Increase In Bilirubin Research Articles

Phase 1 Trial of SPECT-Guided Liver-Directed Ablative Radiotherapy for Patients with Low Functional Liver Volume

Traditional liver dose constraints specify that a critical volume of 700 cc of non-tumor liver should be spared from receiving a hepatotoxic dose. We evaluated the safety of liver-directed ablative radiotherapy for patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or liver metastases (LM) with Child-Pugh (CP) A5 liver function at baseline and with low functional liver volume as estimated by Tc-99m sulfur colloid single photon emission computed tomography (SPECT). We hypothesized that functional liver image guidance with SPECT would allow safe delivery of ablative radiotherapy in patients with limited liver volume. A phase 1 trial with a 3+3 design was conducted to evaluate the safety of comprehensive ablative radiotherapy to the liver disease using escalating functional non-target liver radiation dose constraints. Eligibility criteria included (1) a diagnosis of HCC, iCCA, or LM, (2) prior treatment with irinotecan or oxaliplatin chemotherapy or liver resection, and (3) a minimum functional liver volume of 400 cc as estimated by SPECT using a threshold of 40% maximum intensity. Patients with CP >A5 liver function, prior liver-directed radiotherapy, or prior Yttrium-90 therapy were excluded. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. The volumetric dose constraint for functional non-target liver receiving <24 Gy for 15 fractions or <27 Gy for 25 fractions was determined by the dose level of trial enrollment: level 0 was ≥400 cc and level +1 was ≥300 cc. A level -1 was included if needed. We used standard 15 and 25 fraction dose constraints for other organs at risk. The following dose limiting toxicities (DLTs) were assessed within 6-8 weeks of completing radiotherapy: Grade 3 hypoalbuminemia, increase in INR, increase in bilirubin, or ascites, or Grade 4 hepatic failure or any radiation-related toxicity. Twelve patients enrolled between February 2016 and June 2022. The median (range) GTV was 36 (2-651) cc. The median CT anatomical non-tumor liver volume was 1584 (764-2699) cc, and the median SPECT functional liver volume was 1117 (570-1928) cc, with a Pearson correlation coefficient of 0.98 (p<0.001). The median non-target SPECT functional liver volume below the volumetric dose constraint was 684 (429-1244) cc. None of the 3 patients treated in dose level 0, and none of the 9 patients treated in dose level +1 experienced any DLTs. The 1-year in-treatment-field control rate was 55%, and 1-year overall survival was 71%. Ablative radiotherapy can be safely delivered using functional SPECT image guidance, which enables sparing lower volumes of functional liver than traditionally accepted in patients with CP A5 liver function. Further evaluation with a phase 2 study is warranted.

How the Underlying Etiology of Cirrhosis Impacts Response to SBRT

In the US, incidence rates of hepatocellular carcinoma (HCC) have more than tripled and death rates have doubled since 1980. In 2022, it is expected for 41,260 new cases to be diagnosed with 30,520 deaths. Many etiologies contribute to the development of HCC including alcoholic cirrhosis, cryptogenic cirrhosis, HCV, HBV, NASH, and genetic disorders like hereditary hemochromatosis. An increasing number of patients are not candidates for curative options such as resection or transplant and the role of alternative liver directed as therapies has increased. SBRT has emerged as a safe and effective option, but there is little known about the outcomes related to the etiology of the HCC. The purpose of this study is to characterize the rates of toxicity and efficacy between different HCC etiologies in patients who were treated with SBRT. A single institutional database was compiled of all patients with HCC who were treated with SBRT. Patients with HCC etiologies of HCV, alcoholic cirrhosis, or NASH cirrhosis who received SBRT and monitored with liver function tests and imaging (MRI or CT) and were not transplanted were included Demographic information, disease etiology, all treatment courses, lab values, radiologic response, and follow-up were collected on all patients. SPSS was used to analyze the data. Consecutive patients (n = 37, 43 courses of radiation) who received SBRT between 2013- January 2022 were included. Most patients were male (n = 32, 86.5%) and average age was 64.73 ± 7.42 years (range: 50-82 years). A majority of patients had either HCV or HCV and alcoholic cirrhosis (n = 28, 75.7%) and there were no baseline difference in child Pugh score, tumor size, or number of prior treatments. Most patients were treated with 50Gy/5 fx (n = 26, 70.3%) with 5 others being treated with 45Gy/5fx to meet mean liver constraints. Most patients had a decrease in ALT (n = 22, 59.5%) while almost half of patients had a decrease in AFP (n = 14, 48.3%) at average follow-up of 11.84 ± 5.35 months. There was a significant correlation between HCC etiology and change in bilirubin with patients with HCV being more likely to have increases in total bilirubin (χ2 (6) = 17.5, p < 0.01). Patients with HCV induced cirrhosis may be more fragile and have a significant increased risk of toxicity after SBRT based on total bilirubin changes. Most patients did have a decrease in ALT showing potential for some improvement in liver function with SBRT. However, almost half of patients have some biologic efficacy with SBRT independent of HCC etiology. Further studies should include looking at the biologic differences in the etiologies and what treatment liver-directed therapies may be best for each population.

