Increased Liver Transaminases Research Articles

Safety and efficacy of interleukin-6 blockade for immune-related adverse events: A systematic review and meta-analysis.

e24149 Background: Interleukin-6 blockade (IL-6) - tocilizumab and sarilumab - have shown promising results for steroid-refractory immune-related adverse events (irAEs) in cancer patients treated with immune-checkpoint inhibitors (ICI). However, the ideal scenario for IL-6 therapy use is not well established. Hence, we conducted a systematic review and meta-analysis to investigate the safety and efficacy of IL-6 blockade for patients with ICI-associated irAEs. Methods: PubMed, Embase, and Cochrane databases were searched for studies including at least five patients with ICI-associated irAEs treated with IL-6 blockade. The main outcomes were safety and efficacy, measured as clinical improvement (resolution or improvement of irAEs or steroid taper to < 10mg daily), C-reactive protein (CRP) level changes, and elevated IL-6 levels. Analyses using random-effects model were done in R Software. Heterogeneity was assessed using I2. Results: Eight studies with 202 patients were included: 1 clinical trial, 3 multicenter, and 4 single-center observational studies. The median age was 63 years (30-81), and 59% were male. Melanoma was the predominant tumor type (n = 78, 38.6%), followed by lung (n = 67, 33%), renal cell carcinoma (n = 21, 10%), bladder cancer (n = 12, 6%), and others. Monotherapy with ICI, targeting PD-1, PD-L1, or CTLA-4, was given to 77% of patients, while 23% had combination ICI therapy. Follow-up ranged from 6 to 23 months. Most patients received prior steroids (85%) or steroid-sparing immunosuppression (24%). Pooled analysis of all patients showed an overall clinical improvement rate of 87.9% (95%CI 78.7 to 95.1, I2= 44%). Clinical improvement with IL-6 blockade was significantly higher in patients with cytokine release syndrome (CRS, 100%) and rheumatic irAEs (88%) compared to other irAEs (p < 0.01, Table 1). At the time of irAEs, the median CRP level was 109.3 (11.5 to 233), which decreased to 17 (1 to 60) after IL-6 blockade. The frequency of baseline elevated IL-6 level was 90.6% (95%CI 68 to 100, I2= 80%). Grade 3 or 4 IL-6-related adverse events were reported in 11% (17/151) of patients and included neutropenia (n = 6), increased liver transaminase levels (n = 4), and gastrointestinal perforation (n = 2). Conclusions: This systematic review and meta-analysis provides evidence for the use of IL-6 blockade for steroid-treating refractory irAEs associated with ICI. The vast majority of patients with steroid-refractory CRS and rheumatic irAEs were successfully treated with anti-IL6 therapy.[Table: see text]

Изучение распространенности и клинических проявлений коревой инфекции на современном этапе

Today, the issue of measles is of great importance, since cases of this disease are currently increasingly common. Insufficient immunization coverage and the increase in the rate of measles vaccine refusal are considered to be the main cause of the incidence increase. Furthermore, it is important to note that an almost high rate of the atypical course of measles, specifically the emergence of the trend towards fusion of the rash, itching, no pigmentation period, no pathognomonic symptom (Belsky–Filatov–Koplik spots), the emergence of hepatomegaly, increased liver transaminases, and the development of diarrhea, is reported at the current stage. It is impossible to ignore the fact that measles can lead to severe complications, such as pneumonia, encephalitis, meningitis, hepatitis, etc. Measles can also be fatal, thereforore, it is necessary to understand the importance of prevention, timely treatment and diagnosis of this disease.

