First Week Of Treatment Research Articles

Delayed Onset ICANS Leading to Bilateral Cranial Neuropathies: Two Case Reports (P12-13.005)

<h3>Objective:</h3> To describe two cases of bilateral facial nerve neuropathy from late onset immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor T-cell (CAR-T) therapy for treatment of Multiple Myeloma. <h3>Background:</h3> ICANS is a complication of CAR-T therapy which typically occurs within the first week of treatment. Manifestations can include encephalopathy with confusion and behavioral changes, headache, agraphia, tremors, seizures, cerebral edema, or death. Isolated cranial neuropathies, particularly after this period, have not been reported. <h3>Design/Methods:</h3> Case report. <h3>Results:</h3> Two patients, a 69-year-old male (case 1) and a 67-year-old female (case 2), presented with facial nerve palsy 3 weeks (20 and 21 days respectively) after CAR-T therapy for multiple myeloma. Neither of the patients had developed symptoms of neurotoxicity immediately after CAR-T treatment. Case 1 experienced gradual onset of decreased taste, facial numbness, inability to smile or move his eyebrows, and drooling. Exam showed bilateral facial weakness in a lower motor neuron pattern, worse on the left as compared to the right. Case 2 experienced right-sided facial droop with inability to move her right eyebrow or symmetrically smile, right ear fullness, and right-sided drooling. Exam revealed right-sided facial weakness in a lower motor neuron pattern. MRI of the brain in both patients demonstrated bilateral contrast enhancement of the facial nerves. Cerebrospinal fluid analysis in case 1 showed mildly elevated protein (67 mg/dL), with negative infectious studies, and no evidence of malignancy. Case 2 did not have lumbar puncture, but respiratory viral and bacterial pathogen panel was negative. Both patients were treated with a short course of oral dexamethasone with complete resolution in case 1, and partial improvement of symptoms in case 2. <h3>Conclusions:</h3> Delayed ICANS should be considered in CAR-T patients presenting with isolated cranial neuropathies after ruling out infection and malignancy. Treatment with steroids can lead to recovery. <b>Disclosure:</b> Miss Beck has nothing to disclose. Dr. Hasan has nothing to disclose. Dr. Mehta has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Adamas Pharma. Dr. Mehta has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbott. Dr. Mehta has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for CNS Ratings. Dr. Valencia Sanchez has nothing to disclose.

Treatment of Medication-Resistant Neuropathic Pain in a Tetraplegic Patient Using Repetitive Transcranial Magnetic Stimulation (rTMS): A case report (P9-6.009)

<h3>Objective:</h3> N/A <h3>Background:</h3> Transcranial magnetic stimulation (TMS) is a non-invasive method of neuromodulation currently FDA-approved for the treatment of depression, but has also shown promising results in treating neuropathic pain. Given the risks of invasive neuromodulation and the dangers of long-term opioid use, especially in the face of an opioid crisis, it is imperative to find an effective treatment with minimal side effects. <h3>Design/Methods:</h3> The patient is a 74-year old tetraplegic Caucasian man who suffers from severe medication-resistant neuropathic pain following a spinal cord injury. TMS treatment was initiated, using a two-part protocol consisting of high-frequency (10 Hz) stimulation of the left dorsolateral prefrontal cortex (DLPFC) followed by low-frequency (5 Hz) stimulation of the primary motor (M1) cortex. Patient received daily treatment for the first week and decreased in frequency as treatment continued. Pain was measured using the Visual Analog Scale and tracked over 13 weeks (currently ongoing). <h3>Results:</h3> Patient’s pain level before beginning treatment was 6.35/10. Within the first week of treatment, his baseline pain level was reduced to 4.19/10. The lowest pain immediately following treatment was 1.9/10, a 70.1% decrease in pain scores. During the initial week of treatments, the patient reported that pain relief lasted for a few hours immediately following treatment. As treatment continued, he reported experiencing progressively longer relief, and also decreased his dosage of opioids due to the pain relief from the rTMS treatment. <h3>Conclusions:</h3> The pain protocol reduced medication-resistant neuropathic pain in our patient, as measured by the Visual Analog Scale as well as a decrease in opioid usage. Analgesic effects were additive with continual treatment. TMS treatment is non-invasive and could be administered without moving the patient from his wheelchair. The significant, lasting decrease in pain reported by the patient supports the need for further clinical studies of combined M1-rTMS and DLPFC-rTMS treatment for neuropathic pain. <b>Disclosure:</b> Miss Li has nothing to disclose. Dr. Kuluva has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Piedmont Neuroscience Center. Ms. Paras has nothing to disclose. Mr. Mohammad has nothing to disclose.

Complexation of the Antihypertensive Drug Olmesartan with Zn: In Vivo Antihypertensive and Cardiac Effects.

