Darby J.S. Thompson

Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population

PURPOSE Patients with locally advanced prostate cancer after radical prostatectomy are candidates for secondary therapy. However, this higher risk population is heterogeneous. Many cases do not metastasize even when conservatively managed. Given the limited specificity of pathological features to predict metastasis, newer risk prediction models are needed. We report a validation study of a genomic classifier that predicts metastasis after radical prostatectomy in a high risk population. MATERIALS AND METHODS A case-cohort design was used to sample 1,010 patients after radical prostatectomy at high risk for recurrence who were treated from 2000 to 2006. Patients had preoperative prostate specific antigen greater than 20 ng/ml, Gleason 8 or greater, pT3b or a Mayo Clinic nomogram score of 10 or greater. Patients with metastasis at diagnosis or any prior treatment for prostate cancer were excluded from analysis. A 20% random sampling created a subcohort that included all patients with metastasis. We generated 22-marker genomic classifier scores for 219 patients with available genomic data. ROC and decision curves, competing risk and weighted regression models were used to assess genomic classifier performance. RESULTS The genomic classifier AUC was 0.79 for predicting 5-year metastasis after radical prostatectomy. Decision curves showed that the genomic classifier net benefit exceeded that of clinical only models. The genomic classifier was the predominant predictor of metastasis on multivariable analysis. The cumulative incidence of metastasis 5 years after radical prostatectomy was 2.4%, 6.0% and 22.5% in patients with low (60%), intermediate (21%) and high (19%) genomic classifier scores, respectively (p<0.001). CONCLUSIONS Results indicate that genomic information from the primary tumor can identify patients with adverse pathological features who are most at risk for metastasis and potentially lethal prostate cancer.

A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy

Background:Due to their varied outcomes, men with biochemical recurrence (BCR) following radical prostatectomy (RP) present a management dilemma. Here, we evaluate Decipher, a genomic classifier (GC), for its ability to predict metastasis following BCR.Methods:The study population included 85 clinically high-risk patients who developed BCR after RP. Time-dependent receiver operating characteristic (ROC) curves, weighted Cox proportional hazard models and decision curves were used to compare GC scores to Gleason score (GS), PSA doubling time (PSAdT), time to BCR (ttBCR), the Stephenson nomogram and CAPRA-S for predicting metastatic disease progression. All tests were two-sided with a type I error probability of 5%.Results:GC scores stratified men with BCR into those who would or would not develop metastasis (8% of patients with low versus 40% with high scores developed metastasis, P<0.001). The area under the curve for predicting metastasis after BCR was 0.82 (95% CI, 0.76–0.86) for GC, compared to GS 0.64 (0.58–0.70), PSAdT 0.69 (0.61–0.77) and ttBCR 0.52 (0.46–0.59). Decision curve analysis showed that GC scores had a higher overall net benefit compared to models based solely on clinicopathologic features. In multivariable modeling with clinicopathologic variables, GC score was the only significant predictor of metastasis (P=0.003).Conclusions:When compared to clinicopathologic variables, GC better predicted metastatic progression among this cohort of men with BCR following RP. While confirmatory studies are needed, these results suggest that use of GC may allow for better selection of men requiring earlier initiation of treatment at the time of BCR.

Impact of Patient Use of an Online Patient Portal on Diabetes Outcomes

OBJECTIVE To assess the effect of patient use of an online patient portal on diabetes outcomes. METHODS Patients included were those with diabetes who were newly referred to a Vancouver-based tertiary care diabetologist between April 2008 and October 2012. Each patient was assessed by the diabetologist, received initial diabetes education and was referred, as necessary, for further education and self-management training. All patients who provided an e-mail address at registration were invited to open an online patient portal account. The portal provided access to diabetes education material, personal laboratory values and a messaging system allowing communication with the diabetologist and staff. Patients who logged in 1 or more times were defined as portal users (n=50); patients who never logged in to the portal were defined as non-users (n=107). A1C was measured at 2 time points: at baseline (i.e. initial, in-clinic visit) and at last follow up (visit no less than 6 months and no more than 2 years after the initial visit). Because usership is self-selected, propensity score matching was used to create comparable user/non-user groups based on available baseline covariates. RESULTS Compared to non-users, a higher proportion of users achieved A1C ≤7% at follow up (56% vs. 32%) (p=0.031). CONCLUSION Accessing an online patient portal is associated with improved glycemic control.

Impact of a Genomic Classifier of Metastatic Risk on Postprostatectomy Treatment Recommendations by Radiation Oncologists and Urologists

OBJECTIVE To evaluate how a genomic classifier (GC) that predicts the risk of metastasis after prostatectomy would impact adjuvant treatment recommendations made by radiation oncologists and urologists. The 2 specialties often disagree about postprostatectomy adjuvant treatment recommendations. MATERIALS AND METHODS Twenty-six radiation oncologists and 20 urologists with genitourinary oncology expertise reviewed de-identified clinical results from 11 patients after radical prostatectomy and made adjuvant treatment recommendations. The same cases were later randomized and reassigned, and treatment recommendations were made using the clinical information and GC test results together. RESULTS Using clinical information alone, observation was recommended in 42% of decisions made by urologists vs 23% by radiation oncologists (P < .0001). The GC test results altered 35% and 45% of treatment recommendations made by radiation oncologists and urologists, respectively. Multivariate analysis showed GC risk was the strongest factor influencing treatment recommendations by both specialties, with an adjusted odds ratio of 4.17 (95% confidence interval [CI], 2.26-7.70) and 6.51 (95% CI, 4.29-9.88) for radiation oncologists and urologists, respectively. GC results indicating high metastatic risk resulted in intensification of treatment, whereas low metastatic risk resulted in less aggressive recommendations. The GC results increased interdisciplinary agreement in treatment recommendations, as the odds of a recommendation for adjuvant treatment by urologists vs radiation oncologists increased from 0.27 (95% CI, 0.17-0.44) to 0.46 (95% CI, 0.29-0.75) after results of the GC test were available. CONCLUSION The GC test significantly influenced adjuvant postprostatectomy treatment recommendations, reduced disagreement between radiation oncologists and urologists, and has the potential to enhance personalization of postprostatectomy care.

Right Atrial Volume Is Superior to Left Atrial Volume for Prediction of Atrial Fibrillation Recurrence After Direct Current Cardioversion

BACKGROUND The value of right atrial volume as a predictor for recurrence of atrial fibrillation (AF) after direct current cardioversion (DCCV) is unknown. METHODS We sought to compare the performance of right atrial volume indexed to body surface area (RAVI), left atrial diameter, left atrial volume indexed to body surface area (LAVI), and biatrial volume index (BAVI) for the prediction of AF recurrence at 6 months after DCCV. This study included the first 95 consecutive patients from the AF Clinic at a large tertiary care hospital who underwent DCCV and who had an echocardiogram available within 6 months before DCCV. Maximal LAVI, RAVI, and BAVI were determined from the echocardiogram before DCCV. Electrocardiographic and clinical data were acquired at baseline, before cardioversion, and at each clinic visit. RESULTS Of the 95 patients (64 male; mean age, 63 ± 12 years), history of systemic hypertension, diabetes mellitus, heart failure, and transient ischemic attack/stroke was present in 60 (63%), 14 (15%), 27 (28%), and 5 (5%) patients, respectively. Mean duration from AF diagnosis to DCCV was 3.5 ± 5.0 years. At 6 months after DCCV, 53 (56%) had reverted to AF. RAVI had superior predictive ability (area under the receiver operator characteristic curve: RAVI, 0.77; left atrial diameter, 0.54; LAVI, 0.64; and BAVI, 0.70). RAVI ≥ 42 mL/m(2) provided the best accuracy for prediction of recurrence (76% accuracy, 71% sensitivity, 83% specificity, 90% positive predictive value, and 56% negative predictive value). Best accuracy for LAVI was ≥ 48 mL/m(2) (70% accuracy, 53% sensitivity, 79% specificity, 85% positive predictive value; 43% negative predictive value). CONCLUSIONS RAVI is superior to LAVI for the prediction of AF recurrence at 6 months after DCCV.

Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk

Background:To date, there have been no published trials examining the impact of salvage radiation therapy (SRT) in the post-operative setting for prostate cancer (PCa). We conducted a retrospective, comparative study of post-operative radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathological features, APF).Methods:422 PCa men treated at four institutions with RP and having APF were analyzed with a primary end point of metastasis. Adjuvant radiation treatment (ART, n=111), minimal residual disease (MRD) SRT (n=70) and SRT (n=83) were defined by PSA levels of <0.2, 0.2–0.49 and ⩾0.5 ng ml−1, respectively, before radiation therapy (RT) initiation. Remaining 157 men who did not receive additional therapy before metastasis formed the no RT arm. Clinical–genomic risk was assessed by Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) and Decipher. Cox regression was used to evaluate the impact of treatment on outcome.Results:During the study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on multivariable analysis for metastasis (P<0.05). Adjusting for clinical–genomic risk, SRT and no RT had hazard ratios of 4.31 (95% confidence interval, 1.20–15.47) and 5.42 (95% confidence interval, 1.59–18.44) for metastasis compared with ART, respectively. No significant difference was observed between MRD-SRT and ART (P=0.28). Men with low-to-intermediate CAPRA-S and low Decipher value have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high.Conclusions:The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and patients to balance risks of morbidity with improved oncological outcomes. Post-RP treatment can be safely avoided for men who are low risk by clinical–genomic risk, whereas those at high risk should favor enrollment in clinical trials.

Decipher test impacts decision making among patients considering adjuvant and salvage treatment after radical prostatectomy: Interim results from the Multicenter Prospective PRO-IMPACT study

Patients with prostate cancer and their providers face uncertainty as they consider adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) after undergoing radical prostatectomy. The authors prospectively evaluated the impact of the Decipher test, which predicts metastasis risk after radical prostatectomy, on decision making for ART and SRT.

Detailed analysis of the impact of age on the QT interval

Objective To analyze the effect of age on the ECG QT interval, an important predictor of cardiovascular mortality and drug-induced cardiac arrhythmias, and determine whether QT-heart rate correction formulae (QTc) have differential relationships with age and sex. Methods Data were examined from the US National Health and Nutrition Examination Survey (NHANES) II and III, civilian population aged 25 to 90 years. QT weighted means and standard deviations were calculated for all ages. The QTc were evaluated for six QTc: proposed by Bazett (QTcBZT), Fridericia (QTcFRD), Hodges (QTcHDG), Dmitrienko (QTcDMT), Rautaharju (QTcRTHa) and Framingham (QTcFRM). Results QTc was strongly related to age and gender, for all formulae except for QTcBZT for women. The relationship between QTc and age was significant regardless of whether the relationship was approximated by a linear or non-linear (quadratic or cubic spline) model. QTc increased more dramatically with age in men. There was a significant (P < 0.001) positive relationship between QTc variance and age for each QTc formula for both men and women. There were a greater proportion of individuals with longer QTc with older ages especially age 80 years and above. Conclusion QTc and its variance increase with age. Prolonged QTc is more prevalent in older individuals, especially men.

PD71-01 DECIPHER TEST IMPACTS DECISION-MAKING AMONG PATIENTS CONSIDERING ADJUVANT AND SALVAGE TREATMENT FOLLOWING RADICAL PROSTATECTOMY: INTERIM RESULTS FROM THE MULTICENTER PROSPECTIVE PRO-IMPACT STUDY

Menopause women are known to be sensitive to cold stress, but the mechanism is not clearly known. The aim of this study is to show that menopause causes impairment of micro blood flow in the bladder mucosa and dermis under the skin and up-regulates TRPM8 channels which induces cold stress related frequency in rats. METHODS: A total of 18 Spontaneously Hypertensive rats at postnatal week 10 were used in the experiments. The rats were randomly divided into 2 groups, including 9 with sham operation and 9 with bilateral ovariectomy. At 4 weeks after surgery, cystometography (CMG) was performed. CMG was first performed in room temperature (RT) for 20 minuets. Rats were then put into low temperature (LT) for 40 minutes. After LT, rats were put into RT for 20 minutes. After CMG, the whole bladder and dermis under the lumbar skin was harvested and real-time RT-PCR was performed. Immunohistochemistry was also performed and impairment of micro blood flow was evaluated by hypoxia-inducible factor-1 (HIF-1) staining. RESULTS: Results of the CMG are shown in Fig 1. Basal pressure and micturition pressure did not show a difference between control rats and ovariectomy rats, but change rate with cold stress in voiding interval and micturition volume showed a significant exacerbate. Results of real-time RT-PCR are shown in Fig 2. Up-regulation of TRPM8 in the dermis and TRPV1 in the bladder mucosa was seen in ovariectomy rats. Immunohistochemistry showed increase of HIF-1 in the bladder mucosa and dermis. CONCLUSIONS: Ovariectomy causes impairment of micro blood flow in the bladder mucosa and dermis which induces cold stress frequency by up-regulating TRPM8 channels.

Comparison of Glycated Hemoglobin Results Based on At-Home and In-Lab Dried Blood Spot Sampling to Routine Venous Blood Sampling In-Lab in Adult Patients With Type 1 or Type 2 Diabetes

OBJECTIVES Regular measurement of glycated hemoglobin (A1C) is logistically demanding. Home blotter-paper collection offers an alternative. This study tested the viability of at-home blotter-paper A1C measurement. METHODS Objective: compare accuracy of A1C levels collected on blotter paper at home (home-blotter) and blotter-paper collection in laboratory (lab-blotter) with venous A1C (routine measurement). Agreement was assessed by Pearson correlation, Lin concordance correlation coefficient (CCC), positive and negative predictive values (PPVs, NPVs) and Bland-Altman plots and associated statistics. RESULTS Home-blotter, lab-blotter and venous A1C correlated strongly (0.93, 0.93). Home- and lab-blotter results were upwardly biased (0.387%, 0.1%). Bias increased with time. Bias correction provided agreement for both blotters (CCC >0.9); blotters correctly identifying levels above 7% (53 mmol/mol) were 100% for corrected home-blotters and 87% (95% confidence interval) for corrected lab-blotters. NPVs (% blotters correctly identifying levels of 7% or lower [53 mmol/mol]) were 100% for corrected home-blotters and 83% for corrected lab-blotters. After correction, >92% of corrected blotters had errors of 8% or less. Of our subjects, 88.5% found home sampling preferable to routine laboratory sampling. CONCLUSIONS Home-blotter collection is an alternative to routine collection.