Prevalence of adverse drug reactions associated with emergency department visits and risk factors for hospitalization

Objective: Adverse drug reactions increase morbidity and mortality, prolong hospital stay and increase healthcare costs. The primary objective of this study was to determine the prevalence of emergency department visits for adverse drug reactions and to describe their characteristics. The secondary objective was to determine the predictor variables of hospitalization for adverse drug reactions associated with emergency department visits. Method(s): Observational and retrospective study of adverse drug reactions registered in an emergency department, carried out from November 15th to December 15th, 2021. The demographic and clinical characteristics of the patients, the drugs involved and the adverse drug reactions were described. Logistic regression was performed to identify factors related to hospitalization for adverse drug reactions. Result(s): 10,799 patients visited the emergency department and 216 (2%) patients with adverse drug reactions were included. The mean age was 70 +/- 17.5 (18-98) years and 47.7% of the patients were male. A total of 54.6% of patients required hospitalization and 1.6% died from adverse drug reactions. The total number of drugs involved was 315 with 149 different drugs. The pharmacological group corresponding to the nervous system constituted the most representative group (n = 81). High-risk medications, such as antithrombotic agents (n = 53), were the subgroup of medications that caused the most emergency department visits and hospitalization. Acenocumarol (n = 20) was the main drug involved. Gastrointestinal (n = 62) disorders were the most common. Diarrhea (n = 16) was the most frequent adverse drug reaction, while gastrointestinal bleeding (n = 13) caused the highest number of hospitalizations. Charlson comorbidity index behaved as an independent risk factor for hospitalization (aOR 3.24, 95% CI: 1.47-7.13, p = 0.003, in Charlson comorbidity index 4-6;and aOR 20.07, 95% CI: 6.87-58.64, p = 0.000, in Charlson comorbidity index >= 10). Conclusion(s): The prevalence of emergency department visits for adverse drug reactions continues to be a non-negligible health problem. High-risk drugs such as antithrombotic agents were the main therapeutic subgroup involved. Charlson comorbidity index was an independent factor in hospitalization, while gastrointestinal bleeding was the adverse drug reaction with the highest number of hospital admissions.Copyright © 2022 Sociedad Espanola de Farmacia Hospitalaria (S.E.F.H)

A novel quantification method of lung fibrosis based on Micro-CT images developed with the optimized pulmonary fibrosis mice model induced by bleomycin.

Background and aims: Idiopathic pulmonary fibrosis (IPF) is a fibrosing lung disease with unknown etiology, leading to cough and dyspnoea, which is also one of the most common sequelae affecting the quality of life of COVID-19 survivors. There is no cure for IPF patients. We aim to develop a reliable IPF animal model with quantification of fibrosis based on Micro-Computer Tomography (micro-CT) images for the new drug discovery, because different bleomycin administration routes, doses, and intervals are reported in the literature, and there is no quantitative assessment of pulmonary fibrosis based on micro-CT images in animal studies. Methods: We compared three dosages (1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg) of intratracheal bleomycin administration and experiment intervals (14 and 21 days) in C57BL/6 mice by investigating survival rates, pulmonary histopathology, micro-CT, peripheral CD4+ & CD8+ cells, and cytokines. Moreover, a simple and reliable new method was developed for scoring fibrosis in live mice based on Micro-CT images by using Image J software, which transfers the dark sections in pulmonary Micro-CT images to light colors on a black background. Results: The levels of hydroxyproline, inflammation cytokine, fibrotic pathological changes, and collagen deposition in the lungs of mice were bleomycin dose-dependent and time-dependent as well as the body weight loss. Based on the above results, the mice model at 21 days after being given bleomycin at 1.25 mg/kg has optimal pulmonary fibrosis with a high survival rate and low toxicity. There is a significant decrease in the light area (gray value at 9.86 ± 0.72) in the BLM mice, indicating that a significant decrease in the alveolar air area was observed in BLM injured mice compared to normal groups (###p < 0.001), while the Pirfenidone administration increased the light area (gray value) to 21.71 ± 2.95 which is close to the value observed in the normal mice (gray value at 23.23 ± 1.66), which is consistent with the protein levels of Col1A1, and α-SMA. Notably, the standard deviations for the consecutive six images of each group indicate the precision of this developed quantitation method for the micro-CT image taken at the fifth rib of each mouse. Conclusion: Provided a quantifying method for Micro-CT images in an optimal and repeatable pulmonary fibrosis mice model for exploring novel therapeutic interventions.

Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice.

