Elevated Bilirubin Research Articles

Vactosertib, a Novel TGFb Type I Receptor Kinase Inhibitor, Improves T-Cell Fitness:a Single-Arm, Phase 1b Trial in Relapsed/Refractory Multiple Myeloma

The prognosis for Multiple Myeloma (MM) patients (pts) has improved substantially over the past two decades with the success of immunomodulatory drugs (IMiDs), monoclonal antibodies, chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers (BiTEs) that broke the circulus vitiosus of tumor-induced immunosuppression to reengage the immune system. Functional blockade of the transforming growth factor-beta (TGF) signaling pathway improves the efficacy of cytotoxic and immune therapies, therefore we investigator the impact of TGF-inhibition in an steroid free regimn. Methods: We conducted a phase 1b study to determine the safety, efficacy, and maximal tolerated dose (200 mg po bid) of the potent, orally-available TGF type I receptor kinase inhibitor vactosertib in relapsed and/or refractory multiple myeloma (RRMM) pts who had received -2 lines of chemoimmunotherapy in combination with standard dosage of Pomalidomide without any corticosteroids. Results: Twenty one pts were enrolled in the phase 1b dose escalation cohort and received vactosertib plus pomalidomide as indicated (Fig. 1A). Pts' characteristics are described in Table 1The summary of grade 1-4 adverse events is shown (Table 2). A single grade 4 elevated bilirubin (5%) and a single grade 4 elevated lipase (5%) were observed as well as four grade 4 events of decreased neutrophils (19%). Four pts demonstrated a PR, two had a MR, nine had SD and four had disease progression (Fig. 1B). The median time to response for all pts and the responders eight weeks and median duration of response was ~12 weeks. The best overall response for individual pts to treatment is shown (Fig. 1C). Clinical activity was observed across all four dose levels (Table 3). To probe the tumor intrinsic anti-myeloma activity of vactosertib, we first determined the relative effect of vactosertib compared to the IMiDs pomalidomide and lenalidomide (Fig. 2A, B). The effect of vactosertib was greater than that observed with either lenalidomide or pomalidomide. MMCLs and patient CD138 + cells were then treated with vactosertib in combination with pomalidomide, and importantly, vactosertib with pomalidomide synergistically reduced myeloma viability (Fig. 3A). We next probed the systemic, tumor extrinsic effects of vactosertib by analyzing cytokines immune and tumor cells present within patient BM samples. (Fig. 4A). (Fig. 4B). Therefore, we explored the immunophenotype of CD8 + T-cells isolated from patient BM prior to and at the EOT. The relative percentage of T-cells that expressed the immunosuppressive markers programmed cell death-1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), B and T lymphocyte attenuator (BTLA), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) was reduced following treatment relative to their expression prior to treatment (Fig. 4C). Results indicated that vactosertib and pomalidomide treatment in vivo reduced PD-1, TIM3, BTLA and CTLA-4 expression on patient CD8 + T-cells. Next, CD8 + T-cells were isolated from patient peripheral blood and cultured in the presence of TGF-1, vactosertib, pomalidomide, or vactosertib plus pomalidomide (Fig. 5B). Treatment of patient CD8 + T-cells with vactosertib decreased PD-1 expression up to 40% and decreased TIM3 expression up to 65%. Pomalidomide alone did not significantly reduce PD-1, TIM3, BTLA, or LAG-3 on patient CD8 + T-cells. Vactosertib and pomalidomide also reduced TIM3 levels on CD8 + T-cells from most pts. (Fig. 5C, D). (Fig. 5 G, H). Results indicated that vactosertib or pomalidomide did not increase CD138 + cell death (Fig. 5I). Conclusion: Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, Vactosertib reduced TGF- in patient bone marrow and suppressed PD-1 expression on CD8 + T-cells and lead to reduction of PD-L1/PD-L2 expression on CD138 + cells and enhanced autologous T-cell cytotoxicity. Taken together, our results support the safety and efficacy of vactosertib to treat RRMM and revealed that vactosertib modulates the T-cell immunophenotype and reinvigorates T-cell fitness.

