Individual Patient Data Meta-analysis Research Articles

Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders – An individual patient data meta-analysis

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorderś(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI −0.55–0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05–0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17–0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptomś severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Invasive vs. conservative management of older patients with non-ST-elevation acute coronary syndrome: individual patient data meta-analysis.

Older patients with non-ST-elevation acute coronary syndrome (NSTEACS) are less likely to receive guideline-recommended care including coronary angiography and revascularization. Evidence-based recommendations regarding interventional management strategies in this patient cohort are scarce. This meta-analysis aimed to assess the impact of routine invasive vs. conservative management of NSTEACS by using individual patient data (IPD) from all available randomized controlled trials (RCTs) including older patients. MEDLINE, Web of Science and Scopus were searched between 1 January 2010 and 11 September 2023. RCTs investigating routine invasive and conservative strategies in persons >70 years old with NSTEACS were included. Observational studies or trials involving populations outside the target range were excluded. The primary endpoint was a composite of all-cause mortality and myocardial infarction (MI) at 1 year. One-stage IPD meta-analyses were adopted by use of random-effects and fixed-effect Cox models. This meta-analysis is registered with PROSPERO (CRD42023379819). Six eligible studies were identified including 1479 participants. The primary endpoint occurred in 181 of 736 (24.5%) participants in the invasive management group compared with 215 of 743 (28.9%) participants in the conservative management group with a hazard ratio (HR) from random-effects model of 0.87 (95% CI 0.63-1.22; P = .43). The hazard for MI at 1 year was significantly lower in the invasive group compared with the conservative group (HR from random-effects model 0.62, 95% CI 0.44-0.87; P = .006). Similar results were seen for urgent revascularization (HR from random-effects model 0.41, 95% CI 0.18-0.95; P = .037). There was no significant difference in mortality. No evidence was found that routine invasive treatment for NSTEACS in older patients reduces the risk of a composite of all-cause mortality and MI within 1 year compared with conservative management. However, there is convincing evidence that invasive treatment significantly lowers the risk of repeat MI or urgent revascularisation. Further evidence is needed from ongoing larger clinical trials.

Gastric Volume and Antral Area in the Fasting State: A Meta-analysis of Individual Patient Data.

Pulmonary aspiration of gastric content is a serious anesthetic complication. Gastric point-of-care ultrasound can determine the type and volume of gastric content when clinical information is equivocal. However, a cutoff value of either antral cross-sectional area or volume that may be considered as the upper limit of normal in fasting subjects is still controversial. The aim of this study is to characterize the distribution of baseline antral area and volume in fasting adult subjects and to identify an upper limit (95th percentile) of these distributions. The authors conducted a meta-analysis of individual participant data of primary studies from an academic research network of investigators collaborating in gastric ultrasound. Studies between January 2009 and December 2020 were included. Twelve primary studies met inclusion criteria and were included in the analysis with a sample size of 1,203 subjects. The 95th percentile of area values (measured in the right lateral decubitus) was 9.9 cm2 (95% CI, 9.4 to 10.4), and of volume, 2.3 ml/kg (95% CI, 2.3 to 2.4). In addition, an antrum grade 0 or 1 indicates a 98% probability of an antral area below the 95th percentile. An area of 10 cm2 measured in the right lateral decubitus could be a simple, data-driven upper limit of antral area that could serve as a surrogate of upper limit of normal gastric volume values in fasting adults. These results are limited by the highly selected sampling of the studies included.

Statistical primer: individual patient data meta-analysis and meta-analytic approaches in case of non-proportional hazards.

Individual patient data (IPD) meta-analyses build upon traditional (aggregate data) meta-analyses by collecting IPD from the individual studies rather than using aggregated summary data. Although both traditional and IPD meta-analyses produce a summary effect estimate, IPD meta-analyses allow for the analysis of data to be performed as a single dataset. This allows for standardization of exposure, outcomes, and analytic methods across individual studies. IPD meta-analyses also allow the utilization of statistical methods typically used in cohort studies, such as multivariable regression, survival analysis, propensity score matching, uniform subgroup and sensitivity analyses, better management of missing data, and incorporation of unpublished data. However, they are more time-intensive, costly, and subject to participation bias. A separate issue relates to the meta-analytic challenges when the proportional hazards assumption is violated. In these instances, alternative methods of reporting time-to-event estimates, such as restricted mean survival time should be used. This statistical primer summarizes key concepts in both scenarios and provides pertinent examples.

