Analysis Of Individual Patient Data Research Articles

Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data.

The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease. Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups. Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics. Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.

PROLONGED MECHANICAL VENTILATION IN ACUTE RESPIRATORY DISTRESS SYNDROME.

Purpose: Trajectory of acute respiratory distress syndrome (ARDS) spans from rapidly improving cases to cases receiving prolonged mechanical ventilation (PMV). We attempted to estimate temporal trends of prevalence and mortality of PMV and to identify risk factors associated with mortality of patients with ARDS receiving PMV. Methods: We performed a secondary analysis of individual patient data from six randomized controlled clinical trials conducted by the ARDS Network. Prolonged mechanical ventilation was defined as the need for mechanical ventilation for >21 consecutive days. Results: Of 4,216 patients with ARDS, 646 (15.3%) received PMV. Prevalence of PMV gradually declined from 18.4% in the ARDS Network: Low-Tidal-Volume Trial (published in 2000) trial to 10.9% in the SAILS (2014) trial ( R2 = 0.728, P = 0.031). Ninety-day mortality of patients receiving PMV did not change over time ( R2 = 0.271, P = 0.290) and remained as high as 36.8%. Ιn the three most recent trials, risk factors associated with mortality among the 250 patients with ARDS receiving PMV included age, malignancy, pneumonia as the cause of ARDS, coagulation dysfunction, and hepatic dysfunction during the first 21 days after trial enrollment. Conclusion: Although prevalence of PMV among patients enrolled in ARDS Network trials gradually declined, mortality did not change. Risk factors associated with mortality were mostly nonmodifiable.

Enhancing meningioma resection: a comprehensive study on the safety and effectiveness of Onyx™ presurgical embolization.

Presurgical embolization (PE) has emerged as an interesting strategy to help turn brain tumor resection more amenable. This study aims to systematically review the safety and effectiveness of Onyx™ PE in meningioma resection. We followed Cochrane Collaboration and PRISMA for systematic review and meta-analysis, querying PUBMED, Cochrane Library, Web of Science, and Embase databases. Major complications were defined as other artery occlusion, visual deficits due to PE, or non temporary nerve damage, while minor included transitory conditions and others without clinical implications. A total of 186 patients were included, in which 120 were WHO grade I (80%), II (16%), and III (4%). Patient baseline characteristics and complications were distributed in groups without or with individual patient data analysis. Individual Patient Data Meta-Analysis (IPDMA) was performed on the last category, comprising 51 meningiomas that underwent Onyx™ PE. Among available data, 70%, 17%, and 13% were WHO grade I, II, and III, respectively. Considering all studies, tumor characteristics regarding grade underscored a certain homogeneity. Complications occurred at a rate of 9% (95% CI, 4 to 14%; I2 = 35%), with the rate of major complications significantly lower at only 1% (95% CI, 0 to 3%; I2 = 32%), whereas of minor complications was 7% (95% CI, 3 to 10%; I2 = 0%). Mean surgery blood loss was 668.7 (95% CI, 534.9 to 835.8; I2 = 0%) in IPDMA. Onyx™ PE is promising for safer surgical meningioma resection, despite limitations. Further studies are required to validate efficacy, enhance patient selection, and refine techniques.

CTNI-54. A COMBINED ANALYSIS OF TWO RANDOMISED STUDIES EXPLORING THE IMPACT OF EXTENDED POST-RADIATION TEMOZOLOMIDE ON SURVIVAL OUTCOMES IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Stupp protocol uses 6 months, however, in routine care, it is often extended to 12 months, given its tolerability, lack of effective salvage treatments, and extended regimen in lower grade gliomas. METHODS GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled patients with newly diagnosed glioblastoma without progression at the end of 6 months post-radiation temozolomide. Participants were randomised in a 1:1 allocation to either six additional months (total 12 months) or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required for 80% power to detect an improvement in 6mPFS from 50% to 60%. Neither study recruited sufficient patients, so we performed a combined analysis of individual patient data. RESULTS 205 patients were recruited: 169 in GEINO14-01 (2014–2018) and 46 in EX-TEM (2019–2022). Median follow up was 20 and 14.5 months respectively. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR 0.75, p = 0.4), nor across any subgroups including MGMT methylated. There was no significant improvement in PFS (HR 0.92, P = 0.59, median 7.8 vs 9.7 months) or OS (HR 1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required changes to treatment, with 4.5% requiring dose delay, 7.5% dose reduction and 1.5% discontinuation of temozolomide. CONCLUSION For patients with newly diagnosed glioblastoma, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any individual patient subset that appeared to benefit from extended treatment. Six months should remain standard of care.

