The relationship between radiomics and pathomics in Glioblastoma patients: Preliminary results from a cross-scale association study

: Glioblastoma multiforme (GBM) typically exhibits substantial intratumoral heterogeneity at both microscopic and radiological resolution scales. Diffusion Weighted Imaging (DWI) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) are two functional MRI techniques that are commonly employed in clinic for the assessment of GBM tumor characteristics. This work presents initial results aiming at determining if radiomics features extracted from preoperative ADC maps and post-contrast T1 (T1C) images are associated with pathomic features arising from H&E digitized pathology images. 48 patients from the public available CPTAC-GBM database, for which both radiology and pathology images were available, were involved in the study. 91 radiomics features were extracted from ADC maps and post-contrast T1 images using PyRadiomics. 65 pathomic features were extracted from cell detection measurements from H&E images. Moreover, 91 features were extracted from cell density maps of H&E images at four different resolutions. Radiopathomic associations were evaluated by means of Spearman's correlation (ρ) and factor analysis. p values were adjusted for multiple correlations by using a false discovery rate adjustment. Significant cross-scale associations were identified between pathomics and ADC, both considering features (n = 186, 0.45 < ρ < 0.74 in absolute value) and factors (n = 5, 0.48 < ρ < 0.54 in absolute value). Significant but fewer ρ values were found concerning the association between pathomics and radiomics features (n = 53, 0.5 < ρ < 0.65 in absolute value) and factors (n = 2, ρ = 0.63 and ρ = 0.53 in absolute value). The results of this study suggest that cross-scale associations may exist between digital pathology and ADC and T1C imaging. This can be useful not only to improve the knowledge concerning GBM intratumoral heterogeneity, but also to strengthen the role of radiomics approach and its validation in clinical practice as "virtual biopsy", introducing new insights for omics integration toward a personalized medicine approach

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Introduction As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety. Objective We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals. Methods We queried the US Food and Drug Administration Adverse Event Reporting System (October 2017-September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated. Results Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2-4.4) and gastrointestinal perforations (2.9; 1.2-7.3), tisa-cel with hepatotoxicity (2.5; 1.1-5.7) and pupil disorders (15.3; 6-39.1). Conclusions Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity

Successes and pitfalls in orphan drug development for sickle cell disease

Sickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end point

Tremendous bleeding complication after vacuum-assisted sternal closure

Vacuum-assisted closure (VAC) of complex infected wounds has recently gained popularity among various surgical specialties. The system is based on the application of negative pressure by controlled suction to the wound surface. The effectiveness of the VAC System on microcirculation and the promotion of granulation tissue proliferation are proved. No contraindications for the use in deep sternal wounds in cardiac surgery are described. In our case report we illustrate a scenario were a patient developed severe bleeding from the ascending aorta by penetration of wire fragments in the vessel. We conclude that all free particles in the sternum have to be removed completely before negative pressure is used

Role of Renal Biopsy in the Management of Renal Cancer: Concordance between Ultrasound/CT-Guided Biopsy Results and Definitive Pathology, Adverse Events, and Complication Rate

\ua9 2023 by the authors.(1) Background: In the last decade, the number of detected renal cancer cases has increased, with the highest incidence in Western countries. Although renal biopsy is reported as a safe procedure, it is not adopted in all centres. As it is not possible to accurately distinguish benign tumours using imaging, this may lead to overtreatment. Most of the cancer detected on imaging is treated by surgery, radiofrequency ablation (RFA), or cryotherapy. (2) Methods: This was a single-centre retrospective study of 225 patients studied preoperatively with ultrasound (US)/CT-guided renal biopsy, with the aim of supporting clinical management. Decisions regarding the biopsy were based on either MDT indication or physician preference. US-guided renal biopsy was the first option for all patients; CT-guided biopsy was used when US-guided biopsy was not feasible. The efficacy of renal biopsy in terms of diagnostic performance and the concordance between biopsy results and definitive pathology were investigated. Additionally, adverse events related to the biopsy were recorded and analysed. Data collected throughout the study were analysed using binary logistic regression, Fisher’s exact test, and Pearson’s chi-square test to investigate possible correlations between post-procedural complications and the size of the lesion. (3) Results: Renal biopsy was not diagnostic in 23/225 (10.2%) patients. A CT-guided approach was necessary in 20/225 patients after failure of US-guided biopsy. The complication rate of renal biopsy was 4.8% overall—all Clavien grade I and without any serious sequelae. Interestingly, complications occurred in patients with very different sizes of renal cell carcinoma. No correlation between complications and anticoagulant/antiplatelet drugs was found. No seeding was reported among the patients who underwent partial/radical nephrectomy. (4) Conclusions: Renal biopsy was shown to be safe and effective, with a high concordance between biopsy results and definitive pathology and a low rate of complications. The use of a CT-guided approach whenever the US-guided approach failed improved the diagnostic performance of renal biopsy

Identifying Trauma Patients in Need for Emergency Surgery in the Prehospital Setting: The Prehospital Prediction of In-Hospital Emergency Treatment (PROPHET) Study

Prehospital field triage often fails to accurately identify the need for emergent surgical or non-surgical procedures, resulting in inefficient resource utilization and increased costs. This study aimed to analyze prehospital factors associated with the need for emergent procedures (such as surgery or interventional angiography) within 6 h of hospital admission. Additionally, our goal was to develop a prehospital triage tool capable of estimating the likelihood of requiring an emergent procedure following hospital admission. We conducted a retrospective observational study, analyzing both prehospital and in-hospital data obtained from the Lombardy Trauma Registry. We conducted a multivariable logistic regression analysis to identify independent predictors of emergency procedures within the first 6 h from admission. Subsequently, we developed and internally validated a triage score composed of factors associated with the probability of requiring an emergency procedure. The study included a total of 3985 patients, among whom 295 (7.4%) required an emergent procedure within 6 h. Age, penetrating injury, downfall, cardiac arrest, poor neurological status, endotracheal intubation, systolic pressure, diastolic pressure, shock index, respiratory rate and tachycardia were identified as predictors of requiring an emergency procedure. A triage score generated from these predictors showed a good predictive power (AUC of the ROC curve: 0.81) to identify patients requiring an emergent surgical or non-surgical procedure within 6 h from hospital admission. The proposed triage score might contribute to predicting the need for immediate resource availability in trauma patients