UGT1A1 morpholino antisense oligonucleotides produce mild unconjugated hyperbilirubinemia in cyclosporine A-induced cardiovascular disorders in BLC57 mice

This study aimed to investigate the induction of mild unconjugated hyperbilirubinemia in hepatic UGT1A1 inhibition by Morpholinos antisense in CsA-treated BLC57 mice in comparison with the efficacy of chitosan (CH) as an anti-hypolipidemic natural product. Antisense morpholino oligonucleotides were injected intravenously into CsA-treated mice for 14 days thrice a week. Serum biochemical parameters, antioxidant status, and gene expression analysis of eNOS, PPAR-α, NF-kB, cFn, AT1-R, and ETA-R were determined in cardiac tissues with confirmation by histopathology. Inhibition of UGT1A1 significantly elevated serum unconjugated bilirubin within a physiological range. Furthermore, induced mild hyperbilirubinemia reduces hyperlipidemia, improves antioxidant status, and significantly increases the expression of the cardiac PPAR-α gene while decreasing, ETA-R, iNOS, NF-kB, cFn and AT1-R gene expression in CsA-treated mice. Importantly, mild unconjugated hyperbilirubinemia within physiological ranges may be used as a novel therapeutic strategy to lower hyperlipidemia, atherosclerosis, hypertension, and the CVD outcomes in CsA- treated transplant recipients.

Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis.

Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects. To evaluate thelong-term safety and efficacy of seladelpar in patients with PBC. In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16.

Ethyl acetate fraction of Mucuna pruriens leaves mitigates diclofenac-induced hepatotoxicity via modulation of biochemical and histological parameters changes in Wistar Rats

Mucuna pruriens contains saponins and flavonoids, which help to decrease cholesterol, treat hypertension, provide protein and vitamins and prevent premature ageing. This research followed the NIH guidelines (NIH publication 85–23, revised in 1996). Rats weighing 200–250 g were assigned into six groups (n = 6), normal saline only (control), normal saline (NS), Ethyl acetate fraction of Mucuna pruriens leaves (EAFMP) (100, 200 and 400 mg/kg) and Silymarin (100 mg/kg) treated orally for five days, diclofenac (DFN) was administered on days 3 and 4 via intraperitoneal route, biochemical and histology parameters were determined in serum and liver. This research revealed that treatment with EAFMP reversed the elevation of liver enzymes, total bilirubin, LDL and total cholesterol and lipid peroxidation; liver SOD, GSH, and CAT were elevated in EAFMP and Silymarin groups. The hepatic histological lesions in EAFMP were reduced in a dose-dependent manner. This research shows that EAFMP attenuates the deleterious effect of diclofenac-induced liver toxicity in rats.

Predictors of Survival After Heart Transplant in the New Allocation System: A UNOS Database Analysis.

Clinical predictors of posttransplant graft loss since the United Network for Organ Sharing (UNOS) heart allocation system change have not been well characterized. Single organ adult heart transplants from the UNOS database were identified (n = 10,252) and divided into a test cohort (n = 6,869, 67%) and validation cohort (n = 3,383, 33%). A Cox regression analysis was performed on the test cohort to identify recipient and donor risk factors for posttransplant graft loss. Based on the risk factors, a score (max 16) was developed to classify patients in the validation cohort into risk groups of low (≤1), mid (2-3), high (≥4) risk. Recipient factors of advanced age, Black race, recipient blood group O, diabetes, etiology of heart failure, renal dysfunction, elevated bilirubin, redo-transplantation, elevated pulmonary artery pressure, transplant with a durable ventricular assist device, or transplant on extracorporeal membrane oxygenation (ECMO) or ventilator were associated with more posttransplant graft loss. Donor factors of ischemic time and donor age were also associated with outcomes. One year graft survival for the low-, mid-, high-risk groups was 94%, 91%, and 85%, respectively. In conclusion, easily obtainable clinical characteristics at time of heart transplant can predict posttransplant outcomes in the current era.

Bilirubin impacts microglial autophagy via the Akt-mTOR signaling pathway.

