A Model-Based Approach to Predict Short-Term Toxicity Benefits With Proton Therapy for Oropharyngeal Cancer

Purpose: The aim of this study was to generate normal tissue complication probability (NTCP) models in patients treated with either proton beam therapy (PBT) or intensitymodulated radiation therapy (IMRT) for oropharynx cancer and to use a model-based approach to investigate the added value of PBT in preventing treatment complications. Methods and Materials: For patients with advanced-stage oropharynx cancer treated with curative intent (PBT, n = 30; IMRT, n = 175), NTCP models were developed using multivariable logistic regression analysis with backward selection. For PBTtreated patients, an equivalent IMRT plan was generated to serve as a reference to determine the benefit of PBT in terms of NTCP. The models were then applied to the PBT-treated patients to compare predicted and observed clinical outcomes (calibration- in-the-large). Five binary endpoints were analyzed at 6 months after treatment: dysphagia >= grade 2, dysphagia >= grade 3, xerostomia >= grade 2, salivary duct inflammation >= grade 2, and feeding tube dependence. Corresponding toxicity grading was based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4. Paired t tests and Wilcoxon rank tests were used to compare mean NTCP results for endpoints between PBT and IMRT. Results: NTCP models developed based on outcomes from all patients were applied to those receiving PBT. NTCP values were calculated for the equivalent IMRT plans for all PBT-treated patients, revealing significantly higher NTCP values with IMRT. PBT was associated with statistically significant reductions in the mean NTCP values for each endpoint at 6 months after treatment, with the largest absolute differences in rates of >= grade 2 dysphagia and >= grade 2 xerostomia. Conclusions: NTCP models predict significant improvements in the probability of short-term, treatment-related toxicity with PBT compared with IMRT for oropharyngeal cancer. This study demonstrates an NTCP model-based approach to compare predicted patient outcomes when randomized data are not available. (C) 2019 Elsevier Inc. All rights reserved

Conducting a Supportive Oncology Clinical Trial During the COVID-19 Pandemic: Challenges and Strategies

The coronavirus disease 2019 (COVID-19) pandemic resulted in severe interruptions to clinical research worldwide. This global public health crisis required investigators and researchers to rapidly develop and implement new strategies and solutions to mitigate its negative impact on the progress of clinical trials. In this paper, we describe the challenges, strategies, and lessons learned regarding the continuation of a supportive oncology clinical trial during the pandemic. We hope to provide insight into the implementation of clinical trials during a public health emergency to be better prepared for future instances. Trial registration: ClinicalTrials.gov, a service of the US National Institute of Health (NCT03030859). Registered on 22 January 2017

Liver Is Able to Activate Naïve CD8+ T Cells with Dysfunctional Anti-Viral Activity in the Murine System

The liver possesses distinct tolerogenic properties because of continuous exposure to bacterial constituents and nonpathogenic food antigen. The central immune mediators required for the generation of effective immune responses in the liver environment have not been fully elucidated. In this report, we demonstrate that the liver can indeed support effector CD8+ T cells during adenovirus infection when the T cells are primed in secondary lymphoid tissues. In contrast, when viral antigen is delivered predominantly to the liver via intravenous (IV) adenovirus infection, intrahepatic CD8+ T cells are significantly impaired in their ability to produce inflammatory cytokines and lyse target cells. Additionally, intrahepatic CD8+ T cells generated during IV adenovirus infection express elevated levels of PD-1. Notably, lower doses of adenovirus infection do not rescue the impaired effector function of intrahepatic CD8+ T cell responses. Instead, intrahepatic antigen recognition limits the generation of potent anti-viral responses at both priming and effector stages of the CD8+ T cell response and accounts for the dysfunctional CD8+ T cell response observed during IV adenovirus infection. These results also implicate that manipulation of antigen delivery will facilitate the design of improved vaccination strategies to persistent viral infection

IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation

The features that define autoreactive T helper (Th) cell pathogenicity remain obscure. We have previously shown that Th cells require the transcription factor Bhlhe40 to mediate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here, using Bhlhe40 reporter mice and analyzing both polyclonal and TCR transgenic Th cells, we found that Bhlhe40 expression was heterogeneous after EAE induction, with Bhlhe40-expressing cells displaying marked production of IFN-γ, IL-17A, and granulocyte-macrophage colony-stimulating factor. In adoptive transfer EAE models, Bhlhe40-deficient Th1 and Th17 cells were both nonencephalitogenic. Pertussis toxin (PTX), a classical co-adjuvant for actively induced EAE, promoted IL-1β production by myeloid cells in the draining lymph node and served as a strong stimulus for Bhlhe40 expression in Th cells. Furthermore, PTX co-adjuvanticity was Bhlhe40 dependent. IL-1β induced Bhlhe40 expression in polarized Th17 cells, and Bhlhe40-expressing cells exhibited an encephalitogenic transcriptional signature. In vivo, IL-1R signaling was required for full Bhlhe40 expression by Th cells after immunization. Overall, we demonstrate that Bhlhe40 expression identifies encephalitogenic Th cells and defines a PTX–IL-1–Bhlhe40 pathway active in EAE

Low CCR7-Mediated Migration of Human Monocyte Derived Dendritic Cells in Response to Human Respiratory Syncytial Virus and Human Metapneumovirus

Human respiratory syncytial virus (HRSV) and, to a lesser extent, human metapneumovirus (HMPV) and human parainfluenza virus type 3 (HPIV3), can re-infect symptomatically throughout life without significant antigenic change, suggestive of incomplete or short-lived immunity. In contrast, re-infection by influenza A virus (IAV) largely depends on antigenic change, suggestive of more complete immunity. Antigen presentation by dendritic cells (DC) is critical in initiating the adaptive immune response. Antigen uptake by DC induces maturational changes that include decreased expression of the chemokine receptors CCR1, CCR2, and CCR5 that maintain DC residence in peripheral tissues, and increased expression of CCR7 that mediates the migration of antigen-bearing DC to lymphatic tissue. We stimulated human monocyte-derived DC (MDDC) with virus and found that, in contrast to HPIV3 and IAV, HMPV and HRSV did not efficiently decrease CCR1, 2, and 5 expression, and did not efficiently increase CCR7 expression. Consistent with the differences in CCR7 mRNA and protein expression, MDDC stimulated with HRSV or HMPV migrated less efficiently to the CCR7 ligand CCL19 than did IAV-stimulated MDDC. Using GFP-expressing recombinant virus, we showed that the subpopulation of MDDC that was robustly infected with HRSV was particularly inefficient in chemokine receptor modulation. HMPV- or HRSV-stimulated MDDC responded to secondary stimulation with bacterial lipopolysaccharide or with a cocktail of proinflammatory cytokines by increasing CCR7 and decreasing CCR1, 2 and 5 expression, and by more efficient migration to CCL19, suggesting that HMPV and HRSV suboptimally stimulate rather than irreversibly inhibit MDDC migration. This also suggests that the low concentration of proinflammatory cytokines released from HRSV- and HMPV-stimulated MDDC is partly responsible for the low CCR7-mediated migration. We propose that inefficient migration of HRSV- and HMPV-stimulated DC to lymphatic tissue contributes to reduced adaptive responses to these viruses

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, From Training Through Independent Practice.

BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. METHODS: We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). CONCLUSIONS: In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, From Training Through Independent Practice.

BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. METHODS: We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). CONCLUSIONS: In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416