Stand Trial Research Articles

Prospectively predicting BPaMZ phase IIb/III trial outcomes using a translational mouse-to-human platform.

Despite known treatments, tuberculosis (TB) remains the world's top infectious killer, highlighting the pressing need for new drug regimens. To prioritize the most efficacious drugs for clinical testing, we previously developed a PK-PD translational platform with bacterial dynamics that reliably predicted short-term monotherapy outcomes in Phase IIa trials from preclinical mouse studies. In this study, we extended our platform to include PK-PD models that account for drug-drug interactions in combination regimens and bacterial regrowth in our bacterial dynamics model to predict cure at the end of treatment and relapse 6 months post-treatment. The Phase III STAND trial testing a new regimen comprised of pretomanid (Pa), moxifloxacin (M), and pyrazinamide (Z) (PaMZ) was suspended after a separate ongoing trial (NC-005) suggested that adding bedaquiline (B) to the PaMZ regimen would improve efficacy. To forecast if the addition of B would, indeed, benefit the PaMZ regimen, we applied an extended translational platform to both regimens. We predicted currently available short- and long-term clinical data well for drug combinations related to BPaMZ. We predicted the addition of B to PaMZ to shorten treatment duration by 2 months and to have similar bacteriological success to standard HRZE treatment (considering only treatment success but not withdrawal from side effects and other adverse events), both at the end of treatment for treatment efficacy and 6 months after treatment has ended in relapse prevention. Using BPaMZ as a case study, we have demonstrated our translational platform can predict Phase II and III outcomes prior to actual trials, allowing us to better prioritize the regimens most likely to succeed.

Smaart Criz: Sickle Cell Mechanisms of Activation, Adhesion, Rheology, and Thrombosis (SMAART) in Response to P-Selectin Inhibition

Sickle cell disease (SCD) pathophysiology involves uncontrolled inflammation, dysregulated coagulation, and adherence of erythrocytes, leukocytes, and platelets to endothelium, all contributing to disrupted rheology and ultimately vaso-occlusion. Crizanlizumab (Novartis), an FDA-approved humanized monoclonal antibody, binds to p-Selectin and blocks endothelial interactions with blood cells. The phase 2 SUSTAIN trial demonstrated a reduction in the median rate of pain crisis, as well as prolonged time to first and second crisis ( Ataga 2017). Not all participants benefited, however, nor have all treated patients achieved pain reduction in the post-marketing period. Paradoxical infusion-related pain has also been reported ( Kanter 2022). Baseline differences between responders, non-responders, and those suffering infusion-related pain remain uncharacterized. In January 2023, Novartis issued a preliminary update on the ongoing global crizanlizumab phase 3 STAND trial which indicated no statistically significant pain reduction with crizanlizumab therapy compared to placebo. A better understanding of patient suitability for the various disease modifying therapies for SCD would however be beneficial. Our center is a pilot site for a lab conducting an assay measuring flow adhesion of whole blood to P-selectin (FA-WB-Psel) utilizing a protein coated microfluidic chamber by Functional Fluidics. Previously published data identified a steady state reference range for FA-WB-Psel in non-SCD as well as SCD patients ( Pittman 2021). The SMAART Criz study aims to characterize downstream biological effects of crizanlizumab (FA-WB-Psel) and identify biomarkers with the potential to predict treatment response, with the goal of facilitating more individualized prescribing. This is an interim analysis of an investigator-initiated, prospective, IRB-approved, 18-week longitudinal study at the Children's Hospital of Michigan. Patients desiring crizanlizumab treatment were offered enrollment. Following informed consent, samples were obtained for FA-WB-Psel before and after each crizanlizumab dose. Flow adhesion of whole blood to vascular cell adhesion molecule-1 (FA-WB-VCAM) was assessed as a control substrate. Thromboelastography (TEG) and whole blood platelet aggregometry were performed to evaluate platelet function at baseline, week 6, and week 18. Patient reported response to treatment was used to measure response to therapy. As of August 2023, 7 patients have completed the study with a median age of 20 years (range 16-25 years; 4 female). Genotypes are HbSS (5), HbSC (1), and HbS-G-Philadelphia (1). Four of 7 patients self-reported clinical response to therapy (Table 1). Treatment was discontinued after 1st dose due to treatment-related acute pain in 2 participants, and after the 4th dose due to patient-reported worsening pain trend (Figure 1). Clinical responders had a median baseline FA-WB-Psel adhesion index of 86 cells/mm 2 (n=4, mean 106, range of 56-193). Clinical responders experienced a 65% reduction in FA-WB-Psel from baseline (mean 86) to the mean pre-infusion level calculated using visit 2 and 3 levels (p=0.05, later visits affected by dropout). Non-responders had a median baseline FA-WB-PSel of 49 cells/mm 2 (n=3, mean 46, range 13-75) with widely variable FA-WB-PSel responses (Fig. 1). The two patients with acute treatment-induced pain had the lowest baseline values at 13 and 49 cells/mm 2. No significant trends were observed in adhesion to a control substrate using FA-WB-VCAM. There was an overall decrease in both arachidonic acid (AA) and adenosine diphosphate (ADP) platelet aggregation over time (AA: 23.5 Ohms to 11.3 Ohms, p=0.254; ADP: 23.4 Ohms to 10.6 Ohms, p=0.036). Early indications from SMAART Criz are that administration of crizanlizumab decreases FA-WB-Psel immediately after infusion with continued decreases over time. Interim analysis suggests elevated baseline FA-WB-Psel may predict individuals with SCD likely to benefit from crizanlizumab, while normal FA-WB-Psel levels at baseline may predict non-response or even adverse reactions. This cohort showed an overall decrease in both AA and ADP aggregation, indicating reduced platelet aggregation following crizanlizumab treatment, a potential downstream biological change contributing to treatment effect (Table 1). Further investigation is warranted. Enrollment and analyses are ongoing.

