Identify Subgroups Of Patients Research Articles

Abstract B017: Combining baseline microenvironment biomarkers with hypoxia imaging to predict radiochemotherapy outcomes in head and neck cancer

Abstract Background: Hypoxia contributes to tumor therapy resistance and it can be evaluated through imaging, such as [18F]fluoromisonidazole (FMISO)-PET, or hypoxia-associated gene expression profiling, among other modalities. Integrating imaging with tumor microenvironment features may provide a more comprehensive prognostic assessment. This study evaluates the prognostic value of combining FMISO-PET hypoxia imaging with baseline gene expression profiles in head and neck squamous cell carcinoma (HNSCC) patients undergoing radiochemotherapy (RCTx). Methods FMISO-PET images were obtained at baseline and at weeks 1, 2, and 5 during RCTx to assess tumor-to-background ratios (TBR) and hypoxic volumes (HV). Gene expression from pre-treatment biopsies was analyzed using Affymetrix microarrays. Gene set enrichment analysis of cancer hallmarks was conducted, and cell type fractions were imputed using CIBERSORTx. Correlation and LASSO analyses were conducted to identify baseline gene expression and cell type fractions associated with hypoxia imaging at baseline and during RCTx. Cox regression models were used to integrate imaging and gene expression data for predicting loco-regional tumor control (LRC). Results Baseline Epithelial to Mesenchymal Transition and Hypoxia gene sets were strongly correlated with hypoxia imaging parameters at week 2. A LASSO model identified baseline gene expression associated with FMISO-PET parameters (TBRpeak, HV16, and residual hypoxia) at week 2, indicating a predisposition for hypoxia persistence. AKR1A1, PITPNB, CTSK, and PEF1 gene expression levels were associated with LRC. In the tumor microenvironment, CD4 memory resting T cells and fibroblasts at baseline correlated with hypoxia imaging at weeks 1 and 2, with high levels of these cell fractions linked to decreased LRC. The fibroblast cell fraction positively correlated with CTSK transcript levels (Spearman ρ = 0.59, p < 0.05). K-means clustering based on CTSK and fibroblast levels identified patient subgroups with distinct LRC outcomes (HR [95% CI]: 3.491 [1.165-10.46], p = 0.0256). Importantly, clustering remained an independent predictor of LRC when analyzed with baseline FMISO TBRpeak and HV16 in multivariate Cox regression (HR [95% CI]: 3.883 [1.224-12.321], p = 0.0213). However, when TBRpeak and HV16 at week 2 were included in the model, the impact of the fibroblast cell fraction/CTSK clustering was attenuated (HR [95% CI]: 2.899 [0.918-9.156], p = 0.0697). Conclusion This study highlights the potential for integrating baseline tumor microenvironment markers, such as fibroblast fraction and CTSK expression, with dynamic hypoxia imaging to improve HNSCC prognostic accuracy. High fibroblast cell fraction and CTSK levels at baseline may predispose tumors to treatment-resistant hypoxia, confirmed by persistent hypoxia measured by FMISO-PET at week 2 . By capturing both predisposition to and hypoxia imaging, this approach may enhance the personalization of radiochemotherapy for high-risk HNSCC patients. Citation Format: María J. Besso, Verena Bitto, Cristina Conde-Lopez, Mareike Roscher, Steffen Löck, Annett Linge, Mechthild Krause, Michael Baumann, Ina Kurth. Combining baseline microenvironment biomarkers with hypoxia imaging to predict radiochemotherapy outcomes in head and neck cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B017.

Identifying Patient Subgroups in the Heterogeneous Chronic Pain Population Using Cluster Analysis.