The ameliorative effect of cerium oxide nanoparticles on chlorpyrifos induced hepatotoxicity in a rat model: Biochemical, molecular and immunohistochemical study

BackgroundChlorpyrifos (CPF) is a widely used insecticide that causes toxicity to living organisms through the production of free radicals. Cerium oxide nanoparticles (CeO2NPs) are a new antioxidant agent that has proved therapeutic effects. We evaluated the effect of CeO2NPs on CPF hepatotoxicity. MethodsForty rats were randomized into four groups. Group I: rats received 1 ml corn oil by gastric tube once daily and 0.5 ml PBS by intra-peritoneal injection twice a week for 4 weeks. Group II: received CeO2NPs 0.5 mg/kg in PBS by i.p. injection, twice weekly for four weeks. Group III: were treated with oral administration of CPF 13.5 mg/kg in corn oil daily for 4 weeks. Group IV: received CPF as in group III, then each animal received CeO2NPs twice weekly for four weeks as in group II. Twenty-four hours after the last dose, rats were anesthetized and sera were collected for liver enzymes assessment. Afterwards, rats were sacrificed, livers were excised, the right lobe of each liver was fixed for immunohistochemical studies, and the left lobe was homogenized for oxidative profile assessment and molecular analysis. ResultsCPF group showed significant increase in liver transaminases, disturbance of the oxidative profile with up-regulation of BAX expression and down-regulation in the Bcl-2, Gadd45 and NFE2L2. CPF caused severe histopathological liver damage as well as significant increase in anti-Caspase 3 and TNF immunostaining. The CeO2NPs treated group revealed significant improvement of all previous parameters. ConclusionCeO2NPs could alleviate CPF hepatoxicity through decreasing expression of the inflammatory and apoptotic proteins and increasing the activity of antioxidant enzymes.

Association of the clinical profile and overall survival of pediatric patients with acute lymphoblastic leukemia.

The clarification of etiopathology, the improvement of chemotherapy regimens and their risk stratifications, and the improvement in treatment support have increased the survival of children and adolescents affected by Acute Lymphoblastic Leukemia (ALL) past few years. This study aimed to estimate overall survival (OS) and event-free survival (EFS) in an onco-hematology treatment center in Brazil, reports the main clinical-laboratory characteristics of patients at diagnosis, verify the frequency of treatment-related adverse effects and the main causes of death. Retrospective analysis involving patients diagnosed with ALL, treated with the protocol of the Brazilian Group for Treatment of Leukemias in Childhood (GBTLI), between 2010 and 2020 was carried out; the outcomes (relapse, deaths, development of new neoplasms) were analyzed SPSS® software was used for the statistical analyses, and the p-value was considered significant when less than 0.05 for all analyses. 109 patients were included in the study; the median age was 5 years, with a slight predominance of males. Sixty-six patients were classified as high-risk (HR) group and 43 patients were classified as low-risk (LR) group. After 5 years of diagnosis, the OS was 71.5%, and the EFS was 65%. No statistical difference was found between the HR and LR groups for OS and EFS, while leukocyte counts were statistically associated with the outcome of death (p = 0.028). Among the patients, 28 (25.6%) died due to infection accounting 46.4% of death causes. Among the 34 patients with unfavorable outcomes (death and/or relapse), 32 had no research for the minimal residual disease at the end of remission induction, and 25 were not investigated for the presence of chromosomal abnormalities. The most reported complications and treatment-related adverse effects were increased liver transaminases (85.9%), airway infection (79.4%), oral mucositis (67.2%), febrile neutropenia (64.4%), and diarrhea (36.4%). The rates of OS and EFS obtained in this cohort are similar to those obtained in the few previous similar studies in Brazil and lower than those carried out in developed countries. The unavailability of prognostic tests may have hindered risk stratification and influenced the results obtained.

Oropouche virus infection induces ROS production and oxidative stress in liver and spleen of mice.