Protocol for an independent patient data meta-analysis of prophylactic mesh placement for incisional hernia prevention after abdominal aortic aneurysm surgery: a collaborative European Hernia Society project (I-PREVENT-AAA)

IntroductionIncisional hernia (IH) is a prevalent and potentially dangerous complication of abdominal surgery, especially in high-risk groups. Mesh reinforcement of the abdominal wall has been studied as a potential intervention...

Childhood trauma in adult depressive and anxiety disorders: immuno-metabolic evidences in the NESDA cohort

Abstract Childhood trauma and depression are both associated with increased risk of metabolic disorders, but their joint effects and underlying mechanisms are not well understood. This talk will present recent findings from large-scale epidemiological and biobank studies that explore the metabolic signature of childhood trauma, depression, and their interplay. For example, using longitudinal data from the NESDA cohort, we investigated the association of childhood trauma with metabolic syndrome in ˜3000 adults, including patients with depression and/or anxiety and healthy controls, over 9 years of follow-up. The talk will also describe preliminary results from an individual patient data meta-analysis pooling >160,000 subjects from the Early Cause European Consortium. In this study, we examined the differences in markers of obesity and dyslipidemia across individuals with neither childhood trauma nor depression (controls), those with childhood maltreatment, those with depression, those reporting both of these conditions. The findings described in the talk shed light on the complex interplay between early life stress, mood disorders, and metabolic health.Disclosure of InterestNone Declared

An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis

IntroductionExpert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. MethodsWe conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. ResultsIndividual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. ConclusionWhile the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Anti–Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis

ObjectivesThis study aimed to evaluate the cost-effectiveness of anti–vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. MethodsA discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. ResultsAnti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of −0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. ConclusionsAnti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

Abstract 3826: Predictive and prognostic factors in NUT carcinoma: A systematic review and individual patient data meta-analysis

Abstract Background: NUT carcinoma (NC) is a rare cancer affecting midline structures and involving the lung, bones, and lymph nodes. Data on NC are limited mostly to case reports and case series. Methods: PubMed, Web of Science, and Scopus were systematically searched for original articles describing confirmed NC patients. A quantitative individual patient data meta-analysis (IPD-MA) analyzing overall survival and risk factors for progression was performed for all NC patients with a clear age at diagnosis. Relevant patient characteristics and clinical parameters were compared in a multivariate Cox regression model. Findings: Out of 4,701 studies screened, 175 studies met the inclusion criteria for the systematic review. 117 (66.9%) were case reports. 284 patients were included in the IPD-MA. 139 (48.9%) patients were male, 145 (51.1%) underwent surgery, 156 (54.9%) received radiotherapy, and 173 (60.9%) developed metastasis. The mean age at diagnosis was 35.82±18.33 and the median OS was 9 months. 77 (27.1%) patients received platinum-based agents, 39 (13.7%) received taxanes, and 15 (5.3%) received BET inhibitors as part of their first-line regiment. Age at diagnosis, gender, and the aforementioned drugs did not significantly influence OS. Presence of metastasis was an independent predictor of poor survival, while radiotherapy and surgery were significantly associated with better survival (table 1). Interpretation: NC is associated with poor survival. Surgery and radiotherapy appear to be more effective treatment strategies, while medical modalities may not play a major role in the treatment of NC. Predictors of overall survival in NUT carcinoma patients. Parameter Hazard ratio 95% confidence interval P-value Age at diagnosis 0.99 0.99-1 0.35 BET inhibitors 0.61 0.28-1.15 0.16 Platinum-based agents 0.73 0.47-1.13 0.16 Taxanes 1.29 0.78-2.1 0.31 Surgery 0.41 0.29-0.58 <0.0001 Female gender 1.12 0.83-1.51 0.45 Metastasis 1.76 1.26-2.49 0.0011 Radiotherapy 0.48 0.36-0.67 <0.0001 Citation Format: Sameeha K. Abdulwali, Abduljalil M. El-Sibai, Saad S. Ali, Abdulaziz M. Alaklabi, Hytham M. Abdalla, Ahmad N. Sabbah, Areez Shafqat, Nader A. Fawzy, Belal N. Sabbah, Ahmed Badran, Tarek Z. Arabi. Predictive and prognostic factors in NUT carcinoma: A systematic review and individual patient data meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3826.

Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

Individual patient data meta-analysis of the effects of fluoxetine on functional outcomes after acute stroke.

Three large randomized controlled trials of fluoxetine for stroke recovery have been performed. We performed an individual patient data meta-analysis (IPDM) on the combined data. Fixed effects meta-analyses were performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined. The three trials recruited a combined total of 5907 people (mean age 69.5 years (SD 12.3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, United Kingdom, Sweden, and Vietnam; and randomized them to fluoxetine 20 mg daily or matching placebo for 6 months. Data on 5833 (98.75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0.96, 95% CI 0.87 to 1.05, p = 0.37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit, or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2.64% vs 1.8%, p = 0.03), falls with injury (6.26% vs 4.51%, p = 0.03), fractures (3.15% vs 1.39%, p < 0.0001) and hyponatremia (1.22% vs 0.61%, p = 0.01) but reduced new depression (10.05% vs 13.42%, p < 0.0001). At 12 months, there was no difference in adjusted mRS (n = 5760; common OR 0.98, 95% CI 0.89 to 1.07). Sensitivity analyses gave the same results. Fluoxetine 20 mg daily for 6 months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months.

An individual participant meta-analysis of mirabegron in multiple sclerosis and spinal cord injury.

Our objective was to conduct an individual patient data meta-analysis (IPDMA) of the two published randomized placebo-controlled trials of mirabegron in people with neurogenic lower urinary tract dysfunction (NLUTD) due to spinal cord injury (SCI) or multiple sclerosis (MS). We identified two randomized, placebo-controlled trials. We extracted individual patient data from the trials and evaluated two primary outcomes: change in maximum cystometric capacity and change in the patient perception of bladder condition (PPBC). We also evaluated several secondary outcomes related to urodynamic function and quality of life. We conducted three exploratory analyses to test hypotheses based on our clinical experiences with mirabegron in NLUTD. Analysis of covariance with adjustment for baseline values was used for the statistical analysis. Our IPDMA included 98 patients from the two trials. The results showed that mirabegron was associated with a significant improvement in maximum cystometric capacity (+41 mL, p = 0.04) and in the PPBC (-0.8, p < 0.01) compared to placebo. Secondary outcomes including peak neurogenic detrusor overactivity pressure (-20 cm H2O, p < 0.01), incontinence-QOL score (+12, p < 0.01), and 24 h pad weights (-79 g, p = 0.04) also improved significantly compared to placebo. Exploratory analyses found similar improvements in people with MS and SCI; some outcomes improved to a greater degree among people with incomplete SCI,or SCIs that were below T7. Our IPDMA provides evidence supporting the use of mirabegron in patients with NLUTD due to SCI or MS. Further work evaluating differential responses in people with different SCI lesion characteristics may be warranted.

Does acute malnutrition in young children increase the risk of treatment failure following artemisinin-based combination therapy? A WWARN individual patient data meta-analysis