Wearable devices: underrepresentation in the ageing society

Wearable devices: underrepresentation in the ageing society

Clozapine Use and Forensic Outcomes in Psychiatric Inpatients Deemed Incompetent to Stand Trial.

Referrals for competency restoration increased in the past decade, with the majority of incompetent to stand trial (IST) patients having schizophrenia; 25 percent of schizophrenia patients are treatment resistant. Clozapine is superior to other antipsychotics for treatment resistance but remains underutilized, particularly in forensic settings. Despite the impact of treatment resistance on the legal system, the literature on clozapine for IST patients is limited to two papers comprising 26 patients. A retrospective chart review was conducted of all IST admissions to a California hospital for 2014 to -2018, examining clinical and forensic outcomes in those newly started on clozapine and discharged. There were 191 new clozapine starts among IST patients, 92.7 percent of whom were diagnosed with schizophrenia or another psychosis. Over 90 percent were discharged on clozapine, and 36.1 percent were discharged on clozapine as trial competent; moreover, this cohort also had the shortest length of stay. This analysis indicates that most IST patients needing clozapine can be successfully treated, with a substantial proportion restored to trial competency. These data and earlier studies reinforce the concept that forensic programs have a medical duty to offer IST patients with severe mental illness a clozapine trial when indications exist for its use.

Interface of Law and Psychiatric Problems in the Elderly.

Interface of Law and Psychiatric Problems in the Elderly.

Data on Evaluations as a Foundation for States Rethinking Competency to Stand Trial.

Competency to stand trial policies and processes vary significantly across jurisdictions, and, increasingly, state policymakers are looking for ways to improve their efficiency, equity, and effectiveness. This commentary describes the importance of certain data, including the number of evaluations ordered, to inform state policymaking, drawing on the strategies highlighted in a recently released guide for policymakers, Just and Well: Rethinking How States Approach Competency to Stand Trial.

Community-Based Remediation of Juvenile Competence to Stand Trial: A National Survey

Youth found incompetent to stand trial in U.S. juvenile courts may be ordered to attend Juvenile Competence Remediation Services to assist them in becoming competent to proceed with their case. Representatives from 19 community-based JCRS programs were surveyed about current norms and practices. The results suggest that programs routinely meet some emerging best practices (e.g., dyadic service delivery; developmentally sensitive services), but not others (e.g., providing case management services; services guided by outcome data). The results also reveal a lack of consistency across programs in a variety of areas (e.g., training and experience of providers; educational curricula used by providers).

Effects of neuromuscular electrical stimulation on energy expenditure and postprandial metabolism in healthy men.

