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Integrating behavioral health (BH) and primary care is an important strategy to improve health behaviors, mental health, and substance misuse, particularly at community health centers (CHCs) where disease burden is high and access to mental health services is low. Components of different integrated BH models are often combined in practice. It is unknown which components distinguish developing versus established integrated BH programs.A survey was mailed to 128 CHCs in 10 Midwestern states in 2016. Generalized estimating equation models were used to assess associations between program characteristics and stage of integration implementation (precontemplation, contemplation, preparation, action, or maintenance). Content analysis of open-ended responses identified integration barriers.Response rate was 60% (CHCs have implemented many foundational components of integrated BH. Future work should address barriers to integration and racial disparities in access to integrated BH. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

RATIONALE, AIMS AND OBJECTIVES: To examine factors related to recruitment of eligible patients and retention of enrolled patients in diabetes group visits (GVs).As part of a cluster randomized trial, 272 eligible patients were contacted and 75 patients were eventually enrolled in GVs at six community health centers (CHC). Fisher's exact tests and χIn terms of recruitment and enrollment analysis, patients who received in-person contact only and both phone and in-person contact comprised a greater fraction of the enrolled than unenrolled group, while those who received phone only and both phone and mail comprised a smaller fraction of the enrolled than unenrolled group (p = 0.004). In terms of retention analysis, 70 of the 75 enrolled patients attended at least one GV (93%). The average number of GVs was 3.2 out of 6 visits. Higher GV attendance was associated with lower baseline diabetes empowerment (p = 0.03). Patients' most common self-reported motivating factors to attend GVs were to learn more about diabetes, gain improved blood glucose control and find support from peers.In-person recruitment for GVs at CHCs was more effective than recruitment by telephone/mail. Patients who felt less empowered to manage their diabetes were most motivated to attend GVs. These findings could help clinicians implement targeted recruitment of patient populations who are more likely to attend diabetes GVs and tailor self-management education interventions to their patient populations, particularly for underserved patients who face disparate clinical outcomes.

Triple-negative breast cancer (TNBC) is a leading cause of breast cancer death and is often associated with BRCA1 and BRCA2 mutation. Due to the lack of validated target molecules, no targeted therapy for TNBC is approved. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells, and cancer stem cells in several types of solid cancers, including breast cancer. Here, we report evidence supporting the idea that TF is a surface target in TNBC. We used in vitro cancer lines and in vivo tumor xenografts in mice, all with BRCA1 or BRCA2 mutations, derived from patients' tumors. We showed that TF is overexpressed on TNBC cells and tumor neovasculature in 50% to 85% of TNBC patients (n = 161) and in TNBC cell line–derived xenografts (CDX) and patient-derived xenografts (PDX) from mice, but was not detected in adjacent normal breast tissue. We then describe the development of a second-generation TF-targeting immunoconjugate (called L-ICON1, for lighter or light chain ICON) with improved efficacy and safety profiles compared with the original ICON. We showed that L-ICON1 kills TNBC cells in vitro via antibody-dependent cell-mediated cytotoxicity and can be used to treat human and murine TNBC CDX as well as PDX in vivo in orthotopic mouse models. Thus, TF could be a useful target for the development of immunotherapeutics for TNBC patients, with or without BRCA1 and BRCA2 mutations. Cancer Immunol Res; 6(6); 671–84. ©2018 AACR.

S1. Tissue factor expression on TNBC and non-TNBC lines with BRCA1/2-wild type or mutation by flow cytometry assay. S2. TF expression is detected on the TNBC cancer cells and tumor vascular endothelial cells, but not on adjacent normal tissues, on TNBC CDX and PDX tumors. S3. Immunohistochemical (IHC) staining for TF and CD31 expression on paraffin-embedded whole TNBC tissues and tissue-microarray slides (TMA). S4. Schematic structures of tissue factor-targeting second-generation ICONs (murine and human L-ICON1s) and their binding activities to human and murine breast cancer cells. S5. Coagulation activities of L-ICON1 and ICON determined by Factor VII Human Chromogenic Activity Assay. S6. Generation of a murine breast cancer line 4T1 stably expressing luciferase (Luc) and green fluorescent protein (GFP) and an orthotopic mouse model of murine TNBC. Table S1. Coagulation activities (IU/ml, mean {plus minus} SD) of L-ICON1, ICON(WT) and ICON(K341A). S2. Protein concentrations of L-ICON1 and ICON in vitro in 4-day cell culture serum free medium of adenoviral vector-infected human TNBC MDA-MB231 line and in vivo in mouse plasma two days after last intratumoral injection of Ad vectors in an orthotopic SCID mouse model of human MDA-MB-231 tumor xenograft.

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Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent.Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer.Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR.

