Individual Patient-level Data Research Articles

Overcoming denominator problems in refugee settings with fragmented electronic records for health and immigration data: a prediction-based approach.

Epidemiological studies in refugee settings are often challenged by the denominator problem, i.e. lack of population at risk data. We develop an empirical approach to address this problem by assessing relationships between occupancy data in refugee centres, number of refugee patients in walk-in clinics, and diseases of the digestive system. Individual-level patient data from a primary care surveillance system (PriCarenet) was matched with occupancy data retrieved from immigration authorities. The three relationships were analysed using regression models, considering age, sex, and type of centre. Then predictions for the respective data category not available in each of the relationships were made. Twenty-one German on-site health care facilities in state-level registration and reception centres participated in the study, covering the time period from November 2017 to July 2021. 445 observations ("centre-months") for patient data from electronic health records (EHR, 230 mean walk-in clinics visiting refugee patients per month and centre; standard deviation sd: 202) of a total of 47.617 refugee patients were available, 215 for occupancy data (OCC, mean occupancy of 348 residents, sd: 287), 147 for both (matched), leaving 270 observations without occupancy (EHR-unmatched) and 40 without patient data (OCC-unmatched). The incidence of diseases of the digestive system, using patients as denominators in the different sub-data sets were 9.2% (sd: 5.9) in EHR, 8.8% (sd: 5.1) when matched, 9.6% (sd: 6.4) in EHR- and 12% (sd 2.9) in OCC-unmatched. Using the available or predicted occupancy as denominator yielded average incidence estimates (per centre and month) of 4.7% (sd: 3.2) in matched data, 4.8% (sd: 3.3) in EHR- and 7.4% (sd: 2.7) in OCC-unmatched. By modelling the ratio between patient and occupancy numbers in refugee centres depending on sex and age, as well as on the total number of patients or occupancy, the denominator problem in health monitoring systems could be mitigated. The approach helped to estimate the missing component of the denominator, and to compare disease frequency across time and refugee centres more accurately using an empirically grounded prediction of disease frequency based on demographic and centre typology. This avoided over-estimation of disease frequency as opposed to the use of patients as denominators.

Thrombolysis for Wake-Up Stroke Versus Non-Wake-Up Unwitnessed Stroke: EOS Individual Patient Data Meta-Analysis.

Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella and Mammella Intergruppo trials

Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials. Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer-free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R2≥0.70 were considered as indicators of a clinically relevant surrogacy. Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI. Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials. This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health-5×1000 funds (years 2021-2022).

Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine KinaseInhibitor.

Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor Tcell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95%CI 2.81-38.46]) and complete response (OR 10.11 [95%CI 4.26-24.00]), and improved progression-free survival (HR0.44 [95%CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Adjusted Indirect Treatment Comparison of Progression-Free Survival with D-Rd and VRd Based on MAIA and SWOG S0777 Individual Patient-Level Data.

Daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd) are commonly used treatment combinations for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). D-Rd and VRd demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naïve comparisons of efficacy across the two trials may be biased because MAIA enrolled only TIE patients (median age 73years), whereas SWOG S0777 enrolled both TIE patients and transplant-eligible patients who chose to defer/refuse frontline stem cell transplantation (median age 63years). The present study compared progression-free survival (PFS) in TIE patients with NDMM treated with D-Rd versus VRd based on an adjusted indirect treatment comparison (ITC) that leveraged individual patient-level data from MAIA and SWOG S0777. Harmonized inclusion/exclusion criteria (including age ≥ 65years as a proxy for transplant ineligibility) and propensity-score weighting were used to balance the trial populations on measured baseline characteristics. After differences in trial populations were adjusted for, an anchored ITC was performed wherein within-trial PFS hazard ratios (HRs) for D-Rd versus Rd and VRd versus Rd were estimated and used to make indirect inference about PFS for D-Rd versus VRd. PFS HRs were 0.52 (95% confidence interval [CI] 0.41-0.67) for D-Rd versus Rd based on MAIA data, 0.88 (95%CI 0.63-1.23) for VRd versus Rd based on SWOG S0777 data, and 0.59 (95%CI 0.39-0.90) for the Rd-anchored ITC of D-Rd versus VRd. Sensitivity and subgroup analyses produced results consistent with the primary results. This anchored ITC demonstrated a greater PFS benefit for D-Rd versus VRd in TIE patients with NDMM. In the absence of head-to-head trials comparing D-Rd and VRd, the present trial may help inform treatment selection in this patient population.