Bilirubin encephalopathy is a severe complication of neonatal hyperbilirubinemia. With elevation of serum unconjugated bilirubin (UCB) levels, UCB crosses the blood-brain barrier and possibly leads to neurological dysfunction. Neuroinflammation is recognized as a prominent pathological feature in bilirubin encephalopathy. Recent studies have suggested that autophagy plays a crucial role in the inflammatory response. However, the potential effect of microglial autophagy in the pathogenesis of bilirubin encephalopathy remains uncertain. The invitro findings verified that in primary cultured microglia, UCB significantly reduced the ratio of LC3B-II to LC3B-I and downregulated the expression of ATG5, Beclin-1, and ATG7, while increasing the expression of p62/SQSTM1. The results showed that UCB could decrease the number of mCherry-EGFP-LC3 positive puncta, even when chloroquine (CQ) was applied to block the microglial autophagy flux. Mechanistically, UCB was found to upregulate the expression of TLR4 and increase the phosphorylation levels of Akt and mammalian target of rapamycin (mTOR). Promoting microglial autophagy by treatment with Rapamycin (RAPA), an mTOR inhibitor, decreased the levels of NOD-like receptor protein 3 (NLRP3) inflammasome components and IL-1β, rescued microglial overactivation, and improved neurological functions. These data indicated that UCB could impact microglial autophagy via the Akt-mTOR signaling pathway and synergistically promote neuroinflammatory responses. Enhancing autophagy might disrupt the assembly of NLRP3 inflammasome, attenuate UCB-induced neuroinflammation, and improve the prognosis of model rats with bilirubin encephalopathy. In conclusion, this study implies that regulating microglial autophagy might be a promising therapeutic strategy for bilirubin encephalopathy.

Squamous cell carcinoma of the cystic duct: A case report and literature review.

Pure squamous cell carcinoma (SCC) of the gallbladder is a rare malignant biliary tract tumor predominantly found in the body and neck of the gallbladder. However, its occurrence in the cystic duct is even rarer. Given its rarity, no established guidelines or consensus currently exist regarding the treatment of pure SCC of the gallbladder. We report an unusual case of SCC originating from the cystic duct with the intent of providing insights into the therapeutic approach for this type of malignancy. A male patient presented to our hospital with acute cholecystitis. Unexpectedly, imaging revealed gallbladder malignancy. Pathologic examination after surgery confirmed SCC of the cystic duct. Despite elevated bilirubin levels, we were able to exclude hilar involvement, enabling radical tumor resection. Intraoperatively, we discovered that the tumor was located in the cystic duct, a site associated with a high likelihood of invasion into neighboring organs. The tumor demonstrated a predominantly exophytic growth pattern, which prompted us to refrain from extending the resection range, thereby striking a balance between complete tumor removal and surgical trauma. We performed liver wedge resection only to ensure a negative resection margin while preserving the anatomical structure to the greatest extent possible. Postoperative recovery was rapid and uncomplicated. Pathological examination confirmed pure SCC, which led us to initiate a regimen of nab-paclitaxel and cisplatin, which is known to be effective in other organ SCCs. Remarkably, the patient experienced a rare and severe posttreatment cardiovascular event. Consequently, we switched the patient to a chemotherapy regimen of gemcitabine and cisplatin, which ultimately yielded positive clinical outcomes. no evidence of tumor recurrence was observed within 1 year after surgery. The diagnosis and therapeutic strategy for rare tumors such as gallbladder SCC should be meticulously tailored based on their unique characteristics to optimize postoperative patient outcomes.

Correlation between Bilirubin Elimination with the Cytokine Adsorber CytoSorb® and Mortality in Critically Ill Patients with Hyperbilirubinemia

Introduction: Hyperbilirubinemia is often the first evidence for any kind of liver disorder and over one-third of all patients in intensive care units (ICU) show elevated bilirubin concentrations. In critically ill patients, high concentrations of serum bilirubin are correlated with a poor outcome. Therapies to lower bilirubin concentrations are often just symptomatically and their effect on the patients’ outcome is hardly evaluated. Therefore, this study investigates whether the extracorporeal elimination of bilirubin with the cytokine adsorber CytoSorb^® (CS) reduces mortality in patients with hyperbilirubinemia. Methods: Patients with bilirubin concentrations >10 mg/dL at the ICU were screened for evaluation from 2018 to 2020. Patients with kidney replacement therapy and older than 18 years were included. Patients with continuously decreasing bilirubin concentrations after liver transplantation or other liver support systems (i.e., Molecular Adsorbents Recirculating System [MARS^®], Advanced Organ Support [ADVOS]) were excluded. CS therapy was used in clinical routine and was indicated by the treating physicians. Statistical analysis was performed with IBM SPSS statistics utilizing a multivariate model. Primary outcome measure was the effect of CS on the 30-day mortality. Results: Data from 82 patients (mean Simplified Acute Physiology Score [SAPS] II: 74 points, mean bilirubin: 18 mg/dL, mean lactate: 3.7 mmol/L) were analyzed. There were no significant differences in patients with and without CS treatment. The multivariate model showed no significant effect of CS therapy (p = 0.402) on the 30-day mortality. In addition, a significant effect of bilirubin concentration (p = 0.274) or Model for End-Stage Liver Disease score (p = 0.928) on the 30-day mortality could not be shown. In contrast, lactate concentration (p = 0.001, b = 0.044) and SAPS II (p = 0.025, b = 0.008) had significant impact on 30-day mortality. Conclusion: The use of CS in patients with hyperbilirubinemia did not result in a significant reduction in 30-day mortality. Randomized and controlled studies with mortality as primary outcome measure are needed in the future to justify their use.

