Difference In Restricted Mean Survival Time Research Articles

Exploring the Bidirectional Relationship Between Periodontitis and Rheumatoid Arthritis in a Large Danish Cohort.

We investigated the bidirectional relationship between rheumatoid arthritis (RA) and periodontitis and their cross-sectional association using national administrative health care data. The sample included 3,308,903 individuals aged 20 to 79 years who resided in Denmark in 2000 and had remained free of RA and periodontitis in the previous 10 years. RA and periodontitis were defined using diagnosis and treatment codes. Marginal structural survival models were employed to estimate the effects of RA on periodontitis incidence and vice versa from 2000 to 2017. Using a cross-sectional sample of 2,574,536 individuals from 2017, the association of periodontitis with RA was investigated using regression analyses and probabilistic quantitative bias analyses, simulating RA and periodontitis misclassification and unmeasured confounding of smoking. Between 2000 and 2017, 20,348 individuals developed RA and 740,799 developed periodontitis. The estimated hazard ratio (HR) for the effect of periodontitis on incident RA was 1.05 (95% confidence interval [CI] 0.88-1.25), resulting in a restricted mean survival time difference of one day. The HR for the effect of RA on incident periodontitis was 0.84 (95% CI 0.80-0.88), corresponding to a restricted mean survival time difference of 151 days. Cross-sectionally, the unadjusted prevalence ratio for the association was 1.15 (95% CI 1.11-1.19), whereas the estimate adjusted for measured and simulated confounding was practically null (0.99, 95% simulation interval 0.93-1.04). These findings challenge previously reported bidirectional relationships between periodontitis and RA, pointing to potential residual confounding as an important link and prompting reconsideration of the biologic plausibility and clinical significance of these associations.

Exploring the Bidirectional Relationship Between Periodontitis and Rheumatoid Arthritis in a Large Danish Cohort.

We investigated the bidirectional relationship between rheumatoid arthritis (RA) and periodontitis and their cross-sectional association using national administrative health care data. The sample included 3,308,903 individuals aged 20 to 79 years who resided in Denmark in 2000 and had remained free of RA and periodontitis in the previous 10 years. RA and periodontitis were defined using diagnosis and treatment codes. Marginal structural survival models were employed to estimate the effects of RA on periodontitis incidence and vice versa from 2000 to 2017. Using a cross-sectional sample of 2,574,536 individuals from 2017, the association of periodontitis with RA was investigated using regression analyses and probabilistic quantitative bias analyses, simulating RA and periodontitis misclassification and unmeasured confounding of smoking. Between 2000 and 2017, 20,348 individuals developed RA and 740,799 developed periodontitis. The estimated hazard ratio (HR) for the effect of periodontitis on incident RA was 1.05 (95% confidence interval [CI] 0.88-1.25), resulting in a restricted mean survival time difference of one day. The HR for the effect of RA on incident periodontitis was 0.84 (95% CI 0.80-0.88), corresponding to a restricted mean survival time difference of 151 days. Cross-sectionally, the unadjusted prevalence ratio for the association was 1.15 (95% CI 1.11-1.19), whereas the estimate adjusted for measured and simulated confounding was practically null (0.99, 95% simulation interval 0.93-1.04). These findings challenge previously reported bidirectional relationships between periodontitis and RA, pointing to potential residual confounding as an important link and prompting reconsideration of the biologic plausibility and clinical significance of these associations.

Scaling and interpreting treatment effects in clinical trials using restricted mean survival time.

