Inclusion Criteria For Clinical Trials Research Articles

A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials.Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710

Ensuring the strict and accurate adherence to inclusion criteria in clinical trials for AMD is crucial.

Ensuring the strict and accurate adherence to inclusion criteria in clinical trials for AMD is crucial.

Cryoablation of Primary Breast Cancer in Patients Ineligible for Clinical Trials: A Multiinstitutional Study.

Background: Breast cancer cryoablation clinical trials have strict inclusion criteria that exclude patients with potentially treatable disease. Objective: This study's purpose was to evaluate the safety and outcomes of breast cancer cryoablation without surgical excision in patients ineligible for prospective cryoablation clinical trials due to unfavorable patient or tumor characteristics. Methods: This retrospective study included women who underwent cryoablation of biopsy-proven unifocal primary breast cancer with locally curative intent, without surgical excision, despite being ineligible for (and thus excluded from) cryoablation clinical trials, across seven institutions between January 1, 2000 and August 26, 2021. Adverse events (AEs) were recorded. Cryoablation procedures were classified as technically successful if they were not prematurely terminated and achieved intended treatment parameters and the first imaging follow-up showed no evidence of residual disease. Results of follow-up biopsies were recorded. Ipsilateral breast tumor recurrences (IBTR) diagnosed during follow-up were identified and classified as true recurrence or new primary disease. A competing-risk model was used to estimate the cumulative incidence of IBTR accounting for death before IBTR. Results: The final study sample included 112 patients (median age, 71 years). A total of 7/112 (6.3%) patients had a minor AE; no moderate or major AE occurred. A total of 110/112 (98.2%) cryoablation procedures were technically successful. During median follow-up of 2.0 years, 22/110 (20.0%) patients underwent biopsy for suspicious imaging findings in the ipsilateral breast, yielding benign concordant findings in 9/22 (40.9%) and IBTR in 12/22 (54.5%). Overall, 12/110 (10.9%) patients experienced IBTR, including 7 with true recurrence and 5 with new primary disease; 3/12 (25.0%) patients with IBTR had received earlier adjuvant or neoadjuvant therapy. When accounting for death as a competing risk, the cumulative incidence of IBTR was 5.3%, 12.2%, and 18.2% at 1, 2, and 3 years, respectively. Conclusion: In select individuals with unfavorable patient or tumor characteristics, breast cancer cryoablation provides a safe alternative to surgery with good outcomes. These findings may be particularly relevant in patients who are also poor surgical candidates. Clinical Impact: Breast cancer cryoablation can be safely applied in a larger patient population than defined by clinical trial inclusion criteria.

Integrated genomic and transcriptomic characterization of neuroendocrine carcinomas for improved treatment decision-making.

e15138 Background: Neuroendocrine carcinomas (NECs) are poorly characterized due to their innate heterogeneity, thus limiting treatment and clinical trial options for patients. Here, we used whole exome sequencing (WES) and RNA sequencing (RNA-seq) to explore the genetic and microenvironmental landscape of NECs in order to understand the unique features of different NEC types, with the aim of improving treatment modalities. Methods: We analyzed 51 NEC clinical samples morphologically verified by a pathologist: lung NEC (20 small cell NEC and 1 large cell NEC cases), gastroenteropancreatic NEC (GEP, 12 cases), cancer of unknown primary (7 cases), Merkel cell carcinoma (MCC, 5 cases), genitourinary tract NEC (3 cases), and breast NEC (3 cases). Findings on tumor mutational burden (TMB, mut/Mb), microsatellite instability (MSI), gene expression signatures, and tumor microenvironment (TME) profiling were reported. Small cell lung cancer (SCLC) subtyping was performed as reported by Gay et al. on the entire NEC cohort. Results: Half of the patients with lung NEC and 84% of those with extrapulmonary NEC satisfied the molecular inclusion criteria for clinical trials, with the most frequent criterion being KRAS G12X or G13X mutations. Among the extrapulmonary NEC samples, 13.7% were deemed eligible for targeted therapy, specifically for cases with BRAF V600E mutation and/or high TMB (> 10 mut/Mb). We detected varying TMB and distinct gene expression features across the entire cohort. Specifically, we found 2 MCC cases to be Merkel cell polyomavirus-positive with low TMB and devoid of UV-associated mutations. One GEP-NEC case exhibited a high MSI (MSI-high) status. We detected 6 SCLC cases (3 non-smokers, 3 former smokers) with surprisingly low levels of tobacco-associated mutations (<10% of all mutations). Two GEP-NEC cases had high levels of mutations associated with tobacco smoking. While TME profiling showed no significant difference in cell population makeup across all samples, transcriptional SCLC subtyping revealed significant differences among the cases. Inflammatory SCLC (SCLC-I) samples showed statistically significant enrichment of all subpopulations of the immune microenvironment (i.e., B cells, T cells, NK cells), supporting the use of immune checkpoint blockade for treatment. The POU2F3+ SCLC (SCLC-P) samples showed low expression of all neuroendocrine diagnostic markers (i.e., INSM1, NCAM1, SYP, CHGA). Conclusions: Given the heterogeneous molecular features across diverse NEC tumors, a uniform treatment strategy is unlikely to benefit all NEC patients. Hence, our ability to detect these unique molecular features is crucial for matching individual NEC patients with specific clinical trials and targeted therapies that may improve their outcomes. Thus, a concerted effort using in-depth genomic, transcriptomic, and TME profiling for NEC tumors is warranted.

