improve microcirculation, metabolic processes, and to normalize the consequences of postcovid endotheliitis in the vascular system of pregnant women in general and in the FPC, in particular. This was manifested in the improvement of clinical, laboratory and instrumental indicators of conducted studies and had a positive effect on perinatal results.

AML-109 Preliminary Results of MT-401 in Post-Transplant Measurable Residual Disease Positive (MRD+) Acute Myeloid Leukemia (AML) Patients

Measurable residual disease (MRD) testing has become more prevalent in AML. MRD positivity is associated with increased relapse risk and shorter survival in AML and, currently, there are no approved therapies for these patients. To determine whether MRD+ patients post-allogeneic transplant can be treated safely and effectively with multi-tumor-associated antigen (mTAA)-specific T cells (MT-401/zedenoleucel) Design: A multicenter Phase 2 study (ARTEMIS) evaluating the safety and efficacy of MT-401 in patients with AML post-transplant is ongoing and includes patients with MRD+ disease. Three MRD+ AML patients were enrolled and treated in the ARTEMIS study. MRD testing was done by flow cytometry or molecular testing (e.g., RT-PCR). Patients received up to 3 consecutive infusions of MT-401 as a monotherapy (50-200×106 cells every 2 weeks) at weeks 0, 2, and 4 during the Intervention Period, and entered Follow-up starting at Week 8 for up to 5 years. The primary endpoint includes various safety measurements and incidence of dose-limiting toxicities (DLTs). The secondary endpoint was efficacy evaluations using ELN recommendations for standard AML response criteria. No DLTs were observed. The MRD+ patient had a variety of genetic mutations/abnormalities. One patient with NPM1 mutation converted from MRD+ to MRD- at week 8 evaluation. Another patient with RUNX1 genetic abnormality showed a decrease in MRD by PCR from a starting baseline of 0.8093% to resolution via peripheral blood at approximately 32 weeks post-treatment with MT-401. T cell receptor (TCR) analysis identified 3,117 antigen-specific clones (881 Survivin, 783 NY-ESO-1, 750 PRAME, 709 WT1). Immune monitoring of this patient showed T cell specificity not only for the targeted antigens but also for non-targeted antigens over time, thereby demonstrating epitope spreading. Interestingly, the tumor antigen composition by RNASeq identified an antigen expression profile that changes over time and inversely correlates with the presence of antigen-specific T cells, demonstrating the interplay of tumor cell immunogenicity and antigen-specific T cells. The lead-in portion of the ARTEMIS results showed that administration of MT-401 converted MRD+ patients to MRD-indicating that early intervention with MT-401 administration at MRD+ stage in post-transplant AML can be beneficial.

