High-dose IV Research Articles

CLINICAL CHALLENGE: AORTITIS IN THE EMERGENCY DEPARTMENT

Abstract A 67 yo woman presented to the ED for a sustained episode of palpitations and acute chest pain. Past medical history: suspected psoriatic arthritis previously treated with steroids and hydroxychloroquine; previous suspicion of rheumatic polymyalgia and Horton arteritis, regressed with steroids; gastroesophageal reflux disease; mild hypercholesterolemia and a family history of premature coronary artery disease. In the ED the patient was hemodynamically stable. On physical examination: tachyarrhythmic heart sounds with no murmurs. The peripheral arterial pulses were preserved and symmetrical. The remaining physical examination was unremarkable. ECG: atrial fibrillation at 150 bpm. The D–dimer was increased, normal hs–troponin and normal haemoglobin. On echocardiography: normal biventricular structure and function; normal aortic root with dilatation of proximal ascending aorta (47 mm), without visible intimal flaps. The anterior wall of the proximal ascending aorta was thickened. A moderate circumferential pericardial effusion was present, without signs of hemodynamic impact. On suspicion of an acute aortic syndrome with possible intramural haematoma of an ascending aortic aneurism, an urgent CT scan was ordered. It showed a severe dilatation of ascending aorta (52 mm) involving of the proximal aortic arch. The anterior aortic wall was thickened (5 mm), without clear images of IMH, aortic dissection or penetrating ulcer. The pericardial effusion had a supra–fluid density without blood density. A repeated CT at 6 hours showed no changes. The case was suggestive of an inflammatory aetiology. The patient was admitted to the cardiac intensive care unit. A PET–CT scan showed signs of an inflammatory disease of the great vessels. A serological autoimmunity screening was negative. The patient was diagnosed with inflammatory aortitis (giant cell vs Takayasu arteritis) and started on high dose iv glucocorticoid therapy. Given the high risk of severe aortic complications, adjunctive therapy with tocilizumab was prescribed. The therapy was gradually tapered, with subsequent switch to oral steroids plus tocilizumab. At one and a half month of follow–up, a CT scan was repeated, documenting stable aortic diameters and the disappearance of the abnormal thickness and of the enhancement of the aortic wall. A follow–up PET–CT scan has been scheduled at 6 months time. An elective aortic intervention has been indicated after remission of the inflammatory phase.

Randomized trial comparing low- vs high-dose IV dexamethasone for patients with moderate to severe migraine.

Randomized trial comparing low- vs high-dose IV dexamethasone for patients with moderate to severe migraine.

Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias

Background: Clonal cytopenia(s) of undetermined significance ( CCUS) is defined as persistent cytopenias arising in the context of myeloid neoplasm ( MN)-associated somatic mutations ( MT) in hematopoietic stem cells. Patients ( PTs) with TET2MT CCUS have a high probability of progression to MN. To date, no FDA-approved therapies exist for CCUS, and PTs often have similar cytopenias/transfusion needs as those with myelodysplastic syndromes ( MDS). TET2 is an ascorbic acid (AA)-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine ( 5mC) to 5-hydroxymethylcytosine ( 5hmC), providing rationale to study high-dose IV (HI)-AA in TET2MT CCUS. Here we report the final results of this pilot trial. Methods: This is an investigator-initiated, single-institutional, phase II trial assessing the safety and efficacy of HI-AA in PTs with TET2MT CCUS (NCT03418038). PTs≥ 18 years with ≥1 TET2MT with or without additional somatic MTs, without prior treatment, and with any of the following laboratory criteria: (1) hemoglobin ( Hb) ≤10g/dL, (2) absolute neutrophil count ( ANC) ≤1(10^9/L), (3) platelet count ( PLT)≤100 (10^9/L) were eligible. HI-AA (1g/kg, maximum 100g) was given 3 times weekly for 12 weeks. The primary endpoint was hematologic response rates determined by MDS IWG 2018 criteria at week 20. (Platzbecker Blood 2018) and reported as hematologic improvement ( HI)- erythropoietic ( HI-E), platelets ( HI-P), neutrophils ( HI-N). Secondary endpoints include safety and adverse events ( AEs), graded by NCI-CTCAE v4.03. Correlative studies include changes in TET2MT variant allele fraction ( VAF), in vitro colony formation and differentiation, global and sequence-specific DNA methylation/hydroxymethylation, and quantitative 5hmC estimated by IHC in bone marrow biopsy specimens. Results: Ten patients were enrolled, with a median age of 71.4 (range: 65, 79) years, 8 (80%) males. The median number of mutations was 3, with 9 (90%) having co-mutations. All PTs but one [-Y] had normal karyotype. Baseline Hb levels were normal in all but one who was red blood transfusion dependent. Five (50%) PTs were thrombocytopenic, and 5 (50%) PTs had ANC<1 (10^9/L). ( Table). HI-AA was well tolerated with the most common AEs being infusion-related polyuria (40%) and polydipsia (40%, 3 Grade 1, 1 Grade 2). One (10%) PT had constipation and headaches (both Grade 1), and 1 (10%) experienced dyspepsia. No treatment-related Grade 3 or 4 AEs' or deaths were reported. The median follow-up duration was 16.8 months (range: 9.4, 24.1). Overall, no PTs met the criteria for HI. There were no significant differences with regards to median Hb, PLT, and ANC values at baseline, week 20, and 1-year (median Hb: 13.3, 12.5, and 12.7 g/dL, p=0.93; PLT: 97 vs. 120 vs. 92.5X10^9/L, p>0.99, and ANC: 0.9 vs. 1.2 vs. 1.3X10^9/L, p=0.99). By CTCAE grading criteria for cytopenias, 3 (30%) PTs had an improvement in severity of cytopenias, while 2 had worsening. One (10%) PT had an improvement in PLT (baseline vs. week 20: 62 vs 192X10^9/L) but was morphologically deemed to meet criteria for CMML-1 at week 20. Four (40%) PTs met criteria for disease progression (PT_4, 7,8,10); CMML-1- 2 and MDS-2. The median time to progression was 5 months (95% CI: 4.9, unreached). Two PTs had mutational clonal evolution, with 1 (PT_8) acquiring a RUNX1 (VAF: 20%) and 1 (PT_9) acquiring 2 CBL mutations (both VAF:4%) at one-year follow-up. There were no significant differences regarding the clinical characteristics or the TET2 variants between PTs who had stable disease vs. progression. There were no significant differences in TET2 VAF at baseline, week 20, and 1-year (median: 39% vs. 43% vs. 42%, p=0.54). We profiled changes in 5-mC and 5-hmC (Ilumina EpicArray) in PTs pre- and post-IV AA treatment and did not observe global changes. However, we were able to highlight site-specific changes in differentially methylated regions, largely resulting in hypomethylation at enhancer sites and affecting actively transcribed states in PTs with an improvement in cytopenia(s) severity by CTACE criteria ( Figure). Conclusion: We report the final safety and efficacy analysis of HI-AA in PTs with TET2 MT CCUS. The trial data suggest that HI-AA is safe and well tolerated. Although there were no significant responses by IWG MDS criteria, alleviation in severity of cytopenias in a subset of PTs (n=3) along with correlative epigenetic changes in enhancer regions, needs further exploration.

1833P Concurrent high-dose IV Vitamin C (IVC) and docetaxel for metastatic castrate-resistant prostate cancer (mCRPC): A randomized, placebo-controlled, double-blind phase II trial

1833P Concurrent high-dose IV Vitamin C (IVC) and docetaxel for metastatic castrate-resistant prostate cancer (mCRPC): A randomized, placebo-controlled, double-blind phase II trial

Randomized placebo-controlled trial of intravenous vitamin C plus docetaxel in metastatic prostate cancer.

e17050 Background: Some phase I/II trials showed that combining high dose IV vitamin C with chemotherapies decreased toxicities and improved QoL in advanced cancers, while others failed to show benefits. While grade ¾ AEs are not typically a co-primary endpoint, they are a measure of cumulative toxicity. We investigated whether high-dose IV vitamin C could improve prostate-specific antigen (PSA) response rate and mitigate docetaxel toxicities in patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving docetaxel. Methods: Patients were randomized (2:1) to receive docetaxel (75mg/m2 IV every 3 weeks) plus IV vitamin C (1g/kg) or placebo twice a week. The primary endpoints were PSA50 response by24 weeks and adverse events (AEs) of fatigue, nausea, bone pain, and anorexia. Secondary endpoints included overall survival (OS) and QoL measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Results: 50 patients were randomized, 47 received therapy (treatment N = 32, control N = 15), 3 untreated (withdrawal, elevated creatine, low hemoglobin). The median age was 74 years (range 45-85) and ECOG 1. The median PSA was 108.3 ng/mL (range: 0.3, 2102.3). The median number of chemotherapy cycles was 6 (IQR 3-8). The study was suspended after the pre-specified interim analysis for primary endpoints showed futility. The PSA50 response was 41% for treatment and 33% for control (P = 0.44). Grade 1-2 and grade 3-4 prespecified AEs occurred in 69% and 6% of treatment group patients versus 60% and 0% of control group patients (one-sided Cochran Armitage test, P =0.90). Diarrhea (72% vs 19%) and anemia (47% vs 25%) and neutropenia (22% vs 19%) are more frequent in the Vit C group. Compared with the control group, treatment group patients showed a trend towards shorter median OS. FACT-P was not significantly different at any timepoints. Conclusions: Initial concurrent high-dose IV vitamin C with docetaxel did not improve PSA response, toxicity, or clinical outcomes. MCRPC patients receiving docetaxel should be advised against seeking concurrent high-dose IV vitamin C. Clinical trial information: NCT02516670 .