Molecular profiling in ABC: Is complementary testing with tissue and plasma necessary and clinically relevant?

e12566 Background: This retrospective analysis explores the concordance between molecular analyses of tissue and plasma amongst Advanced Breast Cancer (ABC) patients and investigates the utility of simultaneous profiling for enhanced clinical insights. Methods: A total of 187 (177 Cancertrack paired and 10 Guardant 360) patient samples with availability of both tissue and ctDNA specimens, were subjected to comparative molecular profiling. Median age was 52 years (Range 23 – 82 years), 174 (93%) patients had advanced breast cancer and 177 (95%) patients had received prior treatments. We assigned tier 1 status to predictive biomarkers with FDA approved or guideline recommended therapies in breast cancer. Tier 2 status was assigned to alterations for which therapies were approved in different tumor type. Tier 3 had either clinical evidence in small studies or had clinical trial inclusion criteria. Results: Paired tissue-ctDNA profiling showed 139/187 (74%) samples had at least one concordant molecular alteration. Simultaneous tissue and ctDNA profiling led to the opportunity to offer Tier 1 recommended therapies in 113/187 (60%) patients. Amongst these, 71/113 (63%) exhibited concordance in tissue and circulating free DNA (cfDNA). ctDNA missed Tier 1 alterations in 14 patients which were detected by tissue biopsy. On the contrary tissue biopsy failed to detect Tier 1 alterations in 18 patients which were identified by ctDNA only. When Tier 2 and 3 alterations were considered, ctDNA identified additional alterations compared to tissue in 29 patients (37 variants), whereas tissue identified additional alterations in 20 patients (24 variants). Complementary tissue and ctDNA profiling showed alterations with potential to impact clinical management (Tier1/2/3) in 82% patients. When including only Tier 1 and 2 alterations, simultaneous profiling approach gives an opportunity to offer personalized therapy in 68% patients. The Tier1 ctDNA only alterations were most frequent in ESR1 gene. In fact, a total of a total of 29 ESR1 mutations were detected in these patients, of which 10 mutations were detected in both tissue and liquid. In 3 patients’ tissues were positive for ESR1 mutations but the corresponding ctDNA was negative. Similarly, ctDNA detected 16 ESR1 variants which were negative in the tissue sample. The most common ESR1 variants were D538G and Y537S. Conclusions: The simultaneous profiling of tissue and ctDNA enhanced overall clinical utility of molecular analysis in advanced breast cancer by identifying predictive biomarkers. The integration of data from both sources allowed for comprehensive understanding of the molecular heterogeneity in breast cancer. It underscores the potential of simultaneous profiling to guide treatment decisions and improve patient outcomes. By detecting acquired resistance ESR1 mutations more effectively, ctDNA serves as a valuable tool for monitoring as well.

