Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers.

PURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. METHODS: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. RESULTS: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. CONCLUSION: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.

Association of QT interval-prolonging drugs with clinical trial eligibility in patients with advanced cancer.

Introduction: Drug-induced prolongation of the heart rate-corrected QT interval (QTc) is associated with increased risk for the potentially fatal arrhythmia torsades de pointes. Due to arrhythmia risk, clinical trials with cancer therapeutics often exclude patients based on thresholds for QTc prolongation. Our objective was to assess associations between prescriptions for QT-prolonging drugs and the odds of meeting cancer trial exclusionary QTc thresholds in a cohort of adults with advanced cancer. Methods: Electronic health records were retrospectively reviewed for 271 patients seen at our institutional molecular solid tumor clinic. Collected data included demographics, QTc measurements, ventricular arrhythmia-related diagnoses, and all inpatient and outpatient prescriptions. Potential associations were assessed between demographic and clinical variables, including prescriptions for QT-prolonging drugs, and QTc measurements. Results: Women had longer median QTc measurements than men (p = 0.030) and were prescribed more QT-prolonging drugs during the study (p = 0.010). In all patients, prescriptions for QT-prolonging drugs were associated with longer median and maximum QTc measurements at multiple assessed time points (i.e., for QT-prolonging drugs prescribed within 10, 30, 60, and 90 days of QTc measurements). Similarly, the number of QT-prolonging drugs prescribed was correlated with longer median and maximum QTc measurements at multiple time points. Common QTc-related exclusionary criteria were collected from a review of ClinicalTrials.gov for recent cancer clinical trials. Based on common exclusion criteria, prescriptions for QT-prolonging drugs increased the odds of trial exclusion. Conclusion: This study demonstrates that prescriptions for QT-prolonging drugs were associated with longer QTc measurements and increased odds of being excluded from cancer clinical trials.

Use of outpatient care by juvenile detainees upon community reentry: effects of mental health screening and referral.

OBJECTIVE: This study assessed rates of mental health care utilization among juvenile detainees upon community reentry and examined the impact of a mental health screening and referral program. METHODS: A pre-post cohort design was used: 24 months before and after implementation of the program. The sample included 7,265 observations from 6,345 participants age 13 to 18 (first cohort, 4,812; second, 2,453). Outcomes included mental health care utilization (30 and 60 days postdetention) and recidivism (three and six months postdetention). RESULTS: Logistic regression models of utilization at 30 days, controlling for cohort differences with propensity scores, found that males were less likely than females to have a mental health visit (odds ratio [OR]=.54, 95% confidence interval [CI]=.45­.64, p<.01); the likelihood was also lower among black (OR=.52, CI=.44­.62, p<.01) and Hispanic (OR=.12, CI=.07­.22, p<.01) youths, compared with white youths, and among older youths (OR=.53, CI=.50­.57, p<.01) (similar results at 60 days). No overall significant differences between cohorts were found in visits at 30 (first cohort, 14%; second, 16%) and 60 (17% and 19%, respectively) days postrelease. An age interaction with cohort indicated a cohort difference among adolescents in the middle tertile (14.6­16.5 years) in utilization at 30 (first cohort, 12%; second, 17%) and 60 (16% and 21%) days. Compared with the preimplementation cohort, the postimplementation cohort had higher recidivism rates at three (first cohort, 24%; second, 31%) and six (36% and 43%) months. CONCLUSIONS: Connection to services upon community reentry was poor among detained youths. A screening and referral program was not sufficient to increase utilization rates.

The consequences of juvenile detention reform for mental health and sexually transmitted infection screening among detained youth.

PURPOSE: To understand how diversion of low-risk youth from juvenile detention affected screening practices for detained youth. METHODS: In a 22-month cross-sectional study of 2,532 detainees (age, 13-18 years), mental health and sexually transmitted infection (STI) screening data were compared before and after the beginning of diversion efforts through implementation of a Risk Assessment Instrument (RAI). RESULTS: Detention diversion resulted in a 30% census reduction. In a logistic regression, younger age (odds ratio [OR] = 1.10 for a 1-year increase; confidence interval [CI]: 1.03, 1.17), Hispanic versus white race/ethnicity (OR = .53; CI: .35, .82), and less severe crime (OR = .90 per 1 point; CI: .89, .91) predicted reduced likelihood of detention. Mental health and STI screening increased significantly after implementation of the RAI. Additionally, the rate of positive STI tests increased among detained males (9% pre-RAI to 14% after implementation of the RAI, p = .01). However, implementation of the RAI did not result in a significant increase in the number of positive mental health screens. CONCLUSIONS: Universal mental health and STI screening are increasingly common public health practices in detention centers. The results of this study indicate that juvenile justice diversion programming affects public health screening rates among detained youth in our population. Future study of the possible unintended consequences of criminal justice initiatives on public health outcomes is recommended.

Race and medication adherence and glycemic control: findings from an operational health information exchange.

The Central Indiana Beacon Community leads efforts for improving adherence to oral hypoglycemic agents (OHA) to achieve improvements in glycemic control for patients with type 2 diabetes. In this study, we explored how OHA adherence affected hemoglobin A1C (HbA1c) level in different racial groups. OHA adherence was measured by 6-month proportion of days covered (PDC). Of 3,976 eligible subjects, 12,874 pairs of 6-month PDC and HbA1c levels were formed between 2002 and 2008. The average HbA1c levels were 7.4% for African-Americans and 6.5% for Whites. The average 6-month PDCs were 40% for African-Americans and 50% for Whites. In mixed effect generalized linear regression analyses, OHA adherence was inversely correlated with HbA1c level for both African-Americans (-0.80, p<0.0001) and Whites (-0.53, p<0.0001). The coefficient was -0.26 (p<0.0001) for the interaction of 6-month PDC and African-Americans. Significant risk factors for OHA non-adherence were race, young age, non-commercial insurance, newly-treated status, and polypharmacy.

Exploring potential noninvasive biomarkers in eosinophilic esophagitis in children.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil-derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE. SUBJECTS AND METHODS: Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed. RESULTS: Sixty subjects with EE (46 [75%] boys, mean age 7.5 ±â€Š4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 ±â€Š4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls' 1-time measurement. CONCLUSIONS: Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence.

Chlamydia screening among young women: individual- and provider-level differences in testing.

OBJECTIVE: We assessed differences in chlamydia screening rates according to race/ethnicity, insurance status, age, and previous sexually transmitted infection (STI) or pregnancy. METHODS: A retrospective cohort study was performed using electronic medical record and billing data for women 14 to 25 years of age in 2002-2007, assessing differences in the odds of a chlamydia test being performed at that visit. RESULTS: Adjusted odds of a chlamydia test being performed were lower among women 14 to 15 years of age (odds ratio: 0.83 [95% confidence interval: 0.70-1.00]) and 20 to 25 years of age (20-21 years, odds ratio: 0.78 [95% confidence interval: 0.70-0.89]; 22-23 years, odds ratio: 0.76 [95% confidence interval: 0.67-0.87]; 24-25 years, odds ratio: 0.64 [95% confidence interval: 0.57-0.73]), compared with women 18 to 19 years of age. Black women had 3 times increased odds (odds ratio: 2.96 [95% confidence interval: 2.66-3.28]) and Hispanic women nearly 13 times increased odds (odds ratio: 12.89 [95% confidence interval: 10.85-15.30]) of testing, compared with white women. Women with public (odds ratio: 1.74 [95% confidence interval: 1.58-1.91]) and public pending (odds ratio: 6.85 [95% confidence interval: 5.13-9.15]) insurance had increased odds of testing, compared with women with private insurance. After first STI diagnosis, differences according to race/ethnicity persisted but were smaller; after first pregnancy, differences persisted. CONCLUSIONS: Despite recommendations to screen all sexually active young women for chlamydia, providers screened women differently according to age, race/ethnicity, and insurance status, although differences were reduced after first STI or pregnancy.

Mental health screening and STI among detained youth.

Our objective was to understand the relationship between mental health screening results, health disparity, and STI risk among detained adolescents. In this 24-month cross-sectional study of 1,181 detainees (age 13-18 years), we examined associations between race, gender, mental health screening results (as measured by the Massachusetts Youth Screening Instrument-2nd Edition) and sexually transmitted infection rates (STI; chlamydia, gonorrhea, and trichomonas). Consistent with previous research, females and black youth were disproportionately affected by STI. Race and gender differences were also noted in mental health screening. The odds of having an STI increased by 23% (OR = 1.23, 95% CI = 1.06, 1.37) with each one-unit increase in the alcohol/drug subscale score for females. Gender-specific STI interventions for detained youth are warranted. For young women with substance abuse, specific interventions are necessary and may help reduce health disparity in this vulnerable population.

Incidental gastric eosinophils in patients with eosinophilic esophagitis: do they matter?

BACKGROUND AND AIM: Some patients with eosinophilic esophagitis (EE) (>15 eosinophils/high-power field on esophageal mucosal biopsies and lack of response to acid suppression and/or normal pH probe study) demonstrate incidental eosinophilic inflammation of the gastric mucosa. It is unclear whether patients with EE and normal gastric biopsies (EE-N) are phenotypically different from patients with EE and gastric mucosal abnormalities (EE-A) (ie, >10 eos/hpf on gastric biopsies). The aim of the study was to compare the clinical features and response to therapy among patients with EE-N and EE-A. PATIENTS AND METHODS: Medical records of all of the EE-A and a random group of patients with EE-N diagnosed during an 8-year period were reviewed. A subgroup analysis of patients treated with swallowed fluticasone with a repeat esophagogastroduodenoscopy within 6 months of starting therapy was also performed. RESULTS: During the study period, 41 patients had EE-A. When compared to 50 random patients with EE-N, no clinical differences were noted, including sex, age, presenting symptoms, esophageal histology, and atopy history. Eleven (27%) of the 41 EE-A and 14 (28%) of the 50 EE-N patients were treated with swallowed fluticasone, and the response was similar among the groups. The mean esophageal eosinophils/high-power field among the EE-A group dropped from 47 to 8 compared with a 46 to 7 drop among the EE-N group treated with fluticasone therapy (P = 0.91). In 9 (82%) of the 11 patients with EE-A treated with fluticasone, there was resolution (7 of 9) or significant improvement (2 of 9) of gastric eosinophilia. CONCLUSIONS: Patients with EE-A and EE-N have similar clinical presentations. Incidental gastric inflammation does not predict a worse response of esophageal inflammation to fluticasone and should not exclude its use in patients with EE-A. In fact, gastric inflammation responded to swallowed fluticasone in the majority of patients with EE-A. This observation should foster further investigation into pathogenesis of EE and presumed esophagogastric inflammatory axis.

Adequacy of hospital discharge summaries in documenting tests with pending results and outpatient follow-up providers.

BACKGROUND: Poor communication of tests whose results are pending at hospital discharge can lead to medical errors. OBJECTIVE: To determine the adequacy with which hospital discharge summaries document tests with pending results and the appropriate follow-up providers. DESIGN: Retrospective study of a randomly selected sample PATIENTS: Six hundred ninety-six patients discharged from two large academic medical centers, who had test results identified as pending at discharge through queries of electronic medical records. INTERVENTION AND MEASUREMENTS: Each patient's discharge summary was reviewed to identify whether information about pending tests and follow-up providers was mentioned. Factors associated with documentation were explored using clustered multivariable regression models. MAIN RESULTS: Discharge summaries were available for 99.2% of 668 patients whose data were analyzed. These summaries mentioned only 16% of tests with pending results (482 of 2,927). Even though all study patients had tests with pending results, only 25% of discharge summaries mentioned any pending tests, with 13% documenting all pending tests. The documentation rate for pending tests was not associated with level of experience of the provider preparing the summary, patient's age or race, length of hospitalization, or duration it took for results to return. Follow-up providers' information was documented in 67% of summaries. CONCLUSION: Discharge summaries are grossly inadequate at documenting both tests with pending results and the appropriate follow-up providers.

Prenatal syphilis screening rates measured using medicaid claims and electronic medical records.

BACKGROUND: To prevent congenital syphilis, the Centers for Disease Control and Prevention and professional organizations recommend universal prenatal syphilis screening. State-level or larger-scale evaluations of adherence to these guidelines have relied on administrative data. We measured prenatal syphilis screening rates in Indiana women with prenatal Medicaid coverage and also used electronic medical records to examine the completeness of syphilis screening claims in Medicaid administrative data. METHODS: In statewide Indiana Medicaid claims data, diagnosis and procedure codes were used to identify women who delivered an infant between October 1, 1998, and September 30, 2002. Claims for prenatal (that is, during the 40 weeks before and including the delivery date) syphilis screens, including the "obstetric panel" of tests, and for prenatal visits were extracted. A subset of the study population received prenatal care in a large public hospital and its affiliated clinics served by an electronic medical records system. For these women, claims data were compared with laboratory reports. RESULTS: Among 74,188 women with one delivery in Medicaid claims data, 60% had at least 1 prenatal syphilis screening claim, and 15% had 2 or more. Women with continuous Medicaid enrollment during pregnancy or with at least one prenatal visit claim had higher rates. Among the 3960 women for whom Medicaid claims and laboratory data were available, 49.8% had at least one prenatal syphilis screen in Medicaid claims, but 99.3% had at least one laboratory report of a syphilis screen. CONCLUSIONS: Measurements made using Medicaid administrative data appear to substantially underestimate true prenatal syphilis screening rates.

Hospital resource utilization in childhood cancer.

To describe the patterns and predictors of hospital resource utilization in a cohort of children with newly diagnosed cancer, a retrospective cohort study of 195 consecutively diagnosed children with cancer at a single large Midwestern children's hospital was conducted. Patients were diagnosed between November 1995 and March 1997. All hospital encounters for these patients starting from the time of diagnosis to 3 years from diagnosis were identified using hospital administrative data. The patients were categorized into four diagnostic groups: lymphoid malignancies (acute lymphoblastic leukemia and lymphoma), myeloid leukemias (acute myeloid leukemia and chronic myeloid leukemia), central nervous system tumors, and solid tumors. Hospital charges and length of stay for patients in each diagnostic category were described. Predictive models for total resource consumption (total hospital charges) and intensive care use were derived. One hundred sixty-five of the 195 were admitted to Riley Hospital for Children at least once during the 3-year period following diagnosis. Among these 165, mean age at diagnosis was 6.9 years (minimum newborn, maximum 18.7 years). The ratio of boys to girls was 99:66 (1.5:1). The distribution of 165 diagnoses was as follows: 65 (39%) with lymphoid malignancy, 13 (8%) with myeloid leukemia, 36 (22%) with central nervous system tumors, and 51 (31%) with solid tumors. Sixty-two patients (38%) used the pediatric intensive care unit (PICU) at least once; 22 patients (13%) underwent stem cell transplantation. Sixty-five patients (39%) entered clinical trials. One hundred thirty-nine patients (84%) were alive at the end of 3 years. Three-year cumulative hospital charges were USD 16 million--almost USD 100,000/child hospitalized. Half of these charges were incurred in the first 4.5 months after diagnosis. Half of all hospital charges accrued to only 12.7% of patients; these patients were more likely to have a diagnosis of myeloid leukemia, to have undergone stem cell transplantation, and to have used the PICU. There were three independent predictors of hospital charges (log transformed): stem cell transplantation, PICU utilization, and death within 3 years of diagnosis. PICU utilization was predicted by tumor type (myeloid leukemia and central nervous system tumors were positive predictors of PICU utilization; lymphoid malignancy and solid tumors were negative predictors), stem cell transplantation, and death within 3 years of diagnosis. The authors conclude that hospitalization for childhood cancer is common, costly in the short term, and to some extent predictable. These data suggest that failures of current treatment not only lead to death but also add significantly to hospital resource utilization.

Prevalence of adrenocorticotropin deficiency in children with idiopathic growth hormone deficiency.

We sought to determine the prevalence of ACTH deficiency in children with GH deficiency (GHD) of unknown etiology with and without TSH deficiency and to correlate the structural characteristics of the hypothalamic-pituitary region on magnetic resonance imaging (MRI) with TSH and ACTH status. The electronic medical records system of a children's hospital was used to identify all patients less than 18 yr of age with GHD. TSH and ACTH deficiency were defined as being present if the patient was prescribed replacement hormone therapy. The medical records of 236 GHD subjects were reviewed, and the results of their MRI scans were recorded. Ninety had hypothalamic-pituitary-adrenal axis testing, and nine were ACTH deficient (10% of those tested; 4% of all subjects). Twenty-one (9%) of 236 were TSH deficient. All of the ACTH-deficient subjects were also TSH deficient: eight of nine had a gross abnormality on MRI, and one did not have an MRI report in the medical record. We conclude that patients with GHD, normal thyroid function, and no gross abnormalities on MRI do not need hypothalamic-pituitary-adrenal testing because no ACTH-deficient subjects would have been missed using this strategy (95% confidence interval, 0-5%).

Syphilis testing in association with gonorrhea/chlamydia testing during a syphilis outbreak.

We used an electronic medical records system retrospectively to evaluate how frequently, in a public hospital and its clinics, combined gonorrhea/chlamydia tests were accompanied by a syphilis test before and during a syphilis outbreak. Among 70,330 gonorrhea/chlamydia tests (1996-2000), the proportion with a syphilis test increased from 13% (preoutbreak) to 50% (intervention period) for men and from 6% to 13% for nonpregnant women. The increased syphilis testing coincided with a multifaceted public health intervention.