Chronic pain is an ill-defined disease with complex biopsychosocial aspects, posing treatment challenges. We hypothesized that treatment failure results, at least partly, from limited understanding of diverse patient subgroups. We aimed to identify subgroups using psychological variables, allowing for more tailored interventions. In a retrospective cohort study, we extracted patient-reported data from two Dutch tertiary multidisciplinary outpatient pain clinics (2018-2023) for unsupervised hierarchical clustering. Clusters were defined by anxiety, depression, pain catastrophizing, and kinesiophobia. Sociodemographics, pain characteristics, diagnosis, lifestyle, health-related quality of life and treatment efficacy were compared among clusters. A prediction model was built utilizing a minimum set of questions to reliably assess cluster allocation. Among 5,466 patients with chronic pain, three clusters emerged. Cluster 1 (n=750) was characterized by high psychological burden, low health-related quality of life, lower educational levels and employment rates, and more smoking. Cluster 2 (n=1,795) showed low psychological burden, intermediate health-related quality of life, higher educational levels and employment rates, and more alcohol consumption. Cluster 3 (n=2,909) showed intermediate features. Pain reduction following treatment was least in cluster 1 (28.6% after capsaicin patch, 18.2% after multidisciplinary treatment), compared to >50% for both treatments in clusters 2 and 3. A model incorporating 15 psychometric questions reliably predicted cluster allocation. In conclusion, our study identified distinct chronic pain patient clusters through 15 psychological questions, revealing one cluster with notably poorer response to conventional treatment. Our prediction model, integrated in a web-based tool, may help clinicians improve treatment by allowing patient-subgroup targeted therapy according to cluster allocation. PERSPECTIVE: Hierarchical clustering of chronic pain patients identified three subgroups with similar pain intensity and diagnoses but distinct psychosocial traits. One group with higher psychological burden showed poorer treatment outcomes. A web-based tool using this model could help clinicians tailor therapies by matching interventions to specific patient subgroups for improved outcomes.

The 2024 Assisi think tank on breast cancer: Focus on the use of a tumour bed boost after breast conserving therapy.

At the Fifth Assisi Think Tank Meeting (ATTM) on breast cancer, one key topic was the role of tumor bed boost in invasive breast cancer and ductal carcinoma in situ. The need for a tumor bed boost after whole breast irradiation is controversial. A literature review assessed boost indications, target volume definition, techniques, dose fractionation, and ongoing trials. Findings indicated that while a boost halves the risk of local recurrence at 10 years, it also leads to worsened cosmetic outcomes and increased fibrosis without improving overall survival. Therefore, we would recommend to omit the boost if the estimated reduction in local recurrence at 10 years is less than 3%, and to apply shared decision-making with patients, if the boost is expected to reduce the local recurrence rate with >3% at 10 years. Future research will focus on identifying patient subgroups that can safely omit the boost and improving boost volume precision.

Hearing loss rather than vestibular loss identifies patient subgroups with different outcomes in Meniere’s disease

Objective This study investigates the relationship between Meniere’s disease (MD) duration and both hearing thresholds and vestibular dysfunction. Design Retrospective cohort study. First, the relationships between MD duration and pure-tone audiometry thresholds for each frequency, the canal paresis (CP) ratio, and the vestibulo-ocular reflex (VOR) gain were analysed. Second, clinical characteristics, CP values, and VOR gains were compared between patient groups with low and high hearing thresholds to determine whether they exhibited different clinical presentations. Study sample The study included 69 patients diagnosed with unilateral MD within a duration of 10 years. A hearing dataset from 306 MD Spanish patients was used to cluster patients according to the hearing profile overtime. Results The thresholds at 250–2000 Hz frequencies increased with the duration of the disease. Conversely, vestibular function tests were not related to the duration of MD. Additionally, no statistically significant differences were observed in clinical characteristics, CP values, or VOR gain between patient groups with low and high hearing thresholds. Conclusions Hearing loss involves all frequencies in most patients and hearing outcome, rather than vestibular loss, may define patient subgroups in MD. Moreover, not all patients with MD experience hearing loss progression as the duration of the disease increases.

The impact of deep response to ursodeoxycholic acid in primary biliary cholangitis - should it be the new clinical standard?