This study is based on the premise that the application of chemical synthesis strategies to structurally modify commercial drugs by complexation with biometals is a valid procedure to improve their biological effects. Our purpose is to synthesize a compound with greater efficacy than the original drug, able to enhance its antihypertensive and cardiac pharmacological activity. Herein, the structure of the coordination compound of Zn(II) and the antihypertensive drug olmesartan, [Zn(Olme)(H2O)2] (ZnOlme), is presented. After 8 weeks of treatment in SHR male rats, ZnOlme displayed a better blood pressure-lowering activity compared with olmesartan, with a noticeable effect even in the first weeks of treatment, while ZnCl2 showed similar results than the control. ZnOlme also reduced left ventricle (LV) weight and left ventricle/tibia length ratio (LV/TL), posterior wall thickness (PWT), and intraventricular septum in diastole (IVSd) suggesting its potential to prevent LV hypertrophy. Besides, ZnOlme reduced interstitial fibrosis (contents of collagen types I and III, responsible for giving rigidity and promoting vascular elasticity, respectively). The recovery of heart function was also evidenced by fractional shortening (diastolic left ventricular/systolic left ventricular) diameter determinations. Furthermore, ZnOlme increased the antioxidant capacity and prevented cardiac oxidative stress: it enhanced the reduction of reactive oxygen species generation, exerted a significant decrease in lipid peroxidation and enhanced glutathione contents in heart tissues compared to the control, Zn, and olmesartan treatments. Our results demonstrate that continuous oral administration of ZnOlme causes a better antihypertensive effect and grants enhancement of cardioprotection through antioxidant activity, in combination with hemodynamic improvement.

Real-life use of trametinib after immunotherapy failure in BRAF wild-type advanced melanoma.

BRAF V600 wild-type advanced melanomas quickly reach a therapeutic dead-end, after immunotherapy failure. Even if preclinical studies have suggested sensitivity to MEK inhibitors such as trametinib in NRAS, NF1 or GNA mutated melanoma, therapeutic options are limited for these patients. We present a retrospective monocentric study of 22 patients with advanced melanoma treated by trametinib after immunotherapy resistance. Melanomas harboured NRAS (20), NF1 (1) or GNA 11 (1) mutations. For most of them (18), anti-PD1 was associated with trametinib. A disease-control was reported in 36% of patients (8/22), with six stable diseases and two partial responses according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Median progression-free survival was 2 months (1-14) and median overall survival was 6.5 months (2-24). In patients with progressive disease (14/22), dissociated radiologic responses and clinical benefits such as pain reduction were seen in five patients. High blood level of lactate dehydrogenase (LDH) seemed associated with trametinib failure, without significance ( P = 0.06). Adverse events (grade 1-3) occurred in 91% of patients during the first weeks of treatment, mainly papulo-pustular rashes (77%), leg oedemas (36%), asthenia (18%) and diarrhoea (14%). This real-life study showed that trametinib may benefit some metastatic melanoma that progressed after chemotherapy and immune checkpoint inhibitors. Objective disease control (partial response or stable disease) using RECIST criteria was observed in 36% of patients. Because of frequent side-effects which can alter the quality of life and the short response duration, this off-label option has to be discussed with the patient. Studies with combination therapy with trametinib to improve relapse-free survival and lower side-effects are ongoing.

Combined intravitreal dexamethasone and bevacizumab injection for the treatment of persistent diabetic macular edema (DexaBe study): a phase I clinical study

PurposeThe aim of this study is to investigate the safety of combined intravitreal injection of dexamethasone aqueous-solution (IVD) and bevacizumab (IVB) in patients with refractory diabetic macular edema (DME) and its effect on intraocular pressure (IOP), best-corrected visual acuity (BCVA) and central subfield thickness (CSFT).MethodsThis prospective study included 10 patients (10 eyes) with DME refractory to laser photocoagulation and/or anti-vascular endothelial growth factor (anti-VEGF) therapy. A complete ophthalmological examination was performed at baseline, during the first week of treatment, and monthly through week 24. Therapy consisted of monthly injections of combined IVD and IVB “pro re nata” (PRN) if CST > 300 µm. We investigated the impact of the injections on intraocular pressure (IOP), cataract development, Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA), and central sub-foveal thickness (CSFT) measured by spectral-domain optical coherence tomography (OCT).ResultsEight patients (80%) completed 24 weeks of follow-up. Compared to baseline, mean IOP increased significantly (p < 0.05) and anti-glaucomatous eye drops were necessary for 50% of the patients, CSFT was significantly reduced at all follow-up visits (p < 0.05), although mean BCVA showed no significant improvement. One patient developed dense cataract progression and another showed vitreoretinal traction at week 24. No inflammation or endophthalmitis was observed.ConclusionTreatment of DME refractory to laser and/or anti-VEGF therapy with combined PRN IV dexamethasone aqueous solution and bevacizumab was associated with adverse effects related to the use of corticosteroids. However, there was a significant improvement in CSFT meantime best-correct visual acuity remained stable or improved in 50% of patients.

