Kaplan-Meier Survival Plots Research Articles

Investigating synergy between beta-blockers and transarterial chemoembolization in the treatment of hepatocellular carcinoma: preliminary data from a propensity matched analysis

PurposeFavorable clinical outcomes have been reported with the adjunct use of beta-blockers in cancer treatment, hypothetically secondary to their anti-angiogenic/anti-proliferative effects. Hereby, we investigate whether there is synergy between beta-blockers and TACE in the treatment of HCC. Methods36 HCC patients on beta-blockers (mean dose of 48 mg daily) at the time of first-line treatment with TACE at our institution were retrospectively identified out of a cohort of 221 patients between 2008 and 2019. Using propensity scoring, a matched cohort of 36 patients not exposed to beta-blockers was generated based on age, gender, ethnicity, etiology of liver disease, BCLC, child Pugh score, PS/ECOG, cirrhosis, largest mass treated, type of TACE and treated liver segments. Tumor response was assessed at 1st and 2nd post-TACE imaging timepoints (1.4 and 4.1 months on average respectively). Variables were compared using chi-square test and Student's t-test. Kaplan-Meier transplant-free survival plots were generated using IBM® SPSS® software. Cox regression analysis was used to evaluate survival predictors. A p values < 0.05 was considered significant. ResultsComparing the control and beta-blocker cohorts, there were no differences in baseline characteristics, post-TACE imaging timepoints, tumor response or transplant free survival (p > 0.05). Tumor size was found to be a predictor of survival when the two cohorts were combined (p = 0.03). ConclusionTransplant-free survival and HCC response to first-line TACE treatment were similar in the control and beta-blocker groups. Large tumor sizes were associated with higher mortality in combined analysis of the cohorts.

Transcervical Endoscopic Esophageal Mobilization: An Approach to Transhiatal Esophagectomy

BackgroundTranscervical endoscopic esophageal mobilization (TEEM) is an approach to transhiatal esophagectomy that aims to minimize blood loss and decrease the operative time commonly associated with traditional transhiatal technique. MethodsA retrospective chart review was conducted on patients who underwent TEEM esophagectomy between 2009 and 2020. Baseline characteristics, perioperative outcomes, and postoperative complications were recorded. To report survival, a Kaplan-Meier survival plot was developed using SAS software (SAS Institute). ResultsA total of 241 patients underwent TEEM esophagectomy. The mean operative time was 185.1 ± 59.3 minutes, blood loss was 251.4 ± 212.3 mL, the number lymph nodes dissected was 13.6 ± 6.2, and the length of stay was 11.9 ± 8.5 days. In the postoperative setting, 68 (28.2%) patients experienced hoarseness, 62 (25.7%) had postoperative atrial fibrillation, 30 (12.4%) had an anastomotic leak, and 12 (4.6%) experienced chylothorax. The overall 30- and 90-day mortality rates were 2.1% (5 of 241) and 4.6% (11 of 241), respectively. The median overall survival was 2.36 years, with 60% 3-year survival and 40% 5-year survival. ConclusionsTEEM esophagectomy is a safe approach with acceptable postoperative morbidity and mortality and shorter operative times compared with historical norms.

The prognostic role of cardiopulmonary exercise testing in obesity.

Poor cardiorespiratory fitness has been suggested to increase the risk of chronic diseases in obesity. We investigated the ability of key variables from cardiopulmonary exercise testing (CPET) to predict all-cause mortality in an obese cohort. The sample included 469 participants of both sexes (mean age 40 ± 13 years) who underwent a CPET for clinical reasons between 1 March 2009 and 1 December 2023. All-cause mortality was the prognostic endpoint. A receiver operating characteristic analysis was performed to establish optimal cut-points for CPET variables. Kaplan-Meier and Cox regression analyses were used to determine the association between CPET variables and all-cause mortality. There were 46 deaths during a mean follow-up period of 69 ± 48 months, resulting in an annual mortality rate of 2%. Despite the sample being made up of mostly women (70%), there were more deaths in men (18 vs. 6%, p < 0.001).The optimal thresholds for discrimination of survival were as follows: (a) peak oxygen uptake (pVO2) ≤16 mL/kg/min; (b) minute ventilation/carbon dioxide production (VE/VCO2) slope ≥31; (c) ventilatory power ≤5.8 mmHg; and (d) circulatory power ≤2980 mmHg/mL O2/min. Kaplan-Meier survival plots revealed a significant positive association between lower pVO2, circulatory power and ventilatory power values and survival (log-rank, p < 0.001) and higher mortality for men than women. Adjusted Cox regression models showed that a pVO2 ≤16 mL/kg/min had a 20-fold higher risk of mortality when compared with >16 mL/kg/min. Given the strong association of VO2, ventilatory efficiency, circulatory and ventilatory power with all-cause mortality, our findings support the notion that poorer cardiorespiratory fitness is associated with a poor prognosis in patients with obesity.