Humanity has suffered from the coronavirus disease 2019 (COVID-19) pandemic over the past two years, which has left behind millions of deaths. Azithromycin (AZ), an antibiotic used for the treatment of several bacterial infections, has shown antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as against the dengue, Zika, Ebola, and influenza viruses. Additionally, AZ has shown beneficial effects in non-infective diseases such as cystic fibrosis and bronchiectasis. However, the systemic use of AZ in several diseases showed low efficacy and potential cardiac toxicity. The application of nanotechnology to formulate a lung delivery system of AZ could prove to be one of the solutions to overcome these drawbacks. Therefore, we aimed to evaluate the attenuation of acute lung injury in mice via the local delivery of an AZ nanoformulation. The hot emulsification-ultrasonication method was used to prepare nanostructured lipid carrier of AZ (AZ-NLC) pulmonary delivery systems. The developed formulation was evaluated and characterized in vitro and in vivo. The efficacy of the prepared formulation was tested in the bleomycin (BLM) -mice model for acute lung injury. AZ-NLC was given by the intratracheal (IT) route for 6 days at a dose of about one-eighth oral dose of AZ suspension. Samples of lung tissues were taken at the end of the experiment for immunological and histological assessments. AZ-NLC showed an average particle size of 453 nm, polydispersity index of 0.228 ± 0.07, zeta potential of -30 ± 0.21 mV, and a sustained release pattern after the initial 50% drug release within the first 2 h. BLM successfully induced a marked increase in pro-inflammatory markers and also induced histological changes in pulmonary tissues. All these alterations were significantly reversed by the concomitant administration of AZ-NLC (IT). Pulmonary delivery of AZ-NLC offered delivery of the drug locally to lung tissues. Its attenuation of lung tissue inflammation and histological injury induced by bleomycin was likely through the downregulation of the p53 gene and the modulation of Bcl-2 expression. This novel strategy could eventually improve the effectiveness and diminish the adverse drug reactions of AZ. Lung delivery could be a promising treatment for acute lung injury regardless of its cause. However, further work is needed to explore the stability of the formulation, its pharmacokinetics, and its safety.

A review: The phytochemistry, pharmacology, and pharmacokinetics of Curcumae Longae Rhizoma (Turmeric)

Curcumae Longae Rhizoma (CLR) is the rhizome of Curcuma longa L. Pharmacological studies show that CLR can be used to treat cervical cancer, lung cancer, lupus nephritis, and other conditions. In this paper, we review botany, traditional application, phytochemistry, pharmacological activity, and pharmacokinetics of CLR. The literature from 1981 to date was entirely collected from online databases, such as Web of Science, Google Scholar, China Academic Journals full-text database (CNKI), Wiley, Springer, PubMed, and ScienceDirect. The data were also obtained from ancient books, theses and dissertations, and Flora Reipublicae Popularis Sinicae. There are a total of 275 compounds that have been isolated from CLR, including phenolic compounds, volatile oils, and others. The therapeutic effect of turmeric has been expanded from breaking blood and activating qi in the traditional sense to antitumor, anti-inflammatory, antioxidation, neuroprotection, antibacterial, hypolipidemic effects, and other benefits. However, the active ingredients and mechanisms of action related to relieving disease remain ill defined, which requires more in-depth research and verification at a clinical level.

Promoting improved healing: Lessons learned from the fetus

Background: It has long been known that the fetal response to skin injury is regenerative, with a lack of abnormal collagen deposition or scar, and restoration of normal dermal architecture. This response is associated with minimal inflammation.We have shown that the decreased inflammation is due to decreased production of pro-inflammatory cytokine production compared to the adult response. In addition, we have shown fetal tendon and the fetal heart can heal by regeneration, with restoration of structure and function, and is also associated with decreased proinflammatory cytokine production and decreased inflammation. We hypothesized that strategies targeting inflammation and associated oxidative stress could be used in adult diseases. We have identified diabetic wounds, acute lung injury, and colitis where inflammation and oxidative stress plays a central role in the pathogenesis the disease. Material(s) and Method(s): We have developed a novel strategy using nanotechnology to target inflammation and oxidative stress. We have conjugated novel cerium oxide nanoparticles, which act as potent scavengers of reactive oxygen species, to the anti-inflammatory microRNA miR146a, which suppresses the NFkB pathway and the production of the pro-inflammatory cytokines IL-6 and IL-8. Result(s): In diabetic wounds, impaired healing is associated with chronic inflammation and oxidative stress. We have demonstrated, in both small and large diabetic animals models, that CNP-miR146a can decrease inflammation and oxidative stress and correct the diabetic wound healing impairment and promote regeneration, similar to rates of healing in non-diabetic animals. We have also examined other disease states where inflammation and oxidative stress is pathogenic. Following acute lung injury, inflammation and oxidative stress leads to the development of adult respiratory distress syndrome or ARDS, the number one cause of mortality with COVID-19, and is associated with a 30-50% mortality. Inflammation and oxidative stress play a central role in the pathogenesis of ARDS. We have shown in models of acute lung injury, including bleomycin, LPS, MRSA, ventilator induced lung injury (VILI) and mustard gas, that CNP-miR146a decreases inflammation and oxidative stress, promotes regeneration and restoration of function, and decreased mortality. Finally, pathogenic inflammation plays a central role in the development of colitis or inflammatory bowel disease. We have shown that CNP-miR146a enemas can prevent progression of disease, restore weight gain, and lacks the adverse effects of systemic immunosuppression. Conclusion(s): We have used our understanding of the mechanisms of fetal regeneration following injury, which progresses with minimal inflammation and oxidative stress, to develop strategies targeting these processes to promote regeneration in adult disease.