The Case Files

The Case Files

1246: CALCIUM CHANNEL BLOCKER TOXICITY TREATED WITH METHYLENE BLUE AND LIPID EMULSION: A RARE SURVIVOR

Introduction: Calcium channel blocker (CCB) toxicity due to intentional overdose (OD) is associated with high morbidity and mortality. Depending on the CCB subclass, symptoms can include altered mentation, hypotension, and bradycardia. The lack of formally recognized guidelines in the treatment of CCB toxicity can complicate management. Description: A 67-year-old female with history of depression was admitted to the ICU after suicidal ingestion of thirty amlodipine 5 mg tablets for shock refractory to volume resuscitation and vasopressor support. Initial vitals were reported as blood pressure 55/29, pulse 86, respirations 18, pulse oximeter 94% on room air, Glascow coma scale of 13 with stuporous mentation. Despite fluids, initiation of norepinephrine, intravenous (iv) calcium and glucagon, her shock persisted. Toxicology was contacted and recommended high dose iv insulin and dextrose which transiently improved blood pressures, however low mean arterial pressures (MAP) necessitated initiation of vasopressin and epinephrine drips. Methylene blue was started, followed by escalation to iv lipid emulsion (ILE) therapy. With this regimen, distributive shock and mentation improved. With time, vasopressor support was weaned and the patient made a complete recovery from severe CCB toxicity. Discussion: Conventional treatment with iv calcium, glucagon, atropine, cardiac pacing and pressors often fail to improve the hemodynamics associated with intentional CCB OD. Adjunct therapy with insulin may improve cardiac myocyte contractility and methylene blue is postulated to improve distributive shock via inhibition of nitric oxide synthase but current literature lacks case control data. ILE therapy should also be considered early in the treatment course and utilized with the guidance of a toxicologist as ILE is not without risk of complications including but not limited to acute pancreatitis, fat embolism, cardiac arrest, kidney injury, ARDS, seizure, and coagulopathy. Despite its growing utility in the treatment of lipophilic drug toxicity, most studies with CCB OD are case reports and based on animal studies rather than clinical trials. This case demonstrates the potential benefits of adjunct treatment with methylene blue and iv lipid emulsion to improve refractory distributive shock.

Effects of oral administration and intravenous injection of polygalacturonic acid on the immunomodulation and gut microbiota in UC mice

This study aimed to compare the differences between oral administration and intravenous injection of polygalacturonic acid (PGA) in the regulation of immune and intestinal microflora in ulcerative colitis (UC) mice. PGA was administered orally or intravenously. PGA in the high-dose ig group was the most effective in treating UC by increasing colon length and downregulating disease activity index, histopathological score and proinflammatory cytokine levels. In spleen, the efficacy of PGA on restoring Th17/Treg balance in the high-dose iv group was better than that in the high-dose ig group, the opposite was observed in the lamina propria. The level of colonic IL-17A in the high-dose ig group was lower than that in the high-dose iv group, the opposite was observed for that of colonic IL-10. Western blot and immunohistochemistry analysis revealed that PGA in the high-dose ig group decreased the protein expression of RORγt, and increased that of FOXP3. Furthermore, PGA in the high-dose ig group was more effective than that in the high-dose iv group in improving the intestinal microflora structure. Our results suggest that in immune regulation, oral PGA is more effective in the lamina propria and gut microbiota while intravenous PGA is more effective in the spleen.

741 A complex clinical mosaic of severe autoimmune calcific constrictive pericarditis with striking haemodynamic response to immunosuppressive therapy

