Brucellosis-associated hepatitis.

AIM: Brucellosis is a zoonotic infection that can affect almost every organ. A mild elevation of aminotransferase levels is usually observed in liver involvement. However, the development of clinical hepatitis is rare. In this study, we aimed to present the hospitalized cases with brucellosis hepatitis in our clinic in a 13-year period. METHODS: A hundred and three patients with significant hepatobiliary involvement, diagnosed by microbiological analysis, were included in the study. For the presence of hepatitis, it was required that the aminotransferases must be ≥ 5 times more than the upper limit and/or the total bilirubin level must be ≥ 2 mg/dl and/or the local hepatic lesion must be demonstrated. RESULTS: Of the cases, 35.9%, 17.5%, and 46.6% had clinical hepatitis, cholestatic hepatitis, and both clinical and cholestatic hepatitis, respectively. The most frequent symptom was fever (85.4%) while the most preferred treatment options were combinations containing aminoglycosides. It was observed that the mean time-interval to decrease to normal values of ALT, AST, and bilirubin values was 15.2 ± 7.8 days while the patients having their treatment regimens. In our study, which focused on liver involvement, it was found that a chronic liver disease did not develop in any of the cases. CONCLUSION: Our study showed that, even in the presence of hepatitis, clinical response and laboratory improvement were high with appropriate treatment. It was observed that the improvement in aminotransferases and total bilirubin values delayed in the cases with blood culture positivity, secondary organ involvement, and alanine aminotransferase/aspartate aminotransferase > 1.

Elevated liver transaminases among patients with psychiatric disorders.

Hepatocyte injury is assessed by serum aspartate transaminase and alanine transaminase estimation. In psychiatric populations, antipsychotic drugs (AD) are culprit in hepatic dysfunction. To assess transaminitis among psychiatric patients treated by AD. This cross-sectional study was conducted in Zagazig University Hospitals in Egypt, from December 2022 to February 2023. A total of 135 adult patients aged ≥ 18 years, were diagnosed with psychiatric disorders after exclusion of patients receiving any hepatotoxic drugs, viral hepatitis, having chronic liver or kidney diseases, diabetes mellitus, mental retardation, and pregnant females. Among the 135 patients, 104 (77.0%) were males. Their age was 32 ±â€…9, The most popular used class of AD was atypical AD 84 (62.2%). The overall incidence of transaminitis among patients receiving AD was 23/135 (17.04%) of patients; 13 (56.5%) were on atypical AD compared to 10 (43.5%) patients receiving combined AD, without any statistically significant difference. The use of AD in patients with psychiatric disorders is potentially safe with minimal transaminitis (

A retrospective study to investigate the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis with ulcerative colitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis has a poor prognosis and can be accompanied by ulcerative colitis. Infection control is essential, so immunosuppressive drugs should ideally be preferably. Granulocyte and monocyte adsorptive apheresis does not suppress the immune system and is used to treat ulcerative colitis. Therefore, this study investigated the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis and ulcerative colitis. METHODS: We retrospectively evaluated data from patients with primary sclerosing cholangitis with ulcerative colitis who visited our hospital from April 2000 to December 2022 and underwent granulocyte and monocyte adsorptive apheresis (n = 10, number of treatment cycles = 15). Study endpoints were remission induction rate and safety, assessed as changes in liver functions and adverse events. RESULTS: Seven of the 10 patients were male. The median (min-max) age was 23 (18-77) years. The most common disease type was right-dominant pancolitis. Remission occurred after 86.6% of cycles (13/15). Serum alkaline phosphatase and Aspartate transaminase were significantly lower after treatment (P = .0124, P = .002), and no negative effects on liver function were seen. The only adverse events were headache (n = 1) and decreased blood pressure (n = 1). CONCLUSIONS: Granulocyte and monocyte adsorptive apheresis has high efficacy for intestinal lesions and improves alkaline phosphatase and aspartate transaminase levels (high levels are a poor prognosis factor). It appears to be a treatment option in patients with primary sclerosing cholangitis associated with ulcerative colitis.

