Cox Regression Research Articles

Lower Late Development Rate of Acute Respiratory Distress Syndrome in Patients with Lower Mechanical Power or Driving Pressure.

For patients on ventilation without acute respiratory distress syndrome (ARDS), there are, as yet, limited data on ventilation strategies. We hypothesized that driving pressure (DP) and mechanical power (MP) may play key roles for the late development of ARDS in patients without initial ARDS. A post hoc analysis of a database from our previous cohort was performed. The mean DP/MP was computed from the data before ARDS development or until ventilator support was discontinued within 28 days. The association between DP/MP and late development of ARDS within 28 days was determined. One hundred and twelve patients were enrolled, among whom seven developed ARDS. Univariate Cox regression showed that congestive heart failure (CHF) history and higher levels of mean MP and DP were associated with ARDS development. Multivariate models revealed that the mean MP and mean DP were still factors independently associated with ARDS development at hazard ratios of 1.177 and 1.226 after adjusting for the CHF effect. Areas under the receiver operating characteristic curves for mean DP/MP in predicting ARDS development were 0.813 and 0.759, respectively. In conclusion, high mean DP and MP values may be key factors associated with late ARDS development. The mean DP had a better predicted value for the development of ARDS than the mean MP.

Abnormal expression of circ_0013958 in patients with acute myocardial infarction (AMI) and its influence on prognosis

ObjectiveThe purpose of this study was to investigate the diagnostic value of circ_0013958 in acute myocardial infarction (AMI) patients and its influence on the prognosis of AMI patients.MethodsThe GSE160717 dataset was downloaded from the NCBI database and differentially expressed genes were analyzed between the control group and the AMI group. The up-regulated genes included circ_0013958. The expression of circ_0013958 in both groups was further verified by RT-qPCR. The Receiver Operating Characteristic curve was used to evaluate the diagnostic value of circ_0013958 in AMI. Pearson correlation analysis was used to examine the correlation between circ_0013958 levles and biochemical indicators. Binary logistic regression was used to analyze the risk factors affecting the occurrence of AMI. Prognostic analysis was performed using COX regression analysis and the Kaplan-Meier Curve.ResultsCompared to the control group, the level of circ_0013958 in AMI patients increased. Circ_0013958 can effectively distinguish AMI patients from non-AMI patients. Circ_0013958 levels were positively correlated with cTnI, LDH, CRP and TC levels. The elevated level of circ_0013958 was an independent risk factor for the occurrence of AMI. Higher circ_0013958 levels were also associated with the occurrence of major adverse cardiac events (MACEs) in AMI patients. Additionally, elevated circ_0013958 levels reduced the survival probability of AMI patients.ConclusionCirc_0013958 levels were up-regulated in AMI patients. It can be used as a diagnosis biomarker for AMI. The level of circ_0013958 was correlated with the disease severity and was an independent risk factor for the occurrence of AMI. Elevated circ_0013958 levels were associated with poor prognosis in AMI patients.

Lung and bone metastases patterns in Ewing sarcoma: Chemotherapy improves overall survival.

Ewing sarcoma (ES) is a small round cell malignancy, mainly in the bone tissue, followed by the soft tissue. Lung metastases (LM) and bone metastases (BM) are the most common types of metastases. From 2010 to 2018, the Surveillance, Epidemiology, and End Results database diagnosed 242 cases of ES with LM, 186 cases of ES with BM, and 74 cases of ES with LM and BM. Univariate and multivariate logistic regression analyses were used to determine the risk factors for LM and/or BM, and Kaplan-Meier curves and Cox regression analysis were used to determine the prognostic factors for LM and/or BM. Tumor size ≥50 mm, N1 stage, BM, liver metastases, and surgical treatment were significantly correlated with LM; tumor size >100 mm, brain metastases, LM, surgical treatment, and chemotherapy were significantly correlated with BM; female, N1 stage, brain metastases, liver metastases, and surgical treatment were significantly correlated with LM and BM. Older age, BM, higher T stage, no surgical treatment, and no chemotherapy were harmful to the survival of ES patients with LM; older age, female, LM, and no chemotherapy were harmful to the survival of ES patients with BM; older age and no chemotherapy were harmful to the survival of ES patients with LM and BM. Larger tumor size, N1 stages, and organ metastases were significantly associated with ES patients with LM and/or BM. Chemotherapy is effective in improving the survival.

Can patients with mild non-neoplastic lesions diagnosed at baseline screening be safely exempt from surveillance: evidence from multicenter community-based cohorts.

