Survival Curves Research Articles

The potential of EZH2 expression to facilitate treatment choice in stage II colorectal adenocarcinoma.

The current selection criteria of patients with stage II colorectal carcinoma (CRC) suitable for adjuvant therapy are not satisfactory. Enhancer of zeste homolog 2 (EZH2) has been demonstrated to be over-expressed in CRC. However, data regarding the role of EZH2 in CRC survival remains controversial, and little is known about it in stage II CRC. Thus, we conducted this study to investigate the clinical significance of EZH2 expression in stage II CRC. Cases with stage II CRC resected between 2015 and 2018 were retrospectively reviewed. EZH2 expression was analyzed by immunohistochemistry using tissue microarrays. The relationship between EZH2 expression and clinicopathological variables was analyzed. Survival curves were estimated by the Kaplan-Meier approach. We found high EZH2 expression in 134 of 221 analyzable stage II tumors (60.63%). No significant associations were observed between EZH2 expression and common clinicopathological factors. Survival analyses showed that cases receiving surgery alone had inferior overall survival (OS) than those receiving surgery and chemotherapy (P=0.0075) in stage II CRC with high EZH2 expression, however, metastasis-free survival (MFS) was similar between these two subgroups. Treatment choice had no impact on the survival of stage II CRC with low EZH2 expression. The OS of stage II CRC with high EZH2 expression improved more strikingly with surgery and adjuvant chemotherapy than with surgery alone, which suggests the potential of EZH2 expression as a biomarker to help identify a subgroup of early-stage CRC benefiting from surgery and adjuvant chemotherapy. More large-scale studies are warranted to corroborate this finding and to further evaluate the predictive nature of EZH2.

Construction and Validation of a Prognostic Model Based on Pyroptosis-related Genes in Bladder Cancer.

Bladder cancer (BCa) is a highly prevalent disease with a poor prognosis. There is no better forecasting method for it yet. Current studies demonstrate that pyroptosis is involved in the development and progression of various cancers. This study employed bioinformatics techniques to analyze the data of BCa patients obtained from the TCGA and GEO databases in order to construct a prognostic risk model. The TCGA dataset was used for the training set, and the multiple external datasets (including GSE13507, GSE31684, GSE48075, IMvigor210, and GSE32894) were applied as the validation sets. Prognostic-associated pyroptosis genes screened by univariate Cox regression analysis were utilized to construct the lasso Cox regression model. GO and KEGG analysis results identified the selected genes that are primarily involved in the inflammation and cell death processes. The related patients were grouped into low- and high-risk groups. Kaplan-Meier survival analysis was performed to compare survival differences between the risk groups. The accuracy of this risk prediction model was assessed by ROC. We also applied the Human Protein Atlas (HPA) to detect the protein expression of these genes. Subsequently, qRT-PCR was performed to verify the expression of these model genes. There are 29 pyroptosis-related genes with significant expression differences between BCa and corresponding adjacent tissues, and 11 genes (SH2D2A, CHMP4C, MRFAP1L1, GBP2, EHBP1, RAD9A, ANXA1, TMEM109, HEYL, APOL2, ORMDL1) were picked by univariate and LASSO Cox regression analysis. Immunological cell infiltration and ssGSEA results further indicated that the low and high-risk groups were substantially correlated with the immune status of BCa patients. According to TCGA and multiple external datasets, Kaplan-Meier survival curves showed the overall survival rate of the high-risk group to be decreased. ROC curves showed the model established to be accurate and reliable. Moreover, the HPA database also demonstrated the verification of the modeled genes' expression in BCa and normal bladder tissue using the HPA database. qRT-PCR results also suggested the up-regulated EHBP1 and down-regulated RAD9A mRNA expression levels to be confirmed in 15 pairs of BCa and corresponding adjacent tissues. This study presents the development and validation of a novel gene signature associated with pyroptosis, which holds the potential for predicting patient outcomes in BCa and providing insights into the immune microenvironment of BCa.

CT data analysis of catheter morphology and displacement in peritoneal dialysis: an exploratory study.