Randomised clinical trial: Design of the SYNERGY-NASH phase 2b trial to evaluate tirzepatide as a treatment for metabolic dysfunction-associated steatohepatitis and modification of screening strategy to reduce screen failures.

The use of histological inclusion criteria for clinical trials of at-risk metabolic dysfunction-associated steatohepatitis (MASH) is often associated with high screen failure rates. To describe the design of a trial investigating tirzepatide treatment of MASH and to examine the effect of new inclusion criteria incorporating the use of the FibroScan-AST (FAST) score on the proportion of patients meeting histological criteria. SYNERGY-NASH is a Phase 2b, multicentre, randomised, double-blinded, placebo-controlled trial in patients with biopsy-confirmed MASH, F2-F3 fibrosis and NAFLD Activity Score ≥4. New inclusion criteria (FAST score >0.35 and an increase in AST inclusion criterion from >20 to >23 U/L) were adopted during the trial, allowing us to examine its impact on the qualification rate. 1583 participants were screened, 651 participants proceeded to liver biopsy and 190 participants were randomised with an overall screen fail rate of 87%. Following the protocol amendment, the overall qualification rate for per-protocol biopsies was minimally changed from 27.5% to 28.9% with considerable variation among different investigator medical speciality types: endocrinology: from 37.5% to 39.3%; gastroenterology/hepatology: from 26.0% to 23.3%; other specialities: from 21.3% to 29.7%. At 29 sites that performed per-protocol biopsies before and after the amendment, qualification rates changed as follows: all: 26.1% to 29.1%; endocrinology: from 35.0% to 40.9%; gastroenterology/hepatology: 25.6% to 20.0%; other specialities: from 16.1% to 27.8%. For at-risk MASH trials based on liver histology, the implementation of inclusion criteria with the proposed FAST score and AST cut-offs in this trial was most effective at non-specialist sites.

Abstract PO2-26-01: Prognostic Role of HER2 Expression in Patients with ER-positive/HER2-negative Breast Cancer. Results from a Population-Based Cancer Registry Study

Abstract Background: Estrogen Receptor (ER)-positive (+)/Human Epidermal Growth Factor Receptor 2 (HER2)-negative (-) breast cancers (BCs) express variable protein levels of HER2, which can influence prognosis. Materials and Methods: This cohort study was conducted using data on all consecutive patients (pts) diagnosed with BC between 2005 and 2017, which were systematically and prospectively collected by the Emilia-Romagna Cancer Registry (Provinces of Piacenza, Parma, Modena, and Ferrara), Italy. The study included 13527 pts with ER+/HER2- BC. Tumors were classified by HER2 IHC score (0 [n=7155], 1+ [n=5186], or 2+ with negative FISH [n=1186]). Comparisons of clinicopathologic characteristics and disease outcome were performed. Results: BCs with late-stage diagnosis, high histological grade, or high proliferative rate were more likely to be HER2 1+ or 2+/FISH- in comparison with earlier stage, low-grade, or low-proliferative tumors (lower bounds of 95% confidence intervals [CIs] for odds ratios [ORs] > 1). BCs with high expression of ER (≥ 80% [n=12383]) were more enriched with HER2 1+ (OR 1.39; 95%CI, 1.2-1.6) or 2+/FISH- tumors (OR 1.26; 95%CI, 1.0-1.6) than ER-low/moderate (1-79% [n=1144]) ones. The 5-year overall survival (OS) for HER2 1+ BCs was lower than that for HER2 0 or 2+/FISH- tumors (P = 0.0018). This finding was confirmed also after stratification by ER status (low/moderate and high expression; P = 0.07 and 0.007, respectively). By multivariate logistic regression, the following variables were significantly associated with HER2 1+, or 2+/FISH- expression compared to HER2 0 tumors: age at diagnosis < 50, high histological grade, ER expression ≥ 80% (lower bounds of 95% CIs for ORs > 1). Multivariate Cox's regression analysis showed that histological grades G2 and G3 were independently associated with poor survival vs. G1 tumors (HR 1.2; 95%CI, 1.1-1.3 and 1.3; 95%CI, 1.1-1.4, respectively). Furthermore, HER2 2+/FISH- status was significantly associated with better survival in comparison with HER2 0 tumors (HR 0.82; 95%CI, 0.7-0.9). This finding was confirmed also after stratification by ER status (ER 1-79% and ≥ 80%). No significant difference in OS was observed between HER2 1+ and 0 BCs. Conclusions: The putative worse prognostic impact of HER2 expression in pts with ER-positive/HER2-negative BCs was not confirmed. The better outcome observed in pts with HER2 2+/FISH- BCs may be related to the known FISH-negative (HER2-non-amplified) status of this subgroup. These findings may help identify optimal patient inclusion criteria for clinical trials with novel anti-HER2 therapies in ER-positive/HER2-negative disease. Citation Format: Antonino Musolino, Olga Serra, Benedetta Pellegrino, Chiara Tommasi, Daniele Zanoni, Fabio Faccini, Maria Michiara, Paolo Sgargi, Giuliano Carrozzi, Stefano Ferretti, Veruska Grossi, Alessandra Ravaioli, Federica Zamagni, Fabio Falcini. Prognostic Role of HER2 Expression in Patients with ER-positive/HER2-negative Breast Cancer. Results from a Population-Based Cancer Registry Study [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 PO2-26-01.

