Jennifer R. Geske

Usefulness of R.E.N.A.L. Nephrometry Scoring System for Predicting Outcomes and Complications of Percutaneous Ablation of 751 Renal Tumors

PURPOSE We applied the R.E.N.A.L. (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior and location relative to polar lines) nephrometry scoring system to renal tumors treated with percutaneous ablation to determine whether this score is associated with oncological outcomes and complications. MATERIALS AND METHODS A total of 751 renal tumors were treated at 679 percutaneous ablation sessions in 627 patients at our institution between 2000 and 2012. Of these renal masses 430 (57%) were treated with cryoablation and the remaining 321 were treated with radio frequency ablation. R.E.N.A.L. tumor scores were analyzed to determine the association of the score with ablation treatment outcomes and complications according to Clavien criteria. RESULTS The mean ± SD R.E.N.A.L. nephrometry score of all ablated tumors was 6.7 ± 1.9. Those treated with cryoablation had higher scores than those treated with radio frequency ablation (mean 7.2 ± 1.9 vs 6.1 ± 1.8, p <0.001). We identified a total of 28 local treatment failures (3.7%) in the 751 tumors during a mean computerized tomography/magnetic resonance imaging followup of 27.9 ± 27.8 months. There was a significant association between R.E.N.A.L. nephrometry score and local treatment failure. Mean nephrometry score was 7.6 ± 2.2 vs 6.7 ± 1.9 for tumors with vs without local treatment failure (p <0.001). Of the 679 ablation treatments 38 (5.6%) major (grade 3 or greater) patient complications occurred. There was a significant association between R.E.N.A.L. nephrometry score and major complications. Patients with vs without a major complication had a mean nephrometry score of 8.1 ± 2.0 vs 6.8 ± 1.9 (p <0.001). CONCLUSIONS The R.E.N.A.L. nephrometry scoring system predicts treatment efficacy and complications following percutaneous renal ablation.

Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting

Objective The objective was to evaluate the potential benefit of an integrated, five-gene pharmacogenomic test and interpretive report (GeneSight) for the management of psychotropic medications used to treat major depression in an outpatient psychiatric practice. Methods The open-label study was divided into two groups. In the first (unguided) group (n=113), pharmacogenomic information was not shared until all participants completed the study. In the second (guided) group (n=114), the pharmacogenomic report was provided to physicians for clinical use. Three depression ratings, the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Quick Inventory of Depressive Symptomatology – Clinician Rated (QIDS-C16), and the Patient Health Questionnaire (PHQ-9), were collected at baseline, and at 2, 4, and 8 weeks. Results The guided group experienced greater percent improvement in depression scores from baseline on all three depression instruments (HAMD-17, P<0.0001; QIDS-C16, P<0.0001; PHQ-9, P<0.0001) compared with the unguided group. Eight-week response rates were higher in the guided group than in the unguided group on all three measurements (HAMD-17, P=0.03; QIDS-C16, P=0.005; PHQ-9, P=0.01). Eight-week QIDS-C16 remission rates were higher in the guided group (P=0.03). Participants in the unguided group who at baseline were prescribed a medication that was most discordant with their genotype experienced the least improvement compared with other unguided participants (HAMD-17, P=0.007). Participants in the guided group and on a baseline medication most discordant with their genotype showed the greatest improvement compared with the unguided cohort participants (HAMD-17, P=0.01). Conclusion These findings replicate previous studies and demonstrate significantly improved depression outcomes with use of GeneSight, an integrated, multigenetic pharmacogenomic testing platform.

The Noninferiority of the Nonparticulate Steroid Dexamethasone vs the Particulate Steroids Betamethasone and Triamcinolone in Lumbar Transforaminal Epidural Steroid Injections

