Early Prognostic Tool Research Articles

Logistic organ dysfunction system as an early risk stratification tool after aneurysmal subarachnoid hemorrhage

AbstractAneurysmal subarachnoid hemorrhage (aSAH) not only causes neurological deficits but also influences extracerebral organ functions. The Logistic Organ Dysfunction System (LODS) reliably captures organ dysfunctions and predicts mortality of critically ill patients. This study investigated LODS in the setting of aSAH as a surrogate marker for early brain injury (EBI). Patients with aSAH treated between 2012 and 2020 were retrospectively analyzed. LODS was calculated within 24 h upon admission applying functional parameters for each organ system. The EBI was evaluated based on 1-persistent loss of consciousness, 2-global cerebral edema, and 3-intracranial blood burden. The outcome was assessed with the modified Rankin scale (mRS) at 3-months after ictus (mRS > 2 = unfavorable outcome). A total of 324 patients with a mean age of 55.9 years were included. Severe EBI (EBI grade ≥ 3) was found in 38% (124/324) of patients. Higher LODS score correlated with severe EBI (p < 0.0001) and poor outcome (p < 0.0001). LODS with a cutoff of 7 allowed a reliable discrimination (AUC 78%, p < 0.0001) of patients with severe from those with mild EBI. The LODS-calculation as an early risk stratification and prognostic tool reliably reflected the severity of EBI after aSAH and correlated with outcome.

Diagnostic accuracy of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and neutrophil-lymphocyte-to-platelet ratio biomarkers in predicting bacteremia and sepsis in immunosuppressive patients with cancer: literature review.

This literature review explores the role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and neutrophil-lymphocyte-to-platelet ratio (NLPR) biomarkers, as potential indicators for predicting bacteremia and sepsis in patients with cancer. Tracing the evolution of interest in this area since 2001, the aim of this review was to report a comprehensive overview of current knowledge and gaps, particularly in patients undergoing immunosuppression. The literature research indicates the potential of NLR, PLR, and other biomarkers in diagnosing and predicting sepsis, with some studies emphasizing their value in mortality prediction. A specific focus on bacteremia shows the effectiveness of NLR and PLR as early indicators and prognostic tools, though mostly in noncancer patient populations. While NLR and PLR are promising in general cancer patient populations, the review addresses the challenges in applying these biomarkers to patients with neutropenic and lymphopenic cancer. The NLPR could be considered a significant biomarker for inflammation and mortality risk in various medical conditions, yet its diagnostic accuracy in patients with immunosuppressed cancer is not extensively validated. This review offers a snapshot of the current research on biomarkers in patients with immunocompromised cancer in the sepsis and bacteremia area. More focused research on their application is necessary. This gap underscores an opportunity for future studies to enhance diagnostic and prognostic capabilities in this high-risk group.

Corneal nerves and amyotrophic lateral sclerosis: an in vivo corneal confocal imaging study.

Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disorder. Diagnosis is challenging due to its clinical heterogeneity and the absence of definitive diagnostic tools, leading to delays averaging between 9.1 and 27months. In vivo corneal confocal microscopy, assessing the sub-basal nerve plexus of the cornea, has been proposed as a potential biomarker for ALS. We aimed to determine whether the assessment of corneal nerves using in vivo confocal microscopy can serve as an imaging biomarker for ALS. A single-centre prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. The corneal sub-basal nerve plexus was analysed using in vivo confocal microscopy. An automated algorithm (ACCMetrics) was used to evaluate corneal parameters: nerve fibre density, nerve branch density, nerve fibre length, nerve fibre area, nerve total branch density, nerve fibre width, and nerve fractal dimension. Twenty-two patients with ALS and 30 controls were included. No significant differences were found between ALS and control groups for all corneal parameters (p > 0.05). Corneal sensitivity did not differ between groups, and no correlation was identified between corneal nerve parameters and ALS disease duration, severity and rate of progression (p > 0.05). The present study does not support the use of in vivo corneal confocal microscopy as an early diagnostic or prognostic tool for ALS. Further research, especially longitudinal investigations, is needed to understand any potential corneal innervation changes as ALS progresses.

