Combined OX40 Agonist and PD-1 Inhibitor Immunotherapy Improves the Efficacy of Vascular Targeted Photodynamic Therapy in a Urothelial Tumor Model.

PURPOSE: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. EXPERIMENTAL DESIGN: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. RESULTS: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. CONCLUSIONS: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.

Comparing two approaches for studying symptom clusters: factor analysis and structural equation modeling.

PURPOSE: We investigated alternative ways of understanding the relationships among co-occurring symptoms in individuals with advanced cancer. While factor analysis has been increasingly used to identify symptom clusters, we argue that structural equation modeling is more appropriate because it permits investigating and testing of a greater variety of potential causal interconnections among symptoms. METHODS: The sample included 82 palliative patients whose symptom scores were obtained from a database of the Capital Health Regional Palliative Care Program in Alberta, Canada, from 1995 to 2000. Data were analyzed using exploratory factor analysis (SPSS PASW 18.0.0, 2009) and compared to previous results obtained using structural equation modeling (LISREL 8.8, 2009). RESULTS: Factor models failed to fit the covariance data, even though a single factor "explained" nearly half the variance. Structural equation models fit the data and explained an average of 66 % of the variance in the dependent latent variables. The factor analytic estimates were not clinically useful because they failed to correspond to the reasonable underlying common causes of the symptoms. Structural equation models, on the other hand, incorporated and tested specific clinically anticipated causal relationships among the symptoms and changes in those symptoms over time. CONCLUSION: We used factor analysis to reanalyze data previously investigated with structural equation modeling and found that the structural equation models fit the data better and were more interpretable from a clinical perspective. We caution that factor models should be tested for consistency with the data and critically examined for inconsistencies with clinical understandings of the causal foundations of coordinated symptoms.

Initiation of Buprenorphine Treatment of Opioid Use Disorder in Pediatric Emergency Departments.

Pediatric emergency departments (EDs) in the United States are facing a rise in the number of children and adolescents who present with opioid use disorder (OUD), often driven by illicitly manufactured fentanyl. Medication treatment of pediatric OUD in the ED setting is often limited to symptomatic treatment of opioid withdrawal. Pediatric patients are rarely offered medications for OUD, especially in the ED setting. Buprenorphine is a partial opioid agonist that is Food and Drug Administration-approved for the treatment of OUD in patients aged 16 years and older. Adult studies have demonstrated that ED initiation of medication for OUD such as buprenorphine is feasible, safely treats withdrawal symptoms, and can improve patient compliance with outpatient follow-up. However, initiation of buprenorphine in the ED has not been well-studied in the pediatric population. We present 2 cases of adolescent patients, a 16-year-old male and 17-year-old female, who presented to the ED with opioid withdrawal. They were both diagnosed with severe OUD because of their use of counterfeit pills containing fentanyl. Both patients were successfully started on buprenorphine/naloxone in the pediatric ED before transitioning to an outpatient addiction clinic for continued treatment. The case series demonstrates the feasibility of ED-based buprenorphine initiation for adolescents, an important and timely intervention for adolescents with OUD.

Comparative study of immune response to local tumor destruction modalities in a murine breast cancer model.

Introduction: Immunotherapy is revolutionizing the management of multiple cancer types. However, only a subset of patients responds to immunotherapy. One mechanism of resistance is the absence of immune infiltrates within the tumor. In situ vaccine with local means of tumor destruction that can induce immunogenic cell death have been shown to enhance tumor T cell infiltration and increase efficacy of immune checkpoint blockade. Methods: Here, we compare three different forms of localize tumor destruction therapies: radiation therapy (RT), vascular targeted photodynamic therapy (VTP) and cryoablation (Cryo), which are known to induce immunogenic cell death, with their ability to induce local and systemic immune responses in a mouse 4T1 breast cancer model. The effects of combining RT, VTP, Cryo with anti-PD1 was also assessed. Results: We observed that RT, VTP and Cryo significantly delayed tumor growth and extended overall survival. In addition, they also induced regression of non-treated distant tumors in a bilateral model suggesting a systemic immune response. Flow cytometry showed that VTP and Cryo are associated with a reduction in CD11b+ myeloid cells (granulocytes, monocytes, and macrophages) in tumor and periphery. An increase in CD8+ T cell infiltration into tumors was observed only in the RT group. VTP and Cryo were associated with an increase in CD4+ and CD8+ cells in the periphery. Conclusion: These data suggest that cell death induced by VTP and Cryo elicit similar immune responses that differ from local RT.

