Phase I Trial of Oral Yeast-Derived β-Glucan to Enhance Anti-GD2 Immunotherapy of Resistant High-Risk Neuroblastoma

Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose.

Immunogenetic features of HIV-infection and allergy comorbidity

Today, the comorbidity of infection caused by the human immunodeficiency virus (HIV) is an important problem due to the complexity of the selection of the optimal antiretroviral therapy and the diagnosing of associated pathological conditions. The study of the comorbidity of HIV-infection and allergy is an important area of research. This article presents a literature review on different types of comorbidity. Special attention is paid to the development of allergic reactions to antiretroviral drugs. The presence of an allergic reaction in a patient can cause low adherence to therapy and subsequent development of HIV resistance to the treatment. The review provides information on the possible causes of the development of hypersensitivity in HIV-infected patients. The data on the development of hypersensitivity reactions in response to treatment with the main classes of antiretroviral drugs (nucleoside and non-nucleoside reverse transcriptase inhibitors, synthesis inhibitors, protease inhibitors, integrase inhibitors, cysteine-cysteine chemokine receptor 5 inhibitors) are presented. The most common allergic reactions to these drug classes are itching and rash, as well as increasing hepatic transaminase levels and cough. The existing scientific data on allergic reactions to drugs prescribed for other concurrent conditions (tuberculosis, fungal diseases) is also considered. The examples of studies reflecting the relevance of using immunogenetic and molecular genetic approaches in the study of comorbidity of HIV-infection and allergy are given. The identification of immunogenetic markers of the development of the hypersensitivity to therapy will optimize the diagnostic and treatment algorithms, especially in complex comorbid conditions.

Efficacy and Safety of PD-1 Immune Checkpoint Inhibitors in Locally Advanced and Advanced NSCLC Patients With Chronic Viral Infection

IntroductionImmune checkpoint inhibitors (ICIs) have become new research hotspots in the treatment of non-small cell lung cancer, but the efficacy and safety of immunotherapy for patients with chronic viral infection are still unclear, because existing clinical trials often exclude those patients. Methods We identified 78 locally advanced or advanced NSCLC patients with chronic viral infection treated with PD-1/PD-L1 inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. ResultsObjective responses were observed in 19 out of 78(24.36%) patients, and the disease control rate (DCR) was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI:3.71-9.27). PFS was 1.44 months (95%CI:0.00-4.34) for monotherapy versus 7.34 months (95%CI:4.50-10.18) for combination therapy (P=0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, P = 0.001; PFS: 7.67 months vs. 5.57 months, P = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs.4.62, P=0.027). The incidence of adverse events of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 adverse events. The incidence of leukopenia was the highest (57.69%), followed by anemia (25.64%) and elevated hepatic transaminase (24.36%). Hepatic transaminase increased in 26.7% (16/60) of HBV patients, and remained unchanged in 65.0% (39/60) patients.ConclusionsThe PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on locally advanced and advanced NSCLC patients with chronic viral infection, but still has the potential to increase the incidence of hepatitis. We recommend that those patients be monitored closely and treated with antiviral therapy.

Compromised liver function in patients with a new coronavirus infection COVID-19

Clinicians have noted an increase in the level of hepatic transaminase in patients with the new coronavirus infection COVID-19 a number of times, and an unambiguous answer to the question of what caused this change in laboratory indices has not been received yet. The course of COVID-19 is often complicated by the development of haemophagocytic syndrome, and preventive anti-inflammatory therapy is required for its treatment, which is represented by biologic drugs (interleukin-6 inhibitors or JAK-kinase blockers) and glucocorticosteroids. It has been noted that the level of ALT and AST increases against the background of biological therapy.The objective of the present study was to analyze the possible effect of biological therapy on the functional state of the liver.Material and methods. The study randomly included 38 patients diagnosed with ICD-10 U07.1 (18 women and 20 men). Inclusion criteria were control of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin at least three times during the period of hospitalization, as well as an increase in these indicators above the reference values. This study was carried out while prescribing preventive anti-inflammatory therapy.Results. The median (Me ± SD) age of the patients was 57 ± 14.67. Mann–Whitney U-test showed no significant difference in the activity of liver enzymes and total bilirubin upon admission to the infectious diseases hospital (p> 0.05). A statistically significant difference in indicators evaluation at admission and at discharge was determined using the Wilcoxon test for ALT levels in the group receiving biologic drugs (p = 0.004). In other cases, there was no statistically significant difference (p > 0.05). When analyzing the level of enzymes for the entire period of hospitalization with the use of Friedman criterion, the level of changes in hepatic transaminases in the group with the use of biologic drugs turned out to be equal for ALT p = 0.001. When assessing changes over the entire period of hospitalization by the de Ritis coefficient, the p-value was also significant (0.001) in this group.Conclusion. This study shows the necessity to control the level of hepatic transaminase, especially when prescribing biological therapy for haemophagocytic syndrome.