Abstract PS11-01: Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients

Abstract BACKGROUND Historic data suggest that incidence of brain metastasis (BM) is relatively distributed over time in HER2-positive (HER2+) breast cancer (BC), occurs early in triple negative BC (TNBC), and occurs late in hormone receptor-positive (HR+) metastatic BC (mBC). However, the timing of BM relative to line of therapy has not been well described. We describe the prevalence per line of therapy and cumulative incidence of BM in a large real-world cohort of patients (pts) with mBC, by BC subtype and line of therapy. METHODS This analysis used data from the longitudinal US Flatiron Health de-identified database, which provides unstructured and structured electronic health record-derived data from >2.6 million pts with cancer in ~800 unique sites of care. Eligible pts had initiated a first line of treatment (index data) for mBC up to March 1, 2021, to allow for ≥2 years potential follow-up time. Baseline characteristics were assessed, and pts categorized by HER2 and HR status: 1) HR+, HER2+; 2) HR+, HER2–, 3) HR–, HER2+ and 4) TNBC (i.e., negative for HR and HER2). For the last two categories, HER2-low subsets were defined based on immunohistochemistry results (1+, 2+, or equivocal). Lines of therapy were derived using both treatment regimens and progression data. The primary outcome was the first diagnosis of BM. The prevalence of BM was evaluated by subtype, at the index date, and by the line of therapy. The cumulative incidence function (CIF) of BM was used to estimate the risk of BM in pts free of BM at the index date, and death was treated as a competing event. RESULTS Overall, 18075 pts were included (HR+, HER2+: 3062 pts [16.9%]; HR–, HER2+: 902 pts [5.0%]; HR+, HER2–: 12331 pts [68.2%] [HR+, HER2-low: 7062 (39.1%)]; TNBC: 1780 pts [9.8%] [HR–, HER2-low: 725 pts (4.0%)]). Median age at the index date was 64 years (interquartile range: 54, 73) and 10271pts (56.8%) had visceral metastasis. In total, 5951 pts (32.9%) had de novo disease, 12090 (66.9%) had recurrent disease, and 34 (0.2%) did not have available data for mBC type. The table shows the number of pts by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date. Of the included pts, 1306 (7.2%) had a BM at the index date; the CIF was run on the remaining 16973 pts. Overall, 2248 pts (13.2%) had an incident BM event during follow-up (HR+, HER2+: 578 events; HR–, HER2+: 237 events; HR+, HER2–: 1119 events [HR+, HER2-low: 619 events]; TNBC: 314 events [HR–, HER2-low: 124 events]), 9314 had a competing event, and 5411 were censored. By fourth-line therapy, the prevalence of BM was 26.1% in HR+, HER2+; 37.1% in HR–, HER2+; 24.7% in TNBC (HR–, HER2-low: 27.9%); but remained low at 7.2% in HR+, HER2– (HR+, HER2-low: 9.4%). The cumulative incidence of BM at 60 months was 23% in HR+, HER2+, 34% in HR–, HER2+, 10% in HR+, HER2–, and, 22% in TNBC. Overall, the HER2-low subsets had BM prevalence and cumulative incidence that were very close to those that were HER2–. CONCLUSIONS This large analysis of real-world data demonstrates that the prevalence of BM across pts with mBC differs by tumor subtype and by line of therapy. Conversely, HER2-low status may have limited impact. The cumulative incidence of BM was highest in the HR–, HER2+ and TNBC subgroups, and lowest in the HR+, HER2– subgroup; despite this, due to the high proportion of HER2–, HR+ mBC cases, the HR+, HER2– group represented the largest number of BM events. These data emphasize the need for clinical and biologic predictors of BM and for strategies to prevent their onset, and provide information on the impact of BM inclusion and exclusion criteria in clinical trials for pts with mBC. Number of patients by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date BM, brain metastasis; HR, hormone receptor, pts, patients; TNBC, triple negative breast cancer. Citation Format: Sarah Sammons, Jose Leone, Thibaut Sanglier, Peter Lambert, Filippo Montemurro, Raf Poppe, Eleonora Restuccia, Sara Tolaney, Nancy Lin. Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients [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 PS11-01.

