Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme.

BACKGROUNDThe recent failure of checkpoint-blockade therapies for glioblastoma multiforme (GBM) in late-phase clinical trials has directed interest toward adoptive cellular therapies (ACTs). In this open-label, first-in-human trial, we have assessed the safety and therapeutic potential of cytomegalovirus-specific (CMV-specific) ACT in an adjuvant setting for patients with primary GBM, with an ultimate goal to prevent or delay recurrence and prolong overall survival.METHODSTwenty-eight patients with primary GBM were recruited to this prospective study, 25 of whom were treated with in vitro-expanded autologous CMV-specific T cells. Participants were monitored for safety, progression-free survival, overall survival (OS), and immune reconstitution.RESULTSNo participants showed evidence of ACT-related toxicities. Of 25 evaluable participants, 10 were alive at the completion of follow-up, while 5 were disease free. Reconstitution of CMV-specific T cell immunity was evident and CMV-specific ACT may trigger a bystander effect leading to additional T cell responses to nonviral tumor-associated antigens through epitope spreading. Long-term follow-up of participants treated before recurrence showed significantly improved OS when compared with those who progressed before ACT (median 23 months, range 7-65 vs. median 14 months, range 5-19; P = 0.018). Gene expression analysis of the ACT products indicated that a favorable T cell gene signature was associated with improved long-term survival.CONCLUSIONData presented in this study demonstrate that CMV-specific ACT can be safely used as an adjuvant therapy for primary GBM and, if offered before recurrence, this therapy may improve OS of GBM patients.TRIAL REGISTRATIONanzctr.org.au: ACTRN12615000656538.FUNDINGPhilanthropic funding and the National Health and Medical Research Council (Australia).

Fast in vivo detection of myocardial norepinephrine levels in the beating porcine heart.

The sympathetic nervous system modulates cardiac function by controlling key parameters such as chronotropy and inotropy. Sympathetic control of ventricular function occurs through extrinsic innervation arising from the stellate ganglia and thoracic sympathetic chain. In the healthy heart, sympathetic release of norepinephrine (NE) results in positive modulation of chronotropy, inotropy, and dromotropy, significantly increasing cardiac output. However, in the setting of myocardial infarction or injury, sympathetic activation persists, contributing to heart failure and increasing the risk of arrhythmias, including sudden cardiac death. Methodologies for detection of norepinephrine in cardiac tissue are limited. Present techniques rely on microdialysis for analysis by high-performance liquid chromatography coupled to electrochemical detection (HPLC-ED), radioimmunoassay, or other immunoassays, such as enzyme-linked immunosorbent assay (ELISA). Although significant information about the release and action of norepinephrine has been obtained with these methodologies, they are limited in temporal resolution, require large sample volumes, and provide results with a significant delay after sample collection (hours to weeks). In this study, we report a novel approach for measurement of interstitial cardiac norepinephrine, using minimally invasive, electrode-based, fast-scanning cyclic voltammetry (FSCV) applied in a beating porcine heart. The first multispatial and high temporal resolution, multichannel measurements of NE release in vivo are provided. Our data demonstrate rapid changes in interstitial NE profiles with regional differences in response to coronary ischemia, sympathetic nerve stimulation, and alterations in preload/afterload.NEW & NOTEWORTHY Pharmacological, electrical, or surgical regulation of sympathetic neuronal control can be used to modulate cardiac function and treat arrhythmias. However, present methods for monitoring sympathetic release of norepinephrine in the heart are limited in spatial and temporal resolution. Here, we provide for the first time a methodology and demonstration of practice and rapid measures of individualized regional autonomic neurotransmitter levels in a beating heart. We show dynamic, spatially resolved release profiles under normal and pathological conditions.

Reflective imaging improves spatiotemporal resolution and collection efficiency in light sheet microscopy.