Pooled Safety Results Through One Year of Two Phase-3 Trials of Guselkumab in Patients with Psoriatic Arthritis

Objective Evaluate safety of guselkumab (monoclonal antibody targeting IL-23p19) in psoriatic arthritis (PsA) patients through 1year (1Y) of the Phase-3 DISCOVER-1&2 trials. Methods Patients with active PsA (N=1120; biologic-naïve except the118 TNFi-treated DISCOVER-1 patients) were randomized to subcutaneous guselkumab 100 mg every 4 weeks (Q4W) or at Week 0, Week4, then Q8W; or placebo. At Week24, placebo patients switched to guselkumab 100 mg Q4W. Treatment continued through 1Y and 2Y for DISCOVER-1&2, respectively. In this pooled analysis, patients with ≥1 adverse event (AE) through 1Y were standardized for 100 patient-years of follow-up [100PY]). Results Through Week24, AEs were consistent between placebo- and guselkumab (Q4W+Q8W)-treated patients: AEs 143/100PY and 151/100PY; serious AEs 7.1/100PY and 4.4/100PY; AEs leading to study agent discontinuation 4.1/100PY and 3.8/100PY, respectively. Through 1Y, no active tuberculosis, opportunistic infections, or inflammatory bowel disease, and low rates of malignancy and major adverse cardiovascular events, were observed in guselkumab-treated patients. Injection-site reactions occurred in 1–2%, and antibodies to guselkumab in 4.5% of guselkumab-treated patients through 1Y; the vast majority of antibodies to guselkumab were non-neutralizing. Serum hepatic transaminase elevations (more common with Q4W than Q8W) and decreased neutrophil counts were generally mild, transient, and did not require treatment discontinuation, with minimal change from Week24 to 1Y. Conclusion Guselkumab 100 mg Q4W and Q8W were well tolerated in PsA patients, with no new safety concerns through 1Y of the Phase-3 DISCOVER trials. Guselkumab safety through 1Y in PsA patients is consistent with that established in guselkumab-treated psoriasis patients.

Identification of a Novel MICU1 Nonsense Variant Causes Myopathy with Extrapyramidal Signs in an Iranian Consanguineous Family

Background: Ca2+ as a universal second messenger regulates basic biological functions including cell cycle, cell proliferation, cell differentiation and cell death. Lack of the protein mitochondrial calcium uptake1 (MICU1) which has been regarded as a gatekeeper of Ca ions, leads to the abnormal mitochondrial Ca2+ handling, excessive production of reactive oxygen species (ROS), and increased cell death. Mutations in MICU1 gene (NM_006077.3) causes a very rare neuromuscular disease, Myopathy with extrapyramidal signs (MPXPS), due to primary alterations in mitochondrial calcium signaling which demonstrates the key role of mitochondrial Ca2+ uptake. To date 6 variants have been reported in MICU1 gene in approximately 21 pedigrees.Case presentation: here we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, elevated hepatic transaminase, elevated serum creatine phosphokinase and gait disturbance. We Identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing and segregation analysis.Conclusions: Our finding along with previous studies provides more evidence on the clinical presentation of the disease caused by pathogenic mutations in MICU1. Finding more variants and expanding the spectrum of the disease increases the diagnostic rate of molecular testing in screening of this kind of diseases and in turn improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children.

Acute Toxicity Test of Amomum cardamomum (Kapulaga) Seed Extract on Hepatic Trasaminase Enzyme in Winstar Rats

