Multivariate Cox Proportional Hazards Analysis Research Articles

#963 Discrepancy between actual and estimated urine creatinine excretion predicts mortality in chronic kidney disease: from the KNOW-CKD study

Abstract Background and Aims Urine creatinine excretion is a surrogate marker of muscle mass and low urine creatinine excretion is a predictor of poor clinical outcome. There are several methods to estimate urine creatinine excretion. However, little is known about the clinical implication of discrepancy between actual and estimated urine creatinine excretion in chronic kidney disease (CKD). The aim of this study is to investigate the association between actual and estimated urine creatinine excretion discrepancy and mortality in CKD. Method This study analysed 1805 participants from the KNOW-CKD cohort. They underwent 24-hr urine collection and measured urine creatinine excretion at baseline. Their estimated urine creatinine excretion was calculated by Joachim's method. Discrepancy between actual and estimated urine creatinine excretion (dUCr) was defined as actual urine creatinine excretion minus estimated urine creatinine excretion. Patients were divided into 3 groups according to their tertile of dUCr. The study endpoint was all-cause death. Results During a follow-up of 13 062 person-years (median 8.0 years), 151 patients (8.4%) died, with a corresponding death rate of 11.6 (95% CI 9.9-13.6) per 1000 patients-years. 86 (14.4%), 41 (6.8%) and 24 (3.4%) patients from each 1st to 3rd tertile of dUCr died (P < 0.001). In multivariate Cox proportional hazard analysis, there was a graded association of dUCr with all-cause mortality. The adjusted hazard ratios (95% CI) of 2nd and 3rd tertile were 0.58 (0.39-0.86) and 0.36 (0.22-0.58) compared with the 1st tertile. Conclusion Higher discrepancy between actual and estimated urine creatinine excretion is associated with lower risk of mortality in predialysis CKD patients. This association was independent of various conventional and CKD-related risk factors.

#619 Serum aldosterone to potassium ratio and hyperkalemia risk in patients with chronic kidney disease

Abstract Background and Aims Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have demonstrated efficacy in improving outcomes in patients with chronic kidney disease (CKD). However, these medications have also been associated with the development of hyperkalemia. The aim of this study was to evaluate the relation of serum aldosterone to potassium ratio to the risk of the development of hyperkalemia in CKD patients receiving ACEIs or ARBs. Method Between January 2017 and December 2021, 186 patients with CKD 3-4 (estimated glomerular filtration rate, eGFR, of 15-59 ml/min/1.73 m2) who were receiving an ACEI or an ARB for at least 3 months and had serum aldosterone and potassium measured simultaneously were analyzed. Serum aldosterone to potassium (Aldo/K) ratio was calculated (ng/ml per mmol/l) and patients were divided into two groups according to the median value of serum Aldo/K ratio above or below 2.42. Follow-up serum potassium concentrations were measured every 2 to 3 months. The primary outcome was the occurrence of hyperkalemia (defined as serum potassium level > 5.5 mEq/l). Incidence rates for hyperkalemic events were computed as the ratio of the total number of hyperkalemic events to the total patient-time at risk. In addition, the times from the index date to the first occurrence of hyperkalemia for were computed. Cox proportional hazards models were used to identify patients at the risk of the occurrence of hyperkalemia. Results During a median follow-up period of 3.1 years, 2505 times of serum potassium were measured (mean ± standard deviation number of annual potassium measurements per patient, 4.5 ± 1.7 measurements/year per patient). A total of 144 hyperkalemic events in 81 patients (43.5%) were identified, yielding an incidence rate of 24.6 per 100 person-years (95% confidence intervals [CIs] 20.4–28.8). The incidence of hyperkalemic events was significantly higher in patients with low serum Aldo/K ratio than in those with high serum Aldo/K ratio (35.8 events/100 patient-years, 95% CI 28.9‒42.7 events/100 patient-years vs. 12.9 events/100 patient-years, 95% CI 8.8‒17.0 events/100 patient-years, p < 0.001). In multivariate Cox proportional hazards analysis, diabetes mellitus (Hazard ratio [HR], 1.842; 95% CI, 1.046-3.243; P=0.034), prior history of hyperkalemia (HR, 2.288; 95% CI, 1.372-3.815; P=0.002), low baseline eGFR (HR, 0.973; 95% CI, 0.948-0.998; P=0.037) and a low serum Aldo/K ratio (HR, 3.654; 95% CI, 2.066-6.463; P < 0.001) were predictors of subsequent development of hyperkalemia. Conclusion This study revealed that low serum Aldo/K ratio ( < 2.42) was strongly associated with the occurrence of hyperkalemia in CKD patients receiving ACEIs or ARBs, suggesting that the identification of patients at a risk for subsequent hyperkalemia could be made by measuring serum aldosterone and potassium levels simultaneously on these drugs.