Restricted mean survival time is the expected duration of survival up to a chosen time of restriction . For comparison studies, the difference in restricted mean survival times between two groups provides a summary measure of the treatment effect that is free of assumptions regarding the relative shape of the two survival curves, such as proportional hazards. However, it can be difficult to judge the magnitude of the effect from a comparison of restricted means due to the truncation of observation at time . In this article, we describe additional ways of expressing the treatment effect based on restricted means that can be helpful in this regard. These include the ratio of restricted means, the ratio of life-years (or time) lost, and the average integrated difference between the survival curves, equal to the difference in restricted means divided by These alternative metrics are straightforward to calculate and provide a means for scaling the effect size as an aid to interpretation. Examples from two randomized, multicenter clinical trials in prostate cancer, NRG/RTOG 0521 and NRG/RTOG 0534, with primary endpoints of overall survival and biochemical/radiological progression-free survival, respectively, are presented to illustrate the ideas. The four effect measures (restricted mean survival time difference, restricted mean survival time ratio, time lost ratio, and average survival rate difference) were 0.45 years, 1.05, 0.81, and 0.038 for RTOG 0521 and 1.36 years, 1.17, 0.56, and 0.12 for RTOG 0534 with = 12 and 11 years, respectively. Thus, for example, the 0.45-year difference in the first trial translates into a 19% reduction in time lost and a 3.8% average absolute difference between the survival curves over the 12-year horizon, a modest effect size, whereas the 1.36-year difference in the second trial corresponds to a 44% reduction in time lost and a 12% absolute survival difference, a rather large effect. In addition to the difference in restricted mean survival times, these alternative measures can be helpful in determining whether the magnitude of the treatment effect is clinically meaningful.

Survival benefits of postoperative radiotherapy in patients with cT1 − 2N1M0 breast cancer after neoadjuvant chemotherapy: a SEER-based population study

BackgroundWhether patients with cT1 − 2N1M0 breast cancer can benefit from postoperative radiotherapy (RT) after receiving neoadjuvant chemotherapy (NAC) has been controversial. Therefore, the purpose of this study was to explore whether postoperative RT can benefit this group of patients in terms of survival.MethodsWe used Surveillance, Epidemiology, and End Results (SEER) data to conduct a retrospective review of women with cT1 − 2N1M0 breast cancer diagnosed between 20 and 80 years of age who received NAC between 2010 and 2015. Our study compared the impact of postoperative RT on overall survival (OS) and cancer-specific survival (CSS) in breast cancer patients using propensity score matching (PSM) and performed subgroup analysis.ResultsThis study finally included 1092 cT1 − 2N1M0 breast cancer patients. Regardless of the patient’s PSM status, postoperative RT was significantly associated with OS of cT1-2N1M0 breast cancer patients who received NAC. Specifically, the 10-year OS rate was 78.7% before PSM matching, compared with 71.1% in patients who did not receive postoperative RT, and the difference was more significant after PSM matching, which was 83.1% and 71.1% respectively. However, postoperative RT did not significantly benefit CSS in patients with cT1 − 2N1M0 breast cancer who received NAC. The 10-year CSS rate was 81.4% VS 76.2% (P = 0.085) before PSM matching and 85.8% VS 76.2%(P = 0.076) after matching. Due to the intersection of OS and CSS curves, this restricted mean survival time (RMST) method was chosen as a supplement. After 60 months, the OS difference in RMST between the postoperative RT group and the non-radiotherapy (noRT) group was 7.37 months (95%CI: 0.54–14.21; P = 0.034), and the CSS difference was 5.18 months (95%CI: -1.31-11.68; P = 0.118). Subgroup analysis found that in patients with right-sided breast cancer, postoperative RT improved the patient’s OS (HR = 0.45, 95%CI: 0.21–0.95, P = 0.037) and CSS (HR = 0.42, 95%CI: 0.18–0.98, P = 0.045).ConclusionsOur results showed that additional postoperative RT improved the OS of cT1 − 2N1M0 breast cancer patients who received NAC, but failed to improve their CSS. It is worth noting that in the subgroup analysis of patients with right-sided breast cancer, we observed significant improvements in OS and CSS. And further prospective studies are still needed to verify the effect of postoperative RT in different subgroups.

Harnessing cell-free orphan non-coding RNAs as a predictive measure of long-term survival in neoadjuvant breast cancer therapy.

