Increase In GGT Research Articles

Investigating the protective effects of epigallocatechin-gallate against polystyrene microplastics-induced biochemical and hematological alterations in rats

BackgroundPolystyrene microplastics (PS-MPs) are widely used and found in drinking water and food, concerns have been raised about their potential health effects, especially in causing oxidative stress and inflammation in living organisms. ObjectivesThe aim of this study was to investigate the protective effects of epigallocatechin-gallate (EGCG), a natural antioxidant and anti-inflammatory compound, against PS-MPs-induced biochemical and hematological alterations in rats. MethodsMale Wistar rats were divided into four groups: control, EGCG-treated (80 mg∙ kg-1/d), PS-MPs-exposed (0.01 mg∙kg-1/d), and PS-MPs+EGCG-treated groups. PS-MPs were orally administered for 56 days, while EGCG was given concomitantly by gavage. At the end of the treatment period, blood samples were collected for hematological and biochemical analyses. Oxido-nitrergic stress markers, including malondialdehyde (MDA), nitric oxide (NO), reactive nitrogen species (RONS) and reduced glutathione (GSH), Superoxide dismutase (SOD), catalase (CAT), as well as inflammatory markers, such as tumor necrosis factor alpha (TNF-α), interferon gamma (IFY-γ) and interleukin-10 (IL-10), were also measured in serum. ResultsTreatment with PS-MPs caused a significant increase in MDA, RONS, NO levels and a decrease in SOD, CAT and GSH levels, indicating the induction of oxido-nitrergic stress. PS-MPs also caused an increase in the levels of TNF-α, IFY-γ, MPO and decreased IL-10, indicating the induction of inflammation. Additionally, PS-MPs caused alterations in hematological and serum transaminase parameters, including a decrease in red blood cell count, hemoglobin, and hematocrit levels, neutrophil and eaosinophil and an increase in white blood cell count, lymphocyte count, AST, ALT, ALP, LDH and GGT. PS-MPs also caused disturbances in electrolyte balance and renal function markers. However, treatment with EGCG significantly attenuated these alterations induced by PS-MPs, indicating its protective effects. ConclusionThe results of this study demonstrate that EGCG can protect against PS-MPs-induced biochemical and hematological alterations in rats, possibly through its antioxidant and anti-inflammatory properties.

Biochemical liver damageduringgender affirmingtherapy in transadults assigned female at birth: a meta-analysis.

To assess the effects of testosterone (T)-based gender affirming hormone therapy (GAHT) on liver blood tests (LBTs) in assigned female at birth adults, using a meta-analytic approach. Prospective and retrospective studies were selected that reported the prevalence of biochemical liver damage (BLD) and LBTs changes during T therapy. Data collected included pre-and-during therapy alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), gamma-glutamyl-transferase (GGT), and alkaline phosphatase (ALP) mean concentration values. The prevalence of BLD in 14 studies on 1698 subjects was 1% (95% CI 0.00-3.00; I2 = 14.1%; p = 0.82). In 17 studies on 2758 subjects, GAHT was associated with a statistically (but not clinically) significant increase in AST, GGT and ALP at 12months and ALT at 3-7 (MD: 1.19IU/l; 95% CI 0.31, 2.08; I2: 0%), at 12 (MD: 2.31IU/l; 95% CI 1.41, 3.21; I2: 29%), but with no more significant increase at 24months (MD: 1.71IU/l; 95% CI -0.02, 3.44; I2: 0%). Analysis of aggregate estimates confirms a low risk of BLD and abnormalities in LBTs, transient in most cases, during T-based GAHT, thus suggesting a limited need for careful liver monitoring in AFAB people.

The question of screening organ donors for hepatitis e virus: a case report of transmission by kidney transplantation in France and a review of the literature

BackgroundHepatitis E is a potentially serious infection in organ recipients, with an estimated two-thirds of cases becoming chronic, and with a subsequent risk of cirrhosis and death. In Europe, transmission occurs most often through the consumption of raw or undercooked pork, more rarely through blood transfusion, but also after solid organ transplantation. Here we describe a case of Hepatitis E virus (HEV) infection transmitted following kidney transplantation and review the literature describing cases of HEV infection transmitted by solid organ transplantation.Case presentationThree weeks after kidney transplantation, the patient presented with an isolated minimal increase in GGT and hepatic cytolysis 6 months later, leading to the diagnosis of genotype 3c hepatitis E, with a plasma viral load of 6.5 log10IU/mL. In retrospect, HEV RNA was detected in the patient's serum from the onset of hepatitis, and in the donor's serum on the day of donation, with 100% identity between the viral sequences, confirming donor-derived HEV infection. Hepatitis E had a chronic course, was treated by ribavirin, and relapsed 10 months after the end of treatment.DiscussionSeven cases of transmission of HEV by solid organ transplantation have been described since 2012 without systematic screening for donors, all diagnosed at the chronic infection stage; two patients died. HEV organ donor transmission may be underestimated and there is insufficient focus on immunocompromised patients in whom mild liver function test impairment is potentially related to hepatitis E. However, since HEV infection is potentially severe in these patients, and as evidence accumulates, we believe that systematic screening of organ donors should be implemented for deceased and living donors regardless of liver function abnormalities, as is already the case in the UK and Spain. In January 2024, the French regulatory agency of transplantation has implemented mandatory screening of organ donors for HEV RNA.

