Dendritic Cell-Based Immunotherapy in Patients With Resected Pancreatic Cancer.

PURPOSE: Immunotherapies have shown limited responses in patients with advanced pancreatic cancer. Recently, we reported that dendritic cell (DC)-based immunotherapy induced T-cell responses against pancreatic cancer antigens. The primary objective of this study was to determine the efficacy of DC-based immunotherapy to prevent recurrence of disease. METHODS: This was a single-center, open-label, single-arm, combined phase I/II trial. The primary end point was the 2-year recurrence-free survival (RFS) rate. A 2-year RFS rate of ≥60% was defined as a clinically meaningful improvement. We included patients with pancreatic cancer after resection and completion of standard-of-care (SOC) treatment without recurrent disease on cross-sectional imaging. Patients were treated with autologous DCs pulsed with an allogeneic mesothelioma tumor cell lysate, comprising antigens also expressed in pancreatic ductal adenocarcinoma. RESULTS: Thirty-eight patients were included in the analysis of the primary end point (47% male, 53% female). The median age was 62 years (IQR, 55-68). Twenty-eight patients (74%) received five DC vaccinations and completed the study protocol. Three patients (8%) received four vaccinations, and seven patients (16%) received three vaccinations. After a median follow-up of 25.5 months, 26 patients (68%) had not developed recurrence of disease. The estimated 2-year RFS was 64%. Vaccination led to the enrichment of circulating activated CD4+ T cells and the detection of treatment-induced immune responses in vitro. T-cell receptor-sequencing analyses of a resected solitary lung metastasis showed influx of vaccine-specific T cells. CONCLUSION: This study reached its primary end point of a 2-year RFS rate of ≥60% following pancreatectomy after SOC treatment and adjuvant DC-based immunotherapy in patients with pancreatic cancer. These results warrant a future randomized trial.

Dendritic cells loaded with allogeneic tumour cell lysate plus best supportive care versus best supportive care alone in patients with pleural mesothelioma as maintenance therapy after chemotherapy (DENIM): a multicentre, open-label, randomised, phase 2/3 study.

BACKGROUND: Dendritic cell immunotherapy has proven to be safe and induces an immune response in humans. We aimed to establish the efficacy of dendritic cells loaded with allogeneic tumour cell lysate (MesoPher, Amphera BV, 's-Hertogenbosch, Netherlands) as maintenance therapy in patients with pleural mesothelioma. METHODS: In this open-label, randomised, phase 2/3 study, patients with histologically confirmed unresectable pleural mesothelioma, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status score of 0-1, and non-progressing disease after four to six cycles of standard chemotherapy (with pemetrexed 500 mg/m2 plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve of 5]) were recruited from four centres in Belgium, France, and The Netherlands. Participants were randomly assigned (1:1), using block randomisation (block size of 4), stratified by centre and histology (epithelioid vs other), to MesoPher treatment plus best supportive care or best supportive care alone. Patients received up to a maximum of five MesoPher infusions, with treatment administered on days 1, 15, and 29, and weeks 18 and 30. At each timepoint, participants received an injection of 25 × 106 dendritic cells (two-thirds of the dendritic cells were administered intravenously and a third were injected intradermally). Best supportive care was per local institutional standards. The primary endpoint was overall survival, assessed in all participants randomly assigned to treatment (full analysis set) and safety assessed in all randomly assigned participants, and who underwent leukapheresis if they were in the MesoPher group. This study is registered with ClinicalTrials.gov, NCT03610360, and is closed for accrual. FINDINGS: Between June 21, 2018, and June 10, 2021, 176 patients were screened and randomly assigned to the MesoPher group (n=88) or best supportive care alone group (n=88). One participant in the MesoPher group did not undergo leukapheresis. Mean age was 68 years (SD 8), 149 (85%) of 176 were male, 27 (15%) were female, 173 (98%) were White, two were Asian (1%), and one (1%) was other race. As of data cutoff (June 24, 2023), after a median follow up of 15·1 months (IQR 9·5-22·4), median overall survival was 16·8 months (95% CI 12·4-20·3; 61 [69%] of 88 died) in the MesoPher group and 18·3 months (14·3-21·9; 59 [67%] of 88 died) in the best supportive care group (hazard ratio 1·10 [95% CI 0·77-1·57]; log-rank p=0·62). The most common grade 3-4 treatment-emergent adverse events were chest pain (three [3%] of 87 in the MesoPher group vs two [2%] of 88 in the best supportive care group), dyspnoea (none vs two [2%]), anaemia (two [2%] vs none), nausea (none vs two [2%]), and pneumonia (none vs two [2%]). No deaths due to treatment-emergent adverse events were recorded. Treatment-related adverse events consisted of infusion-related reactions (fever, chills, and fatigue), which occurred in 64 (74%) of 87 patients in the MesoPher group, and injection-site reactions (itch, erythema, and induration), which occurred in 73 (84%) patients, and all were grade 1-2 in severity. No deaths were determined to be treatment related. INTERPRETATION: MesoPher did not show improvement in overall survival in patients with pleural mesothelioma. Immune checkpoint therapy is now standard of care in pleural mesothelioma. Further randomised studies are needed of combinations of MesoPher and immune checkpoint therapy, which might increase efficacy without adding major toxicities. FUNDING: Amphera BV and EU HORIZON.