The herb frequently used as spices or remedies in the Indonesian community, with the seed as the most common part is kapulaga (Amomum cardamomum). According to earlier evidence, this possessed antibacterial, antifungal and several biological properties, reduced blood glucose and atherogenic parameter, and is developed as standardized herbal cures. However, the application of herbal medicine requires validating evidence of safety and effectiveness, including toxicity tests, particularly in clinical settings. The target organs in this comprised hepar, due to the role in several drug metabolism. This study aimed at discovering the safety profile of kapulaga seed extract based on the hepatic transaminase enzyme (SGOT and SGPT) level, by conducting an acute toxicity test in Winstar rats. Also, this was implemented with the OECD 420 Fixed-Dose Procedure, and the preliminary test employed 300 mg/kg BW dose followed by a maximum single quantity (2000 mg/kg BW) of kapulaga. The main test was executed by a separation into control and treatment groups of 5 rats each. Therefore, a single dose of 2000 mg/kg BW kapulaga seed extract was administered to the treatment group, while the control group received standard pellets and water ad libitum. The blood from orbital vein was acquired on day 14, and SGOT and SGPT were subsequently assessed by an enzymatic-photometric method. Also, this data was analyzed using an independent sample t-test, and the mean of SGOT in both groups were 116.92±22.35 and 98.02±16.38 (p=0.17), with 58.72±8.79 and 47.64±7.30 (p=0.06) as SGPT respectively. Therefore, there was no statistical difference, and no acute toxicity signs were discovered. The maximum dose was not toxic and did not result in poisonous symptoms or alter hepatic transaminase enzyme (SGOT and SGPT) in rats.Keywords: Amomum cardamomum, kapulaga, acute toxicity, SGOT, SGPT Uji Toksisitas Akut Ekstrak Biji Kapulaga (Amomum cardamomum) Berdasarkan Kadar Enzim Transaminase Hepar Tikus WinstarAbstrakKapulaga (Amomum cardamomum), merupakan salah satu herbal Indonesia yang secara umum dimanfaatkan sebagai rempah-rempah maupun obat, terutama bagian biji. Beberapa bukti sebelumnya menunjukkan bahwa kapulaga memiliki berbagai aktivitas biologis seperti antibakteri, antijamur, dan sudah dibuktikan mampu menurunkan glukosa darah dan parameter arterogenik. Bukti tersebut mendukung pengembangan kapulaga sebagai obat herbal terstandar. Penggunaan obat herbal terutama di klinik harus didukung dengan adanya bukti keamanan maupun efektivitasnya termasuk uji toksisitas. Hepar merupakan salah satu target organ dari uji toksisitas karena perannya yang penting pada metabolisme sebagian besar obat. Penelitian ini bertujuan untuk menilai profil keamanan ekstrak biji kapulaga melalui uji toksisitas akut menggunakan tikus Winstar berdasarkan kadar enzim transaminase hepar (SGOT dan SGPT). Uji toksisitas akut berpedoman pada OECD 420 Fixed Dose Procedure. Uji pendahuluan menggunakan ekstrak biji kapulaga dosis 300 mg/kg BB dan diikuti dengan dosis tinggi 2000 mg/kg BB yang diberikan secara tunggal. Uji utama dilakukan dengan membagi tikus ke dalam kelompok kontrol dan perlakuan, masing-masing kelompok terdiri atas 5 tikus. Berdasarkan hasil uji pendahuluan, uji utama menggunakan dosis tunggal 2000 mg/kg BB untuk kelompok perlakuan, sedangkan kelompok kontrol hanya mendapatkan pelet dan air secukupnya. Pada hari ke-14, darah dari vena orbital diambil, lalu kadar SGOT dan SGPT diukur menggunakan metode enzymatic-photometric. Independent sample t-test digunakan untuk menilai data rata-rata kadar SGOT dan SGPT dari kedua kelompok. Rata-rata kadar SGOT pada kelompok kontrol dan perlakuan sebesar 116,92±22,35 dan 98,02±16,38 (p=0,17), sedangkan rata-rata SGPT sebesar 58,72±8,79 dan 47,64±7,30 (p=0,06). Perbedaan rata-rata SGOT dan SGPT pada kedua kelompok tersebut secara statistik tidak bermakna dan tidak ditemukan tanda toksisitas pada semua hewan coba. Ekstrak biji kapulaga dosis maksimal 2000 mg/kg BB tidak toksik pada hepar tikus karena tidak menimbulkan tanda toksisitas maupun mengubah enzim transaminase hati (SGOT dan SGPT). Kata kunci: Amomum cardamomum, kapulaga, toksisitas akut, SGOT, SGPT