Serum Urate as a Surrogate Outcome for Gout Flares: Where Do We Stand Today?

In gout research, serum urate has been widely accepted as the primary endpoint in clinical trials of urate-lowering therapies by both the FDA and EMA for many years. However, for serum urate to be a meaningful outcome measure, it should reflect at least one important patient-centered clinical outcome, such as gout flares. The relationship between achieving a pre-specified “target” serum urate and a corresponding improvement in patient-centered outcomes has been difficult to show due to variation in reporting of both serum urate and gout flares in clinical trials; a paradoxical rise in gout flares after starting urate-lowering therapy and a delay after achieving the pre-specified target serum urate before gout flares settle coupled with the relatively short duration of the trials. However, recent evidence from individual-level patient data from two, two-year randomized controlled trials clearly shows that achieving target urate is associated with a subsequent reduction and cessation of gout flares. In this review, we examine the evidence supporting serum urate as a surrogate outcome for gout flares, the methods, and the challenges of showing the validity of surrogacy.

A Cost-Utility Analysis of Add-On Cannabidiol Versus Usual Care Alone for the Treatment of Seizures Associated with Tuberous Sclerosis Complex in England and Wales.

The aim of this study was to evaluate the cost effectiveness of plant-derived highly purified cannabidiol (Epidyolex® in the UK; 100mg/mL oral solution) as an add-on treatment to usual care for the management of treatment-refractory seizures associated with tuberous sclerosis complex (TSC) in patients aged ≥2 years. A cohort-based model was developed using a National Health Service perspective and lifetime horizon. Health states were based on weekly seizure frequency and seizure-free days, utilizing patient-level data from the GWPCARE6 trial (ClinicalTrials.gov identifier: NCT02544763). Two independent regression models were applied to individual patient-level data to predict seizure-free days and seizure frequency. Healthcare resource utilization data were sourced from a Delphi panel, and patient and caregiver health-related quality of life values were elicited using vignettes valued by the general public. Outcomes relating to TSC-associated neuropsychiatric disorders were modeled with costs and quality-adjusted life-years sourced from published literature. In the base case, compared with usual care alone, 12mg/kg/day cannabidiol was associated with an incremental cost-effectiveness ratio (ICER) of £23,797. The National Institute for Health and Care Excellence disease severity modifier reduced the ICER to £19,831. Probabilities of cost effectiveness at willingness-to-pay thresholds of £20,000 and £30,000 were 30% and 52%, respectively, for the base case and 39% and 66%, respectively, for the disease severity modifier. Results were robust to sensitivity and scenario analyses. At 12mg/kg/day and an ICER threshold of £20,000-£30,000, we provide evidence for the cost effectiveness of add-on cannabidiol treatment for patients with TSC-associated seizures aged ≥2 years who are refractory to current treatment.

Does preoperative opioid use predict outcomes to 6 months following primary unilateral knee or hip arthroplasty for osteoarthritis? A data-linked retrospective study