European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4)

IntroductionThe OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). MethodsGuidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. ResultsModerate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DiscussionThese multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aβ)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). In general linear models lower plasma Aβ42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Evaluation of covariate effects in item response theory models.

Item response theory (IRT) models are usually the best way to analyze composite or rating scale data. Standard methods to evaluate covariate or treatment effects in IRT models do not allow to identify item-specific effects. Finding subgroups of patients who respond differently to certain items could be very important when designing inclusion or exclusion criteria for clinical trials, and aid in understanding different treatment responses in varying disease manifestations. We present a new method to investigate item-specific effects in IRT models, which is based on inspection of residuals. The method was investigated in a simulation exercise with a model for the Epworth Sleepiness Scale. We also provide a detailed discussion as a guidance on how to build a robust covariate IRT model.

Multiomics Blood-Based Biomarkers Predict Alzheimer’s Predementia with High Specificity in a Multicentric Cohort Study

BackgroundThe primary criteria for diagnosing mild cognitive impairment (MCI) due to Alzheimer’s Disease (AD) or probable mild AD dementia rely partly on cognitive assessments and the presence of amyloid plaques. Although these criteria exhibit high sensitivity in predicting AD among cognitively impaired patients, their specificity remains limited. Notably, up to 25% of non-demented patients with amyloid plaques may be misdiagnosed with MCI due to AD, when in fact they suffer from a different brain disorder. The introduction of anti-amyloid antibodies complicates this scenario. Physicians must prioritize which amyloid-positive MCI patients receive these treatments, as not all are suitable candidates. Specifically those with non-AD amyloid pathologies are not primary targets for amyloid-modifying therapies. Consequently there is an escalating medical necessity for highly specific blood biomarkers that can accurately detect pre-dementia AD, thus optimizing amyloid antibody prescription.ObjectivesThe objective of this study was to evaluate a predictive model based on peripheral biomarkers to identify MCI and mild dementia patients who will develop AD dementia symptoms in cognitively impaired population with high specificity.DesignPeripheral biomarkers were identified in a gene transfer-based animal model of AD and then validated during a retrospective multi-center clinical study.SettingParticipants from 7 retrospective cohorts (US, EU and Australia).ParticipantsThis study followed 345 cognitively impaired individuals over up to 13 years, including 193 with MCI and 152 with mild dementia, starting from their initial visits. The final diagnoses, established during their last assessments, classified 249 participants as AD patients and 96 as having non-AD brain disorders, based on the specific diagnostic criteria for each disorder subtype. Amyloid status, assessed at baseline, was available for 82.9% of the participants, with 61.9% testing positive for amyloid. Both amyloid-positive and negative individuals were represented in each clinical group. Some of the AD patients had co-morbidities such as metabolic disorders, chronic diseases, or cardiovascular pathologies.MeasurementsWe developed targeted mass spectrometry assays for 81 blood-based biomarkers, encompassing 45 proteins and 36 metabolites previously identified in AAV-AD rats.MethodsWe analyzed blood samples from study participants for the 81 biomarkers. The B-HEALED test, a machine learning-based diagnostic tool, was developed to differentiate AD patients, including 123 with Prodromal AD and 126 with mild AD dementia, from 96 individuals with non-AD brain disorders. The model was trained using 70% of the data, selecting relevant biomarkers, calibrating the algorithm, and establishing cutoff values. The remaining 30% served as an external test dataset for blind validation of the predictive accuracy.ResultsIntegrating a combination of 19 blood biomarkers and participant age, the B-HEALED model successfully distinguished participants that will develop AD dementia symptoms (82 with Prodromal AD and 83 with AD dementia) from non-AD subjects (71 individuals) with a specificity of 93.0% and sensitivity of 65.4% (AUROC=81.9%, p<0.001) during internal validation. When the amyloid status (derived from CSF or PET scans) and the B-HEALED model were applied in association, with individuals being categorized as AD if they tested positive in both tests, we achieved 100% specificity and 52.8% sensitivity. This performance was consistent in blind external validation, underscoring the model’s reliability on independent datasets.ConclusionsThe B-HEALED test, utilizing multiomics blood-based biomarkers, demonstrates high predictive specificity in identifying AD patients within the cognitively impaired population, minimizing false positives. When used alongside amyloid screening, it effectively identifies a nearly pure prodromal AD cohort. These results bear significant implications for refining clinical trial inclusion criteria, facilitating drug development and validation, and accurately identifying patients who will benefit the most from disease-modifying AD treatments.

Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials.

Injury mechanism is an important consideration when conducting clinical trials in trauma. Mechanisms of injury may be associated with differences in mortality risk and immune response to injury, impacting the potential success of the trial. We sought to characterize clinical and endothelial cell damage marker differences across blunt and penetrating injured patients enrolled in three large, prehospital randomized trials which focused on hemorrhagic shock. In this secondary analysis, patients with systolic blood pressure < 70 or systolic blood pressure < 90 and heart rate > 108 were included. In addition, patients with both blunt and penetrating injuries were excluded. The primary outcome was 30-day mortality. Mortality was characterized using Kaplan-Meier and Cox proportional-hazards models. Generalized linear models were used to compare biomarkers. Chi squared tests and Wilcoxon rank-sum were used to compare secondary outcomes. We characterized data of 696 enrolled patients that met all secondary analysis inclusion criteria. Blunt injured patients had significantly greater 24-h (18.6% vs. 10.7%, log rank p = 0.048) and 30-day mortality rates (29.7% vs. 14.0%, log rank p = 0.001) relative to penetrating injured patients with a different time course. After adjusting for confounders, blunt mechanism of injury was independently predictive of mortality at 30-days (HR 1.84, 95% CI 1.06-3.20, p = 0.029), but not 24-h (HR 1.65, 95% CI 0.86-3.18, p = 0.133). Elevated admission levels of endothelial cell damage markers, VEGF, syndecan-1, TM, S100A10, suPAR and HcDNA were associated with blunt mechanism of injury. Although there was no difference in multiple organ failure (MOF) rates across injury mechanism (48.4% vs. 42.98%, p = 0.275), blunt injured patients had higher Denver MOF score (p < 0.01). The significant increase in 30-day mortality and endothelial cell damage markers in blunt injury relative to penetrating injured patients highlights the importance of considering mechanism of injury within the inclusion and exclusion criteria of future clinical trials.

Oncogenic fusions in renal cell carcinoma.