Efficacy of finerenone in patients with type 2 diabetes, chronic kidney disease and altered markers of liver steatosis and fibrosis: A FIDELITY subgroup analysis.

AIM: Investigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis. MATERIALS AND METHODS: Post hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis-4 (FIB-4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma-glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure. RESULTS: ALT, aspartate aminotransferase and gamma-glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB-4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB-4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction = .01, .13 and .03, respectively). CONCLUSIONS: Finerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB-4 scores who were at high risk of developing cardiovascular complications.

Noninvasive diagnosis of significant liver inflammation in patients with chronic hepatitis B in the indeterminate phase.

The presence of significant liver inflammation is an important indication for antiviral treatment in patients with chronic hepatitis B (CHB) in the indeterminate phase. We aimed to establish a non-invasive nomogram to predict significant liver inflammation in these patients. A total of 195 CHB patients in the indeterminate phase were randomly split into training and validation sets. The least absolute shrinkage and selection operator and logistic regression were applied to identify risk factors and establish a predictive model. A calibration curve, decision curve analysis (DCA), and receiver operating characteristic (ROC) curve were applied to assess the performance of the nomogram. The median age was 42.0 y and 59.5% of the patients were male. Alkaline phosphatase, γ-glutamyl transpeptidase, and prothrombin time were independent predictors for significant liver inflammation and selected to establish the AGP-nomogram. The calibration plot demonstrated that the predicted results matched the actual values. The DCA showed a high net benefit when the threshold probability was 25-83% in the training set and 31-100% in the validation set. The areas under ROC curves of AGP-nomogram in predicting significant inflammation were significantly higher than ALT in the training set (0.744 vs. 0.642, P = 0.049) and validation set (0.766 vs. 0.660, P = 0.047). The ability of AGP-nomogram in predicting advanced inflammation was also superior to ALT. The AGP-nomogram can accurately identify significant inflammation in CHB patients in the indeterminate phase, and its application may reduce the need for liver biopsy and help identify candidates for antiviral treatment.Abbreviations: AASLD: American Association for the Study of Liver Diseases; ALB: albumin; ALP: alkaline phosphatase; ALT: alanine aminotransferase; APRI: aspartate aminotransferase-to-platelet ratio index; AST: aspartate aminotransferase; AUROC: area under the receiver operating characteristic curve; CHB: chronic hepatitis B; CI: confidence interval; DCA: decision curve analysis; FIB-4: fibrosis index based on the four factors; GLB: globulin; GGT: γ-glutamyl transpeptidase; HBcAb: hepatitis B core antibody; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HIV: human immunodeficiency virus; INR: international-normalized ratio; IQR: interquartile range; LASSO: least absolute shrinkage and selection operator; LB: liver biopsy; LR: Likelihood ratio; NAFLD: non-alcoholic fatty liver disease; NPV: negative predictive value; PLT: platelets; PPV: positive predictive value; PT: prothrombin time; ROC: receiver operating characteristic; TB: total bilirubin; TE: transient elastography; ULN: upper limit of normal.

Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-ß receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. CONCLUSIONS: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03710265.

A phase Ib study of camrelizumab in combination with apatinib and fuzuloparib in patients with recurrent or metastatic triple-negative breast cancer.