585 Background: Pathologic complete response (pCR) is a valuable metric for predicting survival following neoadjuvant therapy (NAT) in breast cancer; however, blood-based biomarkers may refine the prediction of treatment outcomes and inform follow-up treatment decisions. Orphan non-coding RNAs (oncRNAs) are a novel category of small RNAs that are present in tumors and largely absent in healthy tissue. Here, we explore the feasibility of a tumor-naive oncRNA-based liquid biopsy assay for predicting distant recurrence-free survival (DRFS) in breast cancer patients using a standard blood draw. Methods: Our cohort included 538 high-risk breast cancer patients from the multicenter I-SPY2 trial having serum available after NAT and before surgery (timepoint T3). Of the 538 patients (mean age: 48.8 ± 10.3), 191 (36%) achieved pCR. We isolated small RNA from 0.8 mL of patient serum and sequenced it at an average depth of 50 million 100-bp single-end reads. We used our catalog of tumor-derived oncRNAs, discovered in The Cancer Genome Atlas, to develop an AI model for predicting tumor burden based on tumor size. Our AI model was trained on oncRNA profiles from an independent cohort of 719 serum samples collected at diagnosis from individuals with cancer. We assessed tumor burden by oncRNA in the I-SPY2 cohort at T3 and associated this measure with DRFS using robust cutpoints established for each of the two pCR groups: high- ( n=70) and low-burden ( n=468) cutpoints were verified through cross-validation and almost all folds converged on a single value, which we used in our analysis. Results: The continuous oncRNA-derived tumor burden at T3 had a hazards ratio (HR) of 2.4 (95% CI: 1.1–5.1) for predicting DRFS. This measure remained significant in multivariate Cox models that included pCR (HR = 2.7 [1.3–5.6]) or residual cancer burden (RCB II/III versus 0/I; HR = 3.4 [1.6–7.1]). Patients with pCR had a 3-year DRFS of 94%; patients with pCR having low ( n=180) versus high ( n=11) oncRNA burden resulted in 95% and 73% 3-year DRFS, respectively (HR = 7.4 [2.3–24]). Those without pCR had a 3-year DRFS of 78% and stratification by oncRNA burden resulted in 85% and 71% 3-year DRFS for the low ( n=288) and high ( n=59) burden groups, respectively (HR=2.4 [1.5–3.9]). Importantly, we saw no restricted mean survival time difference (RMST) at 3 years between those with and without pCR among the high oncRNA burden group (0.1-month difference, p=0.97). Conclusions: We demonstrate the utility of a tumor-naive, oncRNA-derived tumor burden AI model as a predictive measure of treatment outcome and as a prognostic biomarker that can be used in addition to pCR to further stratify patients as low or high risk of recurrence. Integration of our oncRNA assay with existing biomarkers and clinicopathologic variables, has the potential to add value for predicting outcomes and prioritizing patients that would benefit from additional care.

When to stop immunotherapy for advanced melanoma: Emulation of target trials.

9521 Background: Immune checkpoint inhibitors (ICI) have demonstrated their effectiveness with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials allowed treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after cessation shows sustained response and a low risk of relapse in the months following cessation. As of yet, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI. Methods: We conducted emulated trials using the cloning, weighting and censoring approach. Each emulated trial aimed at comparing the causal effect of stopping versus continuing ICI at a specific timepoint, in patients still under treatment and with disease control at that time. Results: The study comprised 1017 participants to the MELBASE cohort. Results of the 6-month discontinuation emulated trial showed a significantly lower OS if treatment was discontinued, compared to continuing treatment for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8 to 60.5), and the corresponding restricted mean survival time difference 8.3 months (95% CI: 4.1 to 12.7). The 12-month and 18-month discontinuation emulated trials both showed no evidence of benefit of either discontinuing or continuing ICI at any of those timepoints. The 24-month discontinuation emulated trial results were more in favor of stopping compared to continuing treatment at that decision point, with an absolute 48-month survival 10.5% higher (95% CI 4.4 to 18.1). Conclusions: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.[Table: see text]

Assessing the effect of metastasis-directed therapy in oligometastatic disease using the restricted mean survival time.

Metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) is emerging as an effective therapeutic option for oligometastatic disease (OMD). However, a lack of phase III data, consensus guidelines, and toxicity concerns limit its widespread use. Randomized controlled trials (RCTs) routinely report hazard ratios (HRs) and medians that lack clear clinical and robust interpretation. Restricted-mean survival time (RMST) is the duration of time a patient is expected to survive over the follow-up period, providing a robust and interpretable alternative. We analyzed the efficacy of SBRT using RMST. All registered RCTs of ablative radiotherapy in OMD in ClinicalTrials.gov through 2022 were identified. Data were reconstructed from Kaplan-Meier curves, and the HRs and RMST differences were estimated for surrogate endpoints (SEs) and overall survival (OS). Six studies comprising 426 patients met the inclusion criteria. The RMST differences for SEs ranged from 4.6 months in a study by Iyengar et al. to 11.1 months in SABR-COMET. The RMST differences for OS in SABR-COMET, Gomez et al., and SINDAS studies were 12.6, 15 and 7.9 months, respectively. RMST demonstrates the efficacy of local treatment in OMD. Representing the expected survival time, this method effectively communicates outcomes to patients and clinicians.