Abstract CT177: SQ3370 in advanced solid tumors: Interim phase 1 results

Abstract Background: SQ3370, a novel therapy, utilizes Shasqi’s proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform where mutually-reactive click chemistry groups release Doxorubicin (Dox) at the tumor site while minimizing systemic exposure. In animals, SQ3370 enhanced T-cell infiltration, survival, and showed activity in both injected and non-injected lesions. Minimal to no toxicity, including no cardiotoxicity was seen in up to 9-fold dose increases in animals. Conventional Dox can induce cardiomyopathy with incidences of 6-20% for cumulative doses of 500 mg/m2 in humans. Here we report interim results of the Phase 1 trial (SQ3370-001; NCT04106492). Methods: SQ3370 has 2 components: 1) Intratumoral injection of a protodrug-activating biopolymer (SQL70); 2) then 5 consecutive daily IV infusions of an attenuated protodrug of Dox (SQP33). Key criteria for enrollment include locally advanced to metastatic solid tumors, ≤300 mg/m2 prior exposure to DOX, ECOG status 0 or 1, and no limit to the number of prior systemic therapies. Primary objectives include safety and determining Phase 2 dose. Dose escalation was assessed in 2 stages: 1) accelerated titration; 2) 3+3 design. Dose-limiting toxicity (DLT) was evaluated in cycle 1. Results: As of 26NOV2021 data cut, 17 patients (pts) in 8 dose escalation cohorts have been enrolled. MTD has not been reached. Median age was 59 years (26-79), 53% were females, and were ECOG 1 (59%). Prior procedures included surgery (82%) and radiation (47%). At study entry, 82% of pts had metastases with a median number of metastatic sites being 2 (1-5). Solid tumors were sarcoma (65%), and cancers of the skin, breast, and gynecologic organs were 12% for each, respectively. Sixteen of 17 (94%) pts received prior chemotherapy with 47% receiving prior Dox. Median number of prior systemic therapies was 2 (1-7). Intratumoral injection sites include soft tissue and chest wall. Of the 17 pts, 65% received &amp;gt;500 mg/m2, 53% (&amp;gt;1000), and 29% (&amp;gt;2000) cumulative Dox given as SQP33. Median duration of treatment was 3 cycles (1-10). No DLTs were observed. Most frequent AEs, regardless of causality, included nausea (n = 9), fatigue (n = 6) and anemia (n = 5). No signs of cardiomyopathy were seen in pts with an echo performed within 1 mo. of study start. Although &amp;gt;50% of pts received &amp;gt;1000 mg/m2, ejection fraction (LVEF) remained normal. No AEs that led to discontinuation or death were related to SQ3370. All pts were evaluable for response. At a median follow-up of 10 wks (4-30), 65% of pts had SD as best response. Median duration of SD was 80 days (37-186) with 64% sustaining SD for ≥60 days, corresponding to an overall disease control rate of 65%. The remainder of pts had PD as best response. Over 35% of pts remain on drug. Conclusions: SQ3370 was well tolerated. No DLTs and normal LVEF were seen with pts receiving &amp;gt;1000 mg/m2 Dox cumulative doses. Dose escalation is ongoing. Preliminary evidence of disease control was observed in this heavily pre-treated, high cancer burden, solid tumor pt population. Citation Format: Sant P. Chawla, Kathleen Batty, Vivek Bhadri, Nam Bui, Alexander D. Guminski, Jose M. Mejia Oneto, Sangeetha Srinivasan, James F. Strauss, Vivek Subbiah, Mia C. Weiss, Rosalind Wilson, Nathan A. Yee, Michael Zacharian, Vineet Kwatra. SQ3370 in advanced solid tumors: Interim phase 1 results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT177.

Interim phase 1 results for SQ3370 in advanced solid tumors.

3085 Background: SQ3370, a novel therapy, utilizes Shasqi’s proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform where mutually-reactive click chemistry groups release Doxorubicin (Dox) at the tumor site minimizing systemic exposure. In animals, SQ3370 enhanced survival, T-cell infiltration and antitumor responses in injected and non-injected tumors. Minimal to no toxicity, including no cardiotoxicity was seen in up to 9-fold dose increases in animals. Conventional Dox can induce cardiomyopathy at incidences of 1-20% for cumulative doses from 300-500 mg/m2 in humans and re-treatment with Dox is less effective in heavily pre-treated patients (pts). Here we report interim results of the Phase 1 ( NCT04106492 ). Methods: SQ3370 has 2 components: 1) Intratumoral injection of a protodrug-activating biopolymer (SQL70: 10 mL or 20 mL); 2) 5 consecutive daily IV infusions of an attenuated protodrug of Dox (SQP33). Key eligibility includes locally advanced or metastatic solid tumors, ≤300 mg/m2 prior exposure to Dox, ECOG 0-1 and no limit to prior systemic therapies. Primary objectives include safety and determining Phase 2 dose. Dose escalation was assessed in 2 stages: 1) accelerated titration; 2) 3+3 design. Results: As of 31JAN2022 data cut, 26 pts were treated, 21 with 10 mL biopolymer (bp) and 5 with 20 mL bp over 9 dose escalation protodrug cohorts. MTD has not been reached. Median age was 61 years (26-84), 62% were females, and 69% were ECOG 1. Prior procedures included surgery (89%) and radiation (62%). At study entry, 77% of pts had metastases with a median number of metastatic sites being 2 (1-5); most frequently lung (50%). Tumors were sarcoma (73%), breast cancer (7.7%), gyne (7.7%) and other (11.5%). Twenty-four of 26 (92%) pts received prior systemic therapies with 50% receiving prior Dox. Median number of prior systemic therapies was 2 (1-7). Of the 26 pts, 62% received &gt; 500 mg/m2 cumulative Dox given as SQP33. Median duration of treatment was 2 cycles (1-12). Most frequent AEs, regardless of causality, for the 10 mL bp group included nausea (n = 11), fatigue (n = 9) and anemia (n = 6), and for the 20 mL bp group included anemia (n = 3) and nausea (n = 2). Ejection fraction (LVEF) remained normal during the study period. No AEs that led to discontinuation or death were related to SQ3370 by investigator. At a median follow-up of 9.2 wks (3-37), 21 pts were evaluable. SD was best response in 71%. Median duration of SD was 80-dys (37-186) corresponding to an overall disease control rate (CR+ PR+ SD x 30-dys) of 71% (68% in 10 mL bp; 100% in 20 mL bp). The remainder of pts had PD as best response. Over 38% of pts remain on drug. Conclusions: SQ3370 with 10 mL or 20 mL biopolymer was well tolerated in pts with half being re-treated with Dox. Although &gt; 60% of pts received &gt; 500 mg/m2 cumulative Dox given as SQP33, LVEF remained normal. Preliminary evidence of disease control was observed in pts despite heavy prior pre-treatment and high cancer burden. Dose escalation is ongoing. Clinical trial information: NCT04106492.