Pilot study on the effect of autologous activated platelet-rich plasma on diabetic foot ulcer wound healing and serum HbA1c levels

Context: Autologous activated platelet-rich plasma (aaPRP) is a platelet-based therapy with high concentrations of growth factors that enhance the process of wound healing and glucose normalization. Aims: To evaluate the safety and efficacy of systemic and local administration of autologous activated platelet-rich plasma in diabetic foot ulcer wound healing and patients’ serum hemoglobin A1C. Methods: Ten subjects were equally randomized to placebo and aaPRP treatment. The aaPRP was administered locally and intravenously. Wound surface area and serum HbA1c levels were recorded on days 0, 7, and 14. Results: Injection of aaPRP for two weeks shows better clinical outcomes in reducing wound surface area non-significantly (40.11 ± 43.22 vs. -8.29 ± 49%; p = 0.136) and serum HbA1c levels non-significantly compared to the control group (2.16 ± 0.54 vs. 1.64 ± 2.218%; p = 0.635). However, patients in the aaPRP group had significantly better control of HbA1c within the first week of treatment (1.39 ± 0.84 vs. -0.08 ± 0.92; p = 0.030). Conclusions: aaPRP could be considered a potential therapeutic strategy in patients with diabetic foot ulcers.

Abstract PD17-02: ctDNA Molecular Response based on breast cancer driver mutations predicts progression in aromatase inhibitor-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer

Abstract Background: The combination of a CDK4/6 inhibitor and an aromatase inhibitor (AI) is the gold standard for AI-sensitive first line treatment of ER+ HER2- advanced breast cancer. Nevertheless, some patients progress rapidly and may benefit from alternative strategies. Early ctDNA dynamics have been shown to predict disease course in several clinical situations. Here, we use samples from the PADA-1 trial to assess this strategy for patients receiving AI and palbociclib as first line treatment. PADA-1 was designed to assess the clinical utility of sequential analysis of ctDNA for emerging ESR1 mutations to trigger an early switch from AI plus palbociclib to fulvestrant plus palbociclib treatment. The study included 1,017 patients and was positive on its primary end-point. The objective of this translational study was to analyze the predictive value of 4-week molecular response (MR) for patient progression. Material &amp; Method: First, a CLIA-validated targeted next-generation sequencing-based test (Guardant360 Response) was used to characterize changes in ctDNA level via detection of somatic single-nucleotide variants (SNVs), insertion/deletion mutations (indels), and gene fusions in 74 genes frequently mutated in cancer. A second analysis was restricted to cancer-associated mutations in 11 genes commonly mutated in breast cancer (PIK3CA, GATA3, TP53, AKT1, ERBB2, BRCA1, BRCA2, ATM, ESR1, PALB2 and RB1). The threshold for molecular response was defined as ≥ 50% decrease in ctDNA (MR score &amp;lt; 0.5). Subjects with ctDNA levels below the test’s limit of quantitation (ctDNA-low) were considered molecular responders. Results: 372 subjects with matched baseline and 4-weeks samples were available for analysis. Of these, 134 subjects (36%) were ctDNA-low, and 238 subjects (64%) quantifiable. Among the quantifiable subjects, 183 (77%) were molecular responders (MR+, MR &amp;lt; 0.5), and 55 (23%) were not (MR–, MR ≥ 0.5). PFS was moderately improved for both MR+ and ctDNA-low relative to MR– (HR=0.61 (95%CI 0.44-0.85), p&amp;lt; 0.01) over the full 29 months of follow up. Differential PFS event rate was observed only in the first 8 months following ctDNA assessment; during this time MR+ and ctDNA-low were associated with more significantly decreased risk of progression (HR 0.24, 95% CI 0.13 – 0.43, p=0.0001). Limiting ctDNA assessment to genes commonly mutated in breast cancer enhanced the predictive power of MR (HR=0.08, 95% CI 0.04 0.17, p&amp;lt; 0.001, for MR+ and ctDNA-low vs. MR– across 8 months post-assessment); however, fewer samples were quantifiable by this method (169 [45%] quantifiable; 203 [55%] ctDNA-low). Combining MR status with additional molecular features (e.g.tumor mutational burden and maximum mutation allele fraction) did not improve prediction of non-response. Conclusion: Changes in ctDNA fraction during the first weeks of treatment are predictive of long term clinical benefit on an individual patient basis, particularly during the first year of therapy. Adjusting the MR threshold and/or limiting to genes known to be relevant in the specific tumor can tailor the assessment of ctDNA change to specific clinical scenarios where greater sensitivity or specificity may be required. The identification of patients at high risk for early clinical failure at the onset of treatment may allow for therapy escalation and/or change to improve outcome in this population. Funding: Pfizer and Guardant Health Citation Format: Caroline Bailleux, Thomas Bachelot, Francois-Clement Bidard, Anne-Claire Hardy-Bessard, Ivan Bièche, Anne Pradines, Florian Clatot, thibault DE LA MOTTE ROUGE, Jean-Luc Canon, Barbara Pistilli, Kyle Chang, Katie J. Quinn, Heather L. Gustafson, Florence Dalenc, Cyril Foa, Hanifa Ammarguellat, Chantal Bernard-Marty, Brigitte Lucas, Sophie Barthier, Fabrice Lorchel, Olivier Gisserot, Laurent Arnould, Marjorie Mauduit, Jérôme Lemonnier, Frédérique Berger, Suzette Delaloge, Fabrice Andre. ctDNA Molecular Response based on breast cancer driver mutations predicts progression in aromatase inhibitor-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-02.