Oropouche virus (OROV) is the aetiological agent of Oropouche fever, the symptoms of which are common to most arboviruses, such as fever, headache, malaise, nausea and vomiting. More than half a million people have been infected with OROV since its isolation in 1955. Although Oropouche fever is classified as a neglected and emerging disease, to date, there are no antiviral drugs or vaccines available against the infection and little is known about its pathogenicity. Therefore, it is essential to elucidate the possible mechanisms involved in its pathogenesis. Since oxidative stress plays a pivotal role in the progression of various viral diseases, in this study, redox homeostasis in the target organs of OROV infection was evaluated using an animal model. Infected BALB/c mice exhibited reduced weight gain, splenomegaly, leukopenia, thrombocytopenia, anaemia, development of anti-OROV neutralizing antibodies, increased liver transaminases, and serum levels of pro-inflammatory cytokines tumour necrosis factor (TNF-α) and interferon-γ (IFN-γ). The OROV genome and infectious particles were detected in the liver and spleen of infected animals, with liver inflammation and an increase in the number and total area of lymphoid nodules in the spleen. In relation to redox homeostasis in the liver and spleen, infection led to an increase in reactive oxygen species (ROS) levels, increased oxidative stress biomarkers malondialdehyde (MDA) and carbonyl protein, and decreased activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Taken together, these results help elucidate some important aspects of OROV infection that may contribute to the pathogenesis of Oropouche.

Frontline combination of ponatinib and hyper-CVAD in Philadelphia chromosome-positive acute lymphoblastic leukemia: 80-months follow-up results.

The combination of ponatinib, a third-generation BCR::ABL1 tyrosine kinase inhibitor, with hyper-CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for stem cell transplantation (SCT) in most patients with Philadelphia chromosome(Ph)-positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients with longer follow-up would establish this regimen as a new standard of care. Adults with newly diagnosed Ph-positive ALL were treated with the hyper-CVAD regimen. Ponatinib was added as 45 mg daily × 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily continuously, with dose reduction to 15 mg daily upon achievement of a complete molecular response (CMR; absence of a detectable BCR::ABL1 transcript by quantitative reverse transcription polymerase-chain reaction at a sensitivity of 0.01%). Maintenance therapy consisted of daily ponatinib and vincristine-prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis. The trial is registered on clinicaltrials.gov with the identifier NCT01424982. Eighty-six patients were treated. Their median age was 46 years (range, 21-80). All 68 patients with active disease at the initiation of therapy achieved complete response (CR) The cumulative CMR rate was 86%. Twenty- patients (23%) underwent allogeneic SCT. With a median follow-up of 80 months (range, 16-129 months), the estimated 6-year event-free survival rate was 65% and the overall survival rate was 75%. There was no difference in outcome by performance of allogeneic SCT in first CR. Common grade 3-5 adverse events included infection (n= 80, 93%), increased liver transaminases (n= 26, 31%) and total bilirubin (n= 13, 15%), hypertension (n= 15, 17%), pancreatitis (n= 13, 15%), hemorrhage (n= 12, 13%), and skin rash (n= 9, 10%). Two ponatinib-related deaths from myocardial infarction (3%; at months 2.6 and 4.3, respectively; both in CR) in the first 37 patients treated led to the ponatinib dose-modifications mentioned earlier, with no further ponatinib-related deaths observed. The long-term results of ponatinib and hyper-CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph-positive ALL.

Спадкова мікросфероцитарна гемолітична анемія в дітей: діагностичний алгоритм типового та атипового перебігу

