Feasibility of structuring electronic health record data to facilitate real-world data research: ICAREdata methods applied to multicenter cancer clinical trials.

Background: The use of electronic health record (EHR) data for research is limited by a lack of structure and a standard data model. The objective of the ICAREdata (Integrating Clinical Trials and Real-World Endpoints Data) project was to structure key research data elements in EHRs using a minimal Common Oncology Data Elements (mCODE) data model to extract and transmit data.

Methods: The ICAREdata project captured two EHR data elements essential to clinical trials: cancer disease status and treatment plan change.

Spatially-dependent model for rods and cones in the retina.

We develop a mathematical model for photoreceptors in the retina. We focus on rod and cone outer segment dynamics and interactions with a nutrient source associated with the retinal pigment epithelium cells. Rod and cone densities (number per unit area of retinal surface) are known to have significant spatial dependence in the retina with cones located primarily near the fovea and the rods located primarily away from the fovea.

Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit.

Unlabelled: Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups.

Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit.

Background: Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction.

Methods: Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit.

Organizational Characteristics and Smoking Cessation Support in Community-Based Lung Cancer Screening Programs.

An evidence-based approach to navigation, shared decision making, and tobacco cessation education, tailored to lung cancer screening, is needed nationwide at imaging centers to achieve maximal mortality reductions from lung cancer screening.

Population-adjusted indirect treatment comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 trials evaluating maintenance olaparib or bevacizumab or the combination of both in newly diagnosed, advanced BRCA-mutated ovarian cancer.

Background: In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm).

Methods: An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled.

Real-World Performance of a Comprehensive Genomic Profiling Test Optimized for Small Tumor Samples.

Purpose: Tissue-based comprehensive genomic profiling (CGP) is increasingly used for treatment selection in patients with advanced cancer; however, tissue availability may limit widespread implementation. Here, we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples.

Materials And Methods: We conducted a post hoc, nonprespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex polymerase chain reaction (PCR)-based comprehensive genomic profiling (PCR-CGP) test, as part of an ongoing observational trial (NCT03061305).

Tear film dynamics with blinking and contact lens motion.

We develop a lubrication theory-based mathematical model that describes the dynamics of a tear film during blinking and contact lens (CL) wear. The model extends previous work on pre-corneal tear film dynamics during blinking by coupling the partial differential equation for tear film thickness to a dynamic model for CL motion. We explore different models for eyelid motion and also account for possible voluntary and involuntary globe (eyeball) rotation that may accompany blinking.

Differences in Transcriptional Dynamics Between T-cells and Macrophages as Determined by a Three-State Mathematical Model.

HIV-1 viral transcription persists in patients despite antiretroviral treatment, potentially due to intermittent HIV-1 LTR activation. While several mathematical models have been explored in the context of LTR-protein interactions, in this work for the first time HIV-1 LTR model featuring repressed, intermediate, and activated LTR states is integrated with generation of long (env) and short (TAR) RNAs and proteins (Tat, Pr55, and p24) in T-cells and macrophages using both cell lines and infected primary cells. This type of extended modeling framework allows us to compare and contrast behavior of these two cell types.

Sequencing Ipilimumab Immunotherapy Before or After Chemotherapy (Nab-Paclitaxel and Bevacizumab) for the Treatment of BRAFwt (BRAF Wild-Type) Metastatic Malignant Melanoma: Results of a Study of Academic and Community Cancer Research United (ACCRU) RU261206I.

Objectives: With the introduction of novel immune therapeutics for the treatment of disseminated malignancies, we sought to evaluate whether deliberate sequencing of immunotherapy before/after conventional cytotoxic chemotherapy would have an impact on clinical outcomes in patients with previously treated metastatic melanoma. We sought to evaluate whether or not ipilimumab immunotherapy administered before or after cytotoxic chemotherapy (nab-paclitaxel+bevacizumab, AB) would impact clinical outcomes.

Methods: We conducted a randomized phase 2 clinical trial of patients with BRAF wild-type metastatic melanoma (up to 2 prior therapies) who received either: (A) AB followed by ipilimumab therapy at progression; or (B) ipilimumab followed by AB treatment at progression.

Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma.

Purpose: Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to symptomatic multiple myeloma.

Methods: We conducted a randomized trial that assessed the efficacy of single-agent lenalidomide compared with observation in patients with intermediate- or high-risk smoldering multiple myeloma.

Foundations of modeling in cryobiology-III: Inward solidification of a ternary solution towards a permeable spherical cell in the dilute limit.

In the previous two manuscripts we outlined the general theory of heat and mass transport in a cell-liquid-ice system with general boundaries and nonideal and nondilute assumptions. Here we simplify the models considerably by presenting a reduction to a spherically symmetric system-a spherical cell with an encroaching spherical ice front. We also reduce to linear approximations of the nonideal nondilute models, essentially assuming dilute and ideal conditions.