BACKGROUND: Strategies to improve activity of immune checkpoint inhibitors for triple-negative breast cancer (TNBC) are needed. Preclinical studies showed that antiangiogenic agents and poly (ADP-ribose) polymerase (PARP) inhibitors might sensitize tumors to immunotherapy. Here, we investigated the tolerability, safety, and preliminary antitumor activity of camrelizumab, an anti-PD-1 antibody, in combination with apatinib, a vascular endothelial growth factor receptor-2 inhibitor, and fuzuloparib, a PARP inhibitor, in patients with recurrent or metastatic TNBC. METHODS: This phase Ib study included a dose-finding part and a dose-expansion part. In the dose-finding part, a 3 + 3 dose escalation scheme was introduced. Patients were given camrelizumab (200 mg every 2 weeks) plus apatinib (375 mg or 500 mg once daily) and fuzuloparib (starting dose 100 mg twice daily) every 28-day cycle. After evaluation of the tolerability and safety of the dosing regimens, a clinical recommended dose was determined for the dose-expansion part. The primary endpoint was dose-limiting toxicity (DLT). RESULTS: A total of 32 patients were enrolled. Three patients received camrelizumab 200 mg + apatinib 375 mg + fuzuloparib 100 mg, and 29 received camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg (clinical recommended dose). No DLTs were observed in either group. The most common grade ≥ 3 treatment-related adverse events were decreased white blood cell count (20.7%), hypertension (13.8%), decreased neutrophil count (10.3%), and increased aspartate aminotransferase (10.3%). Two patients discontinued study treatment due to immune-mediated hepatitis (n = 1) and anemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase, and increased γ-glutamyltransferase (n = 1). One patient died of unknown cause. Two (6.9% [95% CI, 0.9-22.8]) of 29 patients with camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg had objective response. The disease control rate was 62.1% (95% CI, 42.3-79.3). The median progression-free survival was 5.2 months (95% CI, 3.6-7.3), and the 12-month overall survival rate was 64.2% (95% CI, 19.0-88.8). CONCLUSIONS: Combination of camrelizumab plus apatinib and fuzuloparib showed manageable safety profile and preliminary antitumor activity in patients with recurrent or metastatic TNBC. TRIAL REGISTRATION: ClinicalTrials.gov NCT03945604 (May 10, 2019).

Investigating the Relationship between Knowledge and Hepatotoxic Effects with Medication Adherence of TB Patients in Banyumas Regency, Indonesia.

Tuberculosis (TB) still remains the burden in Indonesia. One of the factors that may influence the treatment success of TB is patient's adherence. However, the hepatotoxicity of the TB medicine may decrease the patient's adherence. Our study's aim is to investigate the relationship between the patient's knowledge and the hepatotoxicity with medication adherence of TB patients in Banyumas Regency. This study was conducted at one Community Lung Health Center and two hospitals in Banyumas Regency, Purwokerto, Center of Java, Indonesia. The respondents were 91 TB patients with hepatotoxicity characterized by an increased aspartate transaminase (AST) and alanine aminotransferase (ALT). The level of the patients' knowledge about the hepatotoxicity effect was determined using a questionnaire. The patients' adherence was determined using the Medication Adherence Rating Scale -5 (MARS) questionnaire and pill count methods. Most of the patients were male (53.8%), the age was in the range of 18-29 years old (3.5%), they have no smoking history (59.3%), and their last education majorly was senior high school (46.2%). Most TB patients had poor knowledge (47.3%) and the hepatotoxic effect often appeared in grade 1 (61.5%). The TB patients with a good and moderate level of knowledge were 17.6% and 35.2%, respectively. The TB patients with moderate and severe hepatotoxicity were 39.4% and 1.1%, respectively. The measurement of the level of respondents' adherence using MARS-5 showed that 51.6% of patients had good adherence. We determined the rest of the drug-using pill count method, which resulted in 62.6% of patients adhering to taking antituberculosis drugs. TB patients with a sufficient knowledge and those with mild hepatotoxicity show the higher adherence (p < 0.001). There is a significant relationship between a high level of the patient's knowledge about hepatotoxicity effect, less severity of the hepatotoxic effect, and increased patient adherence in taking the medication.

Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy.

Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin-lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1ß (interleukin-1ß), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1ß, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH4CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.

Sinomenine pretreatment alleviates hepatic ischemia/reperfusion injury through activating Nrf-2/HO-1 pathway.

