Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors.

Palbociclib, an oral CDK 4/6 inhibitor, was evaluated in a Pediatric Brain Tumor Consortium (PBTC) phase 1 (NCT02255461; PBTC-042) study to treat children and young adults with recurrent, progressive, or refractory brain tumors. The objectives of this study were to characterize the palbociclib population pharmacokinetics in children enrolled on PBTC-042, to conduct a population pharmacodynamic analysis in this patient population, and to perform a simulation study to assess the role of palbociclib exposure on neutropenia and thrombocytopenia. The palbociclib population pharmacokinetics and pharmacodynamics were characterized in this patient population (n = 34 patients; 4.

Adaptive Stereotactic Body Radiation Therapy in the Management of Oligometastatic Uterine Leiomyosarcoma: A Clinical Case Report.

Safe delivery of stereotactic body radiation therapy (SBRT) to large (>5 cm) oligometastatic abdominopelvic tumors can often be challenging, especially in tumors that require a higher biologically effective dose (BED) for tumor control. Adaptive stereotactic body radiation therapy (A-SBRT) involves inter-fraction and real-time replanning while the patient is on the treatment table, potentially allowing for improved dose coverage and greater sparing of critical structures. Our case report illustrates the benefit of CT-based A-SBRT in the treatment and management of an oligometastatic uterine leiomyosarcoma patient with a rapidly enlarging pelvic recurrence.

Overview of treatment plan quality in a high dose rate prostate brachytherapy workflow.

Purpose: High dose rate brachytherapy (HDR-BT) has been shown to be an effective treatment for prostate cancer, with treatment plan quality dependent on a number of factors. In this work, we report on the overall performance of our ultrasound (US)-based workflow and the impact of several treatment-specific variables.

Methods And Materials: Patients who underwent HDR-BT (boost, monotherapy, and retreatment) using Varian Bravos/US from 2021 to 2023 were sampled for this study.

The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses.

Purpose: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.

Methods: A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.

Comparison of perioperative and subacute postoperative complications between LDR and HDR monotherapy brachytherapy for prostate cancer.

Purpose: We aim to investigate perioperative and subacute postoperative complications in patients undergoing LDR or HDR monotherapy for prostate cancer. We hypothesize a low rate of complications, and a favorable toxicity profile in patients treated with HDR compared to LDR.

Materials And Methods: A prospectively collected institutional database was queried for patients treated with HDR or LDR prostate monotherapy between 1998 and 2021.

Forecasted infliximab concentrations during induction predict time to remission and sustained disease control of inflammatory bowel disease.

Background: Infliximab (IFX) exposure is established as a predictive factor of pharmacokinetic (PK) origin in inflammatory bowel disease (IBD), and expert consensus is to achieve adequate exposure during induction to achieve and sustain remission.

Methods: We retrospectively evaluated the performance of a Bayesian PK tool in IBD patients starting IFX. Trough IFX serum levels collected immediately before the third (at week 6) and fourth (at week 14) infusions were evaluated from 307 IBD patients (median age=17 years, 50 % females, 83 % with Crohn's disease).

Ommaya reservoir use in pediatric ALL and NHL: a review at St. Jude Children's Research Hospital.

Purpose: The intraventricular route of chemotherapy administration, via an Ommaya Reservoir (OmR) improves drug distribution in the central nervous system (CNS) compared to the more commonly used intrathecal administration. We retrospectively reviewed our experience with intraventricular chemotherapy, focused on methotrexate, in patients with Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL).

Methods: Twenty-four patients (aged 7 days - 22.

The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn's Disease with Infliximab.

Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn's disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to receive standard dosing (n = 37), and the second designed to proactively target therapeutic IFX concentrations (n = 108).

Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation.

A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible.

Pharmacokinetics and safety of bendamustine in the BEABOVP regimen for the treatment of pediatric patients with Hodgkin lymphoma.

Purpose: The Stanford V chemotherapy regimen has been used to treat Hodgkin lymphoma (HL) patients since 2002 with excellent cure rates; however, mechlorethamine is no longer available. Bendamustine, a drug structurally similar to alkylating agents and nitrogen mustard, is being substituted for mechlorethamine in combination therapy in a frontline trial for low- and intermediate-risk pediatric HL patients, forming a new backbone of BEABOVP (bendamustine, etoposide, doxorubicin, bleomycin, vincristine, vinblastine, and prednisone). This study evaluated the pharmacokinetics and tolerability of a 180 mg/m dose of bendamustine every 28 days to determine factors that may explain this variability.

2D IMRT QA passing rate dependency on coronal plane.

Intensity modulated radiation therapy (IMRT) delivery involves a complex series of beam angles and multileaf collimator (MLC) arrangements, requiring quality assurance to be performed to validate delivery before treatment. The purpose of this work is to investigate the effect of dose gradient on quality assurance (QA) passing rate. Many (n = 40) IMRT plans were delivered and measured using a 2D planar array of ion chambers; additionally, eleven plans were measured at several coronal planes.

Preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib for the treatment of T-cell acute lymphoblastic leukemia.

LCK is a novel therapeutic target in ~40% of T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib can act as LCK inhibitors with therapeutic effects. We herein report a comprehensive preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib in LCK-activated T-ALL. In 51 human T-ALL cases, these two drugs showed similar patterns of cytotoxic activity, with ponatinib being slightly more potent.

Model Informed Precision Dosing Tool Forecasts Trough Infliximab and Associates with Disease Status and Tumor Necrosis Factor-Alpha Levels of Inflammatory Bowel Diseases.

Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled.

Real world outcomes and implementation pathways of exome sequencing in an adult genetic department.

Purpose: This study aimed to correlate the indications and diagnostic yield of exome sequencing (ES) in adult patients across various clinical settings. The secondary aim was to examine the clinical utility of ES in adult patients.

Methods: Data on demographics, clinical indications, results, management changes, and cascade testing were collected for 250 consecutive patients who underwent ES through an adult genetics department between 2016 and 2021.

Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and FLT3-Internal Tandem Duplication.

Purpose: To evaluate the safety, activity, and emergence of FLT3-kinase domain (KD) mutations with combination therapy of crenolanib and sorafenib in acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD).

Patients And Methods: After in vitro and xenograft efficacy studies using AML cell lines that have FLT3-ITD with or without FLT3-KD mutation, a pilot study was performed with crenolanib (67 mg/m2/dose, three times per day on days 1-28) and two dose levels of sorafenib (150 and 200 mg/m2/day on days 8-28) in 9 pediatric patients with refractory/relapsed FLT3-ITD-positive AML. Pharmacokinetic, pharmacodynamic, and FLT3-KD mutation analysis were done in both preclinical and clinical studies.

Changes in body mass index, weight, and height in children with acute myeloid leukemia and the associations with outcome.

Little is known about body composition changes in patients with acute myeloid leukemia (AML) during and after treatment or their associations with outcomes. Z-scores for body mass index (BMI), weight, and height at diagnosis, their longitudinal changes from diagnosis to 5 years off therapy, and their associations with adverse effects and outcomes were evaluated in 227 pediatric patients with AML enrolled in the AML02 and AML08 trials at St. Jude Children's Research Hospital between 2002-2017.

The effects of pazopanib on doxorubicin pharmacokinetics in children and adults with non-rhabdomyosarcoma soft tissue sarcoma: a report from Children's Oncology Group and NRG Oncology study ARST1321.

Purpose: The use of tyrosine kinase inhibitors for the treatment for soft tissue sarcomas is increasing given promising signals of activity in a variety of tumor types. The recently completed study in non-rhabdomyosarcoma soft tissue sarcomas, ARST1321, demonstrated that the addition of pazopanib to neoadjuvant ifosfamide, doxorubicin, and radiation improved the pathological near complete response rate compared with chemoradiotherapy alone. Pharmacokinetic (PK) evaluation of doxorubicin with pazopanib has not been previously reported.

P010 Precision Dosing Tool Forecasts Trough Infliximab and Associates With Disease Status in Inflammatory Bowel Diseases.

Background: Substantial inter- and intra-individual variability of infliximab (IFX) pharmacokinetics (PK) necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD).

Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled.

Multiple diagnostic tests demonstrate an increased risk of canine heartworm disease in northern Queensland, Australia.

Background: Canine heartworm (Dirofilaria immitis) is a life-threatening infection of dogs with a global distribution. Information on the prevalence of D. immitis and associated risk factors for canine heartworm antigen positivity-and thus disease-in Australia is scarce or outdated.

Comprehensive analysis of dose intensity of acute lymphoblastic leukemia chemotherapy.

Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St.

Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase.

Purpose: We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL).

Methods: We evaluated CSF asparagine (2114 samples) and serum asparaginase (5007 samples) in 482 children with ALL treated on the Total XVI study (NCT00549848). Patients received one or two 3000 IU/m IV pegaspargase doses during induction and were then randomized in continuation to receive 2500 IU/m or 3500 IU/m IV intermittently (four doses) on the low-risk (LR) or continuously (15 doses) on the standard/high risk (SHR) arms.

A nurse practitioner model of care in the era of direct acting antiviral therapy for hepatitis C virus infection.

Background And Aim: Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection has resulted in high rates of successful disease cure; however, not enough healthcare providers are available to deliver treatment to the population living with chronic HCV. To demonstrate that a nurse practitioner (NP) model of care is non-inferior to specialist gastroenterologist (SG) management of HCV infection, as measured by sustained viral response at 12 weeks (SVR) after initiation of DAA therapy.

Design: Retrospective cohort database study.