A comprehensive analysis of adverse events in the first 30 days of phase 1 pediatric CAR T-cell trials.

The tremendous success of chimeric antigen receptor (CAR) T cells in children and young adults (CAYAs) with relapsed/refractory B-cell acute lymphoblastic leukemia is tempered by toxicities such as cytokine release syndrome (CRS). Despite expansive information about CRS, profiling of specific end-organ toxicities secondary to CAR T-cell therapy in CAYAs is limited. This retrospective, single-center study sought to characterize end-organ specific adverse events (AEs) experienced by CAYAs during the first 30 days after CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events were retrospectively analyzed for 134 patients enrolled in 1 of 3 phase 1 CAR T-cell trials (NCT01593696, NCT02315612, and NCT03448393), targeting CD19 and/or CD22. A total of 133 patients (99.3%) experienced at least 1 grade ≥3 (≥Gr3) AE across 17 organ systems, of which 75 (4.4%) were considered dose- or treatment-limiting toxicities. Excluding cytopenias, 109 patients (81.3%) experienced a median of 3 ≥Gr3 noncytopenia (NC) AEs. The incidence of ≥Gr3 NC AEs was associated with the development and severity of CRS as well as preinfusion disease burden (≥ 25% marrow blasts). Although those with complete remission trended toward experiencing more ≥Gr3 NC AEs than nonresponders (median, 4 vs 3), nonresponders experiencing CRS (n = 17; 37.8%) had the highest degree of NC AEs across all patients (median, 7 vs 4 in responders experiencing CRS). Greater understanding of these toxicities and the ability to predict which patients may experience more toxicities is critical as the array of CAR T-cell therapies expand. This retrospective study was registered at www.clinicaltrials.gov as NCT03827343.

Cytoreduction and HIPEC for Gastric Carcinomatosis: Multi-institutional Analysis of Two Phase II Clinical Trials.

INTRODUCTION: There are no approved locoregional therapies for peritoneal carcinomatosis from gastric adenocarcinoma (GA). Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) represents a potential treatment for advanced GA with isolated peritoneal metastasis. PATIENTS AND METHODS: Two separate single-institution phase II, single-arm studies evaluating CRS-HIPEC using cisplatin with mitomycin C (NIH: NCT03092518, MDACC: NCT02891447) in patients with GA and confirmed peritoneal metastasis were analyzed. The primary endpoint of each trial was overall survival (OS). Clinical, pathologic, and treatment variables were analyzed for association with outcomes. RESULTS: Over 4 years, 41 patients with peritoneal carcinomatosis from GA underwent CRS-HIPEC. All patients had synchronous peritoneal metastasis and received systemic chemotherapy as front-line therapy. A total of 23 patients also received laparoscopic HIPEC prior to open CRS-HIPEC. The majority (63%, n = 26) were male, and median PCI score at CRS-HIPEC was 2. Median OS was 24.9 months from diagnosis and 14.4 months from CRS-HIPEC. Three-year OS was 25% from diagnosis and 22% from CRS-HIPEC. Median RFS was 7.4 months. The rate of 30-day Clavien-Dindo grade ≥ 3 complications was 32%; specifically, the rate of anastomotic leak was 22%. Multivariable analysis identified the number of pathologically positive lymph nodes as an independent predictor of postoperative OS. CONCLUSIONS: In patients with gastric adenocarcinoma and isolated peritoneal metastasis treated with CRS-HIPEC, 3-year OS was 22% from CRS-HIPEC, and complications were common. The number of pathologic lymph node metastases was inversely correlated with overall survival. Further investigation of CRS-HIPEC for GA should include patient selection based on response to systemic chemotherapy or incorporate novel intraperitoneal treatment strategies.

Practical guidance for new multiple myeloma treatment regimens: A nursing perspective.

