Pharmacokinetic-pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia.

In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient.

Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0-45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol.

Background: A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance.

Prevalence of non-adherence and non-compliance during maintenance therapy in adults with acute lymphoblastic leukemia and their associations with survival.

Objectives: Explore patient adherence and physician compliance to protocol guidelines during maintenance therapy, including the association with survival in adults with acute lymphoblastic leukemia (ALL).

Methods: Blood counts, aminotransferase levels and prescribed 6-mercaptopurine (6MP)/methotrexate (MTX) doses were compared with the protocol guidelines to assess compliance. Non-adherence to the prescribed medication was confirmed in patients with unmeasurable 6MP metabolite levels and suspected in patients with low 6MP metabolites concurrent with aminotransferase and white blood cell count within normal ranges, while potential intermittent non-adherence was defined by >1.

Maintenance therapy and risk of osteonecrosis in children and young adults with acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study.

Purpose: Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs.

Methods: We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.

No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study.

Purpose: 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk.

Hepatotoxicity during 6-thioguanine treatment in inflammatory bowel disease and childhood acute lymphoblastic leukaemia: A systematic review.

Background: The recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity.

Objectives: To assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established.

Data Sources: Databases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998-2018.

Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.

Background: Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.

Procedure: In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs.

Symptoms of Central Anticholinergic Syndrome After Glycopyrrolate Administration in a 5-Year-Old Child.

Anesthesia-related central anticholinergic syndrome (CAS) is most commonly associated with administration of atropine or scopolamine, whereas glycopyrrolate is an extremely rare cause of CAS. Here, we report a case of CAS in a 5-year-old boy admitted to the intensive care unit. Immediately after the administration of glycopyrrolate, he became agitated and developed apnea, hypertension, tachycardia, and anuria.

Progressive intracranial hypertension and cerebral hypoperfusion in a fatal case of cerebral aspergilloma.

We report a case of cerebral aspergilloma in a 25-year-old immunoincompetent man admitted to a general intensive care unit. Monitoring of intracranial pressure was instigated and revealed hour-long epochs of severe intracranial hypertension, despite a normal opening pressure, with decreases in cerebral perfusion pressure. We documented that this was associated with cerebral hypoperfusion by transcranial Doppler ultrasound.

Using a classic paper by Robin Fahraeus and Torsten Lindqvist to teach basic hemorheology.

"The viscosity of the blood in narrow capillary tubes" by Robin Fåhraeus and Torsten Lindqvist (Am J Physiol 96: 562-568, 1931) can be a valuable opportunity for teaching basic hemorheological principles in undergraduate cardiovascular physiology. This classic paper demonstrates that a progressive decline in apparent viscosity occurs when blood flows through glass capillary tubes of diminishing radius, which was later designated as the "Fåhraeus-Lindqvist effect." Subsequent studies have shown that apparent viscosity continues to decline at diameters that correspond to the arteriolar segments of the systemic vascular tree, where the majority of the total peripheral resistance resides and is actively regulated in vivo.