Anemic syndrome in a child in the practice of a primary care doctor is a frequent problem that requires a balanced differential diagnosis. Features of the course and difficulties in the diagnosis of hemolytic anemia require attention to key points. Hemolytic anemia is characterized by a reduction in the life span of erythrocytes, which is clinically manifested by jaundice due to indirect hyperbilirubinemia, splenomegaly, and skeletal deformities during a long course. Considering the seriousness of the prognosis for hemolytic anemia, it was considered appropriate to demonstrate specific practical nuances of managing such patients in specific clinical cases. Clinical cases clearly demonstrate the need for careful collection of family anamnesis and additional examination of brothers/sisters, parents when hereditary microspherocytosis is suspected. Diagnostic criteria of hereditary hemolytic anemia are: jaundice (due to indirect hyperbilirubinemia), splenomegaly, anemia, reticulocytosis, similar cases in the family. It is presented a case when hemolytic crises in a child were accompanied by a transient increase in liver transaminases, in the absence of changes in ultrasound examination and negative markers of viral hepatitis. Conclusions. An anemic syndrome established in a child in combination with reticulocytosis requires a targeted examination for hemolytic genesis of anemia. At the same time, it should be remembered that in the case of an atypical course of hereditary microspherocytosis, the patient needs a comprehensive examination and dynamic monitoring of the course of hemolytic anemia in order to prevent serious complications. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the author.

Experience of using lumacaftor/ivacaftor in children with cystic fibrosis in the Astrakhan region

Background. Targeted therapy in patients with cystic fibrosis, which aims to restore the function of the cystic fibrosis transmembrane conductance regulator protein, is currently revolutionary in the treatment of the disease. The first drug available in Russia for the treatment of patients with this genetic disease is lumacaftor/ivacaftor (Orkambi®), which was registered on December 2, 2020.The aim. To study the efficacy of lumacaftor/ivacaftor during 12 weeks of administration in children in Astrakhan region.Materials and methods. This article presents the clinical experience of Orkambi medicine use in 3 children with F508del/F508del genotype and a severe course of cystic fibrosis for 12 weeks. According to the study design, such indices as body mass index, indexes of external respiratory function, character of respiratory tract microbiota, level of chloride in sweat fluid and pancreatic elastase in feces, dynamics of biochemical blood indexes were evaluated. The study was performed within the time periods specified in the study protocol, namely, before the start of therapy, 2, 4, and 12 weeks of treatment.Results. Two patients had a decrease in sweat test values by 11 and 19 mmol/l from the baseline, a significant increase in forced vital capacity of lungs. One patient had an adverse event in the form of hepatobiliary disorders manifested by increased liver transaminase activity, which was the reason for discontinuing the drug.Conclusions. The short-term experience of using pathogenetic therapy with lumacaftor/ ivacaftor in children in the Astrakhan region demonstrated both the expected effect on chlorine channel function and the possibility of side effects, including severe ones, that can lead to withdrawal of the drug.

Generation of pro-and anti-inflammatory mediators after acetaminophen overdose in surviving and non-surviving patients

Acetaminophen (APAP) overdose causes liver injury in animals and humans. Although well-studied in animals, limited longitudinal data exist on cytokine release after APAP overdose in patients. The purpose of this study was to quantify concentrations of cytokines in APAP overdose patients to determine if early cytokine or complement measurements can distinguish between surviving and non-surviving patients. Plasma was obtained from healthy controls, APAP overdose patients with no increase in liver transaminases, and surviving and non-surviving APAP overdose patients with severe liver injury. Interleukin-10 (IL-10), and CC chemokine ligand-2 (CCL2, MCP-1) were substantially elevated in surviving and non-surviving patients, whereas IL-6 and CXC chemokine ligand-8 (CXCL8, IL-8) had early elevations in a subset of patients only with liver injury. Day 1 IL-10 and IL-6 levels, and Day 2 CCL2, levels correlated positively with survival. There was no significant increase in IL-1α, IL-1β or TNF-α in any patient during the first week after APAP. Monitoring cytokines such as CCL2 may be a good indicator of patient prognosis; furthermore, these data indicate the inflammatory response after APAP overdose in patients is not mediated by a second phase of inflammation driven by the inflammasome.