Prognostic Factor Risk Groups for Clinical Stage I Seminoma: An Individual Patient Data Analysis by the European Association of Urology Testicular Cancer Guidelines Panel and Guidelines Office

BackgroundThe relapse rate in patients with clinical stage I (CSI) seminomatous germ cell tumor of the testis (SGCTT) who were undergoing surveillance after radical orchidectomy is 4–30%, depending on tumor size and rete testis invasion (RTI). However, the level of evidence supporting the use of both risk factors in clinical decision-making is low. ObjectiveWe aimed to identify the most important prognostic factors for relapse in CSI SGCTT patients. Design, setting, and participantsIndividual patient data for 1016 CSI SGCTT patients diagnosed between 1994 and 2019 with normal postorchidectomy serum tumor marker levels and undergoing surveillance were collected from nine institutions. Outcome measurements and statistical analysisMultivariable Cox proportional hazard regression models were fit to identify the most important prognostic factors. The primary endpoint was the time to first relapse by imaging and/or markers. Relapse probabilities were estimated by the Kaplan-Meier method. Results and limitationsAfter a median follow-up of 7.7 yr, 149 (14.7%) patients had relapsed. Categorical tumor size (≤2, >2–5, and >5 cm), presence of RTI, and lymphovascular invasion were used to form three risk groups: low (56.4%), intermediate (41.3%), and high (2.3%) risks with 5-yr cumulative relapse probabilities of 8%, 20%, and 44%, respectively. The model outperformed the currently used model with tumor size ≤4 versus >4 cm and presence of RTI (Harrell’s C index 0.65 vs 0.61). The low- and intermediate-risk groups were validated successfully in an independent cohort of 285 patients. ConclusionsThe risk of relapse after radical orchidectomy in CSI SGCTT patients under surveillance is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse. Patient summaryThe risk of relapse after radical orchidectomy in patients with clinical stage I seminomatous germ cell tumor of the testis is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse.

Stimulation of the pulvinar nucleus of the thalamus in epilepsy: A systematic review and individual patient data (IPD) analysis

Emerging neuromodulatory treatments, such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), have shown promise in reducing drug-resistant seizures. While centromedian thalamic nucleus and anterior thalamic nucleus stimulation have been effective in certain types of seizures, limited research has explored pulvinar nucleus stimulation for epilepsy. To address this gap, we conducted a systematic review and individual patient data analysis. Of 78 resultant articles, 5 studies with transient stimulation and chronic stimulation of the pulvinar nucleus were included. Of the 20 patients reviewed, 65% of patients had temporal lobe seizures, while 20% had temporooccipital/occipital lobe seizures. Transient stimulation studies via stereoelectroencephalography (SEEG) showed pulvinar evoked potential response rates of 80% in the mesial temporal region, 76% in the temporal neocortex, and 67% in the TP junction. Another study reported clinically less severe seizures in 62.5% of patients with pulvinar stimulation. In chronic stimulation studies, 80% of patients responded to RNS or DBS, and 2 of 4 patients experienced > 90% seizure reduction. The pulvinar nucleus of the thalamus emerges as a potential target for chronic stimulation in drug-resistant epilepsy. However, knowledge regarding pulvinar connectivity and chronic stimulation remains limited. Further research should investigate specific subregions of the pulvinar for epilepsy treatment. Understanding the role of pulvinar stimulation and its cortical connectivity will advance therapeutic interventions for epilepsy patients.