Assessment of bilirubin levels in patients with cirrhosis via forehead, sclera and lower eyelid smartphone images.

One of the key biomarkers evaluating liver disease progression is an elevated bilirubin level. Here we apply smartphone imaging to non-invasive assessment of bilirubin in patients with cirrhosis. Image data was processed using two different approaches to remove variation introduced by ambient conditions and different imaging devices-a per-image calibration using a color chart in each image, and a two-step process using pairs of flash/ no-flash images to account for ambient light in combination with a one-time calibration. For the first time, results from the forehead, sclera (white of the eye) and lower eyelid were compared. The correlation coefficients between the total serum bilirubin and the predicted bilirubin via the forehead, sclera and lower eyelid were 0.79, 0.89 and 0.86 (all with p<0.001, n = 66), respectively. Given the simpler image capture for the sclera, the recommended imaging site for this patient cohort is the sclera.

FRI097 A Case Of Evolocumab-induced Transaminitis Revealing A Gastrointestinal Melanoma

Abstract Disclosure: C. Nava Suarez: None. J.V. Mayrin: None. J. Prater: None. W. Jiang: None. Introduction: Proprotein convertase subtilisin/Kexin type 9 (PCSK-9) inhibitors, like evolocumab, are anti-lipid drugs with potent lipid-lowering effect, potential cardiovascular benefits, and good tolerability. They are monoclonal antibodies directed against the PCSK-9 hepatic receptor decreasing serum LDL-cholesterol. Although PCSK-9 inhibitors are usually safe, transaminitis has been reported in the literature a few times. Little is known about the mechanism of action of this injury and many clinicians are not familiar with this complication. Currently, there are no guidelines for dose adjustment in patients with advanced liver disease, and conflicting data on their effect on patients with established liver disease is emerging. We report a case of acute and intermittent transaminitis with the use of evolocumab that lead to the discovery of malignant melanoma in the patient’s gallbladder and jejunum. Case: A 74-year-old male with a past medical history of dyslipidemia, type 2 Diabetes Mellitus, and cutaneous melanoma 9 years priorly presented for a routine follow-up. He had been on evolocumab for a year after developing statin-induced myalgias. His physical exam was unremarkable. Routine blood work revealed new onset transaminitis almost 5 times above the upper limit of normal with AST 174 IU/L and ALT 230 IU/L (40 IU/L and 44 IU/L respectively). The rest of his liver panel was unremarkable. A liver ultrasound showed a 5 cm hyperechoic polypoid lesion within the gallbladder. No signs of choledocholithiasis were seen, potentially explaining the lack of bilirubin elevation; hepatic steatosis without cirrhosis was also seen. Given its higher sensitivity, MRCP confirmed the gallbladder mass. Liver enzymes were trended for more than 80 days, and intermittent elevation of serum transaminases coincided with the administration of evolocumab with normalization of the transaminases in between episodes. An open cholecystectomy confirmed the diagnosis of malignant melanoma of the gallbladder with an incidental jejunal metastasis. Oncologic treatment was initiated. Serum transaminases normalized following discontinuation of evolocumab and remain normal. Conclusion: As this case illustrates, serial monitoring of transaminases can reveal the presence of liver injury after initiation of PCSK-9 inhibitors, and further investigation with specialized liver imaging should be considered to exclude other differential diagnoses. Currently, there is little known about the hepatotoxic effect of these drugs and researchers are currently looking for possible causes. Theoretical mechanisms of injury include autoimmune cross-reactivity like with other monoclonal antibodies or progression of chronic liver disease. Clinicians should be aware of this potential side effect even though it is not a common one, given that many patients who start treatment may have underlying liver disease. Presentation: Friday, June 16, 2023