The effects of residential segregation on cognition among U.S. older adults: a systematic review based on the social determinants of health model.

OBJECTIVES: This systematic review aims to advance the understanding of the complicated effects of segregation on older adults' cognition and provide guidance for future research. METHOD: A systematic review using the Social Determinants of Health framework to examine the relationship between segregation and cognition across the selected literature. RESULTS: Eight papers met the criteria for inclusion. All selected studies examined the influence of living in a segregated area on older adults' cognition, covering older adults from different racial/ethnic groups. The association between segregation and cognition was found in different directions across different racial/ethnic groups. The effects can be varied depending on race/ethnicity, level of education, neighborhood socioeconomic status, or social context. CONCLUSION: This review identified existing gaps in understanding the relationship between segregation and cognition. Future studies should carefully adopt the segregation measures, acknowledge the varying segregation experience among different racial/ethnic groups, and consider more social determinant factors in research.

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRASG12C-Mutated NSCLC Treated With Sotorasib.

INTRODUCTION: For patients with KRASG12C-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression. METHODS: Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected before sotorasib treatment, at first-response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency analysis. Tumor response and progression-free survival were assessed per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Pretreatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior progression-free survival (hazard ratio [HR] 2.13 [95% confidence interval [CI]: 1.06-4.30], p = 0.031) and overall survival (HR 2.61 [95% CI: 1.16-5.91], p = 0.017). At first-response evaluation (n = 40), 29 patients (73%) had a molecular response. Molecular nonresponders had inferior overall survival (HR 3.58 [95% CI: 1.65-7.74], p = 0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p = 0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations. CONCLUSIONS: Our data suggest detectable pretreatment KRASG12C ctDNA as a marker for poor prognosis and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.

Genomic characterization and detection of potential therapeutic targets for peritoneal mesothelioma in current practice.

Peritoneal mesothelioma (PeM) is an aggressive tumor with limited treatment options. The current study aimed to evaluate the value of next generation sequencing (NGS) of PeM samples in current practice. Foundation Medicine F1CDx NGS was performed on 20 tumor samples. This platform assesses 360 commonly somatically mutated genes in solid tumors and provides a genomic signature. Based on the detected mutations, potentially effective targeted therapies were identified. NGS was successful in 19 cases. Tumor mutational burden (TMB) was low in 10 cases, and 11 cases were microsatellite stable. In the other cases, TMB and microsatellite status could not be determined. BRCA1 associated protein 1 (BAP1) mutations were found in 32% of cases, cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) and neurofibromin 2 (NF2) mutations in 16%, and ataxia-telangiectasia mutated serine/threonine kinase (ATM) in 11%. Based on mutations in the latter two genes, potential targeted therapies are available for approximately a quarter of cases (i.e., protein kinase inhibitors for three NF2 mutated tumors, and polyADP-ribose polymerase inhibitors for two ATM mutated tumors). Extensive NGS analysis of PeM samples resulted in the identification of potentially effective targeted therapies for about one in four patients. Although these therapies are currently not available for patients with PeM, ongoing developments might result in new treatment options in the future.

The Neo-Open Reading Frame Peptides That Comprise the Tumor Framome Are a Rich Source of Neoantigens for Cancer Immunotherapy.

Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate the whole-genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOP) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of noncoding regions of the genome downstream of a rearrangement breakpoint, i.e., where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T cells specific for hidden NOPs in peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for the detection of NOPs.

Hyaluronic acid-ibuprofen conjugation: a novel ototherapeutic approach protecting inner ear cells from inflammation-mediated damage.