Surveillance recommendations for gastric cancer (GC) in current guidelines focused on advanced precancerous lesions and were based on precise diagnosis of severity/extent of baseline lesions. We aimed to develop a less endoscopy-related equipment-dependent risk-stratification tool, and assessed whether mild-precursor-lesion patients can be safely exempt from surveillance. In the multicenter community-based cohort, 75,051 participants receiving baseline endoscopy were enrolled during 2015-2017 and followed-up until 2021. Cumulative incidence rates (CIRs) of GC for precancerous-conditions were calculated by Kaplan-Meier method and compared by Log-rank tests. Mixed-effects Cox regression models were used to detect potential factors for progression towards GC. A risk score was calculated as counts of selected factors. An independent cohort, including 26,586 participants was used for external validation. During a median follow-up of 6.25 years, CIRs of GC were 0.302%, 0.436%, and 4.756% for normal group, non-neoplastic (atrophic gastritis/intestinal metaplasia) and neoplastic lesions (low-grade/high-grade dysplasia), respectively (Ptrend<0.001). Four predictors, including male, ⩾60 years, smoking, and limited vegetable consumption, were selected for risk-stratification. High-risk patients (⩾3 risk factors) with non-neoplastic lesions showed higher GC risks (adjusted HR=7.73, 95%CI: 4.29-13.92), and their four-year CIR reached the one-year CIR of neoplastic lesions. Further categorizing non-neoplastic lesions by histological grade, both patients with moderate-to-severe lesions (aHR=3.07, 95%CI: 1.67-5.64) and high-risk patients with mild lesions (aHR=7.29, 95%CI: 3.58-14.86) showed higher risks. Consistent trends were observed in validation cohort. High-risk mild-precursor-lesion patients should receive surveillance within 3-5 years after baseline screening. Our study provides evidence on supplementing current guideline recommendations.

Construction of a prognostic risk model for uveal melanoma based on immune-related long noncoding RNA.

Uveal melanoma (UM) is a common health challenge worldwide as a prevalent intraocular malignancy because of its high mortality rate. However, clinical workers do not have an accurate prognostic tool now. Immune function is closely related to tumor development. Interestingly, researchers have identified that long noncoding RNAs (lncRNAs) are tightly associated with biological processes at the cellular level, particularly their involvements in immune response and its regulation of the growth of tumor cells. Hence, lncRNAs may be involved in the progression of uveal melanoma. UM patients' RNA expression matrices were extracted from TCGA database. The targeted immune genes were filtered by weighted correlation network analysis and the immune-related lncRNAs with a high prognostic relevance were obtained by Cox regression analysis and least absolute shrinkage and selection operator regression analysis. Each sample was scored according to those lncRNA expression and divided into high-risk and low-risk group. We confirmed the sensitivity and independence of our risk model compared to the tumor mutation burden score. Finally, we demonstrated the clinical relevance of our model by examining its sensitivity to different drugs. The risk score based on our risk model was significantly independent of other clinical parameters in either univariate (hazard ratio = 109.852 [15.738-766.749], P value < .001) or multivariate (hazard ratio = 114.075 [15.207-855.735], P value < .001) analyses. The ROC curves of this model imply high predictive accuracy for 1-year, 3-year, and 5-year survival (1-year area under the curve [AUC] = 0.849, 3-years AUC = 0.848, and 5-years AUC = 0.761). Our study revealed that immune-related lncRNAs are significant in the clinical diagnosis, treatment and prognosis of UM patients. We successfully constructed a lncRNA-based prognostic risk model which may serve as a future reference for the diagnosis and prognosis of UM. Based on this model we also validated the sensitivity of some cancer drugs, which has implications for the future immunotherapy and drug development.

Anti-diabetic drug use and reduced risk of Parkinson's disease: A community-based cohort study