Treatment of refractory or relapsed myelodysplastic neoplasms with luspatercept: a multicenter Chinese study.

Few effective therapies are available to treat patients with relapsed/refractory myelodysplastic neoplasms (MDS). Luspatercept was shown to display good efficacy in a phase 3 clinical trial for lower-risk MDS (LR-MDS) patients, yet real-world data are limited, especially in China. Therefore, data from patients diagnosed as having MDS with low blasts and SF3B1 mutation (MDS-SF3B1) and MDS with SF3B1 mutation and thrombocytosis were retrospectively analyzed. Of the 23 enrolled patients, 17 (73.9%) were males (median age 67years: range 29 to 80years). Previously, a total of 22 (95.7%) patients had received recombinant human erythropoietin (rhEPO), 9 (39.1%) roxadustat, 7 (30.4%) lenalidomide and 3 (13.0%) hypomethylating agents (HMA). The median treatment time was 22.9weeks (9.0-32.4). At week 12, 60.9% (14/23) of the patients achieved a hematologic improvement-erythroid (HI-E) response. Red blood cell transfusion independence (RBC-TI) for ≥ 8weeks was found in 57.1% (8/14) of transfusion-dependent patients. The median hemoglobin concentration was 84g/L, and patients had significantly higher hemoglobin concentrations after 12weeks of treatment (P < 0.001). It is noteworthy that responders had a greater reduction in serum ferritin (P = 0.021). Those with serum EPO < 500IU/L at baseline tended to have a higher HI-E rate (P = 0.081), but only patients in non-transfusion and low transfusion burden (LTB) subgroups had statistical differences (P = 0.024). The most commonly occurring adverse events were blood bilirubin increase (17.4%), fatigue (13.0%) and dizziness (13.0%). Luspatercept was effective and tolerated well in refractory LR-MDS-SF3B1 patients. In particular, baseline non-transfusion and LTB patients exhibited a greater response rate to treatment.

Bilirubin is a superior biomarker for hepatocellular carcinoma diagnosis and for differential diagnosis of benign liver disease

Abstract Objectives To develop a novel diagnostic model combining bilirubin, protein induced by vitamin K absence or antagonist-II (PIVKA-II), and alpha-fetoprotein (AFP) to improve hepatocellular carcinoma (HCC) diagnosis. Methods The serum levels of PIVKA-Ⅱ, AFP, and bilirubin in 718 HCC patients and 2,763 benign liver disease (BLD) patients were measured. A mathematical model was used as the combined diagnostic model (PIVKA-Ⅱ, AFP, and bilirubin: PAB combination) for improving HCC diagnosis. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic value of the individual markers, the PIVKA-II and AFP (PA) combination, and the PAB combination for HCC diagnosis. Results With the increase in bilirubin, the positive predictive value (PPV) of bilirubin in HCC diagnosis decreased (p&lt;0.001) while the negative predictive value (NPV) increased (p&lt;0.001). The areas under the ROC curves (AUCs) of the PAB combination were 0.935 and 0.862 for the diagnosis of HCC and HCC&lt;3.0 cm, respectively, which were significantly higher than those of PIVKA-Ⅱ, AFP, and the PA combination (p&lt;0.001). The AUC values for PIVKA-Ⅱ, AFP, and the PA combination were significantly decreased for the diagnosis of HCC and HCC&lt;3.0 cm when serum levels of PIVKA-Ⅱ≥40 mAU/mL and/or AFP≥20 ng/mL were used for diagnosis, while the AUC value of the PAB combination increased. Conclusions Bilirubin is a superior biomarker for diagnosing HCC and distinguishing HCC from BLD. The combination of bilirubin with PIVKA-Ⅱ and AFP has superior diagnostic value for HCC and early-stage HCC.