Risk for progression to type 1 diabetes in first-degree relatives under 50 years of age.

The detection of pancreatic autoantibodies in first-degree relatives of patients with type 1 diabetes (T1D) is considered a risk factor for disease. Novel available immunotherapies to delay T1D progression highlight the importance of identifying individuals at risk who might benefit from emerging treatments. The objective was to assess the autoimmunity in first-degree relatives of patients with T1D, estimate the time from autoimmunity detection to the onset of clinical diabetes, and identify the associated risk factors. Retrospective multicenter study of 3,015 first-degree relatives of patients with T1D recruited between 1992 and 2018. Pancreatic autoantibodies (IAA, GADA, IA2A, and ZnT8A) were determined by radioimmunoassay, starting the analyses at diagnosis of the proband. All those with positive autoimmunity and normal fasting blood glucose without clinical symptoms of diabetes were followed up in the study. The progression rate to T1D was assessed according to sex, relationship with the proband, age at autoimmunity detection, type/number of autoantibodies, and HLA-DRB1 genotype. Cox proportional-hazard models and Kaplan-Meier survival plots were used for statistical analyses. Among the relatives, 21 progenitors [43.7 years (IQR: 38.1-47.7)] and 27 siblings [7.6 years (IQR: 5.8-16.1)] had positive autoantibodies. Of these, 54.2% (95% CI: 39.2%-68.6%) developed T1D (age at autoimmunity detection 11 months to 39 years) in a median of 5 years (IQR: 3.6-8.7; ranged from 0.9 to 22.6 years). Risk factors associated with faster progression to T1D were multiple autoimmunity and <20 years at autoimmunity detection. Younger relatives (<20 years) with multiple autoantibodies had a 5-year cumulative risk of developing diabetes of 52.9% (95% CI: 22.1%-71.6%) and a 20-year risk of 91.2% (95% CI: 50.5%-98.4%). The 20-year risk decreased to 59.9% (95% CI: 21.9%-79.5%) if only one risk factor was met and to 35.7% (95% CI: 0.0%-66.2%) if the relative was older than 20 years with one autoantibody. In first-degree relatives with autoimmunity, the time to progression to T1D is faster in children and adolescents with multiple autoantibodies. Young adults are also at risk, which supports their consideration in screening strategies for people at risk of developing T1D.

A comprehensive meta-analysis of tissue resident memory T cell shaping non-small-cell lung cancer immune microenvironment and patient prognosis.

210 Background: Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Methods: Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. A machine learning model was developed to prognosticate survival, tested in multiple independent NSCLC cohorts. Model performance was corroborated through Kaplan-Meier survival plots, receiver operating characteristic (ROC) curves, principal component analysis, and t-SNE analyses. Results: We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the TCGA dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Conclusions: Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification. Keywords: Tissue resident memory T cell, non-small-cell lung cancer, prognosis, tumor immune microenvironment, machine learning.

Histopathologic predictors of recurrence and survival in early T stage oral tongue squamous cell carcinoma.

Recurrence and survival in early T-stage oral tongue squamous cell carcinoma (OTSCC) may be impacted by histopathologic risk factors. This study aims to examine which of these factors predict long-term outcomes of T1 and T2 OTSCC. A retrospective review of T1 and T2 OTSCC patients treated with surgery at a single tertiary care center was conducted. Multivariate regression and Kaplan-Meier survival plots were used to identify predictors of recurrence and compare disease-free survival respectively. 100 consecutive patients were studied. Of these, 51 were staged pT1, 49 pT2, 69 pN0, 10 pN1, and 21 pN2. Multivariate regression analysis revealed that >4 nodes was the strongest predictor of overall recurrence [odds ratio 1.68 (1.23-2.28), p = 0.001], while >4 nodes [odds ratio 1.14 (1.09-1.85), p = 0.008] and pT2 [odds ratio 1.15 (1.01-1.30), p = 0.033] were predictors of local recurrence (R2 = 0.112). Five-year disease-free survival was not significantly impacted by any risk factors except for the number of positive nodes-86% for ≤4 nodes vs. 20% for >4 nodes (p < 0.001)-and pathologic T-stage-90% for pT1 vs. 75% for pT2 (p = 0.035) regardless of adjuvant radiation and/or chemotherapy use. Patients who underwent adjuvant radiation and/or chemotherapy had similar survival to those who did not despite having worse overall tumor prognostic factors. Adding adjuvant therapy may equalize some high-risk histopathologic factors. In the highest risk patients-specifically those with pathologic >4 nodes and pT2 staging-adjuvant therapy should be considered.

