Eric A. Sherer

The effect of colonoscopy preparation quality on adenoma detection rates

BACKGROUND Colonoscopy reduces the risk of colorectal cancer mortality by removing precancerous adenomas. The detection rate of subcentimeter (<10 mm) polyps is lower for procedures with inadequate preparation quality. OBJECTIVE To compare the adenoma detection rates of small (6-9 mm) and diminutive (≤ 5 mm) adenomas in patients with poor and fair quality preparations with those with adequate quality preparations. DESIGN Cross-sectional study and multivariable, hierarchical model. SETTING Roudebush Veterans Affairs Medical Center. PATIENTS This study involved 8800 colonoscopies performed from 2001 to 2010. MAIN OUTCOME MEASUREMENTS Preparation quality rating, polyp size, and polyp histology. RESULTS Preparation quality was rated as fair in 2809 (31.9%) and poor in 829 (9.4%) colonoscopies. In patients with poor compared with adequate quality, the detection rate was lower for diminutive adenomas (odds ratio [OR] 0.57; 95% CI, 0.47-0.70) but not for small adenomas (OR 0.84; 95% CI, 0.65-1.07). There were no differences in the detection rate of diminutive (OR 1.08; 95% CI, 0.94-1.24]) or small (OR 1.09; 95% CI, 0.94-1.27) adenomas in patients with fair compared with adequate quality preparation. Detection of advanced histology in patients with poor preparation quality was lower than in those with adequate quality (P = .027; 3.3% vs 5.0%), but there was no difference in those with fair compared with adequate quality (P = .893; 4.9% vs 5.0%). LIMITATIONS Single-center study; no standardization of preparation quality or size measurements. CONCLUSIONS A fair preparation quality rating does not decrease the detection rate for adenomas of any size or for advanced histology, suggesting that fair quality may be considered adequate and that follow-up intervals may not need to be shortened. Poor preparation quality decreases the detection rate of diminutive adenomas and advanced histology, suggesting substandard colonoscopy performance.

Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of patients experience a disease relapse. However, it has been shown that individualizing therapy for childhood ALL patients by adjusting doses based on the blood concentration of active drug metabolite could significantly improve treatment outcome. An adaptive model predictive control (MPC) strategy is presented in which maintenance therapy for childhood ALL is personalized using routine patient measurements of red blood cell mean corpuscular volume as a surrogate for the active drug metabolite concentration. A clinically relevant mathematical model is developed and used to describe the patient response to the chemotherapeutic drug 6-mercaptopurine, with some model parameters being patient-specific. During the course of treatment, the patient-specific parameters are adaptively identified using recurrent complete blood count measurements, which sufficiently constrain the patient parameter uncertainty to support customized adjustments of the drug dose. While this work represents only a first step toward a quantitative tool for clinical use, the simulated treatment results indicate that the proposed mathematical model and adaptive MPC approach could serve as valuable resources to the oncologist toward creating a personalized treatment strategy that is both safe and effective.

A predictive model of longitudinal, patient-specific colonoscopy results

We suggest a model framework, in which an individual patients risk for colonic neoplasia varies based on findings from his previous colonoscopies, to predict longitudinal colonoscopy results. The neoplasia natural history model describes progression through four neoplasia development states with patient age. Multiple natural history model parameter sets are assumed to act concurrently on the colon and parameter set prevalence combinations, whose a priori likelihoods are a function of patient sex, provide a basis set for patient-level predictions. The novelty in this approach is that after a colonoscopy, both the parameter set combination likelihoods and their model predictions can adjust in a Bayesian manner based on the results and conditions of the colonoscopy. The adjustment of model predictions operationalizes the clinical knowledge that multiple or advanced neoplasia at baseline colonoscopy is an independent predictor of multiple or advanced neoplasia at follow-up colonoscopy--and vice versa for negative colonoscopies--and the adjustment of parameter set combination likelihoods accounts for the possibility that patients may have different neoplasia development rates. A model that accurately captures serial colonoscopy results could potentially be used to design and evaluate post-colonoscopy treatment strategies based on the risk of individual patients. To support model identification, observational longitudinal colonoscopy results, procedure details, and patient characteristics were collected for 4084 patients. We found that at least two parameter sets specific to each sex with model adjustments was required to capture the longitudinal colonoscopy data and inclusion of multiple possible parameter set combinations, which account for random variations within the population, was necessary to accurately predict the second-time colonoscopy findings for patients with a history of advanced adenomas. Application of this model to predict CRC risks for patients adhering to guideline recommended follow-up colonoscopy intervals found that there are significant differences in risk with patient age, gender, and preparation quality and demonstrates the need for a more rigorous investigation into these recommendations.