Ceftriaxone Therapy of Bacterial Meningitis in Children

Twenty-nine children, age 3 months to 11 years, admitted with the clinical diagnosis of bacterial meningitis to the Department of Child Health, were included in a prospective treatment study of ceftriaxone (RocephinHoffmann- La Roche AG Bas/e, Switzerland). Ceftriaxone was used as the only antibiotic agent in single daily dose of 100 mg/kg body weight given intravenously for a minimum of 10 days. Of these 29 patients, 25 (86.2%) recovered, 3 (10.3%) died and 1 (3.4%) no respond to treatment. Among fatal cases, two patients had subdural empyema and one had a cerebral abscess. The microorganisms isolated from cerebrospinal fluid were: Streptococcus pneumoniae (5), Pseudomonas sp. (4), Proteus sp. (2), Salmonella typhi (1), Escherichia coli (1), Clostridium sp. (1), Pseudomonas aeruginosa (1), Staphylococcus aureus {1), and Streptococcus haemolyticus (1). In 12 patients (41,4%), organisms were not identified. The diagnosis was made based on clinical symptoms, Gram staining, cell count. ~!·tease, and protein in the CSF. In all patients, repeated spinal fluid cultures had no bacterial growth at 24 hours after initation of intravenous therapy. No evidence of clinical important drug toxicity was observed. Three p'Oiients, however, had lightly elevated hepatic transaminase levels, and one patient had rnild neutropenia. These clinical and bacteriological results suggested that ceftriaxone is reasonably safe and effective in the treatment of bacterial meningitis caused by the most common pediatric pathogens in Indonesian children over one month of age.

Hematological and Serum Biochemical Analysis of Streptozotocin-Induced Insulin Dependent Diabetes Mellitus in Male Adult Wistar Rats

BackgroundThis investigation is concentrated on how hematological and serum biochemical markers would change in streptozotocin-induced Insulin-Dependent diabetes mellitus(IDDM) in male adult wistar rats. Hematological parameters, serum protein electrophoresis parameters and hepatic transaminases level (SGOT-SGPT) were all measured in both control group rats (N=6) and diabetic group rats (N=6) and comparison between two groups was performed.Material and MethodSingle dose intraperitoneal injection of 60 mg/kg dose of streptozotocin(STZ) in male adult wistar rats, induces extensive necrosis in langerhans β-cell islets, because of its cytotoxicity. Experimental diabetes mellitus can be induced completely in less than 72 hours after STZ intraperitoneal injection. Streptozotocin(STZ) was purchased from Sigma company. Diabetic and control group rats were kept separately in different metabolic cages, and their blood glucose(BG), hematological parameters, serum protein electrophoretic pattern and hepatic transaminases level were analyzed and comparison was done.ResultsIn our investigation, Insulin-Dependent Diabetes Mellitus(IDDM) was completely induced one week after single intraperitoneal injection of 60 mg/kg BW. Diabetes mellitus induction was verified by measuring fasting plasma glucose level in blood samples of rats. Level of blood glucose, hematological parameters, serum protein electrophoretic pattern and hepatic transaminase enzymes level, were all measured. In diabetic group rats level of blood glucose (BG), hepatic transaminase enzymes (SGOT & SGPT), serum α1-globulin and β-globulin were significantly increased but in albumin, albumin/globulin ratio (A/G ratio) and serum α2-globulin a significant decrease was observed in diabetic rats in comparison with normal rats.ConclusionExtensive inflammation and tissue necrosis induced following diabetes mellitus induction in rats. Significant alterations were observed in serum protein electrophoresis fractions and hepatic transaminase enzymes level due to streptozotocin cytotoxic impacts on some tissues specifically liver.Because of extensive β-cells necrosis and degeneration caused by streptozotocin exposure, high level of blood glucose(diabetic hyperglycemia) was observed in diabetic rats. This type of experimentally induced diabetes mellitus would highly affect hematological parameters. Insulin-Dependent Diabetes Mellitus induced by streptozotocin, can lead to anemia, neutrophilia and lymphocytosis and also has decreasing effects on red blood cell indices (HGB, MCV, MCH, MCHC) in diabetic group rats.

Brucellosis as the Cause of Non-Viral Bacterial Hepatitis: A Case Report

BACKGROUND: Brucellosis can lead to different clinical pictures such as hepatomegaly, granulomatous liver disease, hepatic abscess, and it can cause mild hepatic transaminase elevation in the laboratory investigations.CASE REPORT: We found out that the etiologic agent was Brucella in our two cases admitted with acute hepatitis presentation in the investigations conducted. Liver transaminases were as follows for case 1 and case 2; AST: 306/187U/L, ALT: 368/312U/L, ALP: 355/264U/L, GGT: 116/197U/L, LDH: 887/549U/L, respectively. Sacroiliitis also accompanied the clinical picture in our first case. Our patients showed clinical and laboratory improvement with rifampicin, doxycycline, (additional streptomycin for 21 days in the patient with sacroiliitis) treatment.CONCLUSION: Brucellosis which may manifest as a clinical picture regarding numerous medical branches should be considered in case of acute hepatitis, especially in endemic regions, along with viral hepatitis.