Immune profiling of patients with extranodal natural killer/T cell lymphoma treated with daratumumab.

Natural killer/T cell lymphoma (NKTCL) is a highly aggressive, heterogeneous non-Hodgkin lymphoma resulting from malignant proliferation of cytotoxic natural killer (NK) or T cells. Previous studies demonstrated variable expression of CD38 on NKTCL tumors. Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, was hypothesized to be a novel therapeutic option for patients with relapsed or refractory (R/R) NKTCL. In the phase 2 NKT2001 study (ClinicalTrials.gov Identifier: NCT02927925) assessing the safety and efficacy of daratumumab, a suboptimal overall response rate was seen in R/R NKTCL patients. One patient, whose tumors did not express CD38, responded to treatment, suggesting that the immunomodulatory activities of daratumumab may be sufficient to confer clinical benefit. To understand the suboptimal response rate and short duration of response, we investigated the immune profile of NKTCL patients from NKT2001 in the context of daratumumab anti-tumor activity. Tumor tissue and whole blood were, respectively, analyzed for CD38 expression and patient immune landscapes, which were assessed via cytometry by time-of-flight (CyTOF), multiparameter flow cytometry (MPFC), clonal sequencing, and plasma Epstein-Barr virus (EBV)-DNA level measurements. Changes observed in the immune profiles of NKTCL patients from NKT2001, including differences in B and T cell populations between responders and nonresponders, suggest that modulation of the immune environment is crucial for daratumumab anti-tumor activities in NKTCL. In conclusion, these findings highlight that the clinical benefit of daratumumab in NKTCL may be enriched by B/T cell-related biomarkers.

Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial.

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .

Data Science Methods for Nursing-Relevant Patient Outcomes and Clinical Processes: The 2019 Literature Year in Review.

Data science continues to be recognized and used within healthcare due to the increased availability of large data sets and advanced analytics. It can be challenging for nurse leaders to remain apprised of this rapidly changing landscape. In this article, we describe our findings from a scoping literature review of papers published in 2019 that use data science to explore, explain, and/or predict 15 phenomena of interest to nurses. Fourteen of the 15 phenomena were associated with at least one paper published in 2019. We identified the use of many contemporary data science methods (eg, natural language processing, neural networks) for many of the outcomes. We found many studies exploring Readmissions and Pressure Injuries. The topics of Artificial Intelligence/Machine Learning Acceptance, Burnout, Patient Safety, and Unit Culture were poorly represented. We hope that the studies described in this article help readers: (1) understand the breadth and depth of data science's ability to improve clinical processes and patient outcomes that are relevant to nurses and (2) identify gaps in the literature that are in need of exploration.

Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study.

BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL. METHODS: This phase 2 study with Simon's two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). RESULTS: In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5-43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29-339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43-106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94-438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab. CONCLUSIONS: In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.

Modeling Flowsheet Data to Support Secondary Use.

The purpose of this study was to create information models from flowsheet data using a data-driven consensus-based method. Electronic health records contain a large volume of data about patient assessments and interventions captured in flowsheets that measure the same "thing," but the names of these observations often differ, according to who performs documentation or the location of the service (eg, pulse rate in an intensive care, the emergency department, or a surgical unit documented by a nurse or therapist or captured by automated monitoring). Flowsheet data are challenging for secondary use because of the existence of multiple semantically equivalent measures representing the same concepts. Ten information models were created in this study: five related to quality measures (falls, pressure ulcers, venous thromboembolism, genitourinary system including catheter-associated urinary tract infection, and pain management) and five high-volume physiological systems: cardiac, gastrointestinal, musculoskeletal, respiratory, and expanded vital signs/anthropometrics. The value of the information models is that flowsheet data can be extracted and mapped for semantically comparable flowsheet measures from a clinical data repository regardless of the time frame, discipline, or setting in which documentation occurred. The 10 information models simplify the representation of the content in flowsheet data, reducing 1552 source measures to 557 concepts. The amount of representational reduction ranges from 3% for falls to 78% for the respiratory system. The information models provide a foundation for including nursing and interprofessional assessments and interventions in common data models, to support research within and across health systems.

Performance of a multiplexed dual analyte immunoassay for the early detection of non-small cell lung cancer.

OBJECTIVES: "PAULA's" test (Protein Assays Utilizing Lung cancer Analytes) is a novel multiplex immunoassay blood test that incorporates both tumor antigens and autoantibodies to determine the risk that lung cancer (LC) is present in individuals from a high-risk population. The test's performance characteristics were evaluated in a study using 380 retrospective clinical serum samples. METHODS: PAULA's test is performed on the Luminex xMAP technology platform, and detects a panel of 3 tumor antigens (CEA, CA-125, and CYFRA 21-1) and 1 autoantibody marker (NY-ESO-1). A training set (n = 230) consisting of 115 confirmed diagnoses of non-small cell lung carcinoma (NSCLC) cases and 115 age- and smoking history-matched controls was used to develop the LC predictive model. Data from an independent matched validation set (n = 150) was then used to evaluate the model developed, and determine the ability of the test to distinguish NSCLC cases from controls. RESULTS: The 4-biomarker panel was able to discriminate NSCLC cases from controls with 74% sensitivity, 80% specificity, and 0.81 AUC in the training set and with 77% sensitivity, 80% specificity, and 0.85 AUC in the independent validation set. The use of NY-ESO-1 autoantibodies substantially increased the overall sensitivity of NSCLC detection as compared to the 3 tumor markers alone. Overall, the multiplexed 4-biomarker panel assay demonstrated comparable performance to a previously employed 8-biomarker non-multiplexed assay. CONCLUSIONS: These studies confirm the value of using a mixed panel of tumor antigens and autoantibodies in the early detection of NSCLC in high-risk individuals. The results demonstrate that the performance of PAULA's test makes it suitable for use as an aid to determine which high-risk patients need to be directed to appropriate noninvasive diagnostic follow-up testing, especially low-dose CT (LDCT).

Post-translational N-glycosylation of type I transmembrane KCNE1 peptides: implications for membrane protein biogenesis and disease.

N-Glycosylation of membrane proteins is critical for their proper folding, co-assembly and subsequent matriculation through the secretory pathway. Here, we examine the kinetics of N-glycan addition to type I transmembrane KCNE1 K(+) channel ß-subunits, where point mutations that prevent N-glycosylation at one consensus site give rise to disorders of the cardiac rhythm and congenital deafness. We show that KCNE1 has two distinct N-glycosylation sites: a typical co-translational site and a consensus site ∼20 residues away that unexpectedly acquires N-glycans after protein synthesis (post-translational). Mutations that ablate the co-translational site concomitantly reduce glycosylation at the post-translational site, resulting in unglycosylated KCNE1 subunits that cannot reach the cell surface with their cognate K(+) channel. This long range inhibition is highly specific for post-translational N-glycosylation because mutagenic conversion of the KCNE1 post-translational site into a co-translational site restored both monoglycosylation and anterograde trafficking. These results directly explain how a single point mutation can prevent N-glycan attachment at multiple sites, providing a new biogenic mechanism for human disease.