Abstract Autoimmune constrictive pericarditis constitutes a conundrum to modern cardiology with much uncertainty surrounding both pathophysiology and optimal treatment strategies. We hereby describe the case of a 35-year-old woman of Nigerian origin with severe right heart failure secondary to calcific constrictive pericarditis. Her past medical history included coagulation factor XI deficiency, leukopenia, 2nd trimester miscarriage and premature labour due to placenta previa with fibrin deposition. Further investigations revealed atrial fibrillation, severe biatrial enlargement, moderate tricuspid and mitral regurgitation, pericardial thickening, post-capillary pulmonary hypertension and right ventricular dip-and-plateau pattern, compatible with severe constrictive pericarditis. Extensive screening for infectious and autoimmune causes only revealed borderline positive ANA (1:80). Thereafter, the patient underwent complete surgical pericardiectomy with pericardial biopsies revealing fibrous thickening, diffuse calcification and lymphocyte/macrophage infiltrates, in the absence of giant multinucleated cells or granulomas. The patient was later discharged but soon experienced relapse of exertional dyspnoea presenting with right-sided haemo-pneumothorax (requiring pleural drainage), diffuse alveolar haemorrhage, large right-sided basal and infrascissural pleural effusion, and ascites. She was treated with high dose iv furosemide, oral ibuprofen and colchicine, suspension of rate control medications, achieving initial reduction in pulmonary oedema and ascites, relapsing however after attempts to switch to oral diuretic therapy. Due to the finding of persistent lymphopenia, further immunological tests were conducted, revealing raised IgG1 levels as well as altered peripheral lymphocyte populations (raised CD4+/CD8+ ratio and CD8+ central memory, reduced CD8 effector memory). This finding in conjunction with the history of factor XI deficiency, 2nd trimester miscarriage and placental fibrin deposition as well as the observation of painful cutaneous nodules at sites of venepuncture, suggestive of Koebner’s phenomenon, veered the diagnostic focus to a potential autoimmune aetiology and in particular to systemic lupus erythematosus (>10 ACR-EULAR score points with case reports describing all the above as potential disease manifestations). Furthermore, revision of thoracic CT scans, demonstrated bilateral migratory peribronchovascular nodules with ground-glass halo. CT- guided biopsies thereof were performed revealing focal alveolar damage with capillaritis and alveolar haemorrhage, further corroborating the clinical suspicion of autoimmune disease and justifying the introduction of high-dose oral corticosteroid therapy. In liaison with our tertiary rheumatology centre, the patient was later switched to mycophenolate with gradual weaning from corticosteroid. Concurrent cardiological follow-up revealed persistence of good haemodynamic status (NYHA class II, absence of pulmonary oedema and ascites) with oral diuretic therapy, regression of cutaneous symptoms and echocardiography demonstrating consistent reduction in both mitral and tricuspid regurgitation. This constitutes to our knowledge the first report of autoimmune calcific constrictive pericarditis with significant haemodynamic response to immunosuppressive therapy. Despite the relative rarity of this disease entity, early recognition and instatement of immunosuppressive treatment may prove fundamental to halt and potentially reverse the haemodynamic progression of this highly morbid condition.

Tranexamic Acid in Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.

Tranexamic acid is proposed as a treatment for gastrointestinal bleeding. The Haemorrhage Alleviation with Tranexamic Acid-Intestinal System trial evaluated extended-use (24 hr) high-dose tranexamic acid, prompting a reappraisal for tranexamic acid in gastrointestinal bleeding. We conducted a systematic review and meta-analysis of randomized controlled trials comparing tranexamic acid with usual care or placebo in adults with gastrointestinal bleeding. We searched MEDLINE, EMBASE, and CENTRAL (inception to September 2019). Two reviewers independently screened citations, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool in duplicate. The main outcomes were mortality, bleeding, and adverse events. Studies were analyzed as high-dose IV tranexamic acid versus all other dosing strategies for tranexamic acid using fixed-effects models. We assessed certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. Five randomized controlled trials evaluated extended-use high-dose IV tranexamic acid, seven evaluating low-dose IV or enteral tranexamic acid. Extended-use high-dose IV tranexamic acid did not reduce mortality (relative risk, 0.98%; 95% CI, 0.88-1.09; I2 = 63%; high certainty) or bleeding (relative risk, 0.92; 95% CI, 0.82-1.04; p = 0.17 and absolute risk differences, -0.7%; 95% CI, -1.5 to 0.3; high certainty) but resulted in a small increase in deep venous thrombosis (relative risk, 2.01; 95% CI, 1.08-3.72; I2 = 0%), pulmonary embolism (relative risk, 1.78; 95% CI, 1.06-3.0; I2 = 0%), and seizure (relative risk, 1.73; 95% CI, 1.03-2.93) with high certainty. Low-dose IV/enteral tranexamic acid did not reduce mortality (relative risk, 0.62; 95% CI, 0.36-1.09; I2 = 0%) but did reduce risk of rebleeding (relative risk, 0.5; 95% CI, 0.33-0.75; I2 = 9%) and need for surgery (relative risk, 0.58; 95% CI, 0.38-0.88; I2 = 11%), with moderate certainty. Extended-use high-dose IV tranexamic acid does not improve mortality or bleeding outcomes and increases adverse events. Low-dose/enteral tranexamic acid may be effective in reducing hemorrhage; more evidence is required to demonstrate its safety.

