Cox Proportional Hazard Ratios Research Articles

Chlorhexidine gluconate pocket lavage to prevent cardiac implantable electronic device infection in high-risk procedures

Infection is the most dreaded complication of cardiac implantable electronic devices (CIEDs), particularly in patients undergoing high-risk procedures (eg, generator change, device upgrade, lead/pocket revision). The purpose of this study was to describe the impact of chlorhexidine gluconate (CHG) pocket lavage in high-risk procedures. Patients from a prospective multicenter registry undergoing high-risk procedures were included. CHG lavage was performed by irrigating the generator pocket with 20 cc of 2% CHG without alcohol followed by and normal saline (NS) irrigation. Only NS irrigation was performed in the comparison group. The primary efficacy outcome was CIED-related infection at 12 months. The primary safety outcome was any CHG-associated adverse event. The secondary outcome was CIED infection during long-term follow-up. Propensity score matching (PSM) analysis was performed for the primary efficacy outcome. A total of 1504 patients were included. At 12-month follow-up, the primary efficacy outcome occurred in 4 of 904 CHG (0.4%) and 14 of 600 NS (2.3%) subjects (log-rank P = .005). On multivariate analysis, the use of CHG irrigation was associated with a lower risk of infection at 1-year follow-up (Cox proportional hazard ratio [HR] 0.138; 95% confidence interval [CI] 0.04-0.45; P= .001). This effect persisted during long-term follow-up. PSM demonstrated a significant reduction in CIED-related infection for the CHG group (0.2% vs 2.5%; Cox proportional HR 0.08; 95% CI 0.01-0.59; P = .014). No adverse events were associated with the use of CHG. CHG lavage during high-risk procedures was associated with a reduction in CIED-related infections without any adverse events reported. The benefits of CHG lavage were observed even during long-term follow up and in PSM analysis.

Exclusive waterpipe smoking and the risk of nasopharynx cancer in Vietnamese men, a prospective cohort study

Tobacco smoking is carcinogenic to humans. Besides cigarettes, the most common form of tobacco smoking, there was sparse evidence of waterpipe’s carcinogenicity-induced nasopharyngeal cancer (NPC). This study investigated the association between waterpipe smoking and NPC mortality. Our study followed up with 20,144 eligible man participants from nine northern Vietnam communes between 2007 and 2019. Face-to-face interviews were conducted to gather data on exclusive waterpipe and cigarette smoking and dietary intake using structured semi-quantitative food frequency and lifestyle questionnaires. Nasopharyngeal cancer was determined by accessing the medical records at the state health facilities. We estimated the Cox proportional hazard ratio and 95% confidence intervals, HR (95% CI). The proportion of never smokers, exclusive waterpipe, exclusive cigarette, and dual waterpipe and cigarette smokers was 55.8%, 14.5%, 16.6%, and 13.1%, respectively. Exclusively waterpipe smokers increased the risk of NPC death compared to exclusively cigarette smokers, HR (95% CI): 4.51 (1.25, 16.31), p = 0.022. A dose-dependent positive relationship between NPC and exclusive waterpipe smoking was significantly seen for higher intensity HR (95% CI): 1.35 (1.07, 1.71), earlier age of smoking initiation HR (95% CI): 1.26 (1.06, 1.50), longer duration HR (95% CI): 1.31 (1.04, 1.66), and the cumulative number of a smoke lifetime HR (95% CI): 1.37 (1.08, 1.74). We observed a significant positive association between exclusive waterpipe smoking and NPC in men. The findings suggested that waterpipe smoking is likely more harmful than cigarettes in developing this cancer. A firm tobacco control against waterpipe smoking is highly recommended.

TIPS-23 SAFETY AND FEASIBILITY RESULTS FROM A PHASE 1/2 CLINICAL TRIAL OF RHENIUM (186RE) OBISBEMEDA (186RNL) IN RECURRENT GLIOMA: THE RESPECT-GBM TRIAL

Abstract OBJECTIVES 186RNL is BMEDA-chelated 186Re encapsulated in nanoliposomes. 186Re’s ~2 mm beta emission path length provides direct delivery of radiation therapy while sparing surrounding healthy tissue. 186RNL is delivered via convection enhanced delivery (CED) to achieve durable, localized tumor retention with high absorbed radiation doses. We present results from our ongoing ReSPECT-GBM trials (NCT01906385). METHODS ReSPECT-GBM is a multi-center, sequential cohort, open-label, dose escalation, Phase 1/2 clinical trial in adults with recurrent glioma to evaluate the safety, tolerability, and activity of a single dose of 186RNL administered by CED. Following computer-assisted MRI guidance treatment planning for CED catheter placement, patients received a single administration of 186RNL before whole body planar and SPECT/CT imaging for dosimetry and distribution. Patients were followed for safety, progression, and survival. RESULTS 25 patients across 8 dosing cohorts including 23 with recurrent GBM were treated with a single dose of 186RNL ranging from 1.0-41.5mCi. Average absorbed radiation dose (AARD) to the tumor was ~300 Gy over a wide range. Exposure outside the brain was negligible. A single dose of 186RNL was well-tolerated, with no dose limiting toxicities. No patient had treatment-related death or withdrawals and most AEs mild or moderate (Grade 1 or 2) and non-serious. 5 patients remain alive. mOS for all patients was >12 months, with an OS30 of 25% overall and 50% for those receiving >100Gy. Cox Proportional Hazards Ratio and Accelerated Failure Time modeling both demonstrate absorbed dose and percent tumor treated to significantly correlate with overall survival (p<0.003-0.0001). Five patients have subsequently enrolled in Phase 2 and all are alive. CONCLUSION A single dose of 186RNL in recurrent glioma patients achieves high absorbed doses without significant toxicity, is well tolerated, and shows favorable OS. Cohort 8 and Phase 2 continue enrolling. Development progress and data will be reported.

