Multivariate Cox Regression Model Research Articles

Use of chemotherapy and loco-regional therapy in stage IA triple-negative breast cancer and their association with oncologic outcomes: A cancer registry study.

We aimed to evaluate the role of adjuvant chemotherapy and loco-regional therapy for stage IA (pT1, pN0) triple-negative breast cancer (TNBC) in a real-world setting. We identified patients with pT1, pN0 TNBC diagnosed between 2009 and 2021 within the Baden-Württemberg cancer registry (BWCR), Germany. Overall survival (OS) was assessed using Kaplan-Meier statistics and multivariate Cox regression models (adjusted for age, use of chemotherapy, local therapy (breast conserving therapy [breast conserving surgery + radiotherapy] vs. mastectomy), and tumor histologic subtype). A total of 1231 patients with a median follow-up of 45.9 months were identified: 1.0% (12 of 1231) with pT1mi stage, 9.5% (117 of 1231) with pT1a, 23.7% (292 of 1231) with pT1b, and 65.8% (810 of 1231) with pT1c. Multivariate Cox regression analysis revealed no significant influence for the use of chemotherapy on OS in pT1b patients (HR 0.90, 95% CI 0.43-1.90). For pT1c patients with Grade 1-2 tumors, the use of chemotherapy was not significantly associated OS (HR 1.01, 95% CI 0.48-2.11) but breast conserving therapy was associated with improved OS (HR 0.41, 95% CI 0.18-0.93). For pT1c patients with Grade 3 tumors, the use of chemotherapy (HR 0.51, 95% CI 0.33-0.78) as well as breast conserving therapy (HR 0.42, 95% CI 0.23-0.76) was associated with OS. This data suggests that OS in stage IA TNBC is strongly influenced by local therapy rather than the use of chemotherapy, except for pT1c patients with Grade 3 tumors. Larger studies with longer-term follow-up are welcomed to fully inform this discussion.

Consumption of milk and other dairy products and incidence of Parkinson's disease: a prospective cohort study in French women.

Previous studies showed positive associations between milk intake and Parkinson's disease (PD) in men but not in women, but few studies were available in women. Due to the long prodromal PD phase, reverse causation represents a major threat to investigations of diet in PD; cohort studies with a long follow-up are needed. We investigated associations between intake of milk and other dairy products with PD incidence in women from the E3N cohort study (1993-2018). PD diagnoses were validated using medical records and drug claim databases. Diet was assessed via a dietary questionnaire. Hazard ratios (HR) were estimated using multivariable Cox regression models. Exposures were lagged by 5y in main analyses and longer lags in sensitivity analyses. We examined the impact of adjustment for premotor symptoms (constipation/depression). During a mean follow-up of 18.8y, 845 of 71,542 women developed PD. Main analyses showed a J-shaped association between total milk intake and PD (P-non linearity = 0.045), with a significant linear positive association among drinkers (HR/1-SD = 1.09, 95% CI = 1.01-1.18, P = 0.024), that was explained in secondary analyses by a different pattern of association for plain milk (alone or with cereals) and milk added to drinks (tea/coffee/chicory). PD incidence increased significantly with plain milk consumption (HR/1-SD = 1.08 [1.02-1.14], P = 0.014). A U-shaped relation was observed for milk added to drinks (P-non linearity = 0.038), with lower PD incidence in women with moderate consumption (HR = 0.77 [0.61-0.97], P = 0.030) and no difference between non-drinkers and those with the highest consumption (HR = 0.98 [0.79-1.21], P = 0.848). Findings were similar in analyses using longer lags and adjusted for constipation/depression. Consumption of other dairy products was not associated with PD. A J-shaped association between total milk intake and PD was explained by a different pattern of association for plain milk intake and milk added to drinks. Reverse causation is unlikely to explain a positive association of plain milk with PD incidence in women. The U-shaped relation for milk added to drinks could be explained by an interaction between milk and coffee/tea/chicory. Further studies are warranted to elucidate the underlying mechanisms.

Saturated fatty acids and total and CVD mortality in Norway: a prospective cohort study with up to 45 years of follow-up.