INTRODUCTION: Ischemia-reperfusion (IR) injury is induced by an interrupted blood flow and succeeding blood restoration, which is common in the operation of liver transplantation. Serious IR injury is a major reason leading to transplant failure. Hepatic IR is featured by excessive inflammatory response, oxidative stress, and apoptosis. Sinomenine (SIN) is derived from the herb Sinomeniumacutum and shows properties of anti-inflammation and antiapoptosis in multiple IR-induced organ injuries. However, the effect of SIN in hepatic IR has not been investigated. METHODS: This study aims to investigate impacts of SIN on hepatic IR and the involved signaling pathway. An in vivo rat model of syngeneic orthotopic liver transplantation was constructed to induce the hepatic IR injury. RESULTS: Results showed that SIN pretreatment provided a significant prevention against IR-induced hepatic injury as manifested by the downregulated activities of serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, the alleviatedoxidative stress as shown by increased activities of serum superoxide dismutase and glutathione peroxidase, and decreased serum level of malondialdehyde, the suppressed inflammatory responses as shown by downregulated serum tumor necrosis factor-α, interleukin (IL)-6, IL-8 levels, and upregulated IL-10 level, as well as attenuated apoptosis as shown by decreased protein expression of cleaved caspase-3 and -9. In line with these results, SIN pretreatment also alleviatedthe hepatic histopathological changes in IR rats and induced Nrf-2/HO-1 activation. The use of brusatol, a selective inhibitor for Nrf-2, effectively reversed SIN-induced above effects. CONCLUSIONS: Altogether, our results demonstrate that SIN might be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.

Iron Chelators, Such as Deferasirox, When Combined With Hydroxyurea, Provide an Additional Benefit of Iron Chelation in Patients Receiving Chronic Transfusion Therapy.

Red blood cell (RBC) transfusions have been established as one of the primary therapies in treating sickle cell anemia. However, they are not free of side effects, with overloading the body with iron being one of the most important. Iron chelation therapy greatly reduces the iron load of the body. In addition, hydroxyurea (HU), an oral chemotherapeutic drug also has a significant role in the treatment of the disease with beneficial effects on many of the clinical problems that arise, mainly in reducing painful crises. The aim of this study was to investigate the effect of synergistic transfusion therapy and HU on the response to deferasirox (DFX) chelation therapy. Eighteen patients with sickle cell disease were divided into two groups based on their treatment, either with simple transfusions and DFX or with a combination of transfusion therapy, DFX and HU, and were evaluated with magnetic resonance imaging (MRI) for liver iron concentration (LIC) and biochemistry. All patients completed the study. The results of the study showed improvement in serum ferritin (FER) levels and LIC after 12 months of therapy in both groups, especially in the group receiving the combination therapy with HU. In addition, there was a noteworthy improvement in serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and lactate dehydrogenase (LDH) levels with serum creatinine (Cr) levels remaining stable during the study in both groups. Hydroxyurea, when combined with iron chelators such as DFX, provides an additional benefit of iron chelation in patients receiving chronic transfusion therapy.

Preventive Effect and Mechanism of Anthocyanins from Aronia Melanocarpa Elliot on Hepatic Fibrosis Through TGF-ß/Smad Signaling Pathway.

In order to explore the effect and mechanism of Aornia mealnocarpa Elliot anthocyanins (AMA) at the cellular level on hepatic fibrosis (HF), molecular docking, RT-PCR and Western Blotting were used to explore the molecular mechanism and the effects of different doses AMA on HSC-T6 cells by TGF-ß1 induction. The results showed that the binding energy of anthocyanins on TGF-ß1 (PDB ID: 3KFD) was in the range of -9.5 to 8.6 kcal/mol, with good low energy parameters and binding positions. AMA could effectively inhibit the expressions of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total serum bilirubin (TSB), and improved the expressions of total protein (TP) and albumin (ALB). RT-PCR and Western bloting results showed that AMA could inhibited the secretion of inflammatory cytokines IL-1, IL-6, TNF-α and COX-2, and inhibit the expression of TGF-ß1, P-Smad2, α-SMA and Collagen I in TGF-ß /Smad signaling pathway. This study revealed the AMA's inhibition effects and mechanism of malignant biological behavior of HSC-T6 cells, in order to provide theoretical basis for the prevention and treatment of HF by Aronia melanocarpa Elliot.

Xanthorrhizol Ameliorates Oxidative Stress and Inflammation in Freund's Complete Adjuvant-Induced Rheumatoid Arthritis in Rats.