Catheter displacement is a common complication of peritoneal dialysis. The aim of this study was to explore the correlation between catheter morphology and displacement by analyzing CT data, providing a scientific basis for optimizing catheter morphology within abdominal wall layers. We retrospectively analyzed the clinical data of 94 patients. The parameters for analyzing catheter morphology were defined based on six key points identified from CT images. The covariates considered in the analysis included demographics, primary disease, body size, peritoneal dialysis method, and total weekly urea clearance index. During a mean follow-up period of 1056 ± 480 days, only the angle of the intramuscular part (IM angle) of the catheter significantly correlated with the time to first catheter displacement according to the multivariate analysis (hazard ratio [HR]: 1.039, 95% confidence interval [CI] 1.02-1.058, 0.01). When the cut-off value of IM angle was 39.4 , the area under receiver-operating characteristic (ROC) curve for predicting catheter displacement was 0.791 (95% CI 0.701-0.881, 0.01), with a sensitivity and specificity of 82.9% and 66.0%, respectively. Kaplan-Meier survival curves showed that the catheter survival rate was significantly higher in the group with an IM angle < 39.4 than in the group with an IM angle > 39.4 (log-rank =19.479, 0.01). None of the catheter morphology parameters were significantly correlated with technique survival in the multivariate analysis. There is a correlation between catheter morphology and catheter displacement. An IM angle > 39.4 is an independent risk factor for catheter displacement, while the position and angle of the subcutaneous part are not correlated with catheter displacement.

A clinical randomized controlled study on the psycho-cardiological therapy for patients with coronary atherosclerosis disease

Objective: To explore the prognosis efficacy of psycho-cardiological therapy and management on patients with coronary atherosclerosis disease (CAD). Methods: This was a clinical randomized controlled study. This study included inpatients with CAD at the cardiology department in Beijing Anzhen Hospital, Capital Medical University from August 2021 to January 2024. The patients enrolled in this study were asked for basic information, and received measurements for depression, anxiety, sleep quality and living quality by the scales of Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder scale-7 (GAD-7), Athens Insomnia Scale (AIS), EuroQol 5-dimension 5-level (EQ-5D-5L) respectively. The patients were randomly grouped into a regular treatment group and a psycho-cardiological treatment group which included WeChat management or antidepressant/antianxiety medical therapy according to the situation. After the patients discharging from hospital for 2, 4, 12, 24, 48, 72, and 96 weeks, professional cardiovascular doctors would follow up by telephone, WeChat, and outpatient department, including scales (2-48 weeks), and cardiac events (2-96 weeks). Kaplan-Meier survival curve and multivariate Cox proportional hazards model were used for analyzing the association between psycho-cardiological treatment and cardiac events. Results: This study recruited a total of 552 patients with CAD, aged 61.0(54.0, 67.0) years, and 379 (68.7%) were male. There were 279(50.5%) in the regular treatment group and 273(49.5%) in the psycho-cardiological treatment group. After treatment for 4, 12 and 48 weeks, the PHQ-9 score in psycho-cardiological was significantly lower than the regular treatment group; After treatment for 12 weeks, the EQ-5D-5L effective value in psycho-cardiological group was higher than the regular treatment group; After treatment for 2, 4, 12, 24 and 48 weeks, the EQ-5D-5L VAS score in psycho-cardiological group was higher than the regular therapy group (all P<0.05). The Kaplan-Meier survival curve showed that, during the different follow-up periods, the rate of cardiac events in psycho-cardiological treatment group was lower than regular treatment group (log-rank P<0.001). The multivariate Cox proportional hazards model adjusted the factor of age, the psycho-cardiological treatment contributed to reducing the cardiac events rate by 80.3% (HR=0.197, 95%CI: 0.067-0.582, P=0.003). Conclusion: Psycho-cardiological treatment is beneficial for improving psychological stress, living quality, and reducing cardiac events, and helps to improve prognosis and psycho-cardiological rehabilitation in CAD patients.

Comprehensive analysis of NOTCH pathway with tumor environment in pancreatic adenocarcinoma

Abstract Objectives Pancreatic adenocarcinoma (PAAD) ranks among the most prevalent malignant neoplasms, and multiple pathways are involved in its pathogenesis, including the NOTCH pathway. However, the variable biological functions of the pathway in PAAD are controversial. Methods RNA-seq data for PAAD was analyzed using data from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Utilizing Kaplan-Meier survival curves and Cox regression analyses, we examined the prognostic significance. The tumor microenvironment and immunotherapy responses were investigated using ssGSEA, ESTIMATE, and TIDE models. Functional enrichment analysis was used to explore gene functions. Results We identified NOTCH2, JAG1, NOTCH4, and DLL3 as high-priority members of the NOTCH pathway that modulates PAAD. Elevated NOTCH2 and JAG1 levels were markedly linked to reduced overall survival (OS), while increased NOTCH4 and DLL3 levels were significantly related to extended OS. Immune analyses showed that NOTCH-based scores were closely related to the immune microenvironment. NOTCH scores were not only closely correlated with tumor-infiltrating immune cells, but also with immunologically activated and immune checkpoint gene expression. The high NOTCH score group had a higher proportion of tumor-infiltrating immune cells and had better responses to immune checkpoint inhibitor therapy. Conclusions These data indicate that NOTCH2, JAG1, NOTCH4, and DLL3 could function as efficient prognostic biomarkers and therapeutic targets in PAAD, and patients with a high NOTCH score may have a significant response to immune checkpoint inhibitor treatment.