#553 Renal tubular damage is an independent risk factor for all-cause and cardiovascular mortality in a community-based population: the Takahata Study

Abstract Background and Aims Renal tubulointerstitial damage is a risk for renal failure. However, the association between renal tubulointerstitial damage and all-cause and cardiovascular mortality in the general population remains unclear. In this prospective cohort study, we examined this point using urinary β2-microglobulin/creatinine ratio (UBCR) as a marker of renal tubulointerstitial damage in the general Japanese population. Methods We examined the association between UBCR values at entry and all-cause and cardiovascular mortality during the follow-up period (median 9.2 years) in 3 427 residents (mean age 62.5 years, 45.1% male, mean eGFR 81.6 ml/min/1.73 m², ≥1+ protein 4.4%) of Takahata Town in Japan. Results Study participants were divided into two groups (low < 300 μg/gCre, high ≥300 μg/gCre) based on UBCR at entry. Kaplan-Meier analysis showed a significantly higher incidence of all-cause and cardiovascular mortality in the high UBCR group (Log-rank P < 0.01). A multivariate Cox proportional hazards analysis adjusted for age, sex, eGFR, urinary protein level, comorbidities, smoking status, and other background factors showed a hazard ratio of 1.47 (95% CI 1.09-2.00, P = 0.01) for all-cause mortality and a hazard ratio of 1.82 (95% CI 1.06-3.12, P = 0.03) for cardiovascular death in the high-UBCR group. The addition of high UBCR to conventional risk factors, including eGFR and urinary protein level, significantly improved the net reclassification improvement (NRI) for all-cause and cardiovascular mortality (P < 0.01). Conclusions UBCR, a marker of tubulointerstitial damage, was identified as a risk factor for all-cause and cardiovascular mortality in the general population independent of eGFR and urinary protein levels.

Clinical predictive value of the CRP-albumin-lymphocyte index for prognosis of critically ill patients with sepsis in intensive care unit: a retrospective single-center observational study.

Sepsis is a complex syndrome characterized by physiological, pathological, and biochemical abnormalities caused by infection. Its development is influenced by factors such as inflammation, nutrition, and immune status. Therefore, we combined C-reactive protein (CRP), albumin, and lymphocyte, which could reflect above status, to be the CRP-albumin-lymphocyte (CALLY) index, and investigated its association with clinical prognosis of critically ill patients with sepsis. This retrospective observational study enrolled critically ill patients with sepsis who had an initial CRP, albumin, and lymphocyte data on the first day of ICU admission. All data were obtained from the Affiliated Hospital of Jiangsu University. The patients were divided into quartiles (Q1-Q4) based on their CALLY index. The outcomes included 30-/60-day mortality and acute kidney injury (AKI) occurrence. The association between the CALLY index and these clinical outcomes in critically ill patients with sepsis was evaluated using Cox proportional hazards and logistic regression analysis. A total of 1,123 patients (63.0% male) were included in the study. The 30-day and 60-day mortality rates were found to be 28.1 and 33.4%, respectively, while the incidence of AKI was 45.6%. Kaplan-Meier analysis revealed a significant association between higher CALLY index and lower risk of 30-day and 60-day mortality (log-rank p < 0.001). Multivariate Cox proportional hazards analysis indicated that the CALLY index was independently associated with 30-day mortality [HR (95%CI): 0.965 (0.935-0.997); p = 0.030] and 60-day mortality [HR (95%CI): 0.969 (0.941-0.997); p = 0.032]. Additionally, the multivariate logistic regression model showed that the CALLY index served as an independent risk predictor for AKI occurrence [OR (95%CI): 0.982 (0.962-0.998); p = 0.033]. The findings of this study indicated a significant association between the CALLY index and both 30-day and 60-day mortality, as well as the occurrence of AKI, in critically ill patients with sepsis. These findings suggested that the CALLY index may be a valuable tool in identifying sepsis patients who were at high risk for unfavorable outcomes.

Different Patterns of Care and Survival Outcomes in Transplant-Centre Managed Patients with Early-Stage HCC: Real-World Data from an Australian Multi-Centre Cohort Study.