The contribution of dietary saturated fatty acids (SFA) to cardiovascular disease (CVD) and mortality remains debated after decades of research. Few previous studies had repeated dietary assessments and power to assess mortality. Evidence for individual SFA is limited. In this large population-based cohort study, we investigated associations between intake of total and individual SFA and risk of total and CVD mortality. Adult residents (mean 41·1 years at baseline) in three Norwegian counties were invited to repeated health screenings between 1974 and 1988 (> 80 % attendance). We calculated cumulative average intakes of macronutrients from semi-quantitative FFQ. Median (interquartile range) intake of SFA was 14·6 % (12·8-16·6 %) of total energy (E%). Hazard ratios (HR) and 95 % CI were estimated using multivariable Cox regression models to assess total, CVD, ischaemic heart disease (IHD) and acute myocardial infarction (AMI) mortality. Among 78725 participants, 28555 deaths occurred during a median follow-up of 33·5 years, with 9318 deaths due to CVD. Higher intake of SFA (replacing carbohydrates) was positively associated with all mortality endpoints, including total (HR per 5 E% increment, 1·18; 95 % CI 1·13, 1·23) and CVD mortality (1·16; 95 % CI 1·07, 1·25). Theoretical isoenergetic substitution of SFA with carbohydrates or MUFA was associated with lower risk. Of individual SFA, myristic (14:0) and palmitic acid (16:0) were positively associated with mortality. In summary, dietary SFA intake was strongly associated with higher total and CVD mortality in this long-term cohort study. This supports policies implemented to reduce SFA consumption in favour of carbohydrates and unsaturated fats.

Abstract B070: TGFB2 mRNA levels prognostically interact with Interferon-alpha receptor activation of IRF9 and IFI27, and makers for tumor-associated macrophages impacting overall survival in PDAC

Abstract Background: The treatment of pancreatic ductal adenocarcinoma (PDAC) is an unmet challenge, with the median overall survival rate remaining less than a year, even with the use of FOLFIRINOX-based therapies. Methods: In this study, we analyzed archived macrophage- associated mRNA expression using datasets deposited in the UCSC Xena web platform to compare normal pancreatic tissue and PDAC tumor samples. We also utilized TCGA datasets deposited in cBioportal (https://www.cbioportal.org/study/summary?id=paad_tcga_pan_can_atlas) and KMplotter (http://kmplot.com/analysis/index.php?p=service&cancer=pancancer_rnaseq) to relate mRNA expression levels to overall survival outcomes. The prognostic impact of TGFB2 mRNA expression levels was determined by comparing patients expressing high versus low levels of TGFB2 (50th percentile cut-off) in low macrophage TME. Results: The TGFB2 gene exhibited low mRNA expression levels in normal tissue, with less than one TPM, while, in tumor tissue, TGFB2 expression levels exhibited a 7.9-fold increase in mRNA expression relative to normal tissue (P < 0.0001). Interferon Alpha Inducible Protein 27 (IFI27), the downstream product of Interferon regulatory factor 9 (IRF9) and Signal transducer and activator of transcription 1 (STAT1) transcriptional activation by Interferon alpha/beta receptor 1 (IFNAR1) exhibited a significant 66.3-fold increase in expression in tumor tissue compared to normal tissue (P < 0.0001). The statistical contrast between the expression of IRF9 mRNA also displayed a significant (P<0.0001) 4.2-fold increase in mRNA expression levels. These increased levels of mRNA expression were found to be prognostically significant, whereby patients with high expression levels of either TGFB2, IRF9, or IFI27 showed median OS times ranging from 16 to 20 months (P<0.01 compared to 72 months for patients with low levels of expression for both TGFB2 and either IRF9 or IFI27). In TME with low macrophage levels, patients with high levels of TGFB2 mRNA exhibited significantly shorter OS outcomes than patients with low TGFB2 mRNA levels (Median OS of 72.2 versus 15.3 months, P<0.0001). Furthermore, expression of TGFB2 mRNA and TAM markers exhibited TGFB2 prognostic impact independent of 17 TAM markers suggested by multivariate Cox regression models. Conclusions: The results of our study suggest that a combination of pharmacological tools can be used in treating PDAC patients, targeting both TGFB2 and the components of the type-I interferon signaling pathway to improve OS outcomes. TGFB2 expression impacts OS independent of TAM markers, but the expression of TAM markers impacts the prognostic effect of TGFB2 mRNA expression. Citation Format: Sanjive Qazi, Wen-Han Chang, Cynthia Lee, Vuong Trieu. TGFB2 mRNA levels prognostically interact with Interferon-alpha receptor activation of IRF9 and IFI27, and makers for tumor-associated macrophages impacting overall survival in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B070.

Attrition of older adults in web-based health interventions: Survival analysis within an observational cohort study.

To identify demographics and personal motivation types that predict dropping out of eHealth interventions among older adults. We conducted an observational cohort study. Participants completed a pre-test questionnaire and got access to an eHealth intervention, called Stranded, for 4 weeks. With survival and Cox-regression analyses, demographics and types of personal motivation were identified that affect drop-out. Ninety older adults started using Stranded. 45.6% participants continued their use for 4 weeks. 32.2% dropped out in the first week and 22.2% dropped out in the second or third week. The final multivariate Cox-regression model which predicts drop-out, consisted of the variables: perceived computer skills and level of external regulation. Predicting the chance of dropping out of an eHealth intervention is possible by using level of self-perceived computer skills and level of external regulation (externally controlled rewards or punishments direct behaviour). Anticipating to these factors can improve eHealth adoption.