Correlation between Progression-Free Survival and Overall Survival in Patients with Relapsed Hodgkin Lymphoma: An Analysis of Individual Patient Data from Randomized GHSG Trials

Background: Progression-free survival (PFS) and overall survival (OS) are predominant measures of treatment efficacy in Hodgkin lymphoma (HL). Despite preference for OS from many regulatory authorities, PFS is most relevant to patients and frequently serves as primary endpoint in clinical trials. Recently we found a strong correlation between treatment effects on PFS and OS in the first-line setting (Bröckelmann PJ et al. EHA23/ICML23). However, their relationship in the relapsed setting remains unclear. We aimed to evaluate the correlation of PFS with OS after treatment of relapsed HL. Methods: We evaluated individual patient data of 375 patients with relapsed HL treated within the prospective randomized GHSG trials HDR1 (N= 141) and HDR2 (N= 234) between 02/1993 - 06/2007. Briefly, both trials included patients of 18 to 60 years of age with histologically confirmed relapsed HL after ≥1 prior line of treatment, who had not previously received high-dose chemotherapy and autologous stem-cell transplantation (ASCT). In HDR1 patients received two cycles of Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and ASCT. In HDR2, patients were assigned to two cycles of dexamethasone, cytarabine, and cisplatin (DHAP), and thereafter randomly assigned to either BEAM followed by ASCT or sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM followed by ASCT. All patients who received at least one dose of salvage chemotherapy within the respective trial were included in the analysis. We correlated treatment effects and risk factor effects on PFS and OS with the Wei-Lin-Weissfeld (WLW) method and adjusted the analysis for age and sex. Additionally, we applied copula models to correlate the time-to-event variables PFS and OS themselves using their marginal distributions. Results: With a median follow-up of 4.5 years, at least one PFS event, defined as relapse or progression of relapsed HL or death for any reason, was recorded in 146 of 375 patients (38.9%). At least one OS event, defined as death for any reason, was documented in 111 of 375 patients (29.6%). The hazard ratios for treatment effects on PFS and OS were 0.61 (95% confidence interval, CI= 0.38-0.98) and 1.01 (95% CI= 0.63-1.63) for HDR1 and 1.1 (95% CI= 0.69-1.75) and 0.8 (95% CI= 0.44-1.47) for HDR2, respectively. The WLW analysis revealed high correlations of treatment effects on PFS and OS at patient level within the trials. Pearson correlation r of the treatment effects on PFS and OS were r= 0.72 (95% confidence interval CI= 0.66-0.76, P&amp;lt; 0.001) in all 375 patients analyzed, r= 0.72 (95% CI= 0.63-0.79, P&amp;lt;0.001) in the HDR1 trial and r= 0.74 (95% CI= 0.67-0.79, P&amp;lt; 0.001) in the HDR2 trial. The analysis with different risk factors and copula models revealed similarly high correlations, confirming a strong relation between PFS and OS in relapsed HL patients. Conclusions: PFS and OS as well as treatment effects and prognostic effects on PFS and OS are highly correlated in patients treated for relapsed HL. Confirming results in first-line treatment, PFS thereby constitutes a highly relevant endpoint also in the setting of relapsed HL.

Minimal Residual Disease-Negative Complete Remission at the End of Induction Is a Prognostic Indicator of Long-Term Survival in Adult Patients with Ph+ Acute Lymphoblastic Leukemia Receiving First-Line Therapy