As is the case for solid tumors, treatment paradigms have shifted from non-specific chemotherapeutic agents towards novel targeted drugs in the treatment of patients with multiple myeloma (MM). Currently, multiple targeted therapies are available to treat patients augmenting the arsenal of modalities which also includes chemotherapy, immunotherapy, radiation therapy, hematopoietic stem cell transplantation (HSCST) and chimeric antigen T-cell therapy (CAR-T). These novel, targeted agents have dramatically increased optimism for patients, who may now be treated over many years with successive regimens. As fortunate as we are to have these new therapies available for our patients, this advantage is juxtaposed with the challenges involved with delivering them safely. While each class of agents has demonstrated efficacy, in terms of response rates and survival, they also exert class effects which pose risks for toxicity. In addition, newer generation agents within the classes often have slightly different toxicity profiles than did their predecessors. These factors must be addressed, and their risks mitigated by the multidisciplinary team. This review presents a summary of the evolution of drug development for MM. For each targeted agent, the efficacy data from pivotal trials and highlights of the risks that were demonstrated in trials, as well as during post-marketing surveillance, are presented. Specific risks associated with agents within the classes, that are not shared with all new class members, are described. A table presenting these potential risks, with recommended nursing actions to mitigate toxicity, is provided as a quick reference that nurses may use during the planning, and provision, of patient care.

Impact of Prior Treatment on the Efficacy of Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma.

PURPOSE: Adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can mediate durable responses in patients with metastatic melanoma. This retrospective analysis provides long-term follow-up and describes the effect of prior therapy on outcomes after ACT-TIL. PATIENTS AND METHODS: Patients with metastatic melanoma underwent surgical resection of a tumor for generation of TILs and were treated with a lymphodepleting preparative regimen followed by adoptive transfer of TILs and intravenous IL2. Clinical characteristics of enrolled patients and treatment characteristics of TIL infusion products over two decades of ACT were analyzed to identify predictors of objective response. RESULTS: Adoptive transfer of TILs mediated an objective response rate of 56% (108/192) and median melanoma-specific survival of 28.5 months in patients naïve to anti-programmed cell death-1 (PD-1) therapy compared with 24% (8/34) and 11.6 months in patients refractory to anti-PD-1 (aPD-1). Among patients with BRAF V600E/K-mutated disease, prior treatment with targeted molecular therapy was also associated with a decreased response rate (21% vs. 60%) and decreased survival (9.3 vs. 50.7 months) when compared with those patients naïve to targeted therapy. With a median potential follow-up of 89 months, 46 of 48 complete responders in the aPD-1-naïve cohort have ongoing responses after a single treatment and 10-year melanoma-specific survival of 96%. CONCLUSIONS: Patients previously treated with PD-1 or MAPK inhibition are significantly less likely to develop durable objective responses to ACT-TIL. While ACT-TIL is currently being investigated for treatment-refractory patients, it should also be considered as an initial treatment option for eligible patients with metastatic melanoma. See related commentary by Sznol, p. 5156.

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor-transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma.

A deletion variant of epidermal growth factor receptor (EGFRvIII) is a known driver mutation in a subset of primary and secondary glioblastoma multiforme. Adoptive transfer of genetically modified chimeric antigen receptor (CAR) lymphocytes has demonstrated efficacy in hematologic malignancies but is still early in development for solid cancers. The surface expression of the truncated extracellular ligand domain created by EGFRvIII makes it an attractive target for a CAR-based cancer treatment. Patients with recurrent glioblastoma expressing EGFRvIII were enrolled in a dose escalation phase I trial, using a third-generation CAR construct derived from a human antibody. Transduced cells were administered after lymphodepleting chemotherapy and supported posttransfer with intravenous interleukin-2. The dose escalation proceeded at half-log increments from 10 to >10 cells. Primary endpoints were safety and progression-free survival. Eighteen patients were treated with final infusion products ranging from 6.3×10 to 2.6×10 anti-EGFRvIII CAR T cells. Median progression-free survival was 1.3 months (interquartile range: 1.1-1.9), with a single outlier of 12.5 months. Two patients experienced severe hypoxia, including one treatment-related mortality after cell administration at the highest dose level. All patients developed expected transient hematologic toxicities from preparative chemotherapy. Median overall survival was 6.9 months (interquartile range: 2.8-10). Two patients survived over 1 year, and a third patient was alive at 59 months. Persistence of CAR cells correlated with cell dose, but there were no objective responses. Administration of anti-EGFRvIII CAR-transduced T cells did not demonstrate clinically meaningful effect in patients with glioblastoma multiforme in this phase I pilot trial.

