Immune-related Liver Injury is a Poor Prognostic Factor in Patients with Nonsmall Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

It remains unclear whether severe liver immune-related adverse events (liver-irAEs) can affect the prognosis in nonsmall cell lung carcinoma (NSCLC) patients. Of the 365 NSCLC patients treated with immune checkpoint inhibitors (ICIs), 19 suffered from severe liver-irAEs (grade ≥3). The median time-to-onset of liver-irAEs was 53 days postinjection of the first ICI. The progression-free survival and overall survival of the liver-irAEs group (median 69 and 262 days, respectively) were significantly worse than the nonliver-irAEs group (128 and 722 days; P = 0.010 and P = 0.007; respectively). In conclusion, liver-irAEs were associated with poor prognosis in NSCLC patients.

Treatment outcomes among patients admitted to hospital with antiretroviral and/or antituberculosis drug-induced liver injury.

BACKGROUND: South Africa (SA) has among the highest rates of HIV and tuberculosis (TB) in the world. Antituberculosis and antiretroviral treatment (ART) can cause drug-induced liver injury (DILI), consequences of which are disease relapse, treatment failure and drug resistance. OBJECTIVES: To: (i) determine the demographics of patients with DILI and the proportion of patients on antituberculosis drugs v. antiretroviral therapy or both; (ii) determine the median time to DILI after starting medication, and patterns of clinical presentation; (iii) determine the numbers of patients successfully re-challenged to initial therapy as inpatients; and (iv) determine the in-hospital mortality rate and predictors of all-cause mortality. METHODS: This was a retrospective record review of adult patients with DILI admitted to a tertiary hospital in Johannesburg, SA, between October 2015 and February 2017. Data on drug history, biochemical investigations and relevant imaging were collected. RESULTS: The total sample was 129 records: 79 (61.2%) were males, 46 (35.7%) had TB DILI, 29 (22.5%) had ART DILI, and 54 (41.9%) had mixed TB/ART DILI. Only 7.4% (2/27) of those with ART DILI and 30.6% (11/36) with TB DILI were re-challenged to their original regimen by discharge. Patients were followed from admission until the earlier of death (10 with TB DILI, 2 with ART DILI and 9 with mixed DILI) or discharge (after a median (interquartile range) of 14.0 (9 - 23) days). In adjusted analysis, severe DILI at admission predicted all-cause mortality (adjusted hazard ratio 8.58; 95% confidence interval 1.13 - 65.4). CONCLUSIONS: This study is one of only a few analyses of hospitalised patients with DILI in SA. Among those with severe DILI, outcomes are poor, the majority cannot tolerate standard regimens, and mortality is high.

Drug-induced liver injury in Australia, 2009-2020: the increasing proportion of non-paracetamol cases linked with herbal and dietary supplements.

OBJECTIVE: To compare the characteristics and outcomes of drug-induced liver injury (DILI) caused by paracetamol and non-paracetamol medications, particularly herbal and dietary supplements. DESIGN: Retrospective electronic medical record data analysis. SETTING, PARTICIPANTS: Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009-2020. MAIN OUTCOME MEASURES: 90-day transplant-free survival; drugs implicated as causal agents in DILI. RESULTS: A total of 115 patients with paracetamol-related DILI and 69 with non-paracetamol DILI were admitted to our centre. The most frequently implicated non-paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti-tuberculosis medications (six, 9%), and anti-cancer medications (five, 7%). The number of non-paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009-11 to 9 of 19 (47%) during 2018-20 (linear trend: P = 0.011). Despite higher median baseline model for end-stage liver disease (MELD) scores, 90-day transplant-free survival for patients with paracetamol-related DILI was higher than for patients with non-paracetamol DILI (86%; 95% CI, 79-93% v 71%; 95% CI, 60-82%) and herbal and dietary supplement-related cases (59%; 95% CI, 34-85%). MELD score was an independent predictor of poorer 90-day transplant-free survival in both paracetamol-related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09-3.74) and non-paracetamol DILI (aHR, 1.24; 95% CI, 1.14-1.36). CONCLUSION: In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety-day transplant-free survival for patients with non-paracetamol DILI, especially those with supplement-related DILI, is poorer than for those with paracetamol-related DILI.