This review explores the emerging concept of "deep response" in primary biliary cholangitis (PBC), defined by the normalization of biochemical markers, particularly alkaline phosphatase and bilirubin. It examines its potential as a new standard for disease management and its implications for long-term patient outcomes, health policies, and clinical decision-making. Recent studies suggest that achieving a deep response significantly improves long-term outcomes in some patients with PBC. In particular, a significant complication-free survival gain was observed among patients who at baseline were at high risk for disease progression. However, limitations in data and the variability in patient populations pose challenges for universal adoption of this standard. Deep biochemical response represents a promising new standard for optimizing PBC management, offering measurable goals for clinicians and potentially improved long-term outcomes for patients. However, further research is necessary to better define the appropriate biochemical thresholds, understand the risks of overprescribing, and identify patient subgroups that are most likely to benefit from this strategy. A balanced, patient-centered approach incorporating deep response into comprehensive management could improve care for high-risk PBC patients.

Classification and Regression Trees analysis identifies patients at high risk for kidney function decline following hospitalization.

Estimated glomerular filtration rate (eGFR) decline is associated with negative health outcomes, but the use of decision tree algorithms to predict eGFR decline is underreported. Among patients hospitalized during the first year of the COVID-19 pandemic, it remains unclear which individuals are at the greatest risk of eGFR decline after discharge. We conducted a retrospective cohort study on patients hospitalized at Stony Brook University Hospital in 2020 who were followed for 36 months post discharge. Random Forest (RF) identified the top ten features associated with fast eGFR decline. Logistic regression (LR) and Classification and Regression Trees (CART) were then employed to uncover the relative importance of these top features and identify the highest risk patients. In the cohort of 1,747 hospital survivors, 61.6% experienced fast eGFR decline, which was associated with younger age, higher baseline eGFR, and acute kidney injury (AKI). Multivariate LR analysis showed that older age was associated with lower odds of fast eGFR decline whereas length of hospitalization and vasopressor use with greater odds. CART analysis identified length of hospitalization as the most important factor and that patients with AKI and hospitalization of 27 days or more were at highest risk. After grouping by ICU and COVID-19 status and propensity score matching for demographics, these risk factors of fast eGFR decline remained consistent. CART analysis can help identify patient subgroups with the highest risk of post-discharge eGFR decline. Clinicians should consider the length of hospitalization in post-discharge monitoring of kidney function.

Investigation of selective glucocorticoid receptor modulation in high-grade serous ovarian cancer PDX models.

In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA (NR3C1) and protein were treated with chemotherapy +/- SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography. One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.

Impact of early goal-directed therapy on outcomes in adult septic shock: a systematic review

Septic shock is a critical form of sepsis, a life-threatening illness marked by organ failure due to an aberrant immunological response from the host. This condition frequently leads to multiple organ dysfunction syndrome, primarily caused by microbial imbalance. As septic shock poses significant challenges requiring immediate medical intervention to prevent organ failure and reduce mortality, research into its management is crucial. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify relevant literature on EGDT's effects. Searches were conducted in PubMed, Web of Science, Cochrane Library, and EBSCOHost databases. Data were analyzed with RevMan software, and the Newcastle-Ottawa Quality Assessment Scale along with Cochrane's Risk of Bias tool were used to evaluate the quality of included studies. Studies were classified as having a high (0–3), moderate (4–6), or low (7–9) risk of bias. Results showed no significant differences in Sequential Organ Failure Assessment (SOFA) scores. Although EGDT reduced mortality rates, it did not demonstrate significant improvements in outcomes compared to standard treatment. The findings suggested that non-invasive, protocolized treatments might improve hemodynamics and mortality. The review indicated that advancements in standard sepsis management might have reduced the relative benefits of EGDT. Future research should focus on identifying patient subgroups that benefit most from EGDT, refining resuscitation techniques, and exploring less invasive approaches. Research into biomarkers and advanced monitoring technologies might provide deeper insights into patient responses, enabling more tailored and effective interventions.