The management of early-stage hepatocellular carcinoma (HCC) is complex, with multiple treatment strategies available. There is a paucity of literature regarding variations in the patterns of care and outcomes between transplant and non-transplant centres. We conducted this real-world multi-centre cohort study in two liver cancer referral centres with an integrated liver transplant program and an additional eight non-transplant HCC referral centres across Australia to identify variation in patterns of care and key survival outcomes. Patients with stage Barcelona Clinic Liver Cancer (BCLC) 0/A HCC, first diagnosed between 1 January 2016 and 31 December 2020, who were managed at a participating site, were included in the study. Patients were excluded if they had a history of prior HCC or if they received upfront liver transplantation. A total of 887 patients were included in the study, with 433 patients managed at a liver cancer centre with a transplant program (LTC) and 454 patients managed at a non-transplant centre (NTC). Management at an LTC did not significantly predict allocation to resection (adjusted OR 0.75, 95% CI 0.50 to 1.11, p = 0.148). However, in those not receiving resection, LTC and NTC patients were systematically managed differently, with LTC patients five times less likely to receive upfront ablation than NTC patients (adjusted OR 0.19, 95% CI 0.13 to 0.28, p < 0.001), even after adjusting for tumour burden, as well as for age, gender, liver disease aetiology, liver disease severity, and medical comorbidities. LTCs exhibited significantly higher proportions of patients undergoing TACE for every tumour burden category, including those with a single tumour measuring 2 cm or less (p < 0.001). Using multivariable Cox proportional hazards analysis, management at a transplant centre was associated with reduced all-cause mortality (adjusted HR 0.71, 95% CI 0.51 to 0.98, p = 0.036), and competing-risk regression analysis, considering liver transplant as a competing event, demonstrated a similar reduction in risk (adjusted HR 0.70, 95% CI 0.50 to 0.99, p = 0.041), suggesting that the reduced risk of death is not fully explained by higher rates of transplantation. Our study highlights systematic differences in HCC care between large volume liver transplant centres and other sites, which has not previously been well-described. Further work is needed to better define the reasons for differences in treatment allocation and to aim to minimise unwarranted treatment variation to maximise patient outcomes across Australia.

Hsa_circ_0070440 mediates the prognosis and progress of human prostate cancer.

This study was designed to explore whether hsa_circ_0070440 was dysregulated in prostate cancer (PCa), and assess the effects of hsa_circ_0070440 alteration on PCa prognosis and cell function. The expression levels of hsa_circ_0070440 were assessed in PCa tissues and cell lines. After the classification of patients with PCa based on mean hsa_circ_0070440 level in 138 cases, Chi-square test and survival analyses (Kaplan-Meier method and multivariable Cox proportional hazards analysis) were performed to assess the predictive value of hsa_circ_0070440 in treatment failure (TTF), time to PSA progression (TTPP) and overall survival time. To examine the function of hsa_circ_0070440 in PCa cells, 22Rv1 and C4-2B cells were used for CCK-8 proliferation and Transwell migration assays. Hsa_circ_0070440- and TXNDC5-specific bindings with miR-382/383-5p were validated by bioinformatic analysis and luciferase gene reporter assay. An increased expression of hsa_circ_0070440 was found in PCA tissues and cell lines, associated with clinical T stage (p=0.021) and lymph node metastasis. Hsa_circ_0070440 predicted poor overall survival, TTPP, and TTF, acting as independent prognostic factors for overall survival, TTPP, and TTF in patients with PCa. Knockdown of hsa_circ_0070440 inhibited cell proliferation and migration in vitro. Furthermore, hsa_circ_0070440 could sponge miR-382/383-5p. TXNDC5 was a common target gene for miR-382/383-5p in PCa cells. This study demonstrated that hsa_circ_0070440 can predict the prognosis of PCa patients. Hsa_circ_0070440 can facilitate the proliferation and migration of PCa cells, possibly by sponging miR-382/383-5p.

Superiority of high sensitivity cardiac troponin I over NT-proBNP and adiponectin for 7-year mortality in stable patients receiving haemodialysis

Patients on haemodialysis (HD) have high mortality risk, and prognostic values of the major cardiovascular biomarkers cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), and adiponectin should be ascertained over longer follow-up periods using higher-sensitivity assays, which we undertook. In 221 HD patients, levels of high-sensitivity (hs)-cTnI, NT-proBNP, and adiponectin, were measured using high-sensitivity assays, and their associations with all-cause mortality (ACM) and cardiovascular mortality (CVM) were prospectively investigated for 7 years. Higher hs-cTnI and NT-proBNP levels were significant risk factors for ACM and CVM in the Kaplan–Meier analysis. Multivariate Cox proportional hazards analyses in a model including hs-cTnI and NT-proBNP identified log hs-cTnI, but not log NT-proBNP, as an independent risk factor for ACM (HR 2.12, P < 0.02) and CVM (HR 4.48, P < 0.0005). Stepwise analyses identified a high hs-cTnI tertile as a risk factor for ACM (HR 2.31, P < 0.01) and CVM (HR 6.70, P < 0.001). The addition of hs-cTnI to a model including age, CRP, DM, and NT-proBNP significantly improved the discrimination of ACM and CVM each over 7 years. Conclusively, hs-cTnI was superior to NT-proBNP and adiponectin in predicting ACM and CVM over 7 years in HD patients, suggesting the significance of baseline hs-cTnI measurements in long-term management.

Chronic Kidney Disease Stage and Cardiovascular and Mortality Events Among Older Adults: The SPRINT Trial

Rationale & ObjectiveThe risk implications of the Kidney Disease: Improving Global Outcomes (KDIGO) CKD classification in older adults are controversial. We evaluated the risk of adverse outcomes in this population across categories of estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). Study DesignProspective cohort. Settings & Participants2509 participants aged ≥75 years in the Systolic Blood Pressure Intervention Trial (SPRINT). ExposuresKDIGO eGFR and UACR categories. We combined KDIGO categories G1 and G2, G3b and G4, as well as A2 and A3. OutcomesPrimary SPRINT outcome (composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes), and all-cause death. Analytical ApproachMultivariable Cox proportional hazard models. ResultsMean age was 79.8 years, 37.4% were female, mean eGFR was 64.0 ml/min/1.73 m2, and median UACR 13.1 mg/g. In multivariable Cox proportional hazard analysis, compared with participants with eGFR ≥60 ml/min/1.73 m2 and UACR <30 mg/g, there was no statistically significant difference in the risk of the primary outcome among participants with eGFR 45-59 or 15-44 ml/min/1.73 m2 and UACR <30 mg/g. However, those with eGFR 45-59 or 15-44 ml/min/1.73 m2 and UACR ≥30 mg/g had higher risk of the primary outcome (HR [95% CI], 1.97 [1.27, 3.04] and 3.32 [2.23, 4.93], respectively). The risk for all-cause death was higher for each category of abnormal eGFR and UACR, with the highest risk observed among those with eGFR 15-44 ml/min/1.73 m2 and UACR ≥30 mg/g (3.34 [2.05, 5.44]). LimitationsIndividuals with diabetes and urine protein >1 g/day were excluded from SPRINT. ConclusionAmong older adults SPRINT participants, low eGFR without albuminuria was associated with higher mortality but not with increased risk of cardiovascular events. Additional studies are needed to evaluate an adapted CKD stage-based risk stratification for older adults.

The landscape of etiological patterns of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in Thailand.

Thailand is among countries with the highest global incidence and mortality rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). While viral hepatitis and liver fluke infections have been associated with HCC and iCCA, respectively, other environmental risk factors, overall risk factor commonality and combinatorial roles, and effects on survival have not been systematically examined. We conducted a TIGER-LC consortium-based population study covering all high-incidence areas of both malignancies across Thailand: 837 HCC, 1474 iCCA, and 1112 controls (2011-2019) were comprehensively queried on lifelong environmental exposures, lifestyle, and medical history. Multivariate logistic regression and Cox proportional hazards analyses were used to evaluate risk factors and associated survival patterns. Our models identified shared risk factors between HCC and iCCA, such as viral hepatitis infection, liver fluke infection, and diabetes, including novel and shared associations of agricultural pesticide exposure (OR range of 1.50; 95% CI: 1.06-2.11 to 2.91; 95% CI: 1.82-4.63) along with vulnerable sources of drinking water. Most patients had multiple risk factors, magnifying their risk considerably. Patients with lower risk levels had better survival in both HCC (HR 0.78; 95% CI: 0.64-0.96) and iCCA (HR 0.84; 95% CI: 0.70-0.99). Risk factor co-exposures and their common associations with HCC and iCCA in Thailand emphasize the importance for future prevention and control measures, especially in its large agricultural sector. The observed mortality patterns suggest ways to stratify patients for anticipated survivorship and develop plans to support medical care of longer-term survivors, including behavioral changes to reduce exposures.

Association between red cell distribution width and all-cause mortality in patients with breast cancer: A retrospective analysis using MIMIC-IV 2.0.

Investigating the association between red cell distribution width (RDW) and all-cause mortality in patients with breast cancer, to evaluate the potential clinical prognostic value of RDW. Based on the RDW index, patients with breast cancer in the Medical Information Mart for Intensive Care (MIMIC-IV) database were categorized into quartiles. The primary outcomes included in-hospital mortality from all causes during the first six months, the first year, and the first three years. Cox hazards regression and restricted cubic spline (RCS) models were developed to investigate the effects of RDW on primary outcomes. The study included 939 patients (female). The 6-month, 1-year, and 3-year mortality rates were 14.0%, 21.4%, and 28.4%, respectively. Multivariate Cox proportional hazards analyses demonstrated that RDW exhibited an autonomous association with an increased risk of all-cause mortality. After adjusting for confounders, higher RDW quartiles were significantly associated with 6-month mortality (adjusted hazard ratio (HR), 3.197; 95% confidence interval (CI), 1.745-5.762; P < 0.001), 1-year mortality (adjusted HR, 2.978; 95% CI, 1.867-4.748; P < 0.001), and 3-year mortality (adjusted HR, 2.526; 95% CI, 1.701-3.750; P < 0.001). The RCS curves demonstrated that high RDW (> 14.6) was associated with a greater risk of all-cause mortality. Subgroup analyses revealed no statistically significant differences in the interactions between the subgroups. The study revealed a highly pronounced relationship between RDW and overall mortality, indicating its potential as an autonomous prognostic factor for increased mortality among patients with breast cancer.

The Discovery of Oral Cancer Prognostic Factor Ranking Using Association Rule Mining.

A 5-year survival rate is a predictor for the assessment of oral cancer prognosis. The purpose of this study is to analyze oral cancer data to discover and rank the prognostic factors associated with oral cancer 5-year survival using the association rule mining (ARM) technique. This study is a retrospective analysis of 897 oral cancer patients from a regional cancer center between 2011 and 2017. The 5-year survival rate was assessed. The multivariable Cox proportional hazards analysis was performed to determine prognostic factors. ARM was applied to clinicopathologic and treatment modalities data to identify and rank the prognostic factors associated with oral cancer 5-year survival. The 5-year overall survival rate was 35.1%. Multivariable Cox proportional hazards analysis showed that tumor (T) stage, lymph node metastasis, surgical margin, extranodal extension, recurrence, and distant metastasis of tumor were significantly associated with overall survival rate (p < 0.05). The top associated death within 5 years rule was positive extranodal extension, followed by positive perineural and lymphovascular invasion, with confidence levels of 0.808, 0.808, and 0.804, respectively. This study has shown that extranodal extension, and perineural and lymphovascular invasion were the top ranking and major deadly prognostic factors affecting the 5-year survival of oral cancer.

Gender differences in tumor characteristics, treatment allocation and survival in stage I–III pancreatic cancer: a nationwide study

IntroductionSex and gender are modulators of health and disease and may have impact on treatment allocation and survival in patients with cancer. In this study, we analyzed the impact of sex and gender on treatment allocation and overall survival in patients with stage I-III pancreatic cancer. MethodsPatients with stage I-III pancreatic cancer diagnosed between 2015 and 2020 were selected from the nationwide Netherlands Cancer Registry. Associations between sex and gender and the probability of receiving surgical and/or systemic treatment were examined with multivariable logistic regression analyses. Overall survival was assessed with log rank test and multivariable Cox proportional hazard analysis. ResultsAmong 6855 patients, 51.2 % were female. Multivariable logistic regression analyses with adjustment for known confounders (age, performance status, comorbidities, tumor location, tumor stage and previous malignancies) showed that females less often received systemic chemotherapy compared to males (OR 0.799, 95 %CI 0.703–0.909, p < .001). No difference was found in the probability for undergoing surgical resection. Furthermore, females had worse overall survival compared to males (median OS 8.5 and 9.2 months respectively, 95 %CI 8.669–9.731). ConclusionThis nationwide study found that female patients with stage I-III pancreatic cancer significantly less often received systemic treatment and had worse overall survival as compared to males. Disparities in pancreatic cancer care can be decreased by recognizing and resolving potential obstacles or biases in treatment decision-making.

Contact aspiration for basilar artery occlusion safely reduces the puncture-to-recanalization time

ObjectiveEffective thrombectomies in the posterior circulation remain controversial. Previous reports have demonstrated the superiority of contact aspiration in anterior circulation. Aspiration catheters and stent retrievers are often used alone on a global scale, while combined techniques are commonly used in Japan. This study evaluated the effect of first-line contact aspiration with other strategies for the treatment of basilar artery occlusion. MethodsThe primary outcome was the frequency of the first-pass effect, and the secondary outcome was the time from puncture to the first-pass effect. A multicenter observational registry including 16 Japanese stroke centers was used. Between December 2013 and February 2021, enrolled patients underwent endovascular thrombectomy for basilar artery occlusion. The efficacy of contact aspiration compared to other methods (including stent retrievers and combined techniques) was evaluated. ResultsEighty-four patients were included, all of whom had achieved effective recanalization. Twenty-six patients were treated with contact aspiration, 13 with combined technique, and 45 with stent retrievers. The two groups: contact aspiration and non-contact aspiration, had different backgrounds. Both had similar frequencies of effective recanalization and first-pass effects. The contact aspiration group experienced better functional outcomes without statistical significance, while this strategy was significantly associated with a shorter puncture-to-recanalization time (38 vs. 55 minutes, P=0.036). In particular, in the 55 patients with the first-pass effect, multivariate Cox proportional hazard analysis showed that contact aspiration was significantly associated with a shorter time from puncture to first-pass effect, independent of age and etiology of large-artery atherosclerosis (hazard ratio 2.02, 95% confidence intervals 1.10–3.69, P=0.023). ConclusionThis study suggested that contact aspiration for basilar artery occlusion may shorten the puncture-to-first-pass effect, compared to stent retrievers and combined techniques.

Geriatric nutritional risk index and controller nutritional status score before metastatic first-line chemotherapy predict survival in patients over 70 years of age with metastatic bladder cancer.

Several prognostic factors have been identified in patients with metastatic bladder cancer (BC). As it is known, older adult patients are prone to nutritional deficiency. The knowledge about nutrition and impact on survival in older patients with metastatic bladder cancer is missing. It is necessary to specifically examine this population. Because timely interventions can make a positive impact on this patients population. This retrospective study aimed to evaluate the prognostic effect of the Geriatric Nutritional Risk Index (GNRI), Controller Nutritional Status (CONUT) score and Prognostic Nutritional Index (PNI) before first-line chemotherapy in the metastatic stage in patients with metastatic bladder cancer over 70. Patients over 70 with pathologically confirmed denovo metastatic or recurrent metastatic bladder cancer were included in the study. Patients with infections diagnosed at the time of diagnosis, autoimmune diseases or history of steroid use were excluded. Since our population consists of a specific age group with a specific cancer, we found a new cut-off value by performing ROC analysis to ensure optimal sensitivity and specificity in terms of progression. Low GNRI value was related with poor nutritional status. Low PNI value was related with poor nutritional status and high CONUT score was related with poor nutritional status. Factors predicting overall survival (OS) and Progression-Free Survival (PFS) were assessed using both univariate and multivariate Cox proportional hazards analyses. 106 patients were included in the study and the average age was 75.5 years. In the GNRI-Low group, PFS was significantly shorter than that in the GNRI-High group [HR (95% CI) = 57.1 (12.8-255.5), (p < 0.001)]. Among those with a low-CONUT score, PFS was found to be longer than that in the high-CONUT group [HR (95% CI) = 1.7 (1.0-3.0), (p = 0.039)]. The median PFS of the PNI-Low group wasn't significantly shorter than that of the PNI-High group [HR (95% CI) = 1.8 (0.5-6.2), (p = 0.359)]. Our study suggests that the GNRI and CONUT scores are useful for predicting survival in patients over 70 years of age with BC.

Canine Mammary Tumors as a Potential Model for Human Breast Cancer in Comparative Oncology.

Clinical and molecular similarities between canine mammary tumors (CMTs) and human breast cancer (HBC) propel scientists to further study their application in comparative oncology as a model for human breast cancer. In total, 64 canine mammary tumors were selected to study the most common markers, which are applicable for human breast cancer treatment, including estrogen and progesterone receptors (ER and PR), human epidermal growth factor (HER2/neu), Ki67, and cyclooxygenase 2 (Cox2). Immunohistochemistry (IHC) was used to assess the protein expression. The Veterinary Nottingham Prognostic Index (Vet-NPI) was also computed. Moreover, univariate and multivariable Cox proportional hazard analyses were applied to estimate hazard ratios (HRs). The results demonstrated that Ki67 was strongly expressed in the triple-negative tumors, and Ki67 protein expression continuously increased over the increase of Cox2 protein expression (p < 0.001). Further analysis revealed a significant difference among canine mammary subtypes and Vet-NPI, in which triple-negative tumors displayed the highest mean score compared to other subtypes (p < 0.001). In addition, the multivariable analysis revealed that the regional mastectomy procedure (adjusted HR = 2.78 (1.14-6.8)), the triple-negative tumors (adjusted HR = 48.08 (7.74-298.8)), strong Ki67 protein expression group (adjusted HR = 7.88 (2.02-30.68)), and strong Cox2 protein expression group (adjusted HR = 29.35 (5.18-166.4)) demonstrated significantly lower disease-free survival rates compared to other corresponding groups. Overall, canine mammary tumors showed strong similarities to human breast cancer in terms of clinical and molecular aspects; therefore, they could be suggested as a model for human breast cancer in comparative oncology.

Associations between in-hospital daily protein intake and adverse clinical outcomes in older patients with heart failure.

The adverse effects of low daily protein intake (DPI) on clinical outcomes in patients with heart failure (HF) are known; however, an optimal DPI to predict event adverse outcomes remains undetermined. Moreover, whether protein restriction therapy for chronic kidney disease is applicable in patients with HF and renal dysfunction remains unclear. In this single-centre, ambispective cohort study, we included 405 patients with HF aged ≥65years (mean age, 78.6±7.5years; 50% women). DPI was estimated from consumption over three consecutive days before discharge and normalized relative to the ideal body weight [IBW, 22kg/m2×height (m)2]. The primary outcome was a composite of all-cause mortality and HF-related readmission within the 2year post-discharge period. During an average follow-up period of 1.49±0.74years, 100 patients experienced composite events. Kaplan-Meier survival curves revealed a significantly lower composite event-free rate in patients within the lowest quartile of DPI than in the upper quartiles (log-rank test, P=0.02). A multivariate Cox proportional hazards analysis after adjusting for established prognostic markers and non-proteogenic energy intake revealed that patients in the lowest DPI quartile faced a two-fold higher risk of composite events than those in the highest quartile [hazard ratio (HR), 2.03; 95% confidence interval (CI), 1.08-3.82; P=0.03]. The composite event risk linearly increased as DPI decreased (P for nonlinearity=0.90), with each standard deviation (0.26g/kg IBW/day) decrease in DPI associated with a 32% increase in composite event risk (HR, 1.32; 95% CI, 1.10-1.71; P=0.04). There was significant heterogeneity in the effect of DPI, with the possible disadvantage of lower DPI in patients with HF with cystatin C-based estimated glomerular filtration rate <30mL/min/1.73m2. The cutoff value of DPI for predicting the occurrence of composite events calculated from the Youden index was 1.12g/kg IBW/day. Incorporating a DPI<1.12g/kg IBW/day into the baseline model significantly improved the prediction of post-discharge composite events (continuous net reclassification improvement, 0.294; 95% CI, 0.072-0.516; P=0.01). Lower DPI during hospitalization is associated with an increased risk of mortality and HF readmission independent of non-proteogenic energy intake, and the possible optimal DPI for predicting adverse clinical outcomes is >1.12g/kg IBW/day in older patients with HF. Caution is warranted when protein restriction therapy is administered to older patients with HF and renal dysfunction.

Abstract PO1-07-11: Radiogenomic-based imaging intratumor heterogeneity model predicts breast cancer prognosis and unveils therapeutic targets

Abstract Background: Intratumor heterogeneity (ITH) refers to variations observed among cancer cells within a single tumor, posing significant challenges in clinical practice due to its contribution to treatment resistance and unfavorable outcome. However, the inconvenience of multi-region biopsy and limitations of genomic sequencing based on limited tissue impede the practical detection of ITH. Consequently, there is an urgent need for a non-invasive method that comprehensively captures ITH from a holistic perspective of the entire tumor. Methods: We utilized a large multicenter dataset comprising dynamic contrast-enhanced magnetic resonance images from breast cancer patients (n = 1423) along with matched multiomics data (n = 468) to develop a non-invasive machine learning approach for measuring ITH. We extracted quantitative radiomic features from both the entire tumor and peritumor regions, with a specific focus on features associated with imaging heterogeneity. Using these radiomic features, we established an imaging ITH (IITH) model. The robustness of IITH evaluation was determined by assessing its correlation with genomic ITH (employing the mutant-allele tumor heterogeneity [MATH] algorithm) and pathological cellular ITH (analyzing variation in quantitative nuclear features extracted through digital pathology). Prognostic power was evaluated using Kaplan-Meier and multivariate Cox proportional hazards analyses. Integrated multiomics analyses were performed to investigate the molecular basis of different IITH subgroups. Results: We developed a non-invasive radiomic signature to quantify imaging ITH (IITH) in the FUSCC cohort. Breast cancer patients were retrospectively categorized into high and low IITH groups. Multivariate Cox analysis identified high IITH as an independent predictor of poor prognosis in breast cancer patients, even after adjusting for clinical risk factors such as tumor size, positive lymph nodes, clinical subtype and lymphovascular invasion status. These findings were further validated in the DUKE cohort, confirming the prognostic value of IITH. Moreover, we substantiated the robustness of IITH by demonstrating its association with genomic and pathological ITH. Multiomics analysis revealed the activation of oncogenic pathways and metabolic dysregulation in high-IITH tumors. Intriguingly, our investigation also highlighted ferroptosis as a vulnerability and potential therapeutic target in high-IITH tumors, which was further supported by evidence from the TCGA cohort. Conclusion: Radiomic-based assessment of ITH provides a non-invasive approach to comprehensively capture ITH and predict the prognosis of breast cancer patients. Targeting ferroptosis may hold promise as a treatment strategy for patients with high IITH. Citation Format: Guan-Hua Su, Yi Xiao, Chao You, Ren-Cheng Zheng, Shen Zhao, He Wang, Yi-Zhou Jiang, Ya-Jia Gu, Zhi-Ming Shao. Radiogenomic-based imaging intratumor heterogeneity model predicts breast cancer prognosis and unveils therapeutic targets [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-07-11.

Abstract PO3-29-05: Clinical risk score to predict overall survival and breast cancer recurrence in phase 3 TAILORx trial and the Surveillance, Epidemiology, and End Results (SEER) Database populations

Abstract Background: Overall survival (OS) is the gold standard and most relevant endpoint in oncology research and patient care. It underscores a need to develop methods to estimate the likelihood of mortality in breast cancer. Methods: We evaluated molecular and clinical measures that predicted mortality risk using multiple logistic regression and developed a clinical risk score (CS) in 8,905 patients from the phase 3 TAILORx trial. Association of CS with mortality in patients at low, intermediate, and high risks was analyzed by Kaplan-Meier and multivariable Cox proportional-hazards regression analyses. The score was validated in an independent population of 148,301 patients with node-negative, hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in the SEER database. Likelihood ratio (LR) test and c-index were used to compare prognostic information provided by CS and a 21-gene recurrence score (RS) to OS, invasive disease-free survival (DFS), recurrence-free interval (RFI), and distant recurrence-free interval (dRFI). Results: The 10-year mortality rates in low-risk, intermediate risk, and high-risk groups were 3.9% (95% CI 3.1 to 4.8), 37.2% (95% CI 23.4 to 51.1), and 75.8% (95% CI 54.1 to 97.4), respectively (P&amp;lt; 0.0001). Compared with low-risk score, intermediate (adjusted HR 45.5, 95% CI 32.2 to 64.9) and high-risk scores (HR 2026, 95% CI 1194 to 3483) were associated with risk of mortality, independent of demographics, tumor grade, RS, tumor size, PR, and treatment factors. The algorithm also predicted DFS, dRFI, and RFI outcomes (P&amp;lt; 0.0001 each), outperforming RS by both LR test and c-index estimate. Its validity was corroborated in the SEER population (intermediate risk: HR 9.3, 95% CI 6.7 to 13.3 and high-risk: HR 125.9, 95% CI 85.2 to 189.6). Conclusions: Clinical risk score robustly predicts risk of mortality in early-stage breast cancer populations. It provides more prognostic information than RS to survival and breast cancer recurrences. Citation Format: Sherry Yang, John Yu, Ninet Sinaii. Clinical risk score to predict overall survival and breast cancer recurrence in phase 3 TAILORx trial and the Surveillance, Epidemiology, and End Results (SEER) Database populations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-29-05.