Hepatic Toxicity After Selective Chemoembolization Is Associated With Decreased Survival Among Patients With Hepatocellular Carcinoma.

OBJECTIVE. The purpose of this study was to identify risk factors for and outcomes of hepatotoxicity after selective chemoembolization of hepatocellular carcinoma. MATERIALS AND METHODS. This retrospective study included 182 patients (136 men and 46 women; median age, 63 years [interquartile range, 57-70 years]) who underwent 338 consecutive doxorubicin drug-eluting bead (DEB) chemoembolization procedures between 2011 and 2014. Outcomes were assessed until November 2019. In 97% of procedures, two or fewer segments were targeted. The Barcelona Clinic Liver Cancer (BCLC) stage was 0 or A for 77 procedures (22.8%), B for 75 (22.2%), C for 122 (36.1%), and D for 64 (18.9%). Hepatotoxicity was defined as worsened ascites or encephalopathy or as grade 3 or 4 elevations in liver function test results, creatinine levels, or the international normalized ratio within 30 days. Risk factors were assessed by univariate and multivariable generalized estimating equations. Transplant-free survival was assessed using Cox proportional hazard models. RESULTS. Hepatotoxicity was observed after 84 of 338 procedures (24.9%) performed for 70 of 182 patients (38.5%) and was irreversible for 40 procedures (11.8%). On multivariable analysis, risk factors for irreversible toxicity included Child-Pugh class C liver function (odds ratio [OR], 4.4; 95% CI, 1.0-19.0; p = .04), BCLC stage C (OR, 5.0; 95% CI, 1.6-16.0; p = .006) or D (OR, 7.4; 95% CI, 2.1-25.5; p = .002) disease, TIPS or hepatofugal portal venous flow (OR, 6.3; 95% CI, 2.3-17.0; p < .001), and a serum α-fetoprotein level of 200 ng/mL or greater (OR, 2.6; 95% CI, 1.1-6.1; p = .03). Irreversible toxicity was associated with reduced transplant-free survival among patients who were ineligible for liver transplant (hazard ratio, 2.5; standard error, 0.42; p = .03). CONCLUSION. Irreversible hepatotoxicity was common after selective chemoembolization in patients with advanced stage disease, an elevated serum α-fetoprotein level, or reduced hepatic portal venous perfusion, and it may hasten death among patients who are ineligible for liver transplant.

Prognostic Value of the 13 C-Methacetin Breath Test in Adults with Acute Liver Failure and Non-acetaminophen Acute Liver Injury.

BACKGROUND AND AIMS: The 13 C-methacetin breath test (MBT) is a noninvasive, quantitative hepatic metabolic function test. The aim of this prospective, multicenter study was to determine the utility of initial and serial 13 C-MBT in predicting 21-day outcomes in adults with acute liver failure (ALF) and non-acetaminophen acute liver injury (ALI). APPROACH AND RESULTS: The 13 C-MBT BreathID device (Exalenz Biosciences, Ltd.) provided the percent dose recovery (PDR) for a duration of 60 minutes after administration of 13 C-methacetin solution as the change in exhaled 13 CO2 /12 CO2 compared with pre-ingestion ratio on study days 1, 2, 3, 5, and 7. Results were correlated with 21-day transplant-free survival and other prognostic indices. A total of 280 subjects were screened for enrollment between May 2016 and August 2019. Median age of the 62 enrolled patients with adequate data was 43 years, 79% were Caucasian, 76% had ALF with the remaining 24% having ALI. The mean PDR peak on day 1 or day 2 was significantly lower in nonsurvivors compared with transplant-free survivors (2.3%/hour vs. 9.1%/hour; P < 0.0001). In addition, serial PDR peaks were consistently lower in nonsurvivors versus survivors (P < 0.0001). The area under the receiver operating characteristic curve (AUROC) of the 13 C-MBT in the combined cohort was 0.88 (95% CI: 0.79-0.97) and higher than that provided by King's College (AUROC = 0.70) and Model for End-Stage Liver Disease scores (AUROC = 0.83). The 13 C-MBT was well tolerated with only two gastrointestinal adverse events reported. CONCLUSIONS: The 13 C-MBT is a promising tool to estimate the likelihood of hepatic recovery in patients with ALF and ALI. Use of the PDR peak data from the 13 C-MBT point-of-care test may assist with medical decision making and help avoid unnecessary transplantation in critically ill patients with ALF and ALI.