Identifying factors associated with perfluorohexyloctane treatment response in dry eye disease patients with meibomian gland dysfunction: A post‐hoc analysis

Aims/Purpose: The heterogeneous nature of dry eye disease (DED) associated with meibomian gland dysfunction (MGD) poses challenges for effective treatment, necessitating a deeper understanding of associated factors. Perfluorohexyloctane eye drops (PED, SHR8058) have shown efficacy in DED treatment, yet variability in treatment response remains unclear. This post‐hoc analysis explores factors associated with PED treatment response to identify patient subgroups benefiting most.Methods: Using data from a phase 3, randomized, double‐blind, salinee‐controlled, multicenter clinical study (NCT05515471), this post hoc responder analysis aggregated data from 156 patients in the PED treatment group. Response outcomes for signs and symptoms were assessed using total corneal fluorescein staining (tCFS, ≥ 3 reductions from baseline) and eye dryness score (EDS, ≥ 30% reduction from baseline), respectively. Univariate and multivariate logistic regression using stepwise selection method, with the cutoff p‐value to enter of 0.1 and stay in the model set at 0.05 were applied to explore potential variables associated with response outcomes.Results: Among 156 patients treated with PED, the mean (SD) of tCFS and EDS was 6.2 (1.9), and 64.7 (15.1) at baseline. In both univariate and multivariate regression analysis for signs response, tCFS score and ametropia showed association with signs response (odds ratio [OR] 1.4; 95% confidence interval [CI], 1.08‐1.73 and OR 3.0; 95% CI, 1.27‐7.25 respectively in multivariate analyses). Regarding symptoms, EDS (OR 1.1; 95% CI, 1.02‐1.11), awareness of DED symptoms (OR 1.0; 95% CI, 0.93‐0.99), dryness frequency (OR 1.0; 95% CI, 0.93‐1.00), and tCFS (OR 1.4; 95% CI, 1.05‐1.77) were independent associated factor of EDS in multivariate analysis.Conclusions: These post hoc findings suggest that tCFS score, ametropia, EDS, awareness of DED symptoms and dryness frequency are associated with PED treatment response.

Factors and outcomes associated with under- and overdiagnosis of sepsis in the first hour of emergency department care.

Sepsis remains the leading cause of in-hospital death and one of the costliest inpatient conditions in the United States, while treatment delays worsen outcomes. We sought to determine factors and outcomes associated with a missed emergency physician (EP) diagnosis of sepsis. We conducted a secondary analysis of a prospective single-center observational cohort of undifferentiated, critically ill medical patients (September 2020-May 2022). EP gestalt of suspicion for sepsis was measured using a visual analog scale (VAS; 0%-100%) at 15 and 60 min post-patient arrival. The primary outcome was an explicit hospital discharge diagnosis of sepsis that was present on arrival. We calculated test characteristics for clinically relevant subgroups and examined factors associated with initial and persistent missed diagnoses. Associations with process (antibiotics) and clinical (mortality) outcomes were assessed after adjusting for severity. Among 2484 eligible patients, 275 (11%) met the primary outcome. A VAS score of ≥50 (more likely than not of being septic) at 15 min demonstrated sensitivity 0.83 (95% confidence interval [CI] 0.78-0.87) and specificity 0.85 (95% CI 0.83-0.86). Older age, hypoxia, hypotension, renal insufficiency, leukocytosis, and both high and low temperature were significantly associated with lower accuracy due to reduced specificity, but maintained sensitivity. Of 48 (17%) and 23 (8%) missed cases at 15 and 60 min, elevated lactate, leukocytosis, bandemia, and positive urinalysis were more common in the missed sepsis compared to nonsepsis cases. Missed diagnoses were associated with median (interquartile range) delay of 48 (27-64) min in antibiotic administration but were not independently associated with inpatient mortality as risk ratios remained close to 1 across VAS scores. This prospective single-academic center study identified patient subgroups at risk of impaired diagnostic accuracy of sepsis, with clinicians often overdiagnosing rather than underdiagnosing these groups. Prompt abnormal laboratory test results can "rescue" initial missed diagnoses, serving as potential clinician- and systems-level intervention points to reduce missed diagnoses. Missed diagnoses delayed antibiotics, but not mortality after controlling for severity of illness.