Major depressive disorder with anxious features - the role of pregabalin

IntroductionPatients with unipolar major depression often present with symptoms of anxiety. Presentations with high levels of anxiety, restlessness, and somatic correlates of anxiety can be clinically identified as anxious depression. The comorbidity of anxious and depressive symptoms is a marker of poor prognosis, with greater risk of relapse and increased suicidal risk.ObjectivesBrief review of the role of pregabalin in the treatment of major depressive disorder (MDD), based on a case study.MethodsConsultation of the clinical record and brief review of the literature on this subject.ResultsWe present the case of a 25-year-old woman, with no past psychiatric history, admitted to a psychiatric consultation with depressive symptoms, and marked anxiety and somatic complaints, such as restlessness, palpitations, gastrointestinal discomfort. She fulfilled diagnostic criteria for Major depressive disorder (MDD), and was initially treated with sertraline 50 mg, with partial response, but maintenance of prominent anxious symptoms with important functional impairment. Then, we raised the dose of sertraline to 100 mg and added pregabalin 50 mg, with up-titration to 150 mg per day, divided in three doses. We observed rapid response, particularly on the anxious symptoms, and subsequently on the patient functionality.The anxiety symptoms can increase in the first days of treatment with a selective serotonin reuptake inhibitor, which is the first-line therapy for major depression. Those are particularly difficult to treat, resulting often in treatment resistance and functional impairment. Pregabalin has a proven rapid-onset anxiolytic effect, with less cognitive and motor effects and less risk for dependence than benzodiazepines. It has demonstrated efficacy for the treatment of generalized anxiety disorder, but the use for patients with MDD has not been clearly studied.ConclusionsAlthough the evidence on this subject is sparse, pregabalin augmentation of antidepressants could be an adequate option for the treatment of depression, allowing a faster action on the anxiety symptoms, especially on the first weeks of treatment, without some of the risks of the benzodiazepines.Disclosure of InterestNone Declared

Immobilization of Heavy Metals in Contaminated Soil using Calcium Phosphate Amendment and Phosphate-solubilizing Fungi (Penicillium sp) in Benin City, Edo state, Nigeria

Soil is a limited resource that is continually contaminated by the presence of heavy metals as a result of human activities. This study used a combination of calcium phosphate amendment and phosphate-solubilizing fungi to immobilize heavy metals in polluted soil. Bovine bones were collected at an Abattoir Market in Aduwawa, Benin City, Nigeria with coordinates 6°22’6.24” N and 5°41’0.24” E and calcined to extract calcium-phosphate (hydroxyapatite), serial dilution and plating on Pikovskaya medium were utilized to obtain fungi extract from fertile soil. Prior to remediation, heavy metal analysis of polluted soil indicated high value of metal concentrations zinc 120.60mg/kg, chromium 22.67 mg/kg, cadmium 11.23 mg/kg, lead 18.43 mg/kg, iron 187.27 mg/kg and nickel 10.62 mg/kg above the World Health Organization permissible limit. There was a decrease in zinc and iron contents after the first week of treatment. The second week demonstrated a significant decrease in all metal concentrations; 27.53% for Zn, Cr 39.83%, Cd 46.13%, Pb 7.60%, Fe 46.26% and Ni 15.07% – indicating the treatment’s effectiveness.

Effects of thyme on halitosis in gingivitis patients: Can thyme mouthwash prevent halitosis-A randomized trial.