There is a substantial need of effective drugs for the treatment of hearing loss, which affects nearly 500 million individuals globally. Hearing loss can be the result of intense or prolonged noise exposure, ototoxic drugs, infections, and trauma, which trigger inflammatory signaling cascades that lead to irreversible damage to cochlear structures. To address this, we developed and characterized a series of covalent conjugates of anti-inflammatory drugs to hyaluronic acid (HA), for potential use as topical ototherapeutics. These conjugates were tested in in vitro assays designed to mirror physiological processes typically observed with acoustic trauma. Intense noise exposure leads to macrophage recruitment to the cochlea and subsequent inflammatory damage to sensory cells. We therefore first tested our conjugates' ability to reduce the release of inflammatory cytokines in macrophages. This anti-inflammatory effect on macrophages also translated to increased cochlear cell viability. In our initial screening, one conjugate, ibuprofen-HA, demonstrated significantly higher anti-inflammatory potential than its counterparts. Subsequent cytokine release profiling of ibuprofen-HA further confirmed its ability to reduce a wider range of inflammatory markers, to a greater extent than its equivalent unconjugated drug. The conjugate's potential as a topical therapeutic was then assessed in previously developed tympanic and round window membrane tissue permeation models. As expected, our data indicate that the conjugate has limited tympanic membrane model permeability; however, it readily permeated the round window membrane model and to a greater extent than the unconjugated drug. Interestingly, our data also revealed that ibuprofen-HA was well tolerated in cellular and tissue cytocompatibility assays, whereas the unconjugated drug displayed significant cytotoxicity at equivalent concentrations. Moreover, our data highlighted the importance of chemical conjugation of ibuprofen to HA; the conjugate had improved anti-inflammatory effects, significantly reduced cytotoxicity, and is more suitable for therapeutic formulation. Overall, this work suggests that ibuprofen-HA could be a promising safe and effective topical ototherapeutic for inflammation-mediated cochlear damage.

In vitro characterization of novel hyaluronan-antioxidant conjugates as potential topical therapeutics against hearing loss.

Noise-induced hearing loss affects roughly 430 million people worldwide. Current treatment options often require invasive medical procedures, and to date, there are no FDA-approved drug therapies. While the causes can be diverse, noise induced hearing loss is unequivocally associated with oxidative stress and inflammation, and subsequent damage to the inner ear structures. Several studies have shown that various antioxidants such as glutathione, cysteine, and methionine can be used to mitigate oxidative damage from reactive oxygen species; however, these studies relied on invasive or systemic drug delivery methods. This study focused on the development and characterization of a novel series of antioxidant compounds that would be suitable for non or minimally invasive topical inner ear delivery and could mitigate reactive oxygen species associated cellular damage. Specifically, a series of covalent conjugates were synthesized by using hyaluronan as a drug carrier, and methionine, cysteine or glutathione as antioxidant drugs. The conjugates were tested for their ability to readily permeate though in vitro round window membrane and tympanic membrane permeation models, as well as their in vitro internalization into cochlear cells. Our data revealed interdependence between the molecular weight of the hyaluronan carrier, and the tissue and cellular membrane permeation capacity. Subsequent screening of the adequately sized conjugates in in vitro acellular assays revealed the strongest antioxidant activity for the cysteine and glutathione conjugates. These oxidative stress protective effects were further confirmed in cellular in vitro assays. Collectively, the data herein showcase the potential value of these conjugates as therapeutics against oxidative-stress-mediated cellular damage specific to noise-induced hearing loss.

Rintatolimod in Advanced Pancreatic Cancer enhances Anti-Tumor Immunity through Dendritic Cell-Mediated T Cell Responses.

PURPOSE: Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the anti-tumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of advanced PDAC patients. PATIENTS AND METHODS: Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunological factors on survival outcomes was assessed through univariate Cox proportional hazards models. RESULTS: Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1s) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronounced DC and T cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1. CONCLUSIONS: This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunological tolerance by enhancing anti-tumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes.

Hepatotoxicity in patients with non-small cell lung cancer treated with sotorasib after prior immunotherapy: a comprehensive clinical and pharmacokinetic analysis.