Baseline eosinophil proportion is a useful predictor of immune-related adverse events following immune checkpoint inhibitor treatment for recurrent metastatic head and neck cancer

Background Immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs. However, predictors of irAEs remain unidentified. Objectives We evaluated the predictors of irAEs and compared the outcomes of ICIs with and without irAEs in patients with recurrent/metastatic head and neck cancers (R/M HNCs). Materials and methods We retrospectively analyzed 157 patients with R/M HNCs who were administered an anti-PD-1 antibody between September 2014 and December 2022. We examined whether various pretreatment factors were associated with irAEs. The overall survival (OS) and progression-free survival (PFS) in patients with and without irAEs were analyzed. Results Overall, 44 patients (28.0%) developed irAEs. The survival curve estimated for patients with and without irAEs showed a significant difference in PFS (p = 0.018), but not in OS (p = 0.208). Multivariate analysis revealed significant differences in relative eosinophil counts (p < 0.001), TP (p = 0.014), and NLR (p = 0.002), which may be independent predictors of irAEs. Conclusion IrAEs may be associated with higher efficacy of ICIs and longer PFS. The relative eosinophil count may be predictors of irAEs and useful in routine medical practice. Using these biomarkers to predict irAEs will help predict ICI effects and manage irAEs.

Relative biological effectiveness of clinically relevant photon energies for the survival of human colorectal, cervical, and prostate cancer cell lines

Abstract Objective: Relative biological effectiveness (RBE) differs between radiation qualities. However, an RBE of 1.0 has been established for photons regardless of the wide range of photon energies used clinically, the lack of reproducibility in radiobiological studies, and outdated reference energies used in the experimental literature. Moreover, due to intrinsic radiosensitivity, different cancer types have different responses to radiation. This study aimed to characterize the RBE of clinically relevant high and low photon energies in vitro for three human cancer cell lines: HCT116 (colon), HeLa (cervix), and PC3 (prostate). Approach: Experiments were conducted following dosimetry protocols provided by the American Association of Physicists in Medicine. Cells were irradiated with 6 MV x-rays, an 192Ir brachytherapy source, 225 kVp and 50 kVp x-rays. Cell survival post-irradiation was assessed using the clonogenic assay. Survival fractions were fitted using the linear quadratic model, and the survival curves were generated for RBE calculations. Main results: The cell killing was more efficient with decreasing photon energy: the HCT116 RBESF0.1 for 6 MV x-rays, 192Ir, and 50 kVp x-rays using 225 kVp x-rays as the reference were 0.89 ± 0.03, 0.95 ± 0.03, and 1.24 ± 0.04; the HeLa RBESF0.1 were 0.95 ± 0.04, 0.97 ± 0.05, and 1.09 ± 0.03, and the PC3 RBESF0.1 were 0.84 ± 0.01, 0.84 ± 0.01, and 1.13 ± 0.02, respectively. HeLa and PC3 cells had varying radiosensitivity when irradiated with 225 and 50 kVp x-rays. Significance: This difference supports the notion that RBE may not be 1.0 for all photons through experimental investigations that employed precise dosimetry. It highlights that different cancer types may not have identical responses to the same irradiation quality. Additionally, the RBE of clinically relevant photons was updated to the reference energy of 225 kVp x-rays.

Isoliensinine suppressed gastric cancer cell proliferation and migration by targeting TGFBR1 to regulate TGF-β-smad signaling pathways