Coagulopathy, Bleeding Events, and Outcome According to Rotational Thromboelastometry in Patients With Acute Liver Injury/Failure.

BACKGROUND AND AIMS: Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival. APPROACH AND RESULTS: A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 109 /L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation [P < 0.001], assembly [P = 0.02], firmness at 10 minutes [P = 0.05], and maximal firmness [P = 0.06]). Patients with more severe systemic complications (high-grade hepatic encephalopathy and need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypocoagulable ROTEM parameters (clot initiation (P = 0.005), stiffness at 10 minutes (P = 0.05), and maximal stiffness by fibrin assembly (P = 0.004)) were observed in patients who died or underwent liver transplantation than those who survived with their native liver. CONCLUSIONS: In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.

Current fatality rate of suspected cyclopeptide mushroom poisoning in the United States.

OBJECTIVE: This study was designed to determine the fatality rate of suspected cyclopeptide-containing mushroom ingestions reported to the National Poison Data System (NPDS). BACKGROUND: Although silibinin reportedly improves survival in suspected cyclopeptide-containing mushroom ingestions, the greater than 20% untreated fatality rate that is often cited is based on decades-old data. An ongoing open-label silibinin trial will likely use historical cases as comparators. A recent single poison control center (PCC) study showed a fatality rate of 8.3%. This study was designed to validate those findings in the NPDS. METHODS: This study was an 11-year (1/1/2008-12/31/2018) retrospective review of suspected cyclopeptide-containing mushroom ingestions reported to NPDS. Inclusion and exclusion criteria were the same as the ongoing silibinin trial: Age >2-years-old; history of eating foraged mushrooms; gastrointestinal symptoms within 48 h of mushroom ingestion; and aminotransferases above the upper limit of normal within 48 h after ingestion. Each original participating PCC confirmed eligibility, diagnosis, treatment, and outcome on included cases. RESULTS: During the study period, 8,953 mushroom exposures were reported to NPDS, of which 296 met inclusion criteria. The PCC survey response rate was 60% (28/47 PCCs), and the individual case response rate was 59% (174/296). Twenty-six cases were subsequently excluded leaving 148 included cases. The overall mortality rate was 8.8% (13/148). Mortality in silibinin/silymarin-treated vs untreated cases was 9.5% (4/42), vs 8.5% (9/106), respectively. A mycologist identified mushrooms in 16.9% of cases (25/148), of which 80% (20/25) were cyclopeptide-containing. Among these confirmed cases, the mortality rate was 10% (1/10) in both silibinin/silymarin-treated and untreated cases. CONCLUSIONS: The contemporary mortality rate of patients with presumed cyclopeptide-mushroom poisoning is only 8.8%. This likely represents improved supportive care for patients with acute liver injury and should be considered the current standard for historical controls in the United States.

Acute Liver Injury With Therapeutic Doses of Acetaminophen: A Prospective Study.