Clinical and hematological сhanges in viral panleukopenia in cats

Cat infectious diseases have become widespread due to the increase in the number of stray cats; feline viral panleukopenia is no exception. It is caused by a single-stranded DNA virus of feline parvovirus, characterized by high contagiousness, fever, damage to the gastrointestinal tract, respiratory organs, heart, general intoxication, and body dehydration. The research aimed to study the hematological indices of blood and biochemical indices of plasma in viral panleukopenia of cats. During the development of intestinal panleukopenia syndrome in animals, vomiting and diarrhea were noted. The development of inflammatory processes in the digestive organs causes pain in the abdominal cavity, due to which a specific “sitting posture” occurs. An acute course was most frequently noted, characterized by a sudden increase in temperature to 42 °C, vomiting, diarrhea, and cachexia. Studies of hematological indices of blood indicate the development of thrombocytosis, neutrophilia, monocytosis, and lymphocytosis, which corresponds to the acute course of the disease with a focal inflammatory process. Erythropenia leads to systemic disorders of the cardiovascular system, which provoke the weakening of the body, accompanied by cachexia. Studies of biochemical parameters of plasma indicate systemic disorders of organs developing in the body. Thus, an increase in total protein indices and globulin fractions indicates inflammatory processes in the body, particularly the digestive and urinary organs. In addition, one of the renal impairment indices was an increase in creatinine and urea, and an increase in glucose, total bilirubin, AST, and α-amylase indicates liver and pancreas dysfunction. In some cases, hepatitis and infectious toxicosis may develop. The study of hematological indices of blood and biochemical indices of plasma will ensure a complex picture of morphological changes that develop in the body of cats with panleukopenia. The obtained data will permit the monitoring of an animal's condition with the applied therapeutic scheme and the form of a prognosis.

The protective role of α-tocopherol, vitamin C and quercetin against ibuprofen-induced liver damage in male Wistar rats

Aim: Ibuprofen which is one of the frequently used analgesics has been associated with some adverse effects, including liver injury. The protective role of α-tocopherol, vitamin C and quercetin against ibuprofen-induced liver damage in male Wistar rats were investigated in this study. Method: The study design included; induction of liver damage using ibuprofen, and secondly, determination of the protective role of α-tocopherol, vitamin C and quercetin against ibuprofen-induced liver injury. In the first phase, two groups of animals were used; one group treated with 120 mg/kg ibuprofen daily for 14 days, while the other served as control and given distilled water. After treatment, the serum malondialdehyde, liver enzymes and total bilirubin were estimated, and the liver harvested for histology. In the protection study, there were four treatment groups, each having three sub-groups, treated with 120 mg/kg Ibuprofen and graded doses of vitamin E, vitamin C and quercetin respectively, while the fifth group given distilled-water served as control. After 14 days, antioxidant enzymes and liver parameters were estimated, while the liver harvested for histology. Results: Showed increase in aspartate transaminase and Alkaline phosphatase activities, and significant (p&lt;0.05) increase in malondialdehyde levels, alanine transaminase and total bilirubin, after ibuprofen administration. Conversely, there was significant (p&lt;0.05) reduction in liver parameters after co-administration of antioxidants with ibuprofen, and significant (p&lt;0.05) increase in the activity of total glutathione and catalase enzymes. The estimated antioxidant’s percentage protection showed the antioxidants offered variable degree of protection on the liver against ibuprofen-induced damage. Histology revealed cellular and portal infiltration of inflammatory cells, macrophage aggregation, and some parenchymal necrosis, after ibuprofen administration, but showed normal histo-architecture after co-administration with antioxidants.

Hepatoprotective effect of Vernonia amygdalina and Ocimum gratissimum on Wistar rats exposed to long-term administration of artemisinin-based combination therapies

In this study the protective effect of Vernonia amygdalina (VA) and Ocimum gratissimum (OG) on rats exposed to long term oral administration of artesunate-amodiaquine and arthemeter-lumefantrine were investigated. Forty-two albino rats were divided into seven groups. They were given the drugs, artesunate amodiaquine (AA) and artemether lumefantrine (AL) base on their body weight. Group 1: Control, received distilled water, group 2, received of 2.86 mg/7.7 mg AA, group 3, received of 1.14 mg/6.86 mg AL, group 4 received of 2.86 mg/7.7 mg AA + 200 mg VA, group 5 received of 1.14 mg/6.86 mg AL + 200 mg VA, group 6 received of 2.86 mg/7.7 mg AA + 200 mg OG and group 7 received of 1.14 mg/6.86 mg AL + 200 mg OG. The animals were sacrificed and blood samples obtained through cardiac puncture for biochemical investigations. Biochemical assay for total protein, albumin, total bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (γ-GT) were done. Co-administration of artesunate-amodiaquine and arthemeter-lumefantrine significantly decreased (P&lt; 0.05) total protein and albumin while there was significant increase (P&lt; 0.05) in total bilirubin, direct bilirubin, AST, ALT, ALP and γ-GT when compared with control group. The administration of VA and OG significantly increased the total protein and albumin and significantly decreased (P&lt; 0.05) total bilirubin and liver enzymes when compared with control group. The results indicate hepatic injury in the rats exposed to long term administration of artemisinin-based combination therapies (ACTs) which was reversed by the administration of VA and OG. There is need for caution while taking ACTs as malaria chemotherapy.

