Differential distribution of ivacaftor and its metabolites in plasma and human airway epithelia.

Ivacaftor is the first clinically approved monotherapy potentiator to treat CFTR channel dysfunction in people with cystic fibrosis. Ivacaftor (Iva) is a critical component for all current modulator therapies, including highly effective modulator therapies. Clinical studies show that CF patients on ivacaftor-containing therapies present various clinical responses, off-target effects, and adverse reactions, which could be related to metabolites of the compound.

Pharmacogenetic actionability and medication prescribing in people with cystic fibrosis.

Although major advancements have been made in the therapeutics for people with cystic fibrosis (PwCF), many still require the use of multiple medications to manage acute exacerbations of disease and maintain health. Iterative trial and error processes of pharmacotherapeutic management can be optimized by assessing and incorporating pharmacogenetics. For 82 PwCF, we reviewed 2 years of medication use and response history and interrogated metabolizer status for common pharmacogenes, revealing 3336 medication exposure events (MEEs) to 286 unique medications.

Proton therapy for isolated local regional recurrence of breast cancer after mastectomy alone.

Purpose/objectives: To assess adverse events (AEs) and disease-specific outcomes after proton therapy for isolated local-regional recurrence (LRR) of breast cancer after mastectomy without prior radiotherapy (RT).

Materials/methods: Patients were identified from a multi-institutional prospective registry and included if diagnosed with invasive breast cancer, initially underwent mastectomy without adjuvant RT, experienced an LRR, and subsequently underwent salvage treatment, including proton therapy. Follow-up and cancer outcomes were measured from the date of RT completion.

Quantitation of cystic fibrosis triple combination therapy, elexacaftor/tezacaftor/ivacaftor, in human plasma and cellular lysate.

The triple combination modulator therapy (ETI, elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)) is a recent advancement for the care of patients with cystic fibrosis. To aid in the development of clinical pharmacokinetics studies of this treatment, we developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for quantifying the component compounds in human plasma and cell lysate. This assay was optimized for small volumes (10 µL), uses stably labeled isotopes of the ETI compounds as internal standards, and employs a simple methanol protein precipitation method.

A Prospective Study of Mucosal Sparing Radiation Therapy in Resected Oropharyngeal Cancer Patients.

Purpose: Our objective was to report the prospective results of mucosal sparing radiation therapy in human papillomavirus-related oropharyngeal squamous cell carcinoma.

Methods And Materials: From March 2016 through May 2019, patients were enrolled in this institutional review board-approved prospective cohort study at a multisite institution. Inclusion criteria included p16+ American Joint Committee on Cancer seventh edition pathologic T1 or T2, N1 to N3, and M0 oropharyngeal cancers.

Patient-reported outcomes for patients with breast cancer undergoing radiotherapy: A single-center registry experience.

Background: We present Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for patients undergoing adjuvant radiotherapy for breast cancer with curative intent. We describe the frequency and severity of PRO-CTCAE and analyze them with respect to dose fractionation.

Methods: Patients were included in this study if they were treated with curative intent for breast cancer and enrolled on a prospective registry.

Plasma and cellular ivacaftor concentrations in patients with cystic fibrosis.

Access to cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been gradually increasing for people with cystic fibrosis, the first of which was ivacaftor, a CFTR potentiator that is part of all clinically available modulator treatments. In this study, we hypothesized that the steady-state concentrations in blood and tissue are highly variable in patients taking ivacaftor in a real-world context, which may have an impact on the treatment approach. We collected nasal epithelial cells to estimate target site concentrations and blood samples to estimate pharmacokinetic parameters at a steady state.

Early Experience Using Proton Beam Therapy for Extremity Soft Tissue Sarcoma: A Multicenter Study.

Purpose: Proton beam therapy (PBT) may provide an advantage when planning well-selected patients with extremity soft tissue sarcoma (eSTS), specifically for large, anatomically challenging cases. We analyzed our early experience with PBT on toxicity and outcomes.

Materials And Methods: A retrospective study was performed for eSTS treated between June 2016 and October 2020 with pencil beam scanning PBT at 2 institutions.

Empirical Relative Biological Effectiveness (RBE) for Mandible Osteoradionecrosis (ORN) in Head and Neck Cancer Patients Treated With Pencil-Beam-Scanning Proton Therapy (PBSPT): A Retrospective, Case-Matched Cohort Study.

Purpose: To retrospectively investigate empirical relative biological effectiveness (RBE) for mandible osteoradionecrosis (ORN) in head and neck (H&N) cancer patients treated with pencil-beam-scanning proton therapy (PBSPT).

Methods: We included 1,266 H&N cancer patients, of which, 931 patients were treated with volumetric-modulated arc therapy (VMAT) and 335 were treated with PBSPT. Among them, 26 VMAT and 9 PBSPT patients experienced mandible ORN (ORN group), while all others were included in the control group.