Circadian Rhythm Effects on the Extraction and Identification of Semen on Semen-Stained Fabrics Using Seminal Fluid Biochemistry

The rate of rape and other sexually induced crimes is rapidly on the increase worldwide with weak empirical confirmational tools, and expensive financial implications This is further compounded by poor proof of the time of the committal of the crime and its attendant effect on the parameter of interest. This called for a cheap and accurate approach involving the use of biochemical parameters indicative of seminal fluids on fabrics and other ancillary materials found in a crime scene. This study was therefore designed to validate a suitable seminal fluid biochemical approach to detecting seminal stained fabrics and the attendant circadian rhythm effects. Seminal fluid biochemical parameters used for the study include prostate-specific antigen, gamma-glutamyl transferase, acid phosphatase, magnesium, zinc, and inorganic phosphorus. These parameters were analyzed using WHO-approved methods after the extraction phase from dried stained fabrics. Forty (40) participants were recruited for the study divided into two groups; nocturnal and diurnal. The mathematical and empirical analysis data were analyzed using One-way ANOVA (Post Hoc) on an SPSS 25 version platform. The result showed a significant increase (p< 0.05) in seminal PSA, GGT, and ACP in the semen-stained fabrics when compared to distilled water-stained fabrics. In a similar vein, there was a significant increase in seminal ACP and PSA concentrations in the nocturnal group when compared to the diurnal, whereas seminal GGT decreased. In conclusion, this study has shown that semen-stained fabric can be detected for the presence of seminal fluids using seminal PSA, ACP, and GGT. Also, the effect of circadian rhythm should be considered during result interpretation.

Abstract CT059: Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas

Abstract Background: AXL is a cell surface receptor tyrosine kinase widely expressed in solid tumors (ST), including sarcomas. ADCT-601 (Mipasetamab uzoptirine; Mipa) is an antibody-drug conjugate comprising a humanized anti-AXL antibody conjugated via a cleavable linker to SG3199 (pyrrolobenzodiazepine dimer cytotoxin). Mipa demonstrated antitumor activity in pre-clinical mice models of sarcoma, adrenocortical carcinoma and pancreatic cancer, and clinical activity in ST patients (pts) in its first-in-human trial. Here, we report initial clinical data in pts with advanced bone and soft tissue sarcomas treated in dose escalation with Mipa. Objective: To characterize the safety and tolerability of Mipa in pts with sarcoma indications who exhausted standard of care therapy. Method: This is a phase 1b, open-label, dose-escalation, dose expansion study of Mipa (NCT05389462; EudraCT: 2021-00566-18). Pts received Mipa every 3 weeks (Q3W) at escalating dose levels, in a 3+3 dose escalation design. Results: As of 04 December 2023, 18 sarcoma patients (15 [83%], soft tissue sarcoma [STS] and 3 [17%] bone sarcoma), unselected for AXL expression, with a median number of 3 prior lines of therapy (1-10), were enrolled in 4 different dose cohorts: 7.5mg, 11mg, 13mg and 15mg. Reasons for treatment discontinuation were disease progression (10 pts [55.6%]), adverse events (3 pts [16.7%]) and consent withdrawal (2 pts [11.1%]). Treatment emergent adverse events (TEAE) were seen in 17 pts (94.4%). Most common TEAE (all grades and relationship [≥20%]) were palmar-plantar erythrodysesthesia syndrome (7 pts [38.9%]); anemia (6 pts [33.3%]); rash maculopapular (5 pts [27.8%]); cheilitis and constipation (4 pts each [22.2%]). TEAE≥grade 3 were seen in 9 pts (50%). Most common TEAE≥grade 3 (≥10%) were GGT increase (2 pts [11.1%]). Two dose limiting toxicities were seen: cheilitis grade 2 and grade 3 at 15mg and 13mg respectively. Cutaneous reactions, all grades, are more prominent in higher doses. Maximum tolerated dose (MTD) has not been established. In 17 sarcoma pts evaluable per RECISTv1.1, best overall response was partial response (PR) (2 pts [11.8%]), including a confirmed PR; stable disease (SD) (8 pts [47.1%]); progressive disease (7 pts [41.2%]). Tumor reductions was observed at 7.5mg, 11mg and 13mg. By week 12, 6/17 pts (35.3%) did not demonstrate PD . Initial IHC staining showed AXL expression in all sarcoma baseline biopsies tested so far. Initial pharmacokinetic (PK) data indicate exposures with moderate to marked interpatient variability; rapid clearance with no accumulation by Cycle 2. Updated biomarkers and PK data will be presented. Conclusion: The MTD was not established. Due to the incidence of TEAE judged related to Mipa and the preliminary activity observed, 15mg was selected as the highest dose to be tested in a fixed dose Q3W regimen. The study continues to enroll to further optimize Mipa dosing regimen and in dose escalation with gemcitabine. Citation Format: Brian Andrew Van Tine, Christopher T. Chen, Victor Moreno, Elizabeth J. Davis, Maria J. de Miguel, Antoine Italiano, Esma Saada-Bouzid, Mohammed Milhem, Claudia Valverde, Sant P. Chawla, Abdul Rafeh Naqash, Louise Carter, Robin Jones, Ilaria Conti, Joe Boni, Karin Havenith, Yvan LeBruchec, Serafino Pantano, Jean-Yves Blay. Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT059.