BackgroundGastric cancer (GC) ranks as the fifth most prevalent cancer globally, and its pronounced invasiveness and propensity to spread provide significant challenges for therapy. At present, there are no efficacious medications available for the treatment of patients with GC. Isoliensinine (ISO), a bisbenzylisoquinoline alkaloid, was isolated from Nelumbo nucifera Gaertn. It possesses anti-tumor, antioxidant, and other physiological effects. Nevertheless, there is currently no available study on the impact of ISO on GC, and further investigation is needed to understand its molecular mechanism.MethodsISO target points and GC-related genes were identified, and the cross-target points of ISO and GC were obtained. We then examined cross-targeting and found genes that were differentially expressed in GCs. Kaplan-Meier survival curves were used to screen target genes, and the STRING database and Cytoscape 3.9.1 were used to construct protein-protein interactions and drug-target networks. In addition, molecular docking studies confirmed the interactions between ISO screen targets. Finally, in vitro tests were used to establish the impact of ISO on GC cells.ResultsThrough bioinformatics research, we have identified TGFBR1 as the target of ISO in GC. In addition, we noticed a substantial inhibition in GC cell proliferation, migration, and invasion activities following ISO treatment. Moreover, we noticed that ISO treatment effectively suppressed TGF-β-induced epithelial-mesenchymal transition (EMT) and activation of the TGF-β-Smad pathway. Furthermore, we discovered that siTGFBR1 nullified the impact of ISO on TGF-β-triggered migration, invasion, and activation of the TGF-β-Smad pathway.ConclusionOur research suggests that ISO specifically targets TGFBR1 and regulates the TGF-β-Smad signaling pathway to suppress the proliferation and migration of GC cells.

TOPAS-Tissue: A Framework for the Simulation of the Biological Response to Ionizing Radiation at the Multi-Cellular Level

This work aims to develop and validate a framework for the multiscale simulation of the biological response to ionizing radiation in a population of cells forming a tissue. We present TOPAS-Tissue, a framework to allow coupling two Monte Carlo (MC) codes: TOPAS with the TOPAS-nBio extension, capable of handling the track-structure simulation and subsequent chemistry, and CompuCell3D, an agent-based model simulator for biological and environmental behavior of a population of cells. We verified the implementation by simulating the experimental conditions for a clonogenic survival assay of a 2-D PC-3 cell culture model (10 cells in 10,000 µm2) irradiated by MV X-rays at several absorbed dose values from 0–8 Gy. The simulation considered cell growth and division, irradiation, DSB induction, DNA repair, and cellular response. The survival was obtained by counting the number of colonies, defined as a surviving primary (or seeded) cell with progeny, at 2.7 simulated days after irradiation. DNA repair was simulated with an MC implementation of the two-lesion kinetic model and the cell response with a p53 protein-pulse model. The simulated survival curve followed the theoretical linear–quadratic response with dose. The fitted coefficients α = 0.280 ± 0.025/Gy and β = 0.042 ± 0.006/Gy2 agreed with published experimental data within two standard deviations. TOPAS-Tissue extends previous works by simulating in an end-to-end way the effects of radiation in a cell population, from irradiation and DNA damage leading to the cell fate. In conclusion, TOPAS-Tissue offers an extensible all-in-one simulation framework that successfully couples Compucell3D and TOPAS for multiscale simulation of the biological response to radiation.

Elevated serum albumin-to-creatinine ratio as a protective factor on clinical outcomes among critically ill patients with sepsis: a retrospective study

BackgroundThe aim of this study was to examine the prognostic significance of serum albumin-to-creatinine ratio (ACR) in critically ill patients with sepsis.MethodsThis retrospective study analyzed sepsis cases admitted to the Affiliated Hospital of Jiangsu University between January 2015 and November 2023. The patients were divided into four groups based on their ACR upon admission to the intensive care unit (ICU). Laboratory data were collected at the time of ICU admission, and the primary outcome measure was in-hospital all-cause mortality. Kaplan–Meier survival curves were generated to illustrate the differences in 30−/60-day mortality among the various groups. Multivariate Cox regression models and restricted cubic splines (RCS) were utilized to explore the association between ACR and all-cause mortality in sepsis patients. Subgroup analyses were conducted to examine the impact of other covariates on the relationship between ACR and all-cause mortality.ResultsA total of 1,123 eligible patients were included in the study, with a median ACR of 0.169. The in-hospital mortality rate was 33.7%, the ICU mortality rate was 31.9%, and the 30-day mortality rate was 28.1%. Kaplan–Meier survival analysis demonstrated that patients with higher ACR had a significantly lower risk of 30−/60-day mortality (log-rank p &amp;lt; 0.001). Multivariable Cox proportional hazards analyses revealed that ACR was an independent predictor of in-hospital death (HR: 0.454, 95% CI 0.271–0.761, p = 0.003), ICU death (HR: 0.498, 95% CI 0.293–0.847, p = 0.010), and 30-day death (HR: 0.399, 95% CI 0.218–0.730, p = 0.003). For each 1-unit increase in ACR, there was a 1.203-fold decrease in the risk of death during the hospital stay. The RCS curve illustrated a non-linear negative correlation between ACR and in-hospital mortality (p for non-linear =0.018), ICU mortality (p for non-linear =0.005), and 30-day mortality (p for non-linear =0.006). Sensitivity analysis indicated consistent effect sizes and directions in different subgroups, confirming the stability of the results.ConclusionLow ACR levels were identified as independent risk factors associated with increased in-hospital, ICU, and 30-day mortality in sepsis patients. ACR can serve as a significant predictor of the clinical outcome of sepsis.