Plasma microRNAs Associate Positive, Negative, and Cognitive Symptoms with Inflammation in Schizophrenia.

Schizophrenia is a complex and heterogenous psychiatric disorder characterized by positive, negative, and cognitive symptoms. Our previous study identified three subgroups of schizophrenia patients based on plasma microRNA (miRNA) profiles. The present study aims to (1) verify the reproducibility of the miRNA-based patient stratification and (2) explore the pathophysiological pathways linked to the symptoms using plasma miRNAs. We measured levels of 376 miRNAs in plasma samples of schizophrenia patients and obtained their Positive and Negative Syndrome Scale (PANSS) scores and the Brief Assessment of Cognition in Schizophrenia (BACS) scores. The plasma miRNA profiles identified similar subgroups of patients as in the previous study, suggesting miRNA-based patient stratification is potentially reproducible. Our multivariate analysis identified optimal combinations of miRNAs to estimate the PANSS positive and negative subscales and BACS composite scores. Those miRNAs consistently enriched 'inflammation' and 'NFκB1' according to miRNA set enrichment analysis. Our literature-based text mining and survey confirmed that those miRNAs were associated with IL-1β, IL-6, and TNFα, suggesting that exacerbated positive, negative, and cognitive symptoms are associated with high inflammation. In conclusion, miRNAs are a potential biomarker to identify patient subgroups reflecting pathophysiological conditions and to investigate symptom-related molecular mechanisms in schizophrenia.

COMPARATIVE ANALYSIS OF DIFFERENT MANUAL THERAPY TECHNIQUES IN THE MANAGEMENT OF CHRONIC LOW BACK PAIN

Chronic low back pain (CLBP) is a widespread and debilitating condition that affects the quality of life and productivity of individuals globally. Manual therapy techniques, such as spinal manipulation (SMT), mobilization, massage therapy, soft tissue mobilization (STM), manual traction, and joint mobilization of the pelvis and sacroiliac joint, are widely used interventions for managing CLBP. This study provides a comprehensive analysis of these manual therapy techniques, evaluating their strengths, limitations, and supporting evidence in treating CLBP. A literature review reveals key insights into the effectiveness, safety, and clinical utility of these techniques. The findings emphasize the importance of tailoring treatment to individual patient needs and preferences. Spinal manipulation and mobilization have shown benefits in reducing pain and improving function, while massage and soft tissue techniques enhance relaxation and flexibility. Manual traction and joint mobilization provide targeted relief for specific conditions. This abstract underscores the role of manual therapy as part of multimodal treatment approaches, integrating therapeutic interventions to optimize outcomes. Future research should focus on refining manual therapy practices and identifying patient subgroups most likely to benefit. The findings inform clinicians about evidence-based approaches to CLBP, highlighting the need for patient-centered care and interdisciplinary collaboration.

Distinct patient characteristics are associated with clinical presentation and prognosis in thromboangiitis obliterans.

Background: Thromboangiitis obliterans (TAO) is a rare but threatening disease associated with significant morbidity and mortality. The pathophysiology is poorly understood, the diagnosis is often obscure and causal treatment options are limited. In the current study, we aimed to identify distinct TAO patient clusters that differed in clinical presentation and prognosis. Patients and methods: We retrospectively analysed a cohort of 48 patients with the working diagnosis TAO who were assessed for clinical presentation at hospital admission. We applied hierarchical clustering to divide patients into clinically meaningful subgroups. Results: Patients were followed-up for a median of 95 months. We found that cluster analyses including a variety of demographic and diagnostic parameters were valuable to identify patient subgroups with similar clinical presentation, but with different clinical course of the disease, including the individual risk for mortality and major amputation. Patients treated with statins showed a significantly better survival, which may allow us to hypothesize that a conventional secondary prevention strategy, which is recommended for atherosclerotic artery diseases, may be of benefit also in patients that present with TAO. Conclusions: The current data may help to develop strategies to identify high-risk TAO patients. Furthermore, statins may serve as a readily available therapeutic option to this rare but serious disease.