BACKGROUND: Sotorasib given after immunotherapy could put patients at increased risk of hepatotoxicity. Therefore, there is a need to gain insight into the potential correlation between anti-PD-(L)1 treatment, anti-PD-(L)1 concentrations, sotorasib concentrations, and the incidence of hepatotoxicity during sotorasib. METHODS: Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker cohort study (NCT05221372). Plasma samples were collected prior and during sotorasib treatment for anti-PD-1 and sotorasib concentrations. ALT/AST/ALP/GGT increases were collected prospectively and graded according to CTCAEv5.0. Severe hepatotoxicity was defined as grade ≥3 ALT/AST/ALP/GGT increase. FINDINGS: Of the 91 included patients, 80 (88%) received prior anti-PD-(L)1. Prior anti-PD-(L)1 and prior immune-related hepatotoxicity were associated with a higher incidence of severe hepatotoxicity (35% versus 0%, p = 0.016 and 75% versus 31%, p = 0.019, respectively). Patients with an interval of ≤6 weeks between anti-PD-(L)1 and sotorasib (n = 18) had a significantly higher incidence of severe hepatotoxicity than those with a 6-12 week (n = 24) and ≥12 week (n = 38) interval (83% versus 33% versus 13%, respectively, p < 0.0001). Sotorasib trough concentrations did not differ significantly between those with or without severe hepatotoxicity (106 versus 126 ng/mL, p = 0.16). Pembrolizumab concentrations were higher in those with severe hepatotoxicity versus those without (25.6 versus 6.1 µg/mL, p < 0.0001). INTERPRETATION: In this preliminary prospective study, sotorasib after PD-(L)1 blockade was associated with severe hepatotoxicity, especially in patients with a short interval between treatments, prior immune-related hepatitis and higher anti-PD-1 plasma concentrations. Our results suggest a minimum interval of 6 weeks between anti-PD-(L)1 and sotorasib to minimize the risk of hepatotoxicity. FUNDING: None.

Patients' evaluation of aftercare following hospitalization for COVID-19: satisfaction and unmet needs.

BACKGROUND: Patient experiences with COVID-19 aftercare remain largely unknown. We evaluated COVID-19 aftercare from a patient perspective one year after hospitalization, assessing satisfaction and its associated factors, and unmet needs. METHODS: The Satisfaction with COVID-19 Aftercare Questionnaire (SCAQ) was developed as part of a multicenter prospective cohort study and administered one year after hospital discharge. The SCAQ assesses (1) patient satisfaction, comprising information provision, rehabilitation, follow-up by hospitals and general practitioners (GPs), the most important aftercare topics, and overall satisfaction, and (2) unmet needs. RESULTS: 487/561 (87%) COVID-19 patients completed the SCAQ, all had been discharged from the hospital between March 2020 and May 2021. Among responders, the median age of patients was 60 (IQR 54-67) years, 338 (69%) were male, and the median length of stay in the hospital was 13 (6-27) days. Patients were least satisfied with information on who could be contacted with questions when health problems arise (59% satisfied or very satisfied). Many patients (75%) received rehabilitation, most frequently community-based (70%). Across the different community-based therapies, ≥ 60% of patients were satisfied with shared-decision making and ≥ 70% with the received therapy; a majority (≥ 79%) indicated a preference for receiving the same therapy again if needed. Regarding follow-up by hospitals, 86% of patients received this follow-up, most frequently visiting a pulmonologist (96%), being generally satisfied with the received aftercare. Aftercare from GPs was received by 39% of patients, with 88% being satisfied with the GP's availability and 79% with referral to appropriate aftercare providers. Patients (> 50%) considered information-related items most important in aftercare. Overall, patients rated their satisfaction with aftercare 8/10 (7-9) points. Those who received medical rehabilitation (versus no rehabilitation, adjusted beta 0.61 [95%CI 0.11 to 1.11], p = 0.02) or aftercare by a hospital medical specialist (1.1 [0.46 to 1.64], p < 0.001) or GP (0.39 [0.053 to 0.72], p = 0.023) reported significantly higher satisfaction than those without such aftercare. Unmet needs were reported by 35% of patients, with lack of information (20%) and lack of additional aftercare and/or involvement of their GP (19%) being the most frequently reported. CONCLUSION: Despite the forced quick development of COVID-19 aftercare, patients were generally satisfied. Follow-up by healthcare professionals and information provision is important to meet patients' aftercare needs.

Combining Genomic Biomarkers to Guide Immunotherapy in Non-Small Cell Lung Cancer.

PURPOSE: The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease. EXPERIMENTAL DESIGN: To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB). RESULTS: In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival. CONCLUSIONS: The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.

Acute COVID-19 treatment is not associated with health problems 2 years after hospitalization.