BackgroundFew Australian studies have examined the incidence of prescribed opioid use prior to primary total knee or total hip arthroplasty (TKA, THA) and whether it predicts post-surgery outcomes. A recent Australian study demonstrated that the prevalence of pre-arthroplasty opioid use was approximately 16%. In the United States, approximately 24% of people undergoing TKA or THA are chronic opioid users preoperatively.PurposeThis study aimed to determine (i) the proportion of TKA and THA patients who use prescribed opioids regularly (daily) before surgery (i.e., opioid use reported between the time of waitlisting and any time up to 3 months before surgery), (ii) if opioid use before surgery predicts (a) complication/readmission rates to 6-months post-surgery, and (b) patient-reported outcomes to 6-months post-surgery.MethodsA retrospective cohort study of patients who underwent TKA or THA between January 2013 and June 2018 from two Australian public hospitals was undertaken utilizing linked individual patient-level data from two prospectively collected independent databases comprising approximately 3,500 and 9,500 people (database contained known opioid usage data within the 5-year time frame). Inclusion criteria included (i) primary diagnosis of osteoarthritis of the index joint, (ii) primary elective THA or TKA, and (iii) age ≥ 18 years. Exclusion criteria included (i) revision arthroplasty, (ii) non-elective arthroplasty, (iii) hip hemiarthroplasty, (iv) uni-compartmental knee arthroplasty, and (v) previous unilateral high tibial osteotomy.ResultsAnalysis was completed on 1,187 study participants (64% female, 69% TKA, mean (SD) age 67 [9.9]). 30% were using regular opioids preoperatively. Adjusted regression analyses controlling for multiple co-variates indicated no significant association between preoperative opioid use and complications/readmission rates or patient-reported outcomes to 6 months post-surgery. Model diagnostics produced poor discrimination for area under the curves and non-significant goodness of fit tests. Pre-arthroplasty opioid use was associated with lower health-related quality of life (EuroQol-Visual Analogue Scale) compared to non-opioid users undergoing primary THA (mean difference -5.04 [-9.87, -0.22], P = 0.04, Adjusted R2 = 0.06)ConclusionIn this study, 30% of patients were using prescribed opioids daily prior to primary TKA or THA. Pre-arthroplasty opioid use was not associated with postoperative adverse events or patient-reported pain, function, or global perceived improvement up to six months post-surgery.

Comparing Efficacy of Guselkumab versus Ustekinumab in Patients with Psoriatic Arthritis: An Adjusted Comparison Using Individual Patient Data from the DISCOVER and PSUMMIT Trials.

Two biologic therapies for psoriatic arthritis (PsA), guselkumab and ustekinumab, have demonstrated superior efficacy versus placebo in clinical trials. However, no head-to-head studies have been conducted comparing these two treatments for PsA. The objective was to indirectly compare guselkumab and ustekinumab on joint and skin efficacy up to week 52, using pooled individual patient-level data (IPD) from PsA trials. IPD, including baseline characteristics, American College of Rheumatology (ACR) scores and Psoriasis Area Severity Index (PASI) response from guselkumab (DISCOVER-1 and -2) and ustekinumab (PSUMMIT 1 and 2) trials were pooled. Differences in patient characteristics across trials were adjusted using multivariate logistic regression. Odds ratios (OR) were used to derive absolute response probabilities in the guselkumab trial population and were presented with 95% confidence intervals. Most baseline characteristics for guselkumab-treated patients (100 mg every 8 weeks [Q8W]; 100 mg every 4 weeks [Q4W]) were comparable to ustekinumab-treated patients (45/90 mg). In biologic-naïve patients, both guselkumab doses showed significantly higher ACR 20 (Q8W: 1.97; 1.37, 2.84; Q4W: 2.04; 1.40, 2.96) and PASI 90 (Q8W: 2.33; 1.52, 3.56; Q4W: 2.57; 1.67, 3.97) versus ustekinumab from week 16 onwards. In biologic-experienced patients, both guselkumab doses showed significantly higher ACR 20 (Q8W: 2.57; 1.11, 5.93; Q4W: 2.63; 1.12, 6.17) versus ustekinumab from week 24 onwards; for PASI 90, both guselkumab doses were superior to ustekinumab at week 16 and 52 (Q8W: 3.96; 1.39, 11.27; Q4W: 13.10; 4.18, 41.04). Guselkumab efficacy was similar and robust across primary, scenario, and sensitivity analyses. IPD analysis demonstrated that both guselkumab doses were superior to ustekinumab for ACR 20 from weeks 16 (biologic-naïve) and 24 (biologic-experienced) onwards, and for PASI 90 at weeks 16 and 52 for both subgroups.

A Federated Database for Obesity Research: An IMI-SOPHIA Study.

Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.