Exploring Genomic Biomarkers for Pembrolizumab Response: A Real-World Approach and Patient Similarity Network Analysis Reveal DNA Response and Repair Gene Mutations as a Signature.

Purpose: Single-agent immune checkpoint inhibitor (IO) therapy is the standard for non-oncogene-addicted advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score ≥ 50%. Smoking-induced harm generates high tumor mutation burden (H-TMB) in smoking patients (S-pts), while never-smoking patients (NS-pts) typically have low TMB (L-TMB) and are unresponsive to IO. However, the molecular characterization of NS-pts with H-TMB remains unclear. Experimental design: Clinical data of 142 aNSCLC patients with PD-L1 ≥ 50% treated with first line pembrolizumab were retrospectively collected. Next-generation sequencing was performed using the FoundationOne®CDx assay to correlate genomic alterations with clinical characteristics and response outcomes. Detected mutations were classified into eleven main pathways and enrichment analysis identified patient subgroups based on mutated pathways. Additionally, a patient similarity network was constructed to analyze molecular characterization. Results were validated using data from 853 aNSCLC patients in POPLAR and OAK trials. Results: Among the patients, S-pts had higher TMB than NS-pts. Interestingly, 11 (8%) NS-pts exhibited H-TMB and were enriched in β-catenin/Wnt and DDR pathway mutations. DDR pathway mutations were confirmed to be enriched in NS-pts with H-TMB using data from POPLAR and OAK trials. In the real-world cohort, the NS/H-TMB subgroup with DDR pathway mutations demonstrated improved IO outcome. Patient similarity network analysis confirmed the clustering of NS/H-TMB patients with DDR mutations and their association with improved overall survival in both the real-world cohort and the trials. Conclusions: The DDR signature has a potential role as an additional generator of H-TMB in NS-pts. This subgroup of IO-responsive NS-pts may have better prognosis. Our findings suggest that DDR-based mutational profiling may help identify NS-pts who could benefit from IO therapy.

Identification of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease Subgroups by Machine Learning Implementation in Electronic Health Records.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) are heterogeneous. Machine learning (ML) has previously been used to dissect some of the heterogeneity in COPD. The widespread adoption of electronic health records (EHRs) has led to the rapid accumulation of large amounts of patient data as part of routine clinical care. However, it is unclear whether the implementation of ML in EHR-derived data has the potential to identify subgroups of AECOPD. To determine whether ML implementation using EHR data from severe AECOPDs requiring hospitalization identifies relevant subgroups. This study used 2 retrospective cohorts of patients with AECOPDs (non-COVID-19 and COVID-19) treated at Yale-New Haven Hospital. K-means clustering was used to identify patient subgroups. We identified 3 subgroups in the non-COVID cohort (n=1736). Each subgroup had distinct clinical characteristics. The reference subgroup was the largest (n=904), followed by cardio-renal (n=548) and eosinophilic (n=284). The eosinophilic subgroup had milder severity of AECOPD, including a shorter hospital stay (p<0.01). The cardio-renal subgroup had the highest mortality during (5%) and in the year after hospitalization (30%). Validation of the severe AECOPD classifier in the COVID-19 cohort recapitulated the characteristics seen in the non-COVID cohort. AECOPD subgroups in the COVID-19 cohort had different interleukin (IL)-1 beta, IL-2R, and IL-8 levels (false discovery rate ≤ 0.05). These specific leukocyte and cytokine profiles resulted in inflammatory differences between the AECOPD subgroups based on C-reactive protein levels. Incorporating ML with EHR data allows the identification of specific clinical and biological subgroups for severe AECOPD.

Endomyocardial biopsy in patients with myocarditis-still justified in the CMR era? A single-centre experience.