Identifying potential biomarkers of idiopathic pulmonary fibrosis through machine learning analysis

Idiopathic pulmonary fibrosis (IPF) is the most common and serious type of idiopathic interstitial pneumonia, characterized by chronic, progressive, and low survival rates, while unknown disease etiology. Until recently, patients with idiopathic pulmonary fibrosis have a poor prognosis, high mortality, and limited treatment options, due to the lack of effective early diagnostic and prognostic tools. Therefore, we aimed to identify biomarkers for idiopathic pulmonary fibrosis based on multiple machine-learning approaches and to evaluate the role of immune infiltration in the disease. The gene expression profile and its corresponding clinical data of idiopathic pulmonary fibrosis patients were downloaded from Gene Expression Omnibus (GEO) database. Next, the differentially expressed genes (DEGs) with the threshold of FDR < 0.05 and |log2 foldchange (FC)| > 0.585 were analyzed via R package “DESeq2” and GO enrichment and KEGG pathways were run in R software. Then, least absolute shrinkage and selection operator (LASSO) logistic regression, support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) algorithms were combined to screen the key potential biomarkers of idiopathic pulmonary fibrosis. The diagnostic performance of these biomarkers was evaluated through receiver operating characteristic (ROC) curves. Moreover, the CIBERSORT algorithm was employed to assess the infiltration of immune cells and the relationship between the infiltrating immune cells and the biomarkers. Finally, we sought to understand the potential pathogenic role of the biomarker (SLAIN1) in idiopathic pulmonary fibrosis using a mouse model and cellular model. A total of 3658 differentially expressed genes of idiopathic pulmonary fibrosis were identified, including 2359 upregulated genes and 1299 downregulated genes. FHL2, HPCAL1, RNF182, and SLAIN1 were identified as biomarkers of idiopathic pulmonary fibrosis using LASSO logistic regression, RF, and SVM-RFE algorithms. The ROC curves confirmed the predictive accuracy of these biomarkers both in the training set and test set. Immune cell infiltration analysis suggested that patients with idiopathic pulmonary fibrosis had a higher level of B cells memory, Plasma cells, T cells CD8, T cells follicular helper, T cells regulatory (Tregs), Macrophages M0, and Mast cells resting compared with the control group. Correlation analysis demonstrated that FHL2 was significantly associated with the infiltrating immune cells. qPCR and western blotting analysis suggested that SLAIN1 might be a signature for the diagnosis of idiopathic pulmonary fibrosis. In this study, we identified four potential biomarkers (FHL2, HPCAL1, RNF182, and SLAIN1) and evaluated the potential pathogenic role of SLAIN1 in idiopathic pulmonary fibrosis. These findings may have great significance in guiding the understanding of disease mechanisms and potential therapeutic targets in idiopathic pulmonary fibrosis.

A High De Ritis Ratio is Associated with Mortality in Adult Trauma Patients.

The De Ritis ratio, which is the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT), has been suggested as a potential prognostic marker for various diseases. This study aimed to investigate the association between the De Ritis ratio and in-hospital mortality in adult trauma patients. A total of 17,472 adult trauma patients hospitalized between January 1, 2009, and December 31, 2020, were allocated into groups according to the De Ritis ratio. The normal range of the De Ritis ratio was calculated from 3320 individuals in the National Taiwan Biobank. Statistical analyses were performed using SPSS software. Patients with a De Ritis ratio >1.6 had a significantly higher in-hospital mortality rate (7.3% vs 1.5%, odds ratio 5.29; Q1-Q3 2.72-10.30; p < 0.001) and a 2.71-fold higher in-hospital mortality rate (Q1-Q3 1.24-5.92; p = 0.012), after adjusting for sex, age, comorbidities, consciousness level, and injury severity, than those with a De Ritis ratio within the reference values. This study revealed that a De Ritis ratio >1.6 may serve as an early prognostic tool to identify adult trauma patients at high risk of in-hospital mortality.

COVID19 biomarkers: What did we learn from systematic reviews?

The coronavirus disease 2019 (COVID19) pandemic continues to represent a substantial public health concern. It can rapidly progress to severe disease, with poor prognosis and a high mortality risk. An early diagnosis and specific prognostic tools can help healthcare providers to start interventions promptly, understand the likely prognosis and to identify and treat timely individuals likely to develop severe disease with enhanced mortality risk. Here we focused on an impressive set of systematic reviews and meta-analyses that were performed since the start of the COVID19 pandemic and summarized their results related to the levels of hematologic, inflammatory, immunologic biomarkers as well as markers of cardiac, respiratory, hepatic, gastrointestinal and renal systems and their association with the disease progression, severity and mortality. The evidence outlines the significance of specific biomarkers, including inflammatory and immunological parameters (C-reactive protein, procalcitonin, interleukin-6), hematological (lymphocytes count, neutrophil-to-lymphocyte ratio, D-dimer, ferritin, red blood cell distribution width), cardiac (troponin, CK-MB, myoglobin), liver (AST, ALT, total bilirubin, albumin) and lung injury (Krebs von den Lungen-6) that can be used as prognostic biomarkers to aid the identification of high-risk patients and the prediction of serious outcomes, including mortality, in COVID19. Thus, these parameters should be used as essential tools for an early risk stratification and adequate intervention in improving disease outcomes in COVID19 patients.

Profiling of cell-free DNA methylation and histone signatures in pediatric NAFLD: A pilot study.

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-β (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve >0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.

Abstract 5842: High resolution melting technique as an economic prognostic tool for identifying deleterious mutations in BRCA1, BRCA2, and P53 genes amongst breast cancer women

Abstract Introduction: The incidence of breast cancer (BC) has substantially increased among women younger than 50. Due to fragile economic situation in the middle east and lack of awareness, BC women are characterized by late diagnosis and thus, there is an urgent need for a cheap early prognostic tool. BC progression involves several genetic mutations via activating oncogenes or disrupting the functions of tumor suppressor genes, such as; BRCA1, BRCA2, P53. Mutation in these genes are associated with an increased risk of breast cancer and thereof, can be used as prognostic markers. High throughput technologies such as next generation sequencing (NGS) with help of different bioinformatic analysis tools give massive data about deleterious mutations in tumor suppressor genes. Therefore, in this study we aimed to establish High Resolution Melting (HRM) technique as an economic prognostic tool for identifying deleterious mutations in BRCA1/2 and P53 genes amongst familial and non-familial breast cancer patients. Patients and Methods: Forty-eight breast cancer patients (15 Familial and 33 non-familial) and 2 healthy volunteers were enrolled in the present study. Genomic DNA was extracted from breast cancer tissues and screened using NGS to identify types of mutations in both BRCA1/2 genes. All positive samples were screened for presence of mutations in BRCA 1(exon 19), BRCA2 (Exon 11F) and P53 (exon 5) using HRM. All samples were analyzed for identifying types of mutations using sanger sequencing. Results: Our results identified 57 different mutations in the three genes. Deleterious mutations are identified as follows; 13 frameshift (c.5345delA (36.3%), c.5321delC (36%), c.5337delA (27.2%)) and 8 missense mutations (c.T5320C (36.3%), c.T5330W(A/T) (27.2%)) in BRCA1 (Exon 19). 6 frameshift mutations (c.3528delA (27.2%)), 13 missense mutations (c.T3840G (72.7%), c.G3839K(G/T) (27.2%)) and 6 synonymous mutations (c.A3895R (A/G) (45.4%)) in BRCA2 (exon11F). Regarding P53 (exon 5), 10 frameshift mutations (c.813insC (63.6%)) were detected. Additionally, some of the sequences were sent to GenBank and obtained the following accession numbers; (OL512955 and OL512956 for BRCA1(Exon 19) and OL512957 for BRCA2 (Exon 11)). Moreover, mutations in the three high penetrance genes; BRCA1, BRCA2 and P53 were correlated with some clinical parameters and results showed that young age and family history were the most prominent ones. Conclusion: The present study successfully established HRM as an economic prognostic tool for identifying the presence of deleterious mutations in BRCA1/2 and P53 genes which will help correlate the presence of mutations on other affected exons when present with other risk factors as prognostic tool in BC women. STDF Acknowledgement: This project was funded by the Science and Technology Development Fund (STDF), Egypt Grant No.22944. Citation Format: Shaza Ahmed, Nasra F. Abdel Fattah, Shimaa A. Metwally, Marwa A. Abdelwahed, Hossam Taha Mohamed, Sara H. Agwa, AbdelWahab El Ghareeb, Gehan Safwat, Ahmed A. El Sherif, Mohamed M. Moneer, Samah A. Loutfy. High resolution melting technique as an economic prognostic tool for identifying deleterious mutations in BRCA1, BRCA2, and P53 genes amongst breast cancer women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5842.