BackgroundEmerging evidence suggests a potential association between certain anti-diabetic drugs and a reduced risk of Parkinson's disease (PD). Limited population-based studies have investigated users of newer anti-diabetic drugs such as GLP-1 agonists or SGLT2 inhibitors. ObjectiveThe aim of this study was to assess the risk of PD among individuals with type 2 diabetes mellitus (T2DM) who were treated with various types of anti-diabetic drugs over time. MethodsA population-based cohort comprising T2DM patients aged over 30 who used metformin, GLP-1 agonists, thiazolidinediones, sulfonylureas, DPP4 inhibitors, SGLT2 inhibitors, or meglitinides between January 1, 1999 and December 31, 2018. Data were obtained between the diabetes registration and drug purchase databases of Maccabi Healthcare Services. Time-dependent Cox regression models, adjusted for sex, age, and comorbidities were employed to calculate the adjusted hazard ratios (HRs) for the PD risk associated with different anti-diabetic drugs over time. ResultsThe study population comprised 86,229 T2DM patients, with 53.9 % males. The mean age at the first anti-diabetic drug purchase was 59.0 ± 11.0 and 62.0 ± 11.0 years for men and women respectively. Compared to metformin, several drug types were associated with a significantly lower PD risk: thiazolidinediones (HR = 0.91, 95 % CI:0.074–1.14); DPP4 inhibitors (HR = 0.60, 95 % CI:0.53–0.67); meglitinides (HR = 0.63, 95 % CI:0.53–0.74); GLP-1 agonists (HR = 0.54, 95 % CI:0.39–0.73); and SGLT2 inhibitors (HR = 0.15, 95 % CI:0.10–0.21). ConclusionsOur results suggest a reduced risk of PD with certain anti-diabetic drugs, particularly SGLT2 inhibitors and GLP-1 agonists. Validation through extensive big-data studies is essential to confirm these results and to optimize PD prevention and management.

Proteogenomic Identification and Analysis of KIF5B as a Prognostic Signature for Hepatocellular Carcinoma.

Metabolic disorders are significant risk factors for liver cancer, particularly Hepatocellular Carcinoma (HCC). However, the molecular genetic basis of metabolic reprogramming in the liver remains largely uncertain. This study aimed to investigate some novel prognostic biomarkers in HCC by using proteogenomic and transcriptomic analysis and explore the potential role of specific prognostic genes in HCC. Here, we have presented a proteogenomic analysis of 10 pairs of HCC. Protein co-expression and pathway analysis were performed to investigate the biological characteristics of HCC. Protein and mRNA expression profiles of multi-cohorts were integrated to detect novel prognostic protein markers of HCC. The carcinogenic roles of candidate prognostic markers were further evaluated by MTS assay, colony formation, monolayer wound healing assay, and xenograft models. A total of 2086 proteins with significantly different expressions were detected in HCC. Pathways related to oncogenic signaling and insulin-related metabolism have been found to be dysregulated and differentially regulated in HCC. We have identified the novel prognostic biomarkers, KIF5B, involved in liver metabolic reprogramming. The biomarkers were identified using multivariable COX regression analysis from two independent proteomic datasets (Fudan Cohort and our recruited cohort) and the TCGA mRNA database. Both the protein and mRNA up-regulation of KIF5B have been found to be associated with a poor clinical outcome in HCC. Insulin activated the protein expression of KIF5B in HCC. Knocking out KIF5B expression by sgRNA decreased the protein expression of FASN and SCD1 and the intracellular triglyceride concentration. Silencing KIF5B suppressed HCC cell proliferation and colony formation in vitro, as well as HCC growth in xenograft models. Our findings have suggested KIF5B protein to function as a novel prognostic biomarker in HCC. KIF5B expression has been found to activate the AKT/mTOR pathway and reprogram triglyceride metabolism, leading to HCC development. Targeting KIF5B may be an effective strategy in the clinical treatment of HCC.

Association between muscle mass and overall survival among colorectal cancer patients at tertiary cancer center in the Middle East

Recent reports have shown that pre-treatment low muscle mass may lead to poorer outcomes for cancer patients. We explored the correlation between Visceral Adipose Tissue (VAT), Subcutaneous Adipose Tissue (SAT), and Muscle Mass (MM) as measured by CT scans, and overall survival (OS) following diagnosis of colorectal cancer (CRC). We conducted a retrospective review of medical records and CT scans of patients diagnosed with CRC between 2007 and 2018. Demographics, pathology, and clinical parameters were collected. Using Image-J software, we measured VAT, SAT, and MM. Survival rates were analyzed using Kaplan–Meier curves, and prognostic factors were assessed using multivariate Cox regression. Analysis included 408 patients with a mean age of 56.9 years and a median follow-up of 93.3 months. Colon and rectum/rectosigmoid colon cancers were equally distributed. The 5-year OS rate was 67.8%. There was no significant difference in OS rates based on SAT or VAT. However, higher MM was associated with a improved 5-year OS rate. Factors such as age, stage, grade, and surgery were also associated to OS rates. These findings suggest that higher muscle mass may lead to better outcomes for CRC patients, highlighting the potential impact of exercise and nutritional interventions on patient outcomes.