DRUG-INDUCED PNEUMONITIS IN THE SETTING OF SARS-COV-2 INFECTION

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Interstitial pneumonitis (ILD) is inflammation of lung interstitium leading to scarring and pulmonary fibrosis. Various etiologies include idiopathic, connective tissue disorders, sarcoidosis and drug induced1. Many chemotherapy agents have been implicated in drug related ILD such as bleomycin, taxanes. However, newer chemotherapeutic drugs such as molecular agents such as anti-VEGF, anti-EGFR (panitumumab) could be causative of drug induced ILD. CASE PRESENTATION: A 75-year-old female with stage IV sigmoid colon cancer treated with surgery, adjuvant FOLFOX chemotherapy and Panitumumab. She presented to the emergency department with shortness of breath and hypoxia after known COVID-19 exposure. Initial imaging with chest radiography showed bilateral ground glass opacities. A chest CT pulmonary embolism protocol was negative for pulmonary embolism but showed bilateral ground glass opacities (GGOs) and some interstitial thickening (L>R) not typical of COVID-19 infection. She was treated with remdesivir and dexamethasone, however her oxygen requirements continued to rapidly escalate. A repeat CT chest without contrast showed bilateral asymmetric interstitial thickening and GGOs. Given persistence of CT chest abnormalities, workup for interstitial lung disease was initiated. The results include ANA titer 1:80, otherwise negative ANCA profile, rheumatoid factor, anti-CCP, Scl-70, Sjogren antibodies. Given clinical history and imaging findings, diagnosis of ILD was suspected, and she was started on solumedrol 1 mg/kg. Her oxygen requirements decreased significantly over the next 2 days, and she was discharged home on oral steroid taper and pneumocystis pneumonia prophylaxis. DISCUSSION: Panitumumab is a fully humanized monoclonal antibody against EGFR. Approved by the US Food and Drug Administration in 2006 for advanced or recurrent colorectal cancer exhibiting wild-type KRAS mutation.2 ILD is rarely reported with panitumumab monotherapy, but higher incidence when used as a combination treatment such as with FOLFOX or FOLFIRI. A Japanese post-marketing surveillance study from 2010-2015 showed an ILD incidence of 1.3% but mortality rates of 51.3%.2 EGFR is expressed on basal cells and non-cilia cells of the bronchioles and type II cells of the alveolus. EGFR mediated mechanisms are important in tissue repair.3 Therefore inhibition of this pathway has been postulated to play a role in development of ILD. Another mechanism was decreased surfactant production by type II cells in pre-clinical study.4,5 ILD secondary to Panitumumab can occur at any point during therapy and up to 1 year after administration of drug.6 The role of infectious processes, in this case, COVID-19 pneumonia, could synergistically worsen ILD presentation. CONCLUSIONS: Although the incidence of ILD is low, the mortality rate is high, therefore early recognition and treatment is associated with improved clinical outcomes. Reference #1: Mudawi D, Heyes K, Hastings R, Rivera-Ortega P, Chaudhuri N. An update on interstitial lung disease. Br J Hosp Med (Lond). Jul 2 2021;82(7):1-14. Reference #2: Osawa M, Kudoh S, Sakai F, et al. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. Int J Clin Oncol. Dec 2015;20(6):1063-1071. Reference #3: The FASEB Journal - 2000 - Puddicombe - Involvement of the epidermal growth factor receptor in epithelial repair in asthma.pdf. DISCLOSURES: No relevant relationships by Navitha Ramesh No relevant relationships by Uba Udeh

FOOL'S MOLD: UNUSUAL SEQUELAE OF COVID-19 INFECTION IN A YOUNG PATIENT

SESSION TITLE: Pathologies of the Post-COVID-19 World SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: COVID-19 Associated Pulmonary Aspergillosis (CAPA) is a subset of invasive pulmonary aspergillosis occurring in patients actively infected with or recovering from COVID-19. It has mostly been described in immunocompromised or severely ill patients requiring invasive mechanical ventilation[1-6]. The authors report a case of CAPA infection in an ambulatory and immunocompetent patient with prior lung resection. CASE PRESENTATION: A 20-year-old male presented to a Comprehensive Cancer Center for fever and hemoptysis. He carried a diagnosis of metastatic germ cell tumor to his lungs, status post left upper-lobe wedge resection. He had completed bleomycin, etoposide, and cisplatin (BEP) chemotherapy one year earlier. He was recently diagnosed with COVID-19 one month prior to admission and treated as an outpatient with monoclonal antibodies. He reported ongoing cough productive of clear sputum since his diagnosis, which had worsened over the previous two days and was now blood-tinged. He had been afebrile for weeks before noting new fevers over the same period. Physical examination was notable for fever to 38.6°C and lungs clear to auscultation. His labs were significant for a WBC of 14.5 K/mcl (82.5% neutrophils), Cr 2.1 mg/dL (baseline 1.5 mg/dL), and normal platelets and coagulation studies. Serum Aspergillus galactomannan was normal. Repeat SARS-CoV-2 PCR was negative. Chest x-ray was unchanged. V/Q scan showed no evidence of pulmonary embolism. Non-contrast CT chest performed on hospital day #4 revealed a partial opacification and increased wall thickness of patient's largest left upper lobe surgical cavitation (see Image 1). A bronchoscopy was performed day #6, with bronchoalveolar lavage (BAL) galactomannan >5.56 (normal <0.5)7;fungal culture was significant for septate hyphae. He was started on voriconazole with improvement in his symptoms and discharged day #9. DISCUSSION: Immunocompromised patients with prolonged neutropenia, solid-organ or stem cell transplants, and patients with advanced AIDS are at highest risk of contracting PA[8-9]. ARDS secondary to viral pneumonia is also a common precipitant in immunocompetent patients[1-6,10,11]. The exact mechanism of this association remains unknown, but it is postulated to occur due to multiple factors, including host immune dysregulation[1,2], widespread exposure to corticosteroids[1,2], concomitant lung disease[1], and viral-induced lymphopenia[2]. We report a case of an immunocompetent patient with prior lung resection recovering from COVID-19 who experienced a secondary worsening of symptoms ultimately found to have CAPA to further highlight the link between these conditions. CONCLUSIONS: While many of CAPA case reports describe patients with typical risk profiles for CAPA, this case suggests that clinicians should consider structural lung disease alone in an otherwise immunocompetent, ambulatory individual to be a potential risk factor. Reference #1: See Image 2 for full list of references. DISCLOSURES: No relevant relationships by Raphael Rabinowitz No relevant relationships by Matthew Velez