Construction and validation of a prognostic model for bladder cancer based on disulfidptosis-related lncRNAs.

Bladder cancer (BLCA) is a prevalent and aggressive cancer associated with high mortality and poor prognosis. Currently, studies on the role of disulfidptosis-related long non-coding RNAs (DRLs) in BLCA are limited. This study aims to construct a prognostic model based on DRLs to improve the accuracy of survival predictions for patients and identify novel targets for therapeutic intervention in BLCA management. Transcriptomic and clinical datasets for patients with BLCA were obtained from The Cancer Genome Atlas. Using multivariate Cox regression and least absolute shrinkage and selection operator techniques, a risk prognostic signature defined by DRLs was developed. The model's accuracy and prognostic relevance were assessed through Kaplan-Meier survival plots, receiver operating characteristic curves, concordance index, and principal component analysis. Functional and pathway enrichment analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis, were conducted to elucidate the underlying biological processes. Immune cell infiltration was quantified using the CIBERSORT algorithm. Differences and functions of immune cells in different risk groups were evaluated through single-sample Gene Set Enrichment Analysis. The Tumor Immune Dysfunction and Exclusion predictor and tumor mutational burden (TMB) assessments were utilized to gauge the likelihood of response to immunotherapy. Drug sensitivity predictions were made using the Genomics of Drug Sensitivity in Cancer database. A robust 8-DRL risk prognostic model, comprising LINC00513, SMARCA5-AS1, MIR4435-2HG, MIR4713HG, AL122035.1, AL359762.3, AC006160.1, and AL590428.1, was identified as an independent prognostic indicator. This model demonstrated strong predictive power for overall survival in patients with BLCA, revealing significant disparities between high- and low-risk groups regarding tumor microenvironment, immune infiltration, immune functions, TMB, Tumor Immune Dysfunction and Exclusion scores, and drug susceptibility. This study introduces an innovative prognostic signature of 8 DRLs, offering a valuable prognostic tool and potential therapeutic targets for bladder carcinoma. The findings have significant implications for TMB, the immune landscape, and patient responsiveness to immunotherapy and targeted treatments.

Effect of AFPGC immune-microenvironment and resistance to immunotherapy.

e16041 Background: Alpha-fetoprotein producing gastric cancer (AFPGC) is a rare subtype GC with high with high morbidity and mortality rates. Even though immunotherapy has become the cornerstone of first-line treatment, our previous results suggest that AFPGC was resistant to immunotherapy, standard regimen remains unclear. It is warranted to explore precision immunotherapy strategies for AFPGC. Methods: A retrospective cohort of 98 patients with gastric cancer receiving mono-immunotherapy was included. Kaplan-Meier survival plots for PFS and OS were generated based on the AFP levels. Log-rank tests were used to compare the survival curves. Chi-square test was used to analyze the differences in the efficacy of immunotherapy between patients with different levels of AFP. AFPGC in vivo models were constructed, and after in vivo administration, RNA-seq, flow cytometry, and Western blot were used to explore and validate the features of the AFPGC microenvironment and explore immunotherapy combination strategies. Results: Retrospectively analysis demonstrated that the response of mono-immunotherapy in AFPGC was inferior to that in non-AFPGC (ORR: 16.7% vs 29.3%; DCR: 33.0% vs 55.4%). The response of the subcutaneous transplant tumor model with AFP overexpression to PD-1 antibody was significantly reduced. Meanwhile, RNA-seq results from the secondary PD-1 antibody resistant model showed that the mRNA level of AFP was significantly upregulated in the resistant model. RNA-seq results from transplant tumors of AFPGC compared to nAFPGC revealed that the differentially expressed genes were significantly enriched in pathways related to neutrophil chemotaxis and angiogenesis. Flow cytometry confirmed that the proportion of neutrophils in AFPGC was significantly higher than that in nAFPGC. SB265610 (neutrophil chemokine receptor inhibitor) combined with PD-1 antibody and apatinib (anti-angiogenesis) plus PD-1 antibody were administrated in animal models. Both of the regimens could release the primary resistance to PD-1 antibody. Based on these preclinical findings, we designed and conducted a clinical study (NCT04609176) to explore the reponse of apatinib combined with PD-1 antibody in AFPGC. Primary endpoints were achieved and will be announced in the near future. Typical case is depicted as follows: A 79 years old male patients diagnosed with low-differentiated adenocarcinoma of GC, AFP: 135220 ng/ml. After fail in chemotherapy, patients were treated with third-line apatinib 250mg po d1-d21, PD-1 monoclonal antibody 200mg d1, q21d for 6 cycles. Patient was evaluated as partial response (PR) for 4 months and AFP sharply decreased to 945 ng/ml. Conclusions: AFPGC is resistant to PD-1 monoclonal antibody. Combined treatment with SB265610 or apatinib can alleviate or reverse the resistance, making it the most promising treatment regimen for AFPGC.