It is unclear whether neuromuscular electrical stimulation (NMES) has meaningful metabolic effects when users have the opportunity to self-select the intensity to one that can be comfortably tolerated. Nine healthy men aged 28 ± 9 y (mean ± SD) with a body mass index 22.3 ± 2.3 kg/m2 completed 3 trials involving a 2-h oral glucose tolerance test whilst, in a randomised counterbalanced order, (1) sitting motionless (SIT), (2) standing motionless (STAND); and (3) sitting motionless with NMES of quadriceps and calves at a self-selected tolerable intensity. The mean (95% confidence interval [CI]) total energy expenditure was greater in the NMES trial (221 [180-262] kcal/2 h) and STAND trial (178 [164-191] kcal/2 h) than during SIT (159 [150-167] kcal/2 h) (both, p < 0.05). This was primarily driven by an increase in carbohydrate oxidation in the NMES and STAND trials compared with the SIT trial (p < 0.05). Postprandial insulin iAUC was lower in both NMES and STAND compared with SIT (16.4 [7.7-25.1], 17 [7-27] and 22.6 [10.8-34.4] nmol·120 min/L, respectively; both, p < 0.05). Compared with sitting, both NMES and STAND increased energy expenditure and whole-body carbohydrate oxidation and reduced postprandial insulin concentrations in healthy men, with more pronounced effects seen with NMES. Self-selected NMES is a potential strategy for improving metabolic health. This trial is registered at ClinicalTrials.gov (ID: NCT04389736). Novelty: NMES at a comfortable intensity enhances energy expenditure and carbohydrate oxidation, and reduces postprandial insulinemia. Thus, self-selected NMES represents a potential strategy to improve metabolic health.

Gender and Malingering in Defendants Deemed Incompetent to Stand Trial.

The relationships between gender and malingering have received little attention in the literature. Our study examined data from 1,748 patients committed as incompetent to stand trial between 2008 and 2017, of whom 397 were women. Scores on a structured assessment of feigned psychiatric symptoms were only slightly higher for men than for women. Yet evaluators believed that over 23 percent of men but less than 15 percent of women were malingering. Our data suggest that these gender differences in rates of malingering may be attributable to symptom constellations and extent of criminal arrest history.

Incompetent to Stand Trial, Not Restorable, and Dangerous.

This article focuses on the preferred disposition for an individual charged with a serious crime against another person, adjudicated incompetent to stand trial and not restorable to competence, whose original criminal charges are dismissed without prejudice, and who is regarded by the state as dangerous to the general public. Three current models used today in California, Oregon, and Ohio are described. All three rely on modifications of various aspects of civil commitment law. We then propose a fourth model based on a modified version of the 1989 American Bar Association (ABA) Criminal Justice Mental Health Standards, in which individuals who are found incompetent to stand trial and not restorable to competence and are considered dangerous would be committed under the same special procedures governing the management and treatment of insanity acquittees.

A Partially-Randomised Phase 3 Trial of Pretomanid, Moxifloxacin and Pyrazinamide in Combination for the Treatment of Drug-Susceptible and Drug-Resistant Pulmonary Tuberculosis