Association of Vitamin E Intake with All-Cause Mortality Among Individuals with Rheumatoid Arthritis: A Cohort Study from the NHANES 1999-2018

Background The relationship between dietary vitamin E intake and mortality rates among rheumatoid arthritis (RA) patients remains a relatively uncharted territory in nutritional epidemiology, underscoring an important gap in research. Objectives This study is to explore the potential association between dietary vitamin E intake and all-cause mortality in the RA patient population. Methods This longitudinal cohort study analyzed 2,906 RA patients aged 20 years or older who participated in the National Health and Nutrition Examination Survey from 1999 to 2018. Comprehensive data on mortality, dietary vitamin E intake, and pertinent confounding variables were systematically collected and analyzed using Cox regression and spline curve fitting to analyze the potential association. Results Following the adjustment for confounding factors, a significant inverse relationship was identified between dietary vitamin E intake and the risk of all-cause mortality in patients with RA. The adjusted hazard ratios (HRs) for the second (Q2), third (Q3), and fourth (Q4) quartiles of vitamin E intake were 0.85, 0.60, and 0.68, respectively. Non-linear modeling indicated a threshold effect characterized by a curve that associated dietary vitamin E intake with mortality risk (p = 0.016). An intake threshold of 7.097 mg/day was identified, below which each unit increment in vitamin E intake was associated with a 11.1% decrease in all-cause mortality risk (HR = 0.889). Conversely, for intakes surpassing this threshold, no significant relationship with mortality risk was detected (HR = 1.0038). Conclusion The findings of this study indicate a beneficial relationship between elevated dietary vitamin E intake and a reduced risk of all-cause mortality in RA patients. The dose-response relationship exhibits a non-linear pattern, featuring a critical inflection point at an intake of approximately 7.097 mg/day.

Cardiovascular health and cancer mortality: evidence from US NHANES and UK Biobank cohort studies

BackgroundThe American Heart Association recently introduced a novel cardiovascular health (CVH) metric, Life's Essential 8 (LE8), for health promotion. However, the relationship between LE8 and cancer mortality risk remains uncertain.MethodsWe investigated 17,076 participants from US National Health and Nutrition Examination Survey (US NHANES) and 272,727 participants from UK Biobank, all free of cancer at baseline. The CVH score, based on LE8 metrics, incorporates four health behaviors (diet, physical activity, smoking, and sleep) and four health factors (body mass index, lipid, blood glucose, and blood pressure). Self-reported questionnaires assessed health behaviors. Primary outcomes were mortality rates for total cancer and its subtypes. The association between CVH score (continuous and categorical variable) and outcomes was examined using Cox model with adjustments. Cancer subtypes-related polygenic risk score (PRS) was constructed to evaluate its interactions with CVH on cancer death risk.ResultsOver 141,526 person-years in US NHANES, 424 cancer-related deaths occurred, and in UK Biobank, 8,872 cancer deaths were documented during 3,690,893 person-years. High CVH was associated with reduced overall cancer mortality compared to low CVH (HR 0.58, 95% CI 0.37–0.91 in US NHANES; 0.51, 0.46–0.57 in UK Biobank). Each one-standard deviation increase in CVH score was linked to a 19% decrease in cancer mortality (HR: 0.81; 95% CI: 0.73–0.91) in US NHANES and a 19% decrease (HR: 0.81; 95% CI: 0.79–0.83) in UK Biobank. Adhering to ideal CVH was linearly associated with decreased risks of death from lung, bladder, liver, kidney, esophageal, breast, colorectal, pancreatic, and gastric cancers in UK Biobank. Furthermore, integrating genetic data revealed individuals with low PRS and high CVH exhibited the lowest mortality from eight cancers (HRs ranged from 0.36 to 0.57) compared to those with high PRS and low CVH. No significant modification of the association between CVH and mortality risk for eight cancers by genetic predisposition was observed. Subgroup analyses showed a more pronounced protective association for overall cancer mortality among younger participants and those with lower socio-economic status.ConclusionsMaintaining optimal CVH is associated with a substantial reduction in the risk of overall cancer mortality. Adherence to ideal CVH correlates linearly with decreased mortality risk across multiple cancer subtypes. Individuals with both ideal CVH and high genetic predisposition demonstrated significant health benefits. These findings support adopting ideal CVH as an intervention strategy to mitigate cancer mortality risk and promote healthy aging.