Predictors of Hepatotoxicity in Patients with Metastatic Solid Tumors Treated with Immune Checkpoint Inhibition (ICI) and Liver-Directed SBRT

Liver-metastasis-directed SBRT (LM-SBRT) alone provides durable local control for liver metastases with low rates of toxicity when adhering to established dose constraints. Whether these constraints are sufficient in the context of concurrent ICI is not established. To determine whether LM-SBRT contributes to hepatotoxic adverse events (HAE) in patients receiving ICI, we analyzed potential predictors of HAE in a prospectively evaluated cohort of clinical trial patients treated with both SBRT and ICI. Patients with metastatic solid tumors were included from three trials of multi-site SBRT with ICI given concurrently or shortly after SBRT provided they received all study treatments and were monitored for adverse events. ICI agents included pembrolizumab alone or dual agent ICI with nivolumab and either cabiralizumab, urelumab, or ipilimumab. LM-SBRT was delivered to 45 Gy in 3 fr with mean liver dose (MLD) limited to 16 Gy and <700 cc of liver receiving 17.1 Gy. HAE were defined using CTCAE 4.0 as: elevation of AST, ALT, bilirubin or alkaline phosphatase; autoimmune hepatitis; hepatic failure; or cholecystitis. HAE were included if rated at least possibly related to treatment by the trial monitoring committee. Cumulative incidence (CI) of HAE was modeled with death as a competing risk. Competing risks regression was performed using Fine-Gray modeling. Two hundred thirteen patients were evaluable. Median follow-up was 10 months. Median age was 61, 90 had liver metastases at treatment, 65 received SBRT to a liver lesion, 15 had underlying liver disease (cirrhosis or hepatic steatosis) and 13 patients had a primary liver cancer. Dual agent ICI was given to 97 patients. Table 1 shows CI at 6 months of grades 1-4 HAE in all patients, LM-SBRT patients and non-liver SBRT patients (NL-SBRT). None experienced grade 5 HAE. There was no significant difference in CI of any grade of HAE between LM-SBRT and NL-SBRT patients. This was also true when comparing LM-SBRT patients to NL-SBRT patients with <0.1 Gy MLD. ICI dose reduction or cessation due to HAE occurred in 4 patients, none of whom received LM-SBRT. On univariate analysis, underlying liver disease and dual agent ICI were significantly associated with grade 2+ HAE while age, LM-SBRT, MLD, primary liver cancer and presence of liver metastases at treatment were not. On multivariate analysis, underlying liver disease and dual agent ICI remained significantly associated with grade 2+ HAE (HR: 6.7, 95% CI 2.3 - 19.1; 4.7, 95% CI 1.7 - 13.0). LM-SBRT and MLD were not significant on MVA. LM-SBRT did not significantly increase the risk for hepatotoxicity in patients receiving ICI when respecting the above dose constraints. Risk for hepatotoxicity appears to be driven by dual agent ICI and underlying liver disease.

Clinical and genotypic analysis of hereditary spherocytosis combined with cholestasis among pediatric patients

Objective: To understand the clinical and genetic characteristics of hereditary spherocytosis (HS) combined with cholestasis among pediatric patients. Methods: 12 cases of HS children accompanied by cholestasis at Hunan Children's Hospital were selected as the research subjects between January 2013 and December 2022. Clinical data were collected. Whole-exome sequencing was performed by second-generation sequencing. Suspected pathogenic mutation sites were verified by Sanger sequencing. Results: All pediatric patients were admitted to the hospital due to their yellow skin tone. Eight cases (66.67%) had a positive family history. The clinical manifestations were jaundice, splenomegaly (12/12), abdominal pain, anemia (4/12), and hepatomegaly (5/12). All pediatric patients had decreased hemoglobin, an increased reticulocyte ratio, total bilirubin and direct bilirubin, a positive erythrocyte fragility test, and remarkable spherical erythrocytes in their peripheral blood. Seven cases had elevated aminotransferase; four cases had severely elevated aminotransferase and bilirubin; eight cases had biliary calculi; and two cases had a dilated biliary tract. Liver pathological examination showed mild damage to the liver cells (G1S1) in three pediatric cases. Five children had a total of six unreported mutations: SPTB gene c.2431_2450del, c.4974-2A > G, c.2575G > A, and exon 22-35 deletion; ANK1 gene: c.2379-2380delC; and c .6dupC. Children still had abnormal bilirubin levels following treatment. Two pediatric cases underwent splenectomy. Bilirubin and hemoglobin levels returned to normal after surgery. Conclusion: Children with HS may experience cholestasis, and those with poor treatment results may consider undergoing a splenectomy. Six new types of variants have expanded the HS gene mutation spectrum.