OBJECTIVES: Various mechanisms, such as immune dysregulation, viral reservoir, and auto-immunity, are hypothesized to underlie the pathogenesis of long-term health problems after hospitalization for COVID-19. We aimed to assess the effect of in-hospital COVID-19 treatments on prominent long-term health problems. METHODS: In this prospective multicenter cohort study, we enrolled patients (age ≥18 years) who had been hospitalized for COVID-19 in the Netherlands between July 2020 and October 2021. We retrospectively collected data on in-hospital COVID-19 treatments, including steroid, anti-inflammatory, and antiviral treatments. Patients completed questionnaires on self-reported recovery, dyspnea, fatigue, cognitive failures, and health-related quality of life and performed the 6-minute walk test at the 2-year follow-up visit. RESULTS: Five hundred two patients with COVID-19 were included, all were discharged from the hospital between March 2020 and June 2021. The median age at admission was 60.0 (IQR 53.0-68.0) years and 350 (69.7%) patients were male. At hospital admission, 5/405 (1.2%) of the patients had been vaccinated against SARS-CoV-2. Among all 502 patients, the majority (248 [49.4%]) received steroids only, 57 (11.4%) anti-inflammatory treatment, 78 (15.5%) antiviral treatment, and 119 (23.7%) none during hospitalization. Long-term health problems were common in all groups. We found that in-hospital treatments were not significantly associated with health problems at 2 years after hospital discharge, nor after adjusting for confounders. CONCLUSION: Many patients with COVID-19 suffer from long-term health problems 2 years after hospital discharge. Acute treatment for COVID-19 is not associated with long-term health problems.

Exploring the Cost Effectiveness of a Whole-Genome Sequencing-Based Biomarker for Treatment Selection in Patients with Advanced Lung Cancer Ineligible for Targeted Therapy.

OBJECTIVE: We aimed to perform an early cost-effectiveness analysis of using a whole-genome sequencing-based tumor mutation burden (WGS-TMB), instead of programmed death-ligand 1 (PD-L1), for immunotherapy treatment selection in patients with non-squamous advanced/metastatic non-small cell lung cancer ineligible for targeted therapy, from a Dutch healthcare perspective. METHODS: A decision-model simulating individual patients with metastatic non-small cell lung cancer was used to evaluate diagnostic strategies to select first-line immunotherapy only or the immunotherapy plus chemotherapy combination. Treatment was selected using PD-L1 [A, current practice], WGS-TMB [B], and both PD-L1 and WGS-TMB [C]. Strategies D, E, and F take into account a patient's disease burden, in addition to PD-L1, WGS-TMB, and both PD-L1 and WGS-TMB, respectively. Disease burden was defined as a fast-growing tumor, a high number of metastases, and/or weight loss. A threshold of 10 mutations per mega-base was used to classify patients into TMB-high and TMB-low groups. Outcomes were discounted quality-adjusted life-years (QALYs) and healthcare costs measured from the start of first-line treatment to death. Healthcare costs includes drug acquisition, follow-up costs, and molecular diagnostic tests (i.e., standard diagnostic techniques and/or WGS for strategies involving TMB). Results were reported using the net monetary benefit at a willingness-to-pay threshold of €80,000/QALY. Additional scenario and threshold analyses were performed. RESULTS: Strategy B had the lowest QALYs (1.84) and lowest healthcare costs (€120,800). The highest QALYs and healthcare costs were 2.00 and €140,400 in strategy F. In the base-case analysis, strategy A was cost effective with the highest net monetary benefit (€27,300), followed by strategy B (€26,700). Strategy B was cost effective when the cost of WGS testing was decreased by at least 24% or when immunotherapy results in an additional 0.5 year of life gained or more for TMB high compared with TMB low. Strategies C and F, which combined TMB and PD-L1 had the highest net monetary benefit (≥ €76,900) when the cost of WGS testing, immunotherapy, and chemotherapy acquisition were simultaneously reduced by at least 47%, 39%, and 43%, respectively. Furthermore, strategy C resulted in the highest net monetary benefit (≥ €39,900) in a scenario where patients with both PD-L1 low and TMB low were treated with chemotherapy instead of immunotherapy plus chemotherapy. CONCLUSIONS: The use of WGS-TMB is not cost effective compared to PD-L1 for immunotherapy treatment selection in non-squamous metastatic non-small cell lung cancer in the Netherlands. WGS-TMB could become cost effective provided there is a reduction in the cost of WGS testing or there is an increase in the predictive value of WGS-TMB for immunotherapy effectiveness. Alternatively, a combination strategy of PD-L1 testing with WGS-TMB would be cost effective if used to support the choice to withhold immunotherapy in patients with a low expected benefit of immunotherapy.