Provider acceptance, safety, and effectiveness of a computer-based decision tool for colonoscopy preparation

PURPOSE To assess provider acceptance of recommendations by a decision tool that scans the electronic medical record and determines whether sodium phosphate may be taken. In addition, to determine decision tool effects on a composite outcome of colonoscopies canceled, rescheduled, aborted, or repeated sooner than recommended due to preparation (prep) quality; prep quality; colonoscopy duration; and patient satisfaction with and tolerance of the preparation. METHODS We used 4 alternating 4-week periods to compare the decision tool with usual care for outpatient colonoscopy. All decision tool decisions were reviewed in real-time by gastroenterology nurses and/or physicians. Patients completed a survey about the prep process. Endoscopists blindly rated prep quality. Colonoscopy duration and findings were recorded. RESULTS Of 354 persons in the decision tool group, 4 prep decisions were overridden because of patient preference or prior prep failure, but none for medical reasons. Sodium phosphate was used more frequently in the decision tool group (73% vs. 41%; P < 0.01). There was no difference between the decision tool and usual care groups in the composite outcome (26% vs. 30%, respectively; P = 0.29), acceptable prep quality (62% vs. 56%; P = 0.22), colonoscopy duration (28 vs. 30 min; P = 0.17), patient satisfaction (P = 0.38), or preparation tolerance (P = 0.37). CONCLUSIONS An electronic medical record-based decision tool can safely and effectively tailor the prep for colonoscopy and may improve colonoscopy efficiency and patient satisfaction. LIMITATIONS This study was performed at a single VA medical center and endoscopy unit, relies on the presence of relevant medical conditions and laboratory data in the electronic medical record, and had a higher than expected use of sodium phosphate during usual care.

Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

The objective of chemotherapy is to eradicate all cancerous cells. However, due to the stochastic behavior of cells, the elimination of all cancerous cells must be discussed probabilistically. We hypothesize, and demonstrate in the results, that the mean and standard deviation of a cancer cell population, derived through the probabilistic interpretation of population balance equations, are sufficient to estimate the likelihood of cancer eradication. Our analysis of a binary cell division model reveals that an expected cancer population that is six standard deviations less than one cell provides a good estimate for the treatment durations that nearly ensures treatment successes. This approximation is evaluated and tested on two other physiologically likely scenarios: variable patient response to chemotherapy and the presence of a dormant population. We find that early identification of individual patient susceptibility to the chemotherapeutic agent is extremely important to all patients as treatment adjustments for non-responders greatly enhances their likelihood of cure while responders need not be subjected to needlessly harsh treatments. Presence of a dormant population increases both the required treatment duration and population variability, but the same estimation method holds. This work is a step toward using stochastic models for a quantitative evaluation of chemotherapy.

Suppression of the reticuloendothelial system using λ-carrageenan to prolong the circulation of gold nanoparticles

AIM Gold nanoparticles are employed for imaging and treatment of surgically inaccessible tumors owing to their inherent optical absorption and ability to extravasate through intravenous distribution. These nanoparticles are cleared from the blood by the reticuloendothelial system (RES) as expected given their size. MATERIALS & METHODS This study demonstrates the effects of RES blockade through the intravenous administration of λ-carrageenan, resulting in a decrease in the median clearance rate from 18.9 (95% CrI: 15.9-22.6) to 11.2 (95% CrI: 8.8-13.9) μl/min and an increase in nanoparticle circulation half-life t(½)( = 264 ± 73 vs 160 ± 22 min; p < 0.01). RESULTS This 59.3% decrease in clearance is greater than the 15% previously reported for liposomes [ 1 ]. CONCLUSION The primary benefit of nontoxic RES blockade is to increase the circulation time, where traditional particle modification is ineffective or impractical.