Biliary fistula and late recurrence of liver hydatid cyst: Role of cysto-biliary communication: A prospective multicenter study.

Hydatid cyst disease (HCD) is common in certain locations. Surgery is associated with postoperative biliary fistula (POBF) and recurrence. The primary aim of this study was to identify whether occult cysto-biliary communication (CBC) can predict recurrent HCD. The secondary aim was to assess the role of cystic fluid bilirubin and alkaline phosphatase (ALP) levels in predicting POBF and recurrent HCD. To identify whether occult CBC can predict recurrent HCD. The secondary aim was to assess the role of cystic fluid bilirubin and ALP levels in predicting POBF and recurrent HCD. From September 2010 to September 2016, a prospective multicenter study was undertaken involving 244 patients with solitary primary superficial stage cystic echinococcosis 2 and cystic echinococcosis 3b HCD who underwent laparoscopic partial cystectomy with omentoplasty. Univariable logistic regression analysis assessed independent factors determining biliary complications and recurrence. There was a highly statistically significant association (P ≤ 0.001) between cystic fluid biochemical indices and the development of biliary complications (of 16 patients with POBF, 15 patients had high cyst fluid bilirubin and ALP levels), where patients with high bilirubin-ALP levels were 3405 times more likely to have biliary complications. There was a highly statistically significant association (P ≤ 0.001) between biliary complications, biochemical indices, and the occurrence of recurrent HCD (of 30 patients with recurrent HCD, 15 patients had high cyst fluid bilirubin and ALP; all 16 patients who had POBF later developed recurrent HCD), where patients who developed biliary complications and high bilirubin-ALP were 244.6 and 214 times more likely to have recurrent hydatid cysts, respectively. Occult CBC can predict recurrent HCD. Elevated cyst fluid bilirubin and ALP levels predicted POBF and recurrent HCD.

Fetal Third-Trimester Functional Cardiovascular Abnormalities and Neonatal Elevated Bilirubin Level.

The aim of the study was to analyze the neonatal outcomes of fetuses with diagnosed functional cardiovascular abnormalities, also considering the connection with neonatal hyperbilirubinemia. It was an observational study of 100 neonates who had fetal echocardiography examinations in the third trimester (mean gestational age during the last echocardiography was 34 ± 3 weeks and mean birth weight was 3550 g). There were two groups: A: normal heart anatomy + no functional anomalies; group B: normal heart anatomy + functional abnormalities. Hyperbilirubinemia was defined as a bilirubin level of >10 mg%. In group A, there were 72 cases and only 5 cases despite having normal heart anatomy and normal heart study that presented additional problems. In group B (28 cases), the prenatal functional findings included tricuspid regurgitation (TR) (15 cases, 53%), pericardial effusion (4 cases, 14%), myocardial hypertrophy (4 cases, 14%), cardiomegaly (2 cases, 7%), abnormal bidirectional blood flow across the foramen ovale (3 cases, 11%), aneurysm of atrial septum (2 case, 7%), abnormal E/A ratio for mitral and tricuspid valve (1 case, 3%), bright spot (3 case, 11%), abnormal Doppler flow in ductus arteriosus compared to aortic arch (difference >60 cm/s) (1 case, 3%), supraventricular tachycardia (SVT) (1 case), and mitral regurgitation (1 case, 3%). In group A (n = 72 cases), bilirubin levels of >10 mg/dL were observed in 8% of newborns. In group B (n = 28), bilirubin levels of > 10 m/dL were observed in 46% of cases and TR was present in group B in 53% of cases (15/28 cases). The difference between group A and B in terms of elevated bilirubin levels was statistically significant (p < 0.001). In the case of fetal normal heart anatomy and normal heart study, a good neonatal outcome may be expected. When fetal cardiovascular functional abnormalities in normal heart anatomy are detected, with special attention paid to tricuspid valve regurgitation, a neonatal elevated bilirubin level (mean 11 mg/dL, range 10-15 mg/dL) may be expected.