475 Background: Detecting actionable or diagnostic fusions in solid tumors may significantly alter clinical decisions, including therapy selection. Some fusions have matched drugs approved for use in the patient’s cancer, or in another cancer. Others have published evidence of benefit with particular drugs but are not included in guidelines, and some may represent an inclusion criterion for clinical trials. While diagnostic fusions may not have associated therapies, they are cancer-defining and can lead to re-classification of tumors. Here we describe actionable and diagnostic fusions we have observed in renal cell carcinoma (RCC). Methods: Tumor samples from patients diagnosed with RCC were analyzed using the OncoExTra assay, which identifies somatic mutations and gene fusions through tumor-normal, whole-exome DNA and whole-transcriptome RNA sequencing. All actionable fusions, defined as those with associated FDA-approved targeted therapies in any cancer type, those that made patients eligible for an active clinical trial, or those with evidence in guidelines or the literature for possible matched therapies in any cancer, are detectable using this assay. We examined samples from patients with RCC who had the OncoExtra assay performed between May 2018 and Mar 2023 and identified both actionable and diagnostic fusions. Results: Among 389 tumor samples from patients diagnosed with RCC, there were 11 (2.8%) actionable and 1 (0.3%) diagnostic fusion identified. The actionable fusions included 6 (1.5%) TFE3, 1 (0.3%) ALK, 1 (0.3%) EGFR, 1 (0.3%) ERBB4, 1 (0.3%) YAP and 1 (0.3%) FGFR2, and the diagnostic fusion was NAB2/STAT6. The 6 TFE3 oncogene fusions involved 4 different partner genes ( PRCC was the partner in 3 fusions). ALK, EGFR, ERBB and FGFR fusions are found across a variety of cancers, and all have matched FDA-approved drug therapies in at least one cancer type. For example, ALK fusions, including the observed EML4/ALK fusion, which is common in non-small cell lung cancer, have several matched ALK-inhibitor therapies. TFE3 (transcription factor binding to IGHM enhancer 3) gene fusions are a diagnostic genomic alteration in microphthalmia-associated transcription factor (MiT) translocation RCC, which is a rare but aggressive subtype of RCC. While TFE3 fusions do not have FDA-approved matched therapies in any cancer, they are known to result in PIK3K/AKT/mTOR and MET activation, suggesting inhibitors of these pathways may be considered in these patients. The NAB2/STAT6 diagnostic fusion is characteristic of solitary fibrous tumors, suggesting that the patient likely had this kind of tumor. Conclusions: Whole-transcriptome sequencing allowed the identification of actionable fusions with the potential to affect clinical decisions regarding therapy in 2.8% of RCC patient tumors. In addition, one patient was found to have a fusion that is characteristic of a solitary fibrous tumor, demonstrating the power of genomic profiling to aid diagnosis.

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction.

NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood. We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis. NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; βTOPCAT=0.539; P<0.0001; βPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; βTOPCAT=0.571; P<0.0001; βPHFS=0.459; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations. Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.

Validation of the Onychomycosis Severity Index in a Brazilian population.

Onychomycosis is the most frequent nail disorder, but unfortunately, curative treatment is still a challenge, and commonly the infection recurs. A widely disseminated system to accurately assess and classify the severity of this disease, such as the MASI score for melasma or PASI for psoriasis, is lacking in the literature. In 2011, Carney et al. established and successfully validated the Onychomycosis Severity Index (OSI), proving it to be a simple and reproducible tool. To validate the Onychomycosis Severity Index in a Brazilian population. Four experienced dermatologists were taught how to use the OSI system, and then evaluated photographs of 24 nails. There was no consultation between the dermatologists, and the results were evaluated by an impartial third party. A statistically significant (p<0.001) high degree of agreement was observed between the evaluators and overall OSI score (mild, moderate or severe) as well as its subcategories (area of involvement, proximity to the nail matrix and presence of dermatophytoma or hyperkeratosis). OSI is a very useful tool to improve the clinical assessment of onychomycosis and support clinical trial inclusion criteria (p<0.001). It also provides important prognostic data and allows for a better follow-up of treatment efficacy.

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups.

It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years. We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction. In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.

Place of tyrosine kinase inhibitors in the first line of treatment of hepatocellular carcinoma