Evaluation of ceftriaxone pharmacokinetics in hospitalized Egyptian pediatric patients

This study aimed to evaluate ceftriaxone pharmacokinetics that affects the achievement of targets in the treatment of critically ill children (meningitis, pneumonia, urinary tract infection, peritonitis, and infective endocarditis( who were admitted to Zagazig University Pediatric hospital in Egypt to monitor for the drug adverse effects.Blood samples were obtained from 24 hospitalized pediatric patients (ages ranging from 2.5 months to 12 years) after administering the calculated dose of ceftriaxone via intravenous bolus route. Then, ceftriaxone plasma concentrations were measured using a validated HPLC method with ultraviolet detection. The pharmacokinetic analysis was conducted using Phoenix Winnonlin Program® software.Data for total and free ceftriaxone best fitted on a one-compartment model with the first-order elimination process. Clearance of ceftriaxone is reduced for patients with reduced kidney function and increased with those with augmented renal clearance. The volume of distribution and the free fraction are increased in these patients, especially those with hypoalbuminemia with a shorter half-life time were detected. A slight increase in total bilirubin and liver enzymes has been observed after treatment with ceftriaxone in these patients. Conclusion: In most critically ill pediatric patients, the current ceftriaxone treatment regimen (50 to 100 mg/kg) offers adequate pathogenic coverage. The clearance of free ceftriaxone in all patients correlates well with their renal function (eGFR), with r2 = 0.7252. During therapy with ceftriaxone at all doses ranging from 50 to 100 mg/kg, a rise in total bilirubin was observed in these patients. Moreover, liver enzymes (ALT and AST) increased moderately (p 0.0001). So, it is recommended to monitor total bilirubin and liver enzymes during the treatment with ceftriaxone, especially for a long duration (more than 5 days) or use another agent in patients with high baseline values.What is Known:• The dosing regimen of ceftriaxone (50 to 100 mg/kg) provided optimum therapeutic outcomes.• Some studies show data for total and free Ceftriaxone best fitted on a one-compartment model while other studies show data for total and free Ceftriaxone best fitted on a two-compartment model.What is New:• Up to my knowledge this is the first study ,considering individual pharmacokinetic analysis, conducted on hospitalized Egyptian pediatric population most of them with reduced kidney function with ages ranging from 2.5 months to 12 years. Data for total and free Ceftriaxone best fitted on a one-compartment model with linear clearance of the free ceftriaxone.• In all patients, total bilirubin and liver function tests were mildly increased, making them at risk for cholestasis or ceftriaxone-induced cholestatic hepatitis.

Blood biochemical changes upon subclinical intramammary infection and inflammation in Holstein cattle

The aim of this study was to investigate the associations between subclinical intramammary infection (IMI) from different pathogens combined with inflammation status and a set of blood biochemical traits including energy-related metabolites, indicators of liver function or hepatic damage, oxidative stress, inflammation, innate immunity, and mineral status in 349 lactating Holstein cows. Data were analyzed with a linear model including the following fixed class effects: days in milk, parity, herd, somatic cell count (SCC), bacteriological status (positive and negative), and the SCC × bacteriological status interaction. Several metabolites had significant associations with subclinical IMI or SCC. Increased SCC was associated with a linear decrease in cholesterol concentrations which ranged from -2% for the class ≥50,000 and <200,000 cells/mL to -11% for the SCC class ≥400,000 cells/mL compared with the SCC class <50,000 cells/mL. A positive bacteriological result was associated with an increase in bilirubin (+24%), paraoxonase (+11%), the ratio paraoxonase/cholesterol (+9%), and advanced oxidation protein product concentration (+23%). Increased SCC were associated with a linear decrease in ferric reducing antioxidant power concentrations ranging from -3% for the class ≥50,000 and <200,000 cells/mL to -9% for the SCC class ≥400,000 cells/mL (respect to the SCC class <50,000 cells/mL). A positive bacteriological result was associated with an increase in haptoglobin concentrations (+19%). Increased SCC were also associated with a linear increase in haptoglobin concentrations, which ranged from +24% for the class ≥50,000 and <200,000 cells/mL (0.31 g/L) to +82% for the SCC class ≥400,000 cells/mL (0.45 g/L), with respect to the SCC class <50,000 cells/mL (0.25 g/L). Increased SCC were associated with a linear increase in ceruloplasmin concentrations (+15% for SCC ≥50,000 cells/mL). The observed changes in blood biochemical markers, mainly acute phase proteins and oxidative stress markers, suggest that cows with subclinical IMI may experience a systemic involvement.

Effect of Mining Activities on Some Biochemical Parameters of Opanda-Ugya Inhabitants, Toto Local Government of Nigeria