Effectiveness and Safety of Direct-acting Antivirals for Treatment of Adolescents With HCV/HIV Coinfection: Real-world Data From Europe.

We evaluated the effectiveness and safety of direct-acting antivirals in adolescents with hepatitis C (HCV)/HIV coinfection using pooled individual patient-level data from 5 European cohorts. Of 122 participants in follow-up from November 2013 to August 2021, 19 were treated <18 years of age; of 15 with HCV RNA available at/after 12 weeks post-treatment, all had sustained virologic response with acceptable safety. This evidence addresses an important gap in knowledge of treatment outcomes in adolescents with HCV/HIV coinfection in real-life settings.

Effect of Individual Patient Characteristics and Treatment Choices on Reliever Medication Use in Moderate-Severe Asthma: A Poisson Analysis of Randomised Clinical Trials.

Even though increased use of reliever medication, including short-acting beta agonists (SABA), provides an indirect measure of symptom worsening, there have been limited efforts to assess how different patterns of reliever use correlate with symptom control and future risk of exacerbations. Here, we evaluate the effect of individual baseline characteristics on reliever use in patients with moderate-severe asthma on regular maintenance therapy with fluticasone propionate (FP) or combination therapy with fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR). A drug-disease model describing the number of 24-h puffs and overnight occasions was developed with data from five clinical studies (N = 6212). The model was implemented using a nonlinear mixed effects approach and a Poisson function, considering clinical and demographic baseline characteristics. Goodness of fit and model predictive performance were assessed. Heatmaps were created to summarise the effect of concurrent baseline factors on reliever utilisation. The final model accurately described individual patterns of reliever use, which is significantly increased with time since diagnosis, smoking, higher Asthma Control Questionnaire (ACQ-5) score and higher body mass index (BMI) at baseline. Whilst the number of puffs decreases slowly after an initial drop relative to the start of treatment, exacerbating patients utilise significantly more reliever than those who do not exacerbate. The mean effect of FP/SAL (median dose: 250/50μg BID) on reliever use was slightly higher than that of BUD/FOR (median dose: 160/4.5μg BID), i.e. a 75.3% vs 69.3% reduction in reliever use, respectively. The availability of individual-level patient data in conjunction with a parametric approach enabled the characterisation of interindividual differences in the patterns of reliever use in patients with moderate-severe asthma. Taken together, individual demographic and clinical characteristics, as well as exacerbation history, can be considered an indicator of the degree of asthma control. High SABA reliever use suggests suboptimal clinical management of patients on maintenance therapy.

Abstract WP67: Utilization and Impact of Large Vessel Occlusion Stroke Screening Practices and Selected Target Stroke III Strategies in the Get-with-the-Guidelines Registry Hospitals

Background: The utilization and impact of pre-hospital and in-hospital large vessel occlusion (LVO) stroke screening protocols and Target: Stroke phase III (TS III) best-practice strategies on time metrics for endovascular treatment at a national level, have not been studied. Methods: We sent an online survey in July 2022 to hospital representatives of 2528 hospitals participating in the GWTG registry about their EMS systems, clinical and imaging protocols, and utilization of selected TS III best-practice strategies (multiple choice, 0-100 scale, and yes/no questions). We obtained Individual patient-level data from the GWTG-Stroke Registry from January 2017 to March 2022. Multivariable linear regression models were performed to investigate the associations of these strategies with door-to-puncture (DTP) in endovascular (EVT) patients. Results: Out of 2455 sites that met our inclusion criteria, 1455 sites completed the survey, with a response rate of 59.3%. Hospital-level baseline characteristics, utilization of selected LVO screening practices, and site-reported strategies associated with shorter DTP times are shown (Table 1). Strategies associated with shorter DTP were the performance of simultaneous vascular imaging along with non-contrast CT scan on all stroke patients within 24 hours, and the use of newer technologies for LVO detection in the field leading to a 7.1 min (CI -12.8, -1.5) decrease and a 10 min (CI -18.6, -1.3) decrease in DTP with every 25% increase in the utilization of these strategies, respectively (Table 1). Conclusion: The simultaneous performance of vascular imaging with non-contrast CT scan in all stroke patients presenting within 24 hours and the use of newer technologies for LVO detection in the field could lead to shorter DTP times.