OS09.6.A A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY OF INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR (PMLM, NCT 05289908)

Abstract BACKGROUND There has never been a dose-escalation study on intrathecal pemetrexed (IP) with vitamin supplementation. This phase I/II study was to evaluate the maximum-tolerated dosage (MTD) of IP with vitamin supplementation and the antitumor activity for leptomeningeal metastases (LM) from solid tumors. MATERIAL AND METHODS Phase I study followed the classic 3 + 3 design, with the dose of IP escalated from 15 mg. Phase II followed the Simon 2-stage design with the recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Clinically stable or improved patients continued IP once a month (maintenance therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. All patients were assessed to investigate safety, CRR and overall survival (OS). RESULTS Between Feb 2022 and Jan 2023, 34 patients (male: 16; female: 18; age: 45-68 years; median: 56 years) were enrolled, including non-small lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Thirty-three patients had a confirmed LM diagnosis (positive CSF cytology). Remaining one had probable diagnosis (positive neuroimaging with typical clinical signs). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). The dose was escalated to 20 mg. Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. The MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. 41.2% (14/34) patients received maintenance therapy. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs, including myelosuppression (11), elevation of hepatic aminotransferases (EHA) (5), elevation of blood bilirubin (EBB) (1), arachnoiditis (1), radiculitis (1), fatigue (1) and nausea (1). The overall CRR was 41.2% (14/34) by neuro-oncology proposal criteria, including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. In a total of 28 patients receiving IP at 15 mg, 50% (14/28) patients showed grade ≥ 3 AEs, including myelosuppression (9), EHA (10), fatigue (1) and nausea (1). The CRR was 46.4% (13/28) in patients at 15 mg IP. Median survival was 7.6 (range 0.3-13.7) months in phase I, while has not yet been achieved in phase II until March 15, 2023. CONCLUSION MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.

Elevated Serum Total Bilirubin Might Indicate Poor Coronary Conditions for Unstable Angina Pectoris Patients beyond as a Cardiovascular Protector.

Serum total bilirubin (STB) is recently more regarded as an antioxidant with vascular protective effects. However, we noticed that elevated STB appeared in unstable angina pectoris (UAP) patients with diffused coronary lesions. We aimed to explore STB's roles in UAP patients, which have not been reported by articles. 1120 UAP patients were retrospectively screened, and 296 patients were finally enrolled. They were grouped by Canadian Cardiovascular Society (CCS) angina grades. The synergy between PCI with TAXUS stent and cardiac surgery score (SYNTAX score) and corrected thrombolysis in myocardial infarction flow count (CTFC) were adopted to profile coronary features. The results showed that STB, mean platelet volume (MPV), hs-CRP, fasting blood glucose (FBG), red blood cell width (RDW), and CTFC elevated significantly in the CCS high-risk group. STB (B = 0.59, 95% CI: 0.39-0.74, P < 0.01) and MPV (B = 0.86, 95% CI: 0.42-1.31, P < 0.01) could indicate SYNTAX score changes for these patients. STB (≥21.7 μmol/L) could even indicate a coronary slow flow condition (AUC: 0.88, 95% CI: 0.84-0.93, P < 0.01). Moreover, UAP patients with elevated STB had a lower event-free survival rate by the Kaplan-Meier curve. STB ≥21.7 μmol/L could reflect a poor coronary flow status and indicate 1-year poor outcomes for these patients (HR: 2.01, 95% CI: 1.06-3.84, P < 0.01). Elevated STB in UAP patients has a close relationship with changes in SYNTAX score. STB (over 21.7 μmol/L) could even indicate a coronary slow flow condition and poor outcomes for the UAP patients.