Development and experimental verification of novel angiogenesis related prognostic model and immune infiltration characterization in osteosarcoma

BackgroundAs the most common primary bone cancer, osteosarcoma (OS) still lacks satisfactory therapeutic outcomes. Therefore, it is crucial to further evaluate OS at different risk levels and identify new intervention targets. Many evidences suggest the important role of angiogenesis in OS, but further exploration is needed.MethodsWe utilized public databases TARGET and GEO and employed bioinformatics algorithms such as LASSO, univariate and multivariate Cox regression analyses, and unsupervised consensus clustering to explore the role of angiogenesis-related genes (AGRGs) in OS. By calculating AGRG scores, we further analyzed OS molecular subtypes based on AGRGs. The correlation between AGRG scores and immune infiltration was subsequently examined. In vitro experiments, including WB, PCR, siRNA, migration, and invasion assays, were used to determine the value of the selected targets for OS.ResultsUltimately, we established an OS prognosis model based on five AGRGs (COL5A2, CXCL6, FSTL1, NRP1, and TNFRSF21) that can independently validate prognosis levels. In vitro experiments confirmed the aberrant expression of CXCL6 in OS and its potential role in migration and invasion.ConclusionOur study reveals the impact of angiogenesis on OS from a novel perspective and provides potential intervention targets.

The preoperative scoring system combining neutrophil/lymphocyte ratio and CA19-9 predicts the long-term prognosis of intrahepatic cholangiocarcinoma patients undergoing curative liver resection

BackgroundThis study aims to investigate preoperative prognostic factors available for intrahepatic cholangiocarcinoma (ICC) patients and propose a new preoperative prognostic scoring system for ICC that combines CA19-9 and neutrophil/lymphocyte ratio (NLR).MethodsIn this retrospective analysis, 1728 patients diagnosed with ICC and undergoing curative liver resections were studied. This study employed univariate and multivariate Cox regression to find factors affecting recurrence and overall survival (OS), and furthermore assessed how preoperative models influenced tumor traits and postoperative recurrence.ResultsThe results of the multivariate Cox regression analysis indicated that two preoperative variables, NLR and Ca19-9, were independent risk factors affecting postoperative recurrence and OS in ICC patients. Based on this data, assigning a score of 0 (NLR ≤ 2.4 and Ca19-9 ≤ 37U/ml) or 1 (NLR > 2.4 and Ca19-9 > 37U/ml) to these two factors, a preoperative prognostic score was derived. According to the scoring model, patients were divided into three groups: 0 points (low-risk group), 1 point (intermediate-risk group), and 2 points (high-risk group). The 5-year recurrence and OS rates for the three groups were 56.6%, 68.2%, 77.8%, and 56.8%, 40.6%, 27.6%, respectively, with all P values < 0.001. Furthermore, high-risk group patients were more prone to early recurrence (early recurrence rates for high-, intermediate-, and low-risk groups were 56.8%, 51.5%, and 37.1%, respectively, P < 0.001) and extrahepatic metastasis (extrahepatic metastasis rates for high-, intermediate-, and low-risk groups were 31.7%, 26.4%, and 15.4%, respectively, P < 0.001). In terms of tumor characteristics, high-risk group patients had larger tumor diameters and were more likely to experience microvascular invasion, lymph node metastasis, and perineural invasion.ConclusionsThe predictive capacity of postoperative recurrence and OS rates in ICC patients is effectively captured by the preoperative scoring system incorporating NLR and CA19-9 levels.

Integrating Mcm-2 and Ki-67 immunohistochemistry with clinico-pathologic parameters for enhanced prognostic accuracy in oral verrucous lesions

BackgroundOral verrucous lesions (OVLs) present a diagnostic challenge due to their diverse and often confusing histopathological features. Accurate differentiation is essential for improving diagnosis and predicting prognosis. In addition to assessing overall survival (OS) and disease-free survival (DFS) in verrucous squamous cell carcinoma (VSCC) and conventional OSCC, this study seeks to evaluate the expression of Mcm-2 and Ki-67 in verrucous lesions and oral squamous cell carcinoma (OSCC). These findings will be correlated with the nuclear expression of Mcm-2 and Ki-67. MethodologyNinety tissue samples that were paraffin embedded and formalin-fixed were examined using immunohistochemistry to determine the expression of Mcm-2 and Ki-67. Data on survival and clinico-pathologic characteristics were taken from patient records. Statistical analyses were conducted using Independent T-tests, Cox regression models, and Kaplan-Meier survival analysis. ResultsMcm-2 was identified as a more sensitive and prognostic marker compared to Ki-67 across the study groups. Mcm-2 overexpression was observed in all cases of verrucous hyperplasia with dysplasia, verrucous carcinoma (VC), VSCC, and conventional OSCC. The 3-year OS and DFS rates were lower in conventional OSCC (75 % and 64.3 %, respectively) compared to VSCC (90 % and 70 %). ConclusionThis study represents the first initiative to employ both Mcm-2 and Ki-67 as proliferative markers for distinguishing between various oral verrucous lesions. Mcm-2 proves to be a valuable marker for differentiating between potentially malignant and malignant verrucous lesions. However, further validation with larger sample sizes and longer follow-up periods is necessary to confirm its role in predicting OS and DFS.