The geographical, demographic, and socioeconomic distributions of malaria and malnutrition largely overlap. It remains unknown whether malnutrition affects the efficacy of WHO-recommended artemisinin-based combination therapies (ACTs). A previous systematic review was inconclusive as data were sparse and heterogeneous, indicating that other methodological approaches, such as individual patient data meta-analysis, should be considered. The objective of this study was to conduct such a meta-analysis to assess the effect of malnutrition (wasting and stunting) on treatment outcomes in children younger than 5 years treated with an ACT for uncomplicated falciparum malaria. We conducted a meta-analysis of individual patient data from studies identified through a systematic review of literature published between 1980 and 2018 in PubMed, Global Health, and Cochrane Libraries (PROSPERO CRD42017056934) and inspection of the WorldWide Antimalarial Resistance Network (WWARN) repository for ACT efficacy studies, including children younger than 5 years with uncomplicated falciparum malaria. The association of either acute (wasting) or chronic (stunting) malnutrition with day 42 PCR-adjusted risk of recrudescence (ie, return of the same infection) or reinfection after therapy was investigated using Cox regression, and with day 2 parasite positivity using logistic regression. Data were included from all 36 studies targeted, 31 from Africa. Of 11 301 eligible children in 75 study sites, 11·5% were wasted (weight-for-height Z score [WHZ] <-2), and 31·8% were stunted (height-for-age Z score [HAZ] <-2). Decrease in WHZ was associated with increased risk of day 2 positivity (adjusted odds ratio 1·12, 95% CI 1·05-1·18 per unit; p=0·0002), treatment failure (adjusted hazard ratio [AHR] 1·14, 95% CI 1·02-1·26, p=0·016), and reinfection after therapy (AHR 1·09, 1·04-1·13, p=0·0003). Children with milder wasting (WHZ -2 to -1) also had a higher risk of recrudescence (AHR 1·85, 1·29-2·65, p=0·0008 vs WHZ ≥0). Stunting was not associated with reduced ACT efficacy. Children younger than 5 years with acute malnutrition and presenting with uncomplicated falciparum malaria were at higher risk of delayed parasite clearance, ACT treatment failure, and reinfections. Stunting was more prevalent, but not associated with changes in ACT efficacy. Acute malnutrition is known to impact medicine absorption and metabolism. Further study to inform dose optimisation of ACTs in wasted children is urgently needed. Bill & Melinda Gates Foundation. For the French translation of the abstract see Supplementary Materials section.

Analysis methods and case analysis of effect modification (3): effect modification in individual patient data Meta-analysis

This paper briefly introduces the unique advantages, overall analysis ideas and existing analysis methods of individual patient data Meta-analysis in terms of effect modification. In addition to Meta-regression and subgroup analysis, this paper also introduces the analysis methods based on part of individual patient data integrated with aggregated data and summarizes the current reporting of the above mentioned methods. In addition, the application and results interpretation of the above mentioned methods in individual patient data Meta-analysis are presented in this paper by taking "Effects of sodium-glucose cotransporter 2 inhibitors on SBP in patients with type 2 diabetes" as an example and by introducing their advantages and limitations.

External validation of the PC-ECMO score in postcardiotomy veno-arterial extracorporeal membrane oxygenation.

Reliable stratification of the risk of early mortality after postcardiotomy veno-arterial extracorporeal membrane oxygenation (V-A-ECMO) remains elusive. In this study, we externally validated the PC-ECMO score, a specific risk scoring method for prediction of in-hospital mortality after postcardiotomy V-A-ECMO. Overall, 614 patients who required V-A-ECMO after adult cardiac surgery were gathered from an individual patient data meta-analysis of nine studies on this topic. The AUC of the logistic PC-ECMO score in predicting in-hospital mortality was 0.678 (95%CI 0.630-0.726; p < 0.0001). The AUC of the logistic PC-ECMO score in predicting on V-A-ECMO mortality was 0.652 (95%CI 0.609-0.695; p < 0.0001). The Brier score of the logistic PC-ECMO score for in-hospital mortality was 0.193, the slope 0.909, the calibration-in-the-large 0.074 and the expected/observed mortality ratio 0.979. 95%CIs of the calibration belt of fit relationship between observed and predicted in-hospital mortality were never above or below the bisector (p = 0.072). The present findings suggest that the PC-ECMO score may be a valuable tool in clinical research for stratification of the risk of patients requiring postcardiotomy V-A-ECMO.

Differences in excess mortality by recipient sex after heart transplant: An individual patient data meta-analysis

BackgroundIdentification of differences in mortality risk between female and male heart transplant recipients may prompt sex-specific management strategies. Because worldwide, males of all ages have higher absolute mortality rates than females, we aimed to compare the excess risk of mortality (risk above the general population) in female versus male heart transplant recipients. MethodsWe used relative survival models conducted separately in SRTR and CTS cohorts from 1988–2019, and subsequently combined using two-stage individual patient data meta-analysis, to compare the excess risk of mortality in female versus male first heart transplant recipients, accounting for the modifying effects of donor sex and recipient current age. ResultsWe analyzed 108,918 patients. When the donor was male, female recipients 0–12 years (Relative excess risk (RER) 1.13, 95% CI 1.00–1.26), 13–44 years (RER 1.17, 95% CI 1.10–1.25), and ≥45 years (RER 1.14, 95% CI 1.02–1.27) showed higher excess mortality risks than male recipients of the same age. When the donor was female, only female recipients 13–44 years showed higher excess risks of mortality than males (RER 1.09, 95% CI 1.00–1.20), though not significantly (p= 0.05). ConclusionsIn the setting of a male donor, female recipients of all ages had significantly higher excess mortality than males. When the donor was female, female recipients of reproductive age had higher excess risks of mortality than male recipients of the same age, though this was not statistically significant. Further investigation is required to determine the reasons underlying these differences.

Surrogate endpoints in clinical trials of p16-positive squamous cell carcinoma of the oropharynx: an individual patient data meta-analysis

The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy. We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r2 greater than 0·7 was used as criteria for clinically relevant surrogacy. We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r2 0·83), and progression-free survival (Kendall's τ 0·88 and r2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r2 0·88), distant metastasis-free survival (r2 0·96), and progression-free survival (r2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival. We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints. NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

Ruxolitinib for the treatment of acute and chronic graft-versus-host disease in children: a systematic review and individual patient data meta-analysis

Steroid-refractory graft-versus-host disease (SR-GvHD) represents a major complication of pediatric allogenic hematopoietic stem cell transplantation. Ruxolitinib, a selective JAK 1–2 inhibitor, showed promising results in the treatment of SR-GvHD in adult trial, including patients >12 years old. This systematic review aims to evaluate ruxolitinib use for SR-GvHD in the pediatric population. Among the 12 studies included, ruxolitinib administration presented slight differences. Overall response rate (ORR) ranged from 45% to 100% in both acute and chronic GvHD. Complete response rates (CR) varied from 9% to 67% and from 0% to 28% in aGvHD and cGvHD, respectively. Individual-patient meta-analysis from 108 children under 12 years showed an ORR and CR for aGvHD of 74% and 56%, respectively, while in cGvHD ORR was 78% but with only 11% achieving CR. Treatment-related toxicities were observed in 20% of patients, including cytopenia, liver toxicity, and infections. Age, weight, graft source, previous lines of therapy, and dose did not significantly predict response, while a higher rate of toxicities was observed in aGvHD patients. In conclusion, ruxolitinib shows promising results in the treatment of SR-GvHD in children, including those under 12 years. Specific pediatric perspective trials are currently ongoing to definitely assess its efficacy and safety.

Age difference of patients with and without invasive aspergillosis: a systematic review and meta-analysis.

Invasive Aspergillosis (IA) is a life-threatening fungal disease with significant mortality rates. Timely diagnosis and treatment greatly enhance patient outcomes. This study aimed to explore the association between patient age and the development of IA, as well as the potential implications for risk stratification strategies. We searched National Center for Biotechnology Information (NCBI) databases for publications until October 2023 containing age characteristics of patients with and without IA. A random-effects model with the application of inverse-variance weighting was used to pool reported estimates from each study, and meta-regression and subgroup analyses were utilized to assess sources of heterogeneity. A systematic review was conducted, resulting in the inclusion of 55 retrospective observational studies with a total of 13,983 patients. Meta-analysis revealed that, on average, patients with IA were approximately two and a half years older (95% Confidence Interval [CI] 1.84-3.31 years; I2 = 26.1%) than those without the disease (p < 0.0001). No significant moderators could explain the observed heterogeneity in age difference. However, subgroup analysis revealed that age differences were more pronounced within particular patient groups compared to others. For example, patients with and without IA who had primary severe lung infections exhibited a greater difference in mean age than other patient cohorts. Further research, such as individual patient data meta-analysis, is necessary to better understand the potential relationship between increasing age and the likelihood of IA. Improved risk stratification strategies based on patient age could potentially enhance the early detection and treatment of IA, ultimately improving patient outcomes.

Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis.

Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.