Hazard Ratio Estimates Research Articles

#594 Long-term risk of incident/progressive chronic kidney disease, or end-stage kidney disease post-acute kidney injury: systematic review, meta-analysis

Abstract Background and Aims Little is known about which patients to follow-up after an episode of acute kidney injury (AKI) for future risks. The aim of this review is to assess the association between AKI and the incidence or progression of chronic kidney disease (CKD) or end-stage kidney disease (ESKD), stratified by subcategories of AKI-stages, -durations, and clinical settings. Method A systematic search of the literature in PubMed and Embase was performed by two reviewers to identify studies that examined CKD incidence (development of CKD stage ≥3), CKD progression (worsening of kidney function in patients with CKD stage ≥3), or ESKD, in patients with AKI versus patients without AKI. The risk of bias was assessed using the Newcastle-Ottawa Scale. Relative effect estimates (odds and hazard ratios) were pooled using a random effects model. Results In total, 48 retrospective and 13 prospective studies, encompassing 140.985 patients with AKI, were included in this review. All the studies were of moderate or high quality. The pooled effect ratio was 3.36 (95% confidence interval (CI) 2.68-4.03) for CKD incidence (n = 31 studies). This remained 3.40 (95% CI 1.79-5.00) in a sub analysis including patients with a recovered kidney function post-AKI, and 1.49 (95% CI 1.44-1.55) in a sub analysis including patients with an AKI lasting less than 3 days (Fig. 1). Overall, the effect ratio for CKD progression (n = 11 studies) was 1.70 (95% CI 1.38-2.01) and 3.81 (95% CI 2.58-5.04) for ESKD (n = 24 studies). The increased risk of these two outcomes were not seen in the sub analyses only including patients with AKI lasting less than 3 days. Overall, there is an observable higher risk for CKD incidence, CKD progression, and ESKD with increased AKI staging, although not always statistically significant. Minimal variations were observed across clinical settings. Conclusion In our review, including over 60 studies, we found that AKI was associated with an increased risk of CKD incidence, CKD progression, and ESKD. Patients with higher AKI-stages had even larger risks. Notably, even brief episodes of AKI (lasting less than 3 days) were associated with a higher risk of CKD incidence compared to patients without AKI. In contrary, the risk for ESKD is not enlarged in a sub analysis including patients with recovered kidney function compared to patients without AKI. These result warrant close monitoring of the kidney function post-AKI, specifically in patients with AKI lasting 3 days or longer. Future research should focus more on the risk of CKD progression in order to tailor follow-up care in these more vulnerable patients.

#2652 Hemoglobin excursion outside of the target range and their associations with all-cause mortality in hemodialysis patients

Abstract Background and Aims Based on earlier analyses (Mermelstein et al., ASN Renal Week 2023), where we found an improved survival with hemoglobin levels above the currently targeted range of 10 to 11 g/dL quantified as an area under the excursion curve, we hypothesized an independent association between all-cause mortality hazard ratio and a) the number of excursions, and b) the number of days outside of the target range. Method We explored this relationship in a retrospective cohort study of incident hemodialysis patients receiving erythropoietin stimulating agent (ESA) commencing treatment Fresenius Kidney Care clinics in the US. We included patients who were given a long-acting erythropoietin stimulating agent within 90 days of dialysis initiation, considered the first six months as baseline and the following 18 months as the follow-up period. Only patients with at least 5 hemoglobin values over the first 75 days were included. We calculated the ‘area under the curve’ (AUC) above and below the target hemoglobin range of 10-11 g/dL for each patient during the baseline period, as well as days below and above range, and number of excursions below and above range. Cox proportional hazard models additionally adjusted for age, race, sex, diabetes, serum albumin, and phosphate were developed, and the hazard ratio estimates depicted in a forest plot. Results We studied 62,181 patients (57% male, 39% diabetic, mean baseline hgb 10.42 ± 0.72 g/dL, baseline AUC above target 44.36 ± 49.44 g/dL * days and 78.06 ± 86.26 g/dL * days below target). Forest plot of the HR estimates showed an increased risk of death with AUC below the lower limit of the target range (i.e. 10 g/dL), which also held true both for number of excursions and days exposed to lower hgb levels). Conversely, AUC, conversions and days spent at hgb levels higher than the upper limit of the target range (i.e. 11 g/dL), associated with a significant survival advantage. Conclusion In an effort to validate the robustness of our previously shown association between higher hgb levels and survival advantage, and to corroborate the accuracy of the utilized AUC quantification method, we separated both components of the AUC, namely into time and magnitude and quantified the independent associations with the risk of death. This allowed to discern between the associations of both to the risk of death. Consistent with the earlier results, avoiding levels below 10 g/dL and aiming for levels above the upper limit of 11 g/dL, seems to be beneficial for the anemia management of incident hemodialysis patients treated with a long-acting ESA.