Identification of HDAC10 as a candidate oncogene in clear cell renal carcinoma that facilitates tumor proliferation and metastasis

BackgroundClear cell renal cell carcinoma (ccRCC) remains one of the most lethal urological malignancies even though a great number of improvements in diagnosis and management have achieved over the past few decades. Accumulated evidence revealed that histone deacetylases (HDACs) play vital role in cell proliferation, differentiation and apoptosis. Nevertheless, the biological functions of histone deacetylation modification related genes in ccRCC remains poorly understood.MethodBulk transcriptomic data and clinical information of ccRCC patients were obtained from the TCGA database and collected from the Chinese PLA General Hospital. A total of 36 histone deacetylation genes were selected and studied in our research. Univariate cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, random forest (RF) analysis, and protein-protein interaction (PPI) network analysis were applied to identify key genes affecting the prognosis of ccRCC. The ‘oncoPredict’ algorithm was utilized for drug-sensitive analysis. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the potential biological function. The ssGSEA algorithm was used for tumor immune microenvironment analysis. The expression levels of HDAC10 were validated by RT-PCR and immunohistochemistry (IHC). 5-ethynyl-2′-deoxyuridine (EdU assay), CCK-8 assay, cell transwell migration and invasion assay and colony formation assay were performed to detect the proliferation and invasion ability of ccRCC cells. A nomogram incorporating HDAC10 and clinicopathological characteristics was established to predict the prognosis of ccRCC patients.ResultTwo machine learning algorithms and PPI analysis identified four histone deacetylation genes that have a significant association with the prognosis of ccRCC, with HDAC10 being the key gene among them. HDAC10 is highly expressed in ccRCC and its high expression is associated with poor prognosis for ccRCC patients. Pathway enrichment and the experiments of EdU staining, CCK-8 assay, cell transwell migration and invasion assay and colony formation assay demonstrated that HDAC10 mediated the proliferation and metastasis of ccRCC cells and involved in reshaping the tumor microenvironment (TME) of ccRCC. A clinically reliable prognostic predictive model was established by incorporating HDAC10 and other clinicopathological characteristics ( https://nomogramhdac10.shinyapps.io/HDAC10_Nomogram/ ).ConclusionOur study found the increased expression of HDAC10 was closely associated with poor prognosis of ccRCC patients. HDAC10 showed a pro-tumorigenic effect on ccRCC and promote the proliferation and metastasis of ccRCC, which may provide new light on targeted therapy for ccRCC.

Abstract IA004: Risk of therapy-related subsequent cancers in individuals with germline TP53 variants

Abstract Background. Based primarily on in vitro and animal studies, germline TP53 variants are considered to confer sensitivity to ionizing radiation-induced DNA damage, but data in humans are sparse. We sought to quantify risk of developing radiotherapy and chemotherapy-related subsequent neoplasms by pooling individual-level data from nine cohorts of individuals with confirmed pathogenic/likely pathogenic germline TP53 variants. Methods. 891 individuals were followed from six months after first cancer until diagnosis of a subsequent neoplasm, death or date of last follow-up. Radiotherapy and chemotherapy for each cancer were considered as time-dependent covariates in Cox regression models with age as the time-scale, adjusted for sex and occurrence of prior malignant or benign tumors. Subsequent cancers were classified as in- or out-of-field based on the body region of previous cancers. Results. Among 891 individuals, 643 (72.2%) were female and 297 (33.3%) were diagnosed with a first cancer before age 20 years. Breast cancer was the most commonly diagnosed first cancer (N=371), followed by soft tissue sarcoma (N=131) and central nervous system cancers (N=84). First cancer treatment included radiotherapy for 237 (26.6%) and/or chemotherapy for 421 (47.3%) individuals. Analyses are underway to define the characteristics of subsequent neoplasms (including age at diagnosis, latency, and distribution of diagnosis type) and to calculate relative and absolute risk estimates for radiotherapy and chemotherapy overall and by subsequent neoplasm type. Conclusions. This study will quantify the contribution of radiotherapy and chemotherapy to the risk of subsequent cancers among individuals with Li-Fraumeni syndrome. Understanding the magnitude of this risk will support health care providers and patients in making informed decisions about cancer management. Citation Format: Anita Villani, Payal Khincha, Jessica Hatton, Sara Schonfeld, Catherine Goudie, Leatrisse Oba, Kishan Pithadia, Birte Sänger, Christian Kratz, Anh N. Le, Caitlin Orr, Kara N. Maxwell, Anne Naumer, Jennie Vagher, Wendy Kohlmann, Joshua Schiffman, Elizabeth Santana dos Santos, Orli Michaeli, Jacob J. Carson, Derek S. Tsang, Raymond Kim, Jamie L. Maciaszek, Kim E. Nichols, Victoria E. Goodman, Suzanne P. MacFarland, Lara Reichman, Maria Isabel Achatz, Sharon Savage, David Malkin, Lindsay M. Morton. Risk of therapy-related subsequent cancers in individuals with germline TP53 variants [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA004.