In the past decades, cardiovascular magnetic resonance (CMR) was established as a non-invasive tool supporting the diagnosis of myocarditis and there is often reluctance in performing EMB due to potentially severe complications. We sought to identify patient subgroups that could still benefit from EMB in the CMR era. Data of patients presenting with myocarditis between 01/2016 and 06/2023 were analysed according to patient risks. Prespecified risk factors were (i) left ventricular ejection fraction (LVEF) ≤ 30%; (ii) severe arrhythmias; or (iii) pre-existing autoimmune disease. Furthermore, the subgroup of recurrent myocarditis cases was analysed separately. A total of 137 patients (35.5 ± 14.8years, 80.3% male) were included. 26/137 patients had a documented LVEF ≤ 30%, 13/137 a LVEF > 30% with at least one other risk factor and 98/137 a LVEF > 30% without risk factors. EMB was performed in 21/26 patients with LVEF ≤ 30% (80.8%), in 7/13 patients with LVEF > 30% and risk factors (53.8%) and in 16/98 (16%) patients without risk factors. EMB led to the initiation of immunosuppressive therapy in 11/28 patients with risk factors (39.3%) and in none of the patients without risk factors (0/16, 0%, p = 0.003). With respect to the subgroup of patients presenting with recurrent myocarditis (n = 10), no specific therapy was initiated. Due to a high therapeutic yield for initiation of immunosuppressive therapy in non-infectious myocarditis, performing EMB should be considered in all high-risk patients. In patients without clinical risk factors including cases of recurrent or relapsing myocarditis no specific therapy was initiated.

A data-driven framework for identifying patient subgroups on which an AI/machine learning model may underperform

A fundamental goal of evaluating the performance of a clinical model is to ensure it performs well across a diverse intended patient population. A primary challenge is that the data used in model development and testing often consist of many overlapping, heterogeneous patient subgroups that may not be explicitly defined or labeled. While a model’s average performance on a dataset may be high, the model can have significantly lower performance for certain subgroups, which may be hard to detect. We describe an algorithmic framework for identifying subgroups with potential performance disparities (AFISP), which produces a set of interpretable phenotypes corresponding to subgroups for which the model’s performance may be relatively lower. This could allow model evaluators, including developers and users, to identify possible failure modes prior to wide-scale deployment. We illustrate the application of AFISP by applying it to a patient deterioration model to detect significant subgroup performance disparities, and show that AFISP is significantly more scalable than existing algorithmic approaches.

Longitudinal analysis of ARDS variability and biomarker predictive power in burn patients

Acute Respiratory Distress Syndrome (ARDS) is a severe complication in burn patients, characterized by rapid lung inflammation and hypoxemia. Managing ARDS is challenging due to its high mortality rates and the complex interplay of various pathophysiological factors. This study aims to investigate the heterogeneity of ARDS in burn patients admitted to the Intensive Care Unit (ICU) and evaluate the predictive efficacy of biomarkers in comparison to the PaO2/FiO2 (PF) ratio. A retrospective cohort study was conducted at the Burn Intensive Care Unit of Hangang Sacred Heart Hospital in Seoul, Korea, from July 2010 to December 2022, involving 2,318 patients. Longitudinal k-means clustering was employed to identify patient subgroups based on PF ratio trajectories. Biomarkers, including albumin, white blood cell (WBC) count, and lactate, were assessed for their predictive accuracy using multivariable logistic regression, area under the curve (AUC) analysis, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Four distinct patient clusters were identified. Cluster A exhibited the highest mortality rate at 54.9%, while Cluster D showed the lowest at 7.9%. Albumin demonstrated significantly higher predictive accuracy in Cluster A (AUC: 0.905, NRI: 0.421) and Cluster C (AUC: 0.915, NRI: 0.845), outperforming the PF ratio in both groups. However, in Clusters B and D, biomarkers did not significantly improve upon the predictive power of the PF ratio. Across all clusters, the integration of biomarkers with the PF ratio led to modest improvements but did not consistently outperform the PF ratio as a standalone predictor. This study reveals substantial heterogeneity in ARDS progression among burn patients, with varying mortality rates and biomarker efficacy across clusters. While biomarkers such as albumin showed potential in specific subgroups, their overall contribution to predictive accuracy was limited. Further multicenter, prospective studies are required to validate these findings and develop more refined predictive models. Personalized treatment strategies, based on biomarker profiles and traditional clinical metrics, could enhance ARDS management in burn patients.