Bayesian pairwise meta-analysis of time-to-event outcomes in the presence of non-proportional hazards: A simulation study of flexible parametric, piecewise exponential and fractional polynomial models.

Traditionally, meta-analysis of time-to-event outcomes reports a single pooled hazard ratio assuming proportional hazards (PH). For health technology assessment evaluations, hazard ratios are frequently extrapolated across a lifetime horizon. However, when treatment effects vary over time, an assumption of PH is not always valid. The Royston-Parmar (RP), piecewise exponential (PE), and fractional polynomial (FP) models can accommodate non-PH and provide plausible extrapolations of survival curves beyond observed data. Simulation study to assess and compare the performance of RP, PE, and FP models in a Bayesian framework estimating restricted mean survival time difference (RMSTD) at 50 years from a pairwise meta-analysis with evidence of non-PH. Individual patient data were generated from a mixture Weibull distribution. Twelve scenarios were considered varying the amount of follow-up data, number of trials in a meta-analysis, non-PH interaction coefficient, and prior distributions. Performance was assessed through bias and mean squared error. Models were applied to a metastatic breast cancer example. FP models performed best when the non-PH interaction coefficient was 0.2. RP models performed best in scenarios with complete follow-up data. PE models performed well on average across all scenarios. In the metastatic breast cancer example, RMSTD at 50-years ranged from -14.6 to 8.48 months. Synthesis of time-to-event outcomes and estimation of RMSTD in the presence of non-PH can be challenging and computationally intensive. Different approaches make different assumptions regarding extrapolation and sensitivity analyses varying key assumptions are essential to check the robustness of conclusions to different assumptions for the underlying survival function.

Time- vs Step-Based Physical Activity Metrics for Health

Current US physical activity (PA) guidelines prescribe moderate to vigorous PA (MVPA) time of at least 150 minutes per week for health. An analogous step-based recommendation has not been issued due to insufficient evidence. To examine the associations of MVPA time and step counts with all-cause mortality and cardiovascular disease (CVD). This cohort study analyzed data from an ongoing follow-up study of surviving participants of the Women's Health Study, a randomized clinical trial conducted from 1992 to 2004 in the US to evaluate use of low-dose aspirin and vitamin E for preventing cancer and CVD. Participants were 62 years or older who were free from CVD and cancer, completed annual questionnaires, and agreed to measure their PA with an accelerometer as part of a 2011-2015 ancillary study. Participants were followed up through December 31, 2022. Time spent in MVPA and step counts, measured with an accelerometer for 7 consecutive days. The associations of MVPA time and step counts with all-cause mortality and CVD (composite of myocardial infarction, stroke, and CVD mortality) adjusted for confounders. Cox proportional hazards regression models, restricted mean survival time differences, and area under the receiver operating characteristic curve (AUC) were used to evaluate the associations. A total of 14 399 women (mean [SD] age, 71.8 [5.6] years) were included. The median (IQR) MVPA time and step counts were 62 (20-149) minutes per week and 5183 (3691-7001) steps per day, respectively. During a median (IQR) follow-up of 9.0 (8.0-9.9) years, the hazard ratios (HR) per SD for all-cause mortality were 0.82 (95% CI, 0.75-0.90) for MVPA time and 0.74 (95% CI, 0.69-0.80) for step counts. Greater MVPA time and step counts (top 3 quartiles vs bottom quartile) were associated with a longer period free from death: 2.22 (95% CI, 1.58-2.85) months and 2.36 (95% CI, 1.73-2.99) months at 9 years follow-up, respectively. The AUCs for all-cause mortality from MVPA time and step counts were similar: 0.55 (95% CI, 0.52-0.57) for both metrics. Similar associations of these 2 metrics with CVD were observed. Results of this study suggest that among females 62 years or older, MVPA time and step counts were qualitatively similar in their associations with all-cause mortality and CVD. Step count-based goals should be considered for future guidelines along with time-based goals, allowing for the accommodation of personal preferences.

