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Atezolizumab plus bevacizumab is a standard of care, first-line therapy for advanced hepatocellular carcinoma (HCC). Myeloid and T regulatory cells are key immunosuppressive cell types within the hepatic tumor microenvironment associated with clinical resistance to atezolizumab and bevacizumab therapy for HCC and overall poor prognosis. Therapeutic targeting of TIGIT, which is highly expressed in these cells, with tiragolumab may overcome the immunosuppressive environment and improve clinical benefit, a hypothesis supported by positive efficacy signals in the Phase Ib/II MORPHEUS-Liver study. This paper describes the rationale and design of IMbrave152/SKYSCRAPER-14, a randomized, double-blind, placebo-controlled Phase III study comparing atezolizumab and bevacizumab with tiragolumab or placebo in patients with HCC and no prior systemic treatment. Clinical Trial Registration: NCT05904886 (ClinicalTrials.gov) Plain Language Summary This research study is designed to test a new treatment combination for liver cancer, specifically for patients whose cancer cannot be removed with surgery or has spread. The treatment involves three medications: atezolizumab, bevacizumab and tiragolumab. Atezolizumab and bevacizumab are already used together as a standard treatment for liver cancer. Tiragolumab is designed to block the TIGIT receptor, which is normally involved in holding back the immune cells that would attack the tumor. Because tiragolumab may restore the immune response against the tumor, adding tiragolumab might make the treatment more effective. The study is being done worldwide and includes patients who have not received any previous systemic treatment for their advanced liver cancer. Patients participating in the study will be randomly placed into two groups. One group will receive the new combination of three medications, while the other group will receive the standard treatment of two medications plus a placebo (a treatment with no active ingredient). The main goal is to see if the new combination helps patients live longer and slows the cancer's growth compared with the standard treatment. Safety and how patients feel during the treatment are also important parts of the study. Tweetable Abstract IMbrave152/SKYSCRAPER-14: New Phase III trial tests atezolizumab, bevacizumab & tiragolumab in advanced HCC, aiming to revolutionize treatment outcomes. #HCCResearch #OncologyInnovation Article highlights Advanced hepatocellular carcinoma treatment Atezolizumab in combination with bevacizumab has become the standard first-line therapy for advanced hepatocellular carcinoma (HCC). The immunosuppressive hepatic tumor microenvironment may limit the clinical activity of this combination in patients with HCC. TIGIT, a protein often found at high levels within these immunosuppressive cells, is a potential therapeutic target to overcome this resistance. Tiragolumab is an agent that inhibits TIGIT, suggesting a possible improvement in clinical outcomes when combined with the existing therapy. IMbrave152/SKYSCRAPER-14 trial rationale The randomized Phase III trial (NCT05904886) is designed to compare the efficacy and safety of the addition of tiragolumab to the current atezolizumab and bevacizumab regimen for HCC. The trial is designed to confirm efficacy signals from the Phase Ib/II MORPHEUS-Liver study, testing the hypothesis that targeting TIGIT with tiragolumab can enhance treatment response. Study design & eligibility Approximately 650 participants with no prior systemic treatment will be assigned to receive either the triple combination of atezolizumab, bevacizumab and tiragolumab or the standard dual therapy plus placebo. Participants will be randomly divided into two groups with stratification based on geographic region, disease progression, α-fetoprotein levels and HCC etiology. Treatment & trial objectives Patients will be administered intravenous doses of the treatment every three weeks, with outcomes measured in terms of progression-free survival and overall survival. Secondary end points include safety, efficacy, pharmacokinetics, immunogenicity and quality-of-life assessments. Preliminary results & safety profile The MORPHEUS-Liver trial indicated improved outcomes with the addition of tiragolumab to the existing atezolizumab and bevacizumab treatment, suggesting a well-tolerated safety profile with manageable adverse events. Conclusions & implications for hepatocellular carcinoma treatment IMbrave152/SKYSCRAPER-14 aims to establish whether the addition of tiragolumab can redefine the standard of care for unresectable HCC. This trial's findings could significantly impact the therapeutic landscape for HCC, addressing a critical unmet medical need [ABSTRACT FROM AUTHOR]

