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Targeted Oncology Nov 2023Delta-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...
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.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Prognosis; Ligands; Prevalence; Membrane Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 37930513
DOI: 10.1007/s11523-023-01008-x -
Seminars in Arthritis and Rheumatism Oct 2023To determine the prognostic factors of dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a rare disease and often complicated by... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To determine the prognostic factors of dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a rare disease and often complicated by life-threatening, rapidly progressive interstitial lung disease.
METHODS
Herein, we searched the Medline, Embase, and Cochrane Library databases and extracted studies published before August 23, 2022. Pooled analysis of hazard ratios (HRs) or odds ratios was used to identify prognostic factors for mortality among patients with anti-MDA5 antibody-positive dermatomyositis (MDA5+ DM).
RESULTS
Twenty-nine cohorts with 2,645 patients were included in this meta-analysis. Factors related to poor prognosis included old age (HR 1.54, 95% confidence interval (CI) 1.41-1.69, p < 0.01), male sex (HR 2.07, 95% CI 1.34-3.18, p < 0.01), rapidly progressive interstitial lung disease (RP-ILD) (HR 9.34, 95% CI 6.39-13.6, p < 0.01), high levels of ferritin (HR 1.05, 95% CI 1.01-1.08, p < 0.01), C-reactive protein (CRP) (HR 1.12, 95% CI 1.06-1.19, p < 0.01), creatine kinase (HR 1.05, 95% CI 1.03-1.07, p < 0.01), and lactate dehydrogenase (LDH) (HR 1.27, 95% CI 1.12-1.45, p < 0.01), whereas oxygen index (HR 0.990, 95% CI 0.988-0.992, p < 0.01), partial pressure of oxygen (HR 0.933, 95% CI 0.906-0.961, p < 0.01), forced vital capacity (HR 0.962, 95% CI 0.928-0.998, p = 0.038), and lymphocyte count (HR 0.421, 95% CI 0.282-0.629, p < 0.01) were associated with better outcomes.
CONCLUSIONS
Old age, male sex, hypoxemia, low forced vital capacity, lymphocytopenia, and high levels of ferritin, CRP, creatine kinase, and LDH are risk factors for mortality in patients with MDA5+ DM. However, a cautious interpretation of these results and further quality investigation are warranted.
Topics: Humans; Male; Autoantibodies; Dermatomyositis; Disease Progression; Ferritins; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Prognosis; Retrospective Studies; Risk Factors
PubMed: 37348186
DOI: 10.1016/j.semarthrit.2023.152231 -
Physiological Reports Aug 2023Dietary protein ingestion augments post (resistance) exercise muscle protein synthesis (MPS) rates. It is thought that the dose of leucine ingested within the protein... (Review)
Review
BACKGROUND
Dietary protein ingestion augments post (resistance) exercise muscle protein synthesis (MPS) rates. It is thought that the dose of leucine ingested within the protein (leucine threshold hypothesis) and the subsequent plasma leucine variables (leucine trigger hypothesis; peak magnitude, rate of rise, and total availability) determine the magnitude of the postprandial postexercise MPS response.
METHODS
A quantitative systematic review was performed extracting data from studies that recruited healthy adults, applied a bout of resistance exercise, ingested a bolus of protein within an hour of exercise, and measured plasma leucine concentrations and MPS rates (delta change from basal).
RESULTS
Ingested leucine dose was associated with the magnitude of the MPS response in older, but not younger, adults over acute (0-2 h, r = 0.64, p = 0.02) and the entire postprandial (>2 h, r = 0.18, p = 0.01) period. However, no single plasma leucine variable possessed substantial predictive capacity over the magnitude of MPS rates in younger or older adults.
CONCLUSION
Our data provide support that leucine dose provides predictive capacity over postprandial postexercise MPS responses in older adults. However, no threshold in older adults and no plasma leucine variable was correlated with the magnitude of the postexercise anabolic response.