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Depression is most often treated by primary care providers (PCPs), but low self-efficacy in caring for depression may impede adequate management. We aimed to identify which elements of integrated behavioral health (BH) were associated with greater confidence among PCPs in identifying and managing depression.Mailed cross-sectional surveys in 2016.BH leaders and PCPs caring for adult patients at community health centers (CHCs) in 10 midwestern states.Survey items asked about depression screening, systems to support care, availability and integration of BH, and PCP attitudes and experiences. PCPs rated their confidence in diagnosing, assessing severity, providing counseling, and prescribing medication for depression on a 5-point scale. An overall confidence score was calculated (range 4 (low) to 20 (high)). Multilevel linear mixed models were used to identify factors associated with confidence.Response rates were 60% (N=77/128) and 52% (N=538/1039) for BH leaders and PCPs, respectively. Mean overall confidence score was 15.25±2.36. Confidence was higher among PCPs who were satisfied with the accuracy of depression screening (0.38, p=0.01), worked at CHCs with depression tracking systems (0.48, p=0.045), had access to patients' BH treatment plans (1.59, p=0.002), and cared for more patients with depression (0.29, p=0.003). PCPs who reported their CHC had a sufficient number of psychiatrists were more confident diagnosing depression (0.20, p=0.02) and assessing severity (0.24, p=0.03). Confidence in prescribing was lower at CHCs with more patients living below poverty (-0.66, p0.001). Confidence in diagnosing was lower at CHCs with more Black/African American patients (-0.20, p=0.03).PCPs who had access to BH treatment plans, a system for tracking patients with depression, screening protocols, and a sufficient number of psychiatrists were more confident identifying and managing depression. Efforts are needed to address disparities and support PCPs caring for vulnerable patients with depression.

Key Points AHR directly regulates a wide range of genes in NK cells, including those involved in cell signaling, oxidative stress, and metabolism.Knowing of the repertoire of genes regulated by AHR may help us better understand NK-cell dysfunction mediated by AHR ligands in cancer., Visual Abstract, The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular processes in cancer and immunity, including innate immune cell development and effector function. However, the transcriptional repertoire through which AHR mediates these effects remains largely unexplored. To elucidate the transcriptional elements directly regulated by AHR in natural killer (NK) cells, we performed RNA and chromatin immunoprecipitation sequencing on NK cells exposed to AHR agonist or antagonist. We show that mature peripheral blood NK cells lack AHR, but its expression is induced by Stat3 during interleukin-21–driven activation and proliferation, coincident with increased NCAM1 (CD56) expression resulting in a CD56bright phenotype. Compared with control conditions, NK cells expanded in the presence of the AHR antagonist, StemRegenin-1, were unaffected in proliferation or cytotoxicity, had no increase in NCAM1 transcription, and maintained the CD56dim phenotype. However, it showed altered expression of 1004 genes including those strongly associated with signaling pathways. In contrast, NK cells expanded in the presence of the AHR agonist, kynurenine, showed decreased cytotoxicity and altered expression of 97 genes including those strongly associated with oxidative stress and cellular metabolism. By overlaying these differentially expressed genes with AHR chromatin binding, we identified 160 genes directly regulated by AHR, including hallmark AHR targets AHRR and CYP1B1 and known regulators of phenotype, development, metabolism, and function such as NCAM1, KIT, NQO1, and TXN. In summary, we define the AHR transcriptome in NK cells, propose a model of AHR and Stat3 coregulation, and identify potential pathways that may be targeted to overcome AHR-mediated immune suppression.

Diabetes group visits (GVs) have been shown to improve glycemic control, enrich patient self-care, and decrease healthcare utilization among patients with type 2 diabetes mellitus (T2DM). While telehealth has become routine, virtual GVs remain understudied, especially in federally qualified health centers (FQHCs). We conducted a 5-year cluster randomized trial with a waitlist control group to test the impact of diabetes GVs on patients' outcomes in Midwestern FQHCs. Due to COVID-19, the 6 waitlisted FQHCs adapted to virtual GVs. FQHC staff were provided training and support to implement virtual GVs. The GV intervention included 6 monthly 1–1.5-h long education sessions and appointments with a primary care provider. We measured staff perspectives and satisfaction via GV session logs, monthly webinars, and staff surveys and interviews. Adaptations for implementation of virtual GV included: additional staff training, video conferencing platform use, decreased session length and group size, and adjusting study materials, activities, and provider appointments. Sites enrolled a total of 48 adults with T2DM for virtual GVs. Most FQHCs were urban and all FQHCs predominantly had patients on public insurance. Patients attended 2.1 ± 2.2 GVs across sites on average. Thirty-four patients (71%) attended one or more virtual GVs. The average GV lasted 79.4 min. Barriers to virtual GVs included patient technology issues and access, patient recruitment and enrollment, and limited staff availability. Virtual GV facilitators included providing tablets, internet access from the clinic, and technical support. Staff reported spending on average 4.9 h/week planning and implementing GVs (SD = 5.9). On average, 6 staff from each FQHC participated in GV training and 1.2 staff reported past GV experience. All staff had worked at least 1 year at their FQHC and most reported multiple years of experience caring for patients with T2DM. Staff-perceived virtual GV benefits included: empowered patients to manage their diabetes, provided patients with social support and frequent contact with providers, improved relationships with patients, increased team collaboration, and better patient engagement and care-coordination. Future studies and health centers can incorporate these findings to implement virtual diabetes GVs and promote accessible diabetes care.

Background Diabetes group visits (GVs) are a promising way to deliver high quality care but have been understudied in community health centers (CHCs), across multiple sites, or with a focus on patient-centered outcomes. Methods We trained staff and healthcare providers from six CHCs across five Midwestern states to implement a 6-month GV program at their sites. We assessed the impact of diabetes GVs on patient clinical and self-reported outcomes and processes of care compared to patients receiving usual care at these sites during the same period using a prospective controlled study design. Results CHCs enrolled 51 adult patients with diabetes with glycosylated hemoglobin (A1C) ≥ 8% for the GV intervention and conducted chart review of 72 patients receiving usual care. We analyzed A1C at baseline, 6, and 12 months, low-density lipoproteins (LDL), blood pressure, and patient-reported outcomes. GV patients had a larger decrease in A1C from baseline to 6 months (-1.04%, 95% CI: -1.64, -0.44) and 12 months (-1.76, 95% CI: -2.44, -1.07) compared to usual care; there was no change in blood pressure or LDL. GV patients had higher odds of receiving a flu vaccination, foot exam, eye exam, and lipid panel in the past year compared to usual care but not a dental exam, urine microalbumin test, or blood pressure check. For GV patients, diabetes distress decreased, diabetes-related quality of life improved, and self-reported frequency of healthy eating and checking blood sugar increased from baseline to 6 months, but there was no change in exercise or medication adherence. Conclusions A diabetes GV intervention improved blood glucose levels, self-care behaviors, diabetes distress, and processes of care among adults with elevated A1Cs compared to patients receiving usual care. Future studies are needed to assess the sustainability of clinical improvements and costs of the GV model in CHCs.

BACKGROUND: The 2016 American Diabetes Association position statement emphasized that psychosocial and medical care should be integrated and provided to all people with diabetes. OBJECTIVE: To determine whether better integration of diabetes and depression care is associated with better glycemic control. DESIGN: Cross-sectional surveys of Midwestern federally qualified health center (FQHC) leaders and primary care providers (PCPs) in 2016. Responses were linked to FQHC-level data on the percentage of patients with uncontrolled diabetes (glycated hemoglobin ≥ 9%; 75 mmol/mol). PARTICIPANTS: Midwest Clinicians’ Network–affiliated FQHC leaders, and PCPs at the FQHCs. MAIN MEASURES: Multilevel models were used to determine associations between the percentage of patients with uncontrolled diabetes and FQHC and PCP characteristics; presence of diabetes and behavioral health care services; and PCPs’ perception of the stage of integration between diabetes and depression care services based on the transtheoretical model (i.e., pre-contemplation, contemplation, preparation, action, or maintenance). KEY RESULTS: Response rates were 60% for the FQHC survey (N = 77) and 55% for the PCP survey (N = 538). In adjusted models, FQHCs in which PCPs perceived a higher stage of integration between diabetes and depression care had 3% fewer patients with uncontrolled diabetes per 1-level increase in integration stage (p = 0.01); on-site diabetes self-management education was associated with 7% fewer patients with uncontrolled diabetes (p < 0.01). CONCLUSIONS: At Midwestern FQHCs, a higher stage of perceived integration of diabetes and depression care was associated with better FQHC-level glycemic control. Future studies are needed to elucidate what defines integration of diabetes and depression care services. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-020-06585-5.

Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ-aminobutyric acid (GABA) inhibition. In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad-spectrum seizure protection. CBM's preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.

Background: Diabetes is a chronic disease requiring medical treatment and self-management. Group visits (GVs) are one way to deliver care and provide self-management education to patients with diabetes. While studies have examined the impact of GVs on clinical outcomes, no study to date has examined factors related to recruitment and retention of patients in diabetes GVs. Methods: We examined the association between patient characteristics and GV attendance of 83 patients enrolled in a GV intervention in six Midwestern FQHCs in an ongoing cluster randomized trial. Patients with uncontrolled type 2 diabetes (A1C >8%) who were seen in clinic in the past year were eligible. Linear mixed models were used to evaluate associations between retention of patients and race, language, comorbidities burden, diabetes empowerment score, diabetes distress score, diabetes social support, and duration of diagnosis. A Chi-squared analysis was performed to compare enrolled and unenrolled patients and test for association with patient recruitment method. Results: Of 280 eligible patients reached by FQHCs, 44% (24/55) of patients contacted in person were recruited into the study, compared to 25% (56/225) of those contacted by telephone and/or mail (P=0.006). In the multivariate analysis, patients with more GV attendance were associated with higher diabetes empowerment score (P=0.03) and likely heavier comorbidities burden (P=0.08). Conclusion: In-person recruitment for group visits was more effective than recruitment by telephone or mail. Patients with more comorbidities and those who felt less empowered to manage their diabetes at baseline were most motivated to attend GVs, suggesting that patients with multiple chronic conditions who need more support in disease management may be most interested in receiving care in a group setting. This finding may be especially important for FQHC providers taking care of underserved populations who face greater barriers to self-management in traditional care settings. Disclosure A.G. Naik: None. E.M. Staab: None. J. Li: None. W. Wan: None. C.T. Schaefer: None. A. Campbell: None. M.T. Quinn: None. A.A. Baig: None. Funding Office of Minority Health (1 CPIMP171145-01-00)

Expanding access to addiction screening and treatment in primary care, particularly in underserved communities, is a key part of the fight against the opioid epidemic. This study explored correlates of addiction treatment capacity in federally qualified health centers participating in the Midwest Clinicians' Network (MWCN).Two surveys were fielded to 132 MWCN health centers: the Health Center Survey and the Behavioral Health and Diabetes Provider Survey. A total of 77 centers and 515 primary care clinicians, respectively, responded to the surveys. Data were combined with data from the 2016 Uniform Data System and information about receipt of targeted Health Resources and Services Administration (HRSA) grant funding for addiction treatment capacity. Multivariable models examined associations between Medicaid reimbursement for addiction services, HRSA targeted grant funding, and different types of on-site addiction treatment capacity: psychiatrist and certified addiction counselor staffing, addiction counseling services, and medication-assisted treatment (MAT) for opioid addiction.Health centers that received Medicaid behavioral health reimbursement were five times as likely as those that did not to offer addiction counseling and to employ certified addiction counselors. Health centers that received targeted HRSA funding for addiction services were more than 20 times as likely as those that did not to provide MAT and more than three times as likely to employ psychiatrists. Training needs and privacy protections on data related to addiction treatment were cited as barriers to building addiction treatment capacity.Medicaid funding and targeted grant funding were associated with addiction treatment capacity in health centers.

Here, we review the case of a 26 1/7 weeks' gestation premature female infant born to a mother who intentionally ingested a large quantity of Tylenol, aspirin, quetiapine, and prenatal vitamins. The neonate subsequently had markedly elevated levels of both Tylenol and aspirin when checked on the first day of life. While overall clinically stable, the neonate did demonstrate coagulopathy as evidenced by abnormal coagulation studies. Both poison control and a pediatric gastroenterologist/hepatologist were consulted. She successfully tolerated a course of N-acetylcysteine; her subsequent Tylenol level was markedly decreased and the neonate exhibited no further effects of toxicity. The salicylate level decreased on its own accord. To our knowledge, this is the first report of a neonate at 26 weeks' gestation that has been successfully managed for supratherapeutic concentrations of acetaminophen and acetylsalicylic acid secondary to maternal ingestion. While rare, this case may serve as a reference for the effectiveness of N-acetylcysteine in premature infants in such instances.

Triple-negative breast cancer (TNBC) is a leading cause of breast cancer death and is often associated with BRCA1 and BRCA2 mutation. Due to the lack of validated target molecules, no targeted therapy for TNBC is approved. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells, and cancer stem cells in several types of solid cancers, including breast cancer. Here, we report evidence supporting the idea that TF is a surface target in TNBC. We used in vitro cancer lines and in vivo tumor xenografts in mice, all with BRCA1 or BRCA2 mutations, derived from patients' tumors. We showed that TF is overexpressed on TNBC cells and tumor neovasculature in 50% to 85% of TNBC patients (n = 161) and in TNBC cell line–derived xenografts (CDX) and patient-derived xenografts (PDX) from mice, but was not detected in adjacent normal breast tissue. We then describe the development of a second-generation TF-targeting immunoconjugate (called L-ICON1, for lighter or light chain ICON) with improved efficacy and safety profiles compared with the original ICON. We showed that L-ICON1 kills TNBC cells in vitro via antibody-dependent cell-mediated cytotoxicity and can be used to treat human and murine TNBC CDX as well as PDX in vivo in orthotopic mouse models. Thus, TF could be a useful target for the development of immunotherapeutics for TNBC patients, with or without BRCA1 and BRCA2 mutations. Cancer Immunol Res; 6(6); 671–84. ©2018 AACR.

This article discusses development and testing of the Provider and Staff Perceptions of Integrated Care Survey, a 21-item questionnaire, informed by Singer and colleagues’ seven-construct framework. Questionnaires were sent to 2,936 providers and staff at 100 federally qualified health centers and other safety net clinics in 10 Midwestern U.S. states; 332 were ineligible, leaving 2,604 potential participants. Following 4 mailings, 781 (30%) responded from 97 health centers. Item analyses, exploratory factor analysis, and confirmatory factor analysis were undertaken. Exploratory factor analysis suggests four latent factors: Teams and Care Continuity, Patient Centeredness, Coordination with External Providers, and Coordination with Community Resources. Confirmatory factor analysis confirmed these factor groupings. For the total sample, Cronbach’s alpha exceeded 0.7 for each latent factor. Descriptive responses to each of the 21 Provider and Staff Perceptions of Integrated Care questions appear to have potential in identifying areas that providers and staff recognize as care integration strengths, and areas that may warrant improvement.

Background: IL-21 expanded NK cells have high expression of CD16 and have demonstrated antibody-dependent cell-mediated cytotoxicity (ADCC) activity in combination with monoclonal antitumor antibodies (mAb). Mogamulizumab (moga) is a mAb targeting CCR4 that is defucosylated to enhance its binding to CD16, thereby enhancing ADCC of NK cells against targets expressing CCR4. We designed a pilot phase I clinical trial studying this combination in patients with relapsed/refractory (r/r) CTCL and ATLL. The study is soon opening to accrual at the OSU James Cancer Center (NCT04848064). Study is conduced under IND 26888. Preclinical data: Allogeneic NK cells obtained from buffy coat (Red Cross Blood Bank), were expanded for 14 days on CSTX002 feeder cells, cryopreserved, and then thawed and recovered for 48 hours prior to testing. Malignant T-cells were incubated with moga (at 10ng/µl) for 30 minutes prior to co-culture with NK cells and cytotoxicity was determined by the calcein release assay (Somanchi et al, J Vis Exp 2011). Malignant T-cells were obtained from peripheral blood from 3 patients with multiply relapsed CTCL and all have circulating Sezary cells and from CCRF-CEM cell line (T-ALL cell line that expresses CCR4). No significant cytotoxicity was observed with moga alone and significant synergy in cytotoxicity was observed between and moga and NK cells in all 3 patient samples and also CCRF-CEM cell line (figure 1: A and B). Two-fold increase in ADCC was observed with addition of moga to NK cells (p=0.0272; figure 1C) Design: Patients will receive lymphodepleting chemotherapy (Fludarabine/Cyclophosphamide) on days -5 to -3 prior to cell infusion, moga weekly for 4 doses starting on day -7 (prior to the first NK cell infusion) and then every 2 weeks until toxicity or progression. Patients will receive third-party ideal-donor mbIL-21 expanded NK cells once every 2 weeks for 6 total doses (Figure 1D). Donors meeting ideal-donor characteristics from National Marrow Donor Program were identified in collaboration with Be The Match Biotherapies. PBMNC were collected by apheresis, CD3-depleted, expanded for 14 days as previously described, and cryopreserved in ready-to-infuse aliquots. NK cells will be thawed and infused in 2 dosing cohorts; 3x10 7 and 1x10 8 cells/kg in a standard dose-escalation design. Primary endpoint is the maximum tolerated dose of NK cells given in combination with standard-dose moga. Dose-limiting toxicity (DLT) is defined as any steroid refractory graft vs host disease (GVHD), severe NK cell-related toxicities, or other unusual events occurring from D-7 until D+84 post last dose of NK cells. Dose-escalation will proceed in the standard 3+3 fashion. Secondary endpoints include overall response rate (ORR) per ISCL/USCLC/EORTC consensus panel, for CTCL, and international consensus panel, for ATLL and progression-free and overall survival. Correlative endpoints include quality of life impact as captured by Skindex-16 score, serum cytokine levels in blood, persistence of NK cells by chimerism studies, correlation between CCR4 staining of tumor cells in skin and trafficking of NK cells to skin by immunohistochemistry or immunofluorescence in serial skin biopsies and ORR (Figure 1D). Abbreviated eligibility: Eligible patients will be 18 years, or older, with biopsy-proven, measurable, stage IB-IVB relapsed or refractory CTCL or ATLL, progressing on at least one standard chemotherapy. Other eligibility criteria include: ECOG performance status of ≤ 1, no systemic anti-neoplastic therapy within a week or 3 half-lives, adequate laboratory parameters including: absolute neutrophil count ≥1000/mm³, platelet count ≥50,000/mm³, total bilirubin ≤ 2 x upper limit of normal (ULN), AST/ALT ≤ 3 x ULN or ≤ 5 x ULN in patients with documented hepatic involvement by lymphoma, and calculated creatinine clearance ≥ 50 ml/min., disease free of prior malignancies for ≥ 2 years with exception of treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast and life expectancy ≥ 90 days. Patients who were pre-treated with moga, pregnant, HIV positive, with active hepatitis B and C, active CNS involvement, active grade II-IV acute or extensive chronic GVHD or other serious medical comorbid conditions are excluded. Figure 1 Figure 1. Disclosures William: Kyowa Kirin: Consultancy; Incyte: Research Funding; Merck: Research Funding; Dova Pharmaceuticals: Research Funding; Guidepoint Global: Consultancy. de Lima: Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Devine: Be the Match: Current Employment; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Lee: Courier Therapeutics: Current holder of individual stocks in a privately-held company; Kiadis Pharma: Divested equity in a private or publicly-traded company in the past 24 months, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. OffLabel Disclosure: Will discuss combination of mogamulizumab and NK cells in a context of a clinical trial

This exploratory study examined the relationship between mindfulness and multicultural counseling competencies (MCC) in counselor trainees. One hundred fifty-seven masters and doctoral students in counseling and therapy-related fields completed a survey containing the Multicultural Counseling Inventory (MCI), Five-Facet Mindfulness Questionnaire (FFMQ), and the Acceptance and Action Questionnaire-II (AAQ-II). Pearson product-moment correlation coefficients were calculated between scales and subscales of the MCC, mindfulness, and acceptance. A hierarchical regression was used to examine the association of mindfulness and mindfulness practices (the total length of mindfulness practice and the duration of weekly mindfulness practice) on MCC along with multicultural training (number of multicultural counseling courses and practica completed) and demographic factors. The results of the study showed that mindfulness and MCC were positively and strongly correlated (r = .48, p < .01). Moreover, all mindfulness facets were positively and significantly correlated with MCC and majority of its subscales. The results suggested that individuals who believed themselves to be more mindful in their daily lives (especially those who reported observing and describing their experiences without automatically reacting) also tended to think of themselves as more multiculturally competent. In addition, mindfulness and mindfulness practices contributed a significant amount of additional variance on MCC and its subscales above and beyond the multicultural training and demographic variables. Study limitations and directions for future research were discussed.

Fluorescent nanodiamonds (FNDs) are nontoxic, infinitely photostable, and emit fluorescence in the near infrared region. Natural killer (NK) cells and monocytes are part of the innate immune system and are crucial to the control of carcinogenesis. FND-mediated stimulation of these cells may serve as a strategy to enhance anti-tumor activity. FNDs were fabricated with a diameter of 70±28 nm. Innate immune cell FND uptake, viability, surface marker expression, and cytokine production were evaluated in vitro. Evaluation of fluorescence emission from the FNDs was conducted in an animal model. In vitro results demonstrated that treatment of immune cells with FNDs resulted in significant dose-dependent FND uptake, no compromise in cell viability, and immune cell activation. FNDs were visualized in an animal model. Hence, FNDs may serve as novel agents with “track and trace” capabilities to stimulate innate immune cell anti-tumor responses, especially as FNDs are amenable to surface-conjugation with immunomodulatory molecules.

The objective was to identify facilitators and challenges of implementing diabetes group visits in 5 Midwestern community health center (CHC) settings that care for diverse patient populations. Interview data were collected from July to August 2015. An interview guide was developed to explore health center teams' initial experiences with diabetes group visit implementation. Interviews were conducted with 14 individuals who participated in a training prior to diabetes group visit implementation. Four levels of coding (open, in vivo, categorical, and thematic) were used to identify characteristics of group visit implementation in 5 CHCs. A semi-structured model encouraged interprofessional teamwork across all CHC teams. Self-appointed or chosen team champions were the “pulse” or central driving force of implementation. A designated time in the clinic for patients to receive education and psychosocial support enhanced engagement in diabetes self-management. Early buy-in from upper leadership was critical to securing fiscal and human resources as unexpected needs emerged during group visit implementation. Time commitment of clinic staff and providers for ongoing operations, socioeconomic challenges of patients, staff turnover, and billing were reported as challenges in the initial implementation process. This study acknowledges the influence of administrative and sociocultural factors on successful implementation of diabetes group visits. Future research should further explore how these factors influence successful adoption of diabetes group visits in health centers across the United States and the impact of group visit implementation on staff and patient outcomes.

Purpose: mAbs including cetuximab can induce antibody-dependent cellular cytotoxicity (ADCC) and cytokine production mediated via innate immune cells with the ability to recognize mAb-coated tumors. Preclinical modeling has shown that costimulation of natural killer (NK) cells via the Fc receptor and the IL12 receptor promotes NK-cell–mediated ADCC and production of cytokines. Patients and Methods: This phase I/II trial evaluated the combination of cetuximab with IL12 for the treatment of EGFR-expressing head and neck cancer. Treatment consisted of cetuximab 500 mg/m2 i.v. every 2 weeks with either 0.2 mcg/kg or 0.3 mcg/kg IL12 s.c. on days 2 and 5 of the 2-week cycle, beginning with cycle 2. Correlative studies from blood draws obtained prior to treatment and during therapy included measurement of ADCC, serum cytokine, and chemokine analysis, determination of NK cell FcγRIIIa polymorphisms, and an analysis of myeloid-derived suppressor cell (MDSC) frequency in peripheral blood. Results: The combination of cetuximab and IL12 was well tolerated. No clinical responses were observed, however, 48% of patients exhibited prolonged progression-free survival (PFS; average of 6.5 months). Compared with patients that did not exhibit clinical benefit, patients with PFS >100 days exhibited increased ADCC as therapy continued compared with baseline, greater production of IFNγ, IP-10, and TNFα at the beginning of cycle 8 compared with baseline values and had a predominance of monocytic MDSCs versus granulocytic MDSCs prior to therapy. Conclusions: Further investigation of IL12 as an immunomodulatory agent in combination with cetuximab in head and neck squamous cell carcinoma is warranted.

How do theatre practitioners regard reviewers in Ottawa? Can a freelance critic get (paid) work in Halifax? Who is blogging in Edmonton? Is theatre criticism flourishing anywhere in Canada? This article gathers reports commissioned from scholars, critics, and artists from across the country who take the pulse of the critical landscape where they are. They identify the main outlets of criticism and outstanding figures in their regions and discuss the relationship between mainstream journalism and the blogosphere.

The irreversible Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown efficacy against B-cell tumors such as chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma. Fcγ receptors (FcγR) on immune cells such as macrophages play an important role in tumor-specific antibody-mediated immune responses, but many such responses involve Btk. Here we tested the effects of ibrutinib on FcγR-mediated activities in monocytes. We found that ibrutinib did not affect monocyte FcγR-mediated phagocytosis, even at concentrations higher than those achieved physiologically, but suppressed FcγR-mediated cytokine production. We confirmed these findings in macrophages from Xid mice in which Btk signaling is defective. Because calcium flux is a major event downstream of Btk, we tested whether it was involved in phagocytosis. The results showed that blocking intracellular calcium flux decreased FcγR-mediated cytokine production but not phagocytosis. To verify this, we measured activation of the GTPase Rac, which is responsible for actin polymerization. Results showed that ibrutinib did not inhibit Rac activation, nor did the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester). We next asked whether the effect of ibrutinib on monocyte FcγR-mediated cytokine production could be rescued by IFNγ priming because NK cells produce IFNγ in response to antibody therapy. Pretreatment of monocytes with IFNγ abrogated the effects of ibrutinib on FcγR-mediated cytokine production, suggesting that IFNγ priming could overcome this Btk inhibition. Furthermore, in monocyte-natural killer cell co-cultures, ibrutinib did not inhibit FcγR-mediated cytokine production despite doing so in single cultures. These results suggest that combining ibrutinib with monoclonal antibody therapy could enhance chronic lymphocytic leukemia cell killing without affecting macrophage effector function.

Background Tumor-associated macrophages (TAM) are expanded and exhibit tumor-promoting properties within the tumor microenvironment. Current methods to study TAM have not been replicated across cancer types and often do not include exogenous growth factors from the tumor, a key factor in TAM differentiation in vivo. Methods In this study, an in vitro method to generate monocyte- derived TAM using tumor- conditioned media (TCM) and a cytokine cocktail containing IL-4, IL-10, and M-CSF was utilized to study the phenotype, morphology, and function of TAM across multiple cancer types. TCM was generated from two breast cancer cell lines and an Epstein-Barr virus-positive lymphoma cell line. The properties of in vitro generated TAM were compared to in vitro generated M1 and M2- like macrophages and TAM isolated from patients with cancer. Results TAM generated in this fashion displayed an increase in CD163/CD206 co-expression compared to M2- like macrophages (87 and 36%, respectively). TAM generated in vitro exhibited increased transcript levels of the functional markers IL-6, IL-10, CCL2, c-Myc, iNOS, and arginase compared to in vitro generated M2-like macrophages. Functionally, in vitro generated TAM inhibited the proliferation of T cells (47% decrease from M1-like macrophages) and the production of IFN-γ by natural killer cells was inhibited (44%) when co-cultured with TAM. Furthermore, in vitro generated TAM secreted soluble factors that promote the growth and survival of tumor cells. Conclusions Limited access to patient TAM highlights the need for methods to generate TAM in vitro. Our data confirm that monocyte-derived TAM can be generated reliably using TCM plus the cytokine cocktail of IL-4, IL-10, and M-CSF. Given the ability of TAM to inhibit immune cell function, continued study of methods to deplete or deactivate TAM in the setting of cancer are warranted. Electronic supplementary material The online version of this article (10.1186/s40425-019-0622-0) contains supplementary material, which is available to authorized users.

