Individual Patient-level Data Research Articles

Radiation Dose-Volume-Response Relationships for Adverse Events in Childhood Cancer Survivors: Introduction to the Scientific Issues in PENTEC

At its very core, radiation oncology involves a trade-off between the benefits and risks of exposing tumors and normal tissue to relatively high doses of ionizing radiation. This trade-off is particularly critical in childhood cancer survivors (CCS), in whom both benefits and risks can be hugely consequential due to the long life expectancy if the primary cancer is controlled. Estimating the normal tissue-related risks of a specific radiation therapy plan in an individual patient relies on predictive mathematical modeling of empirical data on adverse events. The Pediatric Normal-Tissue Effects in the Clinic (PENTEC) collaborative network was formed to summarize and, when possible, to synthesize dose-volume-response relationships for a range of adverse events incident in CCS based on the literature. Normal-tissue clinical radiation biology in children is particularly challenging for many reasons: (1) Childhood malignancies are relatively uncommon-constituting approximately 1% of new incident cancers in the United States-and biologically heterogeneous, leading to many small series in the literature and large variability within and between series. This creates challenges in synthesizing data across series. (2) CCS are at an elevated risk for a range of adverse health events that are not specific to radiation therapy. Thus, excess relative or absolute risk compared with a reference population becomes the appropriate metric. (3) Various study designs and quantities to express risk are found in the literature, and these are summarized. (4) Adverse effects in CCS often occur 30, 50, or more years after therapy. This limits the information content of series with even very extended follow-up, and lifetime risk estimates are typically extrapolations that become dependent on the mathematical model used. (5) The long latent period means that retrospective dosimetry is required, as individual computed tomography-based radiation therapy plans gradually became available after 1980. (6) Many individual patient-level factors affect outcomes, including age at exposure, attained age, lifestyle exposures, health behaviors, other treatment modalities, dose, fractionation, and dose distribution. (7) Prospective databases with individual patient-level data and radiation dosimetry are being built and will facilitate advances in dose-volume-response modeling. We discuss these challenges and attempts to overcome them in the setting of PENTEC.

Provider Impressions of Inpatient Teleneurology Consultation.

Teleneurology usage has increased during the severe acute respiratory syndrome coronavirus 2 pandemic. However, studies evaluating physician impressions of inpatient teleneurology are limited. We implemented a quality improvement initiative to evaluate neurologists' impression following individual inpatient teleneurology consultation at a satellite hospital of a large academic center with no in-person neurology coverage. A REDCap survey link was embedded within templates used by neurologists for documentation of inpatient consultations to be completed immediately after encounters. All teleneurology encounters with completed surveys at a single satellite hospital of the University of Pennsylvania Health System Neurology Department between May 10, 2021, and August 14, 2022, were included. Individual patient-level and encounter-level data were extracted from the medical record. A total of 374 surveys (response rate of 54.05%) were completed by 19 neurologists; 341 questionnaires were included in the analysis. Seven neurologists who specialized as neurohospitalists completed 231 surveys (67.74% of total surveys completed), while 12 non-neurohospitalists completed 110 (32.36%). The history obtained was rated as worse (14%) or the same (86%) as an in-person consult; none reported the history as better than nonteleneurology encounters. The physician-patient relationship was poor or fair in 25% of the encounters and good or excellent in 75% of visits. The overall experience was judged to be worse than in-person consultation in 32% of encounters, the same in 66%, and better in 2%. Fifty-one percent of providers responded that there were elements of the neurologic examination that might have changed their assessment and plan of care if performed in-person. Encounters with peripheral or neuromuscular-related chief complaints had the most inadequate examinations and worse overall experiences, while the most positive impressions of these clinical experiences were observed among seizure-related chief complaints. Determining best practices for inpatient teleneurology should consider the patient chief complaint to use teleneurology in scenarios with the highest likelihood of a positive experience. Further efforts should be made to the patient experience and to improve the remote examination to enhance the applicability of teleneurology to the full spectrum of inpatient neurologic consultations.