AN UNUSUAL CASE OF ACUTE EOSINOPHILIC PNEUMONIA IN OLD AGE

TOPIC: Allergy and Airway TYPE: Medical Student/Resident Case Reports INTRODUCTION: Acute eosinophilic pneumonia/pneumonitis (AEP) is a rare respiratory illness characterized by eosinophil accumulation in the pulmonary interstitium and airspaces.Due to limited research done in older population, there is delayed and underdiagnosis in patients above age 40.Here we present a unique case of a 96-year-old man with AEP. CASE PRESENTATION: A 96-year-old lifetime non-smoker male with a history of hypertension, DVT on therapeutic enoxaparin presented to the hospital from a nursing home with a productive cough and increasing shortness of breath.He was found to be saturating at 80% on 4 liters of oxygen. Patient had a fever of 100.1F.Physical exam was significant for bilateral diminished breath sounds.His chest x-ray revealed worsening bilateral pulmonary infiltrates since his last admission with pneumonia last month.He was started on empiric antibiotics and High flow oxygen.CT chest showed bilateral ground glass opacities with increased interstitial thickening.Blood cultures, respiratory pathogen panel, SARS-COV2 PCR were negative. The patient's eosinophils increased to 11.7% with a progressive decline in neutrophil count. The bronchoalveolar lavage showed presence of numerous clumps of eosinophils. Patient was diagnosed with AEP and started on methylprednisolone 80 mg twice daily. Antibiotics were stopped and patient's status improved with continuous steroid treatment. Patient improved and was discharged on steroid taper. DISCUSSION: AEP is an idiopathic entity commonly associated with smoking, medications, allergic diathesis and parasitic infections. Furthermore, individuals between 20-40 years of age are most commonly affected. It causes IL-5 release and eosinophils accumulation, resulting in the release of toxic proteins and lipid mediators that promote a pro inflammatory reaction. Eosinophil counts may be normal on presentation, as seen in this case. Symptomatic AEP resembles pneumonia and While diagnosing AEP, it is important to exclude other disorders such as asthma or other atopic illnesses as these also respond to corticosteroids. Gold standard diagnosis of AEP is bronchoscopy with BAL which reveals eosinophilia (>25%). Treatment of AEP requires eliminating the inciting factor and initiating corticosteroids. While there are no clear guidelines on the optimal dosing of corticosteroids, there is evidence to suggest that high-dose IV steroids is effective in patients requiring mechanical intubation, whereas low dose oral prednisone is efficient in patients with minimal hypoxia. CONCLUSIONS: Our case here is unique as it highlights the occurrence of AEP in old age in the absence of associated factors. It is prudent to be vigilant of leukocyte trends in patients with recent history of pneumonia as not to misdiagnose and to consider other possible etiologies, such as AEP.If identified and treated appropriately, the disease has favorable outcomes with no long term sequalae. REFERENCE #1: Rhee CK, Min KH, Yim NY, Lee JE, Lee NR, Chung MP, Jeon K. Clinical characteristics and corticosteroid treatment of acute eosinophilic pneumonia. Eur Respir J. 2013 Feb;41(2):402-9. doi: 10.1183/09031936.00221811. Epub 2012 May 17. PMID: 22599359. REFERENCE #2: Pope-Harman, Amy L.;Davis, Bruce W.;Allen, Elizabeth D.;Christoforidis, John A.;Allen, James N. Acute Eosinophilic Pneumonia A Summary of 15 Cases and Review of the Literature, Medicine: November 1996 - Volume 75 - Issue 6 - p 334-342 DISCLOSURES: No relevant relationships by MohammadAsim Amjad, source=Web Response No relevant relationships by Ajinkya Buradkar, source=Web Response No relevant relationships by Kashyap Kela, source=Web Response No relevant relationships by Pooja Kharbanda, source=Web Response No relevant relationships by jacob miller, source=Web Response No relevant relationships by Princy Shah, source=Web Response

Early high-dose vitamin C in post-cardiac arrest syndrome (VITaCCA): study protocol for a randomized, double-blind, multi-center, placebo-controlled trial

BackgroundHigh-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. The aim of this study is to investigate whether short-term treatment with a supplementary or very high-dose intravenous vitamin C reduces organ failure in post-cardiac arrest patients.MethodsThis is a double-blind, multi-center, randomized placebo-controlled trial conducted in 7 intensive care units (ICUs) in The Netherlands. A total of 270 patients with cardiac arrest and return of spontaneous circulation will be randomly assigned to three groups of 90 patients (1:1:1 ratio, stratified by site and age). Patients will intravenously receive a placebo, a supplementation dose of 3 g of vitamin C or a pharmacological dose of 10 g of vitamin C per day for 96 h. The primary endpoint is organ failure at 96 h as measured by the Resuscitation-Sequential Organ Failure Assessment (R-SOFA) score at 96 h minus the baseline score (delta R-SOFA). Secondary endpoints are a neurological outcome, mortality, length of ICU and hospital stay, myocardial injury, vasopressor support, lung injury score, ventilator-free days, renal function, ICU-acquired weakness, delirium, oxidative stress parameters, and plasma vitamin C concentrations.DiscussionVitamin C supplementation is safe and preclinical studies have shown beneficial effects of high-dose IV vitamin C in cardiac arrest models. This is the first RCT to assess the clinical effect of intravenous vitamin C on organ dysfunction in critically ill patients after cardiac arrest.Trial registrationClinicalTrials.gov NCT03509662. Registered on April 26, 2018. https://clinicaltrials.gov/ct2/show/NCT03509662European Clinical Trials Database (EudraCT): 2017-004318-25. Registered on June 8, 2018. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004318-25/NL