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.

Lymphopenia associated with whole-brain radiotherapy and its effects on clinical outcomes of patients with brain metastases

There is increasing awareness of radiotherapy’s potential side effects, such as lymphopenia. Therefore, this study aimed to establish the association between WBRT and the development of lymphopenia in patients with brain metastases undergoing brain radiotherapy (RT), along with evaluating the corresponding clinical outcomes. Including 116 patients with brain metastases undergoing brain radiotherapy, the study collected the absolute lymphocyte counts (ALC) within 2 weeks before brain radiotherapy (pre-radiotherapy, pre-RT), as well as ones at 1 and 2 months after completing RT (post-RT). Univariate and multivariate analyses were performed to identify associations between radiation modality and post-RT ALC. The relationships between post-RT ALC and overall survival were evaluated with Kaplan–Meier analysis and a multivariate Cox regression model. The median ALC definitely decreased at 1 month post-RT, but at 2 months post-RT, gradually rose but not to the pre-RT ALC. The multivariate analysis identified WBRT and lower pre-RT ALC as independent risk factors associated with the decrease in post-RT ALC at 1 month. It also revealed more than 4 brain metastases, G3-4 lymphopenia at 1 month and lower post-RT ALC at 2 months exhibited significantly worse prognosis regardless of the radiation modality. However, there was indeed an independent correlation between radiation modality and the outcome of intracranial progression-free survival (PFS). To approach the feasibility and reasonableness of treatment, clinicians should carefully consider various factors to achieve long-term survival of patients.

Molecular, Socioeconomic, and Clinical Factors Affecting Racial and Ethnic Disparities in Colorectal Cancer Survival

Disparity in overall survival (OS) and differences in the frequency of driver gene variants by race and ethnicity have been separately observed in patients with colorectal cancer; however, how these differences contribute to survival disparity is unknown. To quantify the association of molecular, socioeconomic, and clinical covariates with racial and ethnic disparities in overall survival among patients with colorectal cancer. This single-center cohort study was conducted at a tertiary-level cancer center using relevant data on all patients diagnosed with colorectal cancer from January 1, 1973, to March 1, 2023. The relative contribution of variables to the disparity was determined using mediation analysis with sequential multivariate Cox regression models. OS, from diagnosis date and from start of first-line chemotherapy. The study population of 47 178 patients (median [IQR] age, 57.0 [49-66] years; 20 465 [43.4%] females and 26 713 [56.6%] males; 3.0% Asian, 8.7% Black, 8.8% Hispanic, and 79.4% White individuals) had a median (IQR) follow-up from initial diagnosis of 124 (174) months and OS of 55 (145) months. Compared with White patients, Black patients had worse OS (hazard ratio [HR], 1.16; 95% CI, 1.09-1.24; P <.001), whereas Asian and Hispanic patients had better OS (HR, 0.66; 95% CI, 0.59-0.74; P <.001; and 0.86; 95% CI, 0.81-0.92; P <.001, respectively). When restricted to patients with metastatic disease, the greatest disparity was between Black patients compared with White patients (HR, 1.2; 95% CI, 1.06-1.37; P <.001). Evaluating changes in OS disparity over 20 years showed disparity decreasing among Asian, Hispanic, and White patients, but increasing between Black patients and White patients (HRs, 1.18; 95% CI, 1.07-1.31 for 2008-2012; 1.24, 95% CI, 1.08-1.42 for 2013-2017; and 1.50; 95% CI, 1.20-1.87 for 2018-2023). Survival outcomes for first-line chemotherapy were worse for Black patients compared with White patients (median OS, 18 vs 26 months; HR, 1.30; 95% CI, 1.01-1.70). Among 7628 patients who had clinical molecular testing, APC, KRAS, and PIK3CA showed higher variant frequency in Black patients (false discovery rate [FDR], 0.01; < 0.001; and 0.01, respectively), whereas BRAF and KIT were higher among White patients (FDR, 0.001 and 0.01). Mediation analysis identified neighborhood socioeconomic status as the greatest contributor to OS disparity (29%), followed by molecular characteristics (microsatellite instability status, KRAS variation and BRAF variation, 10%), and tumor sidedness (9%). This single-center cohort study identified substantial OS disparity and differing frequencies of driver gene variations by race and ethnicity. Socioeconomic status had the largest contribution but accounted for less than one-third of the disparity, with substantial contribution from tumor molecular features. Further study of the associations of genetic ancestry and the molecular pathogenesis of colorectal cancer with chemotherapy response is needed.