Background Deconditioning can masquerade as general fatigue and disease progression, impacting function, confidence, reducing independence and quality of life, increasing the need for adaptions and care. It is a hidden menace. Deconditioning can be reversed with achievable focused strengthening exercises; this is good news for the palliative care patient. Aims To enable identification and management of deconditioning in palliative care patients. To improve outcomes for deconditioned palliative care patients. Method Create a screening process and exercise programmes for healthcare professionals to identify and advise individuals. Provide internal and external training for professionals. Provide online resources for professionals and patients. Provide weekly ‘pop-up gym’ sessions within the hospice for patients to receive individually prescribed exercise programmes. Provide regular talks for patients within the Sunflower Centre, highlighting the importance of exercise and the risks associated with deconditioning. Results Deconditioning screening tools, each with decision-making guide and subsequent exercise programme created (2015). Deconditioning training workshops for professionals (2015), extended to external providers (2017). Word documents created (2015), with online resources of video clips (2016), supporting patients and professionals. Patient resources both generic and individually prescribed according to need. Patients have regained independence within short weeks using the advice and exercise. Healthcare professionals have replicated these results following the training. Positive patient feedback has been received: ‘the greatest benefits are it has given me the strength and belief in myself’ ‘feeling strong enough to pursue further treatment options’ ‘Improved my quality of life… be more positive… enjoy life as much as possible.’ Gym sessions and talks began (2018) within the Sunflower Centre. Nine patients participated with personalised outcome measures identifying the programme benefits. Conclusion Results indicate positive qualitative feedback and increased professional awareness. Progression requires quantitative data, increased signposting for recognition and prevention, along with professional practice support in identification and advice.

The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib has transformed chronic lymphocytic leukemia (CLL) therapy but requires continuous administration. These factors have spurred interest in combination treatments. Unlike with chemotherapy, CD20-directed antibody therapy has not improved the outcome of BTKi treatment. Whereas CD20 antigen density on CLL cells decreases during ibrutinib treatment, the B-cell activating factor (BAFF) and its receptor (BAFF-R) remain elevated. Furthermore, BAFF signaling via noncanonical NF-κB remains elevated with BTKi treatment. Blocking BAFF interaction with BAFF-R by using VAY-736, a humanized defucosylated engineered antibody directed against BAFF-R, antagonized BAFF-mediated apoptosis protection and signaling at the population and single-cell levels in CLL cells. Furthermore, VAY-736 showed superior antibody-dependent cellular cytotoxicity compared with CD20- and CD52-directed antibodies used in CLL. VAY-736 exhibited in vivo activity as a monotherapy and, when combined with ibrutinib, produced prolonged survival compared with either therapy alone. The in vivo activity of VAY-736 is dependent upon immunoreceptor tyrosine–based activation motif (ITAM)–mediated activation of effector cells as shown by using an ITAM-deficient mouse model. Collectively, our findings support targeting the BAFF signaling pathway with VAY-736 to more effectively treat CLL as a single agent and in combination with ibrutinib.

Background: Diabetes group visits (GVs) - shared appointments that incorporate medical care, diabetes self-management education, social support, and goal-setting - were recently examined in a network of U.S. community health centers (HCs) and found to improve glucose control and diabetes-related quality of life. Objective: To evaluate the economic impact of group visits (GV) in adults with diabetes in HCs. Methods: In a pilot prospective matched case-control trial, we implemented 6 monthly GV sessions in 5 HCs and compared intervention patients (n=49) to control patients receiving usual care within the same HCs (n=72). We conducted patient chart reviews to obtain healthcare utilization data for the prior 6 months, at baseline, 6, and 12 months and collected monthly logs of HC expenses and staff time spent on activities related to GVs, including training, planning, implementation, and evaluation. Total costs included HCs’ expenses and activities and patients’ healthcare use over one year. Wilcoxon rank-sum tests, generalized linear models, and modified Park tests were used to compare the healthcare use and cost data. Results: Despite each HC spending $17,342 on average (or $1770 per-patient) for the GV preparation and implementation, the per-patient annual total costs were not different between the groups (GV: $3,982 vs. control: $4,287, p=0.73). Most of the benefits were due to GV patients having fewer hospitalizations (p=0.08) and fewer primary care visits that occurred outside the trial (p=0.01). After excluding the staff training costs (mean $7,962 per HC), the GV group had significantly lower total costs ($3,169) than the control group (p Conclusions: The diabetes group visits in health centers improved patients’ healthcare quality without increasing overall healthcare costs. In subsequent GV sessions, excluding the need for staff training, group visits may be cost saving. Future studies should assess the cost-effectiveness of group visits. Disclosure W. Wan: None. E.M. Staab: None. S.A. Ham: None. A. Campbell: None. C.T. Schaefer: None. M.T. Quinn: None. A. Baig: None.