Rheumatoid arthritis (RA) is an inflammatory disease and a common cause of disability. This study is aimed to ascertain the therapeutic potentials of the xanthorrhizol against Freund's complete adjuvant (FCA)-stimulated RA in rats. The RA was initiated in the rats via injecting FCA (0.1 ml) subcutaneously and then treated with xanthorrhizol (20 mg/kg) for 25 days. The hematological markers were investigated using the automated hematological analyzer. The organ index (spleen and thymus) and paw volume were inspected by standard methods. The ALP, SGOT, and SGPT activities were examined using kits. The levels of inflammatory biomarkers, i.e., IL-1ß, IL-6, IL-10, and TNF-α, were inspected using assay kits. The status of MDA, SOD, CAT, GSH, COX-2, iNOS, and NF-κB was quantified using respective assay kits. The xanthorrhizol treatment appreciably improved the body weight and hematological parameters and reduced the arthritis score, organ index, and paw volume in the RA rats. The levels of RBCs and Hb were effectively improved, and activities of ALP, SGOT, and SGPT were decreased by the xanthorrhizol in the RA rats. The RA rats treated with 20 mg/kg of xanthorrhizol demonstrated the depleted IL-1ß, IL-6, and TNF-α levels. The antioxidant markers SOD, CAT, and GSH were improved, and inflammatory biomarker levels such as COX-2, iNOS, and NF-κB were decreased by the xanthorrhizol in the RA rats. Overall, these outcomes witnessed that the xanthorrhizol effectively ameliorated the oxidative stress and inflammatory responses and attenuated the RA in rats. Hence, it could be a talented anti-arthritic medication to treat RA.

A phase III randomized, controlled trial of nedaplatin versus cisplatin concurrent chemoradiotherapy in patients with cervical cancer.

BACKGROUND: We evaluated the non-inferiority of nedaplatin-based and cisplatin-based concurrent chemoradiotherapy in cervical cancer patients. DESIGN: Patients aged 28-82 years with pathologically diagnosed cervical cancer (stage IB-IVA) were randomly chosen for the study. Patients in both the cisplatin and nedaplatin groups received radiotherapy and weekly intravenous nedaplatin 30 mg/m2 or cisplatin 40 mg/m2 concurrently. RESULTS: One hundred and sixty patients who received treatment between 10 May 2018 and 31 August 2020 were included. The 3-year overall survival in the nedaplatin group (median 30.5 months) was not significantly different from that in the cisplatin group (28.5 months; hazard ratio 0.131, 95% confidence interval 0.016-1.068; P = 0.058). No significant differences in hematological toxicity were observed between the two groups. Vomiting (40 versus 61), nausea (44 versus 67), and anorexia (52 versus 71) were more common in the cisplatin group whereas effects on liver function, including total bilirubin (7 versus 3), alanine aminotransferase (7 versus 2), and aspartate aminotransferase (6 versus 2), were more common in the nedaplatin group. Four patients in the cisplatin group had grade I creatinine elevation, whereas none in the nedaplatin group had abnormal creatinine levels. Two patients in the nedaplatin group discontinued concurrent chemotherapy because of infusion, and one patient in the cisplatin group discontinued treatment because of infusion-induced dizziness. CONCLUSIONS: Our findings suggest that nedaplatin has a milder gastrointestinal reaction but a more significant effect on liver function than cisplatin. In patients with cervical cancer, nedaplatin-based concurrent chemoradiotherapy could serve as an alternative treatment to cisplatin.

Ameliorative role of Cyanus depressus (M.Bieb.) Soják plant extract against diabetes-associated oxidative-stress-induced liver, kidney, and pancreas damage in rats.