Does Thoracic Duct Ligation at the Time of Esophagectomy Impact Long-Term Survival? An Individual Patient Data Meta-Analysis.

Background: Thoracic duct ligation (TDL) during esophagectomy has been proposed to reduce the risk of postoperative chylothorax. Because of its role in immunoregulation, some authors argued that it had an unfavorable TDL effect on survival. The aim of this study was to analyze the effect of TDL on overall survival (OS). Methods: PubMed, MEDLINE, Scopus, and Web of Science were searched through December 2023. The primary outcome was 5-year OS. The restricted mean survival time difference (RMSTD), hazard ratios (HRs), and 95% confidence intervals (CI) were used as pooled effect size measures. The GRADE methodology was used to summarize the certainty of the evidence. Results: Five studies (3291 patients) were included. TDL was reported in 54% patients. The patients' age ranged from 49 to 69, 76% were males, and BMI ranged from 18 to 26. At the 5-year follow-up, the combined effect from the multivariate meta-analysis is -3.5 months (95% CI -6.1, -0.8) indicating that patients undergoing TDL lived 3.5 months less compared to those without TDL. TDL was associated with a significantly higher hazard for mortality at 12 months (HR 1.54, 95% CI 1.38-1.73), 24 months (HR 1.21, 95% CI 1.12-1.35), and 28 months (HR 1.14, 95% CI 1.02-1.28). TDL and noTDL seem comparable in terms of the postoperative risk for chylothorax (RR = 0.66; p = 0.35). Conclusions: In this study, concurrent TDL was associated with reduced 5-year OS after esophagectomy. This may suggest the need of a rigorous follow-up within the first two years of follow-up.

Long-Term Impact of Severe Postoperative Complications after Esophagectomy for Cancer: Individual Patient Data Meta-Analysis.

Severe postoperative complications (SPCs) may occur after curative esophagectomy for cancer and are associated with prolonged hospital stay, augmented costs, and increased in-hospital mortality. However, the effect of SPCs on survival after esophagectomy is uncertain. To assess the impact of severe postoperative complications (SPCs) on long-term survival following curative esophagectomy for cancer, we conducted a systematic search of PubMed, MEDLINE, Scopus, and Web of Science databases up to December 2023. The included studies examined the relationship between SPCs and survival outcomes, defining SPCs as Clavien-Dindo grade > 3. The primary outcome measure was long-term overall survival (OS). We used restricted mean survival time difference (RMSTD) and 95% confidence intervals (CIs) to calculate pooled effect sizes. Additionally, we applied the GRADE methodology to evaluate the certainty of the evidence. Ten studies (2181 patients) were included. SPCs were reported in 651 (29.8%) patients. The RMSTD overall survival analysis shows that at 60-month follow-up, patients experiencing SPCs lived for 8.6 months (95% Cis -12.5, -4.7; p < 0.001) less, on average, compared with no-SPC patients. No differences were found for 60-month follow-up disease-free survival (-4.6 months, 95% CIs -11.9, 1.9; p = 0.17) and cancer-specific survival (-6.8 months, 95% CIs -11.9, 1.7; p = 0.21). The GRADE certainty of this evidence ranged from low to very low. This study suggests a statistically significant detrimental effect of SPCs on OS in patients undergoing curative esophagectomy for cancer. Also, a clinical trend toward reduced CSS and DFS was perceived.

Individualized Treatment Effect Prediction with Machine Learning — Salient Considerations