Do the psychopathic personality traits of fearless dominance and self-centered impulsivity predict attitudes about and influences on research participation?

Little is known about potential participants' views about research, their willingness to participate in research, and the extent to which they might be susceptible to coercive attempts to compel their participation, particularly among populations at risk for exploitation (e.g., offenders). The extent to which individual differences variables, such as personality constructs (e.g., psychopathic traits), might affect participants' attitudes toward research is also essentially unknown. The present study sought to examine the psychopathy constructs of Fearless Dominance (FD) and Self-Centered Impulsivity (SCI) via the Multidimensional Personality Questionnaire-Brief Form (MPQ-BF) to assess the extent to which these traits predict attitudes towards research and susceptibility to coercion within a diverse criminal justice sample (N = 631). SCI was modestly associated with perceptions that illicit pressures regarding research participation were likely to occur, and participants high in these traits appeared somewhat vulnerable to succumbing to coercive influences. In contrast, FD failed to predict the likelihood that illicit pressures regarding research participation would occur as well as the potential that these pressures would have to impact participants' voluntariness and likelihood of participating. Implications for recruiting potential participants for research in correctional settings are discussed.

Examining attitudes about and influences on research participation among forensic psychiatric inpatients.

Although a growing body of research has examined various types of coercive practices that may occur among psychiatric patients over the years, almost no attention has been given to coercive influences that may occur specifically in the context of recruitment into research projects. Particularly for those who are institutionalized (e.g., in-patient insanity acquittees), there are significant concerns that their autonomous decision-making to consent or not may be significantly impaired due to the highly restrictive and controlled environment in which they live. This exploratory study sought to examine patients' perceptions of coercive influences by presenting them with hypothetical research vignettes regarding possible recruitment into either a biomedical or social-behavioral research project. Among 148 multi-ethnic male and female participants across two facilities, participants reported relatively minimal perceptions that their autonomous decision-making would be impacted or that various potentially coercive factors (e.g., pressures from staff) would impair their free choice to participate (or not) in such research. To the extent that such perceptions of coercion did occur, they were moderately associated with patients' more general personality traits and attitudinal variables, such as alienation and external locus of control. Limitations of this study and their implications for future research are discussed.

Voluntary consent in correctional settings: do offenders feel coerced to participate in research?

A major ethical concern in research with criminal offenders is the potential for abuse due to coercive influences that may adversely affect offenders' capacity to give voluntary consent to participate in research conducted in correctional settings. Despite this concern, to date there have been almost no systematic scientific investigations of the extent to which offenders themselves perceive that coercion occurs in these settings or that it is likely to influence their decisions about research participation. In a sample of over 600 ethnically diverse men and women recruited from various prisons and community corrections facilities in Texas and Florida, we used a vignette-based survey concerning a hypothetical research project to measure and compare offenders' global perceptions of coercive processes, as well as the differential salience and perceived coercive influence of specific factors (e.g., coercion by other inmates, inducements from staff). Somewhat surprisingly, across multiple outcome measures our participants on average reported relatively little in the way of significant coercive influences on their capacity to make voluntary decisions concerning research participation. Implications and directions for future research on coercive influences in offender research are discussed.

Awareness of the Tuskegee syphilis study: impact on offenders' decisions to decline research participation.