Hepatotoxicity as dose-limiting toxicity of the combination of bosutinib and atezolizumab in patients with chronic myeloid leukemia. Results of the ZEROLMC study.

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1-2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3-4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies.

Hepatotoxicity in patients with non-small cell lung cancer treated with sotorasib after prior immunotherapy: a comprehensive clinical and pharmacokinetic analysis

Sotorasib given after immunotherapy could put patients at increased risk of hepatotoxicity. Therefore, there is a need to gain insight into the potential correlation between anti-PD-(L)1 treatment, anti-PD-(L)1 concentrations, sotorasib concentrations, and the incidence of hepatotoxicity during sotorasib. Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker cohort study (NCT05221372). Plasma samples were collected prior and during sotorasib treatment for anti-PD-1 and sotorasib concentrations. ALT/AST/ALP/GGT increases were collected prospectively and graded according to CTCAEv5.0. Severe hepatotoxicity was defined as grade ≥3 ALT/AST/ALP/GGT increase. Of the 91 included patients, 80 (88%) received prior anti-PD-(L)1. Prior anti-PD-(L)1 and prior immune-related hepatotoxicity were associated with a higher incidence of severe hepatotoxicity (35% versus 0%, p=0.016 and 75% versus 31%, p=0.019, respectively). Patients with an interval of ≤6 weeks between anti-PD-(L)1 and sotorasib (n=18) had a significantly higher incidence of severe hepatotoxicity than those with a 6-12 week (n=24) and ≥12 week (n=38) interval (83% versus 33% versus 13%, respectively, p<0.0001). Sotorasib trough concentrations did not differ significantly between those with or without severe hepatotoxicity (106 versus 126ng/mL, p=0.16). Pembrolizumab concentrations were higher in those with severe hepatotoxicity versus those without (25.6 versus 6.1μg/mL, p<0.0001). In this preliminary prospective study, sotorasib after PD-(L)1 blockade was associated with severe hepatotoxicity, especially in patients with a short interval between treatments, prior immune-related hepatitis and higher anti-PD-1 plasma concentrations. Our results suggest a minimum interval of 6 weeks between anti-PD-(L)1 and sotorasib to minimize the risk of hepatotoxicity. None.

Association between serum γ-glutamyl transferase and advanced colorectal adenoma among inpatients: a case-control study.

Emerging evidence suggests a link between γ-glutamyl transferase (GGT) and various malignancies. However, the relationship between GGT and advanced colorectal adenoma, a critical precursor to colorectal cancer, remains unclear. This study aimed to elucidate this relationship. We conducted a single-center retrospective study from April 2015 to June 2022, enrolling 3534 inpatients including 525 cases and 3009 controls. Data were extracted from the electronic medical records, encompassing clinicodemographic characteristics, co-morbidities, and several blood biochemical indicators. Utilizing logistic regression and curve fitting, we explored the relationship between GGT and advanced colorectal adenoma. After adjustment for confounding factors, we found that for each 20-unit increase in GGT, the risk of advanced colorectal adenoma increased by 6% (OR= 1.06 [1.01-1.12]). Moreover, individuals with high GGT levels (≥50 U/L) had a 61% higher risk of advanced colorectal adenoma compared to those with low GGT levels (<50 U/L) (OR=1.61 [1.13-2.31]). Subgroup analysis demonstrated the robustness of these findings across subjects with different characteristics. High GGT levels were associated with higher odds of advanced colorectal adenoma. Our findings suggest that elevated GGT levels may serve as a potential diagnostic marker for advanced colorectal adenoma, providing new insights into its screening strategies.

Impact of MTHFR Polymorphisms C677T and A1298C in Acute Lymphoblastic Leukemia and Burkitt Lymphoma Patients Exposed to Methotrexate and Asparaginase

