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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: 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