#367 PROTECT and NefIgArd two-year proteinuria and eGFR outcomes in adults with IgA nephropathy: matching-adjusted indirect comparison

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy is a rare kidney disorder characterized by deposition of IgA in the glomeruli causing progressive loss of kidney function and increased risk of kidney failure. In the absence of a head-to-head trial, this study used unanchored matching-adjusted indirect comparison (MAIC) of clinical trial data to compare two-year efficacy outcomes between Sparsentan in PROTECT and targeted-release formulation (TRF) budesonide plus real-world optimized and stable renin-angiotensin system inhibition (RASi) standard-of-care (SoC) in NefIgArd. Method We conducted an unanchored MAIC using individual patient level data from the PROTECT trial and aggregate data from the NefIgArd trial. Patients in the sparsentan arm of PROTECT were weighted to match key baseline characteristics of patients in the targeted-release formulation (TRF) budesonide + RASi SoC arm of NefIgArd based on publicly accessible, clinically pertinent baseline characteristics and prognostic factors using the method of moments. After weighting, percentage reduction of urine protein-creatinine ratio (UPCR) relative to baseline and two-year eGFR total slope (based on available data, chronic slope estimates are currently not available from NefIgArd) were estimated. A mixed model for repeated measures (MMRM) was used for UPCR relative percentage reduction and a random effect coefficient model for eGFR total slope. A two-tailed z-test with a pooled standard error was conducted for the indirect comparison. Results After assessing PROTECT and NefIgArd cross-trial characteristics on key outcome definitions, inclusion and exclusion criteria, and patient population, the two trials were considered sufficiently similar for unanchored MAIC. After weighting individual patient data from PROTECT, all matched baseline patient characteristics were well-balanced between arms of the two trials. Comparative results showed patients treated with sparsentan in PROTECT (−43.2% relative reduction in UPCR) exhibited a greater mean percentage reduction in proteinuria at two-years compared to TRF budesonide + RASi SoC (−30.7% relative reduction in UPCR), a relative percentage reduction of 18.1% (p = 0.03; Fig. 1A). For eGFR total slope, patients treated with sparsentan exhibited a slower decline in kidney function compared to TRF budesonide + RASi SoC, a difference of 0.54 ml/min/1.73 m2 per year; however, this difference was not statistically significant (p = 0.35; Fig. 1B). Conclusion Aligned to an earlier analysis of percentage reduction in proteinuria at 9-months (−37%, p < 0.0001 favoring sparsentan), our MAIC results show that sparsentan in PROTECT was associated with a greater relative percentage reduction in proteinuria at two-years compared to TRF budesonide plus real-world optimized and stable RASi SoC in NefIgArd. eGFR total slope for sparsentan in PROTECT was comparable to that reported for TRF budesonide plus real-world optimized and stable RASi SoC in NefIgArd. Results comparing chronic slope may provide a better indication of the long-term nephroprotective value of both therapies.

Outcomes in Nonmetastatic Hormone Receptor-Positive HER2-Negative Pure Mucinous Breast Cancer: A Multicenter Cohort Study.

Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties. Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC. Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups. Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.

Re-resection Rates and Disease Recurrence in Crohn's Disease - A Population-Based Study Using Individual-Level Patient Data.

Despite advances in the medical treatment of Crohn's disease (CD), many patients will still need bowel resections and face the subsequent risk of recurrence and re-resection. We describe contemporary re-resection rates and identify disease-modifying factors and risk factors for re-resection. We conducted a retrospective, population-based, individual patient data cohort study covering 47.4% of the Danish population, including all CD patients who underwent a primary resection between 2010 and 2020. Among 631 primary resected patients, 24.5% underwent a second resection, and 5.3% a third. Re-resection rates after one, five, and 10 years were 12.6%, 22.4%, and 32.2%, respectively. Reasons for additional resections were mainly disease activity (57%) and stoma reversal (40%). Disease activity-driven re-resection rates after one, five, and 10 years were 3.6%, 10.1%, and 14.1%, respectively. Most stoma reversals occurred within one year (80%). The median time to recurrence was 11.0 months. Biologics started within one year of the first resection revealed protective effect against re-resection for stenotic and penetrating phenotypes. Prophylactic biologic therapy at primary ileocecal resection reduced disease recurrence and re-resection risk (HR 0.58, 95% CI (0.34-0.99), p=0.047). Risk factors for re-resection were location of resected bowel segments at the primary resection, disease location, disease behavior, smoking, and perianal disease. Re-resection rates, categorized by disease activity, are lower than those reported in other studies and are closely associated with disease phenotype and localization. Biological therapy may be disease-modifying for certain subgroups when initiated within one year of resection.