Topics: Humans; Aged; Leucine; Muscle Proteins; Diet; Muscle, Skeletal; Dietary Proteins; Postprandial Period
PubMed: 37537134
DOI: 10.14814/phy2.15775 -
Circulation Jan 2024Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted.
METHODS
A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up.
RESULTS
In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for (myosin light chain 3) to ≈55% for (myosin-binding protein C3), ≈60% for (troponin T2) and (troponin I3), and ≈65% for (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for and ≈23% for .
CONCLUSIONS
The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.
Topics: Humans; Adult; Penetrance; Mutation; Cross-Sectional Studies; Pedigree; Cardiomyopathy, Hypertrophic; Troponin T
PubMed: 37929589
DOI: 10.1161/CIRCULATIONAHA.123.065987 -
Drugs May 2024The most recently approved biologics for moderate-to-severe psoriasis are the interleukin (IL)-17 and IL-23 inhibitors. Drug survival is a frequently used outcome to... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVE
The most recently approved biologics for moderate-to-severe psoriasis are the interleukin (IL)-17 and IL-23 inhibitors. Drug survival is a frequently used outcome to assess drug performance in practice. An overview of the available drug survival studies regarding IL-17 and IL-23 inhibitors is lacking. Therefore, our objective was to assess the drug survival of IL-17 and IL-23 inhibitors for psoriasis.
METHODS
A search of PubMed, Embase, Cochrane Library and Web of Science was conducted (last search 27 December, 2023). Inclusion criteria were (1) cohort study; (2) patients aged ≥ 18 years with plaque psoriasis; and (3) evaluation of drug survival of at least one of the IL-17 and IL-23 inhibitors. Exclusion criteria were: primary focus on patients with psoriatic arthritis, fewer than ten study subjects and another language than English. The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Survival probabilities at monthly intervals were extracted from Kaplan-Meier curves using a semi-automated tool. Data were pooled using a non-parametric random-effects model to retrieve distribution-free summary survival curves. Summary drug survival curves were constructed per biologic for different discontinuation reasons: overall, ineffectiveness and adverse events, and split for the effect modifier biologic naivety. Results were analysed separately for registry/electronic health record data and for pharmacy/claims data.
RESULTS
A total of 69 studies aggregating drug survival outcomes of 48,704 patients on secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, and tildrakizumab were included. Summary drug survival estimates of registry/electronic health record studies for overall, ineffectiveness and adverse event related drug survival were high (all point estimates ≥ 0.8 at year 1) for included biologics, with highest estimates for guselkumab and risankizumab. All estimates for drug survival were higher in biologic naive than in experienced patients. Estimates of pharmacy/claims databases were substantially lower than estimates from the primary analyses based on registry/electronic health record data.
CONCLUSIONS
This meta-analysis showed that the investigated IL-17 and IL-23 inhibitors had high drug survival rates, with highest rates for guselkumab and risankizumab drug survival. We showed that effect modifiers such as biologic naivety, and the source of data used (registry/electronic health record data vs pharmacy/claims databases) is relevant when interpreting drug survival studies.
Topics: Humans; Psoriasis; Interleukin-17; Interleukin-23; Antibodies, Monoclonal, Humanized; Dermatologic Agents
PubMed: 38630365
DOI: 10.1007/s40265-024-02028-1 -
Journal of Translational Medicine Oct 2023Sepsis is an overwhelming reaction to infection that comes with high morbidity and mortality. It requires urgent interventions in order to improve outcomes. Intravenous... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Sepsis is an overwhelming reaction to infection that comes with high morbidity and mortality. It requires urgent interventions in order to improve outcomes. Intravenous immunoglobulins (IVIG) are considered as potential therapy in sepsis patients. Results of trials on IVIG as adjunctive therapy for sepsis have been conflicting due to the variability in population characteristics, country geography and drug dosage form in different studies.
METHODS
A systematic article search was performed for eligible studies published up to January, 31, 2023, through the PubMed, Embase, Cochrane Library and Chinese National Knowledge Infrastructure database. The included articles were screened by using rigorous inclusion and exclusion criteria. Subgroup analyses were conducted according to different IVIG types, ages and economic regions. All analyses were conducted using Review Manager 5.4. Quality of studies and risk of bias were evaluated.