Bad breath is a condition that negatively affects people's social interactions and quality of life. The aim of this study was to evaluate the effect of thyme mouthwash on intraoral halitosis, gingival index (GI) and plaque index (PI) in patients with gingivitis. In this retrospective study, 60 gingivitis patients (30 women/30 men) received initial periodontal treatment followed by oral hygiene instructions (OHI) and then were divided into four groups: The control group (C) received only OHI, while chlorhexidine (CHX) mouthwash was prescribed to the CHX group, Zinc acetate and CHX diacetate mouthwash was prescribed to the zinc acetate and CHX diacetate (ZnA) group, and the thyme (T) group was instructed to use thyme mouthwash. GI, PI and volatile sulfur compound (VSC) values were recorded at baseline and at the first week of treatment. The initial values of the recorded parameters did not differ significantly between the groups. In all groups, VSCs, GI and PI decreased after treatment (p=0.001). There was no significant difference between the PI values of the groups after treatment (p=0.188). On the contrary, the GI and VSC values after treatment were significantly different between the groups (p=0.001). GI values were highest in the control group and lowest in the CHX group. In terms of VSCs, a significant difference was found between groups T and C, and between groups T and ZnA (p=0.001). This study showed that the use of thyme mouthwash after periodontal treatment was effective in improving bad breath and gingivitis in gingivitis patients.

Early outcomes, associated factors and predictive values of clinical outcomes of tandospirone in generalized anxiety disorder: a post-hoc analysis of a randomized, controlled, multicenter clinical trial

Objective To examine the early outcomes, associated factors and predictive values of clinical outcomes of different tandospirone doses in patients with a generalized anxiety disorder (GAD). Methods This was a posthoc analysis of “a randomized, controlled multicenter clinical trial of the efficacy and safety of different doses of tandospirone on GAD”. A total of 274 patients with GAD were included and randomized into the high-dose (tandospirone 60 mg/d) and low-dose (tandospirone 30 mg/d) groups for a 6-week treatment. The Hamilton Anxiety (HAMA), Clinical Global Impression-Severity (CGI-S), Short-Form-12 (SF-12) scales were used for assessment. The trial was registered at clinical trail.gov (NCT01614041). Results (1) In the first week of treatment, 35.8% of patients in the high-dose group fulfilled the early onset criteria, which was significantly higher than 19.0% found in the low-dose group (p = 0.002). In the second week of treatment, 22.6% of patients in the high-dose group achieved an early response, versus 12.4% in the low-dose group, indicating a significant difference (p = .026). (2) Factors associated with early onset at week 1 included baseline HAMA total score (OR = 0.916, 95%CI 0.882–0.952), age (OR = 0.974, 95%CI 0.950–0.998), drug dose (30 mg vs. 60 mg; OR = 0.298, 95%CI 0.156–0.568) and SF-12 physiological total score (OR = 1.030, 95%CI 1.010–1.050). (3) Early onset was significantly associated with response rate (OR = 18.34, 95%CI 12.10–27.81), remarkable response rate (OR = 27.56, 95%CI 11.65–65.17) and recovery rate (OR = 11.85, 95%CI 4.98–28.18). Group (high dose group vs. low dose group) (χ 2 = 8.535, p = .003) and baseline HAMA total score (χ 2 = 70.840, p < .001) were independent predictors of onset time. Conclusions The early outcomes of high-dose tandospirone in the treatment of GAD are better than those of the low-dose group. Patients with younger age at onset, milder anxiety symptoms and better physiological functions administered high-dose tandospirone showed rapid onset, great early outcomes, high recovery rate and good prognosis. Drug onset time had a good predictive effect on treatment outcome.

Evaluation of the Efficacy of Topical Hydrocortisone in the Treatment of Anal Fissure in Patients Undergoing Pharmacological Treatment

Background and Objective: Anal fissure can be associated with trauma caused by passing hard stools or prolonged diarrhea. The present study aimed to determine the effectiveness of topical hydrocortisone in the treatment of anal fissures in patients under medical treatment referred to Fatemi Hospital and Kausar Clinic of Ardabil Medical Sciences, Ardabil, Iran, in 2019. Materials and Methods: In this clinical trial study, 200 patients with anal fissures were randomly divided into two groups. The intervention group was treated with diltiazem gel, psyllium powder, lactulose syrup, and hydrocortisone topical ointment. Hydrocortisone ointment was not used in the control group. Results: The mean scores of initial pain were 8.06±0.7 and 7.79±1.02 in the intervention and control groups, respectively. The mean pain at the end of the first week was 2.5±1.06 in the intervention group and 3.34±0.89 in the control group. Pain reduction was significantly higher in the intervention group than in the control group in the first week of treatment. Two weeks later, the pain was 1.46±0.7 in the intervention group and 1.86±0.74 in the control group. There was a significant difference between the two groups in the first and second weeks of treatment. Conclusion: The therapeutic combination of a topical corticosteroid with a calcium channel blocker at the beginning of treatment for chronic fissures during the first week of treatment led to a faster response in the form of pain reduction

Treatment of autoimmune hepatitis: Budesonide does not solve our problems.