Utility of Clinical Variables for Deciding Palliative Care in Paraquat Poisoning: A Retrospective Study.

Patients with paraquat poisoning (PP) have a mortality rate comparable to that of advanced malignancies, yet palliative care is seldom considered in these patients. This audit aimed to identify triggers for early palliative care referral in critically ill patients with PP. Medical records of patients with PP were audited. Predictors of mortality within 48 hours of hospitalization and 24 hours of intensive care unit (ICU) admission were considered as triggers for palliative care referral. Among 108 patients, 84 complete records were analyzed, and 53 out of 84 (63.1%) expired. Within 48 hours after hospitalization, the lowest oxygen partial pressure in arterial blood to a fraction of inspired oxygen [the ratio of partial pressure of oxygen in arterial blood (PaO2) to the fraction of inspiratory oxygen concentration (FiO2) (PaO2/FiO2)] was the independent predictor of mortality, cut-off ≤ 197; the area under the curve (AUC), 0.924; sensitivity, 97%; specificity, 78%; p <0.001; and 95% confidence interval (CI): 0.878-0.978. Kaplan-Meier survival plot showed that the mean survival time of patients with the lowest PaO2/FiO2, ≤197, was 4.64 days vs 17.20 days with PaO2/FiO2 >197 (log-rank p < 0.001). Sequential organ failure assessment (SOFA) score within 24 hours of ICU admission had a cut-off ≥9; AUC, 0.980; p < 0.001; 95% CI: 0.955-1.000; 91% sensitivity; and 90% specificity for mortality prediction. Out of the total of 84 patients with PP analyzed, there were 11 patients admitted to the high dependency units (13.1%) and 73 patients admitted to the ICU (86.9%). Out of the total of 84 patients of PP in whom data was analyzed, 53 (63.1%) patients required ventilator support. All the 53 patients who required ventilator support due to worsening hypoxemia, eventually expired. The lowest PaO2/FiO2 ≤ 197 within 48 hours of hospitalization, SOFA score ≥9 within 24 hours of ICU admission or need for mechanical ventilation are predictors of mortality in PP patients, who might benefit from early palliative care. Rao S, Maddani SS, Chaudhuri S, Bhatt MT, Karanth S, Damani A, et al. Utility of Clinical Variables for Deciding Palliative Care in Paraquat Poisoning: A Retrospective Study. Indian J Crit Care Med 2024;28(5):453-460.

Clinical outcomes with utilization of high-potency topical steroids in patients with lichen sclerosus-associated vulvar cancer

ObjectivesTo evaluate the impact of high-potency topical steroid use on risk of recurrence of lichen sclerosus-associated vulvar cancer. MethodsThis is a retrospective cohort study evaluating patients with lichen sclerosus (LS)- associated vulvar squamous cell cancer (VSCC). Demographic and clinical outcome data were compared between two comparison groups: patients who received steroids, mainly clobetasol, and patients who did not receive steroids following treatment of LS-related vulvar cancer. Categorical variables were compared using Fisher's exact test or chi-square test. Continuous variables were compared using a two-sided student's t-test. Time to recurrence (TTR) and overall survival (OS) were analyzed using Kaplan-Meier survival plot and compared using Mantel-Cox log rank test. Cox proportional hazard regression models were conducted to generate hazard ratios for both TTR and OS. A p value of <0.05 was considered statistically significant. ResultsA total of 49 patients were included, with 36 patients receiving steroid treatment and 13 patients in the expectant management group. The median age of diagnosis was 68. The average BMI was 31.7 +/− 7.0. The median length of follow up was 41 months. The majority of patients were diagnosed with stage I VSCC. There was no difference in demographics or oncologic management of vulvar cancer between the two cohorts. Overall recurrence was decreased among patients who received steroid treatment when compared to patients who did not, 12 patients (33.3%) versus 9 patients (69.2%) respectively (p = 0.048). ConclusionsHigh-potency topical steroid use following treatment of lichen sclerosus-associated vulvar squamous cell carcinoma is associated with decreased risk of recurrence and prolonged median time to recurrence.

Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma

BackgroundMetabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear.MethodsThe level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay.ResultsHistone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels.ConclusionsThe glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy.

The effect of NHFOV on hemodynamics in mild and moderately preterm neonates: a randomized clinical trial

The aim of this study is to study cardio-respiratory effects of nasal high-frequency oscillatory ventilation (NHFOV) vs. NCPAP as an initial mode of ventilation in moderate-late-preterm infants. A randomized controlled trial was conducted in NICU of Alexandria University Maternity Hospital (AUMH). One-hundred late-moderate-preterm infants were randomly assigned to either NHFOV-group (n = 50) or NCPAP-group (n = 50). For both groups, functional echocardiography was performed in the first 24 h to detect hemodynamic changes and respiratory outcome was monitored throughout the hospital stay. The main outcomes were hemodynamic measurements and myocardial function using functional echocardiography of those infants along with the respiratory outcome and complications. Kaplan–Meier survival plot was used representing time course of NCPAP and NHFOV failure. Left ventricular output values were not significantly different in both groups with median 202 ml/kg /min and IQR (176–275) in NCPAP-group and 226 ml/kg/min with IQR (181–286) in NHFOV group. Nevertheless, ejection fraction and fractional shortening were significantly higher in NHFOV-group with P 0.001. The time to weaning, the time to reach 30%-FIO2, the need for invasive ventilation, oxygen support duration, and maximal-FIO2 were significantly more in NCAPAP group. Conclusion: NHFOV is an effective and promising tool of non-invasive-ventilation which can be used as a primary modality of respiratory support in preterm infants with variable forms of respiratory distress syndrome without causing detrimental effect on hemodynamics or significant respiratory complications. Trial registration: NCT05706428 (registered on January 21, 2023).What is Known:• NHFOV might be beneficial as a secondary mode of ventilation and might have an impact on hemodynamics.What is New:• NHFOV can be used as an initial mode of ventilation with CDP beyond the reported pressure limits of CPAP without causing neither CO2 retention nor adverse hemodynamic consequences.

Race/Ethnicity and Incidence of Pelvic Organ Prolapse in Midlife Women: The Study of Women's Health Across the Nation.

Background: Pelvic organ prolapse (POP) affects a considerable proportion of women. Limited information exists regarding the incidence of POP as women transition through menopause. Using data from the Study of Women's Health Across the Nation (SWAN), this diverse community-based longitudinal cohort study assessed the incidence of symptomatic POP and risk by race/ethnicity. Methods: Self-reported POP was ascertained by questionnaire at 11 approximately annual SWAN visits over a median of 13.3 years of follow-up. We estimated probabilities for reporting POP using interval-censored Kaplan-Meier survival plots. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using interval-censored Cox proportional hazards models. Results: The estimated cumulative probability of POP increased linearly from 2.1% at age 45 to 10.1% by age 65 (4.0% per decade). At age 65, the probability was 4.2%, 4.8%, 8.9%, 9.7%, and 33.9% for Japanese, Chinese, Black, White, and Hispanic women, respectively. Compared with White women, the unadjusted HR for POP was 3.09 (95% CI = 2.18-4.39), 0.96 (0.71-1.31), 0.43 (0.22-0.85), and 0.48 (0.26-0.88) for Hispanic, Black, Chinese, and Japanese women, respectively. After adjustment for financial strain and vaginal birth, the low hazards among Chinese and Japanese women and the high hazard for Hispanic women remained significant. Conclusion: Incidence of symptomatic POP increased as women aged through midlife. Risks varied by race and ethnicity and were not accounted for by population differences in socioeconomic life contexts or the probability of having had a vaginal birth. Although not associated with menopause, health providers should incorporate screening for and information about POP when treating menopausal symptoms and health needs of midlife women. Research on pathophysiological factors associated with increasing POP in midlife is warranted.

Abstract 3457: Distinct signatures of tumor-associated macrophage subpopulations predict survival in renal cell carcinoma

Abstract Background: Comprising 90% of renal cancer cases in adults, renal cell carcinoma (RCC) is marked by significant heterogeneity in its tumor microenvironment. This study aims to test the hypothesis that tumor-associated macrophages (TAMs) play a role in modulating RCC progression and patient response to treatment. We explored the prognostic implications of TAM signatures on RCC survival, leveraging immunomics to decipher TAM-related alterations in the tumor microenvironment. Methods: Utilizing independent single-cell RNA-seq data from human RCC samples, we crafted 8 distinct RCC TAM signatures reflective of TAM presence. A LASSO Cox regression model was developed to prognosticate survival, tested against the TCGA dataset and independently validated across multiple RCC cohorts. Model performance was corroborated through Kaplan-Meier survival plots, receiver operating characteristic (ROC) curves, principal component analysis, and t-SNE analyses. Results: We identified two TAM signatures that correlate positively with patient survival, indicative of the abundance of specific subsets of TAMs in RCC. These signatures showed a strong association of specific TAM markers and macrophage infiltration. Survival analysis demonstrated that specific TAM signature gene expressions are significant prognostic markers. Forest plots underscored their prognostic relevance. A 32-gene risk score model was established, successfully stratifying patients into distinct risk categories, with low-risk patients exhibiting markedly improved overall survival. Conclusions: The study underscores the positive association between abundance of specific TAM subsets of and RCC patient survival. The precision of our LASSO Cox regression model, informed by novel abundance markers of specific TAM subsets, advances our understanding of TAM roles in TIME and RCC progression. These TAM signatures could potentially provide additional insights and targets to enhance the efficacy of RCC treatments. Keywords: Tumor associated macrophage, renal cell carcinoma, prognosis, tumor microenvironment, immunomics. Citation Format: Youngsoo Han, Aidan Shen, Zhaohui Wang, Aliesha Garrett, Chongming Jiang. Distinct signatures of tumor-associated macrophage subpopulations predict survival in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3457.

A comparison of keratoconus progression following collagen cross-linkage using standard or personalised keratometry thresholds.

To define how estimates of keratoconus progression following collagen cross-linking (CXL) vary according to the parameter selected to measure corneal shape. We estimated progression following CXL in 1677 eyes. We compared standard definitions of keratoconus progression based on published thresholds for Kmax, front K2, or back K2, or progression of any two of these three parameters, with the option of an increased threshold for Kmax values ≥ 55D. As corneal thickness reduces unpredictably after CXL, it was excluded from the principal analysis. We then repeated the analysis using novel adaptive estimates of progression for Kmax, front K2, or back K2, developed separately using 6463 paired readings from keratoconus eyes, with a variation of the Bland-Altman method to determine the 95% regression-based limits of agreement (LoA). We created Kaplan-Meier survival plots for both standard and adaptive thresholds. The primary outcome was progression five years after a baseline visit 9-15 months following CXL. Progression rates were 8% with a standard (≥ 1.5D) threshold for K2 or 6% with the static multi-parameter definition. With a ≥ 1D threshold for Kmax, the progression was significantly higher at 29%. With adaptive Kmax or K2, the progression rates were similar (20%) but less than with the adaptive multi-parameter method (22%). Estimates of keratoconus progression following CXL vary widely according to the reference criteria. Using adaptive thresholds (LoA) to define the repeatability of keratometry gives estimates for progression that are markedly higher than with the standard multi-parameter method.

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial

Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. Bristol Myers Squibb.

To Remplissage or Not to Remplissage Part 1: Prognostic Factors Influencing Recurrent Shoulder Instability in High-Risk Individuals with On-Track Shoulders Undergoing Primary Arthroscopic Anterior Stabilization