Abstract PO4-17-11: Normalized Breast Cancer Survival Outcomes in U.S. Tumor Registries

Abstract Background The largest U.S. tumor registries, NCDB (National Cancer Database) and SEER (Surveillance, Epidemiology, and End Results Program), are vital sources of epidemiological data and are frequently utilized in research. Although the NCDB includes the majority of patients diagnosed with breast cancer, it is a hospital-based registry. In contrast, SEER is a population-based registry, but includes less than half of all breast cancer patients diagnosed each year. While the US Cancer Statistics Public Use Database (USCS) captures nearly all breast cancers, treatment and survival data are not included. As such, we sought to normalize the NCDB and SEER populations to mirror the USCS population and examine survival outcomes after normalization. Methods All patients diagnosed with stage I-IV breast cancer (2010-2018) were selected from the NCDB and SEER. Frequencies of patients by select characteristics were exported from the USCS. Rates from the USCS were then used to normalize the NCDB and SEER cohorts, using patient weighted frequencies for age, sex, race/ethnicity, tumor biomarkers [estrogen receptor (ER), HER2], and extent of disease (local, regional, distant; anatomic staging data not available in USCS). Of note, the USCS does not have individual patient-level data (only summary data for select variables), and thus, weighted frequencies were used for normalization. The weighted frequencies were calculated based on the total number of patients in the USCS database divided by the total number of patients in the NCDB or SEER separately for each variable (age, sex, race/ethnicity, etc). Weighted and unweighted data were summarized with N (%). Unweighted patient and disease characteristics (crude data) were compared using Chi-square tests. Overall survival (OS) was estimated using the Kaplan-Meier method before and after normalization. Results The USCS cohort included 2,473,739 patients; the NCDB included 1,441,556 and SEER 504,938. The median followup was 54.9 months for NCDB and 57 months for SEER. There were minimal differences between the cohorts based on age (age < 50y: USCS 18.1%, NCDB 19.3%, SEER 18.9%) or sex (female: USCS 99.1%, NCDB 99.1%, SEER 99.3%). However, there were notable differences in the racial/ethnic composition; non-Hispanic White: USCS 75%, NCDB 78.2%, SEER 68.2%; non-Hispanic Black: USCS 11.4%, NCDB 11.4%, SEER 9.9%; Hispanic: USCS 8.3%, NCDB 5.9%, SEER 11.7%; p< 0.001 for USCS vs NCDB and USCS vs SEER). There were minimal differences in tumor biomarkers (ER+: USCS 82.9%, NCDB 83%, SEER 84.9%; HER2+: USCS 14.5%, NCDB 14.1%, SEER 13.8%), but significant differences in extent of disease (local: USCS 66.1%, NCDB 80.2%, SEER 68.4%; distant: USCS 6%, NCDB 3.9%, SEER 3.9%; p< 0.001 for USCS vs NCDB and USCS vs SEER). For the variables that were similar without weighting (age, sex, tumor biomarkers), OS was also similar after weighting (Table). After normalizing the NCDB based on race, 8-year OS remained comparable (crude 77.2% vs weighted 77.3%); similar findings were noted after normalizing SEER (crude 75.8% vs weighted 75.3%). After normalizing the NCDB based on extent of disease, 8-year OS was notably worse (crude 77.2% vs weighted 74.2%); similar findings were noted for SEER (crude 75.8% vs weighted 74.4%). Conclusions While national tumor registries afford researchers the opportunity to study large breast cancer cohorts, they do not always fully represent the entire breast cancer population. This limitation should be considered when working with these data sets. Table. Citation Format: Tori Chanenchuk, Kerri-Anne Crowell, Samantha Thomas, Rachel Greenup, Jennifer Plichta. Normalized Breast Cancer Survival Outcomes in U.S. Tumor Registries [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-11.

The Comparative Effects of Monotherapy with Topical Minoxidil, Oral Finasteride, and Topical Finasteride in Postmenopausal Women with Pattern Hair Loss: A Retrospective Cohort Study

Introduction: Oral finasteride and topical minoxidil are long-standing androgenetic alopecia (AGA) treatments; topical finasteride is a more recent medicine. Few studies have compared their therapeutic effects in postmenopausal women. We compared the therapeutic impact of topical finasteride (1–4 sprays of 0.25% topical finasteride solution daily for 12 months), oral finasteride (2.5 mg oral finasteride once daily for 12 months), and topical minoxidil (1 mL of topical minoxidil 5% twice daily for 12 months) in postmenopausal women with AGA. Methods: We conducted Bayesian network meta-analyses of individual patient-level data insofar as four clinically relevant endpoints, namely, 12-month change in (1) total hair density, (2) hair diameter, (3) clinical photographs, and (4) patients’ opinion of efficacy. Data were obtained through medical charts. Regimens’ surface under the cumulative ranking distribution (SUCRA) values and relative effects – as per odds ratios – were computed. Results: As per SUCRA, the most and least effective regimens – across the four outcomes – were oral finasteride, and topical finasteride, respectively; however, no significant statistical differences were found (i.e., p > 0.05). Conclusion: Oral finasteride is ranked more effective than the topical forms of minoxidil and finasteride; however, more studies are needed to confirm this result.