RESULTS
In total, 31 randomized controlled trials were included with a sample size of 6,276 participants. IVIG could reduce the mortality (RR 0.86, 95% CI: 0.77-0.95, p = 0.005), the hospital stay (MD - 4.46, 95% CI: - 6.35 to - 2.57, p = 0.00001), and the APACHE II scores (MD - 1.65, 95% CI: - 2.89 to - 0.63, p = 0.001). Additionally, the results showed that IgM-enriched IVIG was effective in treating sepsis (RR 0.55, 95% CI: 0.40 - 0.76; p = 0.0003), while standard IVIG failed to be effective (RR 0.91, 95% CI: 0.81-1.02, p = 0.10). And the effect of IVIG in reducing neonatal mortality was inconclusive (RR 0.93, 95% CI: 0.81-1.05, p = 0.24), but it played a large role in reducing sepsis mortality in adults (RR 0.70, 95% CI: 0.57-0.86, p = 0.0006). Besides, from the subgroup of different economic regions, it indicated that IVIG was effective for sepsis in high-income (RR 0.89, 95% CI: 0.79-0.99, p = 0.03) and middle-income countries (RR 0.49, 95% CI: 0.28-0.84, p = 0.01), while no benefit was demonstrated in low-income countries (RR 0.56, 95% CI: 0.27-1.14, p = 0.11).
CONCLUSIONS
There is sufficient evidence to support that IVIG reduces sepsis mortality. IgM-enriched IVIG is effective in both adult and neonatal sepsis, while standard IVIG is only effective in adult sepsis. IVIG for sepsis has shown efficacy in high- and middle-income countries, but is still debatable in low-income countries. More RCTs are needed in the future to confirm the true clinical potential of IVIG for sepsis in low-income countries.
Topics: Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Length of Stay; Sepsis
PubMed: 37898763
DOI: 10.1186/s12967-023-04592-8 -
Arthritis Research & Therapy Jul 2023The objective of this systematic review was to assess the effects of interleukin-1β (IL-1β) inhibitors on gout flares. (Review)
Review
OBJECTIVES
The objective of this systematic review was to assess the effects of interleukin-1β (IL-1β) inhibitors on gout flares.
METHODS
Studies published between 2011 and 2022 that evaluated the effects of IL-1β inhibitors in adult patients experiencing gout flares were eligible for inclusion. Outcomes including pain, frequency and intensity of gout flares, inflammation, and safety were assessed. Five electronic databases (Pubmed/Medline, Embase, Biosis/Ovid, Web of Science and Cochrane Library) were searched. Two independent reviewers performed study screening, data extraction and risk of bias assessments (Cochrane Risk of Bias Tool 2 for randomised controlled trials [RCTs] and Downs and Black for non-RCTs). Data are reported as a narrative synthesis.
RESULTS
Fourteen studies (10 RCTs) met the inclusion criteria, with canakinumab, anakinra, and rilonacept being the three included IL-1β inhibitors. A total of 4367 patients with a history of gout were included from the 14 studies (N = 3446, RCTs; N = 159, retrospective studies [with a history of gout]; N = 762, post hoc analysis [with a history of gout]). In the RCTs, canakinumab and rilonacept were reported to have a better response compared to an active comparator for resolving pain, while anakinra appeared to be not inferior to an active comparator for resolving pain. Furthermore, canakinumab and rilonacept reduced the frequency of gout flares compared to the comparators. All three medications were mostly well-tolerated compared to their comparators.
CONCLUSION
IL-1β inhibitors may be a beneficial and safe medication for patients experiencing gout flares for whom current standard therapies are unsuitable.
REVIEW PROTOCOL REGISTRATION
PROSPERO ID: CRD42021267670.
Topics: Adult; Humans; Interleukin Inhibitors; Interleukin-1beta; Interleukin 1 Receptor Antagonist Protein; Gout; Arthritis, Gouty
PubMed: 37491293
DOI: 10.1186/s13075-023-03098-4 -
JNCI Cancer Spectrum Jan 2024Phytonutrient intakes may improve outcomes following breast cancer, but the impact of postdiagnosis introduction vs established prediagnostic exposure as well as optimum... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Phytonutrient intakes may improve outcomes following breast cancer, but the impact of postdiagnosis introduction vs established prediagnostic exposure as well as optimum doses has not been established. Evidence from observational studies for key exposures was evaluated, including dosage and intake time frames.
METHODS
MEDLINE, EMBASE, CINAHL, Cochrane Library, ClinicalTrials.gov, and the ISRCTN registry were searched for prospective and retrospective observational studies investigating the impact of soybean, lignans, cruciferous (cabbage-family) vegetables, green tea, or their phytonutrients on breast cancer survival outcomes. A random-effects model was used to calculate summary hazard ratios (HRs) and 95% confidence intervals (CIs). Nonlinear dose-response analyses were conducted using restricted cubic splines.
RESULTS
Thirty-two articles were included. Soy isoflavones were associated with a 26% reduced risk of recurrence (HR = 0.74, 95% CI = 0.60 to 0.92), particularly among postmenopausal (HR = 0.72, 95% CI = 0.55 to 0.94) and estrogen receptor-positive survivors (HR = 0.82, 95% CI = 0.70 to 0.97), with the greatest risk reduction at 60 mg/day. In mortality outcomes, the reduction was mostly at 20 to 40 mg/day. Soy protein and products were inversely associated with cancer-specific mortality for estrogen receptor-positive disease (HR = 0.75, 95% CI = 0.60 to 0.92). An inverse association was observed for serum or plasma enterolactone, measured prediagnosis and early postdiagnosis, with cancer-specific mortality (HR = 0.72, 95% CI = 0.58 to 0.90) and all-cause mortality (HR = 0.69, 95% CI = 0.57 to 0.83). No effects were observed for cruciferous vegetables. There was a 44% reduced risk of recurrence with prediagnostic green tea for stage I and II breast cancer (HR = 0.56, 95% CI = 0.38 to 0.83).
CONCLUSIONS
Soy, enterolactone, and green tea demonstrated significant risk reductions in outcomes following breast cancer. Evidence is needed regarding the impact of postdiagnostic introduction or substantial increase of these exposures.
Topics: Humans; Female; Prospective Studies; Retrospective Studies; Breast Neoplasms; Receptors, Estrogen; Tea
PubMed: 38070485
DOI: 10.1093/jncics/pkad104 -
Journal of Translational Medicine Aug 2023This paper aimed to examine the effects of probiotics on eight factors in overweight or obese children by meta-analysis, namely, body mass index (BMI), total cholesterol... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This paper aimed to examine the effects of probiotics on eight factors in overweight or obese children by meta-analysis, namely, body mass index (BMI), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), adiponectin, leptin and tumor necrosis factor-α (TNF-α) and summarize the mechanisms of action of probiotics based on the existing researches.
METHODS
Six databases (PubMed, Web of Science, Embase, Cochrane Library, SinoMed and CNKI) were searched until March 2023. Review Manager 5.4 was used for meta-analysis. The data were analysed using weighted mean differences (WMDs) or standardized mean differences (SMDs) under a fixed effect model or random effect model to observe the effects of probiotic administration on the included indicators.
RESULTS
Four publications with a total of 206 overweight or obesity children were included. According to the meta-analysis, probiotics were able to significantly decrease the levels of HDL-C (MD, 0.06; 95% CI 0.03, 0.09; P = 0.0001), LDL-C (MD, - 0.06; 95% CI - 0.12, - 0.00; P = 0.04), adiponectin (MD, 1.39; 95% CI 1.19, 1.59; P < 0.00001), leptin (MD, - 2.72; 95% CI - 2.9, - 2.54; P < 0.00001) and TNF-α (MD, - 4.91; 95% CI - 7.15, - 2.67; P < 0.0001) compared to those in the placebo group. Still, for BMI, the palcebo group seemed to be better than the probiotic group (MD, 0.85; 95% CI 0.04, 1.66; P = 0.04). TC (MD, - 0.05; 95% CI - 0.12, 0.02; P = 0.14) and TG (MD, - 0.16; 95% CI - 0.36, 0.05; P = 0.14) were not different between two groups.
