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Abstract: GBM standard treatment is associated with poor survival. Adjunctive therapy with patient-specific vaccines may improve outcomes by enhancing anti-GBM immune responses. A multi-institutional phase II clinical trial was designed with a primary objective of 75% survival 15 months after intent-to-treat enrollment. IL-4 and GM-CSF were used to generate dendritic cells (DC) from monocytes. DC were incubated with autologous tumor antigens (ATA) from the lysate of cultured GBM cells to produce each patient-specific DC-ATA vaccine. Each dose was admixed with 500 mcg GM-CSF at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Enrollment has been completed in April 2020 (n=60). Three patients withdrew from the study prior to starting treatment leaving 57 patients for whom data is available. So far 57 patients have received 344 doses; 27 have completed all 8 doses, 11 received fewer than 8 doses at the time they discontinued treatment, 19 are currently in treatment. No patient has discontinued treatment because of toxicity. 9 pt had died and the preliminary 12 months overall survival is 74%. In a preliminary serologic analysis 12 of 16 patients (75%) had an increase in markers associated with Th1/NK, Th2/immunoglobulins, and Th2 hypersensitivity (eotaxins, IgE and IL17F) by week-3; 9 of 15 (60%) had a decrease in angiogenesis factors, growth factors, and tumor markers by week-8. Immunologic data for all 55 patients who received at least two injections will be available November 2020. This patient-specific DC-ATA immunotherapy approach is feasible, is associated with changes in serologic markers, and may be increasing intratumor inflammation that may be associated with on-target toxicity and efficacy. A interim survival analysis will be conducted in mid-October 2020, 15 months after the 28th patient was enrolled; results will be available November 2020 [Clinicaltrials.gov NCT03400917].

Abstract Background Literature related to the effectiveness of knowledge translation (KT) strategies used in public health is lacking. The capacity to seek, analyze, and synthesize evidence-based information in public health is linked to greater success in making policy choices that have the best potential to yield positive outcomes for populations. The purpose of this systematic review is to identify the effectiveness of KT strategies used to promote evidence-informed decision making (EIDM) among public health decision makers. Methods A search strategy was developed to identify primary studies published between 2000–2010. Studies were obtained from multiple electronic databases (CINAHL, Medline, EMBASE, and the Cochrane Database of Systematic Reviews). Searches were supplemented by hand searching and checking the reference lists of included articles. Two independent review authors screened studies for relevance, assessed methodological quality of relevant studies, and extracted data from studies using standardized tools. Results After removal of duplicates, the search identified 64, 391 titles related to KT strategies. Following title and abstract review, 346 publications were deemed potentially relevant, of which 5 met all relevance criteria on full text screen. The included publications were of moderate quality and consisted of five primary studies (four randomized controlled trials and one interrupted time series analysis). Results were synthesized narratively. Simple or single KT strategies were shown in some circumstances to be as effective as complex, multifaceted ones when changing practice including tailored and targeted messaging. Multifaceted KT strategies led to changes in knowledge but not practice. Knowledge translation strategies shown to be less effective were passive and included access to registries of pre-processed research evidence or print materials. While knowledge brokering did not have a significant effect generally, results suggested that it did have a positive effect on those organizations that at baseline perceived their organization to place little value on evidence-informed decision making. Conclusions No singular KT strategy was shown to be effective in all contexts. Conclusions about interventions cannot be taken on their own without considering the characteristics of the knowledge that was being transferred, providers, participants and organizations.

Tregs play a pivotal role in inducing and maintaining donor-specific transplant tolerance. The T cell immunoglobulin and mucin domain-3 protein (TIM-3) is expressed on many fully activated effector T cells. Along with program death 1 (PD-1), TIM-3 is used as a marker for exhausted effector T cells, and interaction with its ligand, galectin-9, leads to selective death of TIM-3+ cells. We report herein the presence of a galectin-9-sensitive CD4+FoxP3+TIM-3+ population of T cells, which arose from CD4+FoxP3+TIM-3- proliferating T cells in vitro and in vivo and were often PD-1+. These cells became very prominent among graft-infiltrating Tregs during allograft response. The frequency and number of TIM-3+ Tregs peaked at the time of graft rejection and declined thereafter. Moreover, these cells also arise in a tolerance-promoting donor-specific transfusion model, representing a pool of proliferating, donor-specific Tregs. Compared with TIM-3- Tregs, TIM-3+ Tregs, which are often PD-1+ as well, exhibited higher in vitro effector function and more robust expression of CD25, CD39, CD73, CTLA-4, IL-10, and TGF-β but not galectin-9. However, these TIM-3+ Tregs did not flourish when passively transferred to newly transplanted hosts. These data suggest that a heretofore unrecognized graft-infiltrating, short-lived subset of Tregs can restrain rejection. [ABSTRACT FROM AUTHOR]

Background: Intensive lifestyle interventions (LI) improve outcomes in obesity and type 2 diabetes but are not currently available in usual care., Objective: To compare the effectiveness and costs of two group LI programs, in-person LI and telephone conference call (telephone LI), to medical nutrition therapy (MNT) on weight loss in primary care patients with type 2 diabetes., Design: A randomized, assessor-blinded, practice-based clinical trial in three community health centers and one hospital-based practice affiliated with a single health system., Participants: A total of 208 primary care patients with type 2 diabetes, HbA1c 6.5 to < 11.5, and BMI > 25 kg/m 2 (> 23 kg/m 2 in Asians)., Interventions: Dietitian-delivered in-person or telephone group LI programs with medication management or MNT referral., Main Measures: Primary outcome: mean percent weight change., Secondary Outcomes: 5% and 10% weight loss, change in HbA1c, and cost per kilogram lost., Key Results: Participants' mean age was 62 (SD 10) years, 45% were male, and 77% were White, with BMI 35 (SD 5) kg/m 2 and HbA1c 7.7 (SD 1.2). Seventy were assigned to in-person LI, 72 to telephone LI, and 69 to MNT. The mean percent weight loss (95% CI) at 6 and 12 months was 5.6% (4.4-6.8%) and 4.6% (3.1-6.1%) for in-person LI, 4.6% (3.3-6.0%) and 4.8% (3.3-6.2%) for telephone LI, and 1.1% (0.2-2.0%) and 2.0% (0.9-3.0%) for MNT, with statistically significant differences between each LI arm and MNT (P < 0.001) but not between LI arms (P = 0.63). HbA1c improved in all participants. Compared with MNT, the incremental cost per kilogram lost was $789 for in-person LI and $1223 for telephone LI., Conclusions: In-person LI or telephone group LI can achieve good weight loss outcomes in primary care type 2 diabetes patients at a reasonable cost., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02320253.

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR ≥0.4 ), and ≥15% NAA (AMR ≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10 -4 ; 11p11.12, p = 7.0 × 10 -4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR ≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10 -6 ) in 7q21.3. Among AMR ≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10 -4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10 -4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies., (© 2019 UICC.)

Purpose: To evaluate the results of the randomized, double-blind, placebo-controlled phase II clinical trial of ICT-107 in patients with newly diagnosed glioblastoma., Patients and Methods: We conducted a double-blinded randomized phase II trial of ICT-107 in newly diagnosed patients with glioblastoma (GBM) and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1 + and/or -A2 + -resected patients with residual tumor ≤1 cm 3 received radiotherapy and concurrent temozolomide. Following completion of radiotherapy, 124 patients, randomized 2:1, received ICT-107 [autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2] or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly × 4 followed by 12 months of adjuvant temozolomide. Maintenance vaccinations occurred at 1, 3, and 6 months and every 6 months thereafter., Results: ICT-107 was well tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the ITT population was significantly increased in the ICT-107 cohort by 2.2 months ( P = 0.011). The frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated prespecified subgroups, whereas only HLA-A1 methylated patients had an OS benefit., Conclusions: PFS was significantly improved in ICT-107-treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically., (©2019 American Association for Cancer Research.)

Background: Aims: The REAL HEALTH Diabetes Study is a practice-based randomized clinical trial that compares the effectiveness of lifestyle intervention aimed at weight reduction to medical nutrition therapy in primary care patients with type 2 diabetes. This paper describes a tiered approach to recruitment, the resultant enrollment rates of sequentially more intensive recruitment strategies, and identifies barriers to participation., Methods: Potential participants were identified using patient health registries and classified by recruitment site. Four recruitment strategies were used to achieve target enrollment: (1) mail/telephone outreach; (2) direct referral from providers; (3) orientation sessions; and (4) media/advertising. Reasons for ineligibility and non-participation were tracked., Results: Fifteen thousand two hundred sixty-nine (15,269) potential participants were identified from all sources, with the clear majority coming from patient registries. Mail/telephone outreach alone had the lowest enrollment rate (1.2%). Direct referral and orientation sessions superimposed on mail/telephone outreach was used for fewer participants but had greater enrollment rates (27% and 52%.) Media/advertising was ineffective. The most commonly reported reasons for non-participation were not wanting to be in a research (30%) or a weight loss program (22%); time commitment (20%); and distance/transportation (14%)., Conclusions: The use of population registries to identify potential participants coupled with successively more intensive recruitment strategies, executed in a tiered approach moving toward personal engagement to establish trust and credibility, maximized recruitment enrollment rates. Our findings regarding facilitators and barriers to recruitment could be used to inform other practice-based research or to engage patients in group interventions in usual care settings., Clinical Trial Registration: NCT02320253.