Background: Asparaginase (Asp) and high-dose methotrexate (HDMTX) are pivotal drugs in the treatment of aggressive hematological malignancies as acute lymphoblastic leukemia (ALL) and Burkitt lymphoma (BL). Asp and MTX present specific drug-related toxicities; for Asp, prothrombotic alteration of the coagulation profile, hepatobiliary and pancreatic toxicities, for MTX, renal, hepatobiliary, hematologic, gastro-intestinal and neuro- toxicity. The 5,10-methylenetetrahydrofolate reductase (MTHFR) is the enzyme involved in conversion of homocysteine into methionine. MTHFR most frequent single nucleotide polymorphisms C677T and A1298C are associated with reduced enzymatic activity up to 60%, that implies hyperhomocysteinemia and increased toxicity of MTX. Numerous studies have explored the relationship between C677T and A1298C polymorphisms of MTHFR and MTX toxicity and/or outcome in children ALL, but results are controversial. Nevertheless, it is common practice to reduce MTX dosage in adult patients in homozygosis. Aims: To explore the relationship between the MTHFR C677T and A1298C polymorphisms in homozygosis and development of MTX toxicity in a cohort of adult patients; furthermore, to evaluate the relationship with thrombotic risk in patients exposed to Asp. Materials and Methods: Data from consecutive adult onco-hematologic patients for whom MTHFR C677T and A1298C polymorphism analysis was available, treated with chemotherapeutic regimens containing HDMTX and/or Asp was retrospectively collected at a single center Italian institution. Adverse events (AEs) were graded according to CTCAE 5.0. Statistical analysis was performed with R language. The impact of MTHFR polymorphisms was evaluated by mean of a multivariate analysis adjusting Odds Ratio (OR) estimates for drug dosage and disease status. Results: Data from 78 patients, 57 affected by ALL, 3 by mixed phenotype leukemia (MPAL) and 18 by BL, was retrospectively collected. Overall, 13 (16.7%) of patients were 677TT and 8 (10.3%) were 1298CC. Patients with ALL/MPAL received mostly pediatric-inspired chemotherapy regimens (containing MTX 2.5 - 5 g/m 2 and Asp 1000-2000 UI/m 2), patients with BL received modified Rituxumab (R)-BFM protocol (MTX 1.5 g/m2); age/comorbidities-adjusted dose reduction was performed according to institutional guidelines. Median age for ALL and BL patients was 37.5 (IQR 27.0-54.2) and 33.5 (26.0-49.7) years, respectively; 54/78 (69.2%) of patients were male. Patients received a median of 3 (IQR 2-6) cycles containing HDMTX and/or Asp, for a total number of 299 cycles (94 containing Asp, 184 HDMTX and 24 both); 142 (48.0%) cycles were administered for active disease (AD), at diagnosis/relapse, and 154 (52.0%) in complete remission (CR). The impact of different dosages of Asp &amp;lt; 1000 UI/m 2 and ≥ 1000 UI/m² and of HDMTX &amp;lt;1.5 g/m 2 and ≥ 1.5 g/m 2 as well as the impact of disease status (AD vs CR) on AEs was explored. Concerning Asp therapy and thrombotic risk, 13 deep vein thrombosis (DVT) were observed, but no association between 677TT nor 1298CC was appreciated. AD status was strongly related to DVT (21.4% vs 1.8%, p 0.003). Coherently with the MTHFR-independent drug's mechanism of action, the polymorphisms had no impact on the development of Asp-related toxicities. Diversely, concerning HDMTX, in multivariate analysis, patients with 677TT were more likely to experience AST increase grade ≥3 (OR 10.55, 95%CI 1.34-83.09) while a protective role versus any grade GGT increase was observed (OR 0.09, 95%CI 0.01-0.71) (Figure 1A). Patients with 1298CC exhibited a superior incidence any grade AST/ALT increase, not confirmed for grade ≥3 (Figure 1B). No significant superior toxicity was observed in terms of renal, gastro-intestinal, hematologic AEs. The impact of a MTX dose reduction &amp;gt;25% of expected dose was then explored in a homogeneous population of 45 front-line pediatric-regimen treated ALL patients (35 received MTX dose ≥75% and 10 &amp;lt; 75%) and no impact in terms of OS and RFS was appreciated. Conclusions: The analysis ofMTHFR polymorphisms in adult patients is useful in identifying patients at higher risk for transaminitis, providing a biological parameter to integrate with hepatosteatosis, liver stiffness evaluation and BMI, for a comprehensive hepatic baseline evaluation. Patients at higher risk for hepatic complications may benefit from MTX dose reduction with no impact on disease outcome.

Does gamma-glutamyltransferase correlate with liver tumor burden in neuroendocrine tumors?

PurposeIn patients with neuroendocrine tumors (NETs) and liver metastases, increased gamma-glutamyltransferase (GGT) is commonly assumed as an indicator for progressive disease. To date, however, empirical data are lacking. This study aimed to investigate associations between GGT and liver tumor burden. In longitudinal analyses, associations of GGT and radiographic responses of liver metastases under therapy were investigated.MethodsThe cross-sectional sample consisted of 104 patients who were treated at the University Medical Center Hamburg-Eppendorf from 2008 to 2021 (mean age 62.3 ± 12.6 years, 58.7% male). GGT and liver imaging were identified in a time range of 3 months. Radiologic reassessments were performed to estimate liver tumor burden. In a separate longitudinal sample (n = 15), the course of GGT levels under chemotherapy was analyzed. Data were retrospectively analyzed with a univariate ANOVA, linear regression analyses, and Wilcoxon tests.ResultsOf 104 cross-sectionally analyzed patients, 54 (51.9%) showed a GGT elevation. GGT levels and liver tumor burden were positively correlated (p < 0.001), independently from age, gender, primary tumor location, grading, and cholestasis. Notably, GGT increase was associated with a liver tumor burden of >50%. In the longitudinal sample, 10 of 11 patients with progressive disease showed increasing GGT, whereas 4 of 4 patients with regressive disease showed declining GGT.ConclusionOur findings indicate that GGT is associated with liver tumor burden. Over the course of therapy, GGT appears to change in line with radiographic responses. Further longitudinal studies with larger sample sizes are required to define GGT as a reliable marker for tumor response.

A phase I study of KL590586, a next-generation selective RET inhibitor, in patients with RET-altered solid tumors.