J-shaped association between apolipoprotein B and CV outcomes in statin-treated patients with chronic coronary syndrome

The association between apolipoprotein B (apoB) and residual cardiovascular (CV) risk in patients with chronic coronary syndrome (CCS) remains unclear. We aimed to investigate the association between apoB levels and CV outcomes in statin-treated CCS patients. We enrolled 8641 statin-treated CCS patients at Fuwai Hospital. The patients were divided into 5 groups based on to apoB quintiles (Q1 to Q5). The primary endpoint was 3-year CV events, including CV death, nonfatal myocardial infarction, and nonfatal stroke. During a median follow-up of 3.17 years, there were 232 (2.7%) CV events. After multivariable adjustment, a restricted cubic spline illustrated a J-shaped relationship between apoB levels and 3-year CV events, with the risk remaining flat until apoB levels exceeded 0.73 g/L, after which the risk increased (nonlinear P < .05). Kaplan-Meier curves showed the lowest CV event rate in the Q3 group (0.68-0.78 g/L). Compared with the Q3 group, multivariable Cox regression models revealed that both low (Q1, ≤ 0.57 g/L) and high (Q5, > 0.93 g/L) apoB levels were associated with an increased risk of major adverse cardiac events (all P < .05). Notably, patients with low apoB levels (Q1) had the highest risk of CV death (HR, 2.44; 95%CI, 1.17-5.08). Our analysis indicates that both low and high levels of apoB are associated with elevated CV risk, with the risk being particularly pronounced at higher levels (> 0.73 g/L).

The association between joint Serum Neurofilament Light Chain and type 2 diabetes with all-cause and cardiovascular mortality in US adults: a longitudinal study of NHANES

BackgroundIn the past, there has been a clear conclusion regarding the sole impact of serum neurofilament light chain (sNfL) levels or type 2 diabetes mellitus (DM) on the risk of death. However, the combined effect of sNfL levels and type 2 DM on all-cause and cardiovascular mortality is still uncertain.MethodsThis study was a prospective cohort study based on data from the National Health and Nutrition Examination Survey (NHANES). The sNfL levels were measured through immunological methods using blood samples collected during the survey. The diagnosis of diabetes was based on rigorous criteria, and participants’ mortality data were followed up until December 31, 2019. Firstly, we separately examined the effects of sNfL and type 2 DM on all-cause and cardiovascular mortality, and finally studied the comprehensive impact of the combination of sNfL and type 2 DM on the risk of mortality. Cumulative Kaplan-Meier curves, multivariate logistic regression and sensitivity analysis were incorporated throughout the entire study.ResultsParticipants in the highest quartile of sNfL were observed. Multivariable COX regression model showed that increased sNfL levels and type 2 DM were respectively associated with an increased risk of all-cause and cardiovascular mortality. Furthermore, elevated sNfL levels were significantly associated with an increased risk of all-cause mortality and cardiovascular mortality after adjustment for confounding factors. When considering both elevated sNfL levels and type 2 DM, individuals had a significantly increased risk of mortality. Sensitivity analysis confirmed the robustness of the findings.ConclusionsThese results suggest that elevated levels of sNfL and type 2 DM are associated with an increased risk of all-cause and cardiovascular mortality, and that participants with increased sNfL levels associated with type 2 DM have higher all-cause mortality and cardiovascular mortality.

The Freiburg Index of Post-TIPS Survival accurately predicts mortality in patients with acute decompensation of cirrhosis.

The recently developed Freiburg Index of Post-TIPS Survival (FIPS) allows improved risk classification of patients with decompensated cirrhosis allocated to transjugular intrahepatic portosystemic shunt (TIPS) implantation. This study investigated the prognostic value of the FIPS in patients hospitalized with acute decompensation of cirrhosis (AD), outside the setting of TIPS implantation. A total of 1133 patients with AD were included in a retrospective, multi-centre study. Ninety-day, 180-day and 1-year mortality were recorded and the FIPS' performance in predicting mortality at these time points was analysed using ROC analyses. Ninety-day, 180-day and 1-year mortality were 17.7%, 24.4% and 30.8%. Uni- and multivariable Cox regression models showed that the FIPS independently predicted 1-year mortality in the study cohort (HR 1.806, 95% CI 1.632-1.998, p < .0001). In ROC analyses, the FIPS offered consistently high performance in the prediction of mortality within 1 year after AD (area under the receiver operator characteristic [AUROC]: 1-year mortality .712 [.679-.746], 180-day mortality .740 [.705-.775] and 90-day mortality .761 [.721-.801]). In fact, in the subgroup of patients presenting with variceal bleeding, the FIPS even showed significantly improved discriminatory performance in the prediction of long-term mortality (AUROC 1-year mortality: .782 [.724-.839]) in comparison with established prognostic scores, such as the CLIF-C AD score (.724 [.660-.788], p = .0071) or MELD 3.0 (.726 [.662-.790], p = .0042). The FIPS accurately predicts mortality in patients with AD and seems to offer superior prognostication of long-term mortality in patients with variceal bleeding.

Triple therapy boosts survival in NSCLC patients with brain metastases: a retrospective cohort study of chemotherapy, ICIs, and antiangiogenic agents

BackgroundTreatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood–brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival.MethodsIn this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher’s exact test, and survival curves were estimated with the Kaplan–Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk.ResultsFrom an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43–0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18–0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683).ConclusionOur study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population.

Omission of Axillary Lymph Node Dissection in Patients with Residual Nodal Disease After Neoadjuvant Chemotherapy.

Axillary management after neoadjuvant chemotherapy (NAC) is evolving but axillary lymph node dissection (ALND) remains the standard of care for patients with residual nodal disease. The results of the Alliance A011202 trial evaluating the oncologic safety of ALND omission in this cohort are pending but we hypothesize that ALND omission is already increasing. The National Cancer Database was queried to identify patients diagnosed with cT1-3N1M0 breast cancer who underwent NAC and had residual nodal disease (ypN1mi-2) from 2012 to 2021. Temporal trends in omission of completion ALND were assessed annually. Multivariable logistic and Cox regression models were used to identify factors associated with ALND omission and overall survival (OS), respectively. A total of 6101 patients were included; the majority presented with cT2 disease (57%), with 69% HER2+, 23% triple-negative, and 8% hormone receptor-positive/HER2-. Overall, 34% underwent sentinel lymph node biopsy (SLNB) alone. Rates of ALND were the lowest in the last 4years of observation. After adjustment, treatment at community centers (vs. academic) and lower pathologic nodal burden were associated with omission of ALND. ALND omission was associated with a higher unadjusted OS (5-year OS: 86% SLNB alone vs. 84% ALND; log-rank p=0.03), however this association was not maintained after adjustment. Despite the impending release of the Alliance A011202 results, omission of ALND in patients with residual nodal disease after NAC is increasing. This practice appears more prominent in community centers and in patients with a lower burden of residual nodal disease. No association with OS was noted.

Association of non-high-density lipoprotein to high-density lipoprotein ratio (NHHR) with prognosis in cancer survivors: a population-based study in the United States.

Patients with cancer frequently exhibit alterations in serum lipid profiles associated with chemotherapy. It has been reported that lipid distribution in cancer correlates with tumor progression. However, the prognostic value of serum lipid biomarkers in cancer survivors remains a subject of debate. We aim to explore the relationship between non-high-density lipoprotein to high-density lipoprotein ratio (NHHR) and the prognosis of cancer survivors. In this study, we analyzed cancer survivor data from the National Health and Nutrition Examination Survey (NHANES) from 1999-2000 to 2017-2018. The study included prospective cohorts that included total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels as well as mortality data. Weighted multivariate cox regression models, competing risk models and restricted cubic spline (RCS) models were applied to investigate the association between NHHR and cancer survival. Subgroup and sensitivity analyses were performed to test the robustness of the results. This study involved 4,177 participants, representing about 19.6 million U.S. adults. After adjustment for various factors, the lower NHHR group (≤1.64) had a 31% (HR 1.31; 95% CI [1.11,1.54], p = 0.001) higher risk of death from any cause compared to the higher NHHR group. The link between NHHR and mortality remained stable across most subgroups, with notable interactions for smoking (p = 0.006) and diabetes status (p = 0.046). A J-shaped pattern was observed between NHHR and all-cause mortality, significantly among obesity-related cancer survivors (overall association test p-value = 0.0068, non-linear association test p-value = 0.0016). However, a non-significant negative correlation was observed for cancer-specific mortality (overall association test p-value = 0.48, non-linear association test p-value = 0.66). Considering the competitive risk of heart disease and cancer-specific mortality, there is no difference between the high and low NHHR groups, while the low NHHR group showed an increased risk of non-specific causes of death (p < 0.001). The results of this study suggest that NHHR is an important indicator that is strongly associated with all-cause mortality in cancer survivors, and that this relationship may be influenced by the interaction of diabetes and smoking status. This finding may provide important information for future research and patient management.

α-Klotho is associated with cardiovascular and all-cause mortality in patients with stage3band 4 chronic kidney disease(CKD): a long-term prospective cohort study.