Mining activities are usually associated with environmental pollution and the infiltration of toxic heavy metals into waterways which could be absorbed by plants or used by inhabitants. The aim of this research was to determine the effect of mining activities on some biochemical parameters of Opanda-Ugya inhabitants, Toto Local government of Nigeria. Four hundred and fifty (450) people were interviewed using questionnaires. Eighty (80) of them were carefully grouped into four: Group 1(20 Control), Group 2 (20 inhabitants), Group 3 (20 indirect miners) Group 4 (20 direct miners). The Survey discovered some symptoms that could be associated with heavy metal toxicity among the inhabitants. Biochemical assay of blood samples revealed no significant (P ˃0.05) increase in Serum ALT, AST and Total bilirubin in groups 2, 3 and 4 when compared to control, but a decrease in TP. Serum creatinine levels increased significantly in group 3 when compared to the control. Both creatinine and urea levels elevated significantly in group 2 and group 4 when compared with the control. The result of Oxidative stress markers has indicated a significant increase in the levels of MDA with a concomitant decrease in the levels of GSH in groups 2, 3 and 4 compared to the control. The AChE activity in groups 2, 3 and 4 significantly increased when compared to the control. The levels of CRP increased significantly in groups 3 and 4 when compared to the control. We conclude that the neurological and other disorders observed in some participants could be attributed to chronic inflammation and oxidative stress induced by heavy metal toxicity, thus something should be done by the necessary authority to curtail the long-time effect of Mining activities in this community.

A CROSS SECTIONAL STUDY TO EVALUATE ACUTE KIDNEY INJURY IN SCRUB TYPHUS PATIENTS

Objective: This study was conducted with the objective of estimating the incidence and severity of acute kidney injury (AKI) in scrub typhus patients. Methods: This was a cross-sectional study conducted on 90 patients diagnosed with scrub typhus in a tertiary care center. Basic demographic and treatment details of the patients were recorded. Routine hematological investigations and biochemical profiles were performed upon admission and follow-up. AKI was defined and classified based on the RIFLE criteria. Results: The mean age of the patients was 49.0±19.5 year and a female preponderance was observed. The hemoglobin level was significantly lower in AKI patients as compared to non-AKI patients. Meanwhile, there was a significant increase in mean TLC count, C-reactive protein, and total bilirubin in AKI patients as compared to non-AKI patients. Was significantly higher as compared to those without AKI. Increasing age, Intensive care unit admission, shock, urinary abnormalities, and mechanical ventilation were the factors significantly associated with AKI. Conclusion: AKI is a frequently reported complication in scrub typhus patients. In evaluating febrile illnesses associated with AKI, scrub typhus should be considered.

Bilirubin Concentration in Follicular Fluid Is Increased in Infertile Females, Correlates with Decreased Antioxidant Levels and Increased Nitric Oxide Metabolites, and Negatively Affects Outcome Measures of In Vitro Fertilization.

In a previous study, we showed that various low-molecular-weight compounds in follicular fluid (FF) samples of control fertile females (CFF) have different concentrations compared to those found in FF of infertile females (IF), before and after their categorization into different subgroups, according to their clinical diagnosis of infertility. Using the same FF samples of this previous study, we here analyzed the FF concentrations of free and bound bilirubin and compared the results obtained in CFF, IF and the different subgroups of IF (endometriosis, EM, polycystic ovary syndrome, PCOS, age-related reduced ovarian reserve, AR-ROR, reduced ovarian reserve, ROR, genetic infertility, GI and unexplained infertility, UI). The results clearly indicated that CFF had lower values of free, bound and total bilirubin compared to the respective values measured in pooled IF. These differences were observed even when IF were categorized into EM, PCOS, AR-ROR, ROR, GI and UI, with EM and PCOS showing the highest values of free, bound and total bilirubin among the six subgroups. Using previous results of ascorbic acid, GSH and nitrite + nitrate measured in the same FF samples of the same FF donors, we found that total bilirubin in FF increased as a function of decreased values of ascorbic acid and GSH, and increased concentrations of nitrite + nitrate. The values of total bilirubin negatively correlated with the clinical parameters of fertilization procedures (number of retrieved oocytes, mature oocytes, fertilized oocytes, blastocysts, high-quality blastocysts) and with clinical pregnancies and birth rates. Bilirubin concentrations in FF were not linked to those found in serum samples of FF donors, thereby strongly suggesting that its over production was due to higher activity of heme oxygenase-1 (HO-1), the key enzyme responsible for bilirubin formation, in granulosa cells, or cumulus cells or oocytes of IF and ultimately leading to bilirubin accumulation in FF. Since increased activity of HO-1 is one of the main enzymatic intracellular mechanisms of defense towards external insults (oxidative/nitrosative stress, inflammation), and since we found correlations among bilirubin and oxidative/nitrosative stress in these FF samples, it may reasonably be supposed that bilirubin increase in FF of IF is the result of protracted exposures to the aforementioned insults evidently playing relevant roles in female infertility.