Mikroangiopathien in der Schwangerschaft

Das Wissen um die Differentialdiagnose der Mikroangiopathien ist auch für Geburtshelfer:innen wichtig. So ist die Kombination aus einer Thrombopenie und Hämolysezeichen wegweisend in der Erkennung der Erkrankung. Es sollten die Differenzialdiagnosen bekannt sein, da diese zu unterschiedlichen Therapienotwendigkeiten führen und Langzeitschäden, beispielsweise für die Niere, vermieden werden müssen. Die Differenzialdiagnosen der Thrombopenie stellen den Einstieg für die weitere Diagnostik dar. In der Kombination mit Hämolysezeichen und Veränderungen der Erythrozytenmorphologie (Fragmentozyten) liegen unterschiedliche Ursachen für die Mikroangiopathie vor. Eine thrombotisch-thrombozytopenische Purpura (TTP) kann während der gesamten Schwangerschaft, aber insbesondere im letzten Trimenon, die Ursache für solche Veränderungen sein. Bei dieser finden sich häufig gastrointestinale oder auch zusätzliche neurologische Symptome. Die Präeklampsie, insbesondere beim HELLP(„hemolysis, elevated liver enzymes, and a low platelet count“)-Syndrom, kann ebenfalls zu einer Mikroangiopathie führen, dieses i.d.R. mit entsprechender Erhöhung des Blutdrucks und insbesondere mit einer deutlichen Erhöhung der Lebertransaminasen, ebenfalls typischerweise im letzten Trimenon kombiniert. Wenn entsprechende Veränderungen nach der Geburt auftreten und diese neben der Hämolyse mit einem Nierenversagen verbunden sind, kann es sich hierbei um ein atypisches hämolytisch-urämisches Syndrom (aHUS) handeln, das spezifisch durch Antikörper therapiert werden sollte. Neben der typischen Gerinnungsaktivierung im Sinne einer Thrombosierung findet sich bei COVID-19 („corona virus disease“) auch das gesamte Bild einer entsprechenden Mikroangiopathie, zum Teil durch entsprechende Aktivierung des Gerinnungssystem, zum Teil durch eine Verstärkung der anderen Mikroangiopathien. Für alle Bereiche werden die Differenzialdiagnosen und mögliche Therapien skizziert.

Liver Damage Is Related to the Degree of Being Underweight in Anorexia Nervosa and Improves Rapidly with Weight Gain.

Background: The present study investigates the relationship between hypertransaminasemia and malnutrition on the basis of a very large number of patients. We assume that the level of transaminases not only reflects the extent of underlying liver cell damage but also provides information about the metabolic situation under conditions of energy deficiency. Methods: We present an observational study in two different samples. The first sample consists of 3755 patients (mean age 22.7 years, Range 12–73 years; mean BMI 15.4 kg/m2, range 8.1–25.7) out of a total of 4212 patients with anorexia nervosa treated in the Roseneck Clinic within five years for whom a complete admission laboratory was available. The second sample was obtained from a special ward for medically at-risk patients with eating disorders. During the period in question, four hundred and ten patients with anorexia nervosa were treated. One hundred and forty-two female patients (mean age 26.4 years, Range 18–63 years; mean BMI 11.5 kg/m2, range 8.4–13) had a BMI of thirteen or less and a complete data set was obtained at admission and weekly in the following four weeks after admission. Results: The increase in liver transaminases shows a very high correlation with weight in sample one (N = 3755). The analysis of variance shows highly significant (<0.001) correlations with an F-value of 55 for GOT/AST and 63 for GPT/ALT. Nevertheless, the variance within the groups with the same BMI is quite high. With re-nutrition in sample two, GOT/AST decreased on average from 71 U/L to 26 U/L (MANOVA F 10.7, p < 0.001) and GPT/ALT from 88 to 41 U/L (F = 9.9, p < 0.001) within four weeks. Discussion: Below a BMI of about 13, the nutritional status of the patients becomes so critical that the energy supply of the patient is increasingly dependent on the autophagy of the liver, which can be seen in the very strong increase in transaminases here. Refeeding leads very quickly to the normalisation of the transaminases and, thus, a stabilisation of the metabolism leading also to a decrease in autophagy.