Background: Patient portals have emerged as an important tool through which patients can access online health information and engage in their health care. However, we know little about how patients perceive portals and whether patient perceptions might influence portal adoption., Objective: Apply the diffusion of innovation (DOI) theory to assess perceptions of adopters and non-adopters of a patient portal., Methods: We conducted a cross-sectional survey of adopters and non-adopters of the portal. Our survey consisted of perceived attributes from the DOI theory, socio-demographic characteristics and patient perceptions of technology adoption., Results: Three factors representing perceived attributes from DOI theory accounted for 73% of the variance in the data: Factor 1 - Relative Advantage (27%); Factor 2 - Ease of Use (24%) and Factor 3 - Trialability (22%). Adopters perceived greater Relative Advantage [mean (SD)] = 3.8 (0.71) versus 3.2 (0.89), p < 0.001, Ease of Use = 4.1 (0.71) versus 3.3 (0.95), p < 0.001 and Trialability = 4.0 (0.57) versus 3.4 (0.99), p < 0.001 than non-adopters. In multivariate modelling, age [OR = 3.75, 95% CI: (2.17, 6.46), p < 0.001] and income [OR = 1.87, 95% CI: (1.17, 3.00), p < 0.01] predicted adoption of the portal. Among DOI factors, Relative advantage predicted adoption of the portal [OR = 1.48, 95% CI: (1.03, 2.11), p < 0.05]., Conclusion: Patients will adopt a patient portal if they perceive it to offer a relative advantage over existing practices such as telephoning or visiting the doctor's office. Organisations seeking to increase the adoption of patient portals should implement strategies to promote the relative advantage of portals as, for example, through posters in waiting and exam rooms. A digital divide in the adoption of patient portals may exist with respect to age and income.

Background/aims: The REAL HEALTH -Diabetes Study is a practice-based clinical trial that adapted the Look AHEAD lifestyle intervention for implementation in primary care settings. The trial will compare the effectiveness and cost-effectiveness of in-person group lifestyle intervention, telephone group lifestyle intervention, and individual medical nutrition therapy (MNT), the current recommended standard of care in type 2 diabetes. The primary outcome is percent weight loss at 6 months with outcomes also measured at 12, 18, 24 (intervention completion), and 36 months. Here, we describe the adaptation, trial design, implementation strategies, and baseline characteristics of enrolled participants., Methods: The study is a three-arm, patient-level, randomized trial conducted in three community health centers (CHCs) and one diabetes practice affiliated with one academic medical center., Results: The study used existing clinical infrastructure to recruit participants from study sites. Strategies for successful conduct of the trial included partnering with health-center based co-investigator clinicians, engaging primary care providers, and accommodating clinical workflows. Of 248 eligible patients who attended a screening visit, 211 enrolled, with 70 randomly assigned to in-person group lifestyle intervention, 72 to telephone group lifestyle intervention, and 69 to MNT. The cohort was 55% female, 29% non-white, with mean age 62 years and mean BMI 35 kg/m 2 . Enrollment rates were higher at CHC sites., Conclusions: A practice-based randomized trial of a complex behavioral lifestyle intervention for type 2 diabetes can be implemented in community health and usual clinical settings. Participant and provider engagement was higher at local CHC sites reflecting the study implementation focus., Clinical Trial Registration: NCT02320253., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction Primary central nervous system lymphoma (PCNSL) is a rare tumor without a well-defined standard of care. For immunocompetent patients, therapeutic regimens have largely evolved from treatment with whole-brain radiation therapy (WBRT) to treating initially with systemic chemotherapy regimens that include high-dose (HD) methotrexate (MTX) with or without WBRT. Looking at population-based treatment trends may help define which therapies are most effective. This study was conducted to determine treatment patterns and outcomes for patients with PCNSL in the Louisville, KY metropolitan area during the period 2000 to 2012. Methods Data were collected by retrospective chart reviews of patients identified using the International Classification of Diseases (ICD) code from three major oncology practices in the Louisville metropolitan area during the period 2000 to 2012. Patients were excluded if they were under age 18, positive for human immunodeficiency virus (HIV), had histology other than B-cell lymphoma, or had systemic lymphoma. Results A total of 21 patients were identified. The median age was 65 years (range: 30 to 90). All patients were Caucasian, and the median Karnofsky performance status (KPS) score was 80 (range: 50 to 100). The ratio of males to females was 1:1.3. Median overall survival (OS) for all patients was 22 months (range: 1 to 155 months). Of 21 patients, 11 (52 percent) received chemotherapy regimens that included systemic HD-MTX at their initial diagnosis with a median OS of 22 months (range: 1 to 155 months). Nine of 21 patients (42 patients) were offered other therapies, including WBRT or non-MTX-based chemotherapies; they had a median OS of 5 months (range: 2 to 150 months). The median OS for patients receiving at least four cycles of HD-MTX was 40 months (range: 4 to 155 months). Conclusions This population-based study shows that patients with PCNSL and the ability to undergo HD-MTX-based therapy had a superior survival rate compared to those receiving radiation alone or other non-HD-MTX-based therapies., Competing Interests: The authors have declared that no competing interests exist.