Myocardial contrast echocardiography evaluation of coronary microvascular dysfunction to Predict MACEs in patients with heart failure with preserved ejection fraction follow-up

BackgroundCMD refers to the abnormalities of the tiny arteries and capillaries within the coronary artery system, which result in restricted or abnormal blood flow. CMD is an important mechanism involved in ischemic heart disease and secondary heart failure. CMD can explain left ventricular dysfunction and poor prognosis.The European Association of Cardiovascular Imaging recommends the use of MCE for the assessment of myocardial perfusion. Myocardial contrast echocardiography (MCE) is used to evaluate the accuracy of Coronary microvascular dysfunction (CMD) for predicting major adverse cardiac events (MACEs) in patients with heart failure with preserved ejection fraction (HFpEF) at follow-up.MethodsThe clinical data of 142 patients diagnosed with HFpEF in our hospital from January 2020 to January 2022 were retrospectively summarized and stratified into 77 cases (> 1) in the CMD group and 65 cases (= 1) in the non-CMD group based on the perfusion score index (PSI) of the 17 segments of the left ventricle examined by the admission MCE, and the perfusion parameters were measured at the same time, including the peak plateau intensity (A value), the curve slope of the curve rise (βvalue) and A × β values. At a median follow-up of 27 months till October 2023, MACEs were recorded mainly including heart failure exacerbation, revascularization, cardiac death, etc.ResultsIncreasing age, hypertension, diabetes, and coronary artery disease in the CMD group resulted in decreased left ventricular ejection fraction (LVEF), increased plasma NT-B-type natriuretic peptide (BNP) and left ventricular global longitudinal strain (LVGLS), decreased A-values and A × β-values, and an increased incidence of MACEs (P < 0.05). Univariate and multivariate Cox regression analyses showed that LVGLS (HR = 1.714, 95% CI = 1.289–2.279, P < 0.001) and A × β values (HR = 0.636, 95% CI = 0.417 to 0.969, P = 0.035) were independent predictors of MACEs in patients with HFpEF. The receiver operating characteristic curve (ROC) showed that the area under the curve (AUC) of LVGLS combined with A × β value for diagnosis of MACEs was 0.861 (95% CI = 0.761 ~ 0.961, P < 0.001), which was significantly higher than that of LVGLS or A × β value (P < 0.05). The Kaplan-Meier survival curves showed that the cumulative survival rate in CMD group was significantly lower than non-CMD group (logrank χ2 = 6.626, P = 0.010), with the most significant difference at 20 months of follow-up.ConclusionMCE can evaluate CMD semi-quantitatively and quantitatively, LVGLS combined with A × β value has good performance in predicting the risk of developing MACEs in patients with HFpEF at 3 years of follow-up, and CMD can be used as an important non-invasive indicator for assessing clinical prognosis.

Early B lymphocyte subsets in blood predict prognosis in sepsis

BackgroundB lymphocytes play a key role in immunosuppression. This study investigated the prognostic value of B cell subsets in sepsis.MethodsFlow cytometry was used to assess peripheral B cell subsets from patients with sepsis on the first and seventh days following admission, as well as 111 healthy controls. The patients were divided into survivors and non-survivors, based on 28-day prognosis.ResultsThe analysis showed abnormal distribution and selective depletion of B cells and its subsets in the early stages of sepsis. On day 1, compared with survivors, non-survivors showed significant decreases in the proportion and absolute count of transitional (Tr) B cells, reductions in the proportion of CD5+ B cells, and increases in the proportion of double-negative (DN) B cells. On day 7, the proportions and absolute counts of Tr and CD5+ B cells significantly decreased whereas the proportion of DN B cells significantly increased in non-survivors. Ninety-four survivors and 15 non-survivors were included in our paired-sample rank-sum test. Compared to day 1, only the survivors showed significant increases in absolute B, Tr B, and CD5+ B cell counts by day 7. Multivariate Cox regression analysis showed that the proportion of DN B cells on day 1 (hazard ratio = 1.092 [95% confidence interval: 1.035–1.152], P = 0.001) was a risk factor for mortality, and Kaplan–Meier survival curve analysis showed that patients with proportions of DN B cells &amp;gt; 11.81% on day 1 had poorer prognoses. Receiver operating characteristic curve analysis showed that B cell subset parameters could predict mortality (area under the receiver operating characteristic curve [AUC], 0.741) and enhanced the prognostic value of the Acute Physiology and Chronic Health Evaluation II score (AUC, 0.840).ConclusionOur study revealed that deficiencies of B, Tr B, and CD5+ B cells, as well as a persistent increase in the proportion of DN B cells, were associated with poor prognosis—and that B cell subsets showed predictive value to mortality. These results provide new insights into the roles of B cell subsets in sepsis, as well as ways to better manage its progression and predict its course.