Frailty and Exacerbation of Chronic Obstructive Pulmonary Disease: Is There Any Association?

This study investigated if individuals with chronic obstructive pulmonary disease (COPD) and frailty are more likely to have acute exacerbations of COPD or require hospitalization for exacerbation than those without frailty. Data on 135 outpatients with stable COPD were analyzed with the Cox proportional hazards model to assess the risk of future events. The Kihon Checklist was administered at baseline to classify the participants as robust, pre-frail, or frail. The follow-up period was a maximum of six and a half years. In all, 76 patients (56.3%) experienced an exacerbation and 46 (34.1%) were hospitalized due to it. Multivariate Cox proportional hazards analysis that accounted for FEV1 and sex showed that the frail group was more likely to face future risks of COPD exacerbations [Hazard ratio 1.762 (95% CI 1.011-3.070), p=0.046] and hospitalizations for exacerbation [2.238 (1.073-4.667), p=0.032] than the robust group. No significant differences were observed when comparing robust patients to those who were pre-frail or pre-frail to frail either in exacerbations or hospitalizations. When comparing the C-indices for frailty and FEV1, the former index (exacerbation 0.591 and hospitalization 0.663) did not exceed the latter (0.663 and 0.769) in either analysis. Frail COPD patients have a more unfavorable future risk of acute exacerbations of COPD and hospitalizations for exacerbation than robust patients. However, no significant differences were observed when comparing robust patients to those who were pre-frail or pre-frail to frail, suggesting that the future risk for COPD patients with frailty is only higher compared to those who are considered robust. Additionally, FEV1 was found to be a more reliable predictor of future events than measures of frailty.

Patients with Advanced or Metastasised Non-Small-Cell Lung Cancer with Viscum album L. Therapy in Addition to PD-1/PD-L1 Blockade: A Real-World Data Study.

Immunotherapy with PD-1/PD-L1 inhibitors has significantly improved the survival rates of patients with metastatic non-small-cell lung cancer (NSCLC). Results of a real-world data study investigating add-on VA (Viscum album L.) to chemotherapy have shown an association with the improved overall survival of patients with NSCLC. We sought to investigate whether the addition of VA to PD-1/PD-L1 inhibitors in patients with advanced or metastasised NSCLC would have an additional survival benefit. In the present real-world data study, we enrolled patients from the accredited national registry, Network Oncology, with advanced or metastasised NSCLC. The reporting of data was performed in accordance with the ESMO-GROW criteria for the optimal reporting of oncological real-world evidence (RWE) studies. Overall survival was compared between patients receiving PD-1/PD-L1 inhibitor therapy (control, CTRL group) versus the combination of anti-PD-1/PD-L1 therapy and VA (combination, COMB group). An adjusted multivariate Cox proportional hazard analysis was performed to investigate variables associated with survival. From 31 July 2015 to 9 May 2023, 415 patients with a median age of 68 years and a male/female ratio of 1.2 were treated with anti-PD-1/PD-L1 therapy with or without add-on VA. Survival analyses included 222 (53.5%) patients within the CRTL group and 193 (46.5%) in the COMB group. Patients in the COMB group revealed a median survival of 13.8 months and patients in the CRTL group a median survival of 6.8 months (adjusted hazard ratio, aHR: 0.60, 95% CI: 0.43-0.85, p = 0.004) after adjustment for age, gender, tumour stage, BMI, ECOG status, oncological treatment, and PD-L1 tumour proportion score. A reduction in the adjusted hazard of death by 56% was seen with the addition of VA (aHR 0.44, 95% CI: 0.26-0.74, p = 0.002) in patients with PD-L1-positive tumours (tumour proportion score > 1%) treated with first-line anti-PD-1/PD-L1 therapy. Our findings suggest that add-on VA correlates with improved survival in patients with advanced or metastasised NSCLC who were treated with PD-1/PD-L1 inhibitors irrespective of age, gender, tumour stage, or oncological treatment. The underlying mechanisms may include the synergistic modulation of the immune response. A limitation of this study is the observational non-randomised study design, which only allows limited conclusions to be drawn and prospective randomised trials are warranted.