The relationship between prescription rates of oral corticosteroids for respiratory diseases and deprivation in England

Respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD), are common in England with the worst respiratory outcomes observed in the most deprived areas. There is limited published research to establish whether the rate of oral corticosteroid (OCS) prescribing for asthma and COPD is linked to levels of deprivation. This study carried out a multivariable regression analysis of publicly available data and found that deprivation is associated with a statistically significant increase in the proportion of patients receiving an OCS prescription for asthma or COPD at a GP practice level (p < 0.001). The model estimated that the proportion of prescriptions is 1.88% (95% CI 1.83% to 1.92%) and 2.84% (95% CI 2.70% to 2.98%) for the least deprived GP practice and the most deprived GP practice, respectively. This study lays the groundwork for future research using individual patient level data to consider the impact of variation in OCS prescribing rates.

Application of causal inference methods in individual-participant data meta-analyses in medicine: addressing data handling and reporting gaps with new proposed reporting guidelines

Observational data provide invaluable real-world information in medicine, but certain methodological considerations are required to derive causal estimates. In this systematic review, we evaluated the methodology and reporting quality of individual-level patient data meta-analyses (IPD-MAs) conducted with non-randomized exposures, published in 2009, 2014, and 2019 that sought to estimate a causal relationship in medicine. We screened over 16,000 titles and abstracts, reviewed 45 full-text articles out of the 167 deemed potentially eligible, and included 29 into the analysis. Unfortunately, we found that causal methodologies were rarely implemented, and reporting was generally poor across studies. Specifically, only three of the 29 articles used quasi-experimental methods, and no study used G-methods to adjust for time-varying confounding. To address these issues, we propose stronger collaborations between physicians and methodologists to ensure that causal methodologies are properly implemented in IPD-MAs. In addition, we put forward a suggested checklist of reporting guidelines for IPD-MAs that utilize causal methods. This checklist could improve reporting thereby potentially enhancing the quality and trustworthiness of IPD-MAs, which can be considered one of the most valuable sources of evidence for health policy.

Methods for Indirect Treatment Comparison: Results from a Systematic Literature Review.

Health technology assessment (HTA) agencies express a clear preference for randomized controlled trials when assessing the comparative efficacy of two or more treatments. However, an indirect treatment comparison (ITC) is often necessary where a direct comparison is unavailable or, in some cases, not possible. Numerous ITC techniques are described in the literature. A systematic literature review (SLR) was conducted to identify all the relevant literature on existing ITC techniques, provide a comprehensive description of each technique and evaluate their strengths and limitations from an HTA perspective in order to develop guidance on the most appropriate method to use in different scenarios. Electronic database searches of Embase and PubMed, as well as grey literature searches, were conducted on 15 November 2021. Eligible articles were peer-reviewed papers that specifically described the methods used for different ITC techniques and were written in English. The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 73 articles were included in the SLR, reporting on seven different ITC techniques. All reported techniques were forms of adjusted ITC. Network meta-analysis (NMA) was the most frequently described technique (in 79.5% of the included articles), followed by matching-adjusted indirect comparison (MAIC) (30.1%), network meta-regression (24.7%), the Bucher method (23.3%), simulated treatment comparison (STC) (21.9%), propensity score matching (4.1%) and inverse probability of treatment weighting (4.1%). The appropriate choice of ITC technique is critical and should be based on the feasibility of a connected network, the evidence of heterogeneity between and within studies, the overall number of relevant studies and the availability of individual patient-level data (IPD). MAIC and STC were found to be common techniques in the case of single-arm studies, which are increasingly being conducted in oncology and rare diseases, whilst the Bucher method and NMA provide suitable options where no IPD is available. ITCs can provide alternative evidence where direct comparative evidence may be missing. ITCs are currently considered by HTA agencies on a case-by-case basis; however, their acceptability remains low. Clearer international consensus and guidance on the methods to use for different ITC techniques is needed to improve the quality of ITCs submitted to HTA agencies. ITC techniques continue to evolve quickly, and more efficient techniques may become available in the future.