α-Klotho deficiency may increase cardiovascular risks and worsen survival. We evaluated the association of α-Klotho with cardiovascular and all-cause mortality in pre-dialysis chronic kidney disease (CKD) patients. In this prospective study, 75 non-diabetic CKD stage 3b-4 patients werefollowed-up for a median of 8years. Primary and secondary outcomes were all-cause and cardiovascular mortality, respectively. Human soluble α-Klotho ELISA Assay (IBL-Takara 27,998-96Well), Human Fibroblast Growth Factor-23 ELISA Assay (intact FGF23, Merck Millipore MILLENZ FGF23-32K), and Human Sclerostin ELISA kits (Biomedica, Vienna, BI-20492) were used to measure serum α-Klotho, FGF23 and sclerostin levels in the certified laboratory at the Sechenov University according to the manufacturers' protocols.All patients underwent echocardiography to evaluate left ventricular mass index (LVMI), left ventricular ejection fraction by Simpson method, and cardiac (valve) calcification score by a semi-quantitative point scale. Lateral abdominal radiography by Kauppila method was used to estimate calcificationof the abdominal aorta.Cox multivariate regression and receiver-operating characteristic curve (ROC)-analysis were used to evaluate risk factors for death and their cut-off values. Primary and secondary endpoints were reached in 15 (20%) and 9 (12%) patients, respectively. Median α-Klotho levels in deceased and surviving patients were 344 and 484pg/ml, respectively (p = 0.002). In a multivariate Cox regression model, baseline α-Klotho levels (HR 0.99, 95% CI 0.98-1.00, p = 0.023), aortic calcification (HR 1.18, 95% CI 1.02-1.36, p = 0.029) and left ventricular mass index (LVMI) (HR 1.04, 95% CI 1.00-1.08, p = 0.033) were associated with the primary endpoint, whereas α-Klotho (HR 0.99, 95% CI 0.98-1.00, p = 0.029), aortic calcification (HR 1.23, 95% CI 1.07-1.42, p = 0.003) and LVMI (HR 1.04, 95% CI 1.00-1.08, p = 0.021) were associated with the secondary endpoint. α-Klotho levels had the highest area under the curve (AUC)by ROC analysis, that is, 0.766 (95% CI 0.70-0.82) for the primary endpoint and 0.842 (95% CI 0.79-0.90) for the secondary endpoint with cut-off values of 412pg/ml (HR 3.06, 95% CI 1.36-6.89, p = 0.007) and 368pg/ml (HR 4.84, 95% CI 1.59-14.73, p = 0.005), respectively. In pre-dialysis CKD patients, α-Klotho levels areassociated with all-cause and cardiovascular mortality and may be considered an early prognostic marker.

Prevalence and Prognostic Impact of Multiple Frailty Domain in Japanese Older Adults

ObjectivesIn this observational study, we aimed to evaluate the independent and overlapping effects of multiple frailty domains on long-term care insurance (LTCI) use. DesignPopulation-based cohort design. Setting and ParticipantsIn total, 9804 community-dwelling older adults were recruited from the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes. MethodsThe physical domain of frailty was assessed using the revised Japanese version of the Cardiovascular Health Study criteria. The cognitive domain of frailty was identified as impairment of memory, attention, executive function, or processing speed using standardized thresholds established for each domain in population-based cohorts. The social domain was operationalized using the National Center for Geriatrics and Gerontology-Social Frailty Scale. The use of LTCI was prospectively determined over 60 months using data extracted from the Japanese long-term care insurance system. ResultsThe data from 7745 participants were analyzed, of whom 793 (10.2%) required LTCI certification within 60 months (interquartile range: 60–60 months). The Kaplan–Meier curve analysis demonstrated that a high number of frailty domains was associated with incident LTCI use. The proportions of incident LTCI use were 6.0%, 12.4%, 30.1%, and 43.9% for non-frail participants and those with impairments in 1, 2, and 3 frailty domains, respectively. In the multivariate Cox regression model, physical, cognitive, and social domain impairments independently increased the risk of incident LTCI use (physical domain impairment, hazard ratio [HR], 1.67; 95% CI, 1.39–2.01; cognitive domain impairment, HR, 1.59; 95% CI, 1.37–1.84; social domain impairment, HR, 1.26; 95% CI, 1.05–1.50). Conclusions and ImplicationsOverlapping frailty domains were strongly associated with incident LTCI use among community-dwelling older adults. These findings emphasize the importance of assessing multiple frailty domains and tailoring interventions according to the unique circumstances of older adults to prevent functional disabilities.