OA02 A cohort of 79 children with Paediatric multisystem inflammatory syndrome associated with COVID-19

Abstract Background/Aims COVID-19 can manifest as a significant lung inflammation in adults. Although the course of disease is usually mild in children, it occasionally results in Paediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS). We present a cohort of 79 children treated for PIMS-TS in Yorkshire, UK between May 2020 and September 2021. Methods This retrospective multicentre cohort study includes children fulfilling the case definition of PIMS-TS according to Royal College of Paediatrics and Child Health criteria. The collected data include demographics, clinical symptoms, laboratory results, echocardiographic findings, treatment and outcomes. Results Out of 79 PIMS-TS cases, 50 were male, 29 female. Ages were between 3 months and 16 years (median 7 years). 45 children were within the normal weight range for age, 4 underweight, 30 overweight. 41 children were Caucasian, 34 Asian, 2 African and 2 Afro-Caribbean origin. The median duration of admission was 7 days with range 0-21 days. All children had fever. In 51 cardiac involvement was detected (impaired cardiac function, pericardial effusion or changes on coronary arteries by echocardiographic examination). In 51 children a skin rash was observed (usually macular blanching confluent non-pruritic), 48 children had gastrointestinal symptoms such as abdominal pains, vomiting or diarrhoea, 39 children had non-purulent conjunctivitis, 13 children enlarged cervical lymph nodes. All patients initially received antibiotics and all but two were treated with an anti-platelet dose of aspirin, a small number early on with an anti-inflammatory dose of aspirin, 31 were treated with 3 consecutive infusions of intravenous methylprednisolone (IVMP) 10 mg/kg daily followed by a weaning dose of oral prednisolone, 35 by IVMP and intravenous immunoglobulins (IVIG), 9 by IVIG only. The duration of treatment by oral prednisolone was 3-35 days with median 15 days. Inotropic support for hypotension was needed in 18 cases and oxygen therapy in 11 cases. All children had a good outcome and are being followed-up in our Paediatric Rheumatology / Cardiology clinics at 1-2 weeks, 6 weeks, 6 months and 12 months. To date, follow-up at 12 months has shown resolution of cardiac abnormalities including initial mild dilatation of coronary arteries; most of our patients have fully recovered within 6 weeks. No patients had any thromboembolic event identified. After discharge from hospital self-limiting musculoskeletal pains, lethargy, peeling of palms and/or headaches were common. 3 patients received psychology support. Conclusion We report 100% survival in our cohort of patients with PIMS-TS. None of the patients represented with flare of the symptoms. The majority were treated by corticosteroids alone, or in combination with IVIG. We believe that advance knowledge of PIMS-TS (from colleagues in other regions in the UK, affected earlier), prompt treatment and structured follow-up approach by multi-disciplinary team contributed to the good outcomes so far. Disclosure M. Bohm: None. T. Amin: None. A. Deri: None. K. Gargh: None. M. Wood: None.