Diagnosis and Management of Constipation and Obstipation in Canine: From Current Practices to Future

This study was conducted to understand the present diagnosis and management patterns of constipation and obstipation in dog and accessing about its future holds. A total of 68 dogs both healthy (n=34) and constipated (n=34) brought to a private pet hospital in Kathmandu were included in the study for two-months during Feb-April, 2019 were recorded. The protocol comprised history taking (age, sex, breed and chief complains), physical and clinical examination, hematology/Biochemistry followed by radiography in some cases. Statistical analysis was conducted using MS-Excel 2016 and SPSS v25. We found that starting from the dietary management, rehydration and medical management using laxatives, enemas, antibiotics and supporting liver medications were being followed to manage constipation and obstipation. Anorexia (82.4%) and dehydration were the most common clinical signs. Female dogs (52.9%) were found more affected than male dogs (47.1%). Large and small breed dogs (73.5%) were more prone to constipation than medium sized breeds (26.5%). Older Dogs (&gt;60 months) (34%) were the most affected age groups. Haemato-biochemical blood findings showed significant increase in Total Leucocyte Count (Leukocytosis), Neutrophilia, ALP levels and Blood Urea Nitrogen (p ≤ 0.001) while there was also an increase in Serum bilirubin and Serum albumin levels (p ≤ 0.05) in constipated dog. This research showed increased risk of constipation in old and female dogs. Starting from high fiber diets, mild laxatives and enemas, the treatment can be proceeded to fluid therapy, antibiotic therapy and medications managing liver ailments after haemato-biochemical examination. Use of Novel prokinetic drugs practiced in humans like Cisapride and Pruracalopride, can be considered in veterinary practice. In situations of surgical management, most reliable would be the subtotal colectomy to manage idiopathic megacolon causing constipation and obstipation.

Synthesis of Methylgenipin and Evaluation of Its Anti-Hepatic Injury Activity.

Genipin has been the focus of research as a multifunctional compound for the treatment of pathogenic diseases. However, hepatotoxicity caused by oral genipin raises concerns about its safety. To obtain novel derivatives with low toxicity and efficacy, we synthesized methylgenipin (MG), a new compound, using structural modification, and investigated the safety of MG administration. The results showed that the LD50 of oral MG was higher than 1000 mg/kg, no mice died or were poisoned during the experiment in the treatment group, and there was no significant difference in biochemical parameters and liver pathological sections compared with the control. Importantly, MG (100 mg/kg/d) treatment for 7 days reduced alpha-naphthylisothiocyanate (ANIT)-induced increases in liver index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL) levels. Histopathology demonstrated that MG could treat ANIT-induced cholestasis. In addition, using proteomics to investigate the molecular mechanism of MG in the treatment of a liver injury may be related to enhancing antioxidant function. Kit validation showed that ANIT induced an increase in malondialdehyde (MDA) and a decrease in superoxide dismutase (SOD) and glutathione (GSH) levels, while the MG pretreatments, both of which were significantly reversed to some extent, suggested that MG may alleviate ANIT-induced hepatotoxicity by enhancing endogenous antioxidant enzymes and inhibiting oxidative stress injury. In this study, we demonstrate that the treatment of mice with MG does not cause impaired liver function and provide an investigation of the efficacy of MG against ANIT-induced hepatotoxicity, laying the foundation for the safety evaluation and clinical application of MG.

#4431 PREPARATION OF IMIDAZOLE QUATERNARY AMMONIUM SALT MICROSPHERES WITH HIGH BILIRUBIN ADSORPTION PERFORMANCE AND SELF-ANTICOAGULATION ABILITY

Abstract Background and Aims Bilirubin is a crucial toxin in liver metabolism. Increase of bilirubin is one of common manifestations in patients with abnormal liver function, and large accumulation of bilirubin in the blood can lead to more severe hepatic dysfunction and even death. Due to the poor therapy effect and the shortage of available donor organs, the artificial liver support system has been introduced to maintain the liver function and bridge patients to transplantation. Previous studies have found that imidazole quaternary ammonium salts have great potential to adsorb bilirubin. This work is to develop a novel bilirubin adsorption column by simple and general method, and evaluate the removal efficiency, anticoagulant property and biocompatibility of the bilirubin adsorption column. Method Multifunctional microspheres were fabricated by in situ co-polymerization of 1-vinylimidazole and divinylbenzene. Nuclear magnetic resonance (NMR), thermo-gravimetric analysis and X-ray photoelectron spectroscopy (XPS) etc. were performed to characterize the chemical compositions of the microspheres. Meanwhile, hemolysis test, blood routine test and clotting time test etc. were leveraged to evaluate the biocompatibility of the microspheres. Both static adsorption test and dynamic adsorption test were performed in vitro to evaluate adsorption performance. Results A variety of methods had proved successful synthesis of the adsorption performance. The hemolysis ratios of microspheres were less than 5%. Compared with BS330 microspheres and PES microspheres, the activated partial thromboplastin time (APTT) and thrombin time (TT) were longer in this work. Moreover, the microspheres showed a high adsorption clearance. In PBS solution of bilirubin, the adsorbent could decrease bilirubin from 200 mg/L to 45-55 mg/L. Conclusion The results suggested that the multifunctional microspheres can significantly reduce bilirubin concentration without obvious adverse interactions and could exhibit anticoagulation activity.