Impulsivity is a behavioral trait that is elevated in many neuropsychiatric disorders. Parkinson's disease (PD) patients can exhibit a specific pattern of reward-seeking impulsive-compulsive behaviors (ICBs), as well as more subtle changes to generalized trait impulsivity. Prior studies in healthy controls (HCs) suggest that trait impulsivity is regulated by D 2/3 autoreceptors in mesocorticolimbic circuits. While altered D 2/3 binding is noted in ICB + PD patients, there is limited prior assessment of the trait impulsivity-D 2/3 relationship in PD, and no prior direct comparison with patterns in HCs. We examined 54 PD (36 M; 18 F) and 31 sex- and age-matched HC (21 M; 10 F) subjects using [ 18 F]fallypride, a high-affinity D 2/3 receptor ligand, to measure striatal and extrastriatal D 2/3 nondisplaceable binding potential (BP ND ). Subcortical and cortical assessment exclusively used ROI or exploratory-voxelwise methods, respectively. All completed the Barratt Impulsiveness Scale, a measure of trait impulsivity. Subcortical ROI analyses indicated a negative relationship between trait impulsivity and D 2/3 BP ND in the ventral striatum and amygdala of HCs but not in PD. By contrast, voxelwise methods demonstrated a positive trait impulsivity-D 2/3 BP ND correlation in ventral frontal olfactocentric-paralimbic cortex of subjects with PD but not HCs. Subscale analysis also highlighted different aspects of impulsivity, with significant interactions between group and motor impulsivity in the ventral striatum, and attentional impulsivity in the amygdala and frontal paralimbic cortex. These results suggest that dopamine functioning in distinct regions of the mesocorticolimbic circuit influence aspects of impulsivity, with the relative importance of regional dopamine functions shifting in the neuropharmacological context of PD. SIGNIFICANCE STATEMENT The biological determinants of impulsivity have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease. This is the first study to evaluate a large cohort of Parkinson's disease patients and age-matched healthy controls with a measure of trait impulsivity and concurrent [ 18 F]fallypride PET, a method that allows quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in the trait impulsivity-dopamine relationship, including (1) loss of subcortical relationships present in the healthy brain and (2) emergence of a new relationship in a limbic cortical area. This illustrates the loss of mechanisms of behavioral regulation present in the healthy brain while suggesting a potential compensatory response and target for future investigation., (Copyright © 2023 the authors.)

Objective: To identify factors associated with job satisfaction and retention, we surveyed a large cohort of clinical research coordinators (CRCs). In recent years, the clinical research coordinator has changed from a semi-permanent role to one that has a high turnover rate. The CRCs are integral to clinical research and instability in this role can cause patient stress and increase the burden on clinical teams through unnecessary delegation of resources toward hiring and retraining new talent. The cultural shift toward CRCs as a temporary position may be driven by the perspective that the role positions an individual for other health care careers, but understanding what influences low retention rates are necessary., Methods: A survey containing 13 multiple choice or open-ended and 32 Likert scale questions was distributed to previous and current CRCs using REDCap. The questionnaires were self-administered and completed over a 12-month period between October 11, 2017, and September 16, 2018., Results: A total of 85 CRCs completed the study. From the 32 potential predictors of retention, we investigated 9 significant predictors: salary, work setting, understanding the role, level of CRC, understanding protocol development, actively engaged principal investigator (PI), having a collaborative role with PI, feeling respected by PI, and having a close relationship with PI. Adequate salary, greater respect, collaboration, and engagement from the PI were significantly associated with higher retention. Surprisingly, greater workload and lack of opportunity for professional growth were not associated with retention., Conclusion: The CRCs who feel respected and engaged by the PI and are adequately compensated are more likely to have higher job satisfaction and retention., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D 2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D 2 -like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D 2/3 receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with ( n = 17) and without ( n = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [ 18 F]fallypride, a high affinity D 2 -like receptor ligand that can measure striatal and extrastriatal D 2/3 nondisplaceable binding potential (BP ND ). Striatal differences between ICB+/ICB- patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BP ND In this group, self-reported severity of ICB symptoms positively correlated with midbrain D 2/3 receptor BP ND Group differences in regional D 2/3 BP ND relationships were also notable: ICB+ (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BP ND s. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D 2/3 expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response. SIGNIFICANCE STATEMENT The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D 2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D 2/3 receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions., (Copyright © 2018 the authors 0270-6474/18/383231-10$15.00/0.)