3007 Background: KL590586 (A400/EP0031) is a potent next-generation selective RET inhibitor (SRI) with activity against acquired resistance mutations to first-generation SRIs, and brain metastases (mets). Here we present preliminary data of the phase Ⅰ part from a phase I/II study (KL400-I/II-01, NCT05265091) in patients (pts) with RET-altered advanced tumors to define safety, pharmacokinetics (PK) and efficacy. Methods: The phase Ⅰ of KL400-I/Ⅱ-01 consisted of dose-escalation (Bayesian Optimal Interval design) and dose-expansion. Primary endpoints were to determine the maximum tolerated dose (MTD) and/or Recommended Phase II Dose. Secondary endpoints included safety, PK, objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) as per RECIST 1.1. Results: As of Dec. 30, 2022, 87 pts with RET-altered tumors were treated at 6 doses levels (10 to 120 mg QD). No DLTs were observed, and MTD was not reached. Incidence of treatment-related adverse events (TRAEs, any grade) was 93.1% (81/87), most (74.7%) were grade 1-2, reversible and included (&gt;25%): AST increase (50.6%), ALT increase (48.3%), creatinine increase (33.3%), bilirubin increase (32.2%), constipation (32.2%) and headache (31%). 24.1% of pts had grade ≥3 TRAEs, the most common (occurring in &gt;2% of pts) were ALP increase (2.3%), GGT increase (2.3%), ileus (2.3%). TRAEs led to dose reduction or treatment discontinuation in 4.6% and 6.9% of pts, respectively. Hypertension, QT interval prolongation, platelets decrease and lymphocytes decrease (leading to 1st gen SRI dose delays and modifications frequently) were rare (&lt;5%) and low-grade. The exposure increased dose-dependently and the mean half-life was found to be 34.1-99.8 h. Clinical responses were observed from 40mg onwards. 69 pts treated at the 40-120mg dose levels (57 NSCLC, 10 MTC, 1 pancreatic cancer, 1 ovarian cancer) were evaluable for efficacy analysis, ORR was 64% (NSCLC, MTC and pancreatic cancer). Most pts (58/69) remained on treatment, with the longest &gt;11 months. The ORR in pts with systemic pretreated NSCLC (median prior treatment: 2, range 1-9, 28% pretreated with anti-PD1/PD-L1 therapy) was 63%(20/32, 1 CR), DCR 91% with median DoR not reached. 9 pts received prior 1st gen SRI, 7 with tumor shrinkage of -10% to -69%, with 3 PR and 4 SD. 11 pts with brain mets (without radiotherapy):4/5 with measurable brain disease had 100%, 100%, 80%, and 47% shrinkage. Overall CNS DCR was 100%.The ORR in treatment naïve NSCLC was 76% (19/25, 1 CR), DCR 92% and median DoR not reached. 3/4 pts with brain mets (without radiotherapy) had complete or partial disappearance of baseline brain lesions. Conclusions: KL590586 was well-tolerated, and associated with robust clinical activity in RET-altered tumors regardless of tumor type, including NSCLC pts with resistance to1st gen SRIs and with CNS mets. Pivotal studies are planned. Clinical trial information: NCT05265091 .

Does High-Intensity Exercise Cause Acute Liver Injury in Patients with Fontan Circulation? A Prospective Pilot Study.

The Fontan procedure results in chronic hepatic congestion and Fontan-associated liver disease (FALD) characterized by progressive liver fibrosis and cirrhosis. Exercise is recommended in this population, but may accelerate the progression of FALD from abrupt elevations in central venous pressure. The aim of this study was to assess if acute liver injury occurs after high-intensity exercise in patients with Fontan physiology. Ten patients were enrolled. Nine had normal systolic ventricular function and one had an ejection fraction < 40%. During cardiopulmonary exercise testing, patients had near-infrared spectroscopy (NIRS) to measure oxygen saturation of multiple organs, including the liver, and underwent pre- and post-exercise testing with liver elastography, laboratory markers, and cytokines to assess liver injury. The hepatic and renal NIRS showed a statistically significant decrease in oxygenation during exercise, and the hepatic NIRS had the slowest recovery compared to renal, cerebral, and peripheral muscle NIRS. A clinically significant increase in shear wave velocity occurred after exercise testing only in the one patient with systolic dysfunction. There was a statistically significant, albeit trivial, increase in ALT and GGT after exercise. Fibrogenic cytokines traditionally associated with FALD did not increase significantly in our cohort; however, pro-inflammatory cytokines that predispose to fibrogenesis did significantly rise during exercise. Although patients with Fontan circulation demonstrated a significant reduction in hepatic tissue oxygenation based on NIRS saturations during exercise, there was no clinical evidence of acute increase in liver congestion or acute liver injury following high-intensity exercise.

Ameliorative effect of resveratrol against cymoxanil-mancozeb induced toxicity in rats.

This study was conducted to evaluate the cymoxanil-mancozeb (CM) toxicity and investigate the ameliorative effect of resveratrol (Res) against cymoxanil-mancozeb toxicity. Forty rats were divided into four groups; the first group was used as a control group, the second group was exposed to Res only at a dose of 20 mg/kg body weight for 4 weeks, and the third group was administered CM only at a dose of 799 mg/kg body weight for 4 weeks, The fourth group was co-treated with Res+CM for 4 weeks. Blood samples were analyzed for hematological and biochemical parameters. The comet assay was done on liver and blood specimens and histopathological examinations of the liver and intestine. The results demonstrated that CM exposure caused a significant increase in WBCs, lymphocytes, granulocytes, monocytes ALT, AST, ALP, and GGT, and total cholesterol and triglycerides levels accompanied by a decrease in HGB, HCT, RBCs and MCV, MCH, MCHC, HDL and glucose levels with no significant DNA damage in liver and blood. CM mixture induced severe pathological changes in small intestine and liver. Co-treatment of Res with CM improved hematological picture, lipid and glucose profiles also liver enzymes and decreased changes in the architecture of the liver and intestine.