Tyrosine Kinase Inhibitors

IntroductionAlthough tyrosine kinase inhibitors (TKIs) are effective against NSCLC harboring sensitizing EGFR gene mutations, acquired resistance is inevitable. Preclinical studies suggest that combining EGFR TKI and monoclonal antibody therapies may have activity in EGFR-mutated NSCLC that has progressed on TKI therapy alone. Therefore, we prospectively evaluated afatinib plus necitumumab in patients with EGFR-mutated NSCLC. MethodsThis was a phase 1, dose-escalation, dose-expansion trial assessing the safety and efficacy of afatinib plus necitumumab. Patients had advanced or metastatic EGFR-mutated NSCLC with progression after (1) first-generation TKI if T790M negative, (2) subsequent line third-generation TKI if T790M positive, or (3) third-generation TKI in the first-line setting. Dose-escalation followed a 3+3 design. The primary end point of dose-expansion was objective response rate. ResultsA total of 22 patients with EGFR-mutated NSCLC were enrolled. The maximum tolerated dose was afatinib 40 mg oral daily plus necitumumab 600 mg intravenous on days 1 and 15 every 28 days. There were no grade 4 to 5 adverse events observed, and seven patients (32%) experienced grade 3 treatment-related adverse events (three rash; one each oral mucositis, diarrhea, headache, ventricular arrhythmia, and tachycardia). In the entire cohort, there were no responses observed, the median progression-free survival was 1.8 months, and the disease control rate was 36% but varied between the subgroups. ConclusionsAfatinib plus necitumumab was safe but had limited activity in patients with EGFR-mutated NSCLC. Biomarker studies may identify patient subgroups that are more likely to benefit.

Comparative Efficacy of Adagrasib and Sotorasib in KRAS G12C-Mutant NSCLC: Insights from Pivotal Trials.

Background: The KRAS G12C mutation, prevalent in various malignancies, including non-small cell lung cancer (NSCLC), represents a unique therapeutic target. Adagrasib and sotorasib, two FDA-approved agents specifically targeting this mutation, have shown promise in clinical trials. This study aims to compare their efficacy in treating KRAS G12C-mutated NSCLC, drawing insights from pivotal clinical trials. Methods: We analyzed data from three key clinical trials: KRYSTAL-1, CodeBreak100, and CodeBreak200. Our methodology involved reconstructing individual patient data from published Kaplan-Meier curves using the IPDfromKM tool (Version 0.1.10). The primary endpoints were progression-free survival (PFS) and overall survival (OS), evaluated through hazard ratios (HRs) and the restricted mean survival time (RMST) method. Results: The HR for PFS favored adagrasib (HR: 0.90 [95% CI: 0.69, 1.19], p = 0.473), suggesting a non-significant trend toward better disease control compared to sotorasib. For OS, the HR was 0.99 [95% CI: 0.75, 1.33] (p = 0.969), indicating no significant difference between the two drugs. RMST analysis supported these findings, with adagrasib showing a consistently higher RMST in PFS at 6, 12, and 18 months. However, OS benefits converged over time, with adagrasib marginally surpassing sotorasib by the 18-month mark. Conclusions: This comprehensive analysis reveals that while adagrasib may offer a slight advantage in PFS, both drugs demonstrate comparable efficacy in OS for KRAS G12C-mutated NSCLC. The subtle differences observed, particularly in PFS, could inform clinical decision-making, emphasizing the need for personalized treatment strategies. Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other.