Impact of Metabolomics Technologies on the Assessment of Peritoneal Membrane Profiles in Peritoneal Dialysis Patients: A Systematic Review.

Peritoneal dialysis (PD) is an effective and frequent dialysis modality in adults, particularly preferred in infants and young children with end-stage renal disease (ESRD). Long-term exposure of the peritoneal membrane to dialysis solutions results in severe morphologic and functional alterations. Peritoneal dialysis effluent biomarkers are based on omics technologies, which could predict the onset or confirm the diagnosis of peritoneal membrane dysfunction, would allow the development of accurate early prognostic tools and, potentially, the identification of future therapeutic targets. The purpose of our study was to critically review the literature on the impact and the effectiveness of metabolomics technologies in peritoneal health. The main search was performed in electronic databases (PubMed/MEDLINE, Embase and Cochrane Central Register of Controlled Trials) from inception to December 2020, using various combinations of Medical Subject Headings (MeSH). The main search highlighted nine studies, of which seven were evaluated in detail. Metabolomics technologies may provide significant input in the recognition of peritoneal membrane dysfunction in PD patients and provide evidence of early intervention strategies that could protect peritoneum health and function.

Left ventricular diastolic function in patients with breast cancer treated with anthracycline-based chemotherapy

Abstract Background Despite major progress in novel breast cancer therapeutic regimens, anthracycline-based chemotherapy (ANT) remains among the most effective therapies. Cardiotoxicity, one of the most severe adverse events of ANT, has been defined as a reduction in left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS). However, the role of early diastolic dysfunction has been insufficiently researched. We aimed to determine if diastolic dysfunction could early diagnose and predict ANT cardiotoxicity. Methods Studies that reported on echocardiographic parameters of diastolic function before and at the end of ANT in breast cancer patients without cardiac disease were included. We evaluated parameter derived from pulsed wave Doppler interrogation of the mitral valve inflow (E/A ratio and mitral E-wave deceleration time (EDT)) and tissue Doppler (mean velocities of the mitral ring in the early diastole (E') and E/E' ratio). Results A total of 892 patients from 13 studies were included. E/A ratio was significantly reduced at the end of ANT (OR 2.34, 95% CI [1.49, 3.68], p&amp;lt;0.001), while EDT was not significantly influenced (OR 0.74, 95% CI [0.50, 1.08], p=0.121). Tissue Doppler velocity of the mitral ring E' and the LV filling pressure analysed through E/E' ratio did not show significant changes after ANT (OR 2.32, 95% CI [0.94, 5.72], p=0.068, and OR 0.79, 95% CI [0.56, 1.12], p=0.197, respectively). A modest reduction in LVEF and global longitudinal strain (GLS) was observed at the end of the ANT therapy with a difference in means of 3.77% and −1.08%, respectively. Patients receiving ANT doses over 400 mg/m2 doxorubicin or epirubicin therapeutic equivalent doses showed a significant change in E/A and E' after the therapy. Cardioprotective therapy like carvedilol, nebivolol and spironolactone did not have a significant impact on the parameter of diastolic function. Conclusion ANT has a modest early impact on LV diastolic function in patients with breast cancer without cardiac disease and cannot be validated as an early diagnostic or prognostic tool of ANT-induced cardiotoxicity. Randomized studies on larger population, using new parameter e.g. left atrial function parameter and multimodality imaging are required. Funding Acknowledgement Type of funding sources: None.