Bleomycin-Induced Lung Injury After Intravenous Iron Administration.

Bleomycin is an antibiotic that is often used as a chemotherapeutic agent due to its antitumor activities against a variety of malignancies. A feared and often fatal side effect of this drug is a pulmonary injury causing inflammation that can progress to pulmonary fibrosis. Bleomycin damages lung endothelial cells by the production of free radicals that can only occur when it is bound to certain metals in the body. It forms a complex with iron and once activated by iron reduction, it destroys deoxyribonucleic acid (DNA). Therefore, it is suggested that the availability of iron in the body may play a role in the pathogenesis of bleomycin toxicity although no related cases have been documented. This is a case of a 75-year-old female with no prior history of pulmonary disease who was diagnosed with Hodgkin's lymphoma and received 12 doses of bleomycin over the course of six cycles of chemotherapy. She then presented to the hospital with respiratory failure five months after her completion of treatment. Interestingly, one month prior to presentation, she was given two intravenous iron infusions of ferumoxytol five days apart for the treatment of iron deficiency anemia. Within a week of receiving the iron, she developed dyspnea with a nonproductive cough. About a month after she developed these symptoms, she presented to the hospital and was found to be hypoxic with any activity and was subsequently placed on oxygen via nasal cannula. Her lung imaging showed new reticulonodular and patchy infiltrates bilaterally concerning for pneumonitis and her physical examination was significant for black discoloration of her fingertips and toes along with expiratory rhonchi heard throughout her lungs. During the hospitalization, her oxygen requirements increased, and the patient ended up in the intensive care unit on bilevel positive airway pressure. Her lung imaging, rapid progression, and skin findings made the clinical diagnosis of bleomycin toxicity. Out of concern that the intravenous iron may have played a role in the toxicity, iron chelation was attempted. The patient was given two doses of deferoxamine over two consecutive days and her symptoms of dyspnea along with her oxygen requirements improved. Unfortunately, these positive effects only lasted a few days and the patient continued to decline and ultimately passed away. This case raises many questions regarding iron's role in bleomycin toxicity, including if intravenous iron infusions may increase the risk of pulmonary injury from bleomycin. There are currently no guidelines or recommendations that suggest withholding iron supplementation in patients undergoing chemotherapy with bleomycin. There is also insufficient evidence to support the routine use of iron chelation in a patient that presents with bleomycin-induced lung injury. However, some studies suggest that iron chelation may play a role in preventing pulmonary toxicity. It may also lessen the severity of the toxicity or improve some of the related symptoms, thus warranting further research.

Myeloid-Dependent Immunosuppressive Features Drive and Predict IPF Progression

Rationale: Despite the availability of pharmacologic therapies, idiopathic pulmonary fibrosis (IPF) is still a clinical challenge with several unmet needs. Robust evidence supports monocytes as cellular biomarkers of progression in IPF. Yet, their precise role and whether specific subtypes might predict progression and drive disease is unknown. We reported, for the first time, that myeloidderived suppressor cells (MDSC), immature precursors of monocytes, are increased in numbers, functionally active in IPF. Monocytic MDSC is the predominant subtype in IPF, and yet, functional characterization and immune modulation properties have not been explored. Methods and Results: characterization of circulating myeloid populations in IPF by multicolor FACS confirmed the abundance of MDSC (Lin-, HLA-DRlo, CD33+, CD14+, S100A+, CD28L1+ and ICOSL+) in IPF (n=78) and fILD (n=83), also abundant in whole blood scRNA seq of severe Covid-19 patients that progressed into fibrosis, and not in mild Covid-19. Then, we prospectively followed 83 fILD patients (45% IPF, 55% non-IPF -EAA, CTD-ILD, NSIP-) over 1 year and immunophenotyped them every 3 months. Cross-sectional analysis showed that patients with a higher number circulating MDSC, had a higher GAP index (7-8) (p<0,001). Longitudinal follow-up showed that patients with constant higher circulating MDSC had lower transplant-free survival (p=0.0058). Primary isolated MDSC when co-cultured with autologous T cells induced CD8+ T cell exhaustion (PD1hi, Lag3hi, Tim3hi, TNFalpha lo, INFglo), and downregulation of co-stimulatory T cell signaling (CD28, ICOS, ITK, and LCK), preliminary data support the induction of de-novo FoxP3 Treg formation, creating a suppressive and immunosenescent microenvironment in IPF. FACS analysis of explanted lungs demonstrated the increase of tissue-resident MDSC in fibrosis (HP, NSIP, IPF) compared with donor lungs, as well as in bleomycin-induced fibrosis compared to PBS. Conclusion: Taking together, a high number of circulating MDSC reflects worse lung function and higher GAP index in cross-sectional analysis, and associates with lower transplant-free survival longitudinally. The role that immature and mature monocytes play during promotion of a suppressive microenvironment in IPF is an unexplored area that may lead to a paradigm shift in our understanding of the sequelae of exhaustion and immunosenescence, contributing to the identification of novel targets useful for therapeutic myeloid selection in IPF.