Clinical outcomes for hilar and extrahepatic cholangiocarcinoma with adjuvant, definitive, or liver transplant-based neoadjuvant chemoradiotherapy strategies: a single-center experience.

Background: We report our experience with 3 strategies for treating hilar and extrahepatic cholangiocarcinoma (CCA) including chemoradiotherapy: neoadjuvant chemoradiotherapy (nCRT) and orthotopic liver transplant, surgical resection and adjuvant chemoradiotherapy (aCRT), and definitive chemoradiotherapy (dCRT).

Methods: We included patients treated from 1998 through 2019. Kaplan-Meier estimates, log-rank testing, and univariate/multivariate Cox models were used to assess outcomes (local progression-free survival, disease-free survival, and overall survival).

Implementation of Photon Treatment Back-up Workflow at a High-Volume Proton Center: Safety, Quality, and Patient Considerations.

Purpose: A successful proton beam therapy (PBT) center relies heavily on the proper function and maintenance of a proton beam therapy machine. However, when a PBT machine is non-operational, a proton facility is hindered with delays that can potentially lead to inferior treatment outcome due to treatment interruption. This article reports a viable solution for a photon back-up plan in a proton down event.

Culture and Imaging of Human Nasal Epithelial Organoids.

Individualized therapy for cystic fibrosis (CF) patients can be achieved with an in vitro disease model to understand baseline Cystic Fibrosis Transmembrane conductance Regulator (CFTR) activity and restoration from small molecule compounds. Our group recently focused on establishing a well-differentiated organoid model directly derived from primary human nasal epithelial cells (HNE). Histology of sectioned organoids, whole-mount immunofluorescent staining, and imaging (using confocal microscopy, immunofluorescent microscopy, and bright field) are essential to characterize organoids and confirm epithelial differentiation in preparation for functional assays.

Impact of Cardiac Dose on Overall Survival in Lung Stereotactic Body Radiotherapy (SBRT) Compared to Conventionally Fractionated Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC).

Purpose: To examine possible association between heart irradiation and Overall Survival (OS) in lung SBRT patients and to compare observed associations with cardiac toxicity models previously derived in LA-NSCLC patient studies.

Materials And Methods: 197 Patients treated with lung SBRT at Mayo Clinic Arizona were selected for this IRB-approved study. Multivariate Cox model with Akaike Information Criterion (AIC) was used to select patient specific covariates associated with OS.

CFTR function and clinical response to modulators parallel nasal epithelial organoid swelling.

In vitro biomarkers to assess cystic fibrosis transmembrane conductance regulator activity are desirable for precision modulator selection and as a tool for clinical trials. Here, we describe an organoid swelling assay derived from human nasal epithelia using commercially available reagents and equipment and an automated imaging process. Cells were collected in nasal brush biopsies, expanded in vitro, and cultured as spherical organoids or as monolayers.

No Longer a Match: Trends in Radiation Oncology National Resident Matching Program (NRMP) Data from 2010-2020 and Comparison Across Specialties.

Purpose: To report trends in the number and types of applicants and matched trainees to radiation oncology in comparison to other specialties participating in the National Resident Matching Program (NRMP) between 2010 and 2020.

Methods And Materials: Data from the NRMP and Electronic Residency Application System (ERAS) were obtained for 18 medical specialties between 2010 and 2020. We assessed the numbers and types of applicants and matched trainees relative to available positions in the NRMP and Supplemental Offer and Acceptance Program (SOAP).

Unplanned implant removal in locally advanced breast cancer.

Study conducted to determine frequency and timing of unplanned breast implant removal after mastectomy, reconstruction, and postmastectomy radiation (PMRT). From 2010-2017, 52 patients underwent mastectomy, reconstruction, and PMRT. With median follow-up of 3.

Human Nasal Epithelial Organoids for Therapeutic Development in Cystic Fibrosis.

We describe a human nasal epithelial (HNE) organoid model derived directly from patient samples that is well-differentiated and recapitulates the airway epithelium, including the expression of cilia, mucins, tight junctions, the cystic fibrosis transmembrane conductance regulator (CFTR), and ionocytes. This model requires few cells compared to airway epithelial monolayer cultures, with multiple outcome measurements depending on the application. A novel feature of the model is the predictive capacity of lumen formation, a marker of baseline CFTR function that correlates with short-circuit current activation of CFTR in monolayers and discriminates the cystic fibrosis (CF) phenotype from non-CF.

Acute toxicities after proton beam therapy following breast-conserving surgery for breast cancer: Multi-institutional prospective PCG registry analysis.

We investigated adverse events (AEs) and clinical outcomes for proton beam therapy (PBT) after breast-conserving surgery (BCS) for breast cancer. From 2012 to 2016, 82 patients received PBT in the prospective multi-institutional Proton Collaborative Group registry. AEs were recorded prospectively at each institution.

Variable cellular ivacaftor concentrations in people with cystic fibrosis on modulator therapy.

The development of CFTR modulators has transformed the care of patients with cystic fibrosis (CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. We developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and our analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients.