l-Carnitine relieves cachexia-related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis.

BACKGROUND: Cancer cachexia-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored. METHODS: Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of l-carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model. RESULTS: l-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (>88.2%, P < 0.05) and the collagen fibre area within the gastrocnemius (>57.9%, P < 0.05). At the 5 mg/kg dose, l-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, l-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of l-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with l-carnitine enhancing this interaction to promote Runx2 ubiquitination. l-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of l-carnitine on Runx2, COL1A1 and α-SMA in vitro. The expression of DTX3L was negatively correlated with the levels of Runx2 and COL1A1 in untreated NIH/3T3 cells. CONCLUSIONS: This study revealed a previously unrecognized link between Runx2 and DTX3L in SMF and demonstrated that l-carnitine exerted a significant therapeutic impact on cancer cachexia-associated SMF, potentially through the upregulation of DTX3L.

Development and validation of a diagnostic nomogram for frailty in cancer patients.

BACKGROUND: The presence of frailty decreases the overall survival of cancer patients. An accurate and operational diagnostic method is needed to help clinicians choose the most appropriate treatment to improve patient outcomes. METHODS: Data were collected from 10 649 cancer patients who were prospectively enrolled in the Investigation on Nutritional Status and its Clinical Outcomes of Common Cancers (INSCOC) project in China from July 2013 to August 2022. The training cohort and validation cohort were randomly divided at a ratio of 7:3. The multivariable logistic regression analysis, multivariate Cox regression analyses, and the least absolute shrinkage and selection operator (LASSO) method were used to develop the nomogram. The concordance index and calibration curve were used to assess the diagnostic utility of the nomogram model. RESULTS: The 10 risk factors associated with frailty in cancer patients were age, AJCC stage, liver cancer, hemoglobin, radiotherapy, surgery, hand grip strength (HGS), calf circumference (CC), PG-SGA score and QOL from the QLQ-C30. The diagnostic nomogram model achieved a good C index of 0.847 (95% CI, 0.832-0.862, P < 0.001) in the training cohort and 0.853 (95% CI, 0.83-0.876, P < 0.001) in the validation cohort. The prediction nomogram showed 1-, 3-, and 5-year mortality C indices in the training cohort of 0.708 (95% CI, 0.686-0.731), 0.655 (95% CI, 0.627-0.683), and 0.623 (95% CI, 0.568-0.678). The 1-, 3-, and 5-year C indices in the validation cohort were similarly 0.743 (95% CI, 0.711-0.777), 0.680 (95% CI, 0.639-0.722), and 0.629 (95% CI, 0.558-0.700). In addition, the calibration curves and decision curve analysis (DCA) were well-fitted for both the diagnostic model and prediction model. CONCLUSIONS: The nomogram model provides an accurate method to diagnose frailty in cancer patients. Using this model could lead to the selection of more appropriate therapy and a better prognosis for cancer patients.

Associations of the EAT-Lancet reference diet with metabolic dysfunction-associated steatotic liver disease and its severity: A multicohort study.

BACKGROUND AND AIMS: The EAT-Lancet Commission devised a globally sustainable dietary pattern to jointly promote human health and sustainability. However, the extent to which this diet supports metabolic dysfunction-associated steatotic liver disease (MASLD) has not yet been assessed. This study aimed to investigate the association between the EAT-Lancet diet and the risk of MASLD and its severity. APPROACH AND RESULTS: This prospective multicohort study included 15,263 adults from the Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) cohort, 1137 adults from the Guangzhou Nutrition and Health Study (GNHS) cohort, and 175,078 adults from the UK Biobank. In addition, 228 Chinese adults from the Prospective Epidemic Research Specifically of Non-alcoholic Steatohepatitis (PERSONS) with biopsy-proven MASLD were included. An EAT-Lancet diet index was created to reflect adherence to the EAT-Lancet reference diet. The TCLSIH cohort recorded 3010 MASLD cases during 53,575 person-years of follow-up, the GNHS cohort documented 624 MASLD cases during 6454 person-years of follow-up, and the UK Biobank developed 1350 MASLD cases during 1,745,432 person-years of follow-up. In multivariable models, participants in the highest tertiles of the EAT-Lancet diet index had a lower risk of MASLD compared with those in the lowest tertiles (TCLSIH: HR = 0.87, 95% CI: 0.78, 0.96; GNHS: HR = 0.79, 95% CI: 0.64, 0.98; UK Biobank: HR = 0.73, 95% CI: 0.63, 0.85). Moreover, liver-controlled attenuation parameter decreased with increasing the diet index in individuals with biopsy-proven MASLD (ß = -5.895; 95% CI: -10.014, -1.775). CONCLUSIONS: Adherence to the EAT-Lancet reference diet was inversely associated with the risk of MASLD as well as its severity.

Spatial whole exome sequencing reveals the genetic features of highly-aggressive components in lung adenocarcinoma.

In invasive lung adenocarcinoma (LUAD), patients with micropapillary (MIP) or solid (SOL) components had a significantly poorer prognosis than those with only lepidic (LEP), acinar (ACI) or papillary (PAP) components. It is interesting to explore the genetic features of different histologic subtypes, especially the highly aggressive components. Based on a cohort of 5,933 patients, this study observed that in different tumor size groups, LUAD with MIP/SOL components showed a different prevalence, and patients with ALK alteration or TP53 mutations had a higher probability of developing MIP/SOL components. To control individual differences, this research used spatial whole-exome sequencing (WES) via laser-capture microdissection of five patients harboring these five coexistent components and identified genetic features among different histologic components of the same tumor. In tracing the evolution of components, we found that titin (TTN) mutation might serve as a crucial intratumor potential driver for MIP/SOL components, which was validated by a cohort of 146 LUAD patients undergoing bulk WES. Functional analysis revealed that TTN mutations enriched the complement and coagulation cascades, which correlated with the pathway of cell adhesion, migration, and proliferation. Collectively, the histologic subtypes of invasive LUAD were genetically different, and certain trunk genotypes might synergize with branching TTN mutation to develop highly aggressive components.

COVID-19 Vaccine Hesitancy Among People Living with HIV: A Systematic Review and Meta-Analysis.

Vaccine hesitancy is one of the top 10 threats to global health, which affects the prevalence and fatality of vaccine-preventable diseases over the world. During the COVID-19 pandemic, people living with HIV (PLWH) may have higher risks of infection, more serious complications, and worse prognosis without the protection of the COVID-19 vaccine. A systematic review and meta-analysis aiming to evaluate the prevalence of COVID-19 vaccine hesitancy among PLWH was conducted using PubMed, Embase, and Web of Science databases for studies published between January 1, 2020, and August 31, 2022. The pooled prevalence with a corresponding 95%CI of COVID-19 vaccine hesitancy among PLWH was reported. Subgroup analysis was conducted to explore variation in prevalence across different categories. 23 studies with a total of 19,922 PLWH were included in this study. The prevalence of COVID-19 vaccine hesitancy among PLWH was 34.0%, and the influencing factors included male, influenza vaccination experience, and a CD4 count of more than 200 cells/mm3. Subgroup analysis did not identify significant causes of heterogeneity but showed that the prevalence of COVID-19 vaccine hesitancy among PLWH varies by study period, region, and race. Although all PLWH are recommended to receive the COVID-19 vaccine, a large proportion of them remain hesitant to be vaccinated. Therefore, governments and relevant institutions should take specific measures to encourage and promote vaccination to improve the coverage of the COVID-19 vaccine among PLWH.

Adherence to a healthy lifestyle including sleep and sedentary behaviors and risk of metabolic dysfunction-associated steatotic liver disease in Chinese adults.

OBJECTIVE: Various lifestyle factors including smoking, alcohol, physical activity, sedentary behavior, diet quality, sleep behavior, and overweight have been related to metabolic dysfunction-associated steatotic liver disease (MASLD); however, their joint impact on risk of MASLD is not well known. We prospectively investigated the association between a combination of lifestyle factors and risk of MASLD. METHODS: This prospective cohort study included 13,303 participants (mean age: 39.1 ± 11.3 years, female: 60.1%) in China. A novel healthy lifestyle score was created combining seven healthy factors: not smoking, no alcohol intake, regular physical activity, short sedentary time, healthy diet, healthy sleep, and healthy weight. Incident MASLD cases were ascertained annually by liver ultrasound and cardiometabolic risk factors. Multivariable Cox proportional hazards regression models were used to estimate the association of healthy lifestyle score with risk of MASLD. RESULTS: Within 48,036 person-years of follow-up, 2823 participants developed MASLD. After adjusting for age, sex, education, occupation, household income, personal and family history of disease, and total energy intake, compared with participants with 0-2 healthy lifestyle factors, the multivariable hazard ratios (95% confidence interval) of MASLD were 0.81 (0.73, 0.89), 0.67 (0.61, 0.75), and 0.55 (0.49, 0.62) for healthy lifestyle score of 3, 4, and 5-7, respectively (P for trend <0.0001). Such associations were consistent across subgroup and sensitivity analyses. CONCLUSION: Our results indicate that a higher healthy lifestyle score is associated with a lower risk of MASLD.

Value of the modified Patient-Generated Subjective Global Assessment in indicating the need for nutrition intervention and predicting overall survival in patients with malignant tumors in at least two organs.

BACKGROUND: Although the Patient-Generated Subjective Global Assessment (PG-SGA) is a reference standard used to assess a patient's nutrition status, it is cumbersome to administer. The aim of the present study was to estimate the value of a simpler and easier-to-use modified PG-SGA (mPG-SGA) to evaluate the nutrition status and need for intervention in patients with malignant tumors present in at least two organs. METHODS: A total of 591 patients (343 male and 248 female) were included from the INSCOC study. A Pearson correlation analysis was conducted to assess the correlation between the mPG-SGA and nutrition-related factors, with the optimal cut-off defined by a receiver operating characteristic curve (ROC). The consistency between the mPG-SGA and PG-SGA was compared in a concordance analysis. A survival analysis was used to determine the effects of nutritional intervention among different nutrition status groups. Univariable and multivariable Cox analyses were applied to evaluate the association of the mPG-SGA with the all-cause mortality. RESULTS: The mPG-SGA showed a negative association with nutrition-related factors. Individuals with an mPG-SGA ≥ 5 (rounded from 4.5) were considered to need nutritional intervention. Among the malnourished patients (mPG-SGA ≥ 5), the overall survival (OS) of those who received nutrition intervention was significantly higher than that of patients who did not. However, the OS was not significantly different in the better-nourished patients (mPG-SGA < 5). CONCLUSION: Our findings support that the mPG-SGA is a feasible tool that can be used to guide nutritional interventions and predict the survival of patients with malignant tumors affecting at least two organs.

Association of Cumulative Exposure to Cardiovascular Health Behaviors and Factors with the Onset and Progression of Arterial Stiffness.

AIM: This study aims to explore the association of cumulative exposure to cardiovascular health behaviors and factors with the onset and progression of arterial stiffness. METHODS: In this study, 24,110 participants were examined from the Kailuan cohort, of which 11,527 had undergone at least two brachial-ankle pulse wave velocity (baPWV) measurements. The cumulative exposure to cardiovascular health behaviors and factors (cumCVH) was calculated as the sum of the cumCVH scores between two consecutive physical examinations, multiplied by the time interval between the two. A logistic regression model was constructed to evaluate the association of cumCVH with arterial stiffness. Generalized linear regression models were used to analyze how cumCVH affects baPWV progression. Moreover, a Cox proportional hazards regression model was used to analyze the effect of cumCVH on the risk of arterial stiffness. RESULTS: In this study, participants were divided into four groups, according to quartiles of cumCVH exposure levels, namely, quartile 1 (Q1), quartile 2 (Q2), quartile 3 (Q3), and quartile 4 (Q4). Logistic regression analysis showed that compared with the Q1 group, the incidence of arterial stiffness in terms of cumCVH among Q2, Q3, and Q4 groups decreased by 16%, 30%, and 39%, respectively. The results of generalized linear regression showed that compared with the Q1 group, the incidence of arterial stiffness in the Q3 and Q4 groups increased by -25.54 and -29.83, respectively. The results of Cox proportional hazards regression showed that compared with the Q1 group, the incidence of arterial stiffness in cumCVH among Q2, Q3, and Q4 groups decreased by 11%, 19%, and 22%, respectively. Sensitivity analyses showed consistency with the main results. CONCLUSIONS: High cumCVH can delay the progression of arterial stiffness and reduce the risk of developing arterial stiffness.

Life's Essential 8 and heart failure among patients with chronic kidney disease: the Kailuan Cohort Study.

AIMS: Patients with chronic kidney disease (CKD) are at an increased risk of developing heart failure. The American Heart Association recently released a new metric, Life's Essential 8 (LE8), for health promotion. However, evidence regarding associations between LE8 and heart failure risk among patients with CKD is scarce. METHODS AND RESULTS: A total of 16 190 patients with CKD (mean age 55.9 years), free of cardiovascular disease at recruitment from the Kailuan Study, were included. Cardiovascular health was assessed using the LE8 score. Incident heart failure events were ascertained via linkage of electronic health record data. Cox proportional hazards regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). There were 814 (5.0%) patients in the high LE8 criteria, with 13 180 (81.4%) in the moderate, and 2196 (13.6%) in the low LE8 category, respectively. During a median follow-up of 13.7 years, 724 incident heart failure cases were documented. Compared with the low LE8 category, the HRs (95% CIs) for heart failure were 0.58 (0.48, 0.71) for the moderate LE8 category and 0.32 (0.19, 0.54) for the high LE8 category (P for trend <0.001). In addition, the association was stronger in patients aged ≤65 years compared with their older counterparts (P for interaction = 0.01). CONCLUSION: Our data showed a strong graded inverse association between the LE8-defined cardiovascular health and the risk of heart failure among patients with CKD. Our findings support the importance of adopting the LE8 among patients with CKD to prevent heart failure.

Using the Life's Essential 8 (LE8) score, released by the American Heart Association for cardiovascular health promotion, this study investigated the relationship between cardiovascular health and the risk of heart failure in patients with chronic kidney disease (CKD) in China.Patients with CKD who had better cardiovascular health, as indicated by higher LE8 scores, had a significantly lower risk of heart failure.A stronger association between better LE8 score and lower risk of heart failure among CKD patients aged ≤65 years was observed, compared with their older counterparts.

Comparison of the performance of the GLIM criteria, PG-SGA and mPG-SGA in diagnosing malnutrition and predicting survival among lung cancer patients: A multicenter study.

BACKGROUND & AIMS: The present study aimed to compare the ability of the GLIM criteria, PG-SGA and mPG-SGA to diagnose malnutrition and predict survival among Chinese lung cancer (LC) patients. METHODS: This was a secondary analysis of a multicenter, prospective, nationwide cohort study, 6697 LC inpatients were enrolled between July 2013 and June 2020. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC), and quadratic weighted Kappa coefficients were calculated to compare the ability to diagnose malnutrition. There were 754 patients who underwent follow-up for a median duration of 4.5 years. The associations between the nutritional status and survival were analyzed by the Kaplan-Meier method and multivariable Cox proportional hazard regression models. RESULTS: The median age of LC patients was 60 (53, 66), and 4456 (66.5%) were male. There were 617 (9.2%), 752 (11.2%), 1866 (27.9%), and 3462 (51.7%) patients with clinical stage Ⅰ, Ⅱ, Ⅲ, and Ⅳ LC, respectively. Malnutrition was present in 36.1%-54.2% (as evaluated using different tools). Compared with the PG-SGA (used as the diagnostic reference), the sensitivity of the mPG-SGA and GLIM was 93.7% and 48.3%; the specificity was 99.8% and 78.4%; and the AUC was 0.989 and 0.633 (P < 0.001). The weighted Kappa coefficients were 0.41 for the PG-SGA vs. GLIM, 0.44 for the mPG-SGA vs. GLIM, and 0.94 for the mPG-SGA vs PG-SGA in patients with stage Ⅰ-Ⅱ LC. These values were respectively 0.38, 0.39, and 0.93 in patients with stage Ⅲ-Ⅳ of LC. In a multivariable Cox analysis, the mPG-SGA (HR = 1.661, 95%CI = 1.348-2.046, P < 0.001), PG-SGA (HR = 1.701, 95%CI = 1.379-2.097, P < 0.001) and GLIM (HR = 1.657, 95%CI = 1.347-2.038, P < 0.001) showed similar death hazard ratios. CONCLUSIONS: The mPG-SGA provides nearly equivalent power to predict the survival of LC patients as the PG-SGA and the GLIM, indicating that all three tools are applicable for LC patients. The mPG-SGA has the potential to be an alternative replacement for quick nutritional assessment among LC patients.

Accuracy of minimal residual disease detection by circulating tumor DNA profiling in lung cancer: a meta-analysis.

BACKGROUND: The sensitivity and specificity of minimal residual disease detected by circulating tumor DNA profiling (ctDNA MRD) in lung cancer, with particular attention to the distinction between landmark strategy and surveillance strategy, for predicting relapse in lung cancer patients after definitive therapy has yet to be determined. METHODS: The prognostic value of ctDNA MRD by landmark strategy and surveillance strategy was evaluated in a large cohort of patients with lung cancer who received definitive therapy using a systemic literature review and meta-analysis. Recurrence status stratified by ctDNA MRD result (positive or negative) was extracted as the clinical endpoint. We calculated the area under the summary receiver operating characteristic curves, and pooled sensitivities and specificities. Subgroup analyses were conducted based on histological type and stage of lung cancer, types of definitive therapy, and ctDNA MRD detection methods (detection technology and strategy such as tumor-informed or tumor-agnostic). RESULTS: This systematic review and meta-analysis of 16 unique studies includes 1251 patients with lung cancer treated with definitive therapy. The specificity of ctDNA MRD in predicting recurrence is high (0.86-0.95) with moderate sensitivity (0.41-0.76), whether shortly after treatment or during the surveillance. The landmark strategy appears to be more specific but less sensitive than the surveillance strategy. CONCLUSIONS: Our study suggests that ctDNA MRD is a relatively promising biomarker for relapse prediction among lung cancer patients after definitive therapy, with a high specificity but suboptimal sensitivity, whether in landmark strategy or surveillance strategy. Although surveillance ctDNA MRD analysis decreases specificity compared with the landmark strategy, the decrease is minimal compared to the increase in sensitivity for relapse prediction of lung cancer.

Global trends in the burden of esophageal cancer, 1990-2019: results from the Global Burden of Disease Study 2019.

Background: Esophageal cancer is one of the leading causes of cancer death worldwide. A deeper understanding of the trends in annual incidence, mortality, and disability-adjusted life-years (DALYs) of esophageal cancer is critical for management and prevention. In this study, we report on the disease burden of esophageal cancer in 204 countries and territories between 1990 and 2019 by age, sex, and sociodemographic index (SDI). Methods: Data on incidence, mortality, and DALYs were extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. The estimated numbers and age-standardized rates for esophageal cancer in 2019 are presented in this paper, as well as trends from 1990 to 2019. All estimates are presented as counts and age-standardized rates per 100,000 population, with 95% uncertainty intervals (UIs) for each estimate. Results: In 2019, nearly 535,000 (95% UI: 467,000-595,000) new cases of esophageal cancer occurred globally. Esophageal cancer was responsible for more than 498,000 (95% UI: 438,000-551,000) deaths and 11.7 million (95% UI: 10.4-12.9 million) DALYs. Worldwide age-standardized rates of esophageal cancer, including incidence, deaths, and DALYs, have declined since 1990. However, the trends differ across countries and territories. Notably, there was a nonlinear but generally inverse correlation between age-standardized DALY rates and SDI. Higher age-standardized incidence and death rates were observed in males compared to females, and both increased with age. Regarding risk factors, smoking, alcohol use, and high body-mass index were 3 predominant contributors to esophageal cancer DALYs in 2019 for both sexes worldwide. Conclusions: This study found a global reduction in the esophageal cancer burden, but substantial heterogeneity remains across regions and countries. Hence, the identification of high-risk groups and the exploration of specific local strategies and primary prevention efforts are required.

The genetic liability to rheumatoid arthritis may decrease hepatocellular carcinoma risk in East Asian population: a Mendelian randomization study.

BACKGROUND: Patients with rheumatoid arthritis (RA) have a rising possibility of acquiring certain kinds of cancers than the general public. The causal risk association between RA and hepatocellular carcinoma (HCC) remains unknown. METHODS: Genetic summary data from genome-wide association study (GWAS), including RA (n = 19,190) and HCC (n = 197,611), was analyzed. The inverse-variance weighted (IVW) approach was used as the principal analysis, complemented with weighted median, weighted mode, simple median method, and MR-Egger analyses. The genetic data of RA (n = 212,453) was used to verify the results in eastern Asia populations. RESULTS: The results from the IVW methods indicated that genetically predicted RA was significantly linked with a declined possibility of HCC for East Asians (OR = 0.86; 95% CI: 0.78, 0.95; p = 0.003). The weighted median and the weighted mode also supported similar results (all p < 0.05). Additionally, neither the funnel plots nor the MR-Egger intercepts revealed any directional pleiotropic effects between RA and HCC. Moreover, the other set of RA data validated the results. CONCLUSION: The RA may decrease the risk of being susceptible to the HCC in eastern Asia populations, which was beyond expectation. In the future, additional investigations should be made into potential biomedical mechanisms.

Risk mapping of lung cancer: a comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies.

INTRODUCTION: A comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies was performed to map the different risk factors and assess the causality for lung cancer. METHODS: Systematic reviews and meta-analyses of observational and interventional studies were reviewed based on PubMed, Embase, Web of Science, and Cochrane Library. Mendelian randomization analyses were conducted to validate the causal associations of those various exposures with lung cancer using summary statistics from 10 genome-wide association studies (GWAS) consortia and other GWAS databases in MR-Base platform. RESULTS: In the review of meta-analyses, 105 risk factors associated with lung cancer were identified from 93 articles. It was found that 72 risk factors were nominally significant (P < 0.05) associated with lung cancer. Mendelian randomization analyses were performed to analyze 36 exposures based on 551 SNPs and 4,944,052 individuals, finding that 3 exposures had a consistent risk/protective effect on lung cancer with the results of the meta-analysis. In Mendelian randomization anaylses, smoking (OR 1.44, 95% CI 1.18-1.75; P = 0.001) and blood copper (OR 1.14, 95% CI 1.01-1.29; P = 0.039) significantly associated with increased risk of lung cancer, whereas aspirin use (OR 0.67, 95% CI 0.50-0.89; P = 0.006) showed protective effects. CONCLUSION: This study mapped putative associations of risk factors for lung cancer, revealing the causal hazard effect of smoking, blood copper, and the protective effect of aspirin use in the development of lung cancer. CLINICAL TRIAL REGISTRY: This study is registered with PROSPERO (CRD42020159082).

GLIM-defined malnutrition and overall survival in cancer patients: A meta-analysis.

BACKGROUND: Malnutrition defined by the Global Leadership Initiative on Malnutrition (GLIM) has been associated with cancer mortality, but the effect is limited and inconsistent. We performed this meta-analysis aiming to assess this relationship in patients with cancer. METHODS: We systematically searched Embase, PubMed, Web of Science, Cochrane, CINAHL, CNKI, Wanfang, and VIP databases from January 1, 2019, to July 1, 2022. Studies evaluating the prognostic effect of GLIM-defined malnutrition on cancer survival were included. A fixed-effect model was fitted to estimate the combined hazard ratio (HR) with a 95% CI. Heterogeneity of studies was analyzed using the I2 statistic. Quality assessment were performed using the Newcastle-Ottawa Scale (NOS) and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. RESULTS: The search strategy identified 4378 articles in all databases combined. Nine studies (8829 patients) meeting the inclusion criteria were included for quantitative analysis. Meta-analysis revealed significant associations between GLIM-defined pooled malnutrition (HR = 1.75; 95% CI, 1.43-2.15), moderate malnutrition (HR = 1.44; 95% CI, 1.29-1.62), and severe malnutrition (HR = 1.79; 95% CI, 1.58-2.02) with all-cause mortality. Sensitivity analysis supported the robustness of these associations. The between-study heterogeneity was low (all I2 < 50%), and study quality assessed with NOS was high (all scores > 6). The evidence quality according to the GRADE tool was very low. CONCLUSIONS: Our meta-analysis suggests a significant negative association of malnutrition, as defined by the GLIM, with overall survival in patients with cancer. However, definitive conclusions cannot be made, owing to the low quality of the source data.

Causal effect of beta-blockers on the risk of lung cancer: a Mendelian randomization study.

Background: It remains uncertain whether there is a causal association of the use of beta-blockers (BBs) on lung cancer risk. We used a two-sample Mendelian randomization (MR) approach to identify the causal association of BBs and lung cancer risk. Methods: Twenty-two BB-related single-nucleotide polymorphisms (SNPs) were obtained from the UK Biobank as the instrumental variables (IVs). Genetic summary data information of lung cancer was extracted from the International Lung Cancer Consortium, with a total of 11,348 cases and 15,861 controls. We adopted the inverse-variance weighted (IVW) approach to conduct the MR analyses. Egger-intercept analysis was further performed as sensitivity analysis for pleiotropy evaluation. Additionally, we investigated whether BBs could causally affect the risk of lung cancer through their pharmacological effects. Results: The current IVW analysis suggested a decreased lung cancer risk in BB users [odds ratio (OR) =0.83; 95% confidence interval (CI): 0.73-0.95; P<0.01]. Results of Egger-intercept analysis demonstrated that no pleiotropy was found (P=0.94), which suggested the robustness of the causality. However, there was little evidence that pharmacological effects mediate the association between BBs and lung cancer. Conclusions: The current analysis suggested that BBs could decrease the risk of lung cancer but may be not via its pharmacological effects. Further research is in need for elucidating the underlying mechanisms.

Development and validation of an online dynamic nomogram system for predicting cancer cachexia among inpatients: a real-world cohort study in China.

BACKGROUND: Early recognition of cachexia is essential for ensuring the prompt intervention and treatment of cancer patients. However, the diagnosis of cancer cachexia (CC) usually is delayed. This study aimed to establish an accurate and high-efficiency diagnostic system for CC. METHODS: A total of 4834 cancer inpatients were enrolled in the INSCOC project from July 2013 to June 2020. All cancer patients in the study were randomly assigned to a development cohort (n=3384, 70%) and a validation cohort (n=1450, 30%). The least absolute shrinkage and selection operator (LASSO) method and multivariable logistic regression were used to identify the independent predictors for developing the dynamic nomogram. Discrimination and calibration were adopted to evaluate the ability of nomogram. A decision curve analysis (DCA) was used to evaluate clinical use. RESULTS: We combined 5 independent predictive factors (age, NRS2002, PG-SGA, QOL by the QLQ-C30, and cancer categories) to establish the online dynamic nomogram system. The C-index, sensitivity, and specificity of the nomo-system to predict CC was 0.925 (95%CI, 0.916-0.934, P < 0.001), 0.826, and 0.862 in the development set, while the values were 0.923 (95%CI, 0.909-0.937, P < 0.001), 0.854, and 0.829 in the validation set. In addition, the calibration curves of the diagnostic nomogram also presented good agreement with the actual situation. DCA showed that the model is clinically useful and can increase the clinical benefit in cancer patients. CONCLUSIONS: This study developed an online dynamic nomogram system with outstanding accuracy to help clinicians and dieticians estimate the probability of cachexia. This simple-to-use online nomogram can increase the clinical benefit in cancer patients and is expected to be widely adopted.

Evaluation of Clinical and Safety Outcomes of Neoadjuvant Immunotherapy Combined With Chemotherapy for Patients With Resectable Esophageal Cancer: A Systematic Review and Meta-analysis.

Importance: A considerable number of clinical trials of neoadjuvant immunotherapy for patients with resectable esophageal cancer are emerging. However, systematic evaluations of these studies are lacking. Objective: To provide state-of-the-art evidence and normative theoretical support for neoadjuvant immunotherapy for locally advanced resectable esophageal cancer. Data Sources: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for relevant original articles and conference proceedings that were published in English through April 1, 2022. Study Selection: Published phase 2 or 3 clinical trials that included patients with resectable stage I to IV esophageal cancer who received immune checkpoint inhibitors (ICIs) before surgery as monotherapy or in combination with other therapies. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines for meta-analysis were followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 statistic >50%); otherwise, the common-effects model was used. Data analyses were conducted from April 2 to 8, 2022. Main Outcomes and Measures: Pathological complete response (pCR) rate and major pathological response (MPR) rate were considered to be the primary outcomes calculated for the clinical outcomes of neoadjuvant immunotherapy. Incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. The rate of R0 surgical resection was summarized. Subgroup analyses were conducted according to histologic subtype and ICI types. Results: A total of 27 clinical trials with 815 patients were included. Pooled rates were 31.4% (95% CI, 27.6%-35.3%) for pCR and 48.9% (95% CI, 42.0-55.9%) for MCR in patients with esophageal cancer. In terms of safety, the pooled incidence of treatment-related severe adverse events was 26.9% (95% CI, 16.7%-38.3%). Most patients achieved R0 surgical resection (98.6%; 95% CI, 97.1%-99.6%). Regarding histologic subtypes, the pooled pCR rates were 32.4% (95% CI, 28.2%-36.8%) in esophageal squamous cell carcinoma and 25.2% (95% CI, 16.3%-35.1%) in esophageal adenocarcinoma. The pooled MPR rate was 49.4% (95% CI, 42.1%-56.7%) in esophageal squamous cell carcinoma. Conclusions and Relevance: This study found that neoadjuvant immunotherapy with chemotherapy had promising clinical and safety outcomes for patients with resectable esophageal cancer. Randomized clinical trials with long-term follow-up are warranted to validate the findings and benefits of ICIs.

Causal effects of genetically determined metabolites on cancers included lung, breast, ovarian cancer, and glioma: a Mendelian randomization study.

Background: Previous studies have shown that metabolites play important roles in phenotypic regulation, but the causal link between metabolites and tumors has not been examined adequately. Herein, we investigate the causality between metabolites and various cancers through a Mendelian randomization (MR) study. Methods: We carried out a two-sample MR analysis based on genetic instrumental variables as proxies for 486 selected human serum metabolites to evaluate the causal effects of genetically determined metabotypes (GDMs) on cancers. Summary data from various cancer types obtained from large consortia. Inverse variance weighted (IVW), MR-Egger and weighted-median methods were implemented to infer the causal effects, moreover, we particularly explored the presentence of horizontal pleiotropy through MR-Egger regression and MR-PRESSO Global test. Metabolic pathways analysis and subgroup analyses were further explored using available data. Statistical analyses were all performed in R. Results: In MR analysis, 202 significant causative relationship features were identified. 7-alpha-hydroxy-3-oxo-4-cholestenoate (ORIVW =1.45; 95% CI: 1.06-1.97; PIVW =0.018), gamma-glutamylisoleucine (ORIVW =1.40; 95% CI: 1.16-1.69; PIVW =0.0004), 1-oleoylglycerophosphocholine (ORIVW =1.22; 95% CI: 1.1-1.35; PIVW =0.0001), gamma-glutamylleucine (ORIVW =4.74; 95% CI: 1.18-18.93; PIVW =0.027) were the most dangerous metabolites for lung cancer, ovarian cancer, breast cancer, and glioma, respectively; while pseudouridine (ORIVW =0.50; 95% CI: 0.30-0.83; PIVW =0.007), 2-methylbutyroylcarnitine (ORIVW =0.77; 95% CI: 0.68-0.86; PIVW =2.9×10-6), 2-methylbutyroylcarnitine (ORIVW =0.77; 95% CI: 0.70-0.85; PIVW =3.4×10-7), glycylvaline (ORIVW =0.13; 95% CI: 0.02-0.75; PIVW =0.021) were associated with lower risk of lung cancer, ovarian cancer, breast cancer, and glioma, respectively. Interestingly, 2-methylbutyroylcarnitine was also associated with decreased risk of lung cancer (ORIVW =0.59; 0.50-0.70; P IVW =1.98×10-9) expect ovarian cancer and breast cancer. In subgroup analysis, 2-methylbutyroylcarnitine was associated with decreased risk of estrogen receptor (ER) positive breast cancer (ORIVW =0.72; 0.64-0.80; PIVW =3.55×10-9), lung adenocarcinoma (LAC) (ORIVW =0.60; 0.48-0.70; PIVW =1.14×10-5). Metabolic pathways analysis identified 4 significant pathways. Conclusions: Our study integrated metabolomics and genomics to explore the risk factors involved in the development of cancers. It is worth exploring whether metabolites with causality can be used as biomarkers to distinguish patients at high risk of cancer in clinical practice. More detailed studies are needed to clarify the mechanistic pathways.

Family Socioeconomic Position and Lung Cancer Risk: A Meta-Analysis and a Mendelian Randomization Study.

Background: Family socioeconomic position (SEP) in childhood is an important factor to predict some chronic diseases. However, the association between family SEP in childhood and the risk of lung cancer is not clear. Methods: A systematic search was performed to explore their relationship. We selected education level, socioeconomic positions of parents and childhood housing conditions to represent an individual family SEP. Hazard ratios (HRs) of lung cancer specific-mortality were synthesized using a random effects model. Two-sample Mendelian randomization (MR) was carried out with summary data from published genome-wide association studies of SEP to assess the possible causal relationship of SEP and risk of lung cancer. Results: Through meta-analysis of 13 studies, we observed that to compared with the better SEP, the poorer SEP in the childhood was associated with the increased lung cancer risk in the adulthood (HR: 1.25, 95% CI: 1.10 to 1.43). In addition, the dose-response analysis revealed a positive correlation between the poorer SEP and increased lung cancer risk. Same conclusion was reached in MR [(education level) OR 0.50, 95% CI: 0.39 to 0.63; P < 0.001]. Conclusion: This study indicates that poor family socioeconomic position in childhood is causally correlated with lung cancer risk in adulthood. Systematic Review Registration: identifier: 159082.