Frailty in relation to the risk of carotid atherosclerosis and cardiovascular events in Chinese community-dwelling older adults: A five-year prospective cohort study

ObjectiveTo investigate the frailty, as estimated by accumulated health deficits, in association with the symptomatic carotid atherosclerosis and in relation to five-year cardiovascular (CVD) outcomes. MethodsThis is a five-year prospective cohort study. Secondary analysis of data from the Beijing Longitudinal Study on Aging. Community-dwelling people aged 55+ years (n = 1257) have been followed between 2009 and 2014, and having carotid ultrasonography examinations with no CVD events at baseline. Frailty was quantified using the deficit accumulation-based frailty index (FI), constructed from 37 health deficits assessed at baseline. The association between the degree of frailty and carotid atherosclerosis was examined using odds ratios (OR) with multivariate logistic regression analyses. Effects of frailty on the probability of five-year cardiovascular events and mortality were evaluated using Cox proportional hazard ratios (HR). The analyses were adjusted for demographics, baseline carotid atherosclerosis status, and CVD risk factors. ResultsThe FI showed characteristic properties and was independently associated with the major carotid atherosclerosis symptoms, including carotid artery intima-media thickening (the most frail vs. the least frail: OR = 4.39: 1.98–7.82), carotid plaque (OR = 3.41: 1.28–6.54), and carotid plaque stability (OR = 1.19, 95 % CI: 1.01–3.59). Compared with the least frail, the most frail individuals were more likely to develop a cardiovascular event in five years, including myocardial infarction (HR = 3.38, 95 % CI = 1.84–6.19), stroke (HR = 1.26, 95 % CI = 1.00–5.87), CVD death (HR = 6.33, 95 % CI = 1.69–11.02), and all-cause death (HR = 5.95, 95 % CI = 2.74–8.95). ConclusionDeficit accumulation was closely associated with carotid atherosclerosis risks and strongly predicted five-year CVD events. The frailty index can be used to help identify older adults at high risks of CVD for improved preventive healthcare.

Clinical course of hypertrophic cardiomyopathy patients implanted with a transvenous or subcutaneous defibrillator.

The implantable cardioverter-defibrillator (ICD) is a life-saving therapy in patients with hypertrophic cardiomyopathy (HCM) at risk of sudden cardiac death. Implantable cardioverter-defibrillator complications are of concern. The subcutaneous ICD (S-ICD) does not use transvenous leads and is expected to reduce complications. However, it does not provide bradycardia and anti-tachycardia pacing (ATP). The aim of this study was to compare appropriate and inappropriate ICD interventions, complications, disease-related adverse events and mortality between HCM patients implanted with a S- or transvenous (TV)-ICD. Consecutive HCM patients implanted with a S- (n = 216) or TV-ICD (n = 211) were enrolled. Propensity-adjusted cumulative Kaplan-Meier curves and multivariate Cox proportional hazard ratios were used to compare 5-year event-free survival and the risk of events. The S-ICD patients had lower 5-year risk of appropriate (HR: 0.32; 95%CI: 0.15-0.65; P = 0.002) and inappropriate (HR: 0.44; 95%CI: 0.20-0.95; P = 0.038) ICD interventions, driven by a high incidence of ATP therapy in the TV-ICD group. The S- and TV-ICD patients experienced similar 5-year rate of device-related complications, albeit the risk of major lead-related complications was lower in S-ICD patients (HR: 0.17; 95%CI: 0.038-0.79; P = 0.023). The TV- and S-ICD patients displayed similar risk of disease-related complications (HR: 0.64; 95%CI: 0.27-1.52; P = 0.309) and mortality (HR: 0.74; 95%CI: 0.29-1.87; P = 0.521). Hypertrophic cardiomyopathy patients implanted with a S-ICD had lower 5-year risk of appropriate and inappropriate ICD therapies as well as of major lead-related complications as compared to those implanted with a TV-ICD. Long-term comparative follow-up studies will clarify whether the lower incidence of major lead-related complications will translate into a morbidity or survival benefit.

Does Time to Initiation of Adjuvant Radiotherapy Affect Reconstruction Outcomes after Endoscopic Resection of Skull Base Malignancies?