Efficacy and safety of calcineurin inhibitors (CNIs) for septic patients in ICU: a cohort study from MIMIC database

BackgroundSepsis is marked by a dysregulated immune response to infection. Calcineurin inhibitors (CNIs), commonly used as immunosuppressants, have unique properties that may help mitigate the overactive immune response in sepsis, potentially leading to better patient outcomes. This study aims to assess whether CNIs improve prognosis in septic patients and to evaluate any associated adverse reactions.MethodsWe utilized the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database to identify septic patients who were treated with CNIs and those who were not. Propensity score matching (PSM) was employed to balance baseline characteristics between the CNI user group and the non-user group. The primary outcome was 28-day mortality, analyzed using the Kaplan-Meier method and Cox proportional hazard regression models to examine the relationship between CNI use and patient survival.ResultsFrom the MIMIC-IV database, 22,517 septic patients were identified. After propensity score matching, a sample of 874 patients was analyzed. The CNI group exhibited a significantly lower 28-day mortality risk compared to the non-user group (HR: 0.26; 95% CI: 0.17, 0.41) in the univariate Cox hazard analysis. Kaplan-Meier survival curves also demonstrated a significantly higher 28- and 365-day survival rate for CNI users compared to non-users (log-rank test p-value = 0.001). No significant association was found between CNI use and an increased risk of new-onset infection (p = 0.144), but an association with mild hypertension (P &amp;lt; 0.001) and liver injury (P &amp;lt; 0.001) was observed.ConclusionThe use of calcineurin inhibitors was associated with reduced short- and long-term mortality in septic patients without an increased incidence of new-onset infections, hyperkalemia, severe hypertension, or acute kidney injury (AKI). However, CNI use may lead to adverse effects, such as liver injury and mild hypertension.

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer

Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Prognostic value of PEA3 subfamily gene expression in cholangiocarcinoma

BACKGROUND Cholangiocarcinoma (CCA) is a lethal malignancy with limited treatment options and poor prognosis. The PEA3 subfamily of E26 transformation specific genes: ETV1 , ETV4 , and ETV5 are known to play significant roles in various cancers by influencing cell proliferation, invasion, and metastasis. AIM To analyze PEA3 subfamily gene expression levels in CCA and their correlation with clinical parameters to determine their prognostic value for CCA. METHODS The expression levels of PEA3 subfamily genes in pan-cancer and CCA data in the cancer genome atlas and genotype-tissue expression project databases were analyzed with R language software. Survival curve and receiver operating characteristic analyses were performed using the SurvMiner, Survival, and Procr language packages. The gene expression profiling interactive analysis 2.0 database was used to analyze the expression levels of PEA3 subfamily genes in different subtypes and stages of CCA. Web Gestalt was used to perform the gene ontology/ Kyoto encyclopedia of genes and genomes (GO/KEGG) analysis, and STRING database analysis was used to determine the genes and proteins related to PEA3 subfamily genes. RESULTS ETV1 , ETV4 , and ETV5 expression levels were significantly increased in CCA. There were significant differences in ETV1 , ETV4 , and ETV5 expression levels among the different subtypes of CCA, and predictive analysis revealed that only high ETV1 and ETV4 expression levels were significantly associated with shorter overall survival in patients with CCA. GO/KEGG analysis revealed that PEA3 subfamily genes were closely related to transcriptional misregulation in cancer. In vitro and in vivo experiments revealed that PEA3 silencing inhibited the invasion and metastasis of CCA cells. CONCLUSION The expression level of ETV4 may be a predictive biomarker of survival in patients with CCA.

Differential prognostic value of residual nodal burden in breast cancer subtypes.

Residual cancer burden (RCB) index after neoadjuvant chemotherapy (NAC) is highly prognostic in patients with breast cancer (BC) but does not account for subtype or the precise impact of residual nodal burden (RNB). We aimed to precisely define the effect of RNB on survival by subtypes. Adult women with non-metastatic BC diagnosed from 2006 to 2021 in the National Cancer Database (NCDB) who received NAC followed by surgery within 8months were included. RNB was also evaluated as a predictor of mortality with multivariable logistic regression. Kaplan-Meier analyses were performed to compare overall survival. 51,917 patients were included. After adjustment, ypN stage was the strongest predictor of mortality, with an odds ratio (OR) of 2.24 (95% CI 2.08-2.41) for ypN1 vs ypN0 and increased with increasing nodal burden-ypN2 vs ypN0 OR 5.03, 95% CI 4.60-5.51 and ypN3 vs ypN0 OR 8.85, 95% CI 7.88-9.93. Stratification of survival curves with higher RNB is most pronounced for triple-negative breast cancer (TNBC) with an absolute difference of 64% in 5-year overall survival between ypN0 and ypN3 patients, and lowest for the ER+/HER2- subtype with a 25% absolute difference in 5-year OS between ypN0 and ypN3 patients. On interaction analysis, ypN status was a stronger predictor of mortality for the TNBC subtype compared to other subtypes. RNB has a significantly different impact on survival by BC subtypes. Future study of optimal therapeutic strategies for patients with residual nodal disease after NAC should account for subtype-specific differences in prognosis.

Assocation between trapezium size and failure of total trapeziometacarpal prosthesis. A survival analysis.

To assess the survival function of cementless total trapezium metacarpal prostheses (TTMPs) at 20 years, to compare survival functions by trapezium size, and to evaluate the association between the instantaneous risk of TTMP failure and small trapezium size using a multivariate Cox regression model. This observational cohort study included 221 consecutive patients with a mean follow-up after TTMP of 137.3 months (maximum of 246 months). Kaplan-Meier and actuarial life-table methods were used to evaluate the survival function of thecohort. Kaplan-Meier survival curves were compared by trapezium size. Multivariate Cox regression analysis was used to determine the effect of potential confounders on the association between small trapezium and the instantaneous risk of TTMP failure. At the end of follow-up, there was a 89.01% chance of the TTMP surviving for 246 months or more. There was an association between TTMP survival time and trapezium size showing a significant trend such that the survival curves weresignificantly higher with larger trapezium size (Mantel-Cox test, p = 0.0001; WilcoxonBreslow test, p = 0.0002; Tarone-Ware test, p = 0.0001).The unadjusted Cox regression model showed a significant association between small trapezium size (smaller than 9 mm) and the instantaneous risk of TTPM failure (HR: 7.37, 95% CI: 2.46-22.07). In the multivariate Cox analysis, "age", "trapezium morphology", and "complications" were confounders in the association between small trapezium size and the hazard ratio of prosthetic failure (HR = 3.76; 95% CI 0.96 to 13.82). These results confirm the long-term functional survival of TTMP prostheses and reveal a significant increase in trend of the survival curve with larger trapezium size. Patient age, trapezium morphology, and the presence of post-surgical complications are confounders in the association between small trapezium size and the hazard ratio of TTMP failure.

PSVII-8 Survival analyses of the productive life in U.S. Katahdin ewes

Abstract Ewe productive life (PL), defined as the number of days between the first and last lambing, is a common indicator of longevity. This study aimed to analyze the PL of 10,276 Katahdin ewes, of which 69.3% were uncensored and 30.7% were right-censored records. Ewes were daughters of 1,188 sires and 6,312 dams, born between 1989 and 2021 in 58 flocks located across the U.S., and the National Sheep Improvement Program provided the data. Ewes with lambing interval and age at first lambing greater than 720 d and 1,095 d, respectively, were excluded. Moreover, flocks that did not report lambing records across at least 7 consecutive years or did not have an average of 20 or more lambing records over the year were also left out of the analyses. Survival functions were analyzed using the Kaplan-Meyer (KM) and Cox models, while the Hazard function was analyzed using the Cox model. For the Cox model, contemporary group (concatenation of flock, year, and season of ewe’s birth) was fitted as a random effect; the ewe’s BR class (combined effect of birth/rearing types: 1/1, 2/1, 2/2, 3/2, 3/3, with digit-3 including counts ≥ 3), ewe’s age class at first lambing (≤ 378d; 379 to 700d; and &amp;gt; 700 d), and the ewe’s dam’s age class (A: &amp;lt; 713 d; B: 713 to 1,486 d; C: &amp;gt; 1486 d) were fitted as fixed effects. All survival analyses were performed using the Survival R-package. All factors included in the Cox model were highly significant (P &amp;lt; 0.001), except dam age class (P &amp;gt; 0.05). The proportional hazard assumption was checked using a graphical diagnostic based on the scaled Schoenfeld residuals, and there was no failure in the assumption. Moreover, there was no evidence of influential or outlier records in the graphical analysis of the residuals. The Cox survival curve overlapped with the KM survival curve (Figure 1), indicating a good survival prediction with the Cox model. The median PL was 1,036 d (95%CI: 1001 to 1,056 d) with the KM model and 1,056 d (95%CI: 984 to 1,078 d) with the Cox model. The hazard ratio indicated BR levels 2/2 and 3/3 showed less hazards than group 1/1 (Figure 2), and thereby longer PL; no significant difference was observed between 1/1 and the other two levels (2/1 and 2/3). Ewes that first lambed before 378 d had less hazard than those with the first lambing after this age (Figure 2). There was no significant difference between the dam age classes. In conclusion, over 50% of Katahdin sheep have less than 3 yr PL. Moreover, U.S. Katahdin ewes born from larger litters and having the first lambing before 378 d are likelier to have a greater PL.