27066 Angiosarcoma of the scalp and paraneoplastic encephalopathy: Multidisciplinary approach to diagnosis and treatment

Cutaneous angiosarcomas of the scalp are rare tumors of the skin and soft tissue with an insidious onset and aggressive course. Paraneoplastic syndromes have been reported for skin cancers including melanoma and Merkel cell carcinoma. Here, we describe a case of a 75-year-old man with presumed paraneoplastic neurological syndrome in the context of angiosarcoma of the scalp. The patient initially presented with persistent frontal headaches which rapidly progressed to acute confusion, agitation, and word finding difficulties. CSF studies were negative for infection, and EEG demonstrated nonspecific slow waves. A brief course of high-dose steroids successfully treated his neurological symptoms; however his symptoms resurfaced with each taper. Upon hospitalization during which he was evaluated by a multidisciplinary team including neurology and dermatology, the etiology of his neurologic presentation remained elusive, until two cutaneous scalp lesions were identified and biopsied. Pathology confirmed the presence of angiosarcoma, and neuroimaging showed right parietal and vertex scalp soft tissue masses without bony or brain involvement. The patient responded to high-dose IV steroids and transitioned to oral prednisone 60 mg daily. Medical oncology was able to initiate chemotherapy successfully, but the patient eventually developed additional oncologic concerns. To our knowledge, this is one of the first reported cases of a paraneoplastic neurological syndrome occurring in close temporal association with cutaneous angiosarcoma of the scalp. Paraneoplastic syndromes may be considered in patients with various dermatological malignancies in general and in angiosarcoma. A multidisciplinary approach is key for these complex patient presentations.

Feasibility of Vitamin C in the Treatment of Post Viral Fatigue with Focus on Long COVID, Based on a Systematic Review of IV Vitamin C on Fatigue.

Fatigue is common not only in cancer patients but also after viral and other infections. Effective treatment options are still very rare. Therefore, the present knowledge on the pathophysiology of fatigue and the potential positive impact of treatment with vitamin C is illustrated. Additionally, the effectiveness of high-dose IV vitamin C in fatigue resulting from various diseases was assessed by a systematic literature review in order to assess the feasibility of vitamin C in post-viral, especially in long COVID, fatigue. Nine clinical studies with 720 participants were identified. Three of the four controlled trials observed a significant decrease in fatigue scores in the vitamin C group compared to the control group. Four of the five observational or before-and-after studies observed a significant reduction in pre–post levels of fatigue. Attendant symptoms of fatigue such as sleep disturbances, lack of concentration, depression, and pain were also frequently alleviated. Oxidative stress, inflammation, and circulatory disorders, which are important contributors to fatigue, are also discussed in long COVID fatigue. Thus, the antioxidant, anti-inflammatory, endothelial-restoring, and immunomodulatory effects of high-dose IV vitamin C might be a suitable treatment option.

NIMG-62. AMPHETAMINE-ASSOCIATED CNS VASCULITIS MASQUERADING AS TUMOUR

Abstract Amphetamine-associated CNS vasculitis is controversial. There are few reports but none as a tumor mimic to our knowledge. We describe a pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man presented with six weeks of progressive confusion and left-sided weakness. CT head reported a right thalamic mass with vasogenic edema. Laboratory tests were unremarkable except for cannabinoids and amphetamine in urine. MRI brain showed enhancement in right frontotemporal lobe, basal ganglia, and thalamus concerning for glioblastoma multiforme. After high-dose IV dexamethasone, an initial biopsy showed reactive gliosis, perivascular lymphocytic cuffing by CD3+, rare CD20+ cells and no infection. He continued to decline. MRI 22 days after admission showed increased T2/FLAIR hyperintensity, multifocal areas of enhancement, microhemorrhages, and ischemia. High-grade glioma, lymphoma and infectious encephalitis remained on differentials. Treatment included broad-spectrum antibiotics and acyclovir. Biopsy on 23rd day showed reactive gliosis with parenchymal macrophage infiltration and perivascular cuffing with mixed inflammatory infiltrates. CSF: slightly elevated WBCs (8/µL), elevated protein (139mg/dL), normal glucose, and no infection. MRI whole spine and CT body were unremarkable. The patient was transferred to MDACC 5.5 weeks after initial presentation. He was alert with expressive aphasia, right gaze preference, left hemiplegia, and right hemiparesis. He underwent a right anterior temporal lobectomy. Pathology showed extensive cortical laminar and white matter necrosis with macrophage infiltration and microglial activation. In areas of the preserved cortex, vasculocentric lymphocytic aggregates were present and reticulin staining showed lymphocytic infiltration of the vascular walls. Immunophenotyping (CD3, CD20) showed an almost pure T-cell population. The predominance of intramural T-lymphocytes reflected a vasculitic process. The final diagnosis was cerebral vasculitis with subacute infarction. The patient died six days later. The autopsy findings were identical to the previous resection without evidence of systemic inflammation.