Treatment of autoimmune hepatitis: Budesonide does not solve our problems.

DOP38 Upadacitinib Therapy Reduces Crohn’s Disease Symptoms Within the First Week of Induction Therapy

Abstract Background Upadacitinib (UPA), an oral, selective JAK inhibitor demonstrated superior efficacy for clinical remission compared with placebo (PBO) and an acceptable safety profile in patients with moderately to severely active Crohn’s disease (CD) in 2 phase 3 induction trials, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836).1-2 There remains an unmet need for therapies that provide rapid symptom relief in ambulatory patients with moderate to severe CD experiencing disease flares. This sub-analysis evaluated the efficacy of UPA 45 mg once daily (UPA45) on early symptomatic improvement for the first 15 days of treatment, using pooled data from U-EXCEL and U-EXCEED. Methods U-EXCEL and U-EXCEED were multicentre, double-blind, PBO-controlled trials that enrolled patients who had average daily very soft or liquid stool frequency (SF) ≥4 and/or abdominal pain score (APS) ≥2 at baseline, plus a Simple Endoscopic Score for CD ≥6 (≥ 4 for patients with isolated ileal disease), excluding the narrowing component. Patients (n=1021) were randomized (2:1 ratio) to receive UPA45 (n=674) or PBO (n=347) for 12 weeks. First dose of study drug was administered on day 1. Improvement in daily symptoms of SF and APS, in addition to time to first achievement of daily SF/APS clinical remission were assessed. Results Patients treated with UPA45 experienced a significant improvement in daily symptoms compared with PBO-treated patients, simultaneously achieving SF &amp;lt; 3 and APS ≤ 1 beginning at day 3 (9.6% UPA vs. 5.8% PBO) (P≤0.05, Figure 1A). Difference from PBO was maintained through day 15 (P≤0.05), except for day 4 (P=0.0518). Similar results were found when evaluating each symptom separately, with a higher proportion of patients who received UPA45 achieving either SF &amp;lt; 3, beginning at day 5 (31.6% UPA vs. 23.1% PBO, Figure 1B). UPA-treat patients attained significance for APS ≤ 1 beginning at day 6 (49.1% UPA vs. 39.3% PBO, Figure 1C), compared with patients that received PBO. Differences from PBO were sustained through day 15 for either symptom (P≤0.01 for both endpoints). A greater proportion of patients receiving UPA45 also demonstrated at least a 60% decrease in SF by day 5, compared to PBO, which was maintained through day 15 (P≤0.01, Figure 1D). Patients treated with UPA45 achieved daily SF/APS clinical remission significantly earlier than PBO-treated patients (median time to clinical remission: 13 days UPA45 vs 32 days PBO; P&amp;lt;0.0001, Figure 2). Conclusion Patients who received UPA 45 mg once daily significantly improved daily symptoms of diarrhea or abdominal pain within the first week of treatment and achieved daily clinical remission faster than PBO-treated patients, providing rapid symptom relief.

P897 Longitudinal multi-tissue transcriptomic study reveals patient-specific drug response determinants in Inflammatory Bowel Disease patients

Abstract Background Despite the lack of understanding of Inflammatory Bowel Disease (IBD) pathogenesis, association studies have made inroads into the elucidation of the genetic component of disease diagnosis. The corresponding determinants of drug response, in turn, remain obscure. Primary response is low, secondary loss of response is prevalent and remission rates are low (30% of patients roughly). Along with the expanding repertoire of drugs, it is critical to develop a strategy to reveal the factors contibuting to drug response at the patient level. Our goal is to understand drug response in IBD looking to establish a precision medicine strategy to assign patients a specific treatment based on their transcriptomic profile. Methods We carried out a longitudinal follow-up of 147 IBD patients, from whom we sampled 264 intestinal biopsies and 119 blood extracts. Patients were exclusively treated with one of the three main available biologics: 248 with infliximab (anti-TNF), 47 with ustekinumab (anti-IL12/IL23) and 88 with vedolizumab (anti-α4β7). RNA-seq profiles were obtained at three different times (baseline, 14 weeks and 46 weeks after treatment initiation), resulting in 232, 92 and 59 samples, respectively. Differential expression analysis and pathway enrichment analysis were performed to get drug-specific genes and response signatures. Results The initial exploratory analysis confirms that tissue is the main determinant of expression variability among patients. As for longitudinal response, anti-TNF-specific features are quintessentially inflammatory, especially involved in translation and immune pathways, while response to ustekinumab is associated with extracellular recognition. Of note, vedolizumab-specific profiles strikingly differ between biopsy and blood samples. We also revealed that drug response is determined during first weeks of treatment, as up- and down-regulated genes are shared across time points. This may entail huge consequences in the clinic since the determination of response could be assessed earlier. Using clinical activity to define responders, we identified around 200 differentially expressed genes that could predict response to infliximab at time zero. We also improved our understanding regarding individual response by carrying out trend analyses based on connectivity scores that identify individual-specific regulated pathways. Conclusion While we identified common patterns across time in enriched pathways, we could discern specific drug response profiles. Besides providing a renewed understanding of the molecular effects of biological drugs, we propose that personalised models predicting response are feasible, and a promising venue to develop therapeutic guidelines of biologics in IBD.

A newly developing case of adrenal insufficiency developing after Coronavirus disease

Abstract Introduction Although some short and long-term effects of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection on the endocrine system are shown, there are still much more remaining to be clarified. A few case reports have shown that adrenal insufficiency can develop after COVID-19 infection due to adrenal hemorrhage or infarction. However, the exact effects of infection on cortisol dynamics are still poorly understood. This case report highlights an unusual case of acute adrenal insufficiency in a Covid-19. Clinical Case A 30-year-old female patient with no history of chronic disease applied with complaints of nausea, abdominal pain, and weakness for nearly 2 weeks. She was hospitalized. Her vitals were stable at the admission. Her initial laboratory evaluation showed serum sodium: 119 mEq/L, potassium: 5.38 mEq/L, creatinine: 1.35 mg/dL, aldosterone 2.33 ng/dL (1.46–17.4), plasma renin activity 40.56 ng/ml/h (0.06–4.69). Hemogram and liver function tests were normal. The basal ACTH value was measured 1142 pg/mL (7.2–63.3), and cortisol was 0.29 (6.24–18).The diagnosis of tuberculosis was ruled out with the quantiferon and the PPD test performed. In the detailed questioning of the patient, it was learned that she had Covid-19 infection about 3 months before the onset of symptoms. In this process, the patient's skin color was significantly darkened, and it was confirmed in comparison with the old photographs and from the patient's declaration. She was diagnosed with adrenal crisis, and corticosteroid therapy (80 mg/day intravenous methylprednisolone) and intravenous hydration were started. On the other hand, imaging and endoscopic evaluations were performed to exclude other intra-abdominal pathologies. No pathology was detected. Adrenal glands were normal in abdominal tomography. Stress dose steroid therapy was adjusted by reducing the daily dose. In the follow-up, the patient's complaints decreased and disappeared. Fludrocortisone was added to her treatment because electrolyte disturbances continued as hyponatremia and hyperkalemia. In the first week of treatment the patient's electrolyte disturbances improved and she was discharged with oral hydrocortisone and fludrocortisone treatment. The patient's skin color was observed lighter than before in the control examination, one week after discharge. Conclusion Although cases of adrenal insufficiency due to Covid-19 infection are found in the literature, their number is limited. The underlying causes are usually shown as hemorrhage and thrombosis. The absence of these findings in our case supports that the underlying cause is autoimmune and brought a different perspective to the issue. Our case also drives attention to the evaluation of patients in terms of adrenal insufficiency not only in the acute period but also in the later periods, since the diagnosis was made 3 months after the disease.

Characteristics, clinical outcomes and patient-reported outcomes of patients with ulcerative colitis receiving tofacitinib: a real-world survey in the United States and five European countries

BackgroundTo describe variations in treatment patterns, clinical outcomes, patient-reported outcomes (PRO), and physician and patient satisfaction in patients with moderate-to-severe ulcerative colitis (UC) treated with tofacitinib in a real-world setting.MethodsData were drawn from the Adelphi UC Disease Specific Programme™, a point-in-time survey of physicians and their consulting patients in the US and Europe. For inclusion in this analysis, gastroenterologists completed medical record forms for the next seven consecutive consulting patients with confirmed UC, plus a further two patient record forms for patients treated with tofacitinib. Those same patients then completed a patient-reported questionnaire.ResultsGastroenterologists (n = 340) provided data for 2049 patients with UC, including 642 patients receiving tofacitinib. Physicians’ most frequent reason for choosing tofacitinib was overall efficacy (71.3% of patients). The proportion of patients in remission increased with length of treatment, from 13.7% at [0, 4) weeks to 68.3% at [52+] weeks. Both physicians and patients reported that the Mayo components of stool frequency and blood in stool were reduced with time on treatment. Improvement in symptoms (bloody diarrhea, abdominal pain/cramps, urgency, rectal bleeding, fatigue/tiredness) was reported in the first weeks of treatment, and increased with time. At week [52+], mean score reductions from treatment initiation to current in overall symptom severity, pain, and fatigue were 2.2 (to a current mean score of 1.1), 2.2 (to 0.9), and 2.1 (to 1.0), respectively. Comparing patients at weeks [0, 4) and [52+] (all PROs, p < 0.0001), the increase in EQ-5D-5L index total score was 0.29 points and in SIBDQ total score was 20.5 points; percent reductions in WPAI absenteeism was 34.4%, presenteeism 26.8%, overall work impairment 40.9% and activity impairment was 28.3%. These changes reached the thresholds for minimally clinically important differences. The majority of physicians (91.9%) and patients (93.5%) were satisfied with tofacitinib at week [52+].ConclusionPatients with moderate-to-severe UC treated with tofacitinib show considerable improvement in symptoms and quality of life from tofacitinib initiation to one year and beyond, with high rates of remission. Physicians and patients report satisfaction with UC control at recommended doses in a mostly biologic experienced population.