Light-sheet fluorescence microscopy (LSFM) enables high-speed, high-resolution, and gentle imaging of live specimens over extended periods. Here we describe a technique that improves the spatiotemporal resolution and collection efficiency of LSFM without modifying the underlying microscope. By imaging samples on reflective coverslips, we enable simultaneous collection of four complementary views in 250 ms, doubling speed and improving information content relative to symmetric dual-view LSFM. We also report a modified deconvolution algorithm that removes associated epifluorescence contamination and fuses all views for resolution recovery. Furthermore, we enhance spatial resolution (to <300 nm in all three dimensions) by applying our method to single-view LSFM, permitting simultaneous acquisition of two high-resolution views otherwise difficult to obtain due to steric constraints at high numerical aperture. We demonstrate the broad applicability of our method in a variety of samples, studying mitochondrial, membrane, Golgi, and microtubule dynamics in cells and calcium activity in nematode embryos.

Preparing the Workforce for Behavioral Health and Primary Care Integration.

PURPOSE: To identify how organizations prepare clinicians to work together to integrate behavioral health and primary care. METHODS: Observational cross-case comparison study of 19 U.S. practices, 11 participating in Advancing Care Together, and 8 from the Integration Workforce Study. Practices varied in size, ownership, geographic location, and experience delivering integrated care. Multidisciplinary teams collected data (field notes from direct practice observations, semistructured interviews, and online diaries as reported by practice leaders) and then analyzed the data using a grounded theory approach. RESULTS: Organizations had difficulty finding clinicians possessing the skills and experience necessary for working in an integrated practice. Practices newer to integration underestimated the time and resources needed to train and organizationally socialize (onboard) new clinicians. Through trial and error, practices learned that clinicians needed relevant training to work effectively as integrated care teams. Training efforts exclusively targeting behavioral health clinicians (BHCs) and new employees were incomplete if primary care clinicians (PCCs) and others in the practice also lacked experience working with BHCs and delivering integrated care. Organizations' methods for addressing employees' need for additional preparation included hiring a consultant to provide training, sending employees to external training programs, hosting residency or practicum training programs, or creating their own internal training program. Onboarding new employees through the development of training manuals; extensive shadowing processes; and protecting time for ongoing education, mentoring, and support opportunities for new and established clinicians and staff were featured in these internal training programs. CONCLUSION: Insufficient training capacity and practical experience opportunities continue to be major barriers to supplying the workforce needed for effective behavioral health and primary care integration. Until the training capacity grows to meet the demand, practices must put forth considerable effort and resources to train their own employees.

Gaps in survey data on cancer in American Indian and Alaska Native populations: examination of US population surveys, 1960-2010.

INTRODUCTION: Population-based data are essential for quantifying the problems and measuring the progress made by comprehensive cancer control programs. However, cancer information specific to the American Indian/Alaska Native (AI/AN) population is not readily available. We identified major population-based surveys conducted in the United States that contain questions related to cancer, documented the AI/AN sample size in these surveys, and identified gaps in the types of cancer-related information these surveys collect. METHODS: We conducted an Internet query of US Department of Health and Human Services agency websites and a Medline search to identify population-based surveys conducted in the United States from 1960 through 2010 that contained information about cancer. We used a data extraction form to collect information about the purpose, sample size, data collection methods, and type of information covered in the surveys. RESULTS: Seventeen survey sources met the inclusion criteria. Information on access to and use of cancer treatment, follow-up care, and barriers to receiving timely and quality care was not consistently collected. Estimates specific to the AI/AN population were often lacking because of inadequate AI/AN sample size. For example, 9 national surveys reviewed reported an AI/AN sample size smaller than 500, and 10 had an AI/AN sample percentage less than 1.5%. CONCLUSION: Continued efforts are needed to increase the overall number of AI/AN participants in these surveys, improve the quality of information on racial/ethnic background, and collect more information on treatment and survivorship.

Characteristics of Northern Plains American Indians seeking substance abuse treatment in an urban, non-tribal clinic: a descriptive study.

Because few data exist on substance abuse rates in American Indian (AI) communities, the Methamphetamine and Other Drug project was developed and implemented by five nodes within the National Institute on Drug Abuse Clinical Trials Network (NIDA CTN). This article presents findings from AI clients in a Northern Plains urban non-Native substance abuse treatment setting. Alcohol and marijuana were used earlier, longer, and by more clients, followed by stimulants and prescription opioids. Most regularly smoked tobacco. Differences in substance use patterns were associated with age of onset and victimization. Age of onset was correlated with victimization, gender, cognitive impairment, and suicidal behavior. Despite considerable health and economic disparities, most clients found support for recovery in relationships and elements of Native culture.