Development of Electronic Health Record-Based Machine Learning Models to Predict Barrett's Esophagus and Esophageal Adenocarcinoma Risk.

INTRODUCTION: Screening for Barrett's esophagus (BE) is suggested in those with risk factors, but remains underutilized. BE/esophageal adenocarcinoma (EAC) risk prediction tools integrating multiple risk factors have been described. However, accuracy remains modest (area under the receiver-operating curve [AUROC] ≤0.7), and clinical implementation has been challenging. We aimed to develop machine learning (ML) BE/EAC risk prediction models from an electronic health record (EHR) database. METHODS: The Clinical Data Analytics Platform, a deidentified EHR database of 6 million Mayo Clinic patients, was used to predict BE and EAC risk. BE and EAC cases and controls were identified using International Classification of Diseases codes and augmented curation (natural language processing) techniques applied to clinical, endoscopy, laboratory, and pathology notes. Cases were propensity score matched to 5 independent randomly selected control groups. An ensemble transformer-based ML model architecture was used to develop predictive models. RESULTS: We identified 8,476 BE cases, 1,539 EAC cases, and 252,276 controls. The BE ML transformer model had an overall sensitivity, specificity, and AUROC of 76%, 76%, and 0.84, respectively. The EAC ML transformer model had an overall sensitivity, specificity, and AUROC of 84%, 70%, and 0.84, respectively. Predictors of BE and EAC included conventional risk factors and additional novel factors, such as coronary artery disease, serum triglycerides, and electrolytes. DISCUSSION: ML models developed on an EHR database can predict incident BE and EAC risk with improved accuracy compared with conventional risk factor-based risk scores. Such a model may enable effective implementation of a minimally invasive screening technology.

Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center.

CONTEXT: Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first- or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD. OBJECTIVE: Evaluation of the efficacy and tolerance of mitotane in CD patients. DESIGN AND SETTING: Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center. MAIN OUTCOME MEASURE: Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC). RESULTS: Remission was achieved in 48 (72%) of the 67 long-term treated patients, after a median time of 6.7 (5.2-8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5 ± 8.9 mg/l, with a mean daily dose of 2.6 ± 1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P<0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0-67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32-1.00), P=0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery. CONCLUSION: Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients.

Saturable absorption of sorafenib in patients with solid tumors: a population model.

Sorafenib is an oral tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. By using a population approach, this study aimed to characterise its pharmacokinetics. Plasma concentration-time data (n = 372) from 71 patients under sorafenib were analysed using nonlinear mixed-effect modelling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and different covariates (demographic, biological). Simulations were done to compare different daily dosing regimens in a context of dose-escalation. A 1-compartment model with saturated absorption, first-order intestinal loss and elimination best described the pharmacokinetics of sorafenib. Absolute bioavailability significantly dropped with increasing daily doses of sorafenib. AUC increased less than proportionally with increasing doses [47.3 (41.3-63.3), 60.3 (56.3-64.4), 71.4 (51.3-99.1), 75.9 (45.5-100.9) mg/L.h for 400, 800, 1,200 and 1,600 mg/day, respectively]. According to the simulations, dividing the daily dose in three or four doses for daily dose >800 mg would significantly increase AUC compared with a twice daily dosing regimen (101.7 vs 81.6 mg/L.h for 400 mg q8h and 600 mg q12h respectively; 131.6 vs 91.5 mg/L.h for 400 mg q6h and 800 mg q12h, respectively). Thrice daily regimen may be most suitable in a context of dose-escalation (>800 mg/day) in non-responders to standard-dosing regimen.

Functional and clinical evidence of the influence of sorafenib binding to albumin on sorafenib disposition in adult cancer patients.

PURPOSE: Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (>99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterize in vitro sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients. RESULTS: In vitro estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 µM [CI95 0.20-0.23]. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 µM) to 30 g/L (453 µM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75-2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL (p = 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia (p = 0.0036) was the single parameter independently associated with CL. CONCLUSION: These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in cancer patients.