Role of immunotherapy in gastroesophageal cancer with liver metastasis: A meta-analysis of phase III randomized clinical trials.

319 Background: Recent studies have demonstrated a poor response to immunotherapy in patients with colorectal cancer with liver metastasis. The role of immune checkpoint inhibitors (ICIs) for patients with gastroesophageal (GE) cancer with liver metastasis remains unclear. Our objective was to investigate if ICIs are beneficial in patients with GE cancer with liver metastasis. Methods: We searched PubMed, Embase, ESMO, and ASCO Meeting Abstracts for phase III randomized clinical trials (RCTs) testing ICIs in metastatic/advanced GE cancer from 2017 to 2023. All phase III RCTs of metastatic GE cancer treated with ICIs that had available data on liver metastasis were analyzed. A meta-analysis was conducted on the survival outcomes (overall and progression-free survival), where hazard ratios were obtained, with 95% confidence intervals, using the standard random effects model. To assess the heterogeneity of the study outcomes, the I2 statistic was obtained. The I2 statistic represented the variability in the meta-analysis attributed to study heterogeneity. These analyses were applied to the overall cohort of studies, as well as within the liver metastasis (yes or no) sub-cohorts. All analyses were conducted in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: Seven Phase III RCTs were includedthat had available data on overall survival and/or progressive free survival in patients with liver metastasis. Of these, six were in the frontline setting and one in the later line. Overall, 6,109 patients were included. Overall survival was similar among all patients (HR 0.72 [0.67,0.77], p&lt;0.001, I2=0.0%), patients with no liver metastasis (HR 0.73 [0.67,0.81], p&lt;0.001, I2=0.0%), and patients with liver metastasis (HR 0.74 [0.67,0.81], p&lt;0.001, I2=0.0%), indicating that ICIs’ benefit on OS is consistent. Progression-free survival (PFS) was also similar among all patients (HR 0.63 [0.57,0.70], p&lt;0.001, I2=54.7%); those with no liver metastasis (HR 0.62 [0.51,0.76], p&lt;0.001, I2=62.3%), and with liver metastasis (HR 0.66 [0.57,0.76], p&lt;0.001, I2-0.0%). Funnel plots were used to identify a potential bias for studies included in the analysis and showed no significant sources of bias for OS and PFS. Conclusions: In this meta-analysis, ICIs were beneficial in patients with GE cancer with and without liver metastasis. However, the majority of the trials were in the frontline setting where ICIs were combined with chemotherapy. Further subgroup analyses should be performed with individual patient-level data to identify patients who respond best to ICIs.

Investigating the association of WNT pathway dysregulation and young-onset colorectal cancer.

217 Background: Colorectal cancer (CRC) is the third most common cancer in the United States with studies showing increasing incidence of Young-Onset CRC, defined as cases occurring in individuals 50 years old or younger. Separately, the WNT Signaling Pathway and its subsequent mutation can result in sustained activation and, therefore, unregulated cell proliferation which has been well described in colorectal cancers. Loss of function in APC, AXIN1, AXIN2, GKS3B, and RNF43 can each act to dysregulate WNT signaling, contributing to cancer development. In this study, we aimed to conduct a comprehensive, molecular evaluation of the WNT signaling pathway in colorectal cancer within age-specific cohorts with onset of CRC at 50 years old or less versus greater than 50 years old. Methods: We used published individual patient-level data of 6286 patients with colorectal cancer (CRC) from the 16 CRC datasets included in the cbioportal database. The WNT pathway alterations, including APC, AXIN1, AXIN2, GKS3B and RNF43 mutations were considered to define the WNT mutant CRC cohort. The presence of WNT alterations according to the age (50 years old or younger vs. over 50 years) were evaluated using Chi-square tests. The association between primary tumor distribution (colon vs. rectal) and age were evaluated across patients with and without WNT pathway alterations. The effect of WNT pathway alterations on the overall survival and survival after the metastatic stage was evaluated with Kaplan-Meier survival curves. A type-I error level of 5% (p&lt;0.05) was considered the threshold limit for statistical significance. Results: A total of 2,630 individuals were identified with relevant clinical and molecular information. When comparing WNT alteration patterns between young-onset CRC (&lt; 50 years old) and CRC in cohort &gt;50 years old, there was no statistically significant difference (p-value .215). Analysis of common individual mutations in APC, AXIN1, AXIN2, GKS3B and RNF43 also showed similar incidences across age groups. However, we identified WNT alterations were significantly more common in rectal cancers compared to colon cancer, being found in 75.9% of rectal cancer cases, regardless of age groups (p-value &lt;0.00001). Additionally, individuals identified to have WNT alterations were found to have improved survival with a median overall survival of of 58.19 months versus a median of 41.72 months in those without. Conclusions: Overall, no significant differences were found in WNT alteration expression between Young-onset CRC versus CRC in individuals over the age of 50. However, across all age groups, WNT alterations were frequently found in rectal cancers. Furthermore, these WNT alterations were associated with better outcomes.

Systematic review and meta-analysis for the value of cardiac magnetic resonance strain to predict cardiac outcomes

Cardiac magnetic resonance (CMR) is the gold standard for the diagnostic classification and risk stratification in most patients with cardiac disorders. The aim of the present study was to investigate the ability of Strain-encoded MR (SENC) for the prediction of major adverse cardiovascular events (MACE). A systematic review and meta-analysis was performed according to the PRISMA Guidelines, including patients with or without cardiovascular disease and asymptomatic individuals. Myocardial strain by HARP were used as pulse sequences in 1.5 T scanners. Published literature in MEDLINE (PubMed) and Cochrane’s databases were explored before February 2023 for studies assessing the clinical utility of myocardial strain by Harmonic Phase Magnetic Resonance Imaging (HARP), Strain-encoded MR (SENC) or fast-SENC. In total, 8 clinical trials (4 studies conducted in asymptomatic individuals and 4 in patients with suspected or known cardiac disease) were included in this systematic review, while 3 studies were used for our meta-analysis, based on individual patient level data. Kaplan–Meier analysis and Cox proportional hazard models were used, testing the ability of myocardial strain by HARP and SENC/fast-SENC for the prediction of MACE. Strain enabled risk stratification in asymptomatic individuals, predicting MACE and the development of incident heart failure. Of 1332 patients who underwent clinically indicated CMR, including SENC or fast-SENC acquisitions, 19 patients died, 28 experienced non-fatal infarctions, 52 underwent coronary revascularization and 86 were hospitalized due to heart failure during median 22.4 (17.2–28.5) months of follow-up. SENC/fast-SENC, predicted both all-cause mortality and MACE with high accuracy (HR = 3.0, 95% CI = 1.2–7.6, p = 0.02 and HR = 4.1, 95% CI = 3.0–5.5, respectively, p < 0.001). Using hierarchical Cox-proportional hazard regression models, SENC/fast-SENC exhibited incremental value to clinical data and conventional CMR parameters. Reduced myocardial strain predicts of all-cause mortality and cardiac outcomes in symptomatic patients with a wide range of ischemic or non-ischemic cardiac diseases, whereas in asymptomatic individuals, reduced strain was a precursor of incident heart failure.

The Dark side of the White Matter. Diffuse subcortical White Matter Hypointensity on T2/FLAIR: A systematic review of a frequently underrecognized sign