Association of Renal Hyperfiltration with Incidence of New-Onset Diabetes Mellitus: A Nationwide Cohort Study.

Background and Objectives: While the connection between decreased kidney function and diabetes mellitus (DM) is commonly acknowledged, there is insufficient research examining the relationship between higher-than-normal estimated glomerular filtration rate (eGFR) and the incidence risk of new-onset DM. Our research aimed to explore the relationship between an eGFR and the incidence risk of new-onset DM in the Korean general population through a nationwide longitudinal study. Methods: This research employed the cohort records of the National Health Insurance Service in Korea, analyzing records from 2,294,358 individuals between the ages of 20 and 79 who underwent health check-ups between 2010 and 2011. The eGFR levels from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation were used to assess the renal function. New-onset DM was defined as two or more claims with the International Classification of Diseases-10 classification codes E10 to E14, being prescribed any medication for lowering blood glucose, or having a record of fasting plasma glucose levels of ≥126 mg/dL from a health examination after the index date. Results: The mean age of subjects was 47.34 ± 13.76 years. The 150,813 (6.57%) new-onset DM cases were identified over a median follow-up of 9.63 years. In the multivariable Cox regression analysis, in comparison with the 5th decile, the 10th (≥114.12 mL/min/1.73 m2) (hazard ratio (HR): 0.52, 95% confidence interval (CI) (0.50-0.54), p < 0.001) eGFR decile was significantly associated with a decreased incidence of new-onset DM. Moreover, eGFR >120 mL/min/1.73 m2 was associated with a reduced risk of new-onset DM (HR: 0.40, 95% CI (0.39-0.42), p < 0.001). These results were consistent regardless of the presence of impaired glucose tolerance, age, or obesity. Conclusion: Our study showed higher-than-normal eGFR levels were associated with a lower risk of incidence for new-onset DM regardless of the presence of impaired glucose tolerance, age, or obesity. In general population, higher-than-normal eGFR may be associated with a lower risk of incidence of new-onset DM.

Molecular subtypes and nomogram for predicting the prognosis of cervical cancer based on a matrix-immune signature

Cervical cancer is a kind of tumor related to chronic HPV infection. Currently, the treatment of cervical cancer is guided mainly by clinicopathological factors. The role of tumor microenvironment in the prognosis and treatment of cervical cancer has been ignored. We aimed to use bioinformatics to identify the molecular subtypes in cervical cancer and construct a predictive nomogram combining a matrix-immune signature (MIS) and clinicopathological factors to support treatment decisions. Two cervical cancer subtypes with different prognoses were identified based on matrix- and immune-genes in TCGA-CESC. The MIS was developed using Cox regression and Lasso algorithm and verified in the Cancer Genome Characterization Initiative (CGCI) using time-dependent receiver operating characteristic (ROC) curve analysis. Multivariable analysis identified lymph node metastases, lymphovascular space invasion, and the MIS as independent prognostic factors, which were used to construct the predictive nomogram. The areas under the ROC curve of the model were 0.872, 0.879, and 0.803 for the 1-, 3-, and 5-year periods, respectively. The C-index was 0.845. Calibration curves confirmed the excellent prognosis prediction of the nomogram. The nomogram indicted a 3-year survival rate of > 90% in patients with a total score > 110.1. The constructed predictive nomogram has significant implications for prognostic assessment and treatment selection in cervical cancer.

Association of Snoring and Daytime Sleepiness With Subsequent Incident Hypertension: A Population-Based Cohort Study.