Voxel-Based Dosimetry Predicts Hepatotoxicity in Hepatocellular Carcinoma Patients Undergoing Radioembolization with 90Y Glass Microspheres.

Personalized dosimetry holds promise to improve radioembolization treatment outcomes in hepatocellular carcinoma (HCC) patients. To this end, tolerance absorbed doses for nontumor liver tissue are assessed by calculating the mean absorbed dose to the whole nontumor liver tissue (AD-WNTLT), which may be limited by its neglect of nonuniform dose distribution. Thus, we analyzed whether voxel-based dosimetry could be more accurate in predicting hepatotoxicity in HCC patients undergoing radioembolization. Methods: In total, 176 HCC patients were available for this retrospective analysis; of these, 78 underwent partial- and 98 whole-liver treatment. Posttherapeutic changes in bilirubin were graded using the Common Terminology Criteria for Adverse Events. We performed voxel-based and multicompartment dosimetry using pretherapeutic 99mTc-labeled human serum albumin SPECT and contrast-enhanced CT/MRI and defined the following dosimetry parameters: AD-WNTLT; the nontumor liver tissue volume exposed to at least 20 Gy (V20), at least 30 Gy (V30), and at least 40 Gy (V40); and the threshold absorbed dose to the 20% (AD-20) and 30% (AD-30) of nontumor liver tissue with the lowest absorbed dose. Their impact on hepatotoxicity after 6 mo was analyzed using the area under the receiver-operating-characteristic curve; thresholds were identified using the Youden index. Results: The area under the curve for prediction of posttherapeutic grade 3+ increases in bilirubin was acceptable for V20 (0.77), V30 (0.78), and V40 (0.79), whereas it was low for AD-WNTLT (0.67). The predictive value could further be increased in the subanalysis of patients with whole-liver treatment, where a good discriminatory power was found for V20 (0.80), V30 (0.82), V40 (0.84), AD-20 (0.80), and AD-30 (0.82) and an acceptable discriminatory power was found for AD-WNTLT (0.63). The accuracies of V20 (P = 0.03), V30 (P = 0.009), V40 (P = 0.004), AD-20 (P = 0.04), and AD-30 (P = 0.02) were superior to that of AD-WNTLT but did not differ significantly from each other. The respective thresholds were 78% (V30), 72% (V40), and 43 Gy (AD-30). Statistical significance was not reached for partial-liver treatment. Conclusion: Voxel-based dosimetry may more accurately predict hepatotoxicity than multicompartment dosimetry in HCC patients undergoing radioembolization, which could enable dose escalation or deescalation with the intent to optimize treatment response. Our results indicate that a V40 of 72% may be particularly useful in whole-liver treatment. However, further research is warranted to validate these results.

Talazoparib (Tala) in patients (pts) with solid tumors with BRCA1/2 mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3115 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with BRCA1/2 mut treated with Tala are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (alpha 0.10; 82% power). Secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and SD, and safety. DOR is defined as time from pt’s first documented objective response (OR) to progressive disease (PD). Duration of SD is defined as time from tx start to PD. Results: 28 pts with 16 solid tumors (6/28 pts had lung cancer) with BRCA1 (n=9) , BRCA2 (n=16) , or BRCA1/2 (n=3) mut were enrolled from Dec 2019 to Sept 2021. All pts were included in efficacy analyses. Demographics and outcomes are shown. 1 CR, 9 PR and 6 SD16+ were observed for a DC rate of 57% (1-sided 90% CI: 43% to 100%) and an OR rate of 36% (95% CI: 19% to 56%); the null hypothesis of a 15% DC rate was rejected (p&lt;0.001). 11/16 pts with OR or SD16+ had a BRCA2 mut, 4 had BRCA1 mut, and 1 had both. The pt with a CR (duration of 93 wks) had non-melanoma skin cancer, with BRCA2 and ATM muts, and was microsatellite instability high with 41 muts per megabase. Pts with PR had various solid tumors; 6/9 pts had BRCA2 mut, 2 had BRCA1 mut , 1 had both. Of pts with DC, 11 had tumor types for which PARP inhibitors are not yet FDA approved. Median duration of PR was 20 wks (range, 11-80). 10/16 pts with DC had a co-alteration in the 24 homologous recombination-related genes examined, mainly ATM (3) or ARID1A (2). 13 pts had ≥1 grade 3 tx-related adverse or serious adverse events including: anemia, AST or bilirubin increase, hyponatremia, nausea, vomiting, neutrophil, platelet, or white blood cell decrease. Conclusions: Tala demonstrated antitumor activity in heavily pretreated pts with advanced solid tumors with BRCA1/2 mut. Additional study is warranted to confirm the efficacy of Tala in non-breast, non-ovarian cancer pts with BRCA1/2 mut. Clinical trial information: NCT02693535 . [Table: see text]

Efficacy and safety of dose-escalated alectinib in patients with metastatic ALK-positive NSCLC and CNS relapse on standard dose alectinib.