Management of Cushing's syndrome due to ectopic adrenocorticotropin secretion with 1,ortho-1, para'-dichloro-diphenyl-dichloro-ethane: findings in 23 patients from a single center.

CONTEXT: Effective treatment for the ectopic ACTH secretion syndrome (EAS) remains a therapeutic challenge. Immediate curative surgery of the responsible nonpituitary tumor is often not possible. OBJECTIVE: The objective of the study was to evaluate 1,ortho-1, para'-dichloro-diphenyl-dichloro-ethane (O,p'DDD) therapy in EAS. DESIGN AND PATIENTS: Patients included 36 consecutive patients with EAS from a single center treated between 1990 and 2006. Twenty-three of these patients, including 18 women aged 53.7 +/- 12.9 yr (mean +/- sd), were treated with O,p'DDD. Patient follow-up was 8.04 +/- 9.6 yr. RESULTS: A mean daily O,p'DDD dose of 3.3 +/- 1.2 g Lysodren equivalent was given for a mean duration of 1.8 +/- 2.1 yr. Urinary cortisol decreased from 2603 +/- 3443 microg/d before treatment to 79 +/- 169 microg/d at the time of maximal O,p'DDD efficacy. Urinary cortisol was normalized in 21 of the 23 patients. Adrenal insufficiency was observed in 20 patients. This was associated with clinical improvement of Cushing's syndrome manifestations, including diabetes, hypertension, and hypokalemia. O,p'DDD plasma levels were 10.4 +/- 6.5 microg/ml in the 12 patients tested at the time of adrenal insufficiency. Side effects were observed during the first 6 months in seven of 15 patients (46%). National Cancer Institute-Classification Common Toxicity Criteria grade 1 or 2 digestive or neurologic toxicity resolved after withdrawal or reduction of O,p'DDD. Careful monitoring was essential to long-term control, clinical improvement, and good tolerability. Medical control of the disease allowed the subsequent characterization of tumors in eight of 13 patients with initially occult tumors. CONCLUSION: With close monitoring, O,p'DDD could be a potent medical treatment for long-term control and management of EAS.

Comparison of a new enzymatic assay with a high-performance liquid chromatography/ ultraviolet detection method for therapeutic drug monitoring of mycophenolic acid in adult liver transplant recipients.

Mycophenolic acid (MPA) is used to prevent graft rejection. The methods used for determining the plasma MPA concentration in liver transplant recipients are the enzyme-multiplied immunoassay technique (EMIT), high-performance liquid chromatography with ultraviolet detection (HPLC-UV), and most recently mass spectrometry. EMIT has been reported to overestimate the MPA concentration by 30% to 35% in comparison with HPLC-UV. Recently, a new automated enzymatic assay based on inosine monophosphate dehydrogenase inhibition has been designed. The aim of the present investigation was to compare this technique with validated HPLC-UV in adult liver transplant recipients treated with tacrolimus or cyclosporine. One hundred seventy-six samples from 50 adult liver transplant recipients were analyzed with both techniques. Patients received mycophenolate mofetil (2 or 3 times daily) coadministered with cyclosporine microemulsion (n = 18) or tacrolimus (n = 32). Samples were drawn over an interdose interval during the early or late posttransplantation period. The Passing-Bablok regression and Bland-Altman plot were used to compare the 2 techniques. The Passing-Bablock regression, calculated from 166 samples, showed very good agreement between the enzymatic assay and the HPLC-UV method: enzymatic assay = 1.0204 (95% confidence interval, 0.9942, 1.0478) x HPLC-UV + 0.0201 (-0.0442, 0.0882). No significant bias was found between the techniques (Bland-Altman plot), and the median relative difference was 2.7% (95% confidence interval, -0.4, 6.6). In conclusion, the enzymatic assay showed an excellent correlation with HPLC-UV. Therefore, this method was proved valid and reliable for the monitoring of the plasma MPA concentration in adult liver transplant recipients treated with cyclosporine microemulsion or tacrolimus.