There is a strong association between obstructive sleep apnea and hypertension, but the effects of obstructive sleep apnea symptoms on the risk of incident hypertension are not well documented. The aim of this prospective study was to examine whether snoring and sleepiness are associated with incident hypertension. Data from the French population-based CONSTANCES cohort were analyzed. Normotensive participants, aged 18 to 69 years, were included between 2012 and 2016 and screened for snoring, morning fatigue, and daytime sleepiness in 2017 using items of the Berlin Questionnaire. We used Cox models, adjusted for multiple potential confounders, including body mass index, baseline blood pressure, sleep duration, and depressive symptoms, to compute hazards ratios of incidentally treated hypertension. Among 34 727 subjects, the prevalence of self-reported habitual snoring, morning fatigue, and excessive daytime sleepiness (≥3× a week for each) was 23.6%, 16.6%, and 19.1%, respectively. During a median follow-up of 3.1 years (interquartile range, 3.0-3.5), the incidence of treated hypertension was 4.1%. The risk of de novo treated hypertension was higher in participants who reported habitual snoring (adjusted hazard ratio, 1.17 [95% CI, 1.03-1.32]) and excessive daytime sleepiness (adjusted hazard ratio, 1.42 [95% CI, 1.24-1.62]), and increased with the weekly frequency of symptoms, with a dose-dependent relationship (Ptrend≤0.02 for all symptoms). Self-reported snoring and excessive daytime sleepiness are associated with an increased risk of developing hypertension. Identification of snoring and daytime sleepiness may be a useful public health screening tool in primary care for hypertension prevention.

Outcomes of Adjunctive Corticosteroid Treatment on Hypoxemic Adults Hospitalised for Mycoplasma pneumoniae Pneumonia: a Retrospective Cohort Study.

Corticosteroids appears to be beneficial for severe Mycoplasma pneumoniae pneumonia in children but data in adults are limited. This study investigated effects of adjunctive corticosteroids in hypoxemic adults with M. pneumoniae pneumonia. Adults admitted 2013-2017 with verified M. pneumoniae pneumonia and hypoxemia (SpO2<93% or oxygen treatment) were included in a cohort. Treatment was defined as receipt of at least one glucocorticoid dose.Primary outcome was time to regression of hypoxemia, analysed with a multivariable Cox regression. Secondary outcomes included fever duration, length of stay, and complications. Corticosteroids were given to 31% (122/388) during hypoxemia. Median age was 44 (IQR 34-57) years. Median time to start of corticosteroid treatment was 1.9 (IQR 0.6-3.6) days from admission. Median cumulative dose was equivalent to 15 (IQR 10-19) mg betamethasone. Treatment duration was 5 (IQR 3-6) days. Patients treated with corticosteroids had more severe respiratory disease, longer symptom duration and were more often treated with fluoroquinolones.Time to regression of hypoxemia (HR 0.92 [95% CI 0.72-1.19], P = 0.53) and length of stay (HR 0.91 [95% CI 0.71-1.16], P = 0.44) were not significantly different between corticosteroid treated and controls. Corticosteroid treatment was associated to shorter fever duration (HR 1.44 [95% CI 1.00-2.06], P = 0.046). Complications did not differ significantly between treatment groups. Adjunctive corticosteroids were not associated with reduced time to regression of hypoxemia in adults with M. pneumoniae pneumonia. However, duration of fever was shorter and no increase in complications was seen.

Mid-term Waitlist and Posttransplant Outcomes With Hepatitis C-positive Donor Hearts.

This study evaluates the clinical trends and impact of hepatitis C virus-positive (HCV+) donors on waitlist and posttransplant outcomes after heart transplantation. The United Network for Organ Sharing registry was queried to identify adult waitlisted and transplanted patients from January 1, 2015, to December 31, 2022. In the waitlist analysis, the candidates were stratified into 2 cohorts based on whether they were willing to accept HCV+ donor offers. Waitlist outcomes included 1-y cumulative incidences of transplantation and death/delisting. In the posttransplant analysis, the recipients were stratified into 2 cohorts with and without HCV nucleic acid test (NAT)-positive donors. Outcomes included 1- and 4-y posttransplant survival. Propensity score-matching was performed. Risk adjustment was performed using multivariable Cox regression. During the study period, the number of centers using HCV NAT+ donors increased from 1 to 65 centers, along with the number of transplants. In the waitlist analysis, 26 648 waitlisted candidates were analyzed, and 4535 candidates (17%) were approved to accept HCV+ donors. Approval to accept HCV+ donors was associated with a higher likelihood of transplantation and a lower likelihood of death/delisting within 1 y of waitlisting. In the posttransplant analysis, 21 131 recipients were analyzed, and 997 recipients (4.7%) received HCV NAT+ hearts. The 1- and 4-y posttransplant survival were comparable between the recipients of HCV NAT+ and NAT- donors. Furthermore, the similar 1- and 4-y posttransplant survival persisted in the propensity score-matched comparison and multivariable Cox regression analysis. Utilization of HCV+ donors is rising. Heart transplants using HCV+ donors are associated with improved waitlist and comparable posttransplant outcomes.