Tranexamic Acid in Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis

Background: Tranexamic acid (TXA) is proposed as a treatment for gastrointestinal bleeding (GIB). The HALT-IT trial evaluated extended-use (24 hour) high-dose TXA, prompting a reappraisal for TXA in GIB. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TXA to usual care or placebo in adults with GIB. We searched MEDLINE, Embase, and CENTRAL (inception to September 2019). Two reviewers independently screened and extracted results. The main outcomes were mortality, bleeding, and adverse events. Studies were analyzed as high-dose IV TXA vs. all other dosing strategies for TXA using fixed-effects models. We assessed certainty of evidence using the GRADE approach. Findings: 5 RCTs evaluated extended-use high-dose IV TXA, 7 evaluating low dose IV or enteral TXA. Extended-use high-dose IV TXA did not reduce mortality (RR 0·98% 95%CI 0·88,1·09, I2=63%, high certainty), or bleeding (RR 0·92, 95%CI 0·82,1.04, p=0.17; ARD -0·7% 95%CI -1·5, 0·3; high certainty), but resulted in a small increase in DVT (RR 2·01, 95%CI 1·08,3·72, I2=0%), PE (RR 1·78, 95%CI 1·06, 3·0, I2=0%), and seizure (RR 1·73, 95%CI 1·03,2·93) with high certainty. Low-dose IV/enteral TXA did not reduce mortality (RR 0·62, 95%CI 0·36,1·09, I2=0%), but did reduce risk of rebleeding (RR 0·5, 95% CI 0·33, 0·75, I2=9%) and need for surgery (RR 0·58, 95%CI 0·38,0·88, I2=11%), with moderate certainty. Interpretation: Extended-use high-dose IV TXA does not improve mortality or bleeding outcomes, and increases adverse events. Low-dose/enteral TXA may be effective in reducing hemorrhage, more evidence is required to demonstrate its safety. Funding: None Declaration of Interests: SO received payment as a methodology consultant for the American Thoracic Society. The remainder of the authors have no conflicts of interest.

Glycerol Monolaurate, an Analogue to a Factor Secreted by Lactobacillus, Is Virucidal against Enveloped Viruses, Including HIV-1.

The vaginal microbiota influences sexual transmission of human immunodeficiency virus type 1 (HIV-1). Colonization of the vaginal tract is normally dominated by Lactobacillus species. Both Lactobacillus and Enterococcus faecalis may secrete reutericyclin, which inhibits the growth of a variety of pathogenic bacteria. Increasing evidence suggests a potential therapeutic role for an analogue of reutericyclin, glycerol monolaurate (GML), against microbial pathogens. Previous studies using a macaque vaginal simian immunodeficiency virus (SIV) transmission model demonstrated that GML reduces transmission and alters immune responses to infection in vitro Previous studies showed that structural analogues of GML negatively impact other enveloped viruses. We sought to expand understanding of how GML inhibits HIV-1 and other enveloped viruses and show that GML restricts HIV-1 entry post-CD4 engagement at the step of coreceptor binding. Further, HIV-1 and yellow fever virus (YFV) particles were more sensitive to GML interference than particles "matured" by proteolytic processing. We show that high-pressure-liquid-chromatography (HPLC)-purified reutericyclin and reutericyclin secreted by Lactobacillus inhibit HIV-1. These data emphasize the importance and protective nature of the normal vaginal flora during viral infections and provide insights into the antiviral mechanism of GML during HIV-1 infection and, more broadly, to other enveloped viruses.IMPORTANCE A total of 340 million sexually transmitted infections (STIs) are acquired each year. Antimicrobial agents that target multiple infectious pathogens are ideal candidates to reduce the number of newly acquired STIs. The antimicrobial and immunoregulatory properties of GML make it an excellent candidate to fit this critical need. Previous studies established the safety profile and antibacterial activity of GML against both Gram-positive and Gram-negative bacteria. GML protected against high-dose SIV infection and reduced inflammation, which can exacerbate disease, during infection. We found that GML inhibits HIV-1 and other human-pathogenic viruses (yellow fever virus, mumps virus, and Zika virus), broadening its antimicrobial range. Because GML targets diverse infectious pathogens, GML may be an effective agent against the broad range of sexually transmitted pathogens. Further, our data show that reutericyclin, a GML analog expressed by some lactobacillus species, also inhibits HIV-1 replication and thus may contribute to the protective effect of Lactobacillus in HIV-1 transmission.

Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens

Early high-dose IV vitamin C is being investigated as adjuvant therapy in patients who are critically ill, but the optimal dose and infusion method are unclear. The primary aim of this study was to describe the dose-plasma concentration relationship and safety of four different dosing regimens. This was a four-group randomized pharmacokinetic trial. Patients who were critically ill with multiple organ dysfunction were randomized to receive 2 or 10 g/d vitamin C as a twice daily bolus infusion or continuous infusion for 48 h. End points were plasma vitamin C concentrations during 96 h, 12-h urine excretion of vitamin C, and oxalate excretion and base excess. A population pharmacokinetic model was developed using NONMEM. Twenty patients were included. A two-compartment pharmacokinetic model with creatinine clearance and weight as independent covariates described all four regimens best. With 2 g/d bolus, plasma vitamin C concentrations at 1 h were 29 to 50mg/L and trough concentrations were 5.6 to 16mg/L. With 2 g/d continuous, steady-state concentrations were 7 to 37mg/L at 48 h. With 10 g/d bolus, 1-h concentrations were 186 to 244mg/L and trough concentrations were 14 to 55mg/L. With 10 g/d continuous, steady-state concentrations were 40 to 295mg/L at 48 h. Oxalate excretion and base excess were increased in the 10 g/d dose. Forty-eight hours after discontinuation, plasma concentrations declined to hypovitaminosis levels in 15%of patients. The 2 g/d dose was associated with normal plasma concentrations, and the 10 g/d dose was associated with supranormal plasma concentrations, increased oxalate excretion, and metabolic alkalosis. Sustained therapy is needed to prevent hypovitaminosis. ClinicalTrials.gov; No.: NCT02455180; URL: www.clinicaltrials.gov.

Vandetanib induces a marked anti-tumor effect and amelioration of ectopic Cushing's syndrome in a medullary thyroid carcinoma patient.

SummaryA 55-year-old woman diagnosed with sporadic MTC underwent total thyroidectomy 20 years ago. After the first surgery, elevated calcitonin levels in parallel with local disease persistence were noted and therefore she underwent repeated neck dissections. During follow-up, multiple foci of metastatic disease were noted in the neck and mediastinal lymph nodes, lungs and bones; however, the disease had an indolent course for a number of years, in parallel with a calcitonin doubling time of more than two years and without significant symptoms. During a routine follow-up visit 2 years ago, findings suggestive of Cushing’s syndrome were observed on physical examination. The biochemical evaluation demonstrated markedly elevated serum calcitonin level, in parallel with lack of cortisol suppression after an overnight 1 mg dexamethasone suppression test, lack of cortisol and ACTH suppression after high-dose IV dexamethasone 8 mg, elevated plasma ACTH up to 79 pg/mL (normal <46 pg/mL) and elevated 24-h urinary free cortisol up to 501 µg/24 h (normal 9–90 µg/24 h). After a negative pituitary MRI, she underwent IPSS, which was compatible with EAS. Whole-body CT demonstrated progressive disease at most of the tumor sites. Treatment with vandetanib at a dosage of 200 mg/day was commenced. The patient showed a significant, rapid and consistent clinical improvement already after two months of treatment, in parallel with biochemical improvement, whereas a decrease in tumor size was demonstrated on follow-up CT.Learning points:Ectopic Cushing’s syndrome due to ectopic ACTH secretion (EAS) by MTC is an uncommon and a poor prognostic event, being associated with significant morbidity and mortality.We demonstrate that vandetanib is effective in controlling the signs and symptoms related to the EAS in patients with advanced progressive MTC.We demonstrate that vandetanib is effective in decreasing tumor size and in inducing tumor control.

Protective effect of astragaloside IV against acute liver failure in experimental mice

Objective: To investigate the clinical effect of astragaloside IV in the early treatment of mice with acute liver failure and possible mechanisms. Methods: A mouse model of acute liver failure induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS) was established, and the mice were given astragaloside IV at different doses. The survival rate of mice, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver histopathological changes, apoptosis of hepatocytes, and the expression of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured in each group. The least significant difference test was used for data with homogeneity of variances, the Dunnett's T3 test was used for data with heterogeneity of variance, and the Kaplan-Meier method was used for survival analysis. Results: Compared with the model group, the high-dose astragaloside IV group had a significant increase in the 48-hour survival rate [60% (9/15) vs 13.3% (2/15), P < 0.05], significant reductions in the serum ALT and AST levels (P < 0.01), and significant reductions in liver histopathological indices and the degree of apoptosis of hepatocytes (P < 0.01), as well as a significant reduction in the content of MDA in liver homogenate (P < 0.01) and a significant increase in the activity of SOD (P < 0.05). Conclusion: High-dose astragaloside IV has a significant protective effect against D-GalN/LPS-induced acute liver injury in mice, and its mechanisms may be associated with its effects against cell apoptosis and oxidative damage.