e21079 Background: Central nervous system (CNS) metastases represent a common cause of morbidity and mortality in patients (pts) with ALK-positive (ALK+) non-small cell lung cancer (NSCLC), with limited therapeutic options. We previously reported re-induction of CNS responses using dose intensification of alectinib in two pts with metastatic ALK+ NSCLC who had experienced CNS progression on standard dose alectinib. However, this strategy has not been assessed in larger cohorts. Methods: In this retrospective study, pts were eligible if they had advanced ALK+ NSCLC with CNS relapse on standard dose alectinib (600 mg twice daily) and subsequently received dose-escalated alectinib (900 mg twice daily). Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events (trAEs) were graded per the CTCAE version 5.0. Results: 27 pts were eligible [male, 67%; median age at diagnosis, 53 (range, 31-69)]. Pts had previously received median 3 lines of systemic therapy (range, 1-12) and median 2 ALK TKIs (range, 1-4); all had received standard dose alectinib with CNS progression. 19 pts (70%) had received prior CNS-directed radiotherapy (RT) [median time from most recent RT to dose-escalated alectinib, 13.9 months (mos) (range, 0.2-52.3)]. The median duration of dose-escalated alectinib therapy in this cohort was 7.7 mos (95% CI, 4.8-10.9), with median overall progression-free survival (PFS) of 7.8 mos (95% CI, 4.9-13.7). Among 25 response-evaluable pts with baseline measurable or non-measurable CNS metastases, the CNS objective response rate (ORR) was 8.0% (95% CI, 1.0-26.0), with 2 pts having intracranial complete responses. CNS disease control rate (DCR) was 92.0% (95% CI, 74.0-99.0), with median CNS duration of response (DoR) of 5.3 mos (95% CI, 3.4-8.3) and median CNS PFS of 7.1 mos (95% CI, 4.4-13.7). Of 3 patients with baseline measurable CNS disease, all 3 had best intracranial response of SD, and median CNS PFS was 6.7 mos (95% CI, 6.2-not reached). Dose-escalated alectinib was well tolerated with no drug discontinuation due to trAE and no grade 3 or higher trAEs. One pt required dose reduction to 750 mg twice daily due to intolerable grade 2 fatigue. 23 pts (85%) experienced grade 1-2 trAEs. Grade 1-2 trAEs that occurred in 10% of pts were anemia (52%), fatigue (37%), constipation (26%), bilirubin increase (15%), alkaline phosphatase increase (15%), and peripheral neuropathy (11%). Conclusions: Dose intensification of alectinib demonstrated meaningful efficacy and tolerability in pts with metastatic ALK+ NSCLC who had experienced CNS disease relapse on standard dose alectinib, and may represent a viable therapeutic option for re-establishing CNS disease control.

A prospective, open-label, randomized, controlled trial of radiofrequency ablation versus stereotactic body radiation therapy for recurrent small hepatocellular carcinoma.

4096 Background: Effective treatments are urgently needed to improve the prognosis of patients with recurrent hepatocellular carcinoma (HCC). Previous studies demonstrated that both radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) were promising therapies for recurrent small HCC. This trial was designed to compare the efficacy and safety of RFA versus SBRT in patients with recurrent small HCC. Methods: This is a prospective, open label, randomized controlled trial, in which patients aged between 18 and 75 years with recurrent small HCC (occurred more than 3 months after hepatectomy or RFA, a solitary HCC ≤5.0 cm in diameter without vascular invasion or extrahepatic metastasis), KPS score ≥90, Child-Pugh score ≤6, adequate organ function, and estimated life expectancy ≥6 months were considered eligible. All patients were assigned 1:1 to RFA or SBRT group, and stratification was performed according to tumor size (≤ 2.0 cm or 2.1-5.0 cm). The primary endpoint was 2-year local progression-free survival. Secondary endpoints were progression-free survival, locoregional control, overall survival, and safety. Results: A total of 170 patients were recruited during August 2019 to May 2022 (83 in RFA arm and 87 in SBRT arm). In the ITT population, median age was 56 (range, 33-75) and 15 were female. Baseline characteristics were well balanced between treatment arms. Adverse events occurred in RFA and SBRT were mainly grade 1 or grade 2 in severity, and were gastrointestinal and constitutional symptoms, or abnormal laboratory investigations. The most common adverse events were bilirubin increase（14.6%）and AST increase (13.3%) in RFA group vs ALT increase (20.0%) and AST increase (15.3%) in SBRT group. No Grade 3-4 adverse events or mortality were noted. Late adverse events were hardly observed after 3 months. The follow-up of survival data is ongoing. Conclusions: Both RFA and SBRT are tolerable and safe for patients with recurrent small HCC. This randomized controlled trial will report the survival outcomes in 2024, which will make an important contribution in clinical decision-making for recurrent small HCC. Clinical trial information: NCT04047173 .

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 .