An Integrative Review of Social Determinants of Glycemic Targets Achievement in Adults with Type 2 Diabetes in the United States.

Several individual social determinants of health have been identified as significant factors contributing to achieving glycemic targets (glycated hemoglobin < 7). However, it remains unclear how these social variables individually or collectively contribute to glycemic targets among adults with type 2 diabetes (T2D) in the United States (U.S.) The purpose of the current integrative review (IR) was to describe and synthesize findings from studies on social determinants of glycemic target achievement in adults with T2D in the U.S. and integrate them into the United States Department of Health and Human Services Conceptual Framework. The databases searched included PubMed, CINAHL Plus with Full Text, Medline with Full Text [EBSCO], Google Scholar, bibliography, and hand searching. A total of 948 records were identified. After excluding duplicates and irrelevant studies based on inclusion and exclusion criteria through title, abstract, and full-text screening, 13 studies were finally included in this IR. The results revealed that race/ethnicity, economic access and stability, educational access and quality, healthcare access and quality, neighborhood and built environment, and social and community context contribute to glycemic target achievement among adult patients with T2D in the U.S. Integrating findings from key studies on social determinants of glycemic health may contribute to developing interventions aimed at reducing and eventually eradicating health disparities for individuals with and at risk for T2D in the U.S.

FOLFIRINOX chemotherapy modulates the peripheral immune landscape in pancreatic cancer: Implications for combination therapies and early response prediction.

BACKGROUND: FOLFIRINOX chemotherapy has improved outcomes for pancreatic cancer patients, but poor long-term survival outcomes and high toxicity remain challenges. This study investigates the impact of FOLFIRINOX on plasma proteins and peripheral immune cells to guide immune-based combination therapies and, ideally, to identify a potential biomarker to predict early disease progression during FOLFIRINOX. METHODS: Blood samples were collected from 86 pancreatic cancer patients before and two weeks after the first FOLFIRINOX cycle and subjected to comprehensive immune cell and proteome profiling. Principal Component Analysis and Linear Mixed Effect Regression models were used for data analysis. FOLFIRINOX efficacy was radiologically evaluated after the fourth cycle. RESULTS: One cycle of FOLFIRINOX diminished tumour-cell-related pathways and enhanced pathways related to immune activation, illustrated by an increase in pro-inflammatory IL-18, IL-15, and TNFRSF4. Similarly, FOLFIRINOX promoted the activation of CD4 + and CD8 + T cells, the proliferation of NK(T), and the activation of antigen-presenting cells. Furthermore, high pre-treatment levels of VEGFA and PRDX3 and an elevation in FCRL3 levels after one cycle predicted early progression under FOLFIRINOX. Finally, patients with progressive disease exhibited high levels of inhibitory markers on B cells and CD8 + T cells, while responding patients exhibited high levels of activation markers on CD4 + and CD8 + T cell subsets. CONCLUSION: FOLFIRINOX has immunomodulatory effects, providing a foundation for clinical trials exploring immune-based combination therapies that harness the immune system to treat pancreatic cancer. In addition, several plasma proteins hold potential as circulating predictive biomarkers for early prediction of FOLFIRINOX response in patients with pancreatic cancer.

Strategies to Strengthen Nursing PhD Enrollment: An Ecological Systems Perspective.

BACKGROUND: Nurses with a Doctor of Philosophy (PhD) degree are essential to developing nursing knowledge, promoting health outcomes, and educating the next generation of nurses. Declining enrollment in nursing PhD programs calls for purposeful action. Guided by Bronfenbrenner's Ecological Systems Framework, this article outlines barriers and facilitators, and offers strategies to increase PhD enrollment. METHOD: Extant literature and the authors' cumulative experiences in PhD education and research were reviewed to identify strategies to increase PhD enrollment. RESULTS: Multilevel influences impede or facilitate enrollment in PhD programs. Strategies addressing individual and interpersonal influences included intentional personalized recruiting and early outreach to students at various levels of education. Institutional and organizational strategies included research partnerships and programs, and financial and infrastructure support. Sociocultural strategies included image branding and a positive social media presence supporting nurse scientists. CONCLUSION: Strategies to enhance PhD enrollment across all levels can spark interest in nursing science and PhD enrollment. [J Nurs Educ. 2023;62(12):669-678.].