Clinical trial simulation to evaluate population pharmacokinetics and food effect: Capturing abiraterone and nilotinib exposures

The objectives of this study were to determine (1) the accuracy with which individual patient level exposure can be determined and (2) whether a known food effect can be identified in a trial simulation of a typical population pharmacokinetic trial. Clinical trial simulations were undertaken using NONMEM VII to assess a typical oncology pharmacokinetic trial design. Nine virtual trials for each compound were performed for combinations of different levels of between‐occasion variability, number of patients in the trial, and magnitude of a food covariate on oral clearance. Less than 5% and 20% bias and precision were obtained in individual clearance estimated for both abiraterone and nilotinib using this design. This design resulted in biased and imprecise population clearance estimates for abiraterone. The between‐occasion variability in most trials was captured with less than 30% of percent bias and precision. The food effect was detectable as a statistically significant covariate on oral clearance for abiraterone and nilotinib with percent bias and precision of the food covariate less than 20%. These results demonstrate that clinical trial simulation can be used to explore the ability of specific trial designs to evaluate the power to identify individual and population level exposures, covariate, and variability effects.

Growth of Screen-Detected Abdominal Aortic Aneurysms in Men: A Bayesian Analysis

There is considerable interindividual variability in the growth of abdominal aortic aneurysms (AAAs), but an individuals growth observations, risk factors, and biomarkers could potentially be used to tailor surveillance. To assess the potential for tailoring surveillance, this study determined the accuracy of individualized predictions of AAA size at the next surveillance observation. A hierarchical Bayesian model was fitted to a total of 1,732 serial ultrasound measurements from 299 men in whom ultrasound screening identified an AAA. The data were best described by a nonlinear model with a constant first derivative of the AAA growth rate with size. The area under the receiver operating characteristic (ROC) curves for predicting whether an AAA was ≥40 or ≥50 mm at the next observation were 0.922 and 0.979, respectively, and the median root mean squared error was 2.52 mm. These values were nearly identical for models with or without plasma D‐dimer effects.

Assessment of multi-wavelength pulse photometry for non-invasive dose estimation of circulating drugs and nanoparticles

The feasibility of multi-wavelength photoplethysmography for the real-time sensing of absorptive and scattering agents in pulsatile blood is discussed. The use of pulsatile signals extracted from trans-illumination of an accessible section of tissue allows us to calculate the concentration of the optically extinctive species in the pulsatile blood. This technology, initially used for pulse oximetry and dye densitometry, can be applied to monitor in vivo concentration and clearance of various absorptive species. Recently, our prototype has been used monitor the concentration of therapeutic gold nanoparticles, antimalarial quinine, and the antifungal agent amphotericin B. The assessment of the optical properties, device specifications, and signal quality for each compound are presented. We observe that this technology can be used to monitor numerous extinctive drug and nano-materials that present features in the 350-1100 nm range. The rationale for using this technology in a clinical setting would be to improve outcomes by real-time pharmacological feedback and/or control at point of care in addition to the elimination of invasive blood draws for collection of data.

Achieving targeted granulocyte differentiation through the use of interpolation and optimization techniques

Cellular differentiation is a complex process for which systematic design of control strategies has not been widely investigated. As a first step towards this aim, a control strategy for achieving a desired percentage of differentiating cells is proposed. A population balance model structure parallels the known granulocyte/monocyte differentiation pathway. Transition rate functions that characterize the movement of cells from one differentiation state to the next were identified from experimental data obtained via flow cytometry. An additional experiment demonstrates the efficacy of the proposed model and control strategy.