Background: Tuberculosis (TB) is a leading infectious cause of death globally. Current treatment for drug-susceptible (DS-TB) and rifampicin-resistant (RR-TB) infections is lengthy and toxic. Methods: The STAND trial was a partially-randomised, open-label, non-inferiority phase 3 study. Patients ≥18 years with smear positive sputum were eligible. HIV-positive patients with CD4+ counts <100 cells/mm3 were excluded. DS-TB participants were randomised 1:1:1:1 to receive: 200mg pretomanid (P) daily, 400mg moxifloxacin (M) and 1500mg pyrazinamide (Z) for either 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) in combination for 6 months as control. The primary outcome was treatment failure or relapse 12 months after randomisation. The non-inferiority margin for between-group differences was 12 percent. RR-TB participants were allocated to 6Pa200MZ. Recruitment was paused in September 2015 and did not resume. Findings: In total 43 of 56 (76.8%), 46 of 61 (75.4%), 38 of 57 (66.7%), and 52 of 60 (86.7%) DS-TB participants were favourable on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ, and control respectively. The difference in favourable response between control and 6Pa200MZ was 9.9% [95%CI -4.1 to 23.9%]. Ten of 11 (90.9%) RR-TB participants were favourable. Grade 3 or higher adverse events affected 22 of 67 (32.8%) 6Pa200MZ participants, 21 of 71 (29.6%) on 4Pa200MZ, 25 of 65 (38.5%) on 4Pa100MZ, and 19 of 68 (27.9%) on control. Serious adverse events affected 19 of 203 (9.4%) experimental DS-TB participants, 3 of 68 (4.4%) on control, and 3 of 13 (23.1%) RR-TB cases. Ten of 203 (5%) participants on the experimental arms and 2 of 68 (3%) participants on the control arm died, with 2 deaths on the 4MPa200Z arm and one death on the 4MPa100Z arm attributed to hepatotoxicity. Interpretation: The experimental DS-TB treatment did not achieve non-inferiority in this underpowered trial. The role of Pa200MZ in tuberculosis treatment needs to be investigated further. Trial Registration: (Clinicaltrials.gov identifier NCT02342886) Funding Statement: Sponsored by TB Alliance with financial support from the U.K. Department for International Development, Bill and Melinda Gates Foundation, U.S. Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the Federal Ministry for Education and Research of Germany. Declaration of Interests: The authors declared no conflicts of interest. Ethics Approval Statement: Ethical approval was granted by the national and local ethics committees for the sites participating in the trial.

Crizanlizumab 5.0 Mg/Kg Exhibits a Favorable Safety Profile in Patients with Sickle Cell Disease: Pooled Data from Two Phase II Studies

Crizanlizumab 5.0 Mg/Kg Exhibits a Favorable Safety Profile in Patients with Sickle Cell Disease: Pooled Data from Two Phase II Studies

Mandatory Life Imprisonment, Adjudication of Competence to Stand Trial, and Developmental Disability

In Commonwealth v. Jones , 479 Mass. 1 (2018), the Massachusetts Supreme Court concluded that sentencing a defendant with developmental disability to life in prison without the possibility of parole does not constitute cruel and unusual punishment under the United States Constitution or under the

New Zealand Youth Fitness to Stand Trial: The Impact of Age, Immaturity and Diagnosis on Evaluator Opinions and Court Determinations

International research suggests that a proportion of youth facing legal charges are at risk of being unfit (or incompetent) to stand trial. In New Zealand, only a fraction of youth coming before Youth Court are referred for fitness to stand trial evaluations. Amid debate surrounding notions that youth offending could be deterred by providing harsher penalties, it is important to consider fitness to stand trial in youth facing criminal proceedings. This study sought to capture a cross-sectional view of how fitness (competency) to stand trial is addressed in the Youth Court, and how evaluator opinions relate to ultimate court findings. A retrospective review of reports for fitness to stand trial in 79 youth consecutively referred to the Regional Youth Forensic Service from 2010 to 2015 was conducted. Data were combined with Youth Court outcomes obtained from the Ministry of Justice. The mean age is 15.6 years. Intellectual disability is associated with unfit opinions and legal findings (p = .002 and p = .03, respectively), and cases disposed through the Intellectual Disability (Compulsory Care and Rehabilitation) Act 2003. Immaturity itself does not appear to have a significant effect on evaluator opinions or court findings of fitness to stand trial. The majority of the referred youth were both opined and found fit.

MP87-15 RANDOMIZED PHASE 2 STUDY EVALUATING OPTIMAL SEQUENCING OF SIPULEUCEL-T AND ANDROGEN DEPRIVATION THERAPY (STAND) IN BIOCHEMICALLY RECURRENT PROSTATE CANCER: PRELIMINARY CLINICAL OUTCOMES