623. PERIOPERATIVE THERAPY FOR LIMITED-STAGE SMALL CELL ESOPHAGEAL CARCINOMA: A RETROSPECTIVE COHORT STUDY

Abstract Background The optimal treatment strategy for limited-stage small cell esophageal carcinoma (LS-SCEC) remains uncertain, we aimed to evaluate the efficacy of perioperative therapy in those patients. Methods From June 2005 to November 2022, a total of 156 patients with LS-SCEC who underwent esophagectomy were included in the current study. The primary endpoint was overall survival, and secondary endpoints included progression-free survival. Pathologic staging was determined based on the 8th American Joint Committee on Cancer (AJCC) TNM staging system for esophageal carcinoma. Survival curves were created using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors analysis was carried out using both univariate and multivariate Cox regression models, as well as propensity score matching (PSM) analysis. Statistical significance was defined as P value &amp;lt; 0.05 in a two-tailed test. Results Among 156 LS-SCEC patients, the median age was 62 years (interquartile range [IQR], 56-67), with 120 (76.9%) being males. Thirty-three (21.2%) patients received neoadjuvant chemotherapy; and 2 (1.3%) received neoadjuvant chemoradiotherapy. Seventy-six (48.7%) received adjuvant chemotherapy, 2 (1.3%) received adjuvant radiotherapy, and 13 (8.3%) received adjuvant chemoradiotherapy. Only 7 (4.5%) patients achieved pathological complete remission after neoadjuvant therapy. Following surgery, 33 (21.2%) patients were categorized stage I, 40 (25.6%) as stage II, 61 (39.1%) as stage III, and 22 (14.1%) as stage IV. The median follow-up time of the entire cohort was 72 months. The median disease-free survival (mDFS) was 12.0 months (95% CI, 10.2–13.8 months), and the median overall survival (mOS) was 21.0 months (95% CI, 16.2–25.8 months). The 5-year OS rate was 25.9%, and the DFS rate was 21.9%. Univariate analysis revealed that clinical T stage (P=0.011), clinical N stage (P=0.009), pathological T stage (P=0.027), pathological N stage (P=0.001), pathological TNM stage (P=0.002), adjuvant therapy (P&amp;lt;0.001), and neural invasion (P=0.001) were significant prognostic factors for overall survival. In multivariate analysis, clinical T stage (P=0.049), neural invasion (P=0.002), N stage (P=0.006), and adjuvant therapy (P=0.001) were identified as independent prognostic factors. Furthermore, a PSM analysis was conducted to evaluate the impact of neoadjuvant chemotherapy on LS-SCEC patients. Following PSM, 64 patients were matched, with 32 in each group. Both univariate and multivariate analyses indicated that neoadjuvant chemotherapy could enhance the OS of LS-SCEC patients, with a 5-year OS rate of 37.7% compared to 0.0% in the non-neoadjuvant chemotherapy group (P&amp;lt;0.001, HR=0.319, 95% CI: 0.168-0.604). Subgroup analyses further supported the benefit of neoadjuvant chemotherapy for patients with clinical stages T3-4 and nodal positive (N+), where improved outcomes were observed (P=0.001 and 0.013 respectively). Additionally, subgroup analyses revealed that adjuvant chemoradiotherapy was identified as the optimal treatment model for patients with nodal positive status (adjuvant chemoradiotherapy vs. chemotherapy: OS P=0.01, DFS P=0.004) and those categorized as pathological stage III-IV (adjuvant chemoradiotherapy vs. chemotherapy: OS P=0.03, DFS P=0.017). Conclusions Perioperative therapy is essential for patients with LS-SCEC. Patients with clinical stage T3-4 and nodal positive should undergo neoadjuvant chemotherapy. All patients should receive adjuvant therapy, and adjuvant chemoradiotherapy is recommended for those with nodal involvement or pathologic TNM stages III-IV.

474. SELF EXPANDABLE METAL STENT AS A BRIDGE TO RESECTION IN ESOPHAGEAL CANCER – A NATIONAL REGISTER ANALYSIS ON MORTALITY

Abstract Background Patients with esophageal cancer commonly present with malnutrition and weight loss due to dysphagia. Self Expandable Metal Stent (SEMS) have been used to relieve dysphagia and optimize nutrition prior to surgery and during neoadjuvant treatment. However, SEMS is associated with various complications and studies have further found a decreased survival in patients preoperatively treated with SEMS. The aim of the study was to investigate whether SEMS as a bridge to resection has an impact on mortality. Methods All patients with esophageal cancer in the Swedish National Register for Esophageal and Gastric cancer (NREV) between 2006 and 2018 were included. Patient data, tumor and treatment characteristics were assessed. Resected patients who received SEMS preoperatively were compared to patients who did not receive SEMS with regard to patient, tumor and treatment characteristics. Overall survival was explored by multivariable Cox regression models and adjusted for age, ASA score, preoperative BMI, clinical T-stage and neoadjuvant chemo- or chemoradiotherapy. Primary outcome was mortality. Results In total, 1841 resected patients with esophageal cancer and curative intent were identified. Of these, 83 patients received SEMS as a bridge to resection. T-stage was more advanced in patients with SEMS than those without SEMS, but there was no difference in N-stage, ASA-score or preoperative BMI. Early mortality (&amp;lt;90 days) and total mortality was higher in the SEMS group (12.4% vs 5.3%, p=0.002 and 77.1 % vs 58.2%, p&amp;lt;0.001 respectively. Mean follow-up time was 45 months for the all included patients. SEMS was an independent predictor of earlier death in multivariable analysis (Hazard Ratio 1,710; CI 95% 1,27-2,23; p=&amp;lt;0,001). Conclusion SEMS as a bridge to resection in the treatment of esophageal cancer seem to be associated with poor outcome with regard to both early and late mortality.