Introduction and Objective It is unclear if the length of the time interval to initiation of adjuvant radiation therapy (RT) after endoscopic endonasal surgery affects reconstruction outcomes. In this study we present our experience with adjuvant RT after endoscopic endonasal procedures, to determine if the time to RT after surgery impacts post-RT reconstruction complication rates. Methods A retrospective cohort study of 164 patients who underwent endoscopic endonasal surgery between 1998 and 2021 was conducted. Using Cox proportional hazard ratios (HRs), we evaluated several variables and the complications that occurred during the 1-year period after starting RT. Results Seventy-eight (47.5%) and eighty-six patients (52.5%) received RT before and after the sixth postoperative week, respectively. The overall post-RT complication rates were 28%, most of these were severe infections ( n = 20, 12.2%) and delayed CSF leak ( n = 4, 2.5%). There was no significant difference in the post-RT complications between the patients who received postoperative RT before or after the sixth operative week (HR: 1.13; 95% confidence interval: 0.63-2.02; p = 0.675 ). Univariate analysis demonstrated negative impact associated with smoking history ( p = 0.015 ), the use of neoadjuvant chemotherapy ( p = 0.0001 ), and the use of photon therapy ( p = 0.012 ); and we found a positive impact with the use of multilayer reconstruction techniques (overall, p = 0.041 ; with fat, p = 0.038 ; and/or fascia graft, p = 0.035 ). After a multivariate analysis only, smoking history was an independent risk factor for post-RT complications ( p = 0.012 ). Conclusion Delaying RT for more than 6 weeks after endoscopic endonasal surgery does not provide a significant benefit for reconstruction outcomes. However, special attention may be warranted in patients with smoking history who have received neoadjuvant chemotherapy, or in patients who will receive photon-based RT after surgery as these groups were found to have increased complication rates post-RT.

Association of Renin-Angiotensin System Inhibition With Liver-Related Events and Mortality in Compensated Cirrhosis

While renin-angiotensin system inhibition lowers the hepatic venous gradient, the effect on more clinically meaningful endpoints is less studied. We aimed to quantify the relationship between renin-angiotensin system inhibition and liver-related events (LREs) among adults with compensated cirrhosis. In this national cohort study using the Optum database, we quantified the association between angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) use and LREs (hepatocellular carcinoma, liver transplantation, ascites, hepatic encephalopathy, or variceal bleeding) among patients with cirrhosis between 2009 and 2019. Selective beta-blocker (SBB) users served as the comparator group. We used demographic and clinical features to calculate inverse-probability treatment weighting-weighted cumulative incidences, absolute risk differences, and Cox proportional hazard ratios. Among 4214 adults with cirrhosis, 3155 were ACE inhibitor/ARB users and 1059 were SBB users. In inverse probability treatment weighting-weighted analyses, ACE inhibitor/ARB (vs SBB) users had lower 5-year cumulative incidence (30.6% [95% confidence interval (CI), 27.8% to 33.2%] vs 41.3% [95% CI, 34.0% to 47.7%]; absolute risk difference,-10.7% [95% CI, -18.1% to -3.6%]) and lower risk of LREs (adjusted hazard ratio [aHR], 0.69; 95% CI, 0.60 to 0.80). There was a dose-response relationship: compared with SBB use, ACE inhibitor/ARB prescriptions ≥1 defined daily dose (aHR, 0.65; 95% CI, 0.56 to 0.76) were associated with a greater risk reduction compared with <1 defined daily dose (aHR, 0.87; 95% CI, 0.71 to 1.07). Results were robust across sensitivity analyses such as comparing ACE inhibitor/ARB users with nonusers and as-treated analysis. In this national cohort study, ACE inhibitor/ARB use was associated with significantly lower risk of LREs in patients with compensated cirrhosis. These results provide support for a randomized clinical trial to confirm clinical benefit.

The Efficacy of Ramelteon to Prevent Postoperative Delirium After General Anesthesia in the Elderly: A Double-Blind, Randomized, Placebo-Controlled Trial

Postoperative delirium is common and serious in elderly patients. Several drugs have been proposed as potential prophylactic agents for postoperative delirium. Studies on melatonin receptor agonists showed heterogeneity in age, cognitive function, anesthesia, surgery, interventions, methodologies for assessing outcomes, and results. Our objective was to examine the effect of ramelteon to prevent postoperative delirium in elderly patients, including those with dementia. A stratified, double-blind, randomized, placebo-controlled trial (UMIN000028436, jRCTs031180054). Tertiary medical center. Patients aged older than or equal to 65 years undergoing elective surgery under general anesthesia. Ramelteon (8 mg orally) or placebo (lactose) for six nights (the preoperative night and five consecutive nights from postoperative day 1 to 5) at around 9 P.M. Patients were screened for postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit twice daily until the sixth postoperative day. Patients with positive results were referred to a consultant psychiatrist to establish the diagnosis of delirium. A total of 108 patients were randomly assigned to receive ramelteon (n=55) or placebo (n=53). Most of the patients' characteristics were reasonably well-balanced between the two groups. The stratified log-rank test showed no significant difference in preventing postoperative delirium between ramelteon and placebo (χ2=0.30, degrees of freedom=1, p=0.60). The Cox proportional hazard ratio for ramelteon compared to placebo was 1.40 (95% confidence interval: 0.40-4.85, χ2 for likelihood ratio test=0.29, degrees of freedom=1, p=0.60). There was no significant difference in the incidence of postoperative delirium between ramelteon and placebo after general anesthesia in elderly patients.