Background: Minimal residual disease (MRD) is an established, prognostic indicator for patients with acute lymphoblastic leukemia (ALL), including Philadelphia chromosome-positive (Ph+) ALL. The objective of this study was to evaluate the association between MRD and long-term outcomes (event-free survival [EFS] and overall survival [OS]) in adult patients with Ph+ ALL receiving first-line therapy. Methods: A systematic literature review (SLR) was performed to identify eligible studies, including interventional and observational studies reporting survival outcomes by MRD status in adults ≥18 years of age with Ph+ ALL receiving first-line therapy. Key outcomes and data elements of interest were EFS, OS, and MRD or MRD-negative complete remission (CR) at end of induction (EOI). Aggregate study-level and individual patient data (IPD) meta-analyses were conducted. The IPD approach included a log-level MRD analysis to evaluate the concordance of deepening levels of molecular response with long-term EFS or OS in patients with CR and an analysis evaluating the utility of MRD-negative CR over CR alone. The analyses were conducted using frequentist and Bayesian approaches with fixed-effects and random-effects models. Kaplan-Meier method with log-rank tests was used for survival analysis. Where applicable, Cox regression method with and without adjustment for prognostic factors were applied. Results: The SLR identified 19 publications (18 unique studies), 10 (9 unique studies) of which had sufficient MRD and EFS/OS data. Nine studies (n=704) were included in the aggregate study-level analysis; 3 of the 9 studies (Phase II AP24534-11-001 [Jabbour et al. 2015], Phase II GIMEMAINCB 84344-201 [Martinelli et al. 2017], and Phase III GRAAPH-2005 RCT [Chalandon et al. 2015]) had IPD available. MRD was assessed by polymerase chain reaction in all 9 studies. Findings from the aggregate study-level meta-analysis demonstrated a significant long-term survival benefit (EFS and OS) in favor of patients with MRD-negative CR. This significant benefit was generally consistent across analysis types (base-case or sensitivity analyses), analytic models (fixed- or random-effects), and approaches (frequentist or Bayesian). Evidence from the IPD analysis, based on patients with CR, was mostly consistent with the aggregate study-level meta-analysis, supporting MRD-negative CR at the EOI as being predictive of EFS or OS. Log-level MRD analysis showed that patients who are in CR with deeper molecular response ( BCR::ABL1/ABL1 ≤0.01%) at EOI have significantly better long-term EFS and OS compared with patients with other levels of MRD (ie, BCR::ABL1/ABL1 &amp;gt;0.01%). This significant long-term survival benefit was also demonstrated in patients with MRD-negative CR ( BCR::ABL1/ABL1 ≤0.01%) at EOI compared with patients who were MRD-positive ( BCR::ABL1/ABL1 &amp;gt;0.01%) ( Table 1) or based on achievement of CR alone (regardless of BCR::ABL1/ABL1 values). Results from the IPD analysis standardized for outcome definition, with and without adjustment for prognostic factors (age, gender, white blood cell count at baseline, and stem cell transplant), were consistent with the findings from the log-level MRD analysis. The analysis showed a significant association between MRD-negative/MRD-negative CR status (ie, BCR::ABL1/ABL1 ≤0.01% threshold) at EOI with improved long-term EFS and OS. The results were significant for EFS in both the adjusted and unadjusted models. The OS results were significant only in the unadjusted model. Conclusions: These analyses indicate that a deeper molecular response at EOI results in better long-term EFS and OS; MRD-negative CR has a greater prognostic value than CR and is strongly associated with long-term EFS and OS in patients with Ph+ ALL. Acknowledgement: The authors acknowledge APHP, who provided the individualized patients data for the GRAAPH study.

Safety and tolerability of long-term treatment with darolutamide in patients with metastatic castration-resistant prostate cancer

BackgroundIn patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available.MethodsTreatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies.ResultsAll patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1.ConclusionsLong-term darolutamide treatment was well tolerated; no new safety signals observed.Tweetable abstractIn patients with mCRPC, long-term darolutamide treatment was well tolerated and no new safety signals were observed. These findings are consistent with previous reports, demonstrating a favorable safety and tolerability profile of darolutamide.

Graft Failure After Coronary Artery Bypass Grafting and Its Association With Patient Characteristics and Clinical Events: A Pooled Individual Patient Data Analysis of Clinical Trials With Imaging Follow-Up.

Graft patency is the postulated mechanism for the benefits of coronary artery bypass grafting (CABG). However, systematic graft imaging assessment after CABG is rare, and there is a lack of contemporary data on the factors associated with graft failure and on the association between graft failure and clinical events after CABG. We pooled individual patient data from randomized clinical trials with systematic CABG graft imaging to assess the incidence of graft failure and its association with clinical risk factors. The primary outcome was the composite of myocardial infarction or repeat revascularization occurring after CABG and before imaging. A 2-stage meta-analytic approach was used to evaluate the association between graft failure and the primary outcome. We also assessed the association between graft failure and myocardial infarction, repeat revascularization, or all-cause death occurring after imaging. Seven trials were included comprising 4413 patients (mean age, 64.4±9.1 years; 777 [17.6%] women; 3636 [82.4%] men) and 13 163 grafts (8740 saphenous vein grafts and 4423 arterial grafts). The median time to imaging was 1.02 years (Q1;Q3: 1.00;1.03). Graft failure occurred in 1487 (33.7%) patients and in 2190 (16.6%) grafts. Age (adjusted odds ratio [aOR], 1.08 [per 10-year increment] [95% CI, 1.01-1.15]; P=0.03), female sex (aOR, 1.27 [95% CI, 1.08-1.50]; P=0.004), and smoking (aOR, 1.20 [95% CI, 1.04-1.38]; P=0.01) were independently associated with graft failure, whereas statins were associated with a protective effect (aOR, 0.74 [95% CI, 0.63-0.88]; P<0.001). Graft failure was associated with an increased risk of myocardial infarction or repeat revascularization occurring between CABG and imaging assessment (8.0% in patients with graft failure versus 1.7% in patients without graft failure; aOR, 3.98 [95% CI, 3.54-4.47]; P<0.001). Graft failure was also associated with an increased risk of myocardial infarction or repeat revascularization occurring after imaging (7.8% versus 2.0%; aOR, 2.59 [95% CI, 1.86-3.62]; P<0.001). All-cause death after imaging occurred more frequently in patients with graft failure compared with patients without graft failure (11.0% versus 2.1%; aOR, 2.79 [95% CI, 2.01-3.89]; P<0.001). In contemporary practice, graft failure remains common among patients undergoing CABG and is strongly associated with adverse cardiac events.

