Systematic Literature Review of the Prevalence and Prognostic Value of Delta-Like Ligand 3 Protein Expression in Small Cell Lung Cancer

Background: Delta-like ligand 3 (DLL3), a member of the Notch pathway, has been identified as a potential therapeutic target as it is highly expressed in small cell lung cancer (SCLC), a subtype accounting for 15% of lung cancer cases. Objective: A systematic literature review (SLR) was conducted to understand the prevalence and prognostic impact of DLL3 expression on survival of patients with SCLC and treatment response. Patients and Methods: Systematic literature searches were conducted across multiple databases to capture studies of any SCLC population that evaluated DLL3 expression. Specific outcomes of interest included prevalence of DLL3 expression, method of expression analysis, and impact on outcome, including treatment response and survival (overall, progression-free, disease-free) according to varying levels of DLL3 expression/positivity. Standard risk of bias tools were used to evaluate study quality. Results: Among the 30 included studies, the most common DLL3 testing method was immunohistochemistry (N = 26, 86.7%). For comparability, results focused on the 13 (22.3%) studies that used the Ventana DLL3 (SP347) immunohistochemistry assay. The prevalence of DLL3 positivity ranged from 80.0–93.5% for studies using a threshold of ≥ 1% of tumor cells (N = 4) and 58.3–91.1% for studies with a ≥ 25% threshold (N = 4). DLL3 expression was generally categorized as high using cutoffs of ≥ 50% (prevalence range: 45.8–79.5%; N = 6) or ≥ 75% (prevalence range: 47.3–75.6%; N = 5) of cells with positivity. Two studies used an H-score of ≥ 150 to define high DLL3 expression with prevalence ranging from 33.3–53.1%. No consistent associations were seen between DLL3 expression level and patient age, sex, smoking history, or disease stage. Two studies reported change in DLL3 expression category (high versus low) before and after chemotherapy. No statistically significant differences were reported between DLL3 expression groups and survival (overall, progression-free, or disease-free) or treatment response. Conclusions: There is a high prevalence of DLL3 expression in SCLC. Further research and analytical methods may help to characterize different populations of patients with SCLC based on DLL3 expression. While no significant prognostic factor in the included studies was identified, additional cohort studies using standardized methodology, with longer follow-up, are needed to better characterize any potential differences in patient survival or response by DLL3 expression level in SCLC.</p

The effect of bovine dairy products and their components on the incidence and natural history of infection: a systematic literature review

Abstract Background Dairy products and their components may impact immune function, although the current evidence base has some research gaps. As part of a larger systematic literature review of dairy products/components (including probiotics, dairy proteins, and dairy fats) and immune function, we identified the available epidemiologic research on the impact of dairy products/components on incidence and natural history of infectious diseases. Methods PubMed and Embase databases were systematically searched through May 2022 to identify eligible studies using pre-defined Population, Intervention, Comparator, Outcomes, and Study design criteria. Herein, we focused on describing the impacts of dairy product/component on infectious disease outcomes, including the effect on leukocyte and cytokine response in humans. Risk of bias assessment was performed using the Academy of Nutrition and Dietetics Quality Criteria Checklist. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Results Among 9,832 studies identified from the larger literature search, 133 relevant publications from 128 studies reported on dairy product/component and infectious disease outcomes. Few studies are available on the impact of non-fermented milk and traditional yogurt on infectious disease. Evidence was identified to suggest milk and yogurt drinks fermented with Lactobacillus strains reduce the risk and burden of common infectious diseases (CIDs), although the findings are mixed and difficult to reconcile due to heterogenous study populations, bacterial strains, and study methods. Few studies are available on the impact of dairy products/components on the natural history of infection, with the available findings indicating probiotics may both improve gastrointestinal symptoms among HIV-infected persons and help eradicate and alleviate the symptoms of Heliobacter (H.) pylori. The available evidence also suggests lactoferrin may reduce the virological burden of COVID-19 and hepatitis C virus. No consistent changes in leukocytes or cytokine production were observed for any type of dairy product or their components, but probiotics appeared to enhance natural killer cell levels/activity and the phagocytic process. Conclusions Dairy products, particularly those with added probiotics, may represent an easily accessible nutritional intervention to prevent and improve the course of infectious diseases. This review highlights the need for additional research in this potentially impactful area. Prospero registration CRD42022333780

Additional file 1 of The effect of bovine dairy products and their components on the incidence and natural history of infection: a systematic literature review

Additional file 1. PRISMA checklist

Medically attended anxiety and depression among cold agglutinin disease patients and matched comparisons, 2006–2016.

aHR, adjusted hazard ratio; CAD, cold agglutinin disease; CI, confidence interval; ICD, International Classification of Diseases. Median (range) time to first eventc was 20 (0–110) months for patients with CADa and 35 (0–113) months for their matched comparisons. aIncluded both primary CAD (not due to secondary causes) and secondary cold agglutinin syndrome (coexisting diagnosis of malignancy or infection). bCox proportional hazard models, adjusted for age, gender, race, region, comorbidity score group, and cluster. cThe time to first event was determined as the time from index date (date of diagnosis for both patients with CAD and their matched comparisons) to the confirmation date of the last measure (if >1 measure was used to diagnose anxiety and depression).</p

Demographic and clinical characteristics of cold agglutinin disease (CAD) patients and their matched comparisons, 2006–2016.

Demographic and clinical characteristics of cold agglutinin disease (CAD) patients and their matched comparisons, 2006–2016.</p

International Classification of Diseases (ICD) medications and procedural codes.

International Classification of Diseases (ICD) medications and procedural codes.</p

Medically attended anxiety and depression among primary cold agglutinin disease patients and matched comparisons, 2006–2016.

aHR, adjusted hazard ratio; CAD, cold agglutinin disease; CI, confidence interval; ICD, International Classification of Diseases. Median (range) time to first eventb was 20 (0–110) months for patients with CADc and 35 (0–111) months for their matched comparisons. aCox proportional hazard models, adjusted for age, gender, race, region, comorbidity score group, and cluster. bThe time to first event was determined as the time from index date (date of diagnosis for both patients with CAD and their matched comparisons) to the confirmation date of the last measure (if >1 measure was used to diagnose anxiety and depression). cPrimary CAD only (not due to secondary causes).</p

Diagnoses excluded for sensitivity analysis of primary cold agglutinin disease.

(DOCX)</p

Diagnosis codes for Charlson Comorbidity Index score.

(DOCX)</p

Medically attended anxiety and depression among cold agglutinin disease patients and matched comparisons, 2006–2016.

Benzodiazapene use was not considered in these analyses. (DOCX)</p