Pulmonary Delivery of Hydroxychloroquine Nanostructured Lipid Carrier as a Potential Treatment of COVID-19.

Coronavirus Disease 2019 (COVID-19) is a pandemic caused by severe acute respiratory syndrome coronavirus 2. Pneumonia is considered the most severe and long-term complication of COVID-19. Among other drugs, hydroxychloroquine (HCQ) was repurposed for the management of COVID-19; however, low efficacy and cardiac toxicity of the conventional dosage form limited its use in COVID-19. Therefore, utilizing nanotechnology, a pulmonary delivery system of HCQ was investigated to overcome these limitations. HCQ was formulated in nanostructured lipid carriers (HCQ-NLCs) using the hot emulsification-ultrasonication method. Furthermore, the prepared formulation was evaluated in vitro. Moreover, the efficacy was tested in vivo in a bleomycin-induced acute lung injury mice model. Intriguingly, nanoformulations were given by the intratracheal route for 6 days. HCQ-NLCs showed a mean particle size of 277 nm and a good drug release profile. Remarkably, acute lung injury induced by bleomycin was associated with a marked elevation of inflammatory markers and histological alterations in lung tissues. Astoundingly, all these changes were significantly attenuated with HCQ-NLCs. The pulmonary delivery of HCQ-NLCs likely provided adequate targeting to lung tissues. Nevertheless, there is hope that this novel strategy will eventually lead to the improved effectiveness and diminished probability of alarming adverse drug reactions.

SÍNDROME DE RICHTER: LEUCEMIA LINFOCÍTICA CRÔNICA TRANSFORMADA EM LINFOMA DE HODGKIN CLÁSSICO, UM RELATO DE CASO

Leucemia Linfocítica Crônica (LLC) é a leucemia mais comum em adultos no mundo ocidental, possui comportamento indolente e baixa atividade mitótica, sendo seu diagnóstico feito geralmente em pacientes assintomáticos, com base em exame de sangue rotineiro, segundo a OMS. Já a sua transformação em linfoma agressivo – Síndrome de Richter Clássica (variante Linfoma Difuso de Grandes Células B) - é um evento raro e acontece em cerca de 2 a 8% dos casos e sua variante Linfoma de Hodgkin em menos de 1%. Neste trabalho, o objetivo foi descrever um caso de transformação desta leucemia em Síndrome de Richter variante Linfoma de Hodgkin. O paciente deste relato teve diagnóstico de leucemia linfocítica crônica, estadiado como BINET A. Apresentava IGHV não mutado, ausência de alterações no TP53 e positividade para vírus Epstein-Barr. Após 3 anos e 5 meses do diagnóstico de LLC recebeu quimioterapia convencional (fludarabina e ciclofosfamida) devido ao surgimento de sintomas constitucionais e linfonodomegalia cervical de 3 cm, com linfocitose associada (204.000 leucócitos, 94% linfócitos), sem anemia ou trombocitopenia. Apresentou resposta clínica e laboratorial. Depois de 1 ano do primeiro tratamento iniciou medicação alvo (Acalabrutinibe) pois teve aumento das linfonodomegalias cervicais. Evoluiu com resolução completa em um mês de tratamento. Passados 3 meses (4 anos e 10 meses do diagnóstico de LLC), houve o aparecimento de conglomerado linfonodal no mesmo local, associado a sintomas B. Uma nova biópsia revelou que o paciente enquadrava-se dentro dos 1% de pacientes que transformam LLC em Linfoma de Hodgkin. Seu subtipo foi o clássico, com celularidade mista, estadiado como Ann Arbor IVB, para o qual foi proposto quimioterapia com esquema ABVD (doxorrubicina, bleomicina, vinblastina, dacarbazina). Durante o tratamento apresentou mucosite e hematotoxicidade, recuperou-se e obteve resposta clínica após o primeiro ciclo. Após o segundo ciclo infectou-se por SARS-COV2, esteve internado com necessidade de ventilação mecânica e mesmo com atrasos no tratamento, em reavaliação com PET/CT, apresentou resposta satisfatória (Deauville 2). Atualmente está no terceiro ciclo de quimioterapia e em reabilitação após internamento prolongado que resultou em sequela motora por neuropatia do doente crítico. A terapia nesta situação não está embasada em estudos prospectivos randomizados e por conta disso conflui com o instituído para LH de novo. Este caso raro exemplifica como uma doença indolente pode se tornar agressiva, exigindo um cuidado específico nas reavaliações durante as recaídas de doença.