The Index of Microcirculatory Resistance After Primary PCI: A Pooled Analysis of Individual Patient Data

BackgroundDespite treatment with primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI), the risk of heart failure and late death remains high. Microvascular dysfunction, as assessed by the index of microcirculatory resistance (IMR), after primary PCI for STEMI has been associated with worse outcomes. It is unclear whether IMR after primary PCI predicts cardiac death. ObjectivesThe aims of this analysis were: 1) to determine if IMR is an independent predictor of cardiac death; 2) to assess the optimal cutoff value of IMR after STEMI; and 3) to compare IMR with several cardiac magnetic resonance parameters, including infarct size. MethodsIn a collaborative, pooled analysis of individual patient data from 6 cohorts that measured IMR directly after primary PCI, cardiac mortality up to 5 years was estimated using Kaplan-Meier analyses. The primary endpoint was cardiac death using the predefined IMR cutoff value of 40. ResultsIn total, 1,265 patients were included in this study with a median follow-up of 2.8 years (IQR: 1.2-5.0 years). Cardiac death at 5 years occurred in 2.2% and 4.9% of patients (HR: 2.81; 95% CI: 1.34-5.88; P = 0.006) in the IMR ≤40 and IMR >40 groups, respectively. The composite of cardiac death or hospitalization for heart failure occurred in 4.9% and 8.9% (HR: 1.98; 95% CI: 1.20-3.29; P = 0.008) in the IMR ≤40 and IMR >40 groups, respectively. IMR was an independent predictor of cardiac death, whereas coronary flow reserve was not. The optimal cutoff value of IMR for the prediction of cardiac death in this cohort was 70 (HR: 4.73; 95% CI: 2.27-9.83; P < 0.001). Infarct size was 17.6% ± 13.3% and 23.9% ± 14.6% of the left ventricular mass in the IMR ≤40 and IMR >40 groups, respectively (P < 0.001). Microvascular obstruction and intramyocardial hemorrhage occurred more frequently in the IMR >40 group than in the IMR ≤40 group. ConclusionsIn this large, pooled analysis of individual patient data, IMR measured directly after primary PCI in STEMI was an independent predictor of cardiac death. IMR may be used as a tool to identify patients at the time of primary PCI who are at highest risk for late cardiac mortality and who might benefit most from additional cardioprotective therapies and monitoring.

1770O Refining risk stratification in patients undergoing radiotherapy (RT) and long-term (lt) ADT for high-risk/locally advanced prostate cancer (HR/LA-PC): An individual patient data (IPD) analysis of randomized controlled trials (RCTs) from the ICECaP consortium

1770O Refining risk stratification in patients undergoing radiotherapy (RT) and long-term (lt) ADT for high-risk/locally advanced prostate cancer (HR/LA-PC): An individual patient data (IPD) analysis of randomized controlled trials (RCTs) from the ICECaP consortium

Individual Patient Data Analysis of 17 Randomized Trials vs. Real-World Data for Men with Localized Prostate Cancer Receiving Radiotherapy.

