Efficacy and safety of endoscopic retrograde cholangiopancreatography in recurrent pancreatitis of pediatric asparaginase-associated pancreatitis

BACKGROUND Asparaginase(ASP)is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia(ALL);ASP-associated pancreatitis(AAP)is the main adverse reaction of ASP.Recurrent pancreatitis is a complication of AAP,for which medication is ineffective.AIM To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography(ERCP)in treating recurrent pancreatitis due to AAP.METHODS From May 2018 to August 2021,ten children(five males and five females;age range:4–13 years)with AAP were treated using ERCP due to recurrent pancreatitis.Clinical data of the ten children were collected,including their sex,age,weight,ALL risk grading,clinical symptoms at the onset of pancreatitis,time from the first pancreatitis onset to ERCP,ERCP operation status,and postoperative complications.The symptomatic relief,weight change,and number of pancreatitis onsets before and after ERCP were compared.RESULTS The preoperative symptoms were abdominal pain,vomiting,inability to eat,weight loss of 2-7 kg,and 2-9 pancreatitis onsets.After the operation,nine of ten patients did not develop pancreatitis,had no abdominal pain,could eat normally;the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP,but eating was not affected.The postoperative weight gain was 1.5-8 kg.There was one case of post ERCP pancreatitis and two cases of postoperative infections;all recovered after medication.CONCLUSION ERCP improved clinical symptoms and reduced the incidence of pancreatitis,and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP.

Transient Diabetes Induced by L-Asparaginase

Background: Although hyperglycaemia is one of the known side effects of L-asparaginase, its contribution to the development of diabetic ketoacidosis (DKA) is less well known in the literature. Asparaginase is an essential component of treatment protocols for acute lymphoblastic leukaemia (ALL) in combination with other chemotherapeutic drugs. On further evaluation, she was found to have high anion gap metabolic acidosis, hyperglycaemia and ketonuria. In recent decades, the use of these chemotherapeutic agents has led to a decrease in mortality and disease-free survival in ALL. L-asparaginase is one of the chemotherapy protocols used in the treatment of acute lymphoblastic leukaemia (ALL) and can induce hyperglycaemia which is aggravated by the concomitant use of corticosteroids. We report the observation of a 14-year-old girl treated with chemotherapy (GFA LAL protocol) who developed transient diabetes following the use of L-asparaginase. She was treated at the Donka paediatric haemato-oncology unit by a multidisciplinary team including a paediatric oncologist, a psychologist and a diabetologist. The aim of this study was to highlight blood glucose monitoring before and after the use of asparaginase in acute lymphoblastic leukaemia. Conclusion: We conclude that the occurrence of ketoacidosis following the use of asparaginase is a rare event. We recommend close monitoring of blood glucose levels for hyperglycaemia in patients with ALL receiving L-asparaginase.

Pharmacokinetics of Recombinant E. coli L-asparaginase in Rats

The distribution of ^(125)I recombinant E. coli L-asparaginase in tissues ororgans and the excretion in urine, feces and bile were studied with in vivo radioactive tracertechnique. The amount of radioactivity excreted in urine, feces and bile within 24 h afterintravenous administration of ^(125)I recombinant E. col L-asparaginase to rats was 68.95% ,4.44%and 5.36% of the dose respectively. ^(125)I recombinant E. coli L-asparaginase in plasma samples wasdetermined. The levels of structural intact molecule in plasma samples were evaluated by SDS-PAGEand bio-imaging analyzer system. Pharmacokinetic parameters were assessed with a model-dependentmethod. The concentration-time curves of recombinant E. coli L-asparaginase after intravenousinjection at 1 250 IU·kg^(-1), 2 500, IU·kg^(-1), 5 000 IU·kg^(-1) to rats were consistent withthe two-compartment model. The first and terminal elimination t_(1/2) were 0.52 ~ 0.63 h and 2.39 ~2.76 h respectively. AUC was linearly related to the doses. The results of distribution in tissuesor organs and excretion in urine suggested that the metabolites of the enzyme were cleared bymechanisms of urinary excretion. Pharmacokinetics parameters of recombinant E. coli L- asparaginasein rats are warranted for the design of future clinical trials.

Pharmacogenetics of asparaginase in acute lymphoblastic leukemia

Asparaginase is a key component in leukemias and lymphomas treatment protocols and is suggested as a treatment for other malignancies in which an amino acid depletion strategy is indicated.Asparaginase intolerance is subject to inter-individual variability and can manifest as hypersensitivity reactions,pancreatitis,thrombosis,as well as metabolic abnormalities,and may affect treatment outcome.Pharmacogenetics aims at enhancing treatment efficacy and safety by better understanding the genetic basis of variability and its effect on the pharmacological responses.Many groups tried to tackle the pharmacogenetics of asparaginase but the potential implementation of such findings remains debatable.In this review,we highlight the most important findings reported in studies of the pharmacogenetics of asparaginase related complications and treatment outcome in acute lymphoblastic leukemia.

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

PEGylated-L-asparaginase(PEG-ASNase)is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia(ALL).Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis,with obesity and older age considered risk factors of the injury.Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury.Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1,3,5,and 7 days after drug administration.Liver triglycerides were quantified,and plasma bilirubin,ALT,AST,and non-esterified fatty acids(NEFA)were measured.The mRNA and protein levels of genes involved in hepatic fatty acid synthesis,β-oxidation,very low-density lipoprotein(VLDL)secretion,and white adipose tissue(WAT)lipolysis were determined.Mice developed hepatic steatosis after PEG-ASNase,which associated with increases in bilirubin,ALT,and AST.The hepatic genes Ppara,Lcad/Mcad,Hadhb,Apob100,and Mttp were upregulated,and Srebp-1 c and Fas were downregulated after PEG-ASNase.Increased plasma NEFA,WAT loss,and adipose tissue lipolysis were also observed after PEG-ASNase.Furthermore,we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice,consistent with clinical studies of ASNase-induced liver injury.Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

Homeostatic responses to amino acid insufficiency

This article provides a brief overview describing how two key signaling pathways, namely the integrated stress response and the mammalian target of rapamycin complex 1, work together to facilitate cellular adaptation to dietary amino acid insufficiency. A deeper understanding of these mechanisms is leading to identification of novel targets which aid in disease treatments, improve stress recovery and increase health span through slowed aging and enhanced metabolic fitness.