MiRNA expression affects survival in patients with obstructive sleep apnea and metastatic colorectal cancer

IntroductionThe relationship between obstructive sleep apnea (OSA) and cancer has been recognized for some time now. However, little is known about the mechanisms by which sleep apnea promotes tumorigenesis and the impact of OSA on survival after cancer diagnosis. In the last few years, research has focused on the exploration of different biomarkers to understand the mechanisms underlying this relationship and miRNAs, non-coding single strands of about 22 nucleotides that post-transcriptionally regulate gene expression, have emerged as possible actors of this process.The aim of the study was to evaluate the impact of OSA on survival of metastatic colorectal cancer (mCRC) patients based on the expression of specific miRNAs. MethodsThe expression of 6 miRNAs, respectively miR-21, miR-23b, miR-26a, miR-27b, miR-145 and miR-210, was analyzed by qRT-PCR in patients’ sera. Response to first-line therapy, Kaplan-Meier curves of overall and progression-free survival were used to evaluate survival in mCRC patients with and without OSA stratified for the expression of miRNAs. ResultsThe expression of miR-21, miR-23b, miR-26a and miR-210 was significantly upregulated in mCRCs with OSA compared to no OSA. In mCRC patients with OSA and increasing expression of miR-21, miR-23b, miR-26a and miR-210 risk of progression after first-line therapy was higher and both overall and progression-free survival were significantly worst. Conversely, as miR-27b and miR-145 expression increased, the life expectancy of patients diagnosed with OSA and mCRC improved markedly. ConclusionsThis study highlights the relevance of specific miRNAs on OSA in mCRCs and their significance as non-invasive biomarkers in predicting the prognosis in patients with mCRC and OSA.

Unveiling the impact of cell death-related genes and immune dynamics on drug resistance in lung adenocarcinoma: a risk score model and functional insights

Lung adenocarcinoma (LUAD), characterized by its heterogeneity and complex pathogenesis, is the focus of this study which investigates the association between cell death-related genes and LUAD. Through machine learning, a risk score model was developed using the Coxboost rsf algorithm, demonstrating strong prognostic accuracy in both validation (GSE30219, GSE31210, GSE72094) and training (TCGA-LUAD) datasets with C-indices of 0.93, 0.67, 0.68, and 0.64, respectively. The study reveals that the expression of Keratin 18 (KRT18), a key cytoskeletal protein, varies across LUAD cell lines (DV-90, PC-9, A549) compared to normal bronchial epithelial cells (BEAS-2B), suggesting its potential role in LUAD's pathogenesis. Kaplan–Meier survival curves further validate the model, indicating longer survival in the low-risk group. A comprehensive analysis of gene expression, functional differences, immune infiltration, and mutations underscores significant variations between risk groups, highlighting the high-risk group's immunological dysfunction. This points to a more intricate tumor immune environment and the possibility of alternative therapeutic strategies. The study also delves into drug sensitivity, showing distinct responses between risk groups, underscoring the importance of risk stratification in treatment decisions for LUAD patients. Additionally, it explores KRT18's epigenetic regulation and its correlation with immune cell infiltration and immune regulatory molecules, suggesting KRT18's significant role in the tumor immune landscape. This research not only offers a valuable prognostic tool for LUAD but also illuminates the complex interplay between cell death-related genes, drug sensitivity, and immune infiltration, positioning KRT18 as a potential therapeutic or prognostic target to improve patient outcomes by personalizing LUAD treatment strategies.