Prior work has demonstrated poor correlation between the results of randomized controlled trials (RCTs) and real-world evidence (RWD). However, patients enrolled in RCTs are often considered to poorly represent the real-world population. Herein, we utilize multiple large data repositories to determine differences in baseline characteristics and long-term outcomes between patients enrolled in RCTs and RWD that received radiotherapy for localized prostate cancer. Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was leveraged, and 17 phase III randomized trials were included. RWD were accessed through the Staging Collaboration for Cancer of the Prostate (STAR-CAP) cohort, a cohort that is comprised of >60 centers across the United States and Europe. Additionally, RWD was assessed via the Surveillance, Epidemiology, and End Results (SEER) database. MARCAP and STAR-CAP both contain outcomes for distant metastasis (DM), metastasis-free survival (MFS), prostate cancer-specific mortality (PCSM), and overall survival (OS). SEER only contains PCSM and OS. Wilcoxon signed-rank test and chi-square test were used to compare continuous and categorical variables, respectively. Inverse probability of treatment weighting (IPTW) analysis was conducted, balancing for age, PSA, Gleason score, T stage, and treatment year in the three cohorts. Cox and Fine-Gray regression models were used to compare disease outcomes between RCTs vs. RWD. Data from 10,666 patients from RCTs, 6,530 patients in STAR-CAP, and 117,586 patients in SEER were included. SEER patients were slightly younger (p<0.001, median age 68 (IQR 62-73) than those in RCTs (70, IQR 65-74) and in STAR-CAP (70, IQR 64-74). 10-year OS in RCTs was 65.4%, STAR-CAP 70.2%, SEER 64.1%. OS was superior in STAR-CAP (RCTs as reference; HR 0.91, 95% CI 0.85-0.96, p<0.0001), but there was no significant difference between SEER and RCTs (HR 0.96, 95% CI 0.91-1.02, p = 0.22). 10-year PCSM cumulative incidence was 7.4% in RCTs, 8.1% in STAR-CAP, and 11.0% in SEER. There was no significant difference in PCSM between STAR-CAP RWD and RCTs (HR 0.88, 95% CI 0.78-1.01, p = 0.08), whereas PCSM was worse in SEER than RCTs (HR 1.37, 95% CI 1.21-1.55, p<0.0001). There was no significant difference in DM between STAR-CAP RWD and RCTs (HR 0.93, 95% CI 0.83-1.04, p = 0.2). While baseline differences exist in patients enrolled on localized prostate cancer RCTs and real-world datasets, there were small if any significant relative differences in oncologic outcomes. This provides reassurance that RCT results are generally applicable to patients in routine practice.

Evaluating Response Trends of Chlormethine/Mechlorethamine Gel in Patients With Stage I-IIA Mycosis Fungoides: Analysis of Individual Patient Data From a Randomized Controlled Phase II Study to Facilitate Optimal Treatment Experiences

IntroductionChlormethine (CL) gel was approved for treatment of mycosis fungoides based on the pivotal 201 trial (NCT00168064). Data visualization from individual patients is a powerful tool for discovery of hidden treatment trends. Here, we present a post hoc analysis of individual patient data from the pivotal trial to provide a more granular depiction of treatment and response changes over time, with an emphasis on end of treatment status. Materials and MethodsIndividual patient response data were plotted over a 12-month treatment period to visualize patient experiences while using CL gel. Responder status was assigned according to end-of-treatment Composite Assessment of Index Lesion Severity (CAILS) score, and patients were classified as early (≤4 months) or late responders based on timing of response. Baseline and active treatment characteristics were compared between early and late responders, and baseline body surface area (BSA) was compared between responders and patients with stable or progressive disease. ResultsData from 123 patients with baseline and postbaseline results were included. At the end of treatment, 64.2%/55.3% were responders, 30.9%/34.1% had stable disease, and 4.9%/10.6% had progressive disease by CAILS and mSWAT, respectively. Among patients who responded to treatment, 64.6% and 35.4% were early and late responders, respectively. Response pattern analysis also identified patients with an intermittent response or initial progressive disease. Baseline BSA was not associated with responder status. Late responders had longer treatment duration and higher postbaseline plaque elevation, while early responders had a higher frequency of dermatitis. ConclusionsResults presented here can facilitate optimal treatment experiences for patients starting CL gel.