Foundations of modeling in cryobiology-II: Heat and mass transport in bulk and at cell membrane and ice-liquid interfaces.

Modeling coupled heat and mass transport in biological systems is critical to the understanding of cryobiology. In Part I of this series we derived the transport equation and presented a general thermodynamic derivation of the critical components needed to use the transport equation in cryobiology. Here we refine to more cryobiologically relevant instances of a double free-boundary problem with multiple species.

Numerical solution of inward solidification of a dilute ternary solution towards a semi-permeable spherical cell.

Modeling a cell's response to encroaching ice has informed the development of cryopreservation protocols for four decades. It has been well documented that knowledge of the cellular state as a function of media and cooling rate faciliate informed cryopreservation protocol design and explain mechanisms of damage. However, previous efforts have neglected the interaction between solutes and the encroaching ice front and their effects on the cell state.

A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872.

Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM.

Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies.

Objective: Charcot-Marie-Tooth (CMT) disease is most commonly caused by duplication of a chromosomal segment surrounding Peripheral Myelin Protein 22, or PMP22 gene, which is classified as CMT1A. Several candidate therapies reduce Pmp22 mRNA levels in CMT1A rodent models, but development of biomarkers for clinical trials in CMT1A is a challenge given its slow progression and difficulty in obtaining nerve samples. Quantitative PCR measurements of PMP22 mRNA in dermal nerves were performed using skin biopsies in human clinical trials for CMT1A, but this approach did not show increased PMP22 mRNA in CMT1A patients compared to controls.

Intracerebral hemorrhage after IV tPA for stroke as early symptom of ANCA-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare diseases characterized by a necrotizing small-vessel vasculitis and circulating ANCA that comprise granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (EGPA). Acute ischemic stroke (AIS) can be a manifestation of central nervous system (CNS) involvement in these diseases. Furthermore, intracerebral hemorrhage (ICH) is a potential complication of these necrotizing vasculitides.

Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial.

Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL.

Magnetic Resonance Imaging Characteristics of a Baerveldt Glaucoma Implant.

Purpose: Evaluate for normative postoperative magnetic resonance imaging (MRI) characteristics of a Baerveldt Glaucoma Implant (BGI).

Design: Prospective case series.

Participants: Seven subjects with uncontrolled glaucoma requiring a primary superotemporal BGI.

A randomized comparison of once weekly epoetin alfa to extended schedule epoetin or darbepoetin in chemotherapy-associated anemia.

Erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients with cancer chemotherapy-associated anemia (CAA). Extended-interval ESA dosing (administration less than once weekly) is common with DA, but previous studies suggested that EA might also be administered less often than weekly. In this multicenter prospective trial, 239 CAA patients with Hb <10.

North Central Cancer Treatment Group N10C2 (Alliance): a double-blind placebo-controlled study of magnesium supplements to reduce menopausal hot flashes.

Objective: Hot flashes are a common symptom in breast cancer survivors that can negatively impact quality of life. Preliminary data suggested that magnesium might be used as an effective low-cost treatment of hot flashes with minimal adverse effects.

Methods: A four-arm, double-blind, placebo-controlled, randomized trial was conducted.

Foundations of modeling in cryobiology-I: concentration, Gibbs energy, and chemical potential relationships.

Mathematical modeling plays an enormously important role in understanding the behavior of cells, tissues, and organs undergoing cryopreservation. Uses of these models range from explanation of phenomena, exploration of potential theories of damage or success, development of equipment, and refinement of optimal cryopreservation/cryoablation strategies. Over the last half century there has been a considerable amount of work in bio-heat and mass-transport, and these models and theories have been readily and repeatedly applied to cryobiology with much success.

Modelling the evaporation of a tear film over a contact lens.

A contact lens (CL) separates the tear film into a pre-lens tear film (PrLTF), the fluid layer between the CL and the outside environment, and a post-lens tear film (PoLTF), the fluid layer between the CL and the cornea. We examine a model for evaporation of a PrLTF on a modern permeable CL allowing fluid transfer between the PrLTF and the PoLTF. Evaporation depletes the PrLTF, and continued evaporation causes depletion of the PoLTF via fluid loss through the CL.

A model for wetting and evaporation of a post-blink precorneal tear film.

We examine a fluid dynamic model for the evolution of a precorneal tear film that includes evaporation of the aqueous layer and a wetting corneal surface. Our model extends previous work on the break-up time for a post-blink tear film to include a more realistic model for evaporation. The evaporation model includes the effects of conjoining pressure and predicts the existence of an equilibrium adsorbed fluid layer that serves as a model for a wetting corneal surface/mucin layer.