HEPATOTOXICITY EFFECTS OF PARACETAMOL-DENIK CLEANSER® CO-ADMINISTRATION

Aim and Objective: The concurrent use of herbal products with orthodox medicine is on the rise with the risk of herb-drug interaction that could be beneficial or harmful to the body. Paracetamol (acetaminophen) is an anti-pyretic and analgesic drug metabolized by CYP2E1 to give the major hepatotoxin, N-acetyl-p-benzoquinone imine (NAPQI). Denik cleanserâ is an oral herbal preparation from plants part of Occimum grattissimum, Colocynthis citrullus, Khaya ivorensi. The aim of this study was to evaluate the hepatotoxic effects triggered by Denikâ and paracetamol co-administration in rats. The study sought to mimic conventional usage of Denik cleanserâ followed by ingestion of paracetamol, a likely scenario given the popularity of both compounds. Method: Twenty animals were randomly assigned to four groups, the first group (control) received 0.3 mL distilled water, 2nd group received paracetamol 100 mg/kg, 3rd group received Denik cleanserâ2 mL/kg while the 4th group received both paracetamol and Denik cleanserâ at 100 mg/kg and 2 mL/kg daily for 3 days after which biochemical and histological analysis were carried out. Results: From histological analysis revealed that rats that received Denikâ-only and Denikâ/paracetamol (concomitantly) showed markedly distorted liver architecture compared to control indicating toxicity. Similarly, the biochemical analysis results showed a significant (p&lt;0.05) increase in AST and ALT for the Denikâ/paracetamol group compared to the control group indicating a hepatotoxic event. A non-significant increase in ALP and GGT were also observed in the Denik cleanserâ + paracetamol group. Enhanced metabolism of paracetamol by Denik cleanserâ to NAPQI (hepatotoxic metabolite) is indicated as possible mechanism. Conclusion: The results of this study demonstrated the in vivo potential for a herb/drug interaction involving paracetamol and Denik cleanserâ resulting in liver injury.Therefore, caution is strongly advised against its casual, non-medically supervised usage. Peer Review History: Received: 3 November 2022; Revised: 7 December; Accepted: 9 January 2023, Available online: 15 January 2023 Academic Editor: Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Sangeetha Arullappan, Universiti Tunku Abdul Rahman, Malaysia, sangeetha@utar.edu.my Prof. Hüsniye Kayalar, Ege University, Turkey, husniyekayalar@gmail.com Similar Articles: CO-ADMINISTRATION OF GOKO HERBAL CLEANSER AND PARACETAMOL: A HERB-DRUG INTERACTION STUDY IN-VITRO ANTIOXIDANT, LIPID PEROXIDATION INHIBITION AND LIPID PROFILE MODULATORY ACTIVITIES OF HB CLEANSER®BITTERS IN WISTAR RATS

γ-Glutamyl transferase as a marker of oxidative stress in pre and post-menopausal women

Introduction: Menopause is a physiologic process in women representing complete cessation of menstruation and gradual decrease of estrogen secretion. The antioxidant substances present in the body play a role in combating the oxidative stress in menopause. Since, the enzyme γ-glutamyl transferase plays an important role in the metabolism of the endogenous antioxidant reduced glutathione (GSH), it can reflect the antioxidant ability in vivo. Aim: The present study was conducted to investigate γ-glutamyl transferase as a possible marker of total antioxidant capacity (TAC) of plasma. Materials and Method: The study included 50 female volunteers, selected from medical & paramedical staff, and healthy attendants of patients as per inclusion and exclusion criteria and divided into 2 groups. Group I: Premenopausal women (n = 25); Group II: Postmenopausal women (n = 25). Venous blood samples were collected using aseptic techniques in plain vials for estimating estradiol hormone and Gamma GT and whole blood was collected in EDTA vials for the estimation of Ferric reducing ability of plasma (FRAP) which is a marker of antioxidant capacity. The data collected were analyzed using unpaired “t”-test for evaluating the level of oxidative stress in pre and post menopausal women and the variations in the levels of gamma GT in the two groups. The results were expressed as Mean ± Standard Deviation (SD). Results and Conclusion: Depressed estrogen synthesis in postmenopausal women enhanced oxidative stress and lead to deficit of total antioxidant capacity of plasma. A significant increase in serum GGT in the post-menopausal group relative to the pre-menopausal group was found which was to compensate and correct the reduced glutathione levels by increasing its biosynthesis. Thus, GGT can be used as a marker of total antioxidant capacity of plasma and oxidative stress.

PS-B06-1: LOW DOSE SPIRONOLACTONE ALLEVIATES CARDIO-RENAL DISORDER IN EXPERIMENTAL PCOS RAT MODEL BY REDUCTION OF BAX/INFLAMMASOME IMMUNOHISTOCHEMICAL EXPRESSION

Objectives: Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorders among women of reproductive age. It has been associated with cardio-renal disturbance. In fact, cardiovascular disease and chronic kidney disease remain the major cause of disease burden worldwide. Mineralocorticoid receptor activation has been demonstrated in various pathological conditions, including cardiovascular and renal dysfunction. Spironolactone is a mineralocorticoid receptor blocker that regulates metabolic-related functions. However, the impact of spironolactone (LSPL), on PCOS associated cardio-renal disorder is unknown. Therefore, the present study hypothesized that LSPL would ameliorate cardio-renal disorders in experimental PCOS animal. Materials and Methods: Female Wistar rats that were eight-week-old were allotted into three groups. The control group received vehicle (distilled water; p.o.), LET-treated group designated as PCOS group received letrozole (1 mg/kg; p.o.), while PCOS+LSPL received a combination of letrozole and LSPL (0.25 mg/kg, p.o.). The treatment was done once daily for 21 days uninterrupted. Results: The experimental PCOS rats were characterized with insulin resistance as well as, elevated testosterone and LH/FSH with a significant increase in cardiac and renal lipid profile, oxidative stress, inflammatory biomarkers (NF-kappaB and TNF-alpha), LDH and lactate content, and decrease in cardiac and renal antioxidant system (GPX and GSH) compared with the control rats. There was also a significant increase in cardiac GGT but not renal GGT activity in PCOS animals. In addition, immunohistochemical assessment of cardiac and renal tissue showed severe expression of inflammasome and moderate expression of BAX in animals with PCOS. Nevertheless, these perturbations were attenuated following the administration of LSPL. Conclusion: Collectively, the present results suggests that low dose spironolactone attenuates PCOS-associated cardio-renal disorders by reduction of oxidative stress and BAX/Inflammasome expression.

Influence of lactation stages on haematological and biochemical parameters in blood of Lacaune dairy sheep

The research objective was to determine haematological and biochemical parameters in blood of 30 Lacaune dairy sheep during different stages of lactation (early: 60th, medium: 120th and late: 180th days). The sheep were on average 4 years old, in 3rd lactation. Haematological parameters were determined in whole blood (white blood cell (WBC), red blood cell (RBC), haemoglobin (HGB) concentration, haematocrit (HCT) value, mean corpuscular volume (MCV), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC) and platelet (PLT) count), and a blood smear was used for determination of differential blood cell count. Determined biochemical parameters in blood serum were: concentration of minerals (Ca, P-inorganic, Mg and Fe), concentration of total proteins (TP), albumin (ALB), globulins (GLOB), urea, glucose (GUK), cholesterol (CHOL), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TGC), beta-hydroxybutyrate (BHB) and non-esterified fatty acids (NEFA), enzyme activities (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), creatine kinase (CK), activity of glutathione peroxidase (GPx) and total superoxide dismutase (SOD). With progression of lactation stages, sheep blood tests proved significant increase in WBC, RBC, HGB, HCT, monocytes, Fe, urea, TP, ALB, CHOL, HDL, LDL, BHB, AST, GGT and ALT as well as a decrease in lymphocytes, Mg, GUK and SOD. Determined changes in haematological and biochemical blood parameters of Lacaune dairy sheep during different lactation stages proved good quality nutrition of sheep and indicate the need to include this dairy breed/genotype in prospective schemes for definition of referential values for these indicators in sheep.

S3020 Hepatitis From a Sexually Transmitted Bacterial Infection

Introduction: Syphilis is a multisystemic, sexually transmitted infection (STI) that is caused by the spirochete Treponema pallidum. Hepatic involvement is rare. We present a patient who was diagnosed with syphilitic hepatitis (SH). Case Description/Methods: A 54-year-old male presented to the hospital with one week of sharp upper abdominal pain, jaundice, poor appetite, and a 25-lb. weight loss. He also reported multiple sexual partners and a rash that developed 2 months ago. Vital signs were within normal range. Physical examination revealed scleral icterus, a soft, non-tender abdomen, a plaque-like penile lesion and small, circular lesions on his palms and soles of feet. Laboratory studies revealed aspartate aminotransferase (AST) 164 U/L, alanine aminotransferase (ALT) 207 U/L, alkaline phosphatase (ALP) 1395 U/L, total bilirubin 5.6 mg/dL, gamma-glutamyl transferase 782 U/L. Hepatitis panel, acetaminophen and alcohol levels were negative. Chronic liver disease work-up was unremarkable. Treponemal antibody and rapid plasma reagin test were both positive. HIV test and cerebrospinal fluid venereal disease research laboratory (VDRL) test were negative. Abdominal ultrasound and CT scan of the abdomen were unremarkable. Magnetic resonance cholangiopancreatography was notable for hepatomegaly and hepatitis. Patient received 1 dose of penicillin G 2.4 million units intramuscularly with remarkable improvement in his symptoms and liver function tests. He was discharged home with close follow-up with gastroenterology and infectious disease. Discussion: SH occurs in 0.2-9.7% of patients with syphilis and is most commonly seen in the primary and secondary disease stages. Clinical manifestations include a maculopapular rash (involving the trunk, palms and/or soles of feet), fatigue, poor appetite, hepatomegaly and icterus. Liver function tests (LFTs) may reveal a marked increase in ALP and GGT in comparison to ALT and AST. SH is diagnosed with abnormal LFTs, serological evidence of syphilis, exclusion of other liver diseases and LFTs returning to normal after antibiotic therapy as in our patient. The histological features of SH include inflammatory infiltration of the bile duct and hepatic granulomas. Spirochetes are often difficult to identify in liver tissue. Penicillin is the mainstay of treatment. Clinicians should consider syphilitic hepatitis in a patient with abnormal LFTs (especially ALP) and a rash involving the palms and soles of feet in the appropriate clinical context.

Encorafenib plus binimetinib in patients with locally advanced, unresectable, or metastatic BRAFV600-mutant melanoma: Updated data from the multicenter, multinational, prospective, non-interventional longitudinal study BERINGMELANOMA.

9526 Background: For the treatment of advanced BRAFV600-mutated melanoma, targeted BRAF/MEK-inhibition is a standard of care. Encorafenib + binimetinib (EB) were approved 2018 in the EU and 2019 in Switzerland, based on positive results from COLUMBUS (NCT01909453), median progression-free survival (PFS) 14.9 mo (5-yr PFS: 23%), overall survival (OS) 33.6 mo (5-yr OS: 35%). As data from controlled trials are based on selected populations, BERINGMELANOMA investigates EB-use under real-world conditions in a broader population. Methods: BERINGMELANOMA (NCT04045691) is an ongoing, multi-national, prospective, longitudinal, non-interventional study. It analyzes the effectiveness (prim. endpoint: 1-yr PFS-rate), QoL and safety of EB-therapy in the unresectable advanced or metastatic setting under real-world conditions, focusing on the first- (1L) and second-line setting including an evaluation of the impact of prognostic factors. The project aims to enroll up to 750 patients (pts) in a total of 80 German, Austrian and Swiss sites (study duration: 8 yrs). So far (10/2019-01/2022), 280 pts have been included. Pts with prior BRAF-/MEK-inhibition (except adjuvant use completed &gt; 6 mo) and &gt; 1 prior therapy line with CPI in the palliative setting were excluded (adjuvant CPI allowed). Results: Here we present the 2nd planned interim snapshot based on the initial 200 enrolled pts (186 treated / 182 evaluable; median FU: 14.2 mo). This analysis set shows a median age of 60.5 yrs (range 20.0-89.0), 45% of pts were female. 87% presented with distant metastases (brain: 30%), with an involvement of ≥3 organ systems in 51% and elevated LDH in 43%. 54% of pts underwent any prior systemic therapy (adjuvant: 30%; 1L CPI palliative: 24%, mainly with ipilimumab + nivolumab). EB was mainly administered in the 1L-setting (60%). Main reasons for EB-selection were: efficacy (44%), physician's preference (34%), QoL (17%). Median estimated EB treatment duration was 11.6 mo (95%CI 8.8-18.6), median relative dose intensity for both drugs: 100%, main reasons EB-discontinuation: PD (55%), toxicity (16%). Treatment adaptations were required in 40% of pts (interruption E 26%, B 29%), toxicity as main reason (E 26%, B 29%). Adverse events were reported in 86% of pts (grade 3/4: 34%), mainly (≥10%, all grades): diarrhea, nausea, fatigue (each 17%), CK increase (16%), GGT increase (11%). No fatal toxicities were observed. Conclusions: This 2nd interim snapshot shows an investigation of EB in a real-world population with advanced disease. Despite the poorer prognosis configuration as compared to the pivotal study, the observed tolerability profile is largely consistent with data derived from COLUMBUS without any new safety signals. The 3rd interim snapshot will be performed after enrollment of 300 pts.

Debating capabilities of biochemical markers of liver function in patients with alcoholic liver cirrhosis

Introduction. The diagnosis of alcohol-related liver disease is limited by the lack of a tool to reliably identify whether the present deterioration in the patient’s condition is due to alcohol consumption or other causes.Purpose. to conduct a comparative assessment of the clinical and diagnostic significance of liver function biochemical indicators (AST, ALT, GGT, ALP) and their calculated derivatives (AST/ALT, GGT/ALP, GGT/GGTn, ALP/ALPn) as markers of alcohol consumption in patients with alcoholic liver cirrhosis.Material and methods. The observational study included 112 men over 18 years of age with alcohol-related liver cirrhosis. The patients were assessed the severity of liver cirrhosis according to the Child-Pugh scale, performed general and biochemical blood tests, coagulation test, assessment of the fact of alcohol consumption by the level of phosphatidylethanol. An analysis was made of the relationship between alcohol consumption and changes in laboratory parameters of liver function, with the determination of their sensitivity and specificity.Results. Patients with Child-Pugh B cirrhosis who consumed alcohol on phosphatidylethanol had higher levels of plasma albumin, GGT, and lower values of creatinine, direct and total bilirubin, urea, and aPTT compared with patients who did not drink alcohol (p &lt; 0.05). Alcohol-drinking patients with class C cirrhosis have higher ALT levels compared with abstinent patients with the same severity of cirrhosis (p &lt; 0.05). The relationship between the fact of alcohol consumption, determined by the level of phosphatidylethanol, and the ratio of GGT of patients to the normal GGT value, as well as between the ratio of GGT to alkaline phosphatase and the degree of increase in GGT, turned out to be statistically significant. To assess the fact of alcohol consumption, the level of serum GGT &gt; 65 IU/ l (75.5%) has the highest sensitivity, the highest specificity is the ratio of the patient’s GGT to the normal value of GGT &gt; 2 (82.9%).Conclusion. Compared with the known 100% sensitivity and &gt; 92% specificity of Peth as a alcohol biomarker, among the biochemical indicators of liver function and their calculated derivatives, GGT &gt; 65 IU/l have the greatest sensitivity or specificity (respectively, 75.5% and 65%) and GGTnorm. &gt; 2 (37.7% and 82.9%, respectively), which makes it possible to use the totality of these parameters as an indicator of the continued impact on the patient of the main etiological factor of alcohol-related liver cirrhosis in the routine practice of most medical organizations of the Russian Federation.