In this original article, we aimed to assess the ameliorative role of Cyanus depressus (CD) plant ethanolic extract treatment of streptozotocin (STZ)-induced liver, kidney, and pancreas damage in rats. The rats were divided into five groups (n = 7): control, CD, Diabetes mellitus (DM), DM + CD, and DM + glibenclamide (Gly). The DM groups were injected with a single dose of 50 mg/kg STZ intraperitoneally (i.p.). While the CD and DM + CD groups received 400 mg/kg/day intragastrically for 21 days, the DM + Gly group received 3 mg/kg/day of Gly intragastrically throughout the experiment. Statistically significance was accepted as p < .05. According to our liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) data, quinic acid, cosmosiin, nicotiflorin, apigenin, and protocatechuic acid were the major compounds, in descending order. Weekly blood glucose, serum glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and urea, malondialdehyde (MDA) (liver and pancreas), and blood glycosylated hemoglobin % (HbA1c %) were significantly decreased, whereas finally live body weights (LBWs), reduced glutathione (GSH), glutathione S-transferase (GST) and catalase (CAT) (pancreas), and pancreatic islet diameter and area were increased significantly in the CD-treated diabetic group. Moreover, CD administration was found to be effective in the protection of the histology of the liver, kidneys, and pancreatic islets in the STZ-induced rats. Consequently, we concluded that CD administration reduces hyperglycemia, oxidative stress, and histopathology in STZ-induced experimental rats by improving antioxidant defenses. PRACTICAL APPLICATIONS: Today, the prevalence of diabetes is increasing rapidly throughout the world and it causes complications such as kidney damage, blindness, amputations, and cardiovascular diseases. Despite medical technological advances, people's interest in medicinal herbal products is gradually increasing. Biochemical and histopathological findings showed that the use of the plant CD at the determined dose (400 mg/kg/day) in rats with DM by STZ had strong antioxidant and antidiabetic effects. CD may have a drug potential in preventing DM and its complications because of its phytochemical content including some phenolic acids such as quinic acid, cosmosiin, nicotiflorin, apigenin, and protocatechuic acid. Isolation of bioactive compounds from CD and investigation of their therapeutic effects could be planned as further studies.

Clinical Significance of Transient Asymptomatic Elevations in Aminotransferase (TAEAT) in Oncology.

Monitoring for liver injury remains an important aspect of drug safety assessment, including for oncotherapeutics. When present, drug-induced liver injury may limit the use or result in the discontinuation of these agents. Drug-induced liver injury can exhibit with a wide spectrum of clinical and biochemical manifestations, ranging from transient asymptomatic elevations in aminotransferases (TAEAT) to acute liver failure. Numerous oncotherapeutics have been associated with TAEAT, with published reports indicating a phenomenon in which patients may be asymptomatic without overt liver injury despite the presence of grade ≥3 aminotransferase elevations. In this review, we discuss the occurrence of TAEAT in the context of oncology clinical trials and clinical practice, as well as the clinical relevance of this phenomenon as an adverse event in response to oncotherapeutics and the related cellular and molecular mechanisms that may underlie its occurrence. We also identify several gaps in knowledge relevant to the diagnosis and the management of TAEAT in patients receiving oncotherapeutics, and identify areas warranting further study to enable the future development of consensus guidelines to support clinical decision-making.

Anti-inflammatory effect of mesenchymal stem cells on hepatocellular carcinoma in the xenograft mice model.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Sorafenib is the standard treatment used in the advanced stages of HCC. Cell therapy with mesenchymal stem cells (MSCs)-based cell therapy has proven effective in immune regulation and tumour growth inhibition. OBJECTIVES: In this study, we investigated the anti-inflammatory effect of MSCs on HCC xenografts. METHODS: Human HepG2 cell lines were subcutaneously implanted into the flank of 12 nude mice, divided into three groups: the control group, the IV group (intravenous MSCs injection) and the local group (local MSCs injection). Mice were sacrificed 6 weeks after tumour implantation, and tumours were resected entirety. Quantitative real-time polymerase chain reaction (qRT-PCR) measured the gene expression of inflammatory markers, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1α and IL-10. Aspartate transaminase (AST), alanine transaminase (ALT) and urea levels were measured using spectrophotometry to ensure the safety of MSC therapy. RESULTS: Gene expressions for all three inflammatory markers were reduced in both MSCs groups compared to the control group. AST, ALT and urea levels remained in normal ranges. CONCLUSIONS: MSC therapy can reduce inflammation in HCC xenograft mouse models.

Baseline clinical characteristics predict overall survival in patients undergoing radioligand therapy with [177Lu]Lu-PSMA I&T during long-term follow-up.