Parents' and children's intolerance of uncertainty and their reactions to COVID-19: A story of remarkable similarity.

The COVID-19 viral outbreak is a one in 100 year public health crisis. In addition to the stunning morbidity and mortality rates related to infection, multiple psychiatric sequelae erupted. Unfortunately, children and adolescents are neither immune to infection nor to the emotional consequences associated with the pandemic. Not surprisingly, the field's understanding of the psychological consequences of the viral outbreak are nascent. Consequently, this study examines the relationship between parents' and children's intolerance of uncertainty (IU) and their reactions to COVID-19. Seventy-three parents and 62 children participated in the on-line survey utilizing innovative measures of IU and COVID-19- related thoughts/behaviors. The results revealed remarkable similarities in parents' and children's responses. Parents' and children's reports of the impact of COVID on their lives were highly correlated (r = .53, df = 60, p < .001). Parents' perceptions of children's COVID-19 thoughts and behaviors were strongly aligned with the youths' self-report of their COVID reactions (r = .69, df = 60, p < .001) as well as the appraisal of the virus' impact on their lives (r = .-.42, df = 60, p < .001). Finally, children's reports of their COVID-19 related thoughts and behaviors were significantly linked to their IU (r = .60, df = 60, p < .001). Methodological limitations notwithstanding, the study's findings provide compelling implications for the conceptualization, assessment, and treatment of emotional distress in the peri- and post-pandemic periods.

Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer.

PURPOSE: We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric cancer in conjunction with outcomes from an independent Memorial Sloan Kettering (MSK) cohort. PATIENTS AND METHODS: The significance of pretreatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was evaluated to identify prognostic biomarkers and mechanisms of resistance in patients treated on-protocol with PTC. Additional prognostic features were evaluated using a multivariable Cox regression model of trastuzumab-treated MSK patients (n = 226). Single-cell RNA sequencing (scRNA-seq) data from MSK and Samsung were evaluated for mechanisms of therapy resistance. RESULTS: 89Zr-trastuzumab PET, scRNA-seq, and serial ctDNA with CT imaging identified how pre-treatment intrapatient genomic heterogeneity contributes to inferior progression-free survival (PFS). We demonstrated that the presence of intensely avid lesions by 89Zr-trastuzumab PET declines in tumor-matched ctDNA by 3 weeks, and clearance of tumor-matched ctDNA by 9 weeks were minimally invasive biomarkers of durable PFS. Paired pre- and on-treatment scRNA-seq identified rapid clearance of HER2-expressing tumor clones with expansion of clones expressing a transcriptional resistance program, which was associated with MT1H, MT1E, MT2A, and MSMB expression. Among trastuzumab-treated patients at MSK, ERBB2 amplification was associated with improved PFS, while alterations in MYC and CDKN2A/B were associated with inferior PFS. CONCLUSIONS: These findings highlight the clinical relevance of identifying baseline intrapatient heterogeneity and serial ctDNA monitoring of HER2-positive esophagogastric cancer patients to identify early evidence of treatment resistance, which could guide proactive therapy escalation or deescalation.

The bed nucleus of the stria terminalis in threat detection: task choice and rodent experience.

Behavioural reactivity to potential threat is used to experimentally refine models of anxiety symptoms in rodents. We present a short review of the literature tying the most commonly used tasks to model anxiety symptoms to functional recruitment of bed nucleus of the stria terminalis circuits (BNST). Using a review of studies that investigated the role of the BNST in anxiety-like behaviour in rodents, we flag the certain challenges for the field. These stem from inconsistent methods of reporting the neuroanatomical BNST subregions and the interpretations of specific behaviour across a wide variety of tasks as 'anxiety-like'. Finally, to assist in interpretation of the findings, we discuss the potential interactions between typically used 'anxiety' tasks of innate behaviour that are potentially modulated by the social and individual experience of the animal.

FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.

Influence of the Amount of Carbon during the Synthesis of LaFe0.8Co0.2O3/Carbon Hybrid Material in Oxygen Evolution Reaction.