Ethnic and racial minorities are often under-represented in research. There is considerable speculation that Blacks, in particular, are discouraged from research participation because of researcher improprieties in the U.S. Public Health Service (USPHS) Syphilis Study at Tuskegee (aka the Tuskegee Syphilis Study [TSS]), a 40-year (1932-1972) study in which investigators withheld medical treatment from African-American men infected with syphilis. We debriefed 281 offenders who declined participation in a research study to assess the extent to which knowledge of the TSS impacted their decisions not to enroll. Relatively few (44/281; 15.6%) reported awareness of the TSS. Half (n = 22) of these "aware" individuals could cite factually accurate information about the TSS, and only four individuals indicated that awareness of TSS had "somewhat" influenced their decision to not participate. Findings suggest that the legacy of the TSS played a relatively minor role in these offenders' decisions to decline research participation.

Formal assessment of voluntariness with a three-part consent process.

Informed consent that is voluntary and made by an individual who is knowledgeable and competent is a foundational requirement for protecting human subjects from harm and exploitation that could result from research participation. In 1974 Miller and Willner proposed a two-part consent process that involved disclosure of information and assessment of comprehension. The authors propose a brief third component to the consent process: assessment of voluntariness. Three steps are involved: generate a list of potential coercive influences on the basis of the research population and the study context, develop a set of questions to assess the presence and intensity of the impact of these influences, and identify alternative courses of action should coercion be identified.

Identifying subtypes among offenders with antisocial personality disorder: a cluster-analytic study.

The question of whether antisocial personality disorder (ASPD) and psychopathy are largely similar or fundamentally different constructs remains unresolved. In the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994), many of the personality features of psychopathy are cast as associated features of ASPD, although the DSM-IV offers no guidance as to how, or the extent to which, these features relate to ASPD. In a sample of 691 offenders who met DSM-IV criteria for ASPD, we used model-based clustering to identify subgroups of individuals with relatively homogeneous profiles on measures of associated features (psychopathic personality traits) and other constructs with potential etiological significance for subtypes of ASPD. Two emergent groups displayed profiles that conformed broadly to theoretical descriptions of primary psychopathy and Karpman's (1941) variant of secondary psychopathy. As expected, a third group (nonpsychopathic ASPD) lacked substantial associated features. A fourth group exhibited elevated psychopathic features as well as a highly fearful temperament, a profile not clearly predicted by extant models. Planned comparisons revealed theoretically informative differences between primary and secondary groups in multiple domains, including self-report measures, passive avoidance learning, clinical ratings, and official records. Our results inform ongoing debates about the overlap between psychopathy and ASPD and raise questions about the wisdom of placing most individuals who habitually violate social norms and laws into a single diagnostic category.

Using the PCL-R to help estimate the validity of two self-report measures of psychopathy with offenders.

Two self-report measures of psychopathy, Levenson's Primary and Secondary Psychopathy scales (LPSP) and the Psychopathic Personality Inventory (PPI), were administered to a large sample of 1,603 offenders. The most widely researched measure of criminal psychopathy, the Hare Psychopathy Checklist-Revised (PCL-R), served as a provisional referent for estimating the construct validity of these self-report measures with offenders. Compared with the LPSP, the PPI displayed higher zero-order correlations with the PCL-R, better convergent and discriminant validity, and more consistent incremental utility in predicting PCL-R scores. Furthermore, using a variant of Westen and Rosenthal's approach to evaluating the construct validity of a new measure, compared with the LPSP, the PPI's pattern of associations with measures of 35 external criterion variables was more similar to the pattern observed for the PCL-R. Results generally provide stronger support for the validity of the PPI than the LPSP in offender populations using the PCL-R as a provisional benchmark, particularly for assessing interpersonal and affective features of psychopathy.

Criminal recidivism among juvenile offenders: testing the incremental and predictive validity of three measures of psychopathic features.

We studied the predictive, comparative, and incremental validity of three measures of psychopathic features (Psychopathy Checklist: Youth Version [PCL:YV]; Antisocial Process Screening Device [APSD]; Childhood Psychopathy Scale [CPS]) vis-à-vis criminal recidivism among 83 delinquent youth within a truly prospective design. Bivariate and multivariate analyses (Cox proportional hazard analyses) showed that of the three measures, the CPS was most consistently related to most types of recidivism in comparison to the other measures. However, incremental validity analyses demonstrated that all of the predictive effects for the measures of psychopathic features disappeared after conceptually relevant covariates (i.e., substance use, conduct disorder, young age, past property crime) were included in multivariate predictive models. Implications for the limits of these measures in applied juvenile justice assessment are discussed.

Self-report measures of child and adolescent psychopathy as predictors of offending in four samples of justice-involved youth.

The authors examined the relation between self-report psychopathy measures and official records of offending in four samples of justice-involved youth (total N = 447). Psychopathy measures included the Antisocial Process Screening Device (APSD) and a modified version of the Childhood Psychopathy Scale (mCPS). Measures of offending included the total number of preadmission arrest charges for three samples (n = 392) and the total number of offenses in the year following release for two samples (n = 138). Neither measure was a strong correlate of preadmission offenses. Although mCPS scores were associated with postrelease offending in one sample, effects for the APSD were observed only when reoffending was conceptualized as a dichotomous variable, indicating a lack of robustness in this association. The findings suggest caution in the use of self-report measures of psychopathic features for decision making with respect to issues of delinquency risk among justice-involved youth.

Unlicensed residential programs: the next challenge in protecting youth.

Over the past decade in the United States, the number of private residential facilities for youth has grown exponentially, and many are neither licensed as mental health programs by states, nor accredited by respected national accrediting organizations. The Alliance for the Safe, Therapeutic and Appropriate use of Residential Treatment (A START) is a multi-disciplinary group of mental health professionals and advocates that formed in response to rising concerns about reports from youth, families and journalists describing mistreatment in a number of the unregulated programs. This article summarizes the information gathered by A START regarding unregulated facilities. It provides an overview of common program features, marketing strategies and transportation options. It describes the range of mistreatment and abuse experienced by youth and families, including harsh discipline, inappropriate seclusion and restraint, substandard psychotherapeutic interventions, medical and nutritional neglect, rights violations and death. It reviews the licensing, regulatory and accrediting mechanisms associated with the protection of youth in residential programs, or the lack thereof. Finally, it outlines policy implications and provides recommendations for the protection of youth and families who pursue residential treatment.

The Self-Report Psychopathy Scale and passive avoidance learning: a validation study of race and gender effects.

The reliability and validity of the Self-Report Psychopathy Scale (SRPS) was examined in a noninstitutionalized offender sample of mixed gender and race. Adequate alpha coefficients were obtained for the total sample and across gender and race. The SRPS was compared to measures of trait anxiety and passive avoidance errors. SRPS total, primary, and secondary scores were positively and significantly correlated with trait anxiety and passive avoidance (commission) errors, but not omission errors. Employing hierarchical regression models, no anxiety, gender, or ethnic effects were found. Intelligence confounded the relationship between psychopathic traits and passive avoidance errors. Findings provide tentative support of the SRPS as a valid measure of psychopathy.

The relationship between psychopathic features, violence and treatment outcome: the comparison of three youth measures of psychopathic features.

Few studies have compared self-report and clinician-administered measures of youth psychopathic features in juvenile-justice settings in terms of antisocial behavior and treatment indices. In a sample of 85 adjudicated delinquents, the predictive validities of the Antisocial Process Screening Device (APSD), the modified Childhood Psychopathy Scale (mCPS), and the Hare Psychopathy Checklist: Youth Version (PCL:YV) were tested. Three indices of institutional antisocial behavior (physical aggression; verbal aggression; administrative infractions) and two indices of treatment progress (time to treatment level promotion; whether treatment levels were dropped) were used as external correlates. The self-report measures (mCPS more so than APSD) were more consistently and strongly related to antisocial behavior and to the days required to progress in treatment than the PCL:YV. The following issues are discussed: (i) implications of the potential impact of measurement format on the understanding and predictive validity of youth psychopathy features and measures; (ii) the differential predictive validity of self-report versus clinician-administered measures; and (iii) the potential practical utility of measures of psychopathic features in youth.