Treatment outcomes among children admitted stabilization centers in Eastern Ethiopia: retrospective study.

There is improved access to Sever Acute Malnutrition management in Ethiopia; however, studies have revealed an alarming rate of defaulters' poor recovery and deaths, emphasizing the importance of researching to identify major causes. As a result, the goal of this research is to identify treatment outcome determinants and associated factors in severely malnourished children aged 6-59 months admitted to public hospitals in Eastern Ethiopia's stabilization centers. This study used an institutional-based retrospective cohort study design with 712 children aged 6 to 59 months. Data was gathered using a Sever Acute Malnutrition registration logbook and patient charts. Participants were chosen at random from their respective healthcare facilities based on population proportion. Epi-data was entered and analyzed using STATA version 14. To identify associated factors, the Cox proportional hazard Ratio was calculated, and a p-value of 0.05 at the 95% confidence interval was considered statistically significant. This study revealed that only 70.65% (95% CI = 67.19, 73.88) of the children were cured while 17.84% defaulted from the management and 5.90% died. Children who did not have tuberculosis (AHR = 1.58, 95%CI:1.04, 2.40), anemia (AHR = 1.31, 95% CI:1.03, 1.68), Kwash dermatosis (AHR = 1.41, 95%CI:1.04, 1.91), or on NG-tube (AHR = 1.71, 95%CI:1.41, 2.08) were more likely to be cured from SAM. This study discovered that the cure rate is extremely low and the defaulter rate is extremely high. As a result, intervention modalities that address the identified factor are strongly recommended to accelerate the rate of recovery in Eastern Ethiopia.

Increasing melanoma incidence and survival trend shifts with improved melanoma-specific survival between 1990and 2020 in Sweden.

Melanoma-specific survival (MSS) is heterogenous between stages and is highly dependent on the T stage for primary localized disease. New systemic therapies for metastatic cutaneous melanoma (CM) have been introduced since 2012 in Sweden. To analyse the incidence and MSS time trends between 1990 and 2020 in Sweden. Nationwide, population-based and prospectively collected clinico-pathological data on invasive CM from the Swedish Melanoma Registry (SweMR) were analysed for survival trends between 1990 and 2020 using Kaplan-Meier curves and Cox proportional hazard ratios (HRs). In total, 77 036 primary invasive CMs were diagnosed in 70 511 patients in Sweden between 1990 and 2020. The 5-year MSS [95% confidence interval (CI)] was 88.9% (88.3-89.4) for 1990-2000, 89.2% (88.7-89.6) for 2001-2010 and 93.0% (92.7-93.9) for 2011-2020. The odds ratios for being diagnosed with nodular melanoma (vs. superficial spreading melanoma) was significantly reduced by 20% (2001-2010) and by 46% (2011-2020)vs. the reference period 1990-2000. Overall, the MSS improved over both diagnostic periods (2001-2010 and 2011-2020) vs. the reference period 1990-2000 among men and women, respectively [HRmen: 2001-2010: 0.89 (95% CI 0.82-0.96) and 2011-2020: 0.62 (95% CI 0.56-0.67); HRwomen: 2001-2010: 0.82 (95% CI 0.74-0.91) and 2011-2020: 0.62 (95% CI 0.56-0.70)]. The risk of death from CM was significantly lower in all age groups for both men and women in the most recent diagnostic period (2011-2020 vs.1990-2000). The results emphasize the improved MSS among men and women in Sweden. The MSS improvements, specifically for the period 2011-2020, may be correlated to the introduction of new systemic therapies and are here shown for the first time in detail for Sweden.

Evaluating Disparities in Colon Cancer Survival in American Indian/Alaskan Native Patients Using the National Cancer Database.

Studies demonstrate higher mortality rates from colon cancer in American Indian/Alaskan Native (AI/AN) patients compared to non-Hispanic White (nHW). We aim to identify factors that contribute to survival disparities. We used the National Cancer Database to identify AI/AN (n = 2127) and nHW (n = 527,045) patients with stage I-IV colon cancer from 2004 to 2016. Overall survival among stage I-IV colon cancer patients was estimated by Kaplan-Meier analysis; Cox proportional hazard ratios were used to identify independent predictors of survival. AI/AN patients with stage I-III disease had significantly shorter median survival than nHW (73 vs 77months, respectively; p < 0.001); there were no differences in survival for stage IV. Adjusted analyses demonstrated that AI/AN race was an independent predictor of higher overall mortality compared to nHW (HR 1.19, 95% CI 1.01-1.33, p = 0.002). Importantly, compared to nHW, AI/AN were younger, had more comorbidities, had greater rurality, had more left-sided colon cancers, had higher stage but lower grade tumors, were less frequently treated at an academic facility, were more likely to experience a delay in initiation of chemotherapy, and were less likely to receive adjuvant chemotherapy for stage III disease. We found no differences in sex, receipt of surgery, or adequacy of lymph node dissection. We found patient, tumor, and treatment factors that potentially contribute to worse survival rates observed in AI/AN colon cancer patients. Limitations include the heterogeneity of AI/AN patients and the use of overall survival as an endpoint. Additional studies are needed to implement strategies to eliminate disparities.

How are hearing loss and physical activity related? Analysis from the English longitudinal study of ageing

Although cross-sectional studies suggest that hearing loss in middle- and older-aged adults is associated with lower physical activity, longitudinal evidence is limited. This study aimed to investigate the potential bi-directional association between hearing loss and physical activity over time. Participants were from the English Longitudinal Study of Ageing (N = 11,292) who were 50-years or older at baseline assessment (1998–2000). Individuals were followed-up biannually for up to 20-years (2018–2019) and were classified as ever reporting hearing loss (n = 4946) or not reporting hearing loss (n = 6346). Data were analysed with Cox-proportional hazard ratios and multilevel logistic regression. The results showed that baseline physical activity was not associated with hearing loss over the follow-up. Time (i.e., wave of assessment) by hearing loss interactions showed that physical activity declined more rapidly over time in those with hearing loss, compared to those without (Odds Ratios = 0.94, 95% Confidence Intervals; 0.92–0.96, p < .001). These findings highlight the importance of addressing physical activity in middle- and older-aged adults with hearing loss. As physical activity is a modifiable behaviour that can reduce the risk of developing chronic health conditions, individuals with hearing loss may need additional, tailored support to be more physically active. Mitigating the decline in physical activity could be essential to support healthy ageing for adults with hearing loss.

Survival From Birth Until Young Adulthood Among Individuals With Congenital Heart Defects: CH STRONG.

Limited population-based information is available on long-term survival of US individuals with congenital heart defects (CHDs). Therefore, we assessed patterns in survival from birth until young adulthood (ie, 35 years of age) and associated factors among a population-based sample of US individuals with CHDs. Individuals born between 1980 and 1997 with CHDs identified in 3 US birth defect surveillance systems were linked to death records through 2015 to identify those deceased and the year of their death. Kaplan-Meier survival curves, adjusted risk ratios (aRRs) for infant mortality (ie, death during the first year of life), and Cox proportional hazard ratios for survival after the first year of life (aHRs) were used to estimate the probability of survival and associated factors. Standardized mortality ratios compared infant mortality, >1-year mortality, >10-year mortality, and >20-year mortality among individuals with CHDs with general population estimates. Among 11 695 individuals with CHDs, the probability of survival to 35 years of age was 81.4% overall, 86.5% among those without co-occurring noncardiac anomalies, and 92.8% among those who survived the first year of life. Characteristics associated with both infant mortality and reduced survival after the first year of life, respectively, included severe CHDs (aRR=4.08; aHR=3.18), genetic syndromes (aRR=1.83; aHR=3.06) or other noncardiac anomalies (aRR=1.54; aHR=2.53), low birth weight (aRR=1.70; aHR=1.29), and Hispanic (aRR=1.27; aHR=1.42) or non-Hispanic Black (aRR=1.43; aHR=1.80) maternal race and ethnicity. Individuals with CHDs had higher infant mortality (standardized mortality ratio=10.17), >1-year mortality (standardized mortality ratio=3.29), and >10-year and >20-year mortality (both standardized mortality ratios ≈1.5) than the general population; however, after excluding those with noncardiac anomalies, >1-year mortality for those with nonsevere CHDs and >10-year and >20-year mortality for those with any CHD were similar to the general population. Eight in 10 individuals with CHDs born between1980 and 1997 survived to 35 years of age, with disparities by CHD severity, noncardiac anomalies, birth weight, and maternal race and ethnicity. Among individuals without noncardiac anomalies, those with nonsevere CHDs experienced similar mortality between 1 and 35 years of age as in the general population, and those with any CHD experienced similar mortality between 10 and 35 years of age as in the general population.

Survival analysis: A primer

Abstract Survival analysis is an important time-bound statistical tool used in medical research to gather valuable insights into outcomes, treatment efficacy, and disease progression. This tool employs various models to run the data such as Cox proportional hazards ratio, life tables, Kaplan–Meier estimates among others. This write-up highlights various survival analysis techniques that are used to estimate time to event in research. This article provides insights into the general concepts and a few important tools of survival analytics to the readers.

Evaluation of total tumor volume reduction ratio in initially unresectable colorectal liver metastases after first-line systemic treatment

PurposeTotal tumor volume (TTV) may play an essential role in the estimation of tumor burden. This study is aimed to investigate the clinical value of the reduction ratio of TTV as a valuable indicator of clinical outcomes in patients with colorectal liver metastases (CRLM). MethodsA total of 240 initially unresectable CRLM patients who underwent first-line systemic treatment were enrolled in this study. TTV at baseline and at the end of first-line treatment were assessed using a three-dimensional reconstruction system according to CT or MRI images. Survival was evaluated using Kaplan-Meier analysis and compared using Cox proportional hazard ratios (HR). ResultsA total of 212 (88.3%) patients achieved tumor regression with a median reduction ratio of TTV of 86.0%. An increasing reduction ratio of TTV was associated with a gradually ascending successful conversion outcome. Patients with a reduction ratio >86.0% had better survival than those with a reduction ratio 0–86.0% or <0 (5-year overall survival (OS) rates, 64.4% vs. 44.9% vs. 23.5%, P < 0.001; 5-year progression-free survival (PFS) rates, 36.3% vs. 28.2% vs. 6.5%, P < 0.001). Multivariate analysis indicated that the reduction ratio of TTV ≤ 86.0% (OR [95%CI]: 4.956 [2.654–9.253], P < 0.001) was an independent factor for conversion failure outcome. Cox analyses revealed that the reduction ratio of TTV ≤ 86.0% was an independent factor for both unfavorable OS (HR [95%CI]: 2.216 [1.332–3.688], P = 0.002) and PFS (HR [95%CI]: 2.023 [1.376–2.974], P < 0.001). ConclusionsThe reduction ratio of TTV was an effective indicator for conversion outcome and long-term prognosis in patients with initially unresectable CRLM after first-line systemic treatment.

207-LB: Association of Metformin Use with Primary Open-Angle Glaucoma among Patients with Diabetes Mellitus Using Data from the National Institutes of Health All of Us Program

Purpose: To examine the association between metformin use and the incidence of primary open-angle glaucoma (POAG) in a nationwide cohort of patients with diabetes mellitus. Methods: The National Institutes of Health All of Us Research Program represents a nationwide effort to recruit a diverse participant pool through the inclusion of historically excluded and underrepresented populations. We conducted a retrospective cohort analysis of 18,440 participants in the All of Us database aged 40 years or older, with a diagnosis of diabetes mellitus and without a diagnosis of POAG prior to diabetes diagnosis or metformin use. Bivariate logistic regression, multivariable logistic regression, and survival analysis were used to analyze the association between metformin use and incidence of POAG based on electronic health record (EHR) data. In chi-squared and regression modeling, controls were randomly sampled at a 4:1 control: case ratio, resulting in analysis of data from 1,200 participants. Results: 240 participants acquired a diagnosis of POAG during all available follow-up time, while 18,200 did not. In bivariate analysis, metformin use was significantly associated with a lower odds of developing POAG (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.23-0.42, p&amp;lt;0.001). In multivariable regression analysis, metformin remained protective against POAG (OR 0.33, 95% CI 0.22-0.50, p&amp;lt;0.001), while the use of other diabetic medications was associated with an increased odds of developing POAG (OR 2.06, 95% CI 1.31-3.27, p=0.002). In survival analysis, the probability of developing POAG was significantly lower for participants using metformin than for participants not using metformin (log-rank p&amp;lt;0.001, Cox proportional hazards ratio 0.33, 95% CI 0.25-0.44). Conclusion: This study provides additional large-scale observational health data supporting the protective role of metformin in the development of POAG. Disclosure S. Sidhu: None. B. Radha saseendrakumar: None. J. Wu: None. E. L. Nudleman: Consultant; Roche Pharmaceuticals, EyeBio, Alcon Research, LLC. J. Do: Consultant; Voxelcloud Inc., Other Relationship; Nicox, Research Support; National Eye Institute, Speaker's Bureau; Medical Education Speakers Network. S. M. Moghimi: None. R. Weinreb: Consultant; AbbVie Inc., Alcon, Allergan, Amydis, Equinox, Other Relationship; NIH - National Institutes of Health, Carl Zeiss Meditec, Topcon, Nicox, Novartis, Toromedes, Research Support; Heidelberg. S. L. Baxter: Consultant; voxelcloud, Other Relationship; iVista Medical Education, Research Support; Topcon, Optomed. Funding University of California San Diego; National Institutes of Health (DP5OD029610, P30EY022589); National Institutes of Health, Office of the Director, Regional Medical Centers (1OT2OD026549, 1OT2OD026554, 1OT2OD026557, 1OT2OD026556, 1OT2OD026550, 1OT2OD026552, 1OT2OD026553, 1OT2OD026548, 1OT2OD026551, 1OT2 OD026555); IAA (AOD16037); Federally Qualified Health Centers (HHSN263201600085U); Data and Research Center (5U2COD023196); Biobank (1U24OD023121); The Participant Center (U24OD023176); Participant Technology Systems Center (1U24OD023163); Communications and Engagement (3OT2OD023205, 3OT2OD023206); Community Partners (1OT2OD025277, 3OT2OD025315, 1OT2OD025337, 1OT2OD025276)