Liver enzymes after short-term acetaminophen error in critically ill children: a cohort study.

Although the administration of acetaminophen in critically ill children frequently exceeds the daily recommended limit and vigilance is needed, we did not find any associated increase in liver transaminases following acetaminophen errors. •Acetaminophen dosing errors are common in pediatric outpatients. • Excessive acetaminophen dosing can be associated with harm, including hepatic injury. •Exceeding daily acetaminophen dosing limit occurs 1 in every 9.5 patient-days in children admitted to the critical care unit. • In patients with daily dose excess of acetaminophen, we did not find a significant increase in the measured liver enzymes in the 24 to 96 h following the overdosing.

Real-World Data Regarding Long-Term Administration of Natalizumab Derived from a Neurology Department along with Literature Review.

Natalizumab is a humanized monoclonal antibody with high efficacy and an acceptable safety profile used in the treatment of patients with multiple sclerosis (MS). Our aim was to report data regarding long-term administration of Natalizumab in patients with Relapsing-Remitting Multiple Sclerosis (RRMS) from our clinic. A retrospective observational study was performed including RRMS patients who underwent treatment with ≥ 24 Natalizumab infusions. We analyzed EDSS values, the relapse rate and the rate and type of adverse events related to Natalizumab administration. 51 subjects were included with a predominance of women (62.74%), with an average age of 40.43±1.49 years, a mean disease duration of 9.86±0.7 years and mean number of Natalizumab infusions of 45.58±2.74. An increased number of patients (80.39%) were relapse-free and a mild reduction of the mean EDSS value following Natalizumab initiation in patients who had not been treated with other disease modifying therapies anteriorly was observed. Among the encountered adverse events such as increased liver transaminases (13.72%), local infections (7.84%) and dysmenorrhea in one patient were registered in this study. The rate of severe adverse events was 3.92 and no cases of Progressive Multifocal Leukoencephalopathy (PML) were registered. Natalizumab proves to be effective, has an adequate safety profile and can be administered with good tolerability for a rather extended period of time, provided that the patients are closely monitored.

105. Diagnosis principles of viral hepatitis b in pregnant women as a way to determine approach to the pregnancy

Introduction and aims: The high prevalence of hepatitis B during pregnancy is a difficult task.In the period 2015-2018, only 85 pregnant women were examined for HBeAg in Ukraine, 335 for HDV and viral load, while HBsAg positive – 13520 women. This disproportionate screening of pregnant women indicates a lost opportunity in preventing of mother-to-child transmission of hepatitis B virus, increasing complications during pregnancy (fetoplacental insufficiency, premature birth, preeclampsia, untimely discharge of amniotic fluid).Study design: A retrospective study is based on survey results of 75 pregnant women (2018-2020) with hepatitis B, attending antenatal clinic or being treated in maternity hospital. Statistical analysis has been performed by extensive parameters evaluation. Results: Among all women surveyed, the relationship has been established between various antigens (HBeAg+ or HDV antigen with high viral load of >20 000 MO/ml) and the state of the fetoplacental complex, liver functions, frequency of obstetric pathology. HBeAg positive women, women with HDV, with viral load > 20 000 MO/ml had increased liver transaminases (70 (93,3%), placental dysfunction (67 (89,3%), cases of delayed fetal development (48 (64%), preterm delivery (36 (46,7%). Conclusions: Based on the survey outcomes, we see a strong need to modify HBV diagnosis in pregnant women. It is necessary to examine not only HBsAg in pregnant women, but also other immunological parameters of HBV: HBeAg, viral load, presence of HDV antigen. When diagnosed, it is possible to adjust the treatment approach to avoid any additional complications of HBV for the mother, as well as fetal pathologies.