Background: Dexamethasone (DXM) is commonly used in the management of cerebral edema in patients diagnosed with glioblastoma multiforme (GBM). Bevacizumab (BEV) is FDA-approved for the progression or recurrence of GBM but has not been shown to improve survival when given for newly diagnosed patients concurrently with radiation (RT) and temozolomide (TMZ). Both DXM and BEV reduce cerebral edema, however, DXM has been shown to induce cytokine cascades which could interfere with cytotoxic therapy. We investigated whether DXM would reduce survival of GBM patients in the setting of concurrent TMZ and BEV administration., Methods: We reviewed the treatment of all 73 patients with GBM who received definitive therapy at our institution from 2005 to 2013 with RT (60 Gy) delivered with concurrent daily TMZ (75 mg/m(2)). Of these, 34 patients also were treated with concurrent BEV (10 mg/kg every two weeks). Patients received adjuvant therapy (TMZ or TMZ/Bev) until either progression, discontinuation due to toxicity, or 12 months after radiation completion. All patients who had GBM progression with TMZ were offered BEV for salvage therapy, with 19 (56 %) receiving BEV., Results: With a median follow-up of 15.6 months, 67 (91.8 %) patients were deceased. The OS for the entire cohort was 15.9 months, while the PFS was 7.7 months. The extent of resection was a prognostic indicator for OS (p = .0044). The median survival following gross tumor resection (GTR) was 22.5 months, subtotal resection (STR) was 14.9 months, and biopsy was 12.1 months. The addition of BEV to TMZ with RT was borderline significantly associated with increased PFS (9.4 vs. 5.1 months, p = 0.0574) although was not significantly associated with OS (18.1 vs. 15.3 months respectively, p = 0.3064). In patients receiving TMZ, DXM use concurrent with RT was a poor prognostic indicator of both OS (12.7 vs. 22.6 months, p = 0.003) and PFS (3.6 vs. 8.4 months, p <0.0001). DXM did not reduce OS in patients who received TMZ and BEV concurrently with RT (22.9 vs 22.8 months, p = 0.4818). On multivariable analysis, DXM use predicted an unfavorable OS hazard ratio (HR) = 1.72, p = 0.045)., Conclusions: Our results with TMZ, BEV, and RT are similar to previous studies in terms of PFS and OS. DXM use during RT with concurrent TMZ correlated with reduced OS and PFS unless BEV was administered.

Radiation necrosis (RN) is a serious complication that can occur in up to 10% of brain radiotherapy cases, with the incidence dependent on both dose and brain location. Available medical treatment for RN includes steroids, vitamin E, pentoxifylline, and hyperbaric oxygen. In a significant number of patients, however, RN is medically refractory and the patients experience progressive neurological decline, disabling headaches, and decreased quality of life. Vascular endothelial growth factor (VEGF) is a known mediator of cerebral edema in RN. Recent reports have shown successful treatment of RN with intravenous bevacizumab, a monoclonal antibody for VEGF. Bevacizumab, however, is associated with significant systemic complications including sinus thrombosis, pulmonary embolus, gastrointestinal tract perforation, wound dehiscence, and severe hypertension. Using lower drug doses may decrease systemic exposure and reduce complication rates. By using an intraarterial route for drug administration following blood-brain barrier disruption (BBBD), the authors aim to lower the bevacizumab dose while increasing target delivery. In the present report, the authors present the cases of 2 pediatric patients with cerebral arteriovenous malformations, who presented with medically intractable RN following stereotactic radiosurgery. They received a single intraarterial infusion of 2.5 mg/kg bevacizumab after hyperosmotic BBBD. At mean follow-up duration of 8.5 months, the patients had significant and durable clinical and radiographic response. Both patients experienced resolution of their previously intractable headaches and reversal of cushingoid features as they were successfully weaned off steroids. One of the patients regained significant motor strength. There was an associated greater than 70% reduction in cerebral edema. Intraarterial administration of a single low dose of bevacizumab after BBBD was safe and resulted in durable clinical and radiographic improvements at concentrations well below those required for the typical systemic intravenous route. Advantages over the intravenous route may include higher concentration of drug delivery to the affected brain, decreased systemic toxicity, and a significantly lower cost.