Infarct severity and outcomes in ST-elevation myocardial infarction patients without standard modifiable risk factors – A multicenter cardiac magnetic resonance study

BackgroundStandard modifiable cardiovascular risk factors (SMuRFs) are well-established players in the pathogenesis of ST-elevation myocardial infarction (STEMI). However, in a significant proportion of STEMI patients, no SMuRFs can be identified, and the outcomes of this subgroup are not well described. ObjectivesTo assess the infarct characteristics at myocardial-tissue level and subsequent clinical outcomes in SMuRF-less STEMIs. MethodsThis multicenter, individual patient-data analysis included 2012 STEMI patients enrolled in four cardiac magnetic resonance (CMR) imaging studies conducted in Austria, Germany, Scotland, and the Netherlands. Unstable patients at time of CMR (e.g. cardiogenic shock/after cardiac arrest) were excluded. SMuRF-less was defined as absence of hypertension, smoking, hypercholesterolemia, and diabetes mellitus. All patients underwent CMR 3(interquartile range [IQR]:2–4) days after infarction to assess left ventricular (LV) volumes and ejection fraction, infarct size and microvascular obstruction (MVO). Clinical endpoints were defined as major adverse cardiovascular events (MACE), including all-cause mortality, re-infarction and heart failure. ResultsNo SMuRF was identified in 185 patients (9%). These SMuRF-less patients were older, more often male, had lower TIMI risk score and pre-interventional TIMI flow, and less frequently multivessel-disease. SMuRF-less patients did not show significant differences in CMR markers compared to patients with SMuRFs (all p > 0.10). During a median follow-up of 12 (IQR:12-27) months, 199 patients (10%) experienced a MACE. No significant difference in MACE rates was observed between SMuRF-less patients and patients with SMuRFs (8vs.10%, p = 0.39). ConclusionsIn this large individual patient-data pooled analysis of low-risk STEMI patients, infarct characteristics and clinical outcomes were not different according to SMuRF status.

The effects of advanced factor analysis approaches on outcomes in randomised trials for depression: protocol for secondary analysis of individual participant data.

Modern psychometric methods make it possible to eliminate nonperforming items and reduce measurement error. Application of these methods to existing outcome measures can reduce variability in scores, and may increase treatment effect sizes in depression treatment trials. We aim to determine whether using confirmatory factor analysis techniques can provide better estimates of the true effects of treatments, by conducting secondary analyses of individual patient data from randomised trials of antidepressant therapies. We will access individual patient data from antidepressant treatment trials through Clinicalstudydatarequest.com and Vivli.org, specifically targeting studies that used the Hamilton Rating Scale for Depression (HRSD) as the outcome measure. Exploratory and confirmatory factor analytic approaches will be used to determine pre-treatment (baseline) and post-treatment models of depression, in terms of the number of factors and weighted scores of each item. Differences in the derived factor scores between baseline and outcome measurements will yield an effect size for factor-informed depression change. The difference between the factor-informed effect size and each original trial effect size, calculated with total HRSD-17 scores, will be determined, and the differences modelled with meta-analytic approaches. Risk differences for proportions of patients who achieved remission will also be evaluated. Furthermore, measurement invariance methods will be used to assess potential gender differences. Our approach will determine whether adopting advanced psychometric analyses can improve precision and better estimate effect sizes in antidepressant treatment trials. The proposed methods could have implications for future trials and other types of studies that use patient-reported outcome measures.

Secondary cytoreduction in platinum sensitive relapsed ovarian cancer: an individual patient level meta-analysis

ObjectiveTo synthesize the role of secondary cytoreduction in recurrent ovarian cancer from the results of randomized studies.MethodsWe conducted a meta-analysis of randomized controlled trials which compared secondary cytoreductive surgery versus...

The immune-related adverse events paradoxin locally advanced or metastatic urothelial cancer after atezolizumab immunotherapy: analysis of individual patient data from IMvigor210 and IMvigor211 trials.

To investigate the association between immune-related adverse events (irAEs) and oncological outcomes in patients with advanced urothelial cancer receiving immune checkpoint inhibitors (ICIs), and whether the administration of systemic corticosteroids diminishes therapeutic impact. The association between irAEs occurrence and clinical progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) was tested by means of multivariable Cox or competing-risks regression, when appropriate. Patients experiencing irAEs were further stratified based on systemic corticosteroids administration. A sensitivity analysis was conducted by repeating all the analyses with median time to irAE as landmark point. We relied on individual participant data from two prospective trials for advanced urothelial cancer: IMvigor210 and IMvigor211. A total of 896 patients who received atezolizumab for locally advanced or metastatic urothelial cancer were considered. Overall, irAEs were recorded in 195 patients and the median time to irAEs was 64 days. On multivariable analysis, irAEs were inversely associated with the risk of disease progression (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.40-0.61; P < 0.001), overall mortality (HR 0.51, 95% CI 0.41-0.64; P < 0.001), and cancer-specific mortality (subdistributional HR [sHR] 0.55, 95% CI 0.45-0.72; P < 0.001). Moreover, our results did not refute the supposition that the administration of systemic corticosteroids does not impact oncological outcomes (PFS: HR 0.92, 95% CI 0.62-1.34, P = 0.629; OS: HR 0.86, 95% CI 0.51-1.64, P = 0.613; CSS: sHR 0.90, 95% CI 0.60-1.36, P = 0.630). The sensitivity analysis confirmed our findings. The development of irAEs while receiving atezolizumab treatment was associated with improved oncological outcomes, namely overall and cancer-specific mortality, and PFS. These findings seem to not be substantially affected by administration of systemic corticosteroids.