CONCLUSIONS
This review drew that probiotics might act as a role in regulating HDL-C, LDL-C, adiponectin, leptin and TNF-α in overweight or obesity children. Additionally, our systematic review yielded that probiotics might regulate lipid metabolism and improve obese associated symptoms by some paths. This meta-analysis has been registered at PROSPERO with ID: CRD42023408359.
Topics: Humans; Child; Overweight; Leptin; Pediatric Obesity; Cholesterol, LDL; Adiponectin; Tumor Necrosis Factor-alpha; Probiotics; Triglycerides; Cholesterol, HDL
PubMed: 37542325
DOI: 10.1186/s12967-023-04319-9 -
BMC Nephrology Jan 2024It is crucial to identify patients with monoclonal gammopathy of renal significance (MGRS) from those without MGRS but with monoclonal gammopathy and concomitant kidney... (Meta-Analysis)
Meta-Analysis
BACKGROUND
It is crucial to identify patients with monoclonal gammopathy of renal significance (MGRS) from those without MGRS but with monoclonal gammopathy and concomitant kidney diseases. However, there have been few studies with large sample sizes, and their findings were inconsistent. This study aimed to conduct a meta-analysis of MGRS to describe the general characteristics of MGRS and its predictive factors.
METHODS
Cohort or case-control studies published through December 2022 and related to clinicopathological features of MGRS were retrieved from the PubMed, Cochrane Library, Web of Science, Scopus, and Embase databases. Two researchers searched for studies that met the inclusion criteria. In the univariate analysis, fixed- or random- effects models were used to obtain pooled estimates of the weighted mean difference (WMD) and odds ratio (OR) for risk factors. In the multivariate analysis, the ORs of the independent risk factors from each study were pooled after transforming the original estimates.
RESULTS
The meta-analysis included six studies. Univariate analysis showed that the following variables were statistically significant in MGRS: age (WMD = 1.78, 95%CI 0.21-3.35), hypertension (OR = 0.54, 95%CI 0.4-0.73), diabetes (OR = 0.42, 95%CI 0.29-0.59), albumin (WMD = - 0.26, 95%CI - 0.38--0.14), urinary protein level (WMD = 0.76, 95%CI 0.31-1.2), urinary protein ≥ 1.5 g/d (OR = 1.98, 95%CI 1.46-2.68), lambda-chain value (WMD = 29.02, 95%CI 16.55-41.49), abnormal free light-chain ratio (OR = 4.16, 95%CI 1.65-10.47), bone marrow puncture rate (OR = 5.11, 95% CI 1.31-19.95), and abnormal bone marrow outcome rate (OR = 9.63, 95%CI 1.98-46.88). Multivariate analysis showed urinary protein ≥ 1.5 g/d (OR = 2.80, 95%CI 1.53-5.15) and an abnormal free light-chain ratio (OR = 6.98, 95%CI 4.10-11.91) were associated with predictors of MGRS.
CONCLUSIONS
Compared with non-MGRS patients with monoclonal gammopathy and concomitant kidney diseases, patients with MGRS were older, had fewer underlying diseases, more urinary protein, more abnormal free light-chain ratio, and more abnormal bone marrow results. Urinary protein ≥ 1.5 g/d and an abnormal free light-chain ratio were independent risk factors for MGRS.
Topics: Humans; Paraproteinemias; Kidney; Monoclonal Gammopathy of Undetermined Significance; Kidney Diseases; Immunoglobulin Light Chains
PubMed: 38229028
DOI: 10.1186/s12882-024-03458-5