LINFOMA DE HODGKIN CLÁSSICO RECÉM-DIAGNOSTICADO NO CONTEXTO DE DESABASTECIMENTO DE BLEOMICINA: TRATAMENTO COM DOXORRUBICINA, ETOPOSÍDEO, VIMBLASTINA E DACARBAZINA (AEVD)

Introdução: A combinação de doxorrubicina, bleomicina, vinblastina e dacarbazina (ABVD) representa a principal opção de tratamento em primeira linha para o Linfoma Hodgkin classico (LH). Desde 2018, o desabastecimento de bleomicina no Brasil têm trazido consequências graves aos pacientes com LH. No âmbito da medicina privada, instituições têm feito o uso de A+AVD, esquema no qual a bleomicina é substituída por brentuximabe-vedotina, ou importado a bleomicina de forma independente. Para diversas instituições públicas, entretanto, estas opções não são acessíveis. Objetivo: Avaliar a segurança e a eficácia da combinação AEVD (doxorrubicina;etoposídeo, em substituição à bleomicina, na dose de 100 mg/m2;vinblastina e dacarbazina) para tratamento de LH em primeira linha, nos dias 1 e 15 de ciclos de 28 dias. Métodos: Realizamos estudo clínico aberto não-randomizado para avaliar o regime AEVD como tratamento de primeira linha em pacientes com diagnóstico recente de LH no Hospital Municipal São José em Joinville, Brasil. Resultados: Vinte e cinco pacientes com mais de 18 anos e diagnóstico de LHc entre junho e novembro de 2020 foram incluídos. Quatorze pacientes (56%) eram homens, com mediana de idade de 27 anos (variando de 18 a 66 anos). A maioria dos pacientes tinham doença Estágio II (60%, n = 15), tinham sintomas B (56%, n = 14) e lactate-desidrogenase (LDH, 52%, n = 13). Para estágios III-IV (n = 5), 3 pacientes apresentaram IPS alto risco (escore >2;60%). Para doença localizada (n = 20), alto risco conforme GHSG foi observado em 16 pacientes (n = 80%). Todos os pacientes passaram por 3 a 6 ciclos de quimioterapia e não se observou evento adverso com necessidade de internação hospitalar, interrupção ou descontinuação de tratamento. A realização de PET-CT ocorreu exclusivamente fora da nossa instituição. Oito pacientes tiveram acesso a PET-CT no ínterim, todos com escore Deauville de 1-3. A taxa de resposta global foi de 96%, com um paciente apresentando progressão da doença após 5 ciclos. Sete pacientes tiveram avaliação de final de tratamento (FT) apenas com TC, com 5 respostas completas (RC) e 2 respostas parciais (RP), com ambos os pacientes RP mantiveram remissão após 10 e 12 meses. Avaliação ao FT com PET-CT (n = 18) resultou em DS 1-3 em 72% (n = 13), 4 em 22% (n = 4) e 5 em 6% (n = 1). Todos os 5 pacientes DS 4-5 foram submetidos a biópsia após avaliação FT, com confirmação de LH recidivado ou refratário (RR) em 4 casos (mulher de 22 anos, estágio IV, alto risco com doença progressiva;homem de 65 anos, estágio III, baixo risco, com recidiva 11 meses após FT;homem de 26 anos, estágio II, alto risco com recidiva 6 meses após FT;mulher de 25 anos, estágio II, alto risco com recidiva 4 meses após FT). Dois pacientes LH RR (50%) tiveram atraso de mais de 30 dias no tratamento devido a fatores psicossociais ou financeiros secundários à pandemia Covid-19. Todos os pacientes LH RR tiveram acesso a terapia de resgate. Com mediana de seguimento de 16 meses (variando de 8 a 36 meses), nenhuma morte foi registrada e a probabilidade de sobrevida livre de progressão foi de 66% (IC95%: 72%-100%). Conclusões: A escassez de quimioterápicos tem sido um problema recorrente em todo o mundo, e é mais evidente em medicações citotóxicas sem substituições validadas, como é o caso da bleomicina. O uso do esquema AEVD para tratamento de LH recém-diagnosticado parece ser seguro, eficaz e factível, em uma população composta principalmente por pacientes de alto risco.

Blocking Toll-like receptor 9 attenuates bleomycin-induced pulmonary injury.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is one of the most common complications in coronavirus disease 2019 patients suffering from acute lung injury (ALI). In ARDS, marked distortion of pulmonary architecture has been reported. The pulmonary lesions in ARDS include hemodynamic derangements (such as alveolar edema and hemorrhage), vascular and bronchiolar damage, interstitial inflammatory cellular aggregations, and eventually fibrosis. Bleomycin induces ARDS-representative pulmonary damage in mice and rats; therefore, we used bleomycin model mice in our study. Recently, Toll-like receptor 9 (TLR9) was implicated in the development of ARDS and ALI. METHODS: In this study, we evaluated the efficiency of a TLR9 blocker (ODN2088) on bleomycin-induced pulmonary damage. We measured the apoptosis rate, inflammatory reaction, and fibroplasia in bleomycin- and bleomycin + ODN2088-treated mice. RESULTS: Our results showed a significant amelioration in bleomycin-induced damage to pulmonary architecture following ODN2088 treatment. A marked decrease in pulmonary epithelial and endothelial apoptosis rate as measured by cleaved caspase-3 expression, inflammatory reaction as indicated by tumor necrosis factor α expression, and pulmonary fibrosis as demonstrated by Van Gieson staining and α-smooth muscle actin immunohistochemistry were observed following ODN2088 treatment. CONCLUSIONS: All these findings indicate that blocking downstream TLR9 signaling could be beneficial in prevention or mitigation of ARDS through hemodynamic derangements, inflammation, apoptosis, and fibrosis.