BACKGROUND AND AIMS: Because of the extensive use of this drug, further evaluation of acute liver injury (ALI) with therapeutic doses of acetaminophen (APAP; ≤6 g/d) is required. We characterize ALI with therapeutic doses of APAP and determine the host factors associated with disease severity and the predictors of outcome. APPROACH AND RESULTS: All patients admitted with severe APAP-related ALI in our center were included from 2002 to 2019, either attributable to therapeutic doses or overdose. ALI with therapeutic doses (ALITD) was defined as APAP intake <6 g/d. Overall, 311 of 400 patients with APAP-related ALI had overdose and 89 had taken therapeutic doses. The host factors associated with ALITD were fasting ≥1 day (47.5% of ALITD patients vs. 26% in overdose; P = 0.001), excess drinking (93.3% vs. 48.5%; P < 0.0001), and repeated APAP use (4 vs. 1 day; P < 0.0001). Patients with ALITD were older (44 vs. 30.7 years; P < 0.0001) and had more severe liver injury. In the overall population, the independent predictors of disease severity were older age, longer duration of APAP, and excess drinking. Thirty-day survival was lower in ALITD than in overdose (87.2 ± 3.6% vs. 94.6 ± 1.3%; P = 0.02). Age and the presence of at least one of the King's College Hospital criteria were independent predictors of 30-day survival whereas the pattern of drug intoxication, excess drinking, and bilirubin were not. CONCLUSIONS: ALI with therapeutic doses of APAP is associated with more severe liver injury than overdose. It only occurs in patients with excess drinking and/or fasting. A warning should be issued about the repeated use of nontoxic doses of APAP in patients with those risk factors.

Busulfan-cyclophosphamide versus cyclophosphamide-busulfan as conditioning regimen before allogeneic hematopoietic cell transplantation: a prospective randomized trial.

Busulfan and cyclophosphamide (BuCy) is a frequently used myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). Theoretical considerations and pharmacological data indicate that application of busulfan prior to subsequent cyclophosphamide (BuCy) may trigger liver toxicity. Reversing the order of application to cyclophosphamide-busulfan (CyBu) might be preferable, a hypothesis supported by animal data and retrospective studies. We performed a prospective randomized trial to determine impact of order of application of Bu and Cy before allo-HCT in 70 patients with hematological malignancy, 33 patients received BuCy and 37 CyBu for conditioning. In the short term, there were minimal differences in liver toxicity favoring CyBu over BuCy, significant only for alanine amino transferase at day 30 (p = 0.03). With longer follow-up at 4 years, non-relapse mortality (6% versus 27%, p = 0.05) was lower and survival (63% versus 43%, p = 0.06) was higher with CyBu compared to BuCy. Other outcomes, such as engraftment (p = 0.21), acute and chronic graft-versus-host disease (p = 0.40; 0.36), and relapse (p = 0.79), were similar in both groups. We prospectively show evidence that the order of application of Cy and Bu in myeloablative conditioning in allo-HCT patients has impact on outcome.

Oxidative stress-mediated hepatotoxicity in rats induced by ethanol extracts of different parts of Chloranthus serratus.

CONTEXT: Chloranthus serratus (Thunb.) Roem. et Schult. (Chloranthaceae) is an herb widely used as a folk medicine treating inflammatory diseases, although it is toxic. OBJECTIVE: To investigate hepatotoxicity and related mechanisms induced by ethanol extracts of different parts of C. serratus in rats. MATERIALS AND METHODS: Sprague Dawley rats were divided into control (Con), ethanol extract of roots (ER), stems (ES), and leaves (EL) groups, and acute oral toxicity studies were conducted. The rats received doses of 4.14, 3.20, and 1.16 g/kg/d extracts for 14 days, respectively. Liver index, liver function and oxidative stress biomarkers, liver pathology, ultrastructure, TNF-α, ICAM-1, and Nrf2/HO-1 proteins expression levels were determined. RESULTS: The LD50 of ER, ES, and EL were higher than 10.35, 8.05, and 2.90 g/kg/p.o., respectively. The liver indexes in the extract groups increased significantly. EL dramatically increased TP, GLB, AST, ALT, ALP, TBA, MDA, ICAM-1, and TNF-α levels (p < 0.01), and induced the most obvious pathological and ultrastructural changes. ES and EL obviously decreased the T-SOD, GSH, CAT, and CHOL levels. Nrf2 and HO-1 proteins expression was reduced significantly in ES (0.77 ± 0.06, 2.33 ± 0.20) and EL (0.23 ± 0.04, 2.14 ± 0.16) groups, and reduced slightly in ER (1.08 ± 0.10; 3.39 ± 0.21) group. DISCUSSION AND CONCLUSION: ES and EL induce stronger hepatotoxicity than ER through oxidative stress and the Nrf2/HO-1 pathway, and the root is a better medicinal part, which provides a basis for clinical research, safe applications, and reasonable development of C. serratus.