Background and objectivesMany reversible brain MRI abnormalities have been described, among these the most frequently reported are cortical hyperintensities on FLAIR/T2 occurring during seizures. Much less attention has been given to those situations where White Matter goes Dark: subcortical white matter hypointensity on T2/FLAIR. Our aim is to identify the medical condition “Dark White Matter” (DWM) is more frequently associated with. This is the first systematic review on DWM. MethodsPubMed was searched in August 2023. Included studies were those reporting Diffuse Subcortical White Matter Hypointensity on T2/FLAIR. Mainly case reports were included. Individual patient-level data was included whenever available. Frequency measures of the different diseases were calculated. Results56 studies were included, 228 patients were eligible for analysis. DWM happened in isolation, with no cortical abnormalities, in 71 cases and was associated with seizures in >61.4% of cases. The most frequently DWM-associated disease was Non-Ketotic Hyperglycaemic hyperosmolar state (NKH), followed by Encephalitis, Moyamoya disease, Genetic Causes, and Subdural Hematoma. Frequency of NKH was 32%. NKH was associated with seizures in 100% of cases and the most frequently involved lobe was the occipital one. When considering only the subgroup of patients with seizures, DWM was indicative of NKH in 51.4% of cases and Encephalitis in 26.4% of cases. Key limitations are heterogeneity and missing data. DiscussionDWM is frequently underdiagnosed. This sign can exist alone and it is not merely a consequence of cortical involvement. Moreover, it has important implications, both diagnostic and therapeutic, as it is more frequently associated with NKH, especially in the context of seizures, where anti-seizure medication is not the first line of treatment. We also discuss the pathogenesis of DWM by finding a common link between the most frequently associated diseases.

A combination of mild-moderate hypoxemia and low compliance is highly prevalent in persistent ARDS: a retrospective study

BackgroundThe Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and edema, impairing both oxygenation and lung compliance. Recent studies reported a dissociation between oxygenation and compliance (severe hypoxemia with preserved compliance) in early ARDS and COVID-19-related-ARDS (CARDS). During the pandemic, in patients requiring prolonged mechanical ventilation, we observed the opposite combination (mild-moderate hypoxemia but significantly impaired compliance). The purpose of our study was to investigate the prevalence of this combination of mild-moderate hypoxemia and impaired compliance in persistent ARDS and CARDS.MethodsFor this retrospective study, we used individual patient-level data from two independent cohorts of ARDS patients. The ARDSNet cohort included patients from four ARDS Network randomized controlled trials. The CARDS cohort included patients with ARDS due to COVID-19 hospitalized in two intensive care units in Greece. We used a threshold of 150 for PaO2/FiO2 and 30 ml/cmH2O for compliance, estimated the prevalence of each of the four combinations of oxygenation and compliance at baseline, and examined the change in its prevalence from baseline to day 21 in the ARDSNet and CARDS cohorts.ResultsThe ARDSNet cohort included 2909 patients and the CARDS cohort included 349 patients. The prevalence of the combination of mild-moderate hypoxemia and low compliance increased from baseline to day 21 both in the ARDSNet cohort (from 22.2 to 42.7%) and in the CARDS cohort (from 3.1 to 33.3%). Among surviving patients with low compliance, oxygenation improved over time. The 60-day mortality rate was higher for patients who had mild-moderate hypoxemia and low compliance on day 21 (28% and 56% in ARDSNet and CARDS), compared to those who had mild-moderate hypoxemia and high compliance (20% and 50%, respectively).ConclusionsAmong patients with ARDS who require prolonged controlled mechanical ventilation, regardless of ARDS etiology, a dissociation between oxygenation and compliance characterized by mild-moderate hypoxemia but low compliance becomes increasingly prevalent. The findings of this study highlight the importance of monitoring mechanics in patients with persistent ARDS.

The Efficacy and Safety of Bisphosphonate Therapy for Osteopenia/Osteoporosis in Patients With Chronic Kidney Disease: A Systematic Review and Individual Patient-Level Meta-Analysis of Placebo-Controlled Randomized Trials.