The incidence of hepatocellular carcinoma (HCC) in Russia and worldwide is steadily increasing over time. The majority of HCC patients are diagnosed at a late stage of the disease, which is not suitable for potentially curative treatment methods. Before the emergence of new treatment regimens, the median overall survival for this condition was just over one year. Studying combinations of immunotherapy and targeted therapy has improved clinical outcomes compared to monotherapy with tyrosine kinase inhibitors, but the new treatment regimens cannot be prescribed to all patients with advanced HCC. The combination of atezolizumab with bevacizumab may be prescribed to eligible patients with advanced hepatocellular carcinoma who do not have varicose veins and have no history of hypertensive crises. In real clinical practice, it is extremely difficult to select patients who meet the inclusion criteria for clinical trials. Monotherapy with tyrosine kinase inhibitors is also effective regardless of the etiology of HCC development and can be prescribed to patients with signs of liver insufficiency (Child-Pugh B) as opposed to combined therapy. Double immunotherapy has shown its efficacy in second-line treatment, and in the future, these combinations may also demonstrate their effectiveness in first-line treatment of hepatocellular carcinoma. There is insufficient evidence on the effectiveness of immunotherapy in patients awaiting liver transplantation. For this category of patients, the drugs of choice are lenvatinib and sorafenib. The article highlights the specific considerations in choosing the treatment regimen based on the etiology of the disease, treatment goals, concomitant patient conditions, and the presence/severity of liver insufficiency.

Heterogeneity of Radiological Progression Patterns and Association with Outcomes in Patients with Metastatic Prostate Cancer

BackgroundWith an increasing number of clinical trials using radiographic progression-free survival (rPFS) instead of overall survival as the primary study endpoint, the heterogeneity of different radiological progression patterns in rPFS and postprogression survival (PPS) remains unclear. ObjectiveHerein, we investigate the proportion of various radiological progression patterns in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC), and further explore the differences in rPFS and PPS between patients exhibiting single- or multicategory progression patterns. Design, setting, and participantsThis post hoc, retrospective secondary analysis was based on individual patient data from LATITUDE (phase 3 randomized mHSPC study) and COU-AA-302 (phase 3 randomized mCRPC study). Patients with complete imaging follow-up data and radiological progression were included in the analysis. Outcome measurements and statistical analysisThe rPFS and PPS in LATITUDE and COU-AA-302 were evaluated. The proportion of patients exhibiting each progression pattern was calculated, and a survival analysis was conducted using the Kaplan-Meier method. Results and limitationsOf the 489 mHSPC patients studied, 366 experienced single-category progression, while the remaining 123 patients (25.2%) exhibited simultaneous occurrence of different progressive events (multicategory radiological progression). Of the 534 mCRPC patients studied, 390 experienced single-category progression, while the remaining 144 patients (27.0%) experienced multicategory progressive events. Among mCRPC patients, the rPFS of bone progression was the shortest. In contrast, among mHSPC patients, the rPFS of target lesion enlargement is the shortest, followed by bone progression. Notably, patients experiencing a single-category progression pattern displayed comparable rPFS to but significantly longer PPS than those experiencing multicategory progression patterns (PPS mHSPC cohort: 21.5 vs 6.9 mo, p < 0.0001; mCRPC cohort: 23.6 vs 15.7 mo, p < 0.0001). The study is limited by its hypothesis-generating nature. Therefore, the observed phenomena in our research necessitate validation through future prospective studies. ConclusionsPatients who experience multicategory radiological progression represent a significant proportion, accounting for approximately 25% of all men with mHSPC or mCRPC. Patients with multicategory radiological progression patterns had similar rPFS to but significantly shorter PPS than those experiencing single-category progression patterns. In future clinical trials and clinical practice, radiological progression patterns should be recognized as a crucial determinant of prognosis, while also serving as the stratification or inclusion criteria for second-line treatment clinical trials. Patient summaryIn this study, we observed that among men with metastatic prostate cancer, those who experienced two or more radiological events during a single visit had a worse prognosis than those who experienced isolated radiological events.

Checkpoint Inhibitor Monotherapy in Potentially Trial-Eligible or Trial-Ineligible Patients With Metastatic NSCLC in the German Prospective CRISP Registry Real-World Cohort (AIO-TRK-0315)

IntroductionPatients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of “trial-ineligible” and “potentially trial-eligible” patients. MethodsData from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either “potentially trial-eligible” or “trial-ineligible” according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042). ResultsOf 746 patients included, 343 patients (46.0%) were classified as “trial-ineligible” and had significantly worse outcomes compared with “potentially trial-eligible” patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2–8.4) versus 10.3 (95% CI: 8.4–13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19–1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4–20.3) versus 25.3 (95% CI: 19.8–30.4) months, hazard ratio of 1.36 (95% CI: 1.10–1.67), p equals 0.004. ConclusionsOur data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses.