Landmark Analysis Research Articles

Testosterone Therapy in Men After Radical Prostatectomy for Low-Intermediate Organ-Confined Prostate Cancer.

Testosterone (T) therapy (TTh) in men with T deficiency who have undergone radical prostatectomy (RP) for prostate cancer remains controversial. We aimed to assess the impact of TTh on biochemical recurrence (BCR) rates after RP in men with low-intermediate organ-confined disease. This study included men who underwent an RP at our institution for organ-confined prostate cancer and had grade groups 1 to 3 on RP pathology. A Cox model was created for time to BCR with T use included as a time-dependent covariate, adjusted for age, preoperative PSA, grade group at RP, and the presence of comorbidities. A landmark analysis was used: Patients were included in the analysis if their last PSA in the 18 weeks postoperatively was undetectable and they had not had BCR or been lost to follow-up by that point, and follow-up for BCR began at 18 weeks. BCR was defined as a PSA ≥ 0.1 ng/mL after RP with a second confirmatory rise ≥ 0.1 ng/mL. The study population included 5199 men after RP, with 198 patients receiving T at any point after RP and 5001 not receiving T. The median age was 59 (interquartile range, 55-65) and 61 (interquartile range, 56-66) years, respectively. Men in the T group tended to present with more vascular comorbidities. For those receiving T, clomiphene citrate was prescribed in 49% of men, 32% received transdermal T, and 19% intramuscular T. We found a nonsignificantly decreased risk of BCR associated with the use of T after RP (hazard ratio, 0.84; 95% CI, 0.48-1.46; P = .5), and overall rates of BCR were low, with probability of BCR at 5 years less than 2% in both groups. TTh can be given to select men after RP. We found no evidence that administration of TTh after RP causes BCR.

Immune-related adverse events in a nationwide cohort of real-world melanoma patients treated with adjuvant anti-PD1 – Seasonal variation and association with outcome

IntroductionImmune checkpoint inhibitors (ICIs) carry the risk of immune-related adverse events (irAEs), a significant concern as therapy has transitioned to the adjuvant setting. Balancing therapeutic benefits against potential risks is crucial, necessitating real-world data from an unselected patient population in addition to clinical trial data to ensure optimal clinical decision-making. MethodsThis nationwide real-world study assessed irAEs in patients receiving adjuvant anti-PD1 therapy, primarily nivolumab, for resected stage III-IV melanoma between 2018–2022. Data were retrieved from two national databases: the IMMUNOTOX database and the Danish Metastatic Melanoma Database (DAMMED). IrAEs were sub-grouped according to organ systems graded using CTCAE ver. 5.0 ranging from mild toxicities (grade 1–2) to severe (grade 3–4) and fatal (grade 5). ResultsAmong 792 included patients, (55 % male, median age 62 years (range 16–88)), 697 patients (88 %) experienced an irAE. Severe irAEs occurred in 116 patients (15 %) and five (0.6 %) died due to toxicity. A landmark analysis showed that patients who experienced at least one irAE before the 1st evaluation at 90 days had an increased progression free survival (PFS) (p = 0.032) and overall survival (OS) (p = 0.0071). Additionally, a seasonal pattern was noted with higher incidence of irAEs during summer. ConclusionThe prevalence of irAEs in real-world patients is comparable to the observed risk in clinical trials. Patients experiencing irAEs demonstrate a lower risk of melanoma relapse. Further, gender, age and seasonal variation may impact the incidence of irAEs.

TBI/Cy followed by auto-HSCT is a good choice next to allo-HSCT for patients with T-LBL/ALL

The aim of this retrospective study was to evaluate the efficiency and safety of total body irradiation plus cyclophosphamide (TBI/Cy) followed by autogenetic hematopoietic stem cell transplantation (auto-HSCT) in T-LBL/ALL patients that cannot receive allogeneic hematopoietic stem cell transplant (allo-HSCT). Between 2013 and 2023, 24 patients received auto-HSCT following by TBI/Cy, 26 patients underwent allo-HSCT, all patients achieved completed hematopoietic reconstitution after HSCT. The progression free survival (PFS) and overall survival (OS) had no statistically significant differences between the two groups (P = 0.791, HR 1.127, 95%CI 0.456–2.785; P = 0.456, HR 0.685, 95%CI 0.256–1.828). Although the cumulative incidence of relapse was lower for patients who received allo-HSCT than auto-HSCT (P = 0.033, HR 3.707, 95%CI 1.188–11.570, 2-year relapse 11.5% vs. 33.3%), the incidence of non-relapse mortality (NRM) was higher than that in the auto-HSCT group (P = 0.014, HR 0.000, 95%CI -1.000 - -1.000, 2-year NRM, 23.1% vs. 0%). Trough Landmark analysis, the two groups showed a statistically significant difference in 3-year PFS and 4-year OS curves (Figure S2A&B, P = 0.039, HR 0.426, 95%CI 0.163–1.117; P = 0.014, HR 0.317, 95%CI 0.113–0.887). By COX analysis, poor baseline performance status (ECOG-PS ≥ 2) and CNS involvement were risk factors for PFS and OS. In conclusion, TBI/Cy followed by auto-HSCT is a good choice next to allo-HSCT for patients with T-LBL/ALL.

Is chemotherapy beneficial? A retrospective study of chemotherapy in patients with invasive intraductal papillary-mucinous carcinoma

Background and aimWhether chemotherapy can improve the prognosis of invasive intraductal papillary-mucinous carcinoma (IPMC) still remains unclear. The aim of this study is to observe the difference in survival time of patients with invasive IPMC receiving or not receiving chemotherapy. Methods117 patients with invasive IPMC were included in The Surveillance, Epidemiology, and End Results (SEER) database. These patients were subsequently divided into two subgroups according to whether they received chemotherapy or not: the non-chemotherapy group (patients who did not receivechemotherapy, N = 58), the chemotherapy group (patients who received chemotherapy, N = 59). The overall survival (OS) and cancer specific survival (CSS) of two treatment groups were evaluated. ResultsBefore adjusting for pathology grade, the Kaplan-Meier analysis showed that the difference of survival time is not significant between non-chemotherapy group and chemotherapy group (P > 0.05), but the land-mark analysis showed that short-term death risk of the chemotherapy group is significantly lower than non-chemotherapy group (P < 0.05). After adjust the pathology grade, survival time of the chemotherapy group is significantly longer than non-chemotherapy group (P < 0.05). Univariate and multivariate Cox regression showed that chemotherapy was an independent prognostic protective factor for invasive IPMC (P < 0.05). Land-mark analysis showed that short-term death risk of the chemotherapy group is significantly lower than non-chemotherapy group in N1-N2 subgroup (P < 0.05). ConclusionChemotherapy is an independent protective factor IPMC, especially reducing the risk of short-term death for IPMC patients with lymph node metastasis.

Efficacy of Danlou tablets in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a multicenter prospective cohort study.

Danlou tablets (DLTs) have been widely used to treat coronary heart disease in China. However, the benefits associated with DLT for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in routine practice require further investigation. To investigate the effectiveness of DLT in patients with ACS undergoing PCI. This multicenter prospective cohort study for patients with ACS undergoing PCI was conducted in 40 centers in mainland China from February 2012 to December 2018. This trial is registered under ChiCTR-OOC-14005552. Patients were assigned to either the DLT group or the conventional medicine (CM) group based on whether they used DLT prior to enrollment. The duration of DLT use (1.5 g, three times a day) was 12 months. The primary endpoint comprised of cardiac death, non-fatal myocardial infarction, and urgent revascularization. Secondary endpoint included rehospitalization owing to ACS, heart failure, stroke, and other thrombotic events. The Seattle Angina Questionnaire (SAQ) was used to assess quality of life (QOL). Primary and secondary endpoints were followed up for 36 months, and the SAQ was followed up for 12 months. The Cox proportional hazards regression model was used to analyze the independent effect of DLT on primary and secondary endpoints. Propensity score matching (PSM) analyses were performed to mitigate bias. Survival estimation was performed using Kaplan-Meier survival curves and log-rank tests in the PSM cohort, and landmark analyses were used for further evaluation of primary and secondary endpoints. Subgroup analyses and interactions confirmed the robustness of the findings. Linear mixed effects models were used to assess the QOL. Overall, 936 patients were enrolled in this cohort study, of whom 875 completed follow-up. The primary and secondary endpoints had no significantly difference between the DLT and CM groups after Cox proportional hazards models. Kaplan-Meier survival curves and log-rank tests performed in the PSM cohort also found no significant differences between the two groups on primary and secondary endpoints. However, landmark analysis showed significant benefit in the primary endpoint for the DLT group after 200 days (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.22-0.93, P = 0.03). Landmark analysis also showed a significant benefit in the secondary endpoint in the DLT group within 200 days (HR 0.33, 95% CI 0.15-0.73, P = 0.006). Moreover, DLT improves the SAQ summary score, and scores in the physical limitation, treatment satisfaction, and disease perception domains for patients with ACS undergoing PCI. DLT combined with conventional treatment reduced the risk of the primary endpoint after 200 days and the secondary endpoint within 200 days during the 3-year follow-up. Additionally, DLT can improve the QOL without adverse effects.

Effect of Mechanical Circulatory Support on Mortality After Transcatheter Aortic Valve Replacement: A Landmark Analysis.

A proportion of patients still need mechanical circulatory support (MCS) during the transcatheter aortic valve replacement (TAVR) because of intraoperative hemodynamic instability. However, the outcomes of patients with different MCS type during TAVR are still controversial. A total of 538 patients who underwent TAVR procedure in four centers were included. The time-related outcomes and their predictors of patients who did not have MCS (MCS-, n = 498) were compared with those who underwent emergency MCS (eMCS+, n = 18) and prophylactic MCS (pMCS+, n = 22). We evaluated the association between different MCS groups and all-cause mortality using conditional landmark analysis with Cox regression. There was a significant increase in 30-day mortality in the eMCS+ group (plog-rank < 0.001) and no significant difference in 31-day to 1-year mortality among the groups (plog-rank = 0.789). A significant improvement in the left ventricular ejection fraction was observed in the pMCS+ group at 1 year after TAVR. Emergency MCS was independently associated with 30-day mortality, as well as 1-year mortality. Prophylactic MCS showed good clinical outcomes and might be considered for high-risk patients. Further studies are needed to investigate the predictors that lead to MCS usage and long-term mortality in TAVR patients with MCS.

Prognostic Implications of Maintaining the Target Thyroid-Stimulating Hormone Status Based on the 2015 American Thyroid Association Guidelines in Patients with Low-Risk Papillary Thyroid Carcinoma after Lobectomy: A 5-Year Landmark Analysis

Background: The 2015 American Thyroid Association guidelines recommend the maintenance of serum thyroid stimulating hormone (TSH) levels ≤2 mIU/L in patients with low-risk papillary thyroid carcinoma (PTC) who underwent lobectomy; however, the evidence is insufficient. We investigated the association between maintaining the TSH status at ≤2 mIU/L and tumor recurrence in patients with low-risk PTC who underwent lobectomy through a 5-year landmark analysis. Methods: Between 2010 and 2016, 662 patients with low-risk PTC were included. The postoperative TSH status was determined using the ‘TSH &gt; 2 ratio’, which was calculated using the TSH test results during the 5-year follow-up. The optimal cutoff value of ‘TSH &gt; 2 ratio’ for tumor recurrence was determined using a receiver operating characteristic curve analysis. Recurrence-free survival (RFS) was compared between the groups using Kaplan–Meier and Cox proportional hazard regression analyses. Results: Patients with ‘TSH &gt; 2 ratio’ &gt; 0.1833 (n = 498) had a worse RFS outcome compared to patients with ‘TSH &gt; 2 ratio’ ≤ 0.1833 (n = 164; p &lt; 0.001). ‘TSH &gt; 2 ratio’ &gt; 0.1833 was a significant risk factor for tumor recurrence after the 5-year landmark (hazard ratio: 4.795, 95% confidence interval: 2.102–10.937, p &lt; 0.001). Conclusions: Maintaining TSH levels ≤ 2 mIU/L below a certain percentage among the total TSH tests during the 5-year follow-up period has a negative impact on tumor recurrence.

Exploration of the regional effects of colchicine in the LoDoCo2 trial

The Low Dose Colchicine 2 (LoDoCo2) trial randomized 5,522 patients with chronic coronary disease to colchicine 0.5mg daily or placebo in a 1:1 ratio and demonstrated the cardiovascular benefits of colchicine. In the trial, which was conducted in Australia and The Netherlands, a prespecified subgroup analysis suggested a difference in magnitude of treatment effect of colchicine by region (Australia: HR 0.51; 95% CI 0.39-0.67 vs The Netherlands: HR 0.92; 95% CI 0.71-1.20). The aim of this study was to explore possible explanations for the apparent difference in magnitude of treatment effect of colchicine by region in the LoDoCo2 trial. The analysis explored potential determinants of variations in the magnitude of effectiveness of colchicine treatment across the regions. This included investigating differences in investigational product, clinical characteristics, concurrent medical therapies and the duration of follow-up using a range of statistical techniques, including sub-group, landmark and effect modification analyses. No differences were found in the colchicine product used in each region. Despite minor differences observed in baseline clinical characteristics and concomitant therapies, the effect modifier analyses demonstrated that these factors did not explain the difference in magnitude of treatment effect of colchicine by region. Randomization in Australia began more than 2 years before The Netherlands, with shorter duration of follow-up in The Netherlands compared to Australia. In a landmark analysis, over the period when more than 90% of patients in each region had been followed, the effects of colchicine were similar (Australia hazard ratio [HR] 0.58; 95% CI 0.34-0.97 vs The Netherlands HR 0.67; 95% CI 0.47-0.96). After examining several plausible explanations for the observed differences in the magnitude of treatment effect of colchicine between regions in the LoDoCo2 trial could be due to the differences in duration of follow-up but a substantial portion of the differences remain unexplained. https://www.anzctr.org.au/ACTRN12614000093684.

Eight-Year Outcomes of Patients With Reduced Left Ventricular Ejection Fraction Who Underwent Transcatheter Aortic Valve Replacement With a Self-Expanding Bioprosthesis

Conflicting results have been reported regarding the relationship between impaired left ventricular ejection fraction (LVEF) and adverse outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) and long-term clinical data are lacking.The aims of this study were to investigate the long-term outcomes of patients with reduced LVEF undergoing TAVRData deriving from patients undergoing TAVR between 2007 and 2017 in 13 Italian centers were prospectively collected. Patients were stratified in those with normal LVEF and reduced LVEF. The latter was further classified according to ischemic or non-ischemic etiology. The primary endpoint was a composite of all-cause death and re-hospitalizations, the secondary endpoints were the isolated composers of the primary one and cardiac death. Overall, 2626 patients were included in the analysis, 68.1% with NLVEF and 31.9% with reduced LVEF. At eight years, reduced LVEF was significantly associated with the primary endpoint (adj. HR 1.17 95% CI 1.06-1.29). Consistent findings were evident for the composite endpoint. No differences in these trends were found at 30 days landmark analyses. Compared to non-ischemic etiology, ischemic reduced LVEF was associated with an increased risk of cardiac death (adj. HR 1.43 95% CI 1.02-2.02). In conclusion, patients with reduced LVEF undergoing TAVR are exposed to a progressively increased risk of death and re-hospitalizations even at very long-term follow-up.

Deep PSA response and extended time-to-nadir as robust predictors of survival in Asian patients with de novo metastatic hormone-sensitive prostate cancer receiving upfront intensified treatment.

In de novo metastatic hormone-sensitive prostate cancer (mHSPC) treated with upfront intensification using androgen receptor signaling inhibitor or chemotherapy (Docetaxel), achieving a PSA nadir less than 0.2 ng/mL, indicative of superior survival in trials, may often be unattainable in real-world settings. We explored the predictive value of the degree of PSA decline and time to PSA nadir (TTPN) on oncological outcomes. A prospectively maintained database of consecutive prostate cancer cases in Hong Kong was accessed. Patients diagnosed with de novo mHSPC from 2016 to 2022 and treated with upfront intensification were included in this analysis. Landmark analysis on PSA kinetics at 6-months following treatment intensification was performed. They were classified based on 1) TTPN (≥6 months vs. <6 months), and 2) a combined response (deep responders achieving both ≥95% PSA decline and TTPN ≥ 6 months vs. shallow responders). Multivariable regression analysis was employed to identify the effects of confounders. A total of 131 patients were included in this analysis. Classifying patients by combined response best predicted survival outcomes. Deep responders had better progression-free survival (HR = 0.56; 95%CI = 0.34-0.91; p = 0.019), overall survival (HR = 0.50; 95%CI = 0.26-0.97; p = 0.036), and cancer-specific survival (HR = 0.43; 95%CI = 0.19-0.99; p = 0.042). Difference in overall survival remained significant after adjustment in multivariable regression analysis. Our analysis demonstrates that alternative PSA targets can predict treatment response and survival outcomes in de novo mHSPC patients in a real-world setting, providing valuable information for patient counselling and potentially guiding future trial design.

Survival benefits of radiotherapy in locally advanced unresectable and metastatic pancreatic cancer: a single-institution cohort and SEER database analysis.

Chemotherapy (CT) remains the primary treatment for locally advanced unresectable pancreatic cancer (LAUPC) and metastatic pancreatic cancer (MPC). The role of radiotherapy (RT) in these conditions remains unclear. This study compares the outcomes of CT alone versus CT combined with RT (combined-modality therapy [CMT]) in LAUPC and MPC patients. We conducted a retrospective analysis of LAUPC and MPC patients treated with either CT or CMT from a single institution and Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier curves and Cox hazards models evaluated the association between treatment modalities and overall survival (OS). Propensity score matching (PSM) ensured balanced comparisons. Landmark analysis addressed immortal time bias. Subgroup analyses were based on clinical characteristics. eXtreme Gradient Boosting (XGBoost) and Shapley Additive Explanations (SHAP) assessed outcome prediction and influence of significant predictors. The study included 102 patients receiving CMT and 155 receiving CT at single institution, along with 1733 CMT and 9310 CT patients from the SEER dataset. In the single-institution cohort, CMT showed superior survival compared to CT both before (median OS: 20.5 vs. 11.5 months, hazard ratio [HR]: 0.47, 95% CI: 0.34-0.65, P=0.001) and after PSM (median OS: 22.2 vs. 11.8 months, HR: 0.49, 95% CI: 0.30-0.79, P=0.003). Multivariate analyses confirmed that CMT was independently associated with improved OS both before (HR: 0.54, 95% CI: 0.38-0.77, P=0.001) and after PSM (HR: 0.45, 95% CI: 0.27-0.73, P=0.001). Landmark analysis indicated better OS for patients receiving CMT compared to CT alone. Subgroup analysis revealed an OS benefit for CMT across most subgroups. SHAP value analysis indicated that CMT was the most significant contributor to survival outcomes. SEER database validation confirmed these findings. This study demonstrates that CMT significantly improves OS in LAUPC and MPC patients compared to CT alone. Integrating RT with CT could be beneficial for treating LAUPC and MPC.

Efficacy and Safety of Pembrolizumab plus Axitinib combination for Metastatic Renal Cell Carcinoma in a Real-World Scenario: Data From the Prospective ProPAXI Study

BackgroundPembrolizumab/Axitinib combination is approved as first-line therapy in mRCC. The aim of this study is to evaluate outcomes of PAXI combo in the real-world in Italy. MethodsThis is a prospective study including patients diagnosed with mRCC who received combination as first-line therapy in recruiting Italian Centers. Data about patient characteristics, safety and outcome were collected. Results170 pts have been treated from December 2020 to September 2023. The majority had clear-cell histology (83%). Sarcomatoid feature was present in 33%of available cases. About one half of patients (55%) had synchronous metastasis. In 58% of cases nephrectomy was performed, of which 27% were cytoreductive and 4% were deferred nephrectomies. Lung metastases were identified in 106 patients (62%), bone and liver involvement in 66 and 29 patients (38.8% and 17.1%) respectively. Stratifying by IMDC criteria, 32 patients (18.8%) were at favorable-risk, 106 (62.4%) at intermediate-risk, and 32 (18.8%) at poor-risk. At time of analysis, treatment was ongoing in 49% of patients. Progression occurred in 45% of patients. Median PFS was 19.2 months (95% CI: 15-NR). With a median follow-up of 19.3 months (range 1.3-34.5), at 24-months and 36-months landmark analysis 62% (95% CI, 53-70) and 58% (95% CI, 47-69) of treated patients are still alive respectively. Disease control rate was achieved in 84.6% of patients: 4.3% reached a complete response, 52% had a partial response and 28.8% a stable disease. Primary progression was observed in 15.3% of patients. In the multivariate analysis, the prognostic significance of age ≥ 65 years, non-clear cell histology, IMDC score, and adverse events and gender interaction as predictors of worse OS were confirmed. ConclusionThis is the first available prospective study on first-line Pembrolizumab/Axitinib combination in real world scenario. Our findings support the effectiveness and safety of first-line this combination in mRCC and reveal that gender emerged as a prognostic factor in relation to the occurrence of adverse events.

Ophthalmic Immune-Related Adverse Events and Association with Survival: Results From a Real-World Database

PurposeAssessing immune-related ocular toxicities from immune checkpoint inhibitors (ICIs) is crucial, though rare. This study, utilizing real-world data, examines the occurrence of ophthalmic immune-related adverse events (irAEs) after ICI treatment and their impact on overall survival. DesignA retrospective cohort study MethodsData were obtained from TriNetX, an aggregated electronic health records database. Patients who developed ophthalmic irAEs within 1 year after the first instance of ICI therapy were included. Participants with defined ocular toxicities 6 months before ICI treatment were excluded. Subjects were paired with controls using propensity scores derived from demographics and cancer type. A Cox proportional hazard model was used to determine hazard ratios. A Kaplan-Meier survival function was evaluated with the log-rank test based on the development of ophthalmic irAEs in a 12-month landmark analysis. ResultsA cohort of 41,020 patients comprising 57.4% males with a mean age of 65.2±11.9 years was included. The five most prevalent ophthalmic irAEs in this cohort were dry eye syndrome (2%), conjunctivitis (0.87%), blepharitis (0.51%), anterior uveitis (0.39%), and keratitis (0.38%). Dry eye syndrome was the most common irAE among all ICI classes. Subjects taking CTLA-4 inhibitor plus PD-1 inhibitor and CTLA-4 inhibitors had higher rates of anterior uveitis (1.39% and 1.29%, respectively) than PD-1 inhibitors (0.27%) and PD-L1 inhibitors (0.14%) within 1 year after taking ICI. After a 12-month landmark analysis, there was a significant decreased chance of survival for the following categories: any ophthalmic irAE (HR, 1.37; 95% CI, 1.20-1.56; P < 0.0001), neuro-ophthalmic irAE (HR, 1.53; 95% CI, 1.09-2.14; P = 0.0124), and cornea and ocular surface irAE (HR, 1.34; 95% CI, 1.15-1.56; P < 0.0001). ConclusionsOphthalmic irAEs involving the anterior segment are more frequent than the posterior segment, regardless of ICI class. Ophthalmic irAEs may also portend decreased survival. This insight could help guide clinicians aggressively manage irAEs and allow patients to continue ICI therapy despite having ocular issues.

Incidence, Time Course, and Outcomes of Worsening Tricuspid Regurgitation Following Transvenous Cardiac Implantable Electronic Device Implantation

Data regarding the incidence, time course, and outcomes of worsening tricuspid regurgitation (TR) after transvenous cardiac implantable electronic device (CIED) implantation are limited. We screened 834 consecutive patients who underwent first-time transvenous CIED implantation. After excluding patients without preoperative or follow-up echocardiography (n = 361) and patients with severe TR before implantation (n = 15), the present study population consisted of 458 patients. Worsening TR was defined as moderate or more TR that was newly developed or increased by at least 1 grade compared with baseline. During the median follow-up period of 2.1 years, worsening TR occurred in 93 patients (20%). The cumulative incidence of worsening TR was 10.2% at 1 year and 18.6% at 3 years. Of the 67 patients with worsening TR who underwent follow-up echocardiography, excluding those who underwent tricuspid valve surgery, 76% showed improvement in TR severity, with 70% having none or mild TR. On the landmark analysis, the 5-year cumulative incidence of all-cause death and heart failure hospitalization was significantly higher in patients with worsening TR at 1 year than those without worsening TR at 1 year (24.8% vs 11.4%, p = 0.002 and 35.2% vs 17.9%, p = 0.012, respectively). When considering worsening TR as a time-dependent covariate, worsening TR was significantly associated with an increased risk of all-cause death and heart failure hospitalization after adjustment for the differences in baseline patient characteristics (hazard ratio 1.99, 95% confidence interval 1.21 to 3.27, p = 0.006 and hazard ratio 2.64, 95% confidence interval 1.59 to 4.37, p <0.001, respectively). In conclusion, worsening TR after transvenous CIED implantation was not uncommon and had a dynamic nature with an improvement in the majority of patients, suggesting the functional etiology. Nonetheless, worsening TR was independently associated with an increased risk for mortality and heart failure hospitalization.

Addressing immortal time bias in precision medicine: Practical guidance and methods development.

To compare theoretical strengths and limitations of common immortal time adjustment methods, propose a new approach using multiple imputation (MI), and provide practical guidance for using MI in precision medicine evaluations centered on a real-world case study. Methods comparison, guidance, and real-world case study based on previous literature. We compared landmark analysis, time-distribution matching, time-dependent analysis, and our proposed MI application. Guidance for MI spanned (1) selecting the imputation method; (2) specifying and applying the imputation model; and (3) conducting comparative analysis and pooling estimates. Our case study used a matched cohort design to evaluate overall survival benefits of whole-genome and transcriptome analysis, a precision medicine technology, compared to usual care for advanced cancers, and applied both time-distribution matching and MI. Bootstrap simulation characterized imputation sensitivity to varying data missingness and sample sizes. Case study used population-based administrative data and single-arm precision medicine program data from British Columbia, Canada for the study period 2012 to 2015. While each method described can reduce immortal time bias, MI offers theoretical advantages. Compared to alternative approaches, MI minimizes information loss and better characterizes statistical uncertainty about the true length of the immortal time period, avoiding false precision. Additionally, MI explicitly considers the impacts of patient characteristics on immortal time distributions, with inclusion criteria and follow-up period definitions that do not inadvertently risk biasing evaluations. In the real-world case study, survival analysis results did not substantively differ across MI and time distribution matching, but standard errors based on MI were higher for all point estimates. Mean imputed immortal time was stable across simulations. Precision medicine evaluations must employ immortal time adjustment methods for unbiased, decision-grade real-world evidence generation. MI is a promising solution to the challenge of immortal time bias.

763. TEXTBOOK ONCOLOGIC OUTCOME FOLLOWING TRIMODALITY THERAPY FOR ESOPHAGEAL ADENOCARCINOMA

Abstract Background Although the concept of textbook oncologic outcome (TOO) as an emerging quality benchmark has been validated in the general surgical oncology literature, data regarding the frequency of achieving TOO and its impact on subsequent survival outcomes in patients with esophageal adenocarcinoma (EAC) who undergo trimodality therapy remain undefined. Methods Patients with adenocarcinoma of the esophagus/gastroesophageal junction (GEJ, Siewert I/II) who underwent neoadjuvant chemoradiation and esophagectomy at a single institution (2000-2022) were retrospectively identified. Patients undergoing salvage resection were excluded. TOO was defined according to a published consensus definition: length of stay (LOS) ≤14 days, R0, ≥20 resected lymph nodes, no anastomotic leak (any grade), no Clavien-Dindo (CD) grade ≥3 complications, no hospital or intensive care unit (ICU) readmission, and no reoperation. Multivariable logistic regression was used to identify clinicopathologic features associated with TOO. Multivariable Cox regression and landmark analyses were used to quantify the association between TOO and OS. Results Of 1138 patients, TOO was observed in 38.2% (435): 90.9% (1034) R0, 60.9% (693) ≥20 lymph nodes, 89.9% (1023) no anastomotic leak, and 98.4% (1120) no in-hospital mortality. Features independently associated with reduced odds of TOO included: cervical anastomosis (OR 0.50, P=0.001), preoperative delay ≥90 days after neoadjuvant therapy (OR 0.62, P=0.004), induction chemotherapy (OR 0.74, P=0.039), coronary artery disease (OR 0.67, P=0.043). Among patients who underwent esophagectomy &amp;lt;90 days after neoadjuvant therapy and survived ≥30 days, TOO was independently associated with improved OS (HR 0.80, P=0.018). TOO remained associated with improved OS using 90-day (P=0.014) and 120-day (P=0.037) landmarks. Conclusions Although TOO is difficult to achieve following trimodality therapy for EAC, it is strongly associated with improved long-term overall survival. As such, further efforts are warranted to explore the utility of TOO as a quality benchmark in EAC patients and to validate its impact across varying practice settings.

Temporal Trends in Takotsubo Syndrome: Results From the International Takotsubo Registry

BackgroundThe perception of takotsubo syndrome (TTS) has evolved significantly over the years, primarily driven by increased recognition of acute complications and mortality. ObjectivesThis study aimed to explore temporal trends in demographic patterns, risk factors, clinical presentations, and outcomes in patients with TTS. MethodsPatients diagnosed with TTS between 2004 and 2021 were enrolled from the InterTAK (International Takotsubo) registry. To assess temporal trends, patients were divided into 6 groups, each corresponding to a 3-year interval within the study period. ResultsOverall, 3,957 patients were included in the study. There was a significant demographic transition, with the proportion of male patients rising from 10% to 15% (P = 0.003). Although apical TTS remained the most common form, the diagnosis of midventricular TTS increased from 18% to 28% (P = 0.018). The prevalence of physical triggers increased from 39% to 58% over the years (P < 0.001). There was a significant increase in 60-day mortality over the years (P < 0.001). However, a landmark analysis excluding patients who died within the first 60 days showed no differences in 1-year mortality (P = 0.150). ConclusionsThis study of temporal trends in TTS highlights a transition in patients demographic with a growing prevalence among men, increasing recognition of midventricular TTS type, and increased short-term mortality and rates of cardiogenic shock in recent years. This transition aligns with the rising prevalence of physical triggers, as expression of increased recognition of TTS in association with acute comorbidities.

Phosphodiesterase 5 Inhibitor Treatment Is Associated With Improved Survival in Pulmonary Hypertension Associated With COPD in the Pulmonary Vascular Research Institute GoDeep Meta-Registry

BackgroundPatients with COPD frequently develop pulmonary hypertension (PH-COPD). Severe PH-COPD, identified by a pulmonary vascular resistance (PVR) >5 Wood Units (WU), is closely linked to impaired transplant-free survival. The impact of PH-targeting pharmacotherapy in this context remains unclear. Research QuestionIs PH-targeted therapy associated with improved transplant-free survival in PH-COPD? Study Design and MethodsThis study included PVRI GoDeep meta-registry patients with PH-COPD and available right heart catheterization at diagnosis. We investigated PH-targeted therapy prevalence and its association with transplant-free survival using diverse statistical methods, including Cox regression and subgroup analyses based on PH severity, comorbidities, and pulmonary function tests. Immortal time bias was addressed through a landmark approach. ResultsAs of December 2023, the GoDeep meta-registry included 26981 patients (28% PH-Group 1, 13% PH-Group 2, 12% PH-Group 3, 10% PH-Group 4, 2% PH-Group 5, 26% undefined and 9% control). Out of these, 836 patients were diagnosed as PH-COPD and included in this analysis, with median age 66 [59,73]years, FEV1 51 [34,69]%predicted, mPAP 35 [28,44]mmHg, PVR 5 [4,8]WU, cardiac index 2.5 [2.0,2.9]L/min.m2, and mostly WHO functional class III were included. 5-year transplant-free survival was 42%, significantly worse than group 1 PH. A multivariable Cox proportional hazards model identified PVR, but not FEV1 as a major predictor of outcome. 418 patients (50%) received phosphodiesterase-5 inhibitor (PDE5i) therapy, which was associated with significantly reduced mortality: hazard ratio 0.65 [0.57,0.75] for the entire PH-COPD cohort and 0.83 [0.74,0.94] when performing landmark analysis. This PDE5i effect was robustly reproduced when performing subgroup analyses for patients with moderate/severe PH, various comorbidities, and supplemental oxygen requirement, and when assessing the impact of unobserved confounders. InterpretationPH-COPD patients exhibit poor transplant-free survival, with PVR being a predictor of mortality. In this meta-registry, PDE5i therapy was associated with a significant reduction in mortality across all tested models.