OBJECTIVE To assess whether a nonparticulate steroid (dexamethasone, 10 mg) is less clinically effective than the particulate steroids (triamcinolone, 80 mg; betamethasone, 12 mg) in lumbar transforaminal epidural steroid injections (TFESIs) in subjects with radicular pain with or without radiculopathy. DESIGN Retrospective observational study with noninferiority analysis of dexamethasone relative to particulate steroids. SETTING Single academic radiology pain management practice. SUBJECTS Three thousand six hundred forty-five lumbar TFESIs at the L4-5, L5-S1, or S1 neural foramina, performed on 2,634 subjects. METHODS/OUTCOME MEASURES Subjects were assessed with a pain numerical rating scale (NRS, 0-10) and Roland-Morris disability questionnaire (R-M) prior to TFESI, and at 2 weeks and 2 months follow-up. For categorical outcomes, successful pain relief was defined as either ≥50% reduction in NRS or pain 0/10; functional success was defined as ≥40% reduction in R-M score. Noninferiority analysis was performed with δ = -10% as the limit of noninferiority. Continuous outcomes (mean NRS, R-M scores) were analyzed for noninferiority with difference bounds of 0.3 for NRS scores and 1.0 for R-M scores. RESULTS With categorical outcomes, dexamethasone was demonstrated to be noninferior to the particulate steroids in pain relief and functional improvement at 2 months. Using continuous outcomes, dexamethasone was demonstrated to be superior to the particulate steroids in both pain relief and functional improvement at 2 months. CONCLUSION This retrospective observational study reveals no evidence that dexamethasone is less effective than particulate steroids in lumbar TFESIs performed for radicular pain with or without radiculopathy.

A randomized comparison of ketamine versus methohexital anesthesia in electroconvulsive therapy.

To assess the clinical utility of ketamine as an anesthetic agent for electroconvulsive therapy (ECT), based upon recent findings that ketamine may have antidepressant properties. Depressed ECT patients were randomly assigned to receive anesthesia with either ketamine or methohexital. Outcome measures included assessments of depressive severity, cognition, post-anesthesia side effects, and hemodynamics. Twenty one patients were treated with ketamine and 17 with methohexital. There were no significant differences in depression or cognitive outcomes between the two drugs. Additionally, there were no measures of post-anesthesia tolerability or hemodynamics which favored ketamine. Ketamine anesthesia does not accelerate the antidepressant effect of ECT or diminish the cognitive side effects, at least as measured in this study. Furthermore, there is no apparent benefit of ketamine for speed or quality of post-ECT recovery, and it is associated with higher systolic blood pressures after the treatments. Ketamine is associated with longer motor seizure duration than methohexital.

Clinical phenotype of bipolar disorder with comorbid binge eating disorder

BACKGROUND To explore the relationship between binge eating disorder (BED) and obesity in patients with bipolar disorder (BP). METHODS 717 patients participating in the Mayo Clinic Bipolar Biobank completed structured diagnostic interviews and questionnaires for demographic and illness-related variables. They also had weight and height measured to determine body mass index (BMI). The effects of BED and obesity (BMI≥30 kg/m(2)), as well as their interaction, were assessed on one measure of general medical burden and six proxies of psychiatric illness burden. RESULTS 9.5% of patients received a clinical diagnosis of BED and 42.8% were obese. BED was associated with a significantly elevated BMI. Both BED and obesity were associated with greater psychiatric and general illness burden, but illness burden profiles differed. After controlling for obesity, BED was associated with suicidality, psychosis, mood instability, anxiety disorder comorbidity, and substance abuse comorbidity. After controlling for BED status, obesity was associated with greater general medical comorbidity, but lower substance abuse comorbidity. There were no significant interaction effects between obesity and BED, or BMI and BED, on any illness burden outcome. LIMITATIONS There may have been insufficient power to detect interactions between BED and obesity. CONCLUSIONS Among patients with BP, BED and obesity are highly prevalent and correlated, but associated with different profiles of enhanced illness burden. As the association of BED with greater psychiatric illness burden remained significant even after accounting for the effect of obesity, BP with BED may represent a clinically important sub-phenotype.

Alcohol craving as a predictor of relapse.

BACKGROUND AND OBJECTIVES Alcoholism treatment interventions, both psychosocial and pharmacologic, aim to reduce cravings to drink. Yet, the role of craving in treatment outcomes remains unclear. This study evaluated craving intensity measured with the Penn Alcohol Craving Scale (PACS) at admission and discharge from residential treatment as a predictive factor of relapse after treatment. METHODS The study cohort included 314 alcohol-dependent subjects. Associations between relapse after discharge, PACS score, and clinical variables were investigated using time-to-event analyses. The primary analysis, based on the intent-to-treat principle, presumed relapse in those declining follow-up or not responding to contact attempts. Secondary analysis utilized data from 226 subjects successfully contacted after discharge with a median follow-up time of 365 days. RESULTS The intent-to-treat analysis demonstrated that relapse was associated with higher level of craving at admission (p= .002) and discharge (p < .001). The analysis of data from patients successfully contacted after discharge led to similar results. A multivariable analysis indicated that relapse rates increased as PACS scores increased, and a higher discharge PACS score was significantly associated with relapse (p= .006) even after adjusting for covariates. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE This study demonstrates that higher PACS scores at the time of admission and discharge are associated with relapse following residential addiction treatment. These data support the role of craving in relapse and the utility of craving measurement as a clinical guide in assessing relapse risk.