BackgroundMachine learning–based approaches that seek to accomplish individualized treatment effect prediction have gained traction; however, some salient challenges lack wider recognition.MethodsWe describe key methodologic considerations for individualized treatment effect prediction models using data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial for spironolactone in heart failure with preserved ejection fraction. The causal survival forest algorithm was used for model development. Calibration and discrimination were evaluated using a bootstrapping-based internal validation procedure. Observed benefits were described for predicted benefit quartiles and quartiles of a known effect modifier: ejection fraction. A negative control analysis with noncardiovascular death as the outcome was implemented to detect confounding.ResultsAmong 3445 participants, 671 events occurred over a median of 3.3 years of follow-up. In internal validation, a higher average observed benefit was noted among patients in the highest quartile of predicted benefit. The median (interquartile range) of the observed restricted mean survival time difference at 3.3 years at the highest quartile of model-predicted benefit was 62 days (32 to 83) and was 47 days (26 to 67) at the lowest quartile of ejection fraction. Body-mass index had higher contribution to prediction of benefit relative to other included measures (33.7% vs. glomerular filtration rate [27.3%], ejection fraction [15.1%], and younger age [12.8%]) No benefit was observed for noncardiovascular death at higher model-predicted benefit quartiles, although benefit for noncardiovascular death was observed at lower quartiles.ConclusionsCarefully applied and validated predictive models hold promise in identifying heterogeneous treatment effects and are useful for hypothesis generation regarding the role of phenotypic characteristics in modifying the benefit of experimental interventions in clinical trials. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00094302.)

Arterial Thromboembolism in Japanese Patients With Cancer: Incidence, Predictors, and Survival Impact

BackgroundThromboembolism is a significant complication for patients with cancer, leading to treatment interruptions and poor outcomes. ObjectivesThe aim of this study was to investigate the incidence of arterial thromboembolism (ATE) within cancer populations, identify the predictors of ATE, and determine its survival impact. MethodsA retrospective multicenter study was performed using data from the Osaka Cancer Registry linked with administrative data from 2010 to 2015. Patients were monitored for 5 years after cancer diagnosis, and ATE incidence was calculated with death as a competing risk. Fine and Gray competing risk regression models and Cox proportional hazards models were used to evaluate the predictors of ATE and the survival impact. Restricted mean survival time (RMST) was used to assess whether antithrombotic therapy after ATE contributed to improved survival. ResultsThe cohort comprised 97,448 patients with cancer (42.3% women, median age 70 years). ATE incidence displayed an annual increase, peaking 1 year after cancer diagnosis (1-, 2-, 3-, 4-, and 5-year cumulative incidences were 1.29%, 1.77%, 2.05%, 2.22%, and 2.32%, respectively). Male sex, advanced age, advanced cancer stage, and hematologic malignancies correlated with a high risk for ATE. Patients with ATE had a 2-fold increased risk for mortality compared with those without ATE. The 90-day and 1-year RMST differences for those on antithrombotic therapy were 13.3 days (95% CI: 10.4-16.2 days; P < 0.001) and 57.8 days (95% CI: 43.1-72.5 days; P < 0.001), favoring the antithrombotic therapy group. The RMST differences varied by cancer stage. ConclusionsThe risk for ATE varies according to sex, age, and cancer progression and type. Antithrombotic therapy after ATE is associated with improved survival among patients with cancer.

Impact of Targeted Agents on Survival of Chronic Lymphocytic Leukemia Patients Fit for Fludarabine, Cyclophosphamide, and Rituximab (FCR) Relative to Age- and Sex-Matched Population.

To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7-58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was -0.4 months (95% CI: -0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: -0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: -1.6 months; 95% CI: -2.4 to -0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: -0.9 months; 95% CI: -1.7 to -0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP.

Effect of complete mesocolic excision (cme) on long-term survival after right colectomy for cancer: multivariate meta-analysis and restricted mean survival time estimation.

Debate exists concerning the impact of complete mesocolic excision (CME) on long-term oncological outcomes. The aim of this review was to condense the updated literature and assess the effect of CME on long-term survival after right colectomy for cancer. PubMed, MEDLINE, Scopus, and Web of Science were searched through July 2023. The included studies evaluated the effect of CME on survival. The primary outcome was long-term overall survival. Restricted mean survival time difference (RMSTD), hazard ratio (HR), and 95% confidence intervals (CI) were used as pooled effect size measures. GRADE methodology was used to summarize the certainty of evidence. Ten studies (3665 patients) were included. Overall, 1443 (39.4%) underwent CME. The RMSTD analysis shows that at 60-month follow-up, stage I-III CME patients lived 2.5months (95% CI 1.1-4.1) more on average compared with noCME patients. Similarly, stage III patients that underwent CME lived longer compared to noCME patients at 55-month follow-up (6.1months; 95% CI 3.4-8.5). The time-dependent HRs analysis for CME vs. noCME (stage I-III disease) shows a higher mortality hazard in patients with noCME at 6months (HR 0.46, 95% CI 0.29-0.71), 12months (HR 0.57, 95% CI 0.43-0.73), and 24months (HR 0.73, 95% CI 0.57-0.92) up to 27months. This study suggests that CME is associated with unclear OS benefit in stage I-III disease. Caution is recommended to avoid overestimation of the effect of CME in stage III disease since the marginal benefit of a more extended resection may have been influenced by tumor biology/molecular profile and multimodal adjuvant treatments.