The efficacy and safety of bisphosphonate therapy for the treatment of osteoporosis and osteopenia in the setting of chronic kidney disease (CKD) is unclear. To determine the effect of bisphosphonate therapy on fractures, bone mineral density (BMD), and adverse events in adults across the spectrum of CKD and dialysis. Systematic review and individual patient-level meta-analysis. Searches of Ageline, CINAHL, the Cochrane Library, EMBASE, and Medline from inception to August 25, 2016, supplemented with manual screening and clinicalstudydatarequest.com. Authors were contacted for individual patient-level data. Randomized, placebo-controlled trials with 100 or more participants that evaluated the treatment of primary osteoporosis/osteopenia in adult men and women with bisphosphonate therapy. Study characteristics, quality, and data were assessed independently by 2 reviewers. Outcome measures were fractures, BMD, and adverse events including decline in estimated glomerular filtration rate (eGFR) and hypocalcemia (calcium <2.00 mmol/L). Single-stage individual patient-level meta-analysis. Of 39 eligible studies, individual patient-level data was available for 7 studies, all of which were studies of ibandronate. Of 7428 participants (5010 ibandronate, 2418 placebo), 100% were female, 98.6% were white, the mean body mass index was 25.7 kg/m2 (SD 3.9), 18.9% were smokers and there were 740 fracture events. The mean eGFR was 69.1 mL/min/1.73 m2 (SD 15.9) including 14.5%, 54.9%, 27.5%, 3.0%, and 0.2% stages G1, G2, G3A, G3B, and G4 CKD. Ibandronate increased hip and lumbar spine BMD and decreased the risk of fracture in the overall population (hazard ratio (HR) 0.871, 95% confidence interval (CI) 0.746, 1.018) but in patients with stage G3B CKD, it increased the risk of fracture (HR 3.862, 95% CI 1.156, 12.903). Ibandronate did not impact eGFR over 12 months but increased the risk of hypocalcemia (HR 1.324, 95% CI 1.056, 1.660) with no evidence of any effect modification by CKD stage (all tests of interaction p > 0.05). Clinically significant heterogeneity among studies, lack of long-term follow-up and bone biopsy results, limited representation of stage G4 and G5 CKD patients. Chronic kidney disease potentially modifies the efficacy but not the safety of bisphosphonate therapy in osteopenia and osteoporosis. PROSPERO CRD42020145613.

Reactive cutaneous capillary endothelial proliferation following camrelizumab monotherapy or combination therapy for multi-cancers: a large-scale pooled analysis of 10 studies in China.

Skin toxicities are the most common adverse events related to immunotherapy, such as reactive cutaneous capillary endothelial proliferation (RCCEP) following treatment with the anti-programmed cell death-1 antibody camrelizumab. This study aimed to comprehensively analyze the clinical features and prognostic value of RCCEP in patients with malignancies who received camrelizumab alone (Camre) or in combination with the angiogenesis-targeted agent apatinib (Camre-Apa) or chemotherapy (Camre-Chemo). A large-scale pooled analysis. Individual patient-level data were derived from 10 clinical trials of camrelizumab monotherapy, camrelizumab plus apatinib, or camrelizumab plus chemotherapy (n = 1305). RCCEP occurred in 77.0% (516/670) of patients with Camre, 23.6% (70/296) with Camre-Apa, and 67.8% (230/339) with Camre-Chemo. Most RCCEP lesions were grade 1 or 2 in severity. The median time to onset was 0.8 months [interquartile range (IQR), 0.6-1.2] with Camre, 5.0 months (IQR, 2.7-8.0) with Camre-Apa, and 1.6 months (IQR, 1.0-4.2) with Camre-Chemo; and the median duration was 4.8 months (IQR, 2.6-8.8), 4.4 months (IQR, 1.7-8.9), and 7.2 months (IQR, 4.1-14.3), respectively. In all the three groups, patients with RCCEP showed significantly better clinical outcomes compared with those without [objective response rate: 23.8% versus 1.9% with Camre, 48.6% versus 21.2% with Camre-Apa, and 78.7% versus 54.1% with Camre-Chemo; median progression-free survival: 3.2 versus 1.7 months (hazard ratio (HR) = 0.36), 10.2 versus 4.5 months (HR = 0.39), and 12.7 versus 7.3 months (HR = 0.38); median overall survival: 13.3 versus 3.8 months (HR = 0.34), 29.2 versus 13.5 months (HR = 0.46), and not reached versus 12.8 months (HR = 0.19); all p < 0.0001]. Although RCCEP occurred frequently with camrelizumab, most lesions were mild and self-limiting. The occurrence of RCCEP was strongly associated with the antitumor activity and survival of camrelizumab, both as monotherapy and in combination therapy.