Enhancing Recovery After Acute Ischemic Stroke with Donepezil as an Adjuvant Therapy to Standard Medical Care: Results of a Phase IIa Clinical Trial

BACKGROUND Our aim was to assess the safety, tolerability, and efficacy signal of early donepezil administration with regard to enhancing recovery in a diverse acute ischemic stroke population. METHODS This was a multicenter, single-arm, National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator trial-controlled, modified 2-stage adaptive clinical trial set in 2 tertiary care hospitals in the United States. Adults with ischemic stroke treated within 24 hours after onset of symptoms were included. The intervention studied was donepezil 5 mg/day for 30 days, followed by an increase to 10 mg/day for 60 days. Our main outcome measures included treatment-related adverse events and side effects. The primary favorable outcome was a 90-day National Institutes of Health Stroke Scale (NIHSS) score ≤1. Neurologic, cognitive, functional, and psychological outcomes were assessed longitudinally. RESULTS Thirty-three adults (median age 66 years; 59% female; 39% received tissue plasminogen activator) initiated treatment with donepezil. There were no treatment-related serious adverse events. Three participants (9%) discontinued donepezil because of side effects and 3 participants (9%) required a reduction to 5 mg/day after titration to 10 mg/day. Fifteen participants (45%) had a favorable outcome (NIHSS score ≤1 at day 90), and the study met prespecified criteria for continuing to a randomized trial (P < .10). Statistically significant improvements from baseline were observed with several secondary cognitive measures, including the Trail Making Tests and Mini-Mental State Exam (P < .01 for both). CONCLUSIONS Adjuvant donepezil therapy initiated within 24 hours of acute ischemic stroke was safe and tolerated at 5 mg/day to 10 mg/day. The study met a priori criteria to move forward with a randomized clinical trial.

Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate

Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P=4.6 × 10−5). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P=0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P=0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.

Clinical effectiveness of single lumbar transforaminal epidural steroid injections

OBJECTIVES To assess the clinical effectiveness of single lumbar transforaminal epidural steroid injections (TFESIs) in subjects with radicular pain with or without radiculopathy. DESIGN Retrospective observational series. SETTING Single academic radiology pain management practice. SUBJECTS Two thousand twenty-four subjects undergoing single lumbar TFESIs at the L4-5, L5-S1, or S1 neural foramina. METHODS / OUTCOME MEASURES Subjects were assessed with a pain numerical rating scale (NRS, 0-10) and Roland-Morris disability questionnaire (R-M, 23-point Deyo modification) prior to TFESI and at 2 weeks and 2 months follow-up. Successful pain relief (responders) was defined as either ≥50% reduction in NRS or pain 0/10; functional success was defined as ≥40% reduction in R-M score. RESULTS There were statistically significant (P < 0.0001) reductions in mean NRS and R-M scores at 2 weeks and 2 months postinjection. For NRS, 40.9% were responders at 2 weeks and 45.6% at 2 months. For R-M, 31.9% were responders at 2 weeks and 41.3% at 2 months. The proportion of responders for NRS and R-M was higher when there was <3 months of pain (odds ratio 2-month NRS = 2.42 [95% confidence interval: 1.82, 3.24], odds ratio 2-month R-M = 2.61 [1.96, 3.48]). For subjects with <3 months of pain, the proportion of responders was 62.4% (56.5, 68.3%) for NRS and 59.3% (53.3, 65.3%) for R-M scores. CONCLUSIONS This retrospective observational study suggests TFESIs are clinically effective in the treatment of lumbar radicular pain. Subjects with a shorter duration of pain are more likely to achieve a successful outcome.

Replication of genome wide association studies of alcohol dependence: support for association with variation in ADH1C.

Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.