You have accessJournal of UrologyProstate Cancer: Advanced III1 Apr 2015MP87-15 RANDOMIZED PHASE 2 STUDY EVALUATING OPTIMAL SEQUENCING OF SIPULEUCEL-T AND ANDROGEN DEPRIVATION THERAPY (STAND) IN BIOCHEMICALLY RECURRENT PROSTATE CANCER: PRELIMINARY CLINICAL OUTCOMES Adam Kibel, Charles Drake, George Adams, Lawrence Karsh, Aymen Elfiky, Neal Shore, Nicholas Vogelzang, John Corman, Robert Tyler, Johnathan Maher, Todd DeVries, Nadeem Sheikh, and Emmanuel Antonarakis Adam KibelAdam Kibel More articles by this author , Charles DrakeCharles Drake More articles by this author , George AdamsGeorge Adams More articles by this author , Lawrence KarshLawrence Karsh More articles by this author , Aymen ElfikyAymen Elfiky More articles by this author , Neal ShoreNeal Shore More articles by this author , Nicholas VogelzangNicholas Vogelzang More articles by this author , John CormanJohn Corman More articles by this author , Robert TylerRobert Tyler More articles by this author , Johnathan MaherJohnathan Maher More articles by this author , Todd DeVriesTodd DeVries More articles by this author , Nadeem SheikhNadeem Sheikh More articles by this author , and Emmanuel AntonarakisEmmanuel Antonarakis More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1960AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sipuleucel-T (sip-T) is an autologous cellular immunotherapy targeting prostatic acid phosphatase, approved for the treatment of asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer. The STAND trial (NCT01431391) evaluated optimal sequencing of sip-T and androgen deprivation therapy (ADT) in men with biochemically recurrent prostate cancer at high risk of developing metastases (prostate-specific antigen [PSA] doubling time ≤12 mos). Here, we report preliminary PSA and metastatic outcomes. METHODS Men were randomized (1:1) to sip-T followed by ADT (Arm 1) or ADT followed by sip-T (Arm 2). Planned treatment was to receive 3 doses of sip-T and 12 mos of ADT. PSA response was defined as ≥50% (PSA50) or ≥90% (PSA90) decline from baseline, confirmed ≥3 weeks later. PSA recurrence was defined as at least 2 serial rises in PSA (≥2 weeks apart) and PSA ≥0.2 ng/mL for men with prior radical prostatectomy, or ≥2.0 ng/mL for men with prior radiation therapy alone, and was measured from the date of the last ADT injection. RESULTS A total of 68 men were randomized (n=34 per arm). At baseline, the median PSA was 3.5 ng/mL in Arm 1 and 2.3 ng/mL in Arm 2. As of August 2014, all men have completed treatment and 32/68 (47%) men had 24-mos follow up. At the nadir of PSA response, PSA50 was observed in all men in Arm 1 and 97% of men in Arm 2, and PSA90 was observed in 88% of men in Arm 1 and 91% of men in Arm 2. At 1 year after the last ADT injection, PSA50 was observed in 75% of men in both study arms, and PSA90 was observed in 50% of men in Arm 1 and 63% of men in Arm 2. Of men who completed the study, PSA recurrence was observed in 8/16 in Arm 1 and 11/16 in Arm 2. The median time to PSA recurrence was 16.7 mos for Arm 1 and 14.9 mos for Arm 2 (HR [Arm 2 vs Arm 1] 1.247; 95% CI 0.492, 3.164; P=0.641). Evidence of metastatic disease was seen in 3/16 men in Arm 1 and 2/16 men in Arm 2. Currently available data show no statistically significant differences between treatment arms in any outcome. Data on the remaining patients will be forthcoming. Two Grade 3 treatment-related adverse events were reported in Arm 2 (fatigue and dyspnea). CONCLUSIONS Sip-T + ADT showed durable PSA responses regardless of treatment sequence. Final data, including correlative analyses of clinical data with immune parameters, will be presented. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e1089-e1090 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adam Kibel More articles by this author Charles Drake More articles by this author George Adams More articles by this author Lawrence Karsh More articles by this author Aymen Elfiky More articles by this author Neal Shore More articles by this author Nicholas Vogelzang More articles by this author John Corman More articles by this author Robert Tyler More articles by this author Johnathan Maher More articles by this author Todd DeVries More articles by this author Nadeem Sheikh More articles by this author Emmanuel Antonarakis More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Antigen-specific immune responses through 24 months in the STAND trial: A randomized phase 2 study evaluating optimal sequencing of sipuleucel-T (sip-T) and androgen deprivation therapy (ADT) in biochemically-recurrent prostate cancer (BRPC).