Follow-up of patients with R/R FLT3-mutation–positive AML treated with gilteritinib in the phase 3 ADMIRAL trial

AbstractThe phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation–positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Human Immunodeficiency Virus (HIV) infection with Multiple Comorbidities in COVID-19 Pandemic Era: A Case Report

Coronavirus disease-19 (COVID-19) and Human Immunodeficiency Virus (HIV) were pandemic diseases that affected the healthcare system worldwide. Decline immune system in HIV and accompanying opportunistic infection may worsen the outcome and prognosis of COVID-19 infection. Comprehensive diagnosis and treatment were crucial with HIV patients with a very low immune response. This is our first case report of 50 years old man recently known with HIV and confirmed COVID-19 from PCR swab at once. We found several comorbidities through a comprehensive examination of clinical and laboratory, such as bicytopenia (anemia and thrombocytopenia), acute renal failure, increased liver transaminase, and coagulation disorder (increased PT/APTT) D-dimer), hypoalbuminemia and extremely low CD4. Oral candidiasis, chronic B hepatitis, and lung tuberculosis also present as opportunistic infections in this patient. One dose of antiviral oseltamivir was given each day interval (considering the patient's renal function) accompanied with immediate resuscitation, multivitamins, fluconazole, and cotrimoxazole given. After resolving an acute condition, oral tuberculosis treatment was given, continued with antiretroviral therapy, and advised the patient to routine control in the outpatient department. Future research should address the significance of CD4 lymphocyte count or viral load to measure patients with HIV's immune system and clinical status, risk of opportunistic infection, and prognostic in this pandemic COVID-19 era.

Hepatoprotective, antioxidant, anti-inflammatory, and antiviral activities of silymarin against mayaro virus infection

Infection caused by Mayaro virus (MAYV) is responsible for causing acute nonspecific fever, in which the majority of patients develop incapacitating and persistent arthritis/arthralgia. Mayaro fever is a neglected and underreported disease without treatment or vaccine, which has gained attention in recent years after the competence of Aedes aegypti to transmit MAYV was observed in the laboratory, coupled with the fact that cases are being increasingly reported outside of endemic forest areas, calling attention to the potential of an urban cycle arising in the near future. Thus, to mitigate the lack of information about the pathological aspects of MAYV, we previously described the involvement of oxidative stress in MAYV infection in cultured cells and in a non-lethal mouse model. Additionally, we showed that silymarin, a natural compound, attenuated MAYV-induced oxidative stress and inhibited MAYV replication in cells. The antioxidant and anti-MAYV effects prompted us to determine whether silymarin could also reduce oxidative stress and MAYV replication after infection in an immunocompetent animal model. We show that infected mice exhibited reduced weight gain, hepatomegaly, splenomegaly, anaemia, thrombocytopenia, leukopenia, increased liver transaminases, increased pro-inflammatory cytokines and liver inflammation, increased oxidative damage biomarkers, and reduced antioxidant enzyme activity. However, in animals infected and treated with silymarin, all these parameters were reversed or significantly improved, and the detection of viral load in the liver, spleen, brain, thigh muscle, and footpad was significantly reduced. This work reinforces the potent hepatoprotective, antioxidant, anti-inflammatory, and antiviral effects of silymarin against MAYV infection, demonstrating its potential against Mayaro fever disease.

High anti-TNFα Concentrations Are Not Associated With More Adverse Events in Pediatric Inflammatory Bowel Disease.

Anti-tumor necrosis factor alpha (anti-TNFα) therapy is commonly used to treat refractory pediatric inflammatory bowel disease (IBD) and carry risks for adverse events. We aimed to assess the relationship between anti-TNFα trough concentrations and adverse events rate among pediatric patients with IBD. The medical records of pediatric patients with IBD who were treated with anti-TNFα agents from 2015 to 2020 and had sequential monitoring of trough concentration (TC) were reviewed retrospectively for the presence of adverse events. The study cohort included 135 eligible patients (59 [43.7%] girls, mean age at diagnosis 12.9 [±3] years, 111 [82.2%] Crohn disease) who had 1589 measurements of TCs (1037 [63%] infliximab). During a median follow-up period of 1.7 years (IQR 1.1-2.7), we recorded 156 adverse events in 50 patients (37%). Higher TCs were not associated with higher rate of anti-TNFα-related adverse events whereas these events (excluding increase in liver transaminases) were associated with younger age.

LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort.

3564 Background: Pembrolizumab (pembro), an anti-PD-1 antibody, is approved for the treatment of patients (pts) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient colorectal cancer, both as first-line treatment and after progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and anti-PD-1 treatment showed synergistic antitumor activity in preclinical models. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembro in pts with previously treated advanced solid tumors. We present findings from the colorectal cancer cohort. Methods: In this nonrandomized, open-label, phase 2 study, adult pts (aged ≥18 y) with histologically/cytologically documented metastatic and/or unresectable colorectal cancer, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and a tissue sample evaluable for PD-L1 expression were eligible. Pts received lenvatinib 20 mg QD plus pembro 200 mg Q3W for up to 35 cycles of pembro (̃2 y) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 y in pts with clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to week 102, and Q24W thereafter. Results: 32 pts with colorectal cancer received treatment with lenvatinib plus pembro (median age, 56 y [range, 36-77]; male, 81%; 3L, 91%); median time from first dose to data cutoff (April 10, 2020) was 10.6 mo (range, 5.9-13.1). ORR was 22% (95% CI, 9–40; table). Grade 3–5 treatment-related AEs occurred in 16 (50%) pts. Treatment-related AEs led to treatment discontinuation in 3 pts (grade 2 ischemic stroke [n = 1], grade 3 increased liver transaminases [n = 1], grade 5 intestinal perforation [n = 1]). Conclusions: In pts with previously treated advanced non–MSI-H/pMMR colorectal cancer, lenvatinib plus pembro demonstrated promising antitumor activity and a manageable safety profile. Enrollment in the colorectal cohort was expanded to 100 pts. Clinical trial information: NCT03797326. [Table: see text]

LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort.

94 Background: Pembrolizumab (pembro), an anti-PD-1 antibody, is approved for the treatment of patients (pts) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient colorectal cancer, both as first-line treatment and after progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and anti-PD-1 treatment showed synergistic antitumor activity in preclinical models. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembro in pts with previously treated advanced solid tumors. We present findings from the colorectal cancer cohort. Methods: In this nonrandomized, open-label, phase 2 study, adult pts (aged ≥18 y) with histologically/cytologically documented metastatic and/or unresectable colorectal cancer, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and a tissue sample evaluable for PD-L1 expression were eligible. Pts received lenvatinib 20 mg QD plus pembro 200 mg Q3W for up to 35 cycles of pembro (~2 y) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 y in pts with clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to week 102, and Q24W thereafter. Results: 32 pts with colorectal cancer received treatment with lenvatinib plus pembro (median age, 56 y [range, 36-77]; male, 81%; 3L, 91%); median time from first dose to data cutoff (April 10, 2020) was 10.6 mos (range, 5.9-13.1) ORR was 22% (95% CI, 9-40; Table). Grade 3-5 treatment-related AEs occurred in 16 (50%) pts. Treatment-related AEs led to treatment discontinuation in 3 pts (grade 2 ischemic stroke [n = 1], grade 3 increased liver transaminases [n = 1], grade 5 intestinal perforation [n = 1]). Efficacy Results. Clinical trial information: NCT03797326. NR, not reached aConfirmation was not required for best overall response of SD, but a final visit response of SD or better must have occurred ≥6 wks after starting study treatment Conclusions: In pts with previously treated advanced non–MSI-H/pMMR colorectal cancer, lenvatinib plus pembro demonstrated promising antitumor activity and a manageable safety profile. Enrollment in the colorectal cohort was expanded to 100 pts. [Table: see text]