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Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26–115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P 0 ( P P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

Prior research has shown that bringing functional communication responses under the discriminative control of schedule-correlated stimuli facilitates rapid reinforcement schedule thinning and the transfer of functional communication training (FCT) treatment effects to other therapists and settings. In Experiment 1, we extended this body of research by rapidly transferring FCT treatment effects to a caregiver, despite the caregiver's unique and lengthy history of reinforcement of the child's destructive behavior. In Experiment 2, we evaluated the degree to which FCT treatment effects transferred to another participant's caregivers when the caregivers implemented FCT with and without schedule-correlated stimuli. Rapid transfer of FCT treatment effects occurred only when caregivers used the schedule-correlated stimuli. We discuss the use of schedule-correlated stimuli within FCT procedures as a method of programming for generalization when extending treatment to caregivers.

Purpose/objective(s) Despite the prevalence and importance of peer review, there remains a paucity of evidence on different formats of peer review. The purpose of this study was to understand current perceptions of disease-site specific chart rounds at a single institution considering transitioning from practice-site specific chart rounds to disease-site specific chart rounds. Materials/methods An electronic survey was distributed to faculty (24 attendings and 18 physicists), dosimetrists, nurses, therapists, and trainees at an academic institution that has weekly departmental chart rounds. The survey consisted of 13 questions on demographics, perceptions of current chart rounds, and perceptions of disease-site specific chart rounds. ANOVA and Chi-square testing were used to analyze the data. Criteria for statistical significance was P Results A total of 35 (55%) responses were received, 18 of 24 (75%) attendings responded. Of all respondents, 51% were attendings, 23% were physicists, 14% were residents, 9% were dosimetrists, and 3% was a therapist. Attending responses were distributed across all disease sites which included CNS, Head and Neck, Thoracic, Breast, GI, GU, GYN, Pediatric, Palliative, Skin, Sarcoma, and Hematologic (P = 0.218). Most respondents (19; 54%) favored transitioning to disease-specific chart rounds (26% strongly agreed and 29% agreed, whereas 11% disagreed and 9% strongly disagreed). Most respondents (23; 66%) believed disease-specific chart rounds would improve patient safety (26% strongly agreed and 40% agreed, while 11% disagreed and 3% strongly disagreed). Most respondents (27; 77%) believed disease-site specific chart rounds would improve the quality of patient plans (29% strongly agreed and 49% agreed, whereas 11% disagreed and 3% strongly disagreed). Most respondents (23; 66%) believed disease-site specific chart rounds would improve education for trainees (29% strongly agreed and 37% agreed, while 11% disagreed and none strongly disagreed). Most attendings favored transitioning to disease-specific chart rounds (50% agreed and 17% disagreed). All physicists favored transitioning to disease-specific chart rounds. Respondents who favored transitioning to disease-specific chart rounds were significantly more likely to believe that disease-specific chart rounds would improve patient safety (P Conclusion Most respondents favored transitioning to disease-specific chart rounds. Furthermore, most respondents believed disease-specific chart rounds would improve patient safety, the quality of patient plans, and trainee education. Further research will be conducted and presented measuring the impact after implementation.

When a functional communication response (FCR) can be reliably occasioned, destructive behavior tends to be lower. However, the form of FCR may affect the durability of functional communication training, as missing FCR materials may promote resurgence. Experiment 1 demonstrated that resurgence of target responding was lower when a vocal FCR remained available but was placed on extinction compared to when a card-based FCR was unavailable. Experiment 2 replicated the finding that initiating treatment with a card FCR produced less target responding than when initiating treatment with a vocal FCR. We then evaluated a set of procedures for transitioning the card FCR to the previously unlearned vocal FCR. These findings suggest benefits of training different types of FCRs at different stages of treatment and provide a preliminary set of procedures for transitioning between FCR topographies while occasioning minimal target responding.

Purpose: We conducted a prospective pilot study to evaluate safety and feasibility of TraceIT, a resorbable radiopaque hydrogel, to improve image guidance for bladder cancer radiation therapy (RT). Methods and Materials: Patients with muscle invasive bladder cancer receiving definitive RT were eligible. TraceIT was injected intravesically around the tumor bed during maximal transurethral resection of bladder tumor. The primary endpoint was the difference between radiation treatment planning margin on daily cone beam computed tomography based on alignment to TraceIT versus standard-of-care pelvic bone anatomy. The Van Herk margin formula was used to determine the optimal planning target volume margin. TraceIT visibility, recurrence rates, and survival were estimated by Kaplan-Meier method. Toxicity was measured by Common Terminology Criteria for Adverse Events version 4.03. Results: The trial was fully accrued and 15 patients were analyzed. TraceIT was injected in 4 sites/patient (range, 4-6). Overall, 94% (95% confidence interval [CI], 90%-98%) of injection sites were radiographically visible at RT initiation versus 71% (95% CI, 62%-81%) at RT completion. The median duration of radiographic visibility for injection sites was 106 days (95% CI, 104-113). Most patients were treated with a standard split-course approach with initial pelvic radiation fields, then midcourse repeat transurethral resection of bladder tumor followed by bladder tumor bed boost fields, and 14/15 received concurrent chemotherapy. Alignment to fiducials could allow for reduced planning target volume margins (0.67 vs 1.56 cm) for the initial phase of RT, but not for the boost (1.01 vs 0.96 cm). This allowed for improved target coverage (D95% 80%-83% to 91%-94%) for 2 patients retrospectively planned with both volumetric-modulated arc therapy and 3-dimensional conformal RT. At median follow-up of 22 months, no acute or late complications attributable to TraceIT placement occurred. No patients required salvage cystectomy. Conclusions: TraceIT intravesical fiducial placement is safe and feasible and may facilitate tumor bed delineation and targeting in patients undergoing RT for localized muscle invasive bladder cancer. Improved image guided treatment may facilitate strategies to improve local control and minimize toxicity.

Purpose/Objective(s) To determine the accuracy of prostate multiparametric (mp) MRI in identification of intraprostatic tumor deposits using a systematic and targeted MR-guided transperineal prostate biopsy technique as a reference. Materials/Methods One hundred sixty patients underwent a combined systematic and targeted MRI-guided prostate biopsy using a transperineal approach under general anesthesia. For each patient, a pre-biopsy mpMRI scan was obtained and imported into a prostate biopsy planning system. Transverse images were then reoriented from the supine to dorsal lithotomy position. Dividing the prostate into an apical and base section, a systematic array of transperineal biopsies spaced approximately 10mm apart was planned with additional biopsies targeting mpMRI-identified PI-RADS 3, 4 or 5 lesions. Biopsy procedures were carried out in the dorsal lithotomy position using a transrectal ultrasound with stepper-stabilizer and template grid. Matching of the planning mpMRI images to live ultrasound images was achieved using the template grid as a reference. Results All patients successfully underwent their biopsy procedure as planned. An average of 26 biopsy specimens were obtained per patient (range 11-44). Twenty-nine percent (15/52) of PI-RADS 3 lesions, 49% (46/94) of PI-RADS 4 lesions, and 76% (39/51) of PI-RADS 5 lesions were pathologically confirmed prostate cancer. Forty-two percent (67/160) of patients harbored mpMRI-unidentified prostate cancer. Twenty-two percent (36/160) of patients harbored mpMRI-unidentified GS≥7 disease and four percent (7/160) of patients harbored mpMRI-unidentified GS≥8 disease. Conclusion Using prostate mpMRI to identify intraprostatic tumor deposits without pathologic confirmation would lead to significant numbers of false positive mpMRI identified lesions and miss clinically significant prostate cancer outside of mpMRI identified lesions in over 20% of patients. Use of systematic prostate biopsy information appears necessary to significantly improve the accuracy of mpMRI identification of intraprostatic tumor deposits.

PURPOSE/OBJECTIVE(S) To evaluate the success and toxicity of a nonsurgical prostatic urethral lift system in patients with lower urinary tract symptoms (LUTS) with and without prior prostate cancer radiation therapy. MATERIALS/METHODS From 2018 to 2020, thirty-eight patients underwent a nonsurgical prostatic urethral lift (PUL) procedure for LUTS refractory to alpha blocker medications. All patients had cystoscopic confirmation of lateral lobe obstruction. Nineteen patients underwent prior radiation therapy (RT) for prostate cancer completed an average of 15.3 months (range 3-28) prior to PUL procedure. Nineteen patients had no prior prostate cancer treatment. All patients were assessed with IPSS/quality of life (QOL) scores and urinary post void residual (PVR) ultrasound before and after PUL. Patients were also assessed for ability to discontinue alpha blocker medications for their LUTS and any post PUL toxicity based on CTCAE v5.0 criteria. Statistical comparisons before and after the PUL procedure were made with Wilcoxon signed rank test with P < 0.05 considered significant. RESULTS All patients underwent successful placement of the PUL implants. Median follow up was 10 months (range 3-30). Median prostate volume was 45cc (range 20-85) for no-RT group and 41cc (range 24-80) for RT group. Median pre-PUL IPSS score was 17 (range 9-33) in the no-RT and 20 (range 11-34) in the RT groups. At last follow up, the average improvement in IPSS score was 9 points for all patients (95% CI 7-11, P < 0.001), 8 points for the RT patients (95% CI 5-12, P < 0.001) and 9 points for the no-RT patients (95% CI 7-12, P < 0.001). QOL improved by 1.1 points on average (95% CI 0.6-1.6, P < 0.001) for all patients, with similar improvement for both the RT (0.9, 95% CI 0.1-1.9. P = 0.09) and the no-RT (1.3, 95% CI 0.7-1.8, P < 0.001) patients. The average reduction in PVR was 93cc (95% CI 56-130, P < 0.001) for all patients, similar for both RT (90cc, 95% CI 42-138, P = 0.001) and no-RT (96cc, 95% CI 37-155, P < 0.001) patients. The percentage of patients able to discontinue alpha blockade at last follow-up was 68% for the RT patients and 74% for the no-RT patients. There was no grade 3 or higher GU toxicity in either group. CONCLUSION Use of a nonsurgical prostatic urethral lift system, results in significant improvement of LUTS after radiation therapy without complications, similar to patients without prior prostate radiation therapy.

OBJECTIVE. The purpose of this study was to evaluate agreement among radiologists in detecting and assessing prostate cancer at multiparametric MRI using Prostate Imaging Reporting and Data System version 2 (PI-RADSv2). MATERIALS AND METHODS. Treatment-naïve patients underwent 3-T multipara-metric MRI between April 2012 and June 2015. Among the 163 patients evaluated, 110 underwent prostatectomy after MRI and 53 had normal MRI findings and transrectal ultrasound-guided biopsy results. Nine radiologists participated (three each with high, intermediate, and low levels of experience). Readers interpreted images of 58 patients on average (range, 56-60) using PI-RADSv2. Prostatectomy specimens registered to MRI were ground truth. Interob-server agreement was evaluated with the index of specific agreement for lesion detection and kappa and proportion of agreement for PI-RADS category assignment. RESULTS. The radiologists detected 336 lesions. Sensitivity for index lesions was 80.9% (95% CI, 75.1-85.9%), comparable across reader experience (p = 0.392). Patient-level specificity was experience dependent; highly experienced readers had 84.0% specificity versus 55.2% for all others (p < 0.001). Interobserver agreement was excellent for detecting index lesions (index of specific agreement, 0.871; 95% CI, 0.798-0.923). Agreement on PI-RADSv2 category assignment of index lesions was moderate (κ = 0.419; 95% CI, 0.238-0.595). For individual category assignments, proportion of agreement was slight for PI-RADS category 3 (0.208; 95% CI, 0.086-0.284) but substantial for PI-RADS category 4 (0.674; 95% CI, 0.540-0.776). However, proportion of agreement for T2-weighted PI-RADS 4 in the transition zone was 0.250 (95% CI, 0.108-0.372). Proportion of agreement for category assignment of index lesions on dynamic contrast-enhanced MR images was 0.822 (95% CI, 0.728-0.903), on T2-weighted MR images was 0.515 (95% CI, 0.430-0623), and on DW images was 0.586 (95% CI, 0.495-0.682). Proportion of agreement for dominant lesion was excellent (0.828; 95% CI, 0.742-0.913). CONCLUSION. Radiologists across experience levels had excellent agreement for detecting index lesions and moderate agreement for category assignment of lesions using PI-RADS. Future iterations of PI-RADS should clarify PI-RADS 3 and PI-RADS 4 in the transition zone.

457 Background: Precision image-guided radiotherapy (RT) for patients (pts) with muscle-invasive bladder cancer (MIBC) is limited by daily anatomic variation and difficulty visualizing the tumor bed. We hypothesized that TraceIT, a radiopaque resorbable hydrogel, can be injected around the tumor bed to improve image guidance. We present the results of our pilot trial (NCT03125226) evaluating safety/feasibility of TraceIT in pts undergoing definitive RT. Methods: Eligibility included MIBC with plan to receive definitive RT +/- chemo. Fifteen patients were available for analysis (11 enrolled on trial from 2017-2018, plus an additional 4 received TraceIT off study). TraceIT was injected around the circumference of the tumor bed during pre-radiation maximal re-transurethral resection of bladder tumor (TURBT) for all pts, and again during the mid-radiation TURBT to improve visibility in n = 8 pts. The primary endpoint was assessment of interfraction motion on daily cone-beam CT (CBCTs) based on alignment to fiducial vs standard-of-care pelvic bone anatomy. Van Herk (VH) margin equation was used to determine the planning target volume margin optimized for the clinical target volume receiving at least 95%-prescription dose in 90% of pts. Recurrence rates and survival were estimated by Kaplan Meier. Toxicity was measured by CTCAE v4.03. Results: Patients underwent RT to a median total dose of 63.5 Gy (range 35.75-66.6), typically to an initial small pelvis field follow by a tumor boost. 14/15 received chemo with RT. Median TraceIT volume was 0.5cc (range 0.3-0.75) per injection site for 4 (range 4-6) sites per patient for total volume of 2cc (range 2-3). All pts demonstrated 100% visibility of TraceIT on initial simulation CT and day 1 CBCT. TraceIT visibility declined slightly over time, with 91.5% of patients having visible TraceIT by the end of the initial RT phase (usually week 5) and 82.5% by end of the boost phase. For the initial phase, alignment to fiducials over bone anatomy allowed for reduced VH margins (0.67cm vs 1.56cm). For the boost phase, the VH margin was similar between fiducial and bone alignment (1.01cm vs 0.96cm). There have been no acute or late complications from TraceIT placement. There were no grade grade (G) 4/5 toxicities; three pts had acute G 3 events, and three pts experienced late G 3 toxicity: two related to hematuria and one from ureteral stenosis. There were no late G≥2 GI toxicities. No patients have undergone cystectomy. At a median follow-up of 22 months, 2-yr OS was 79.1% and 2-yr PFS was 75.4%. Conclusions: TraceIT is safe and feasible for use in image-guided RT. TraceIT can increase the precision of RT by facilitating accurate target delineation of the bladder tumor bed and daily motion management which may allow for smaller radiation treatment margins to be used to reduce toxicity and to potentially facilitate safe dose escalation to tumor, which can improve tumor control. Clinical trial information: NCT03125226.

Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) was developed to standardize the interpretation and reporting of multiparametric prostate magnetic resonance imaging and provide guidelines for biopsy of multiparametric magnetic resonance imaging findings. We prospectively evaluated the cancer detection rate at each overall PI-RADSv2 score.This prospective study included 62 consecutive patients with 116 lesions who underwent multiparametric prostate magnetic resonance imaging at 3T with PI-RADSv2 evaluation and subsequent targeted magnetic resonance imaging/transrectal ultrasound fusion guided biopsy and concurrent 12-core systematic prostate biopsy between May and September 2015. Median patient age and prostate specific antigen values were 65.5 years (range 50.3 to 76.6) and 7.10 ng/ml (range 0.47 to 863.0), respectively. Mean lesion size was 12.7 mm overall. Lesion based cancer detection rates for all tumors and for Gleason 3+4 or greater tumors at each PI-RADSv2 score were calculated. Univariate analysis was performed to assess differences in the cancer detection rate among PI-RADSv2 scores.A total of 116 lesions in 62 patients were evaluated prospectively (0 PI-RADS 1, 18 PI-RADS 2, 19 PI-RADS 3, 47 PI-RADS 4, 32 PI-RADS 5), and the patients underwent magnetic resonance/transrectal ultrasound fusion guided biopsy and systematic biopsy. Histopathology revealed 55 of 116 (47.4%) cancers (17 Gleason 3+3, 16 Gleason 3+4, 6 Gleason 4+3, 12 Gleason 4+4, 3 Gleason 4+5 and 1 Gleason 5+4). Based on targeted biopsy on a per lesion basis, the overall cancer detection rates of PI-RADS 2, 3, 4 and 5 scores for all tumors was 22.2%, 15.8%, 29.8% and 78.1%, respectively. The cancer detection rate of PI-RADS 2, 3, 4 and 5 scores for Gleason 3+4 or greater tumors was 5.6%, 0%, 21.3% and 75%, respectively. Differences in the cancer detection rate between overall PI-RADS 4 and 5 scores were significant (p0.001 for Gleason greater than 3+3 and Gleason 3+4 or greater cancers).A PI-RADS score of 5 had the highest prospective cancer detection rate (78%). A PI-RADS score of 4 had only a 30% cancer detection rate, which is lower than expected. Surprisingly, no or few significant cancers were detected at a PI-RADS score of 3 (16%). These early prospective data suggest that current criteria result in a high false-positive rate that lowers the cancer detection rate. Therefore, stricter criteria may be needed in the future to decrease false-positives and increase the cancer detection rate for PI-RADS scores of 3, 4 and 5.

Purpose Multiparametric MRI (mpMRI) improves the detection of clinically significant prostate cancer, but is limited by interobserver variation. The second version of theProstate Imaging Reporting and Data System (PIRADSv2) was recently proposed as a standard for interpreting mpMRI. To assess the performance and interobserver agreement of PIRADSv2 we performed a multi-reader study with five radiologists of varying experience. Materials and Methods Five radiologists (n = 2 prostate dedicated, n = 3 general body) blinded to clinicopathologic results detected and scored lesions on prostate mpMRI using PIRADSv2. The endorectal coil 3 Tesla MRI included T2W, diffusion-weighted imaging (apparent diffusion coefficient, b2000), and dynamic contrast enhancement. Thirty-four consecutive patients were included. Results were correlated with radical prostatectomy whole-mount histopathology produced with patient-specific three-dimensional molds. An index lesion was defined on pathology as the lesion with highest Gleason score or largest volume if equivalent grades. Average sensitivity and positive predictive values (PPVs) for all lesions and index lesions were determined using generalized estimating equations. Interobserver agreement was evaluated using index of specific agreement. Results Average sensitivity was 91% for detecting index lesions and 63% for all lesions across all readers. PPV was 85% for PIRADS ≥ 3 and 90% for PIRADS ≥ 4. Specialists performed better only for PIRADS ≥ 4 with sensitivity 90% versus 79% (P = 0.01) for index lesions. Index of specific agreement among readers was 93% for the detection of index lesions, 74% for the detection of all lesions, and 85% for scoring index lesions, and 58% for scoring all lesions. Conclusion By using PIRADSv2, general body radiologists and prostate specialists can detect high-grade index prostate cancer lesions with high sensitivity and agreement. Level of Evidence: 1 J. Magn. Reson. Imaging 2017;45:579–585.

Previous research has supported functional communication training (FCT) as an effective intervention for reducing challenging behavior. Clinicians often program schedule-thinning procedures to increase the portability of the treatment (i.e., reinforcement is provided less frequently). For individuals with escape-maintained problem behavior, chained schedules have proven effective in increasing task completion and supplemental procedures may ameliorate reemergence of challenging behavior as access to reinforcement is decreased. The present study compared the use of a chained schedule-thinning procedure with and without alternative reinforcement (e.g., toys and activities) embedded in an intervention in which escape from the task is provided contingent on a request for a break.Two individuals with escape-maintained challenging behavior participated. We compared two treatment conditions, escape-only and escape-to-tangibles, using a single-subject, alternating treatments design with each treatment implemented in a distinct academic context.With the escape-to-tangibles treatment, we reached the final schedule in both contexts with both participants (4 successes out of 4 applications). We did not reach the final schedule with either participant with the escape-only intervention (0 successes out of 2 applications).The current results provided preliminary confirmation that providing positive plus negative reinforcement would decrease destructive behavior, increase compliance, and facilitate reinforcer-schedule thinning.

Background: \ud Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.\ud \ud Methods: \ud NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.\ud \ud Findings: \ud Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.\ud \ud Interpretation: \ud Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.\ud \ud Funding: \ud Bayer and Janssen.

We evaluated the combined and sequential effects of 3 toilet-training procedures recommended for use with young children: (a) underwear, (b) a dense sit schedule, and (c) differential reinforcement. A total of 20 children participated. Classroom teachers implemented a toilet-training package consisting of all 3 procedures with 6 children. Of the 6 children, 2 showed clear and immediate improvements in toileting performance, and 3 showed delayed improvements. Teachers implemented components of the training package sequentially with 12 children. At least 2 of the 4 children who experienced the underwear component after baseline improved. Toileting performance did not improve for any of the 8 children who were initially exposed to either the dense sit schedule or differential reinforcement. When initial training components were ineffective, teachers implemented additional components sequentially until toileting performance improved or all components were implemented. Toileting performance often improved when underwear or differential reinforcement was later added.

To evaluate if computer-aided diagnosis (CAD) prior to prostate multi-parametric MRI (mpMRI) can improve sensitivity and agreement between radiologists. Nine radiologists (three each high, intermediate, low experience) from eight institutions participated. A total of 163 patients with 3-T mpMRI from 4/2012 to 6/2015 were included: 110 cancer patients with prostatectomy after mpMRI, 53 patients with no lesions on mpMRI and negative TRUS-guided biopsy. Readers were blinded to all outcomes and detected lesions per PI-RADSv2 on mpMRI. After 5 weeks, readers re-evaluated patients using CAD to detect lesions. Prostatectomy specimens registered to MRI were ground truth with index lesions defined on pathology. Sensitivity, specificity and agreement were calculated per patient, lesion level and zone—peripheral (PZ) and transition (TZ). Index lesion sensitivity was 78.2% for mpMRI alone and 86.3% for CAD-assisted mpMRI (p = 0.013). Sensitivity was comparable for TZ lesions (78.7% vs 78.1%; p = 0.929); CAD improved PZ lesion sensitivity (84% vs 94%; p = 0.003). Improved sensitivity came from lesions scored PI-RADS < 3 as index lesion sensitivity was comparable at PI-RADS ≥ 3 (77.6% vs 78.1%; p = 0.859). Per patient specificity was 57.1% for CAD and 70.4% for mpMRI (p = 0.003). CAD improved agreement between all readers (56.9% vs 71.8%; p < 0.001). CAD-assisted mpMRI improved sensitivity and agreement, but decreased specificity, between radiologists of varying experience. • Computer-aided diagnosis (CAD) assists clinicians in detecting prostate cancer on MRI. • CAD assistance improves agreement between radiologists in detecting prostate cancer lesions. • However, this CAD system induces more false positives, particularly for less-experienced clinicians and in the transition zone. • CAD assists radiologists in detecting cancer missed on MRI, suggesting a path for improved diagnostic confidence.

Purpose To characterize clinically important prostate cancers missed at multiparametric (MP) magnetic resonance (MR) imaging. Materials and Methods The local institutional review board approved this HIPAA-compliant retrospective single-center study, which included 100 consecutive patients who had undergone MP MR imaging and subsequent radical prostatectomy. A genitourinary pathologist blinded to MP MR findings outlined prostate cancers on whole-mount pathology slices. Two readers correlated mapped lesions with reports of prospectively read MP MR images. Readers were blinded to histopathology results during prospective reading. At histopathologic examination, 80 clinically unimportant lesions (5 mm; Gleason score, 3+3) were excluded. The same two readers, who were not blinded to histopathologic findings, retrospectively reviewed cancers missed at MP MR imaging and assigned a Prostate Imaging Reporting and Data System (PI-RADS) version 2 score to better understand false-negative lesion characteristics. Descriptive statistics were used to define patient characteristics, including age, prostate-specific antigen (PSA) level, PSA density, race, digital rectal examination results, and biopsy results before MR imaging. Student t test was used to determine any demographic differences between patients with false-negative MP MR imaging findings and those with correct prospective identification of all lesions. Results Of the 162 lesions, 136 (84%) were correctly identified with MP MR imaging. Size of eight lesions was underestimated. Among the 26 (16%) lesions missed at MP MR imaging, Gleason score was 3+4 in 17 (65%), 4+3 in one (4%), 4+4 in seven (27%), and 4+5 in one (4%). Retrospective PI-RADS version 2 scores were assigned (PI-RADS 1, n = 8; PI-RADS 2, n = 7; PI-RADS 3, n = 6; and PI-RADS 4, n = 5). On a per-patient basis, MP MR imaging depicted clinically important prostate cancer in 99 of 100 patients. At least one clinically important tumor was missed in 26 (26%) patients, and lesion size was underestimated in eight (8%). Conclusion Clinically important lesions can be missed or their size can be underestimated at MP MR imaging. Of missed lesions, 58% were not seen or were characterized as benign findings at second-look analysis. Recognition of the limitations of MP MR imaging is important, and new approaches to reduce this false-negative rate are needed.

Functional communication training (FCT) is an established treatment for destructive behavior that missucceeds in about 37% of cases when the reinforcement schedule for the functional communication response (FCR) is thinned using multiples schedules (mult FCT; Hagopian, Boelter, & Jarmolowicz, 2011). In this investigation, we evaluated the use of response restriction FCT (RR FCT) in a cohort of patients with poorly differentiated responding of the FCR during mult FCT. Results showed that (a) RR FCT maintained high rates of correct FCRs during the reinforcement component of RR FCT without increasing destructive behavior; (b) children displayed highly discriminated FCRs when an FCR card and a control card were simultaneously available during the reinforcement component of RR FCT; and (c) near-zero rates of destructive behavior were observed during the last five sessions of the terminal reinforcement schedule. Results are discussed relative to differences between mult FCT and RR FCT and successive and simultaneous discriminations.

Background and aims Randomised controlled trials demonstrate that the anti-tumour necrosis factor-α (anti-TNFα) therapies infliximab and adalimumab are effective in inducing remission and preventing relapse of Crohn's disease (CD). As few studies have compared costs and efficacy of these two drugs directly, we examined this issue. Methods Data were collected for patients receiving either drug as first-line anti-TNFα for CD. Patients were matched as closely as possible on age, gender, weight, height, and date of commencement of therapy. Response to induction therapy was assessed at 12 weeks, and sustained clinical benefit at last point of follow-up. Resource data were collected for all patients until study end, with National Health Services reference costs applied to calculate the total cost per patient with adalimumab compared with infliximab. Results Thirty-six patients had been treated with adalimumab as first-line anti-TNFα since 2010. We matched an identical number of infliximab patients. Demographic data were similar between the two groups. Costs were significantly lower with adalimumab (£6692.95 less per patient (95% confidence interval £1816.61–£11569.29)), which was largely driven by the drug costs and drug administration costs associated with infliximab. Twenty-nine (80.6%) patients responded to induction therapy with both drugs, and 22 (61.1%) achieved glucocorticosteroid-free sustained clinical benefit with either drug at last point of follow-up. Conclusions Costs of infliximab used as first-line anti-TNFα therapy are greater, which may have implications for selection. Clinical outcomes appeared comparable, although power to detect a statistically significant difference would be limited.

Duchenne muscular dystrophy (DMD) is a progressive primary myodegenerative disease caused by a genetic deficiency of the 427-kDa cytoskeletal protein dystrophin. Despite its single-gene etiology, DMD’s complex pathogenesis remains poorly understood, complicating the extrapolation from results of preclinical studies in genetic homologs to the design of informative clinical trials. Here we describe novel phenotypic assays which when applied to the mdx mouse resemble recently used primary end points for DMD clinical trials. By coupling force transduction, high-precision motion tracking, and respiratory measurements, we have achieved a suite of integrative physiological tests that provide novel insights regarding normal and pathological responses to muscular exertion. A common feature of these physiological assays is the precise tracking and analysis of volitional movement, thereby optimizing the relevance to clinical tests. Unexpectedly, the measurable biological distinction between dystrophic and control mice at early time points in the disease process is better resolved with these tests than with the majority of previously used, labor-intensive studies of individual muscle function performed ex vivo. For example, the dramatic loss of volitional movement following a novel, standardized grip test distinguishes control mice from mdx mice by a 17.4-fold difference of the means (3.5 ± 2.2 vs. 60.9 ± 12.1 units of activity, respectively; effect size 1.99). The findings have both mechanistic and translational implications of potential significance to the fields of basic myology and neuromuscular therapeutics. NEW & NOTEWORTHY This study uses novel phenotypic assays which when applied to the mdx mouse resemble recently used primary end points for DMD clinical trials. A measurable distinction between dystrophic and control mice was seen at early time points in vivo compared with invasive muscle studies performed ex vivo. These assays shed light on normal and pathological responses to muscular exertion and have significant mechanistic and translational implications for the fields of basic myology and neuromuscular therapeutics.

Much criticism has been leveled at screening for prostate cancer using prostate-specific antigen (PSA) testing, yet there is no suitable replacement to improve the detection of clinically significant cancer (CSC). Prostate multiparametric magnetic resonance imaging (mpMRI) combined with mpMRI-guided biopsies is one possible solution, as it reduces detection of low-grade disease and increases detection of CSC. However, mpMRI is critically limited by lack of standardization across institutions and low interobserver agreement. The Prostate Imaging Reporting and Diagnostic System version 2 (PI-RADSv2) aims to address these concerns. We discuss the clinical and technical considerations for implementing PI-RADSv2, how we have adapted to PI-RADSv2, and review current research. While PI-RADSv2 represents a major step forward for standardizing prostate mpMRI, it does not provide a level of standardization that is routine with clinical blood tests and reader reproducibility remains an issue. Future research should seek to further improve quality assurance of mpMRI building on the important contributions of PI-RADSv2. Level of evidence 5 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:11-23.

There is growing consensus that multiparametric magnetic resonance imaging (mpMRI) is an effective modality in the detection of locally recurrent prostate cancer after prostatectomy and radiation therapy. The emergence of magnetic resonance (MR)-guided focal therapies, such as cryoablation, high-intensity focused ultrasound, and laser ablation, have made the use of mpMRI even more important, as the normal anatomy is inevitably altered and the detection of recurrence is made more difficult. The aim of this article is to review the utility of mpMRI in detecting recurrent prostate cancer in patients following radical prostatectomy, radiation therapy, and focal therapy and to discuss expected post-treatment mpMRI findings, the varied appearance of recurrent tumors, and their mimics.

Aliment Pharmacol Ther 2012; 35: 284–291 Summary Background Randomised controlled trials demonstrate that methotrexate is effective in inducing remission and preventing relapse of Crohn’s disease (CD) as a first-line immunosuppressant, but efficacy data after failure with, or intolerance to, thiopurines are limited. Aims To report efficacy of methotrexate in a cohort of refractory CD patients, most of whom had not responded to, or were intolerant of, thiopurines. Methods Data were collected for patients receiving methotrexate for active CD. Response to methotrexate induction therapy at 4 months, and sustained clinical benefit at last point of follow-up with maintenance therapy, were assessed via physician’s global assessment. Demographic and disease factors predicting response, or sustained clinical benefit, were examined by univariate and multivariate analysis. Results Sixty-six [38 (54%) female patients, mean age at diagnosis 29.4 years] patients received methotrexate between 2001 and 2010, 61 (92%) of whom received the drug parenterally. Sixty patients had failed, or were intolerant of, thiopurines. Response to therapy at 4 months occurred in 54 (82%) patients. However, sustained clinical benefit occurred in only 19 (29%) patients at last point of follow-up, including six patients who discontinued the drug for family planning reasons. No predictors of response or sustained clinical benefit were identified. Adverse events occurred in 20 (30%) patients. Conclusions These data suggest that methotrexate is effective in terms of initial response in Crohn’s disease patients who have failed, or are intolerant of, thiopurines. However, efficacy is not sustained in the long term.

Background and Aims Non-response, loss of response, or intolerance to anti-tumour necrosis factor alpha (anti-TNFα) therapy is well recognised in Crohn's disease (CD) patients. Data concerning outcomes following the use of a second anti-TNFα therapy, particularly in patients who do not respond to a first anti-TNFα agent, are still emerging. The aim of this study was to assess response and tolerability to adalimumab following infliximab failure in a single centre cohort of CD patients. Methods Data were collected prospectively on 44 patients who received adalimumab therapy following infliximab failure. Initial response to adalimumab therapy at 6weeks following induction was defined using a two point decrease in the Harvey–Bradshaw Index, with remission at this point defined using a Harvey Bradshaw index≤4. Sustained clinical benefit at the last point of follow up was determined using a physician's global assessment. Corticosteroid-free sustained clinical benefit was also assessed at this point. Results Thirty-four (77%) patients had initial response to adalimumab therapy, with 28 (64%) having sustained clinical benefit. Corticosteroid-free sustained clinical benefit was achieved in nine (53%) of 17 patients requiring steroids at commencement of adalimumab. Four (44%) of the 9 patients who were primary non-responders to infliximab responded to adalimumab. The majority of CD patients who failed adalimumab therapy required surgery. Conclusions Second-line anti-TNFα therapy with adalimumab is effective at both inducing remission and maintaining response in CD patients who have failed infliximab, regardless of the reason for infliximab failure.

Aliment Pharmacol Ther 2010; 32: 1357–1363 Summary Background Infliximab is effective for induction and maintenance of remission in patients with Crohn’s disease. There are few data, however, examining effect of infliximab therapy on management costs of Crohn's disease. Aim To assess Crohn's disease-related costs of care and resource use in a single-centre cohort of patients with Crohn's disease 12 months pre- and post-infliximab therapy. Methods Data on 100 consecutive patients receiving infliximab were collected. Crohn's disease-related resource use was collected 12 months pre- and post-infliximab. National Health Service reference costs were applied to these data and the total Crohn's disease-related health service costs per patient were calculated (£UK). The cost of infliximab therapy was not included in our analysis. Results Cost savings were demonstrated in all areas of Crohn's disease-related resource use following infliximab therapy. Mean total Crohn's disease-related cost reduction, 12 months following commencement of infliximab therapy, was £2750 per patient. Mean costs at 12 months post-infliximab in responders were lower than in nonresponders (£1656 vs. £3608, P = 0.02). The number of hospitalizations was reduced. Requirements for examination under anaesthesia were also significantly decreased. Conclusion Infliximab use resulted in Crohn's disease-related cost savings and hospital resource use, although this was not sufficient to cover the cost of therapy.

Background: Mycophenolate mofetil (MMF) is an immunomodulatory drug, and its use in inflammatory bowel disease has previously been reported. The aim of this study was to review the Leeds Colitis Clinic experience of the safety and efficacy of MMF in treating patients with refractory Crohn's disease (CD) and ulcerative colitis (UC). This is an extension of a previously published study from our center with a longer follow-up period and approximately twice the number of patients. Methods: A retrospective analysis was performed of the records of all patients treated with MMF for inflammatory bowel disease over a 5-year period. Results: Of 70 patients identified, 67 had previously been treated with azathioprine unsuccessfully. Seventeen of the 70 patients had been successfully maintained in remission with MMF for an average duration of 33 months. Treatment with MMF was discontinued for 53 patients, 17 because of side effects and 36 because they had not responded to the treatment. Conclusions: In our series, 17 patients (24.3%) had a sustained steroid-free remission with MMF therapy. Nineteen patients (27%) experienced side effects, of which 17 (24.3% of the total group) had to discontinue therapy. An additional 36 (51.4%) required an escalation in medical therapy or surgery because of failure of the MMF therapy. MMF may have a role in the treatment of refractory inflammatory bowel disease, especially in patients who have previously failed standard therapies such as azathioprine. (Inflamm Bowel Dis 2007)

Background/purpose: Osteoarthritis (OA) affects over 30 million adults in the United States and results in a decline in physical activity level contributing to obesity, diabetes and cardiovascular disease. With

A prostate computer-aided diagnosis (CAD) based on random forest to detect prostate cancer using a combination of spatial, intensity, and texture features extracted from three sequences, T2W, ADC, and B2000 images, is proposed. The random forest training considers instance-level weighting for equal treatment of small and large cancerous lesions as well as small and large prostate backgrounds. Two other approaches, based on an AutoContext pipeline intended to make better use of sequence-specific patterns, were considered. One pipeline uses random forest on individual sequences while the other uses an image filter described to produce probability map-like images. These were compared to a previously published CAD approach based on support vector machine (SVM) evaluated on the same data. The random forest, features, sampling strategy, and instance-level weighting improve prostate cancer detection performance [area under the curve (AUC) 0.93] in comparison to SVM (AUC 0.86) on the same test data. Using a simple image filtering technique as a first-stage detector to highlight likely regions of prostate cancer helps with learning stability over using a learning-based approach owing to visibility and ambiguity of annotations in each sequence.

OBJECTIVE. The purpose of the present study is to determine whether abstinence from ejaculation before undergoing multiparametric prostate MRI increases seminal vesicle (SV) volume and therefore improves diagnostic interpretation of the SVs. MATERIALS AND METHODS. This retrospective study included 238 patients who underwent 3-T MRI of the prostate over a 4-month period. Patients were requested to complete a questionnaire that asked how long it had been since their last ejaculation (i.e., < 3 days vs ≥ 3 days). Forty-two patients (mean patient age, 62.0 years) indicated that it had been less than 3 days since their last ejaculation and were designated as group 1, whereas the remainder indicated an interval of 3 days or more since their last ejaculation. A group of 42 age-matched subjects (mean patient age, 62.1 years) were randomly selected from the remaining 196 patients and were designated as group 2. SV volumes were measured manually. Two radiologists who were blinded to group assignment and patient characteristics scored the right and left SVs separately to determine diagnostic interpretability, which was scored on a 3-point scale as follows: a score of 1 denoted that the SVs were not dilated and the score was nondiagnostic, a score of 2 indicated that the SVs were not dilated but the score was diagnostic, and a score of 3 denoted that the SVs were dilated and the score was diagnostic. Volume differences and interpretability scores were analyzed using a t test. Interobserver agreement was analyzed using the Cohen kappa statistic. A separate analysis was performed to evaluate differences in diagnostic interpretability for patients 60 years and younger versus patients older than 60 years, by use of the chi-square test and relative risk ratio analysis. RESULTS. The right, left, and total SV volumes for group 1 were 3.1 mL, 2.9 mL, and 6.0 mL, respectively, whereas those for group 2 were 4.7 mL, 4.1 mL, and 8.8 mL, respectively (p = 0.011). The mean interpretability scores for group 1 and group 2 were 2.0 and 2.5, respectively. For group 1, reader 1 and reader 2 assigned a nondiagnostic score for 10 and 13 patients, respectively, whereas for group 2, they assigned a nondiagnostic score for two and five patients, respectively (p = 0.01, for reader 1; and p = 0.03, for reader 2). For men in group 1 who were older than 60 years, reader 1 and reader 2 gave a nondiagnostic score for nine and 11 patients, respectively; whereas for men in group 2 who were older than 60 years, the readers gave a nondiagnostic score for two and five patients, respectively (p = 0.01, for reader 1; and p = 0.05, for reader 2). CONCLUSION. For men older than 60 years, abstinence from ejaculation for 3 or more days before undergoing MRI examination resulted in larger SV volumes and lower rates of nondiagnostic evaluation and therefore might improve evaluation of SV invasion on multiparametric MRI. The difference is less striking in men 60 years and younger.

This is the published version, reproduced here with the publisher's permission. This article is also available electronically from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359848/.

Background Infliximab is licenced for use in Crohn's disease (CD). Trial data demonstrate that infliximab is effective for inducing remission of active CD, healing fistulising CD, and preventing relapse once in remission. However, long-term data regarding efficacy, safety, and predictors of response are still emerging. Aim To examine these issues in a large cohort of patients who received infliximab for CD. Methods A retrospective analysis of prospectively collected data was performed for 210 patients receiving infliximab for luminal or fistulising CD. Response to infliximab induction therapy, and sustained clinical benefit, were assessed by a decrease in Harvey–Bradshaw Index (HBI) of ≥2 points. Remission was defined as an HBI ≤ 4. Physician's global assessment was used where HBI could not be obtained. Demographic and disease factors that may predict response to therapy were analysed by Kaplan–Meier plots and univariate and multivariate analyses. Results Overall, 173 (82.4%) patients responded to infliximab induction, with 114 (65.9%) achieving sustained clinical benefit. Almost 40% of the study cohort had an HBI ≤ 4, indicating remission, at last point of follow-up (median 24 months). Concomitant immunosuppression predicted sustained clinical benefit in the first 6 months of therapy (P = 0.03). An inflammatory disease phenotype (P = 0.04 univariate analysis, P = 0.03 Kaplan Meier analysis) and male gender (P = 0.03) also predicted sustained clinical benefit. Episodic therapy was associated with an increased likelihood of secondary non-response. Adverse events, including malignancies, were few. Conclusion In this single centre study, infliximab was efficacious and well-tolerated in CD.

Donation after cardiac death (DCD) has proven effective at increasing the availability of organs for transplantation. We performed a retrospective examination of Massachusetts General Hospital (MGH) records of all 201 donors from 1/1/98 to the 11/2008, including 54 DCD, 115 DBD and 32 DCD candidates that did not progress to donation (DCD-dnp). Comparing three time periods, era 1 (01/98–12/02), era 2 (01/03–12/05) and era 3 (01/06–11/08), DCD's comprised 14.8, 48.4% and 60% of donors, respectively (p = 0.002). A significant increase in the incidence of cardiovascular/cerebrovascular as cause of death was evident in era 3 versus eras 1 and 2; 74% versus 57.1% (p < 0.001), as was a corresponding decrease in the incidence of traumatic death. Interestingly, we noted an increase in utilization of aggressive neurological management over time, especially in the DCD group. We detected significant changes in the make-up of the donor pool over the past decade. That the changes in diagnosis over time did not differ between DCD and DBD groups suggests this difference is not responsible for the increase in DCD rates. Instead, we suggest that changes in clinical practice, especially in management of patients with severe brain injury may account for the increased proportion of DCD.

Carbapenems are a class of antimicrobials structurally related to penicillin. Doripenem, the newest agent in this class, was recently approved by the Food and Drug Administration for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. Its spectrum of activity is similar to that of meropenem and imipenem/cilastatin. Some studies indicate that approximately 29% of carbapenem-resistant Pseudomonas aeruginosa isolates may remain sensitive to doripenem, although the clinical relevance of that finding has not been determined. Clinical studies, which have been published only in abstract form to date, have found doripenem to be similar to comparator agents. The most common adverse effects related to doripenem therapy were headache, nausea, diarrhea, rash, and phlebitis. Doripenem, like the other carbapenems, may also cause seizures. Because of the lack of published data, the lack of clear advantages over meropenem, and the increased cost compared with meropenem, doripenem will not be available for use at Baylor University Medical Center except by infectious diseases specialists.

Purpose/Objective(s): Use of the disease-specific graded prognostic assessment (DS-GPA) for brain metastases is a powerful prognostic tool. The survival estimates obtained for this toolmay not reflect the prognosis of patients with brain metastases at the time of NSCLC who are naive to other therapies. Materials/Methods: We identified all patients with newly diagnosed NSCLC with 1-3 brain metastases treated with gamma knife radiosurgery between 1997 and 2011 from an IRB approved registry. We included both patients treated with GK alone or in combination with whole brain radiation therapy (WBRT) for the initial management of brain metastases. We evaluated potential prognostic factors for overall survival including age, treatment modality, Karnofsky Performance Score (KPS), histology, disease burden in the lungs, location of presenting symptoms, and extracranial metastases by Cox Proportional Hazards. Patients were stratified by NSCLC DS-GPA to evaluate the accuracy of survival estimates in patients with newly diagnosed lung cancer. Results: 164 patients were identified with 85 (52%) treated with gammaknife (GK) alone and 79 (48%) treatedwith up front GK andWBRT. Patients treatedwithGK alone had amedian survival of 9.1months versus 8.5months in patients treated with GK and WBRT (p-valueZ 0.093). Neither group demonstrated differences in disease progression, with GK and GK+WBRT median time to disease progression at 6.7 and 6.1 months respectively, pvalueZ 0.52. Significant risk factors for overall survival on univariate analysis were KPS, HR 0.98 (95% CI 0.97-0.99), symptomatic extracranial disease, HR 0.55 (CI 0.36-0.84), presence of extracranial metastases, HR 0.45 (CI 0.34-0.70), and higher number of brain metastases, 1.61 (CI 1.102.35). Neither age,HR1.0 (CI 0.9-1.0) nor up front addition ofWBRT toGK, HR0.76 (CI 0.55-1.05)were significantly associatedwith improved survival. On multivariate analysis only presence of extracranial metastases was significant for disease progression, HR 0.60 (CI 0.39-0.93). Median overall survival stratified byDS-GPAof 0-1, 1.5-2, 2.5-3 and 3.5-4were 2.8, 6.7, 9.8, and 13.2 months, respectively, consistent with survival estimates for brain metastases in NSCLC as a whole which are 3.0, 6.5, 11.3, and 14.8 months. Conclusion: The prognosis for patients with newly diagnosed NSCLC with synchronous brain metastases is consistent with survival estimates from DS-GPA for NSCLC. In addition to DS-GPA presences of symptoms of systemic disease were associated a worse prognosis. Patients with newly diagnosed NSCLC do not have an improved prognosis compared to what DS-GPA would predict and those with low GPA may not benefit from additional aggressive therapies. Author Disclosure: M. Greer: None. N.M. Woody: None. C.A. Reddy: None.G.M.Videtic:Editor for Thoracic Section ofRed Journal; International Journal of Radiation Oncology. S.T. Chao: Speaker’s Bureau; Varianmedical systems.E.S.Murphy:None.J.H.Suh:Consultant;VarianMedical Systems. L. Angelov: None. G. Barnett: None. M.A. Vogelbaum: Consultant; Neuralstem, Inc., Pharmacokinesis, Inc. Royalty; Infuseon Therapeutics, Inc. Chair and Co-chair; NRG Oncology. K.L. Stephans: None.

Introduction Long term safety data for biologic therapies in Crohn9s disease (CD) is still emerging. A recent study has suggested that serious adverse events occur in 15% of patients receiving infliximab (IFX) therapy for CD, and more frequently in patients on concomitant immunosuppression. However, the TREAT registry observed no increased risk of adverse events with IFX, compared to other therapies. The authors assessed adverse events in patients who have received IFX therapy for CD at their referral centre. Methods All patients who receive IFX therapy for CD in our referral centre for CD were included on a prospective database. Data stored included sex, age at diagnosis, duration of disease, previous surgical history, smoking history and Montreal classification. Response and remission data are also prospectively recorded. Adverse events to infliximab are documented each time a patient attends for an infusion, or at the following clinic visit. Patients who were not receiving concomitant immunosuppression were premedicated with hydrocortisone at each infusion. Results In total, 3165 IFX infusions were administered to 210 patients (median of 24 (IQR 7–48) months), mean Harvey-Bradshaw index of 9. In total, 59 (28.1%) patients experienced adverse events to IFX. 23 patients had a reaction during the infusion, with 9 discontinuing therapy. 12 patients had hypersensitivity reactions and discontinued IFX. Seven patients discontinued IFX due to psoriatiform rashes. There were 14 (6.7%) opportunistic infections (including seven episodes of Varicella zoster reactivation, and one diagnosis of pulmonary tuberculosis in a Caucasian male who had received 3 years of maintenance therapy and had a normal chest x-ray pre-IFX), 3 infections required permanent discontinuation of IFX. There were 3 malignancies (1.4%) all discontinuing IFX. One was an adenocarcinoma in a peri-anal fistula tract. Examination under anaesthesia (EUA) and biopsy pre-IFX had been non-diagnostic, but EUA was repeated after non-response to IFX. One older diabetic patient developed a fatal spindle-cell tumour, and one patient in remission had an incidental finding of a renal cell carcinoma when disease was being reassessed by imaging prior to withdrawal of IFX. Overall, 34 (16.2%) patients discontinued IFX due to adverse events. 21 (35.6%) patients were receiving concomitant immunomodulator therapy at the time of the adverse event. There was no significant difference in adverse events when comparing episodic versus maintenance therapy (p=0.62). Conclusion IFX is safe and well tolerated with low numbers of adverse events, malignancies and mortality in our large single centre cohort of patients with severe active CD. Careful patient selection, pre-IFX screening and monitoring during therapy can optimise the risk benefit ratio.

The purpose of this study was to evaluate the apical sealing ability of two compomers (Dyract and Geristore), IRM, and Super-EBA. Forty single canal roots from human teeth were instrumented until a size 40 file extended 1 mm beyond the apex. One millimeter of root apex was removed and a preparation 3-mm deep was prepared. Roots were divided into 4 groups of 10 roots each and filled with IRM, Super-EBA, Dyract, or Geristore. Canals were not obturated to ensure that any leakage was due to the apical filling material alone. Each root was then affixed to a fluid filtration device and subjected to a pressure of 14 cm of H2O, which has been determined to be the normal pulpal tissue pressure. The integrity of the seal was evaluated for 5 min at 1, 7, 30, and 180 days. Data were analyzed at each time point using one-way analysis of variance on ranks. The results of this study suggest that the new compomers Dyract and Geristore are equal or superior to IRM and equivalent to Super-EBA in their ability to reduce apical leakage when used as retrofilling materials.

To suggest infliximab (IFX) is effective for acute severe ulcerative colitis, from real-life clinical practice.All patients receiving IFX for the treatment of acute severe ulcerative colitis in a single centre were included. Data were extracted from clinical records in order to assess response to IFX therapy. The primary endpoint was colectomy-free survival, and secondary outcomes included glucocorticosteroid-free remission and safety, which was evaluated by recording deaths and adverse events. Demographic and clinical characteristics of those who underwent colectomy and those who were colectomy-free, both at discharge from their index admission, and during follow-up after an initial response to IFX were compared.Forty-four patients (16 females, mean age 36 years) received IFX between May 2006 and January 2012 for acute severe ulcerative colitis. The median duration of follow-up post-first infusion was 396 d (interquartile range = 173-828 d). There were 21 (47.7%) patients with1 year of follow-up, 10 (22.7%) with 1 years to 2 years of follow-up, and 13 (29.5%) with2 years of follow-up post-first infusion of IFX. Overall, 35 (79.5%) responded to IFX, avoiding colectomy during their index admission, 29 (65.9%) were colectomy-free at last point of follow-up (median follow-up 396 d), and 25 (56.8%) were in glucocorticosteroid-free remission at end of follow-up. There was one death from post-operative sepsis, 20 d after a single IFX infusion. Colectomy rates were generally lower among those "bridging" to thiopurine. Of 18 patients "bridged" to thiopurine therapy, 17 (94.4%) were colectomy-free, and 15 (83.3%) were in glucocorticosteroid-free remission at study end. No predictors of response were identified.IFX is effective for acute severe ulcerative colitis in real-life clinical practice. Two-thirds of patients avoided colectomy, and more than 50% were in glucocorticosteroid-free remission.

Introduction Infliximab (IFX) is licensed for use in Crohn9s disease (CD) in the UK. Data from randomised controlled trials demonstrate that IFX is more effective than placebo at inducing remission of active CD, healing fistulising CD and preventing relapse once remission is achieved. Factors predicting response to IFX, and sustained clinical benefit are still emerging. The authors analysed which patient characteristics may predict response, and also loss of response, to IFX, from a large prospective database of CD patients. Methods All patients who receive IFX therapy for CD in our referral centre for CD were included on a prospective database. Data stored included sex, age at diagnosis, duration of disease, surgical history, smoking history and Montreal classification. Concomitant therapy, IFX regimen, duration of therapy and number of infusions, Harvey-Bradshaw indices (HBI), were collected prospectively on commencement of IFX. Response to IFX, following induction or during continuing therapy (sustained clinical benefit), was defined as a ≥2 decrease in HBI, or by physician9s global assessment (PGA). Results In total, 3165 IFX infusions were delivered to 210 patients over a median of 24 (IQR 7–48) months (median of 12 (IQR 4–22) infusions per patient). In total, 173 (82.4%) patients responded to IFX induction as determined by PGA and HBI scores (mean HBI pre- of 9.0 and 4.3 post-IFX induction). There were 18 (8.6%) patients with primary non-response (NR) to IFX induction (mean HBI of 10.1 pre-IFX and 10.3 post-IFX induction). A further 19 (9.0%) patients discontinued IFX during induction for other reasons including adverse events. At the last point of follow-up, 114 (65.9%) of the 173 responders (54.3% of the original cohort) to induction therapy experienced sustained clinical benefit from IFX, as determined by HBI and/or PGA (mean HBI of 3.9, with 84 (40% of the original cohort) having an HBI≥4, indicating remission). Predictors of response to IFX included male sex (p=0.01 for response to induction and p=0.006 for sustained clinical benefit), luminal disease (p=0.02 for sustained clinical benefit) and scheduled 8 weekly therapy (p=0.03 for sustained clinical benefit). There were 32 (18.5%) with secondary NR, 14 received IFX episodically initially and 18 received IFX as scheduled therapy. Patients were significantly more likely to experience secondary NR if treated episodically at induction (p=0.01). Secondary NR occurred sooner in patients with a stricturing or penetrating phenotype (p=0.007). Conclusion IFX therapy is efficacious for treatment of CD. The authors identify a number of predictors of response to therapy. This data support the proposal of scheduled maintenance therapy for IFX responders as per the new NICE guidance.

Introduction Adalimumab (ADA) is efficacious in Crohn9s disease (CD) patients who have lost response to infliximab (IFX).1 However, there are little data detailing the long-term follow-up of IFX failures who are receiving ADA. Our aim was to prospectively analyse long-term outcomes of CD patients treated with ADA as a second line anti-TNF agent in Leeds. Methods CD patient data include demographics, previous IFX regime, reason for IFX discontinuation, disease site, immunomodulator and steroid use, Harvey-Bradshaw indices (HBI), BMI and adverse events. Results Since 2007, 36 CD patients (previously treated with IFX) received ADA in Leeds. 27 females (75%). Mean age 36. 21 had luminal disease (58%), 15 had fistulating disease (42%) 88% of these having perianal fistulae. 16 previously received IFX in a scheduled manner (44%), 11 episodically (31%), with nine switched to scheduled IFX to try and improve response, and nine had three dose induction of IFX only (25%). 22 patients received induction ADA dosing of 80 mg/40 mg (61%), 14 received 160 mg/80 mg (39%). Response was assessed following four injections. 27 patients initially responded (75%) with sustained response in 22 (58%), median follow-up of 12 months. Eight patients were primary non-responders (NR) to ADA, four of whom were primary NR to IFX. One discontinued during ADA induction due to a reaction. Other reasons for discontinuation were: 3 secondary NR, 1 further reaction, 1 patient in remission. The outcomes for patients who discontinued therapy were as follows: 10 patients had surgery (71%), 4 were observed (29%). 20 patients were on steroids prior to ADA therapy (55%), 10 were on steroids at follow-up (28%) with seven patients able to decrease the steroid dose. The mean HBI on commencing ADA was 10.7 and 7.1 after four injections. In 23 responders (four excluded as stoma) the HBI was 10 pre ADA and 5.5 after four injections, with 12 (52%) having HBI of Conclusion ADA is a safe and effective therapy in CD patients who have been exposed to IFX. Our data demonstrate a good initial response to ADA and a sustained response out to 12 months of therapy. Steroid sparing was achieved in 50% of patients and few adverse events have been documented. These data confirm the efficacy of ADA use in IFX failures in a single centre UK experience.

Introduction Spontaneous bacterial peritonitis (SBP) is a life threatening infection of ascitic fluid which occurs primarily in patients with pre-existing ascites in the setting of cirrhosis. Risk factors for developing SBP include: prior episode of SBP, gastrointestinal bleeding, ascitic total protein Escherichia coli (70%), Klebsiella species (10%), Proteus species (4%), Enterococcus faecalis (4%) and Pseudomonas species (2%).1 The choice of antimicrobial therapy must take into consideration the increasing frequency of hospital acquired infections, such as Clostridium difficile infection. Aim To identify the local epidemiology and resistance patterns of culture-positive SBP. Methods We retrospectively assessed the culture results of all ascitic fluid samples that grew a single organism in Leeds during the 3 years 2006–2008. Patients case notes were assessed to establish a diagnosis of SBP. An ascitic fluid neutrophil count ≥ 250/mm 3 in patients with liver disease was used to confirm the diagnosis of SBP.12 We excluded culture-negative SBP. Results Single organism positive ascitic cultures were identifed in 42 patients with liver disease and an ascitic fluid neutrophil count ≥250/mm 3 . Mean age 52.1 years, 32/42 male. Underlying liver disease was ALD 35/42, HCV 3/42, PBC 1/42, NAFLD 1/42, Cryptogenic 1/42 and Post transplant 1/42. At the time of diagnosis of SBP the mean ascitic total white cell count 5.25, mean ascitic neutrophil count 4.08, mean serum Na+ 129.6 mmol/l and mean serum creatinine 147 mmol/l. Overall Child score A 0, B 8/42, C 34/42 and mean MELD score 24.1. The isolated organisms were Escherichia coli 15, Klebsiella spp. 7, other coliforms 10, Gram positive organisms 8 (including Enterococcus 2, Corynebacterium spp. 2). The Gram-negative isolates were resistant to a number of antibiotics: ciprofloxacin 38% (13/34), cefuroxime 29% (10/34), amoxycillin 32% (11/34) and tazocin 17% (6/34). The 30-day mortality was 50%. Conclusion Empirical treatment regimes need to take into account local resistance patterns. Ciprofloxacin has been widely used for treatment and prophylaxis in SBP. Resistance has now become a significant problem.

8142 Background: Cancer of unknown primary site (CUP) accounts for approximately 5% of cancer diagnoses. Numerous chemotherapy strategies have been evaluated in this setting, but the prognosis rema...

8214 Background: Physicians (MD), nurses (RN) and other health care professionals (HCP) receive minimal education in palliative care delivery, with emphasis on acute care. Taking clinicians of dive...

To determine the presence and extent of thrombus formation in the apparatus used for extracorporeal membrane oxygenation we studied various portions of the polyvinylchloride circuit from five infants who received extracorporeal membrane oxygenation for 70 to 330 hours. All infants had right-sided cannulation. Sections were cut from the circuit at the time of decannulation and subjected to light and scanning electron microscopy. The site that contained the most thrombus formation was the membrane oxygenator bypass circuit, which is subjected to repeated periods of unclamping and clamping to direct blood flow through the membrane oxygenator. Autopsy results from nonsurvivors showed evidence of pulmonary and renal infarcts, a left frontal lobe infarct, a thromboembolus of the left external and internal carotid arteries, and thrombi in the lungs, kidney, brain, and coronary arteries. One survivor had computed tomographic evidence of infarction of the left middle cerebral artery distribution. We suggest that the areas of the extracorporeal membrane oxygenation circuit subjected to repeated changes in flow dynamics may be the source of microemboli.

A comparison study was conducted on women who attended a community-based family planning program and women who attended a hospital-based program. Questions concerning the following factors were asked to determine a relationship between the factors and continuance at the clinic: 1)individual; 2)physical environment of the clinic; and 3)personal treatment at the clinic. All the women received free medical examinations birth control information and supplies and family planning counseling. Both groups of women had the same attitudes and level of knowledge when they first attended the clinic. Women reacted most positively to an organized program which was more apparent in the early stages at the hospital-based clinic.