171 Background: Sip-T is an autologous cellular immunotherapy targeting prostatic acid phosphatase (PAP), approved for treatment of asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer. STAND evaluates sequencing of sip-T and ADT in men with BRPC at high risk of metastases. Here we report interim assessments of cellular and humoral responses through 24 mos. Methods: Men (n=68)were randomized 1:1 to sip-T followed by ADT (2 wks after 3rd infusion; Arm 1) or ADT (3-mo lead-in) followed by sip-T (Arm 2). Product parameters (total nucleated cell [TNC] count, antigen presenting cell [APC] count, APC activation) were determined with each product manufacture. Cellular and humoral immune responses were analyzed through 24 mos with a repeated measures statistical model. Results: Sample size ranged 8–28 for cellular responses and 34–64 for humoral responses. PA2024 ELISPOT count increased vs baseline at most timepoints (p&lt;0.05) and was lower in Arm 2 vs Arm 1 (p=0.015). PA2024 antigen-specific T-cell proliferation increased from baseline at all timepoints (p≤0.001) and was lower in Arm 2 vs Arm 1 (p&lt;0.001). PA2024 antibody titers were similar between treatment arms (p=0.976). PA2024 antibody titer was significantly higher at the 3rd sip-T infusion visit and remained elevated at 24 mos (23 times higher on average vs baseline; p&lt;0.001). A similar antibody titer profile was reported for PAP but of lesser magnitude. The number of immune responders (post-baseline antibody titer ≥25,600) was similar at any timepoint between arms (Arm 1: 30/34, 88.1%; Arm 2: 32/34, 94.1%; p=0.673). Higher cumulative TNC and baseline hemoglobin positively correlated with maximum PA2024 antibody titer response (p&lt;0.05). Conclusions: Sip-T induced a robust immune response sustained to 24 mos in men with BRPC. Cellular response appeared to differ according to treatment sequence; humoral response was similar between treatment arms. Given its consistent association with the humoral response, cumulative TNC count may be a potential biomarker of response to sip-T. Clinical trial information: NCT01431391.

775P - A Randomized Phase 2 Study Evaluating Optimal Sequencing of Sipuleucel-T (Sip-T) and Androgen Deprivation Therapy (Adt) in Biochemically-Recurrent Prostate Cancer (Brpc): Variables that Correlate with Immune Response

ABSTRACT Aim: Sip-T is an autologous cellular immunotherapy targeting prostatic acid phosphatase (PAP) approved by the US FDA and EMA for treatment of certain patients with asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer based on a 22% reduction in risk of death in the IMPACT trial. Predictive markers of survival benefit from immunotherapy are needed. Eosinophil counts correlated with humoral response and survival in previous trials of sip-T; here we assess T cell proliferation and variables correlating with immune response in the STAND trial. Methods: STAND evaluates optimal sequencing of sip-T and ADT in men with BRPC at high risk for metastases. Men (N = 68) were randomized 1:1 to Arm 1: sip-T followed by ADT (2 wks after 3rd infusion) or Arm 2: ADT (3 mo lead-in) followed by sip-T. All men had 3 doses of sip-T and 12 mos of ADT. Primary endpoint: cellular immune response. Secondary endpoints: humoral/cytokine responses, product parameters, safety. Spearman's correlations (r) were used to assess the relationship between maximal humoral response, cumulative product parameters, and maximal post-baseline eosinophil count. Results: 65 men have been followed for ≥9 mos post-ADT. Sip-T induced robust immune responses to PA2024 and PAP (T cell memory responses and ELISA antibody responses to PAP and PA2024, a recombinant protein comprising PAP fused to granulocyte-macrophage colony-stimulating factor) in both arms. Variables that correlated with antibody responses included cumulative total nucleated cell (TNC) count (PA2024, P = 0.03; PAP, P = 0.08) and maximum eosinophil count after sip-T treatment (PA2024, P = 0.06; PAP, P = 0.02). Antigen-specific T cell proliferation increased after the 2nd sip-T infusion and persisted to 26 wks. Conclusions: Consistent with other studies, sip-T induced a robust, long-term cellular immune response. Although not different between arms, cumulative TNC count and maximum eosinophil count after sip-T may be markers associated with humoral response, and warrant further study. Disclosure: C.G. Drake: Research funding: Aduro, Bristol Myers Squibb Consultant/advisory role: Bristol Myers Squibb, Dendreon, Janssen, Pfizer, Roche; A.S. Kibel: Advisory Board for Dendreon, Sanofi, and Myraid; G.W. Adams: Speakers bureau for Dendreon & Amgen; L.I. Karsh: Consultant/advisor: Dendreon Investigator: Dendreon Meeting participant/lecturer: Dendreon Scientific study/trial: Dendreon; N.D. Shore: Research/consultant for Algeta, Astellas, Bayer, Pfizer, Millenium, Janssen, Medivation, Sanofi N.J. Vogelzang: Dendreon speakers bureau and research funding from Dendreon; J.M. Corman: Honoraria and Research Funding for Dendreon; R.C. Tyler, C. McCoy, T. Devries and N. Sheikh: Dendreon Corporation: Employee and Stock Holder; E.S. Antonarakis: Dendreon advisory board and Dendreon research funding. All other authors have declared no conflicts of interest.