Natural killer (NK) cells serve a critical role in the immune response against microbes and developing tumors. We have demonstrated that NK cells produce stimulatory cytokines (e.g., IFN-γ) in response to potent stimulation via immobilized IgG (to engage Fc receptors) and interleukin (IL)-12. CD25 is a component of the high-affinity IL-2R, which promotes NK cell activation in response to low doses of IL-2 such as those released by activated T cells. We hypothesized that stimulation of NK cells via IgG and IL-12 would enhance CD25 expression and promote NK cell anti-tumor activity in response to low-dose IL-2. It was confirmed that this dual stimulation strategy significantly enhanced NK cell CD25 expression compared to unstimulated cells or cells treated with IgG or IL-12 alone. Dual stimulated NK cells also were more responsive to low-dose IL-2. Dual stimulated NK cells subsequently treated with low-dose IL-2 (10 pg/mL) displayed enhanced intracellular signaling as indicated by increased pSTAT5 levels. IFN-γ production and cytotoxicity against K562 cells by NK cells stimulated with low-dose IL-2 was comparable to that of cells treated with high-dose IL-2 (10 ng/mL). Importantly, cells isolated from head and neck cancer patients receiving the mAb cetuximab and IL-12 on a clinical trial displayed increased CD25 expression following combination therapy compared to baseline. Altogether, these findings suggest that FcR and IL-12R co-stimulation induces expression of the high-affinity IL-2R and promotes NK cell anti-tumor activity.

Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy. Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent. Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer. Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR.

Sorafenib is an oral multikinase inhibitor that was originally developed as a Raf kinase inhibitor. We hypothesized that sorafenib would also have inhibitory effects on cytokine signaling pathways in immune cells. PBMCs from normal donors were treated with varying concentrations of sorafenib and stimulated with IFN-α or IL-2. Phosphorylation of STAT1 and STAT5 was measured by flow cytometry and confirmed by immunoblot analysis. Changes in IFN-α– and IL-2–stimulated gene expression were measured by quantitative PCR, and changes in cytokine production were evaluated by ELISA. Cryopreserved PBMCs were obtained from cancer patients before and after receiving 400 mg sorafenib twice daily. Patient PBMCs were thawed, stimulated with IL-2 or IFN-α, and evaluated for phosphorylation of STAT1 and STAT5. Pretreatment of PBMCs with 10 μM sorafenib decreased STAT1 and STAT5 phosphorylation after treatment with IFN-α or IL-2. This inhibitory effect was observed in PBMCs from healthy donors over a range of concentrations of sorafenib (5–20 μM), IL-2 (2–24 nM), and IFN-α (101–106 U/ml). This effect was observed in immune cell subsets, including T cells, B cells, NK cells, regulatory T cells, and myeloid-derived suppressor cells. Pretreatment with sorafenib also inhibited PBMC expression of IFN-α– and IL-2–regulated genes and inhibited NK cell production of IFN-γ, RANTES, MIP1-α, and MIG in response to IFN-α stimulation. PBMCs from patients receiving sorafenib therapy showed decreased responsiveness to IL-2 and IFN-α treatment. Sorafenib is a Raf kinase inhibitor that could have off-target effects on cytokine-induced signal transduction in immune effector cells.

Natural killer (NK) cells are large granular lymphocytes that promote the antitumor response via communication with other cell types in the tumor microenvironment. Previously, we have shown that NK cells secrete a profile of immune stimulatory factors (e.g., IFNγ, MIP-1α, and TNFα) in response to dual stimulation with the combination of antibody (Ab)-coated tumor cells and cytokines, such as IL12. We now demonstrate that this response is enhanced in the presence of autologous monocytes. Monocyte enhancement of NK cell activity was dependent on cell-to-cell contact as determined by a Transwell assay. It was hypothesized that NK cell effector functions against Ab-coated tumor cells were enhanced via binding of MICA on monocytes to NK cell NKG2D receptors. Strategies to block MICA–NKG2D interactions resulted in reductions in IFNγ production. Depletion of monocytes in vivo resulted in decreased IFNγ production by murine NK cells upon exposure to Ab-coated tumor cells. In mice receiving trastuzumab and IL12 therapy, monocyte depletion resulted in significantly greater tumor growth in comparison to mock-depleted controls (P < 0.05). These data suggest that NK cell–monocyte interactions enhance NK cell antitumor activity in the setting of monoclonal Ab therapy for cancer. Cancer Immunol Res; 5(9); 778–89. ©2017 AACR.

This study aimed to examine the psychometric properties of the Spiritual Involvement and Beliefs Scale among college students. A total of 243 undergraduate and graduate students participated in this study from a southeastern public research one university in the United States. The scale yields good psychometric results in terms of internal consistency, split-half reliability, convergent validity, and discriminant validity. We discussed the scale’s potential role of serving as an initial assessment tool for spiritually related issues within the college student population.

Many community health center providers and staff care for Latinos with diabetes, but their Spanish language ability and awareness of Latino culture are unknown. We surveyed 512 Midwestern health center providers and staff who managed Latino patients with diabetes. Few respondents had high Spanish language (13%) or cultural awareness scores (22%). Of respondents who self-reported 76–100% of their patients were Latino, 48% had moderate/low Spanish language and 49% had moderate/low cultural competency scores. Among these respondents, 3% lacked access to interpreters and 27% had neither received cultural competency training nor had access to training. Among all respondents, Spanish skills and Latino cultural awareness were low. Respondents who saw a significant number of Latinos had good access to interpretation services but not cultural competency training. Improved Spanish-language skills and increased access to cultural competency training and Latino cultural knowledge are needed to provide linguistically and culturally tailored care to Latino patients.