Higher high-density lipoprotein cholesterol levels increased vertebral osteoporotic fracture, but reduced hip fracture in men based on the National Health Insurance Service-National Health Screening Cohort

BACKGROUND CONTEXTLipids are currently known to play an important role in bone metabolism. PURPOSEThis study aimed to investigate the effect of high-density lipoprotein cholesterol (HDL-C) on osteoporotic fractures beyond its beneficial effects on the cardiovascular system. STUDY DESIGN/SETTINGThis was a retrospective, observational study that used data from the National Health Insurance Service-Health Screening cohort database. PATIENT SAMPLEThis study included 318,237 participants who were 50 years or older and with HDL-C levels of 10 to 200 mg/dL. OUTCOMES MEASURESPhysiologic measure—Diagnosis of osteoporotic fracture during the follow-up period. METHODSThe study participants were categorized into four quartiles according to baseline HDL-C levels. The Cox proportional hazards model was used to assess osteoporotic fracture risk according to HDL-C levels. RESULTSAfter full adjustment and with the Q1 group as the reference group, estimates of hazard ratios (HRs; 95% confidence intervals [CIs]) for any osteoporotic fracture in men were 1.03 (0.94–1.12), 1.02 (0.93–1.11), and 1.07 (0.98–1.18) for the Q2, Q3, and Q4 groups, respectively. After classifying osteoporotic fractures according to the body location, the fully adjusted HRs for vertebral and hip fractures in the men's Q4 groups were 1.16 (1.02–1.31) and 0.74 (0.57–0.96), respectively. In women, fully adjusted HRs (95% CIs) of the female Q4 group for any osteoporotic, vertebral, and hip fractures were 1.03 (0.95–1.11), 0.96 (0.86–1.07), and 1.06 (0.80–1.41), respectively. CONCLUSIONIn this study, HDL-C levels were positively associated with vertebral fractures in both men and women but inversely related to hip fractures in men. Therefore, monitoring the lipid profiles of patients with osteoporosis may be beneficial for the prevention of osteoporotic fractures.

Menopausal hormone therapy and breast cancer risk: a population-based cohort study of 1.3 million women in Norway

BackgroundIt is important to monitor the association between menopausal hormone therapy (HT) use and breast cancer (BC) risk with contemporary estimates, and specifically focus on HT types and new drugs.MethodsWe estimated hazard ratios (HR) of BC risk according to HT type, administration route and individual drugs, overall and stratified by body mass index (BMI), molecular subtype and detection mode, with non-HT use as reference.ResultsWe included 1,275,783 women, 45+ years, followed from 2004, for a median of 12.7 years. Oral oestrogen combined with daily progestin was associated with the highest risk of BC (HR 2.42, 95% confidence interval (CI) 2.31–2.54), with drug-specific HRs ranging from Cliovelle®: 1.63 (95% CI 1.35–1.96) to Kliogest®: 2.67 (2.37–3.00). Vaginal oestradiol was not associated with BC risk. HT use was more strongly associated with luminal A cancer (HR 1.97, 95% CI 1.86–2.09) than other molecular subtypes, and more strongly with interval (HR 2.00, 95% CI: 1.83–2.30) than screen-detected (HR 1.33, 95% CI 1.26–1.41) BC in women 50–71 years. HRs for HT use decreased with increasing BMI.ConclusionsThe use of oral and transdermal HT was associated with an increased risk of BC. The associations varied according to HT type, individual drugs, molecular subtype, detection mode and BMI.

Liver Fibrosis Assessed Via Noninvasive Tests Is Associated With Incident Heart Failure in a General Population Cohort

The aim of this study was to determine whether liver fibrosis is associated with heart failure in a general population cohort, and if genetic polymorphisms (PNPLA3 rs738409; TM6SF2 rs58542926), linked to increased risk of liver fibrosis and decreased risk of coronary artery disease, modify this association. Using UK Biobank data, we prospectively examined the relationship between noninvasive fibrosis markers (nonalcoholic fatty liver disease [NAFLD] fibrosis score [NFS], Fibrosis-4 [FIB-4] and aspartate transaminase [AST] to platelet ratio index [APRI]) and incident hospitalization/death from heart failure (n= 413,860). Cox-regression estimated hazard ratios (HRs) for incident heart failure. Effects of PNPLA3 and TM6SF2 on the association between liver fibrosis and heart failure were estimated by stratifying for genotype and testing for an interaction between genotype and liver fibrosis using a likelihood ratio test. A total of 12,527 incident cases of heart failure occurred over a median of 10.7 years. Liver fibrosis was associated with an increased risk of hospitalization or death from heart failure (multivariable adjusted high-risk NFS score HR, 1.59; 95% confidence interval [CI],1.47-1.76; P < .0001; FIB-4 HR, 1.69; 95% CI, 1.55-1.84; P < .0001; APRI HR, 1.85; 95% CI, 1.56-2.19; P < .0001; combined fibrosis scores HR, 1.90; 95% CI, 1.44-2.49; P < .0001). These associations persisted for people with metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD with alcohol consumption (Met-ALD), and harmful alcohol consumption. PNPLA3 rs738409 GG and TM6SF2 rs58542926 TT did not attenuate the positive association between fibrosis markers and heart failure. For PNPLA3, a statistically significant interaction was found between PNPLA3 rs738409, FIB-4, APRI score, and heart failure. In the general population, serum markers of liver fibrosis are associated with increased hospitalization/death from heart failure. Genetic polymorphisms associated with liver fibrosis were not positively associated with elevated heart failure risk.

Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors in improvement of fatty liver index in patients with type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease: A retrospective nationwide claims database study in Japan.

To date, there are limited clinical studies and real-world evidence investigating whether sodium-glucose cotransporter-2 inhibitors (SGLT2i) are associated with improved hepatic steatosis. This study aimed to evaluate the effectiveness of SGLT2i compared with that of dipeptidyl peptidase-4 inhibitors (DPP4i) in improving the fatty liver index (FLI) in patients with type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). This retrospective cohort study included new users of SGLT2i or DPP4i with T2DM and MASLD from a large claims database (JMDC Claims Database). The primary outcome was the incidence of improvement of the FLI. Cox proportional hazard models, weighted using propensity scores for predicting the initiation of treatment, were fitted to estimate hazard ratios with 95% confidence intervals (CIs). Time-course changes in the FLI values were also assessed. This study included 9127 SGLT2i and 12 286 DPP4i initiators. SGLT2i showed a higher incidence of improvement in the FLI (≥30%, ≥40% and ≥50% reduction from baseline FLI) compared with DPP4i, and the weighted hazard ratios were 1.27 (95% CI 1.18-1.38), 1.24 (95% CI 1.13-1.37) and 1.19 (95% CI 1.05-1.33), respectively. SGLT2i indicated a greater decreased in FLI values compared with DPP4i at up to 3 years of the follow-up period. SGLT2is use appeared to be associated with a greater improvement of the FLI than DPP4i use in patients with T2DM and MASLD. In the absence of direct head-to-head comparisons from clinical studies, our study, using real-world data, may support physicians' decision-making in clinical practice.

Abstract PO5-02-11: Is There A Survival Benefit With Adjuvant Chemotherapy Use In Elderly Breast Cancer Patients? A Retrospective Study Using The National Cancer Database

Abstract Background Geriatric patients (Age &amp;gt;=65 years) with Breast Cancer (BC) face a unique challenge due to the relatively lower functional status, as well as co-existing comorbidities. Studies like the recently published meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) group provide irrefutable evidence for the recurrence free survival benefit of anthracycline and taxane based adjuvant chemotherapy (ACT) regimes in early-stage BC patients. However, the age range of the trials analyzed ranged between 46-55 years, with underrepresentation of the geriatric group. The question on whether ACT results in an overall survival (OS) benefit for the elderly remains at large, which we hope to answer through our study. Methods The 2019 National Cancer Database (NCDB) was used to extract patients aged &amp;gt;= 65 years with breast cancer. We included stage 1-3 patients and stratified them into those who received ACT (ACT+) and those who did not (ACT-). Patients who received ACT were identified from the columns that specified the times of events from diagnosis or from the column for systemic therapy-surgery sequence. Patients should have had definitive surgery for their BC management to be included. Odds Ratio (OR) from logistic regression was used to analyze the utility of ACT based on various factors. Kaplan Meier (KM) survival curves and Hazard Ratio (HR) estimates from multivariate cox model was used to compare OS outcomes. Results Our cohort had 866,071 (ACT+: 642721, ACT-:223350) patients. The age distribution showed that ACT+ had 86.45% in the 65-80 years group and 13.55% in the &amp;gt;80 years group. ACT- had 68.32% aged 65-80 and 31.68% &amp;gt;80 years. The distribution of various demographic, pathologic and clinical factors by ACT use are shown in Table 1. Factors associated with ACT use based on OR estimates are shown in Table 2. ACT use is more likely in younger age group (65-80), lower comorbidity score, poorly differentiated and undifferentiated tumors, ER/PR negativity, T2 and lymph node positivity, those who underwent partial mastectomy and regional lymph node surgery, and HER2 positivity. Both 5-year (86.3 vs 74.2%) and 10-year (66 vs 50.8) OS were better with ACT+ (Table 2). The HR using propensity score (PS) weighted cox model revealed a higher hazard rate on omitting ACT [1.436, 95% Confidence Interval (CI) 1.417,1.456, p&amp;lt; .0001] (Table 2). HR estimates between ACT- vs ACT+, stratified by subgroups [Age (65-80, &amp;gt;80), T stage, grade (G), HER2] favored ACT use in all groups except G1 tumors (Table 3). Discussion Our study using a large national database, supports the use of ACT in the geriatric BC population by showing a clear OS advantage of 15.2% at 10 years. This benefit was observed even in BC patients aged more than 80 years with a HR of 1.683 when compared to ACT-, as represented in Table 3. While the existing literature provides robust evidence for ACT use in situations such as a high oncotype recurrence score, our study provides real-world evidence from a population-based dataset to supports its use in the elderly, including those above 80 years. The geriatric assessment recommended by the American Society of Clinical Oncology guideline for geriatric oncology should be followed in this setting. Utilization of geriatric assessment tools among oncologists has been poor with a survey revealing that 60% of providers did not utilize these tools in making treatment decisions. Limitations of our study include the potential for missing confounding factors and the retrospective nature of the study using a large database. Table 1 Demographic, pathological, and clinical characteristics of the study population and their distribution based on ACT use. Table 2 Odds Ratio for ACT use, KM survival curves and HR estimates of ACT use Table 3 HR estimates of mortality for ACT- vs ACT+ stratified by various subgroups Citation Format: Prashanth Ashok Kumar, Metlapalli Venkata Sravanthi, Dongliang Wang, Danning Huang, Abirami Sivapiragasam. Is There A Survival Benefit With Adjuvant Chemotherapy Use In Elderly Breast Cancer Patients? A Retrospective Study Using The National Cancer Database [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 PO5-02-11.