BACKGROUND: Radioligand therapy (RLT) with 177Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [177Lu]Lu-PSMA I&T RLT in a long-term follow-up. MATERIALS AND METHODS: Ninety-two mCRPC patients treated with [177Lu]Lu-PSMA I&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (intervalDiagnosis-RLT, per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan-Meier analyses. RESULTS: Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95% CI 1.02-1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95% CI 1.01-1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95% CI 1.06-1.26; P = 0.001), and intervalDiagnosis-RLT (HR, 0.95, 95% CI 0.91-0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and intervalDiagnosis-RLT, 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan-Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged intervalDiagnosis-RLT (P ≤ 0.01, respectively). CONCLUSION: In mCRPC patients treated with [177Lu]Lu-PSMA I&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [177Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors.

Diammonium Glycyrrhizinate Preparation for Liver Function Recovery in Chronic Hepatitis B in China: A Meta-analysis with Trial Sequential Analysis.

BACKGROUND: The treatment of chronic hepatitis B (CHB) comprises a global medical problem, and the first-line clinical drugs have obvious shortcomings. The use of the plant extract diammonium glycyrrhizinate (DG) in food and medicine has gradually widened because of its safety and effectiveness. DG is mainly used for liver-disease treatment in clinical practice, but DG intervention for CHB lacks systematic evidence. METHODS: The included randomized controlled trials were analyzed by comparator and control respectively for alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBIL) levels, hepatitis B virus DNA negative conversion ratio, and total effective rate, and subgroup analysis was conducted for intervention time, intervention dosage form, comparator drug, and combination drug, among others. Trial sequential analysis was used to verify the results. RESULT: DG could effectively reduce ALT, AST, TBIL, and other liver-function indexes and had a definite effect on liver-function recovery. From the beginning of the intervention to 3 months, the effect was significantly better than that of conventional treatment. Compared with other drugs, different dosage forms had differences in efficacy, and DG enteric-coated capsules and injections were lower than compound glycyrrhizin and magnesium isoglycyrrhizin. Meanwhile, DG capsules had no significant difference from them. Meanwhile, trial sequential analysis of the main results confirmed the reliability of the conclusion. CONCLUSION: To our knowledge, this was the first relatively complete meta-analysis and systematic evaluation of the efficacy of DG intervention for CHB; liver-function recovery was discussed in the context of traditional Chinese medicine thinking, and DG's therapeutic effect on CHB was defined.

Reinforcement learning evaluation of treatment policies for patients with hepatitis C virus.

BACKGROUND: Evaluation of new treatment policies is often costly and challenging in complex conditions, such as hepatitis C virus (HCV) treatment, or in limited-resource settings. We sought to identify hypothetical policies for HCV treatment that could best balance the prevention of cirrhosis while preserving resources (financial or otherwise). METHODS: The cohort consisted of 3792 HCV-infected patients without a history of cirrhosis or hepatocellular carcinoma at baseline from the national Veterans Health Administration from 2015 to 2019. To estimate the efficacy of hypothetical treatment policies, we utilized historical data and reinforcement learning to allow for greater flexibility when constructing new HCV treatment strategies. We tested and compared four new treatment policies: a simple stepwise policy based on Aspartate Aminotransferase to Platelet Ratio Index (APRI), a logistic regression based on APRI, a logistic regression on multiple longitudinal and demographic indicators that were prespecified for clinical significance, and a treatment policy based on a risk model developed for HCV infection. RESULTS: The risk-based hypothetical treatment policy achieved the lowest overall risk with a score of 0.016 (90% CI 0.016, 0.019) while treating the most high-risk (346.4 ± 1.4) and the fewest low-risk (361.0 ± 20.1) patients. Compared to hypothetical treatment policies that treated approximately the same number of patients (1843.7 vs. 1914.4 patients), the risk-based policy had more untreated time per patient (7968.4 vs. 7742.9 patient visits), signaling cost reduction for the healthcare system. CONCLUSIONS: Off-policy evaluation strategies are useful to evaluate hypothetical treatment policies without implementation. If a quality risk model is available, risk-based treatment strategies can reduce overall risk and prioritize patients while reducing healthcare system costs.