An indirect comparison of acalabrutinib with and without obinutuzumab vs zanubrutinib in treatment-naive CLL

AbstractThe efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy vs zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma without del(17p) were compared using an unanchored matching-adjusted indirect comparison. Individual patient-level data from ELEVATE-TN (acalabrutinib plus obinutuzumab, n = 162; acalabrutinib monotherapy, n = 163) were weighted to match published aggregate baseline data from SEQUOIA cohort 1, which excluded patients with del(17p) (zanubrutinib, n = 241), using variables that were prognostic/predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory Cox regression analysis of ELEVATE-TN. After matching, INV-PFS was longer with acalabrutinib plus obinutuzumab (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.23-0.74) and comparable with acalabrutinib monotherapy (HR, 0.91; 95% CI, 0.53-1.56) vs zanubrutinib. Acalabrutinib monotherapy had significantly lower odds of any grade hypertension vs zanubrutinib (odds ratio [OR], 0.44; 95% CI, 0.20-0.99), whereas acalabrutinib plus obinutuzumab had significantly higher odds of neutropenia (OR, 2.19; 95% CI, 1.33-3.60) and arthralgia (OR, 2.33; 95% CI, 1.37-3.96) vs zanubrutinib. No other significant differences in safety were observed. In summary, acalabrutinib plus obinutuzumab had longer INV-PFS with increased odds of neutropenia and arthralgia than zanubrutinib, whereas acalabrutinib monotherapy had similar INV-PFS with lower odds of any grade hypertension. These trials were registered at www.ClinicalTrials.gov as #NCT02475681 and #NCT03336333.

Cohort Profile: the European Unified Registries On Heart care Evaluation and Randomised Trials (EuroHeart) - Acute Coronary Syndrome and Percutaneous Coronary Intervention.

The European Unified Registries On Heart care Evaluation And Randomized Trials (EuroHeart) aims to improve the quality of care and clinical outcomes for patients with cardiovascular disease. The collaboration of acute coronary syndrome/percutaneous coronary intervention (ACS/PCI) registries is operational in seven vanguard European Society of Cardiology member countries. Adults admitted to hospitals with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) are included, and individual patient-level data collected and aligned according to the internationally agreed EuroHeart data standards for ACS/PCI. The registries provide up to 155 variables spanning patient demographics and clinical characteristics, in-hospital care, in-hospital outcomes, and discharge medications. After performing statistical analyses on patient data, participating countries transfer aggregated data to EuroHeart for international reporting.Between 1st January 2022 and 31st December 2022, 40021 admissions (STEMI 46.7%, NSTEMI 53.3%) were recorded from 192 hospitals in the seven vanguard countries: Estonia, Hungary, Iceland, Portugal, Romania, Singapore, and Sweden. The mean age for the cohort was 67.9 (standard deviation 12.6) years, and it included 12628 (31.6%) women. The EuroHeart collaboration of ACS/PCI registries prospectively collects and analyses individual data for ACS and PCI at a national level, after which aggregated results are transferred to the EuroHeart Data Science Centre. The collaboration will expand to other countries and provide continuous insights into the provision of clinical care and outcomes for patients with ACS and undergoing PCI. It will serve as a unique international platform for quality improvement, observational research, and registry-based clinical trials.

Advancing unanchored simulated treatment comparisons: A novel implementation and simulation study.

Population-adjusted indirect comparisons, developed in the 2010s, enable comparisons between two treatments in different studies by balancing patient characteristics in the case where individual patient-level data (IPD) are available for only one study. Health technology assessment (HTA) bodies increasingly rely on these methods to inform funding decisions, typically using unanchored indirect comparisons (i.e., without a common comparator), due to the need to evaluate comparative efficacy and safety for single-arm trials. Unanchored matching-adjusted indirect comparison (MAIC) and unanchored simulated treatment comparison (STC) are currently the only two approaches available for population-adjusted indirect comparisons based on single-arm trials. However, there is a notable underutilisation of unanchored STC in HTA, largely due to a lack of understanding of its implementation. We therefore develop a novel way to implement unanchored STC by incorporating standardisation/marginalisation and the NORmal To Anything (NORTA) algorithm for sampling covariates. This methodology aims to derive a suitable marginal treatment effect without aggregation bias for HTA evaluations. We use a non-parametric bootstrap and propose separately calculating the standard error for the IPD study and the comparator study to ensure the appropriate quantification of the uncertainty associated with the estimated treatment effect. The performance of our proposed unanchored STC approach is evaluated through a comprehensive simulation study focused on binary outcomes. Our findings demonstrate that the proposed approach is asymptotically unbiased. We argue that unanchored STC should be considered when conducting unanchored indirect comparisons with single-arm studies, presenting a robust approach for HTA decision-making.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. TIL abundance in breast tissue from resected primary tumors. The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

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.