Objectives: Recent studies have shown that a subset of on-track Hill-Sachs lesions (HSL), defined as near-track lesions, may have a high risk of failure after primary arthroscopic Bankart repair (ABR) alone. The aim of this study was to evaluate rates of recurrent shoulder instability among patients with on-track HSL who underwent primary ABR with and without remplissage in the setting of numerous risk factors highlighted in recent literature. We hypothesized that primary ABR with remplissage (ABR+R) would lower postoperative rates of recurrent shoulder instability, particularly for “high-risk” patients defined as “near-track” lesions, hyperlaxity, younger age, contact athletes, and &gt;1 preoperative instability episodes. Methods: Prospectively collected data was retrospectively reviewed for consecutive patients aged 14-40 years who underwent either ABR or ABR+R between 2013 and 2021 for anterior glenohumeral instability. Glenoid bone loss, Hills-Sachs Interval (HSI), glenoid track (GT), and distance-to-dislocation (DTD) values (DTD = GT-HSI) were determined via preoperative magnetic resonance imaging. Additionally, “near-track” lesions are a subset of on-track lesions with a DTD from 0 – 10mm. Capsuloligamentous laxity (i.e., hyperlaxity) was defined as external rotation greater than 85 degrees and/or grade 2+ posterior and inferior load-and-shift on examination under anesthesia. Recurrent shoulder instability was defined as recurrent dislocation and/or subjective subluxation postoperatively. Patients were excluded if the indexed surgery was a revision procedure, &lt; 2-year follow-up, or glenoid bone loss (GBL) &gt;20%. Univariate and multivariate Cox regression analysis was used to determine predictors of recurrent shoulder instability and reoperation. Results: One-hundred-and-fifty-five patients were included for analysis (ABR: 116 | ABR+R: 39) with an average age of 21.6 ± 6.2 years and an average follow-up of 5.1 ± 2.0 years (range: 2.0 – 8.7 yrs). Overall, 30 patients (19%) experienced recurrent shoulder instability postoperatively (4.3 per 100 person-years), and 20 (13%) underwent secondary surgery (2.9 per 100 person-years) for revision stabilization. Among the 116 patients who underwent primary ABR only, 27 (23.3%) experienced recurrent shoulder instability, compared with only three of the 39 ABR+R patients (7.7%). Risk factors assessed included: age, gender, sport, number of preoperative instability episodes, shoulder laxity, GBL, and DTD. Multivariate analysis demonstrated that younger age (p=0.003), increased shoulder laxity (p=0.010), 2+ episodes of preoperative instability episodes (p=0.009), and a lower DTD (p=0.046) were independent risk factors for recurrent shoulder instability postoperatively. However, contact athlete status was not identified as a significant predictor of recurrent shoulder instability. According to multivariate results, patients who underwent primary ABR only were roughly 9-times more likely to experience recurrent shoulder instability (HR: 8.7, p=0.002) and 7-times more likely to undergo reoperation (HR:6.8, p=0.019) than those who underwent primary ABR+R. When considering patients with three or more risk factors (i.e., “near-track” lesions, hyperlaxity, age &lt; 25, or 2+ preoperative instability episodes), 9 of 12 ABR patients (75%) and 2 of 16 ABR+R (13%) experienced recurrent shoulder instability (p = 0.001), Table 1. Survival rates for ABR only versus ABR+R for patients with three or more risk factors are plotted in Figure 1 using Kaplan-Meier survival plots. Conclusions: Arthroscopic primary Bankart repair with remplissage may be an effective approach for decreasing the likelihood of recurrent shoulder instability and the need for secondary surgery among patients with on-track HSL. This surgical approach is especially beneficial for patients with lower DTD, increased shoulder laxity, younger age, or 2+ preoperative instability episodes in a dose-dependent manner. Those with higher risks of recurrence may benefit significantly more with the addition of a remplissage than those with fewer risk factors.

The diagnostic, prognostic, drug sensitivity and ceRNA internet of PPP4R1 in liver hepatocellular carcinoma (LIHC).

Recent studies have reported a role of protein phosphatase 4 regulatory subunit 1 (PPP4R1) in cancer development. However, its expression, diagnostic significance, prognostic value and biological function in liver hepatocellular carcinoma (LIHC) are not known. The expression level of PPP4R1 in pan-cancer was evaluated by analyzing publicly accessible data from the University of California Santa Cruz (UCSC) Xena database. The diagnostic value of PPP4R1 for tumors was assessed using receiver operating characteristic (ROC) curves, whereas the impact of PPP4R1 on tumor prognosis was determined using Kaplan-Meier survival curves, and a prognostic model for LIHC was established using cox regression analysis. In addition, analysis of the correlation between PPP4R1 and anti-cancer drugs using Spearman's correlation coefficient was carried out. Four databases, miRWalk (mRNA-miRNA interactions), MicroT-CDS (mRNA-miRNA interactions), LncBase (miRNA-lncRNA interactions) and Encyclopedia of RNA Interactomes (ENCORI), were used to predict the competitive endogenous RNA (ceRNA) regulatory network of PPP4R1. Finally, the expression of PPP4R1 protein levels was verified using experiments. The findings indicated that the PPP4R1 expression level in cancerous tissues was notably greater than in adjacent tissues (P<0.05). PPP4R1 showed diagnostic significance for 14 tumors based on the ROC curves results area under the curve >0.7. Furthermore, the Kaplan-Meier survival plots demonstrated that PPP4R1 exhibited prognostic significance for all five tumors (P<0.05). According to the cox regression analysis, LIHC patients' prognosis was independently influenced by pathological stage, M stage, and PPP4R1 (P<0.05). The drug sensitivity analysis revealed a positive correlation between the expression level of PPP4R1 and the half maximal inhibitory concentration (IC50) of fludarabine. Additionally, the ceRNA network prediction indicated that the FGD5 antisense RNA 1 (FGD5-AS1)-hsa-miR-22-3p-PPP4R1 ceRNA network could potentially contribute to the progression of LIHC. The experimental results showed that the expression level of PPP4R1 protein was higher in cancer tissues than in paracancerous tissues. PPP4R1 has diagnostic value in most cancers, and high expression of PPP4R1 is associated with poor prognosis, drug resistance and natural killer cell-mediated toxicity, particularly in LIHC. Therefore, PPP4R1 may be a prognostic biomarker and a potential target for immunotherapy in LIHC.

Treatment stability with bonded versus vacuum-formed retainers after 12 months: A randomized clinical trial.

To compare the clinical effectiveness of V-bend bonded retainers (BR) versus vacuum-formed retainers (VFR) regarding their capacity to maintain treatment stability and survival rates after 12 months. Patients finishing orthodontic treatment were randomly allocated into two groups. The BR group received maxillary and mandibular BRs in the lingual surfaces of the anterior teeth. The VFR group received VFRs right after fixed appliances removal. The patients were evaluated at four time-points: at fixed appliances removal (T0), after 3 (T1), 6 (T2) and 12 months (T3). In each time-point digital models were obtained and analysed with the OrthoAnalyzer™ software. Treatment stability based on occlusal outcomes and retainers' survival rates were evaluated. Intergroup comparisons were performed using Mann-Whitney U-tests. The Kaplan-Meier survival plot and the log-rank test were employed to assess the retainers' survival. Both BR and VFR groups included 25 patients. The groups were comparable regarding their baseline characteristics. Up to 6 months, both retainers were equally effective; however, after 12 months, BRs were more effective in maintaining the incisors' alignment in the maxilla and the mandible compared to the VFRs. No differences were noticed in the intercanine and intermolar widths, overjet and overbite. There were no differences regarding the retainers' survivability in both arches. BRs were more effective in maintaining the alignment of the incisors in the maxilla and mandible compared to VFRs after 12 months. Both retainers presented the same survival rates after the same period.

Potent in vivo efficacy of oral gallium maltolate in treatment-resistant glioblastoma.

Treatment-resistant glioblastoma (trGBM) is an aggressive brain tumor with a dismal prognosis, underscoring the need for better treatment options. Emerging data indicate that trGBM iron metabolism is an attractive therapeutic target. The novel iron mimetic, gallium maltolate (GaM), inhibits mitochondrial function via iron-dependent and -independent pathways. In vitro irradiated adult GBM U-87 MG cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. Advanced MRI at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Cox proportional hazards regression models, Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison as indicator of tumor growth rate. In this study we demonstrate non-invasively, using longitudinal MRI surveillance, the potent antineoplastic effects of GaM in a novel rat xenograft model of trGBM, as evidenced by extended suppression of tumor growth (23.56 mm3/week untreated, 5.76 mm3/week treated, P < 0.001), a blunting of tumor perfusion, and a significant survival benefit (median overall survival: 30 days untreated, 56 days treated; P < 0.001). The therapeutic effect was confirmed histologically by the presence of abundant cytotoxic cellular swelling, a significant reduction in proliferation markers (P < 0.01), and vessel normalization characterized by prominent vessel pruning, loss of branching, and uniformity of vessel lumina. Xenograft tumors in the treatment group were further characterized by an absence of an invasive edge and a significant reduction in both, MIB-1% and mitotic index (P < 0.01 each). Transferrin receptor and ferroportin expression in GaM-treated tumors illustrated cellular iron deprivation. Additionally, treatment with GaM decreased the expression of pro-angiogenic markers (von Willebrand Factor and VEGF) and increased the expression of anti-angiogenic markers, such as Angiopoietin-2. Monotherapy with the iron-mimetic GaM profoundly inhibits trGBM growth and significantly extends disease-specific survival in vivo.