Mental illness and legal fitness (competence) to stand trial in New York State: expert opinion and criminal defendants' psychiatric symptoms.

Fitness to Stand Trial is a critical concept in the adjudication of justice-involved persons. A retrospective study was conducted to examine criminal defendants' specific psychiatric symptoms and those symptoms' associations with expert opinions on Competence to Stand Trial. One hundred charts were reviewed: 50 Cases (opined as Not Fit) were compared against 50 Controls (opined as Fit) with respect to ratings on the Brief Psychiatric Rating Scale (BPRS). A significance level of 0.001 was selected a priori. Statistically significant differences were found in seven of the eighteen BPRS symptom constructs (with the highest differences in Conceptual Disorganization and Unusual Thought Content) and two of the four BPRS higher-order syndrome factors (Thinking Disorder and Hostile-Suspiciousness). Consistent with previous reports, psychotic symptoms are found in this study to be inversely associated with Fitness. Validity, reliability, and limitations of this study, as well as directions for future research, are discussed herein.

A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results.

5016 Background: ADT is a standard treatment for men with BRPC after failure of local therapy, and has immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. The STAND trial (NCT01431391) aimed to evaluate optimal sequencing of sipuleucel-T and ADT in men with BRPC at high risk for metastases (ie PSA doubling time ≤12 mo). Methods: Men were randomized (1:1) to Arm 1: sipuleucel-T followed by ADT (2 wks after 3rd infusion); or Arm 2: ADT (3 mo lead in) followed by sipuleucel-T. All men had 3 doses of sipuleucel-T and 12 mo of ADT (45 mg leuprolide SQ at 6 mo intervals). The primary endpoint is cellular immune response (ELISPOT to PA2024 [PAP-GMCSF]). Secondary endpoints are humoral and cytokine responses, product parameters and safety. Results: 68 men were randomized. Preliminary data show higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; elevations were seen in TH1 (IFNγ, IL 12), TH2 (IL 4, 5, 10, 13) and TH17 (IL 17) subsets (all P&lt;.05). The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT responses 2 wk after the 3rd sipuleucel-T infusion in Arm 2 vs Arm 1 (40.5 vs 12.8 spots; P=.086), suggesting increased T cell activation in Arm 2. Antigen-specific humoral responses were induced in both arms with no differences yet observed between arms. Sipuleucel-T product parameters were roughly equivalent in both arms with APC activation data indicating a robust prime-boost effect. Conclusions: While confirmation is required, these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation. These data are consistent with preclinical studies showing that ADT enhances T cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity. Further follow up will determine whether augmented immune responses correlate with clinical parameters (eg PSA recurrence). Clinical trial information: NCT01431391.

The Sovereign Citizen Movement and Fitness to Stand Trial

A sociopolitical movement with strong American roots has been making inroads to Canada, as well as other major jurisdictions around the globe. The Sovereign Citizen movement supports a number of unusual beliefs that may be mistaken for psychotic symptomatology. These individuals present with many features which may appear psychotic in nature, including bizarre and paranoid beliefs as well as unusual speech and behavior. Despite this compelling psychotic mimicry, it is the authors’ opinion that the majority are not truly psychotic. Timely recognition and accurate assessment of Sovereign Citizen patients is crucial in order to minimize harm in the form of unnecessary treatment and hospitalization, as well as delays in court proceedings incurred by questions such as whether they are Unfit to Stand Trial. This paper provides a descriptive profile of distinguishing features which may be observed when assessing a Sovereign Citizen patient, with an emphasis on clinical presentation, diagnostic challenges, and management-related issues.