406. EXPLORING THE OPTIMAL TIMING OF MINIMALLY INVASIVE SURGERY FOR ESOPHAGEAL SQUAMOUS CELL CARCINOMA AFTER NEOADJUVANT CHEMORADIOTHERAPY

Abstract Background Neoadjuvant chemoradiotherapy has gradually become a first-line treatment for esophageal squamous cell carcinoma patients. After the completion of neoadjuvant chemoradiotherapy, patients usually undergo minimally invasive surgery to ensure complete removal of the tumor and lymphatic tissue. However, the optimal interval between neoadjuvant chemoradiotherapy and minimally invasive surgery is still an unknown factor, and whether it affects postoperative disease-free survival (DFS) and overall survival (OS) of patients remains unknown. Therefore, the main purpose of this study is to explore the specific impact of the interval between neoadjuvant chemoradiotherapy and minimally invasive surgery on patients, and to find the optimal interval time. Methods Patients who underwent neoadjuvant chemoradiotherapy and minimally invasive surgery from two institutions between October 2012 and September 2022 were included in this study. The time interval is defined as the days between the last time a patient receives neoadjuvant chemoradiotherapy and the execution of surgery. Determine the optimal interval truncation point using the surv_cutpoint function in the survminer package. The main research result is the OS and DFS of different interval groups. A multivariate Cox regression model was established to determine the main factors affecting Patient's OS. Construct a nomogram based on selected factors to meet clinical needs. Results 252 patients were included in the study. The average interval between patients undergoing neoadjuvant chemoradiotherapy and minimally invasive surgery is 59 days. The earliest interval for patients to undergo surgery is 28 days. Determine the optimal interval of 46 days based on the survminer package and divide the patients into two groups. The five-year OS rates for the short interval group and the long interval group were 82.6% and 61.0% (P = 0.023). The five-year DFS rates for the two groups were 67.6% and 48.2% (P=0.068). Multivariate Cox regression shows that the time interval, patient's sex, tumor differentiation, ypT, and ypN are the main factors affecting overall survival. Conclusions The interval between neoadjuvant chemoradiotherapy and minimally invasive surgery has a certain impact on patient survival, and it is recommended to undergo surgery between 28 and 46 days to improve patient prognosis and survival.

5α-reductase inhibitors with or without alpha-blockers and risk of incident upper tract urothelial carcinoma in men with benign prostatic hyperplasia: Analysis of US insurance claims data

BackgroundIncreasing data suggests that androgen receptor signaling may play an important role in the carcinogenesis of urothelial cancers. While the chemoprotective effect of 5-alpha reductase inhibitors (5-ARi) on bladder cancer risk in men with Benign Prostatic Hyperplasia (BPH) has been explored with conflicting results, the evidence regarding 5-ARi treatment, and the risk of incident Upper Tract Urothelial Carcinoma (UTUC) development is lacking. Therefore, our objective was to investigate the impact of the 5-ARi administration on the incidence of new UTUC cases using a large US database. MethodsThe MerativeTM Marketscan® database was used to identify men ≥ 50 years old with a diagnosis of BPH and an active 5-ARi prescription between 2007 and 2021 and were subsequently matched with paired controls. A multivariable Cox regression model was implemented to ascertain the association of 5-ARi and/or alpha-blocker (α-B) medications on the incidence of UTUC. Additional subgroup analyses were conducted based on exposure risk (with a 2-year threshold) to investigate the relationship between 5-ARi and UTUC over time. ResultsOverall, n=1,103,743 men BPH without prescriptions for BPH, n=31,142 men on 5-ARi, and n=160,049 using 5-ARi + α-B were identified. Over the follow-up period, a total of n=4,761 patients were diagnosed with UTUC. After matching, UTUC incidence ranged from 0.36% to 0.41% in men without active BPH therapy vs. 0.30% and 0.52% for the 5-ARi and 5-ARi + α-B groups, respectively. In multivariable analysis, the chemoprotective effect on UTUC risk was not observed for either 5-ARi monotherapy (adjusted hazard ratio [aHR]: 0.91, 95% CI: 0.58–1.44) or 5-ARi + α-B combination (aHR: 1.02, 95% CI: 0.87–1.19). This remained true for both short-term (≤ 2 years) and long-term (> 2 years) follow-up periods. ConclusionsThe use of 5-ARi for BPH, whether used alone or in combination with α-B, is not associated with incident UTUC.