Gilbert’s syndrome as a protection against the development of other diseases

Introduction and purpose Gilbert's syndrome is a condition caused by a mutation in the gene responsible for the enzyme UDP-glucuronosyltransferase 1A1, which conjugates bilirubin in hepatocytes. Its less efficient functioning results in disorder of bilirubin metabolism which leads to increased level of this compound. It has been observed that there is interesting correlation between elevated levels of bilirubin and the risk of developing certain diseases in patients with this condition. The aim of this review is to understand the correlation between elevated bilirubin levels and the risk of developing selected diseases in individuals with Gilbert's syndrome and how to use this knowledge in innovative therapeutic options. &#x0D; State of knowledge Bilirubin was considered a non-functional waste product of heme breakdown, used to be seen as a concerning indicator of liver disease or even a potentially harmful substance for the nervous system. However, lately it turns out that bilirubin has strong antioxidant properties, which help to scavenge free radicals and inhibit lipid oxidation. Recent studies have shown that even slightly elevated levels of bilirubin in the blood, such as those commonly found in individuals with Gilbert's syndrome may protect these patients against diseases associated with increased oxidative stress, an overactive immune response and metabolic dysfunction. &#x0D; Conclusions As a result, individuals with Gilbert's syndrome are observed to have a lower risk of developing diseases related to oxidative stress, such as cardiovascular diseases and cancer. In these patients mortality rate compared to the population with normobilirubinemia is decreased. Based on available studies, it has also been concluded that inducing mild hyperbilirubinemia - iatrogenic Gilbert's syndrome - using appropriate substances may have health benefits.

The Clinical Presentations of Liver Abscess Development After Endoscopic Retrograde Cholangiopancreatography with Choledocholithiasis: A 17-Year Follow-Up.

Endoscopic Retrograde Cholangiopancreatography (ERCP), used for choledocholithiasis treatment, carries a risk of pyogenic liver abscess (PLA) due to communication between the biliary system and bowel contents. However, limited data exists on this issue. This study aims to identify the risk factors pertaining to liver abscesses following ERCP lithotomy. We conducted a retrospective case series across multiple centers to evaluate patients who developed PLA after ERCP for choledocholithiasis. Data was obtained from the Chung Gung Research Database (January 2001 to December 2018). Out of 220 enrolled patients, 195 were categorized in the endoscopic sphincterotomy (ES) group, while 25 were in the non-ES group for further analysis. The non-ES group had significantly higher total bilirubin levels compared to the ES group (4.3 ± 5.8 vs 1.9 ± 2.0, p<0.001). Abscess size, location, and distribution (single or multiple) were similar between the two groups. The most common pathogens were Klebsiella pneumoniae and Escherichia coli. Pseudomonas infection was significantly less prevalent in the ES group compared to the non-ES group (3.6% vs 16.7%, p=0.007). Patients with concurrent malignancies (HR: 9.529, 95% CI: 2.667-34.048, p=0.001), elevated total bilirubin levels (HR: 1.246, 95% CI: 1.062-1.461, p=0.007), multiple abscess lesions (HR: 5.146, 95% CI: 1.777-14.903, p=0.003), and growth of enterococcus pathogens (HR: 4.518, 95% CI: 1.290-15.823, p=0.001) faced a significantly higher risk of in-hospital mortality. PLA incidence was higher in the ES group compared to the non-ES group following ERCP for choledocholithiasis. Attention should be given to significant risk factors, including concurrent malignancies, elevated total bilirubin levels, multiple abscess lesions, and growth of enterococcus pathogens, to reduce in-hospital mortality.

Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study.

We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC). After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis. Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.

Clinical features of HIV positive talaromycosis marneffei patients and development of a risk prediction model

AimsThe purpose of this study was to establish and verify a nomogram to predict the prognosis of patients with human immunodeficiency virus (HIV)-related talaromycosis marneffei and evaluate the prognosis. MethodsWe examined the acquired immune deficiency syndrome (AIDS) patients hospitalized in the Fourth People's Hospital of Nanning from 2018 to 2020 with an aetiological diagnosis of Talaromyces marneffei infection. Logistic regression analysis was used to identify the independent risk factors for relapse or death of the prognosis of Talaromyces marneffei infection. According to the regression coefficient, the corresponding nomograph prediction model was drawn. ResultsA total of 400 patients were included, including 321 males and 79 females. Recurrence or death occurred in 70 cases (17.5%). The area under the receiver operator characteristic curve (ROC) of the established model was 0.716 with good discrimination, calibration, and clinical effectiveness. The risks of age between 45 and 60 years old and <40 years old were successively higher than that of >60 years old, and the risks of G test <50 pg/ml and >100 pg/ml were higher than that of 50–100 pg/ml. Respiratory failure, decreased albumin and elevated total bilirubin are risk factors for relapse or death in HIV patients infected with Talaromyces marneffei. ConclusionThis model can accurately predict the prognosis of HIV complicated with Talaromyces marneffei infection.