Survival outcomes of surgical resection in perihilar cholangiocarcinoma in endemic area of O. Viverrini, Northeast Thailand

BackgroundPerihilar cholangiocarcinoma (pCCA) is an intractable malignancy and remains the most challenge for surgeon. This study aims to investigate survival outcomes and prognostic factors in pCCA patient. MethodsFrom October 2013 to December 2018, 240 consecutive patients with pCCA underwent surgical exploration were retrospectively reviewed. The clinicopathological parameters and surgical outcomes were extracted. Patients were divided into two groups: unresectable and resectable group. The restricted mean survival time between two groups were analyzed. Factors associated with overall survival in resectable group were explored with multivariable Cox regression analysis. ResultsOf the 240 patients, 201 (83.75%) were received surgical resection. The survival outcomes of resectable group were better than unresectable group significantly. The restricted mean survival time difference were 0.5 (95%CI 0.22–0.82) months, 1.8 (95%CI 1.15–2.49) months, 4.7 (95%CI 3.58–5.87) months, and 9.1 (95%CI 7.40–10.78) months at four landmark time points of 3, 6, 12 and 24 months, respectively. The incidence of major complications and 90-day mortality in resectable group were 35.82% and 11.44%, respectively. Multivariable analysis revealed that Bismuth type IV (HR:4.43, 95%CI 1.85–10.59), positive resection margin (HR:4.24, 95%CI 1.74–10.34), and lymph node metastasis (HR:2.29, 95%CI 1.04–4.99) were all independent predictors of long-term survival. For pM0, R0 and pN0 patients, the median survival time was better than pM0, R1 or pN1/2 patients and pM0, R1 and pN1/2 patients (32.4, 10.4 and 4.9 months, respectively; p < 0.001) ConclusionSurgical resection increased survival in pCCA. Bismuth type IV, positive resection margin and lymph node metastasis were independent factors for long-term survival.

RMST-based multiple contrast tests in general factorial designs.

Several methods in survival analysis are based on the proportional hazards assumption. However, this assumption is very restrictive and often not justifiable in practice. Therefore, effect estimands that do not rely on the proportional hazards assumption are highly desirable in practical applications. One popular example for this is the restricted mean survival time (RMST). It is defined as the area under the survival curve up to a prespecified time point and, thus, summarizes the survival curve into a meaningful estimand. For two-sample comparisons based on the RMST, previous research found the inflation of the type I error of the asymptotic test for small samples and, therefore, a two-sample permutation test has already been developed. The first goal of the present paper is to further extend the permutation test for general factorial designs and general contrast hypotheses by considering a Wald-type test statistic and its asymptotic behavior. Additionally, a groupwise bootstrap approach is considered. Moreover, when a global test detects a significant difference by comparing the RMSTs of more than two groups, it is of interest which specific RMST differences cause the result. However, global tests do not provide this information. Therefore, multiple tests for the RMST are developed in a second step to infer several null hypotheses simultaneously. Hereby, the asymptotically exact dependence structure between the local test statistics is incorporated to gain more power. Finally, the small sample performance of the proposed global and multiple testing procedures is analyzed in simulations and illustrated in a real data example.

Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.POUT was a phase III, randomized, open-label trial, including 261 patients with muscle-invasive or lymph node-positive, nonmetastatic upper tract urothelial cancer (UTUC) randomly assigned after radical nephroureterectomy to platinum-based chemotherapy (132) or surveillance (129). Primary outcome analysis demonstrated that chemotherapy improved disease-free survival (DFS). At that time, the planned secondary outcome analysis of overall survival (OS) was immature. By February 2022, 50 and 67 DFS events had occurred in the chemotherapy and surveillance groups, respectively, at a median follow-up of 65 months. The 5-year DFS was 62% versus 45%, univariable hazard ratio (HR), 0.55 (95% CI, 0.38 to 0.80, P = .001). The restricted mean survival time (RMST) was 18 months longer (95% CI, 6 to 30) in the chemotherapy arm. There were 46 and 60 deaths in the chemotherapy and control arms, respectively. The 5-year OS was 66% versus 57%, with univariable HR, 0.68 (95% CI, 0.46 to 1.00, P = .049) and RMST difference 11 months (95% CI, 1 to 21). Treatment effects were consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage. Toxicities were similar to those previously reported, and there were no clinically relevant differences in quality of life between arms. In summary, although OS was not the primary outcome measure, the updated results add further support for the use of adjuvant chemotherapy in patients with UTUC, suggesting long-term benefits.

Impact of pulmonary complications following esophagectomy on long-term survival: multivariate meta-analysis and restricted mean survival time assessment.

Pulmonary complications (PC) are common after esophagectomy and their impact on long-term survival is not defined yet. The present study aimed to assess the effect of postoperative PCs on long-term survival after esophagectomy for cancer. Systematic review of the literature through February 1, 2023, was performed. The included studies evaluated the effect of PC on long-term survival. Primary outcome was long-term overall survival (OS). Cancer-specific survival (CSS) and disease-free survival (DFS) were secondary outcomes. Restricted mean survival time difference (RMSTD), hazard ratio (HR), and 95% confidence intervals (CI) were used as pooled effect size measures. Eleven studies were included (3423 patients). Overall, 674 (19.7%) patients developed PC. The RMSTD analysis shows that at 60-month follow-up, patients not experiencing PC live an average of 8.5 (95% CI 6.2-10.8; p < 0.001) months longer compared with those with PC. Similarly, patients not experiencing postoperative PC seem to have significantly longer CSS (8months; 95% CI 3.7-12.3; p < 0.001) and DFS (5.4months; 95% CI 1.6-9.1; p = 0.005). The time-dependent HRs analysis shows a reduced mortality hazard in patients without PC at 12 (HR 0.6, 95% CI 0.51-0.69), 24 (HR 0.64, 95% CI 0.55-0.73), 36 (HR 0.67, 95% CI 0.55-0.79), and 60months (HR 0.69, 95% CI 0.51-0.89). This study suggests a moderate clinical impact of PC on long-term OS, CSS, and DFS after esophagectomy. Patients not experiencing PC seem to have a significantly reduced mortality hazard up to 5years of follow-up.

Transvaginal Polytetrafluoroethylene Mesh Surgery for Pelvic Organ Prolapse: One-Year Safety and Efficacy Results

ObjectivesTo evaluate the efficacy and safety of the polytetrafluoroethylene (PTFE) mesh by comparing conventionally used polypropylene (PP) mesh in tension-free vaginal mesh (TVM) surgery for pelvic organ prolapse (POP). MethodsWe conducted an observational cohort study of patients who underwent TVM using a PTFE or PP mesh. PTFE was used from June 2019 to May 2021, and PP mesh from January 2018 to May 2019. Outcomes included POP recurrence, perioperative complications, and patient satisfaction. Restricted mean survival time (RMST) was used to analyze POP recurrence, comparing the time to recurrence between the two groups at 1 year after TVM. ResultsOf 171 patients, 104 underwent PP mesh placement (PP group) and 67 underwent PTFE mesh placement (PTFE group). POP recurrence was observed in 10 and nine patients in the PP and PTFE groups, respectively. The mean time until the recurrence in the PTFE group was significantly shorter than that in the PP group (RMST difference: -20.3 days; 95% CI, -40.1 to -0.5; P=0.044). Subgroup analysis revealed the mean time until recurrence was significantly shorter in the PTFE group for postoperative periods 3 months or less, ages >70 yrs, and POP stage ≥3. There were no intervention cases in either group and no significant differences in the perioperative complications. Patient satisfaction was greater in the PTFE group after three months postoperatively. ConclusionTVM surgery with a PTFE mesh is more prone to recurrence than that with a PP mesh, but with higher patient satisfaction. Within three months of surgery, elderly patients and those with advanced stage POP require care to prevent recurrence.