The oxygen evolution reaction (OER) and the hydrogen evolution reaction occurred at the anode and cathode, which depends on the electronic structure, morphology, electrochemically active surface area, and charge-transfer resistance of the electrocatalyst. Transition metals like cobalt, nickel, and iron have better OER and oxygen reduction reaction activities. At the same time, transition-metal oxide/carbon hybrid has several applications in electrochemical energy conversion reactions. The rich catalytic site of transition metals and the excellent conductivity of carbon material make these materials as a hopeful electrocatalyst in OER. Carbon-incorporated LaFe0.8Co0.2O3 was prepared by a simple solution combustion method for the development of the best performance of the electrocatalyst. The catalyst can deliver 10 mA/cm2 current density at an overpotential of 410 mV with better catalytic stability. The introduction of carbon material improves the dispersion ability of the catalyst and the electrical conductivity. The Tafel slope and onset potential of the best catalyst are 49.1 mV/dec and 1.55 V, respectively.

Positron Emission Tomography/Computed Tomography with Gallium-68-labeled Prostate-specific Membrane Antigen Detects Relapse After Vascular-targeted Photodynamic Therapy in a Prostate Cancer Model.

BACKGROUND: Evaluating the efficacy of focal therapy for prostate cancer is limited by current approaches and may be improved with biological imaging techniques. OBJECTIVE: We assessed whether positron emission tomography/computed tomography with gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) can be used to predict relapse after vascular-targeted photodynamic therapy (VTP). DESIGN, SETTING, AND PARTICIPANTS: A total of 1×106 LNCaP cells were grafted subcutaneously in the flanks of 6-8-wk-old SCID mice. Of 24 mice with measurable tumors 6 wk after tumor implantation, 20 were treated with VTP (150mW/cm2) to ablate the tumors. Blood prostate-specific antigen (PSA) levels were assessed, and 68Ga-PSMA PET/CT images were performed 1 d before VTP and 1 and 4 wk after. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Local tumor relapse was evaluated by histology, and tumors were analyzed by prostate-specific membrane antigen (PSMA) and PSA immunohistochemistry. T tests and Kruskal-Wallis tests were used to determine significance. RESULTS AND LIMITATIONS: Four weeks after VTP, 11 (65%) mice had complete responses and six (35%) had tumor relapses confirmed by histology (hematoxylin and eosin, and PSMA immunohistochemistry). All mice with local relapse had positive 68Ga-PSMA PET/CT findings 4 wk after VTP; all complete responders did not. One week after VTP, the relapse detection sensitivity of 68Ga-PSMA PET/CT was 75%, whereas the sensitivity of PSA was only 33%. Compared with controls, relapsed tumors had a three-fold reduction in the number of cells with strong PSA staining by immunohistochemistry (1.5% vs 4.5%; p=0.01). CONCLUSIONS: In a preclinical prostate cancer model, we show that 68Ga-PSMA PET/CT can identify and predict relapse earlier than blood PSA level. These findings support further testing in clinical trials. PATIENT SUMMARY: Positron emission tomography/computed tomography with gallium-68-labeled prostate-specific membrane antigen may be used to follow and evaluate treatment outcomes in men who receive focal therapy for prostate cancer.

Transitions of male partners of women with breast cancer: hope, guilt, and quality of life.

PURPOSE/OBJECTIVES: To (a) describe the types of transitions experienced by male spousal caregivers of women with breast cancer and the strategies used by male spouses to deal with these transitions and (b) examine factors related to their quality of life, including demographic variables, self-efficacy, caregiver guilt, hope, the quality of life of their partner with breast cancer, and transitions. DESIGN: Cross-sectional, transformational, mixed-methods approach. SETTING: Participants' homes. SAMPLE: 105 dyads of male spouses and their female partners diagnosed with stages I-III breast cancer. METHODS: 600 surveys were mailed to women with breast cancer and their male partners. Significant variables were entered into a multivariate model. MAIN RESEARCH VARIABLE: Male caregiver quality of life. FINDINGS: The quality of life of male spouse participants was positively influenced by hope (p < 0.01). It was negatively influenced by caregiver guilt scores (p < 0.01) and the method of dealing with their transitions by "doing what needs to be done" (p = 0.04). CONCLUSIONS: The male caregivers with higher quality-of-life scores reported higher hope and lower caregiver guilt scores. They reported lower quality-of-life scores if they dealt with transitions by "doing what needs to be done."
 IMPLICATIONS FOR NURSING: Strategies to support male spouses of women with breast cancer should involve ways to foster hope, reduce feelings of guilt, and encourage male caregivers to engage more in supporting their spouses.