Efgartigimod improved health-related quality of life in generalized myasthenia gravis: results from a randomized, double-blind, placebo-controlled, phase 3 study (ADAPT)

There are substantial disease and health-related quality-of-life (HRQoL) burdens for many patients with myasthenia gravis (MG), especially for those whose disease symptoms are not well controlled. HRQoL measures such as the Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r) and EuroQoL 5-Dimensions 5-Levels (EQ-5D-5L) are vital for evaluating the clinical benefit of therapeutic interventions in patients with MG, as they assess the burden of disease and the effectiveness of treatment, as perceived by patients. The phase 3 ADAPT study (NCT03669588) demonstrated that efgartigimod—a novel neonatal Fc receptor inhibitor—was well tolerated and that acetylcholine receptor antibody–positive (AChR-Ab+) participants who received efgartigimod had statistically significant improvements in MG-specific clinical scale scores. The ancillary data reported here, which cover an additional treatment cycle, show that these participants had similar significant improvements in HRQoL measures, the MG-QOL15r and EQ-5D-5L utility and visual analog scales, and that these improvements were maintained in the second treatment cycle. Positive effects on HRQoL were rapid, seen as early as the first week of treatment in both treatment cycles, and maintained for up to 4 weeks in the follow-up–only portion of treatment cycles. The pattern of improvements in HRQoL paralleled changes in immunoglobulin G level, and correlational analyses show that improvements were consistent across HRQoL measures and with clinical efficacy measures in the ADAPT study. The substantial and durable improvements in HRQoL end points in this study demonstrate the broader benefit of treatment with efgartigimod beyond relief of immediate signs and symptoms of gMG.

TREATMENT OF COMBAT GUNSHOT SHRAPNEL TRAUMA OF LARGE DEFECTS OF THE SOFT TISSUES OF THE LOWER EXTREMITIES WITH PLASTIC SURGERY IN COMBINATION WITH VACUUM ASSISTED WOUND CLOSURE (VAC).

The aim: To evaluate efficacy of the tissue defect closure techniques in combination with VAC in the treatment of battle casualities of the lower extremities. Materials and methods: The results of wound healing until complete wound closure, of 62 patients with shrapnel defects of the lower extremities where assessed. Results: Treatment of patients with soft tissue defects of the lower extremities using rotational flaps on the vascular pedicle and VAC significantly reduces the incidence of infectious complications (18.75% in the main group vs. 30% in the control group (p<0.05)), reduces the intensity of pain according to the VAS scale during the first week of treatment in the main group to 5±0.5 versus 7±0.8 in the control group (p<0.05) and reduces the length of hospital stay by 7 days. Conclusions: The use of rotational flaps on the vascular pedicle and local tissue closure techniques in combination with VAC is an effective method of treating patients with combat gunshot wounds of the soft tissues of the lower extremities.

Fenbendazole treatment against Dentostomella translucida in Syrian golden hamsters

Dentostomella translucida is an oxyurid nematode that was first discovered in the Mongolian gerbil but has also been detected in other wild and housed rodents. In conventional laboratory animals, oxyurid nematode parasites are widespread infections. A proven treatment strategy for pinworm eradication is the oral application of benzimidazoles, such as fenbendazole. In general, this drug is regarded as safe with minimal side effects. Nevertheless, in Sprague Dawley rats, a significantly reduced litter size could be seen after longer treatment with fenbendazole. Even though Dentostomella translucida was already described in Syrian golden hamsters (Mesocricetus auratus), data on treatment with fenbendazole and its effects on reproduction is lacking. Therefore, the main purposes of the study were (1) the verification of the effectiveness of fenbendazole as medicated feed (150 ppm) against this parasite in naturally infected Syrian golden hamsters in conventional husbandry and (2) monitoring of possible effects on reproduction during the treatment. Results show that fenbendazole treatment was highly effective against Dentostomella translucida, as numbers of pinworm eggs in the faeces were significantly reduced already after the first week of treatment in all animals. After four weeks of treatment, eggs were eradicated entirely. Interestingly, the average weaning weight was significantly reduced during treatment, but the litters were in good health.