Abstract PO3-22-03: Effect of Radiation Therapy on Survival Outcomes in Elderly ER/PR Positive AJCC Stage T1 Breast Cancer Patients

Abstract Background: The CALGB 9343 study in 2004 reported that women &amp;gt;70 years of age with pT1NO hormone receptor positive breast cancer received no meaningful benefit from breast irradiation following lumpectomy. The effectiveness of adjuvant radiation therapy in node negative, T1 tumor patients has been limited to institutional experiences with relatively lack of information in population-based studies. In this hospital-based study using National Cancer Data Base (NCDB) from 2004 to 2020, we report on adjuvant radiation therapy (XRT) usage and the survival outcomes in stage IA, IB, IC breast cancer patients who received XRT versus those who did not. Materials and Methods: Patients in the National Cancer Database (NCDB) who were registered between 2004 and 2019 and followed up to the end of 2020 were used in this research. We evaluated a cohort of 126,156 female breast cancer patients of age &amp;gt;= 70 years with the American Joint Committee on Cancer (AJCC) stage TIA, TIB, and TIC. All patients were ER/PR positive, received hormonal therapy, all patients were either white or black, were either privately or Medicare insured, received hormonal therapy, and patients were receipt of adjuvant chemotherapy or not. Radiation statuses were grouped as no radiation, radiation only and/or radiation with boost. Other adjusted variables included: age, race, Charlson comorbidity index, payer status, income, education, distance traveled, diagnosing/treating facility, location of treatment and treatment delay. SAS for Windows 9.4 was used for all data management and statistical analysis. Multivariate Cox regression was used to assess the effect of the XRT on overall survival while adjusting for other factors. All p-values &amp;lt; 0.05 or 95% Confidence Limits of Hazards Ratio (HR) does not include 1 were considered statistically significant. Results: Among 126,156 female breast cancer patients, the age distribution was 47.87%, 31.72%, and 20.4% for age group of 70-74, 75-79, 80 or older, respectively. Ninety-three percent of patients were white. 89% of patients were Medicare and 11% were privately insured at diagnosis. 21% of patient were with the Charlson Comorbidity index score 1 or above. 10.77%, 34.42% and 54.81% of patients were AJCC Stage T1A, T1B, and T1C respectively. 11.7% of patients received chemotherapy and 57.9% of patients received radiation therapy. 54.38%, 59.59%, and 57.59% of T1a, T1b, and T1c patients received the XRT, respectively. In univariate analysis, the XRT demonstrated a statistically significant increase of 10-year survival by 9.75%, 9.8%, and 12.6% in T1a, T1b, and T1c (all p &amp;lt; 0.0001) patients respectfully. In multivariate cox regression analysis, age was a predictor of survival outcome with a HR at 1.65, 3.02 for 75-79, and 80 or older as compared to 70-74 years old, respectively. In addition, compared to patients who traveled less than 20 miles, the HR were 0.90 for patients travelled more than 20 miles. AJCC stage was also associated the survival, a HR of 1.05 (95% CI: 1.01-1.186) for T1b, 1.16 (95% CI: 1.11 – 1.21) for T1c as compared for T1a. Adjusting for other factors, the usage of radiation reduced the risk of dying by 25% (HR=0.75, 95% CI: 0.73-0.77) when compared to no radiation therapy. Conclusion: The current study has demonstrated that more than 54% of these patients received radiation therapy. In univariate analysis, the benefit of adjuvant radiation therapy is more than 9.7% for T1a, T1b, and T1c on 10-year overall survival which is statistically significant. Adjusting for other factors, patients receiving radiation therapy in these elderly population have a 25% less chance of dying as compared to no radiation therapy regardless of AJCC Stage. A further propensity score matching method would help assess the effectiveness of radiation therapy on these patients’ population. A randomized prospective clinical trial would be better to define the precise benefit of adjuvant radiation therapy in this elderly population. Table 1 Patients Demographic, Social Economic and Clinical Characteristics XX- XX Table 3 Hazard Ratios estimate from Multivariate Cox Regression XX- XX Radiation Effect on Overall Survival of Elderly Breast Cancer Patients by Stage T1A, T1B, T1C XX- XX Citation Format: Runhua Shi, Gary Burton. Effect of Radiation Therapy on Survival Outcomes in Elderly ER/PR Positive AJCC Stage T1 Breast Cancer Patients [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 PO3-22-03.

Abstract 3035: Associations Of Genetic And Lifestyle Risk Factors With Incident Peripheral Artery Disease: A Prospective Cohort Study

Background: The joint associations between genetic and lifestyle factors, and peripheral artery disease (PAD) remain unclear, yet understanding the connections is crucial for precise PAD prevention. Methods: Genetic susceptibility to PAD was estimated by a polygenic risk score of 50 genetic variants selected by P &lt; 5х10 -8 and r 2 &lt;0.01 from a GWAS including 31,307 cases. Tertiles categorized genetic risk into low, intermediate, and high. A healthy lifestyle score was constructed based on 4 lifestyle factors (never smoking, non-excessive alcohol consumption, high cardiometabolic healthy diet adherence, and regular physical activity) and categorized into favorable (3-4 healthy factors), intermediate (2 healthy factors), and unfavorable (0-1 healthy factors) groups. Cox regression estimated hazard ratios (HR) and 95% confidence interval (CI) with adjustment for age (time scale), sex, BMI, education, baseline cardiovascular risk factors, 20 principal components. Results: Over 11.9 years, 4299 incident PAD cases were diagnosed in 379,228 UK Biobank participants free of baseline PAD. Genetic risk and unhealthy lifestyle categories were monotonically associated with PAD. Compared with low genetic risk, the HR was 1.69 (95% CI 1.56-1.89) for high genetic risk. Compared with favorable lifestyle, the HR for unfavorable lifestyle was 2.70 (95% CI 2.50-2.94). There was no multiplicative interaction between genetic and lifestyle factors ( P = 0.461). The association between unfavorable lifestyle and higher PAD risk was consistent in genetic risk groups. Joint categorization analysis detected an HR for high genetic risk and favorable lifestyle was (1.85, 95% CI 1.54-2.22) reducing by &gt; 50%, compared with high genetic risk and unfavorable lifestyle (HR 4.76, 95% CI 4.00-5.56). Conclusions: Genetic and lifestyle factors independently associated with incident PAD. Adhering to a favorable lifestyle substantially reduced PAD risk, even in individuals at high genetic risk.

Associations between pathological features and risk of metachronous colorectal cancer.

Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer - metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population-based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow-up time of 12 years (incidence: 2.0 per 1000 person-years). CRC cases with a synchronous CRC were 3.4-fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89-5.98) than those without a synchronous tumour. CRC cases with MMR-deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11-2.64) compared to those with MMR-proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06-0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR-deficient.

Risk and predictors of penile cancer in US Veterans with HIV.

People with HIV (PWH) may have an increased burden of penile cancer. We aimed to evaluate the risk of penile cancer in PWH compared with that of the general population. We conducted a nationwide retrospective matched cohort study of penile cancer incidence among veterans with HIV (VWH) compared with veterans without HIV. We compared penile cancer incidence rates in 44 173 VWH to those of veterans without HIV ( N = 159 443; 4 : 1 matched in age). We used Cox regression models to estimate hazard ratios and 95% confidence intervals (CIs) for associations with HIV infection and for penile cancer risk factors. HIV positivity was associated with an increased risk of penile cancer, with adjusted hazard ratios of 2.63 (95% CI 1.64-4.23) when adjusting for age, race/ethnicity, baseline BMI, smoking and alcohol use, economic means test, and history of condyloma. The risk increased to hazard ratio = 4.25 (95% CI 2.75-6.57) when adjusting for all factors except history of condyloma. Risk factors for penile cancer in VWH included lower nadir CD4 + count, less than 50% of follow-up time with undetectable HIV viral load, and history of condyloma. VWH - particularly those with low CD4 + counts, detectable HIV viral loads, or history of condyloma - are at increased risk of penile cancer, suggesting the penile cancer prevention activities are needed in this population.

Remnant cholesterol, LDL cholesterol, and apoB absolute mass changes explain results of the PROMINENT trial

Background and aimsThe PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial. MethodsAmong 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. ResultsIn the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (−0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94–0.99) for a -7 mg/dL (−0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01–1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01–1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96–1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91–1.15) in the PROMINENT trial. ConclusionsAbsolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm.

Evaluating the comparability of osteoporosis treatments using propensity score and negative control outcome methods in UK and Denmark electronic health record databases.

Evidence on the comparative effectiveness of osteoporosis treatments is heterogeneous. This may be attributed to different populations and clinical practice, but also to differing methodologies ensuring comparability of treatment groups before treatment effect estimation and the amount of residual confounding by indication. This study assessed the comparability of denosumab vs oral bisphosphonate (OBP) groups using propensity score (PS) methods and negative control outcome (NCO) analysis. A total of 280 288 women aged ≥50yr initiating denosumab or OBP in 2011-2018 were included from the UK Clinical Practice Research Datalink (CPRD) and the Danish National Registries (DNR). Balance of observed covariates was assessed using absolute standardized mean difference (ASMD) before and after PS weighting, matching, and stratification, with ASMD >0.1 indicating imbalance. Residual confounding was assessed using NCOs with ≥100 events. Hazard ratio (HR) and 95%CI between treatment and NCO were estimated using Cox models. Presence of residual confounding was evaluated with 2 approaches (1) >5% of NCOs with 95% CI excluding 1, (2) >5% of NCOs with an upper CI <0.75 or lower CI >1.3. The number of imbalanced covariates before adjustment (CPRD 22/87; DNR 18/83) decreased, with 2%-11% imbalance remaining after weighting, matching, or stratification. Using approach 1, residual confounding was present for all PS methods in both databases (≥8% of NCOs), except for stratification in DNR (3.8%). Using approach 2, residual confounding was present in CPRD with PS matching (5.3%) and stratification (6.4%), but not with weighting (4.3%). Within DNR, no NCOs had HR estimates with upper or lower CI limits beyond the specified bounds indicating residual confounding for any PS method. Achievement of covariate balance and determination of residual bias were dependent upon several factors including the population under study, PS method, prevalence of NCO, and the threshold indicating residual confounding.

Active and passive smoking and breast cancer in Japan: a pooled analysis of nine population-based cohort studies.

Epidemiological studies have shown inconsistent results regarding the link between smoking and breast cancer risk, despite the biological plausibility of a positive association. Participants were 166 611 women from nine prospective cohort studies in Japan which launched in 1984-1994 and followed for 8-22 years. Information on smoking and secondhand smoke was obtained through self-administered baseline questionnaires. Breast cancer was defined as code C50 according to the International Classification of Diseases for Oncology, 3rd Edition or the International Classification of Diseases, 10th Revision. After adjusting for several potential confounders, relative risks for breast cancer were calculated in the individual studies according to the current or previous status of active and passive smoking using Cox regression, followed by a summary estimate of hazard ratios using random-effects meta-analyses. Of the 60 441 participants who reported being premenopausal and 106 170 who reported being postmenopausal at baseline, 897 and 1168 developed breast cancer during follow-up, respectively. Compared with never smokers, current smokers had a higher risk of developing breast cancer before the age of 50 years. In addition, ever smokers who started smoking at 30 years of age or younger, or who started smoking before first childbirth, had a higher risk of developing breast cancer before the age of 50 years. No association between adulthood or childhood exposure to secondhand smoke and breast cancer was observed. Smoking may increase the risk of premenopausal breast cancer, and smoking earlier in life might be especially harmful. The impact of secondhand smoke needs further investigation.

Augmenting external control arms using Bayesian borrowing: a case study in first-line non-smallcell lung cancer.

Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small-cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using ConcertAI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab+chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR=1.53; 95% CI: 1.21-1.93) than observed in the matched population of the RCT (HR=0.91; 95% CI: 0.73-1.13). The OS HR decreased through the incorporation of BB (HR=1.30; 95% CI: 1.08-1.54, borrowing weight=1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86-1.22, borrowing weight=1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.

Childhood Transitions Between Weight Status Categories: Evidence from the UK Millennium Cohort Study.

Assessing the cost-effectiveness of interventions targeting childhood excess weight requires estimates of the hazards of transitioning between weight status categories. Current estimates are based on studies characterized by insufficient sample sizes, a lack of national representativeness, and untested assumptions. We sought to (1) estimate transition probabilities and hazard ratios for transitioning between childhood weight status categories, (2) test the validity of the underlying assumption in the literature that transitions between childhood bodyweight categories are time-homogeneous, (3) account for complex sampling procedures when deriving nationally representative transition estimates, and (4) explore the impact of child, maternal, and sociodemographic characteristics. We applied a multistate transition modeling approach accounting for complex survey design to UK Millennium Cohort Study (MCS) data to predict transition probabilities and hazard ratios for weight status movements for children aged 3-17. Surveys were conducted at ages 3 (wave 2 in 2004), 5 (wave 3 in 2006), 7 (wave 4 in 2008), 11 (wave 5 in 2012), 14 (wave 6 in 2015), and 17 (wave 7 in 2018) years. We derived datasets that included repeated body mass index measurements across waves after excluding multiple births and children with missing or implausible bodyweight records. To account for the stratified cluster sample design of the MCS, we incorporated survey weights and jackknife replicates of survey weights. Using a validation dataset from the MCS, we tested the validity of our models. Finally, we estimated the relationships between state transitions and child, maternal, and sociodemographic factors. The datasets for our primary analysis consisted of 10,399 children for waves 2-3, 10,729 for waves 3-4, 9685 for waves 4-5, 8593 for waves 5-6, and 7085 for waves 6-7. All datasets consisted of roughly equal splits of boys and girls. Under the assumption of time-heterogeneous transition rates (our base-case model), younger children (ages 3-5 and 5-7 years) had significantly higher annual transition probabilities of moving from healthy weight to overweight (0.033, 95% confidence interval [CI] 0.026-0.041, and 0.027, 95% CI 0.021-0.033, respectively) compared to older children (0.015, 95% CI 0.012-0.018, at ages 7-11; 0.018, 95% CI 0.013-0.023, at ages 11-14; and 0.018, 95% CI 0.013-0.025 at ages 14-17 years). However, the resolution of unhealthy weight was more strongly age-dependent than transitions from healthy weight to non-healthy weight states. Transition hazards differed by child, maternal, and sociodemographic factors. Our models generated estimates of bodyweight status transitions in a representative UK childhood population. Compared to our scenario models (i.e., time-homogeneous transition rates), our base-case model fits the observed data best, indicating a non-time-homogeneous pattern in transitions between bodyweight categories during childhood. Transition hazards varied significantly by age and across subpopulations, suggesting that conducting subgroup-specific cost-effectiveness analyses of childhood weight management interventions will optimize decision-making.

Poorer Outcomes in Bladder Cancer Patients With Diabetes: A Systematic Review and Meta-analysis Addressing Over 226,472 Bladder Cancer Patients

Purpose: Diabetes mellitus, a frequent comorbid condition in cancer patients, has been shown to increase risk of all-site cancer mortality. This relationship has not been systematically studied in bladder cancer patients. This systematic review and meta-analysis aimed to identify, evaluate, and synthesize available evidence on the relationship between history of diabetes and outcomes in bladder cancer patients.Materials and Methods: Systematic searches interrogated OVID MEDLINE, Embase, Web of Science, Google Scholar, and Cochrane Library to identify scholarly reports relating diabetes to all-cause mortality, bladder cancer-specific mortality, recurrence, and progression in bladder cancer patients. After critical review, meta-analysis was used to quantitively synthesize qualifying data and assess potential influence of publication bias, clinical heterogeneity, and residual confounding.Results: We synthesized data on over 226,472 patients treated with curative intent uniquely represented in 28 studies that met quality metrics. Having diabetes was positively associated with each outcome. Hazard ratio estimates were indistinguishable for mortality from any cause, 1.22 (95% confidence interval [CI], 1.12–1.33) and bladder cancer-specific mortality, 1.28 (95% CI 1.17–1.41) and notably stronger in patients with muscle-invasive and high-risk non–muscle-invasive bladder cancer, 1.32 (95% CI, 1.15–1.50) and 1.48 (95% CI, 1.06–2.06). Neither publication bias, systematic error, nor confounding by factors such as smoking or obesity is likely to explain the observed associations.Conclusions: Bladder cancer patients with diabetes experience elevated mortality that is not explained by diabetes-related comorbidities or complications. Future research should explore type, severity, and duration of diabetes in relation to unfavorable bladder cancer outcomes.