Peak Procedural ACT Is Associated With All-Cause Mortality After Femoral Access PCI

BackgroundA minimum threshold activated clotting time (ACT) to guide heparin dosing during percutaneous coronary intervention (PCI) is associated with lower ischemic complications. However, data are variable regarding the risk of high ACT levels. The aim of this study was to assess the impact of peak procedural ACT on complications and mortality for transfemoral and transradial access PCI. MethodsThe UC San Diego Health National Cardiovascular Data Registry CathPCI Registry was used to obtain data on patients who underwent native vessel PCI from January 2007 to September 2022. Coronary artery bypass graft patients and those who received bivalirudin were excluded. Complications and all-cause mortality at 30 days and 1-year post-PCI were assessed by ACT tertile. ResultsA total of 2473 patients (age 65 ± 12 years; 74% male) undergoing PCI with 53% femoral and 47% radial access were included. The majority (82%) had 1-vessel coronary artery disease with heterogeneous clinical presentations (21.8% ST-elevation myocardial infarction, 25.4% non–ST-elevation myocardial infarction, 4.9% unstable angina, 33.8% stable angina, 3.4% atypical chest pain, 10.7% other indication for PCI). With femoral access, patients in the third tertile (ACT ≥ 275) had significantly higher all-cause mortality at 30 days (5.3% vs 2.7% vs 0.9%; P < .001), 6 months (6.3% vs 4.0% vs 2.0%; P = .007), and 1 year (9.0% vs 6.0% vs 2.7%; P < .001) compared to the second (ACT 228-275) and first tertile (ACT ≤ 228), respectively. A 30-day landmark analysis revealed that there was no difference in all-cause mortality beyond 30 days (3.9% vs 3.4% vs 1.8%; P = .176). There were increased bleeding complications in the highest tertile (12.8% vs 9.8% vs 7.5%; P = .034) and a higher need for blood products (10.4% vs 6.7% vs 5.4%; P = .014). There was no difference in ischemic major adverse cardiovascular events specifically periprocedural myocardial infarction or stroke between tertiles. There was no difference in clinical outcomes by peak ACT for patients who had radial access. ConclusionsHigher ACT with transfemoral access PCI was associated with increased 30-day mortality, bleeding complications, and need for blood products post-PCI.

The Impact of Radiation Therapy on Metastatic Rhabdomyosarcoma: Results From the EpSSG MTS 2008 Study

PurposeRadiation oncologists utilize radiation variably for children with metastatic rhabdomyosarcoma (RMS). Data from the XXXX study was retrospectively analyzed to validate the prior observation that the use of radiation is associated with improved outcomes, and guide future recommendations on radiation use in this patient group. Methods and MaterialsThe radiation delivered to 216 patients aged 0-21 years with metastatic RMS was retrospectively reviewed and classified as radical (all sites of disease irradiated within the protocol parameters), partial (some sites irradiated within the protocol parameters) and none (no radiation or delivered outside the protocol parameters). Landmark analysis excluded those with an event prior to day 221. Overall survival (OS) and progression free survival (PFS) were modelled using the Kaplan-Meier method to investigate the impact of radiation. The joint effect of treatment and known prognostic factors was examined using the Cox regression model. ResultsOverall 56 patients received radical, 104 partial and 56 no radiation per protocol. Due to non-randomised data, the groups were heterogeneous, particularly fewer sites of metatatic disease and less with bone metatases in those receiving radical radiation. 3-year PFS was 62.0% (95%CI 47.9-73.4) v 39.5% (29.8-49.1) v 30.1% (18.7-42.3)(p=0.002) for radical v partial v no radiotherapy respectively; 3-year OS was 70.1 % (55.8-80.6) v 53.1% (42.6-62.5) v 52.3% (38.3-64.5)(p=0.019) respectively. Multivariable analysis confirmed incremental improvement in OS with additional radiation with hazard ratio (HR) 1 v 1.8 v 2.4 (p=0.022) for radical v partial v no per protocol radiation. ConclusionsRadiation to all sites of disease seems to improve outcomes for children with metastatic RMS and should be considered when feasible. If not feasible, radiation is still recommended to the primary site and involved regional lymphadenopathy. Randomized clinical trials are required to confirm these findings, given the heterogeneity between the groups and potential confounding factors in this analysis.