Tiron protects against nicotine-induced lung and liver injury through antioxidant and anti-inflammatory actions in rats in vivo.

AIMS: Tobacco smoking is a major health problem associated with lung and liver damage. Lung and liver damage secondary to tobacco smoking is mediated through nicotine-induced oxidative stress. Therefore, we hypothesized that antioxidant treatment with tiron may improve nicotine-induced lung and liver damage. MATERIALS AND METHODS: Rats were divided into six groups, a control, nicotine (10 mg/kg/day, i.p.; for 8 weeks) and tiron (100 or 200 mg/kg/day, i.p.; for 8 weeks) with or without nicotine administration. KEY FINDINGS: Tiron improved survival rate and attenuated lung and liver damage as reflected by decreased total and differential cell counts, lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid (BALF) and decreased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in serum; also histopathological examination confirmed the protective effect of tiron in lung and liver tissues of nicotine treated rats. Tiron attenuated dyslipidemia, which is associated with nicotine. These ameliorative effects of tiron may be mainly due to its antioxidant effect as proved by a significant decrease in malondialdehyde (MDA) content, reactive oxygen species (ROS) and total nitrite/nitrate (NOx) levels, and increase in reduced glutathione (GSH) level, catalase (CAT) and superoxide dismutase (SOD) activities. This is likely related to suppression of protein levels of NADPH oxidase enzyme (NOX1), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α); and up-regulation of protein levels of nuclear factor erythroid-2 (Nrf2). SIGNIFICANCE: This makes tiron (synthetic analogue of vitamin E) good candidate for future use to minimize nicotine's hazards among smokers.

Pattern and impact of hepatic adverse events encountered during immune checkpoint inhibitors - A territory-wide cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancers. We aimed to evaluate the incidence and prognostic impact of hepatic adverse events (AEs) in a territory-wide cohort of patients who received ICIs. METHODS: Patients were identified from a territory-wide database who received ICIs in 2014-2018. Hepatic AEs were defined as any elevation of liver biochemistries including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels. Hepatic AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: Total of 1480 patients were identified (mean age 60 years, male 65.5%) and the commonest malignancies being lung cancer (39.6%), liver cancer (16.5%), and gastrointestinal cancer (10.0%). Grade 1-2 and grade 3-4 hepatic AEs occurred in 41.3% and 14.9% of patients during ICI treatment, respectively. Patients with liver cancer had the highest rate of hepatic AEs (grade 1-2:54.1%; grade 3-4:32.8%). Among 711 patients with hepatic AEs, 383 (53.9%) had raised ALT/AST only, and 328 (46.1%) had concomitant raised ALT/AST and bilirubin levels. In the whole cohort, median overall survival of patients without any hepatic AEs, grade 1-2 and grade 3-4 hepatic AEs during ICI treatment was 9.0 months, 7.2 months, and 3.3 months (P < .001), respectively. Similar results on overall survival were obtained among different types of cancers. CONCLUSIONS: Hepatic AEs occur in more than half of patients receiving ICIs for cancer treatment, with approximately 15% being grade 3-4 AEs. Occurrence of hepatic AEs is associated with worse prognosis.

Drug-induced liver injury in older people.

Drug-induced liver injury (DILI) is a rare, unpredictable, and potentially serious adverse reaction. It is induced by many drugs, herbs, and dietary supplements and represents a diagnostic challenge to clinicians. Older people (aged 65 years and older) are often polymedicated, and their declining physiological function affects drug pharmacokinetics. There is no consistent evidence that age is a general risk factor for DILI; however, age might be a risk factor with specific medications, with antimicrobials and cardiovascular drugs being the most likely medications to cause DILI in older people. Ageing influences DILI phenotypes, making cholestatic damage and chronic DILI more likely. In older people with DILI, comorbidities act as confounding causes and account for higher mortality unrelated to the liver. There are no specific therapies for DILI and supportive measures are still the mainstay of management. This Review highlights current advances and gaps in DILI epidemiology, mechanisms, and diagnosis that are pertinent to older individuals.

Suspension of ulipristal acetate for uterine fibroids during ongoing EMA's review of liver injury risk: Unfortunate timing during the Covid-19 pandemic!

OBJECTIVE: EMA decided that with ulipristal acetate (UPA) treatment for uterine fibroids, should be discontinued due to the associated risk of hepatic failure, We analyzed whether the risk of recurrent symptoms due to fibroids may lead to an increased risk of Covid -19 infection and death, that would exceed the former risk of hepatic failure and transplantation. STUDY DESIGN, SIZE, DURATION: We used a Markov model to generate probabilities. PARTICIPANTS/MATERIALS, SETTING, METHODS: There are currently about 36,250 treated patients in Europe. We estimated bleeding probabilities, while using or discontinuing UPA, which may induce a need of medical or surgical management in symptomatic patients, and increase the risk of acquiring a Covid-19 infection, and die from it. We also estimated the risk of suffering a hepatic failure and hepatic transplantation. MAIN RESULTS AND THE ROLE OF CHANCE: Based on our assumptions, ceasing UPA during a Covid 19 pandemic may be associated with a fatality ratio between 4 and 18, due to the Pandemic, whereas pursuing UPA would be associated with a fatality rate due to the pandemic between 1-2, and an added fatality rate due to hepatic impairment of 1. The added risk of stopping UPA may range between 2 and 15 additional deaths. Our calculations suggest that the decision to stop UPA in the middle of the Covid- 19 pandemic may be untimely, since it may result in an increased risk of Covid-19 infection, due to the recurrence of symptoms and the need for medical and surgical treatment. WIDER IMPLICATIONS OF THE FINDINGS: A decision, like the one EMA took need to be taken in a wider health context of a population, than simply analyzing its role as regulating agent for medications.

Advances in Supportive Care for Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: Tremendous advances have been made in the treatment armamentarium for acute lymphoblastic leukemia in recent years, which have substantially improved outcomes for these patients. At the same time, unique toxicities have emerged, and without early intervention, are life-threatening. This article will review the novel therapies in acute leukemias and highlight the clinically relevant supportive care advances. RECENT FINDINGS: The American Society for Transplantation and Cellular Therapy (ASTCT) has put forth the most recent recommendations in managing the cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells (CAR-T) and blinatumomab. The hepatic injury incurred by inotuzumab, and the vascular toxicity of tyrosine kinase inhibitors, other relatively novel agents, require subspecialist intervention and multidisciplinary care. Asparaginase, a long-established and key element of pediatric regimens, has made a comeback in the young adult leukemia population. Updated guidelines have been outlined for management of asparaginase thrombotic complications. Lastly, although there have been few changes in the applications of growth factor, antimicrobial prophylaxis, and management of neuropathy, these encompass exceedingly important aspects of care. While the rapidly changing treatment paradigms for acute lymphoblastic leukemia have transformed leukemia-specific outcomes, treatment emergent toxicities have forced much necessary attention to better definitions of these toxicities and on improving supportive care guidelines in acute lymphoblastic leukemia.

Drug induced liver injury is associated with high mortality-A study from a tertiary care hospital in Pakistan.

BACKGROUND AND AIM: In light of few established drug induced liver injury (DILI) registries, this study aims to evaluate the clinical spectrum and predictors of mortality and morbidity of hospitalized patients with suspected DILI. PATIENTS AND METHODS: DILI cases were identified and categorized on basis of COIMS/RUCAM score and the exclusion of other liver diseases. Clinical and laboratory parameters were analyzed to identify the predictors of morbidity (prolonged hospital stay > 5 days) and mortality. RESULTS: Out of 462 patients, there were 264 (57.6%) males and the mean age of the cohort was 50.83 years (range: 20-94 years). DILI was classified as definite or highly probable in 31.1%, probable in 62.5%, and possible in 7.4% of cases. Pattern of liver injury was hepatocellular in 25.1%, cholestatic in 56.17%, and mixed in 18.72% of patients. Anti-tuberculosis drugs (ATDs) were found to be the most common category of drugs causing DILI, in 295 (63.9%) patients. Clinically, encephalopathy was present in 21.6% patients; other presenting symptoms included abdominal pain (57.1%), vomiting (57.1%), jaundice (54.1%) and pruritus (42.3%). In-hospital mortality was 26.5% and prolonged hospital stay (> 5 days) was observed in 35.93% of patients. Mortality was significantly greater in patients with encephalopathy, male gender, hepatocellular pattern of DILI, increased INR and use of ventilator support. CONCLUSION: In our study, the most frequent cause of DILI in hospitalized patients was ATDs. More than a quarter of patients died during hospital stay. A close control of clinical and biochemical parameters are required to prevent and monitor DILI, especially in patients taking ATDs in our region.

Presentations, Causes and Outcomes of Drug-Induced Liver Injury in Egypt.

Drug-induced liver injury (DILI) is a frequent cause of liver injury and acute liver failure. We aimed to review all hospitalized DILI cases in a tertiary Egyptian center from January 2015 through January 2016. Cases with elevated alanine aminotransferase more than 3-fold and/or alkaline phosphatase more than 2-fold the upper limit of normal value were prospectively recruited and followed for one year. Drug history, liver biopsy whenever feasible and application of Roussel Uclaf Causality Assessment Method (RUCAM) were the diagnostic prerequisites after exclusion of other etiologies of acute liver injury. In order of frequency, the incriminated drugs were: Diclofenac (31 cases, 41.3%), amoxicillin-clavulanate (14 cases, 18.7%), halothane toxicity (8 cases, 10.7%), ibuprofen (4 cases, 5.3%), Khat (3 cases, 4%), tramadol (3 cases, 4%), Sofosbuvir with ribavirin (2 cases, 2.7%), and acetylsalicylic acid (2 cases, 2.7%) with one offending drug in 93.3% of cases. Forty-four cases (58.7%) were males; while 56 cases (74.7%) had HCV related chronic liver disease. Thirty-two cases (42.7%) presented with pattern of hepatocellular injury, while 23 cases (30.7%) were with cholestasis, and 20 cases (20.7%) with a mixed hepatocellular/cholestatic injury. One case received a transplant (0.75%), 7 cases died (9.3%), 23 cases (30.6%) developed liver decompensation (hepatic encephalopathy and ascites), and 44 cases completely resolved (58.7%). In conclusion, Diclofenac is the commonest offender in DILI occurrence in an Egyptian cohort. Age and prothrombin concentration were the only predictors of unfavorable outcomes of DILI.

The concentration of tumor necrosis factor-α determines its protective or damaging effect on liver injury by regulating Yap activity.

Previous studies have shown that tumor necrosis factor (TNF)-α is a mediator of hepatotoxicity in liver injury. Moreover, TNF-α has also been reported to have a protective effect in liver regeneration, yet the function of TNF-α during liver injury remains controversial. Here, we report that the concentration of TNF-α determines its functions. High concentrations of TNF-α could aggravate LPS-induced liver injury. However, the TNF-α level was unchanged during APAP-induced liver injury, which exerted a protective effect. We expected that the concentration of TNF-α may affect its function. To test this hypothesis, TNF-α-/- rats or hepatocyte cells were treated with different concentrations of TNF-α. We found low TNF-α could reduce the levels of ALT and AST in the plasma of TNF-α-/- rats and promote the proliferation of hepatocyte cells. However, the levels of ALT and AST increased gradually with increasing TNF-α concentration after reaching the lowest value. Moreover, we showed that TNF-α affects the cell proliferation and cell death of hepatocytes by regulating Yap activity. Low TNF-α promoted Yap1 nuclear translocation, triggering the proliferation of hepatocytes. However, high TNF-α triggered the phosphorylation and inactivation of Yap1, preventing its nuclear import and consequently promoting cell death. Collectively, our findings provide novel evidence that the concentration of TNF-α is an important factor affecting its function in liver injury, which may provide a reference for the clinical treatment of liver injury.

Evaluating lactate prognostic value in children suspected of acetaminophen-induced liver failure in Liberia.

BACKGROUND: The prognostic significance of hyperlactatemia in young children with liver injury suspected to be attributed to repeated supratherapeutic doses of acetaminophen remain understudied. METHODS: We conducted a retrospective medical chart review including children aged <5 years admitted with hepatocellular injury. The study was conducted in Bardnesville Junction Hospital operated by Médecins Sans Frontières in Monrovia, Liberia. RESULTS: We analyzed 95 children with liver injury in whom a blood lactate measurement on admission was available. Eighty children (84%) were aged <2 years; 49 children (52%) died during hospitalization. The median acetaminophen concentration on admission was 20 mg/L with 60 (70%) children presenting concentrations exceeding 10 mg/L. Median lactate was significantly higher in children who died (10.7 mmol/L; interquartile range (IQR): 8.5-15.7) than those who survived (6.1 mmol/L; IQR: 4.1-8.5), P value < 0.001). The optimal threshold obtained was 7.2 mmol/L with a sensitivity of 84% and specificity 70% (area under curve = 0.80). The previously established thresholds of 3.5 and 4 mmol/L lactate had very low specificity identifying non-survival in children included in this study. CONCLUSION: In this setting, young children with ALF possibly attributed to acetaminophen toxicity were unlikely to survive if the venous blood lactate concentration exceeded 7.2 mmol/L.

PROGNOSIS OF THE COURSE OF CHORNOBYL-ORIGINATED ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN IN UKRAINE DEPENDING ON THE REASON OF STANDARD CHEMOTHERAPY INTERRUPTION. / PROGNOZ PEREBIGU GOSTRYKh LIMFOBLASTNYKh LEY̆KEMIY̆ ChORNOBYL'S'KOGO POKhODZhENNIa U DITEY̆ UKRAÏNY ZALEZhNO VID PRYChYN PERERV PRY PROVEDENNI STANDARTNOÏ KhIMIOTERAPIÏ.

OBJECTIVE: Estimation of the bone marrow haemopoietic status depending on the reasons and duration of breaks in a standard chemotherapy (BFM-ALL protocol) to predict the course of acute lymphoblastic leukemia (ALL) in chil- dren exposed to low doses of ionizing radiation after the Chornobyl accident. MATERIALS AND METHODS: The ALL patients (n = 34) were examined within 5 stages of a program chemotherapy. The clinical symptoms, hemogram and myelogram data were analyzed. The radiation dose on bone marrow, initial leuko- cyte count, variants and prognosis of ALL course were accounted. Days of the stopped chemotherapy, type and fre- quency of complications (septic processes, febrile neutropenia, toxic hepatitis, granulocytopenia degree), and the prognosis of disease course (child living status, i.e. alive or died) were estimated. RESULTS: There were abnormal differentiation processes and high percentage of lymphoblasts (86.2 ± 3.3) % in bone marrow in the 1st acute period. Hematological remission was established in all patients on the 33rd day of chemothe- rapy. In a half of cases the haematopoietic recovery occurred by a granulocyte-monocyte type. One third of patients presenting an erythroid type of haemopoiesis died later. The inverse correlation was found between the number of myelocaryocytes and disease prognosis (rs = -0.49). Breaks in chemotherapy for various reasons were recorded. The number of patients with granulocytopenia was greater at the phase 1 and 2 of protocol I and protocol M application, coinciding with a higher incidence of complications. An inverse correlations between the prediction of ALL course and sum of days of breaks between the protocol M and phase 1 of protocol II (rs = -0.56), as well as the duration of the phase 2 of protocol II (rs = -0.62) were found. The radiation dose on bone marrow was (5.37 ± 1.23) mSv. No relationship was found between the radiation doses, ALL variants and disease course. CONCLUSIONS: Prognosis of ALL course in children depends on the type of haemopoietic recovery and reasons of breaks in a standard chemotherapy. Interaction between the haemopoiesis functioning and microenvironment and that of their regulation are the key mechanisms of above-mentioned abnormalities, which is the basis for further research.