Prognostic impact of positive microscopic margins (R1 resection) in patients with GIST (gastrointestinal stromal tumours): Results of a multicenter European study

BackgroundAlthough several prognostic factors in GIST have been well studied such as tumour size, mitotic rate, or localization, the influence of microscopic margins or R1 resection remains controversial. The aim of this study was to evaluate the influence of R1 resection on the prognosis of GIST in a large multicentre retrospective series of patients. MethodsFrom 2001 to 2013, 1413 patients who underwent surgery for any site of GIST were identified from 61 European centers. 1098 patients were included, excluding synchronous metastases, concurrent malignancies, R2 resection or GIST recurrence. Tumour rupture (TR) was reclassified according to the Oslo sarcoma classification. Cox proportional hazards ratio and Kaplan-Meier survival estimates were used to analyse 5-year recurrence-free survival (RFS). ResultsOf 1098 patients, 38 (3%) underwent R1 resection with a risk of TR of 11%. The 5-year RFS was 89.6% with a median follow-up of 81 months [range: 31.2–152 months]. On univariate analysis, lower RFS was significantly associated with R1 resection [HR = 2.13; p = 0.04], high risk score according to the modified NIH classification, administration of adjuvant therapy [HR = 2.24; p < 0.001] and intraoperative complications [HR = 2.82; p < 0.001]. Only intraoperative complications [HR = 1.79; p = 0.02] and high risk according to the modified NIH classification including the updated definition of TR [HR = 3.43; p = 0.04] remained significant on multivariate analysis. ConclusionThis study shows that positive microscopic margins are not an independent predictive factor for RFS in GIST when taking into account the up-dated classification of TR. R1 resection may be considered a reasonable alternative to avoid major functional sequelae and should not lead to reoperation.

Comparing major and mild cognitive impairment risks in older type-2 diabetic patients: a Danish register-based study on dipeptidyl peptidase-4 inhibitors vs. glucagon-like peptide-1 analogues

IntroductionThe prevalence of major and mild cognitive impairment (CI) in type-2 diabetes older patients is 15–25% and 30–60%, respectively, thus affecting quality of life and health outcomes. There is, therefore, the need of head-to-head studies aiming at identifying the optimal treatment for individuals with type-2 diabetes at increased risk of mild and major CI. This study focuses on the risk of developing mild and major CI in Danish patients treated with dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 analogues (GLP-1a) using administrative and healthcare registers.MethodsAn active comparator design with a 3-year follow-up period was used. The main outcome was the hospital admission with a diagnosis of mild CI or major CI. Multivariate Cox Regression analysis was performed using the high-dimensional propensity score to obtain adjusted Hazard Ratio (HR) estimates. Inverse probability of treatment weighting (IPTW) and marginal structured model were used to calculate risk differences while accounting for the variations of confounders throughout the follow-up period.ResultsOur results show a significant higher risk of major CI between DPP-4i and GLP-1a in unadjusted [HR (95% CI) = 3.13 (2.45–4.00), p < 0.001] and adjusted analyses [HR (95% CI) = 1.58 (1.22–2.06), p = 0.001]. No statistically significant differences were observed for mild CI. IPTW resulted stable throughout the follow-up period. Marginal structure modeling (β (95% CI) = 0.022 (0.020–0.024), p < 0.001) resulted in a higher risk of major CI for DPP-4i when compared to GLP-1a.DiscussionDPP-4i was associated with an increased risk of developing major CI when compared to GLP-1a among older individuals with type-2 diabetes.

Abstract 3407: Physical activity and post-menopausal breast cancer in the Multiethnic Cohort Study

Abstract Much research has been conducted on the relationship between physical activity and breast cancer, with meta-analyses showing 10 – 21% reduction in breast cancer risk for postmenopausal women with high compared to low level of physical activity. However, few studies have explored this relationship in non-Caucasian women. We analyzed data from 74,177 post-menopausal African American, Caucasian, Japanese American, Latina, and Native Hawaiian women in the Multiethnic Cohort in Hawaii and California. Data on physical activity (hours and metabolic equivalents (METs)) was based on a self-administered questionnaire at baseline (1993–1996). Multivariate Cox proportional hazards models provided estimates of hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for risk factors. We observed no associations between breast cancer risk and hours of moderate/vigorous activity per week (HR=1.01, 95% CI: 0.91-1.10, Ptrend=0.71), MET-hours of moderate/vigorous activity per week (HR=1.03, 95% CI: 0.94-1.13, Ptrend=0.92), and total METs-measured as average MET level per day multiplied by 7 (HR=0.94, 95% CI: 0.86-1.03, Ptrend=0.37) when comparing the highest quartile to the lowest. When examining the data across race/ethnicity, we observed a reduction in risk of breast cancer for total METs (HR=0.75, 95% CI: 0.61-0.94, Ptrend=0.05) among Latina women. Analysis across strata of BMI showed no differences across subgroups. In this study, we did not observe any consistent protective association between physical activity and breast cancer risk. Citation Format: Jasmeet K. Gill, Gertraud Maskarinec, Song-Yi Park, Lynne Wilkens, Loic Le Marchand. Physical activity and post-menopausal breast cancer in the Multiethnic Cohort Study [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 3407.