Primary intracranial histiocytic sarcomas: a report of six cases and a pooled analysis of individual patient data.

Primary intracranial histiocytic sarcomas (PIHSs) are extremely rare with limited reported cases, making their prognostic factors and management uncertain. This study aims to describe the clinical characteristics of PIHSs and propose a treatment protocol for this entity. Clinical data were collected from six patients diagnosed with PIHSs at Beijing Tiantan Hospital between March 2011 and October 2022. Additionally, a comprehensive search of the PubMed database was conducted using the keywords "primary intracranial" or "primary central nervous system" combined with "histiocytic sarcoma" or "histiocytic sarcomas" between 1996 and 2022, identifying 24 cases. A pooled analysis of individual patient data was performed to assess risk factors for overall survival (OS). The six cases included four males and two females, with a mean age of 42.2 ± 13.3years. In total, 24 cases of PIHSs were identified from previous studies. Multivariate Cox regression analysis revealed that gross total resection (GTR) was the only factor predicting a longer OS (p = 0.027). Kaplan-Meier analysis demonstrated that GTR (p = 0.0013), solitary lesions (p = 0.0048), and radiotherapy (p = 0.0492) were associated with a longer OS. PIHSs are rare brain tumors with poor clinical prognosis. Patients with solitary lesions have a longer OS than those with multifocal lesions. Gross total resection must be the first choice. Radiotherapy may bring benefits for these patients, but chemotherapy may not be useful. Further studies involving larger cohorts are necessary to validate these findings.

Prognostic value of the right ventricular ejection fraction using three-dimensional echocardiography: Systematic review and meta-analysis.

Three-dimensional echocardiography (3DE) is a robust method for measuring the right ventricular (RV) ejection fraction (EF), which is closely associated with outcomes. We performed a systematic review and meta-analysis (1) to examine the prognostic value of RVEF and (2) to compare its prognostic value with that of left ventricular (LV) EF and LV global longitudinal strain (GLS). We also performed individual patient data analysis to validate the results. We searched articles reporting the prognostic value of RVEF. Hazard ratios (HR) were re-scaled using the within-study standard deviation (SD). To compare predictive values of RVEF and LVEF or LVGLS, the ratio of HR related to a 1-SD reduction of RVEF versus LVEF or LVGLS was calculated. Pooled HR of RVEF and pooled ratio of HR were analyzed in a random-effects model. Fifteen articles with 3,228 subjects were included. Pooled HR of a 1-SD reduction of RVEF was 2.54 (95% confidence interval (CI): 2.15-3.00). In subgroup analysis, RVEF was significantly associated with outcome in pulmonary arterial hypertension (PAH) (HR: 2.79, 95% CI: 2.04-3.82) and cardiovascular (CV) diseases (HR: 2.23, 95%CI: 1.76-2.83). In studies reporting HRs for both RVEF and LVEF or RVEF and LVGLS in the same cohort, RVEF had 1.8-fold greater prognostic power per 1-SD reduction than LVEF (ratio of HR: 1.81, 95%CI: 1.20-2.71), but had predictive value similar to that of LVGLS (ratio of HR: 1.10, 95%CI: 0.91-1.31) and to LVEF in patients with reduced LVEF (ratio of HR: 1.34, 95%CI: 0.94-1.91). In individual patient data analysis (n = 1,142), RVEF < 45% was significantly associated with worse CV outcome (HR: 4.95, 95% CI: 3.66-6.70), even in patients with reduced or preserved LVEF. The findings of this meta-analysis highlight and support the use of RVEF assessed by 3DE to predict CV outcomes in routine clinical practice in patients with CV diseases and in those with PAH.