#3296 ADVERSE MUSCLE COMPOSITION ASSESSED BY MRI ASSOCIATES TO POOR FUNCTIONAL PERFORMANCE AND METABOLIC COMORBIDITIES IN CKD

Abstract Background and Aims CKD is associated with alterations in body composition, such as reduced muscle mass, increased amount of fat or both simultaneously. Furthermore, both sarcopenia and sarcopenic obesity are associated with worse physical functioning, poor quality of life, increased morbidity and mortality in CKD. Magnetic resonance imaging (MRI) is considered an accurate method for the study of body composition. A water/fat separated MRI scan with automated image analysis can quantify the skeletal muscle volume and allows a quantitative measure of muscle quality by assessing muscle fat infiltration. The combined observation of low muscle volume and high muscle fat infiltration, i.e. adverse muscle composition (AMC), has been shown to be linked to poor function and metabolic comorbidities within subjects with non-alcoholic fatty liver disease. The aim of this study was to investigate the prevalence of AMC and its association with poorer muscle function and metabolic comorbidity within CKD in the large UK Biobank imaging study. Method This is a cross-sectional and prospective study including a total of 647 UK Biobank participants with eGFR cystatin C &amp;lt; 60 ml/min/1,73 m2. A control group was created by selecting participants (matched on sex, age, and BMI) with an eGFR cystatin ≥ 60 ml/min/1,73 m2. Fat-tissue free muscle volume and muscle fat infiltration (MFI) were quantified using a rapid whole-body water and fat separated MRI protocol and automated image analysis (AMRA® Researcher). For each participant, a personalized muscle volume z-score (sex- and body size-specific) was calculated and combined with muscle fat infiltration for AMC detection. AMC was defined as having low muscle volume in combination with high muscle fat infiltration. Sarcopenia was calculated according to the last published recommendation by the European Working Group on Sarcopenia in Older People. Data describing muscle function (hand strength, walking test, stair climbing and number of falls) and metabolic comorbidity (coronary heart disease (CHD) and type 2 diabetes (T2D) have been included and obtained from the study database linked to the study participants' electronic health records. A Cox proportional hazards ratio model, corrected for age, sex, BMI, low hand grip strength, T2D, smoking, and alcohol consumption, was used to assess the association between AMC and CHD incidence. Results • The prevalence of AMC was 1,4x higher in CKD participants compared with the control group without CKD (27.7% vs 20.4%, p&amp;lt;0.001). CKD participants had significantly higher prevalence of sarcopenia (7.2% vs 4.4%, p = 0.004), low hand grip strength (16.0% vs 11.8%, p = 0.006), slow walking pace (17.3% vs 9.9%, p &amp;lt;0.001), CHD (17.4% vs 8.9%, p &amp;lt;0.001) and T2D (13.7% vs 9.2%, p = 0.001) compared with the control group without CKD (Fig. 1). • CKD participants with AMC (179 out of 647) had a significantly higher prevalence of sarcopenia (17.3% vs 3.5%, p&amp;lt;0.001), low hand grip strength (22.8% vs 13.4%, p = 0.006), slow walking pace (27.0% vs 13.6%, p &amp;lt;0.001), as well as prevalence of CHD (23.6% vs 15.0%, p = 0.014) and T2D (18.6% vs 11.8%, p = 0.033) compared with CKD participants without AMC (Fig. 2). • CKD participants with prevalent CHD at the study had higher prevalence of AMC (37.5% vs 25.5%, p = 0.014) compared to CKD participants without CHD. • AMC was associated with 1.9x higher incidence of CHD (95% confidence interval 1.15–3.15, p = 0.012) compared to those without AMC. Conclusion AMC, as determined by MRI with automated image segmentation, is highly prevalent within CKD and associates with poor function, high prevalence of metabolic comorbidities and an increased risk for CHD. CKD patients with poor muscle health is a highly vulnerable group and this technique enables them to be targeted for accurate interventions in order to improve outcomes.

Association Between the Use of Topical Calcineurin Inhibitors and the Risk of Cancer Among Patients with Atopic Dermatitis: A Nationwide, Population-Based, Retrospective Cohort Study.

The cancer risks associated with treatment withtopical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations. This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers. This study was a nationwide, population-based, retrospective cohort study. Taiwan's National Health Insurance Research Database. Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model. Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs). The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database. After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Exceptfor leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia. Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population.

Trastuzumab emtansine vs lapatinib and capecitabine in HER2-positive metastatic breast cancer brain metastases: A real-world study.