Avenue - Avelumab in the Frontline Treatment of Advanced Classic Hodgkin Lymphoma - a Window Study

AVENuE - Avelumab in the frontline treatment of advanced classic Hodgkin lymphoma - a window study Background Response adapted ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) has become a standard of care in many countries for advanced stage classic Hodgkin Lymphoma (cHL), as investigated in the RATHL study: following 2 cycles of ABVD patients with negative (Deauville 1-3) interim PET (iPET2) proceeded to 4 cycles of AVD;those with positive (Deauville 4-5) iPET2 intensified therapy to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone (escBEACOPP) or BEACOPP every 14 days. Overall this strategy was associated with a 3-year progression free survival (PFS) of 82.6%, and outcomes for patients with positive iPET2 were disappointing with 3y progression-free survival (PFS) of 67.5%. More intensive treatment such as upfront use of escBEACOPP has been reported to produce higher PFS (89% at 5 years), but it is unclear whether overall survival (OS) is improved. More intensive treatment is, however, associated with higher risk of toxicity. Inhibitors of programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have established efficacy in relapsed / refractory cHL with response rates of 55-87%. In the front line setting PD-1 inhibitors have a reported complete metabolic response (CMR) rate of 18-37%. Response to PD-L1 inhibitors in the frontline setting has not been explored. Serial serum TARC (thymus and activation-regulated chemokine) is reported to be prognostic in the frontline treatment of cHL and may aid response assessment because PET interpretation with checkpoint inhibitors is often complex. In the context of PD-1 inhibition, PD-1 expression by immunohistochemistry (IHC) and 9p24.1 copy gain by fluorescence in situ hybridisation (FISH) are reported to correlate with response. Methods AVENuE is a Phase II single-arm multicentre study with sites in the UK and Australia assessing the safety and efficacy of 2 cycles (4 doses) of the PD-L1 inhibitor avelumab for untreated high-risk stage II-IV cHL prior to the iPET2 response adapted approach described above. Eligible patients must be 16-60 years, ECOG 0-1, and have adequate organ function. Patients with;compressive symptoms from lymphoma, autoimmune disorders or immunosuppressive treatment within 2 months are excluded. The primary endpoint is the centrally reviewed PET CMR rate to avelumab. Secondary endpoints are: the safety and tolerability of sequential avelumab and combination chemotherapy as assessed by CTCAE v 5.0;the iPET2 CMR rate after avelumab and 2 cycles of ABVD;PFS and OS at one year. Using a single stage A'hern design, target recruitment is 47 patients to give 90% power at a 0.05% one sided alpha to exclude an overall response rate (ORR) to 2 cycles of avelumab of < 20%;an ORR of 40% would be considered worthy of further study. Recruitment has continued during the COVID-19 pandemic. 29 patients have been enrolled. Exploratory endpoints include correlating disease response with baseline PD-1 copy number by FISH and PD-1 expression by IHC. Serial serum TARC is being explored as an aid to response assessment and changes in peripheral blood immune cell subset are being investigated as possible biomarkers of response. Trial funder: Pfizer Ltd in alliance with Merck KGaA Pfizer Ltd is providing funding as part of an Alliance between Pfizer and Merck KGaA Clinical trials.gov NCT03617666 EUDRACT No.: 2018-002227-42 Disclosures: Hawkes: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau;Regeneron: Speakers Bureau;Merck KgA: Research Funding;Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Janssen: Speakers Bureau;Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Boa d of Directors or advisory committees;Antigene: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding;Specialised Therapeutics: Consultancy. Barrington: Bristol Myers Squibb international corporation: Research Funding;Pfizer Inc: Research Funding;Amgen Ltd: Research Funding;Takeda Speakers Bureau: Honoraria. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead: Honoraria, Other: Travel Support;KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support;Janssen: Honoraria, Other: Travel Support;Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Iyengar: Janssen: Other: conference support, Speakers Bureau;Abbvie: Other: conference support;Beigene: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau;Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau. Radford: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau;AstraZeneca: Current holder of individual stocks in a privately-held company;ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau;BMS: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Clifton-Hadley: Bristol-Myers Squibb Pharmaceuticals Ltd.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Amgen: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Celgene: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Merck Sharp and Dohme: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Janssen-Cilag: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Pfizer: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Millennium pharmaceutics inc.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials. Collins: Beigene: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Speakers Bureau;Pfizer: Honoraria;Celgene: Research Funding;Amgen: Research Funding;AstraZeneca: Honoraria, Research Funding;ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. OffLabel Disclosure: Avelumab prior to frontline chemotherapy in advanced stage classic Hodgkin lymphoma.