Trastuzumab emtansine (T-DM1) has demonstrated improvements in survival and neurological symptoms in patients with breast cancer with brain metastases (BCBM). This real-world study investigated the effectiveness of T-DM1 versus lapatinib plus capecitabine (LC) in patients with BCBM. This retrospective, observational study evaluated patients with HER2-positive BCBM using a real-world database. Eligible patients had initiated T-DM1 or LC with a prior diagnosis of brain metastasis and ≥1 prior metastatic breast cancer treatment. The primary endpoint was overall survival (OS); secondary endpoints were time to next relevant treatment or death (TTNT) and real-world progression-free survival (rwPFS). An inverse probability of treatment weighting (IPTW) approach was used to account for differences in potential baseline characteristics between treatment groups. Outcomes were described using the Kaplan-Meier method, and the average treatment effect of initiating T-DM1 versus LC was estimated using weighted Cox proportional hazard models and hazard ratio (HR). A total of 214 patients were available for analysis (T-DM1, n=161; LC, n=53). Demographics and baseline characteristics were generally well-balanced between treatment groups after weighting. After weighting, median OS was 17.7 (T-DM1) versus 9.6 (LC) months (HR, 0.55 [95% CI, 0.34-0.89]; P=0.013). Median TTNT was 9.0 (T-DM1) versus 6.0 (LC) months (HR, 0.55 [95% CI, 0.36-0.85]; P=0.005). After weighting, median rwPFS was 6.0 (T-DM1) versus 4.0 (LC) months (HR, 0.50 [95% CI, 0.36-0.69]; P<0.001). These results support the superior effectiveness and clinical relevance of T-DM1 versus LC in patients with HER2-positive BCBM in the real world.

Sequential monitoring of tumor macrophage fusion cells in the circulation of metastatic breast cancer and their prognostic value.

3054 Background: Tumor Macrophage Fusion Cells (TMFCs) are hybrids fusions of tumor cells and macrophage/immune cells that have recently been documented in advanced solid tumors, such as metastatic Breast Cancer (mBC). Further, TMFCs are found in the blood of patients (pts) as a CD45+/CD14+ binucleated subtype of standard circulating tumor cells (CTCs), which are Cytokeratin+ (CK+) &amp; CD45 negative, but distinct from highly hyperploidy cells known as cancer associated macrophage-like cells. However, no study has explored the clinical meaning of TMFCs in blood. To better elucidate the clinical meaning of TMFCs, we prospectively pooled 137 mBC pt samples prior to induction of new therapy, ie baseline (BL), and after therapy induction (FU). Both TMFCs or standard CTCs were identified and enumerated to analyze their prognostic value for progression-free survival (PFS) and overall survival (OS). Methods: In this prospective study, we collected 7.5 mL blood samples from n=137 mBC pts enrolled in prospective trials from multiple institutions before starting new treatment lines for newly progressive mBC. If possible, an optional FU sample was collected (n=73) after BL (median=4.9 weeks). TMFCs &amp; CTCs were isolated using a CellSieve microfilter and differentiated by staining for CK, CD45, CD14, and DAPI. Cox proportional regression hazard ratios (HRs) with 95% Confidence Intervals (CI) for PFS &amp; OS by univariate &amp; multivariate analyses were based on RECIST v1.1, determined by local institutional pathologist over 24 months (M). Results: TMFCs were detected in 26.3% (n=36/137) at BL and associated with significantly worse PFS (HR=3.3, CI 1.9-5.7, p&lt;0.001) &amp; OS (HR=2.7, CI 1.4-5.1, p=0.005). TMFCs were also detected in 27.4% (n=20/73) at FU (n=73) and prognostic for PFS (HR=5.2, CI 2.3-11.9, p&lt;0.001) &amp; OS (HR=5.1, 1.8-14.2, p=0.004). Further, pts with increases in TMFCs between BL and FU had worse PFS (HR=4.3, CI 1.9-10.1, p=0.001) &amp; OS (HR=4.5, CI 1.6-12.7, p=0.011). In contrast, pts with CTCs were found in 39.4% (n=54/137) at BL, which were prognostic for worse PFS (HR=2.0, CI 1.3-3.2, p=0.005) and not prognostic for OS (HR=1.7, CI 0.9-3.0, p=0.103). At FU, pts with CTCs were found in 38.4% (n=28/73), which were prognostic for worse PFS (HR=3.6, CI 1.8-7.3, p=0.001) &amp; OS (HR=3.2, CI 1.3-8.0, p=0.021). Overall at BL, pts without CTCs or TMFCs had a 5.7 M mPFS &amp; &gt;24M mOS, CTCs alone had a 5.0 M mPFS &amp; 20.3 M mOS, TMFCs had 2.0 M mPFS &amp; 5.8 M mOS. At FU, pts without CTCs or TMFCs had a 5.8 M mPFS &amp; 14.5 M mOS, CTCs alone had a 3.3 M mPFS &amp; 14.6 M mOS, while TMFCs pts had a 1.7 M mPFS &amp; 4.8 M mOS. Conclusions: TMFCs appear to represent a CTC subgroup with additional prognostic value to standard CTCs, that may correlate with significantly faster PFS and OS versus pts with CTCs alone, or without CTCs. Subtyping treatment regimens is ongoing to determine if the TMFC populations are responsive to specific therapy types in these mBC pts.