Doxorubicin, Etoposide, Vinblastine and Dacarbazine (AEVD) for Newly Diagnosed Classic Hodgkin Lymphoma

[Formula presented] Introduction: Combination of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is the standard of care in frontline therapy for classic Hodgkin lymphoma (cHL). Since 2018, bleomycin shortages have been reported in Brazil, with severe consequences for cHL patients. In the private setting, many institutions chose to use A+AVD, in which bleomycin is replaced by brentuximab-vedotin, or to import bleomycin from vendors not registered at the national drug agency. For public institutions, however, these costly strategies are largely unattainable. Methods: We conducted a single-arm open-label study to evaluate the substitution of bleomycin with etoposide 100 mg/m2 on days 1 and 15 of every 28-day cycle (AEVD) in previously untreated cHL, at Hospital Municipal São José, in Joinville, Brazil. Here we present preliminary data on the safety and efficacy of this combination in a scenario of lack of approved treatment options for this patient population. Results: Twenty-five patients aged 18 or more with cHL diagnosed between June 2018 and November 2020 were included. Fourteen patients (56%) were male, with median age of 27 years (range: 18-66). Most patients were stage II (60%, n=15), presented with B symptoms (56%, n=14) and high lactate dehydrogenase (LDH, n=13, 52%). For stage III-IV (n=5), high-risk IPS was present in 3 patients (score >2;60%). For localized disease (n=20), unfavorable features according to the GHSG were seen in 16 patients (n=80%). All patients received between 3 and 6 chemotherapy cycles, with no recorded adverse event requiring hospitalization, treatment interruption or discontinuation. PET-CT was performed solely outside of our institution. Eight patients had access to interim PET-CT, all with Deauville scores (DS) 1-3. Overall response rate was 96%, with one disease progression after 5 cycles. Seven patients had CT scan-alone end-of-treatment (EOT) assessment, with 5 complete responses (CR) and 2 partial responses (PR), with both PR patients sustaining remissions after 10 and 12 months. EOT assessment with PET-CT (n=18) resulted in DS 1-3 in 72% (n=13), 4 in 22% (n=4) and 5 in one (6%). All 5 patients with DS 4-5 underwent biopsy after EOT assessment, with confirmation of relapsed or refractory (RR) cHL in 4 cases (22 year-old, stage IV high-risk female with progressive disease;65 year-old, stage III low-risk male with relapse 11 months after EOT;26 year-old, stage II high-risk male with relapse 6 months after EOT;25 year-old, stage II high-risk female with relapse 4 months after EOT). Two RR cHL patients (50%) had treatment delays exceeding 30 days due to psychosocial or financial impacts emerging from the COVID-19 pandemic. All RR cHL patients had access to salvage treatments. At a median follow-up of 16 months (range: 8-36), no death was recorded and 12-month progression-free survival probability was 86% (95%CI: 72%-100%). Conclusions: Drug shortages impacting chemotherapy treatments have been a recurring problem worldwide, most noticeably among cytotoxic agents without in-class validated substitutions, as is the case with bleomycin. AEVD, as a novel approach to newly diagnosed cHL, appears to be safe, feasible and highly active in a population composed mostly of high-risk patients. [Formula presented] Disclosures: Boettcher: Novartis: Speakers Bureau.

Case report: Challenges, treatment, prognosis and outcome of a patient with partially treated seminomatous testicular carcinoma.

BACKGROUND: Testicular carcinoma is a rare malignancy in men. It is ranked the 18th most common male cancer in Malaysia with seminoma representing 40% of the primary testicular neoplasms. Early detection of the tumour and the immediate initiation of treatment and disease management provide high possibilities of positive outcomes for patients. CASE PRESENTATION: A 36-year-old male was initially diagnosed with a left cryptorchidism and metastatic testicular seminoma. However, due to socioeconomic circumstances and the Coronavirus-19 (COVID-19) pandemic, he defaulted on his chemoradiotherapy follow-up treatments. He returned to us four years later with a progressively enlarging testicular mass with normal tumour marker values and subsequently underwent a successful radical left orchidectomy. Histopathological examination revealed features of regressed germ cell tumour (GCT). He successfully underwent chemoradiotherapy treatment and surveillance follow-ups did not show tumor recurrences. DISCUSSION: Seminoma is the commonest type of testicular carcinoma with good prognosis among young patients. In huge masses, as seen in our patient, early chemoradiotherapy with the intention to reduce tumor bulk and invasiveness after which will be followed by radical orchidectomy. Residual mass post chemotherapy for patients with seminomas should be properly assessed for viability of tumor cells within it. CONCLUSION: Undescended testis and cryptorchidism present key risk factors for developing testicular carcinomas which are uncommon among men. Early detection, surgery and chemoradiotherapy on seminomas would usually lead to positive outcomes. The remarkable chemosensitivity of a seminomatous type tumour towards a platinum-based regiment in combination with radical resection entails good prognosis and effective local disease control.

Protective Effect of Remdesivir Against Pulmonary Fibrosis in Mice.

Pulmonary fibrosis is a known sequela of severe or persistent lung damage. Existing clinical, imaging and autopsy studies have shown that the lungs exhibit a pathological pulmonary fibrosis phenotype after infection with coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pulmonary fibrosis may be one of the most serious sequelae associated with coronavirus disease 2019 (COVID-19). In this study, we aimed to examine the preventative effects of the antiviral drug remdesivir on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of remdesivir on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of remdesivir in lung fibroblasts and alveolar epithelial cells in vitro. The preventive remdesivir treatment was started on the day of bleomycin installation, and the results showed that remdesivir significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro experiments showed that remdesivir dose-dependently suppressed TGF-ß1-induced lung fibroblast activation and improved TGF-ß1-induced alveolar epithelial to mesenchymal transition. Our results indicate that remdesivir can preventatively alleviate the severity of pulmonary fibrosis and provide some reference for the prevention of pulmonary fibrosis in patients with COVID-19.