566 A Study to Investigate CRP and WBC As Early Prognostic Tools in Severe Pancreatitis

Abstract Aim To establish the prognostic value of raised inflammatory markers on Day 3 in patients with severe acute pancreatitis Method A retrospective study between 01/02/18 till 31/01/19 including all patients with acute pancreatitis. Patient demographics, the aetiology, treatment, severity (as per modified Atlanta's criteria) and inflammatory markers on Day 3 of the hospital admission were included. ROC curves were subsequently generated. Results 127 patients were included with a median age of 59 years. 113 patients were diagnosed with mild acute pancreatitis while 14 patients had severe acute pancreatitis. The ROC curve illustrates that the value of CRP which maximises discrimination was 176 mg, with a sensitivity of 83% and specificity of 76%. For WBC with a value of 12.11 showed 100% sensitivity and 80% specificity. Conclusions This study highlights that elevated CRP and WBC on Day 3 could both be good predictive tools for patients who develop severe pancreatitis.

Abstract P459: Inversion of T Waves on Admission is Associated With Mortality in Spontaneous Intracerebral Hemorrhage

Introduction: Cardiac dysfunction directly caused by spontaneous intracerebral hemorrhage (ICH) is a poorly understood phenomenon, and its impact on outcome is still uncertain. Aim of this study is to investigate the relationship between electrocardiographic (EKG) abnormalities and mortality in ICH. Methods: This is a retrospective study analyzing EKG patterns on admission in patients admitted with ICH at a tertiary care center over eight-year period. For each patient, demographics, medical history, clinical presentation, EKG on admission and repeated during hospitalization, and head CT at presentation were reviewed. Mortality was noted. Results: A total of 301 ICHs were included in the study. The most prevalent EKG abnormalities were QTc prolongation in 56% of patients (n=168) followed by inversion of T waves (TWI) in 37% of patients (n=110). QTc prolongation was associated with ganglionic location (p=0.03) and intraventricular hemorrhage (IVH) (p=0.01), TWI was associated with ganglionic location (p=0.02), PR prolongation with IVH (p=0.01), while QRS prolongation was associated with lobar location (p&lt;0.01). Volume of ICH, hemispheric laterality, and involvement of insular cortex were not correlated with specific EKG patterns. In a logistic regression model, after correcting for ICH severity and prior cardiac history, presence of TWI was independently associated with mortality (OR: 3.04, CI:1.6-5.8, p&lt;0.01). Adding TWI to ICH score improved its prognostic accuracy (AUC 0.81). Disappearance of TWI during hospitalization did not translate in improvement of survival (p=0.5). Conclusion: Presence of TWI on admission is an independent and unmodifiable factor associated with mortality in ICH. TWI may be implemented as an additional early prognostic tool in clinical practice.

Methods for assessing the severity of perinatal asphyxia and early prognostic tools in neonates with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia.

Despite the progress in perinatal care, perinatal asphyxia (PA) remains a significant problem in neonatology. The development of therapeutic hypothermia (TH) has improved the prognosis, but it still remains uncertain in hypoxic neonates. The evaluation of the severity of ischemia/hypoxia after birth is crucial to the choice of treatment, and with accurate long-term prognosis, appropriate further patient care can be planned. This article presents various methods for the preliminary assessment of brain damage and prognosis in newborns with PA treated with TH. The importance of assessing the neurological condition and the usefulness of laboratory and electrophysiological testing and imaging are discussed. New methods are also noted, which are at the stage of clinical trials. A combination of the prognostic tests presented in this article can provide greater prognostic accuracy for predicting long-term neurological outcomes in infants with hypoxic-ischemic encephalopathy (HIE) undergoing TH than either of these tests independently. Acknowledging the limitations of individual tools in certain clinical situations and the integration of the information available from multiple biomarkers may help improve the accuracy of prognostication.

Background Frequency Patterns in Standard Electroencephalography as an Early Prognostic Tool in Out-of-Hospital Cardiac Arrest Survivors Treated with Targeted Temperature Management.

We investigated the prognostic value of standard electroencephalography, a 30-min recording using 21 electrodes on the scalp, during the early post-cardiac arrest period, and evaluated the performance of electroencephalography findings combined with other clinical features for predicting favourable outcomes in comatose out-of-hospital cardiac arrest (OHCA) survivors treated with targeted temperature management (TTM). This observational registry-based study was conducted at a tertiary care hospital in Korea using the data of all consecutive adult non-traumatic comatose OHCA survivors who underwent standard electroencephalography during TTM between 2010 and 2018. The primary outcome was a 6-month favourable neurological outcome (Cerebral Performance Category score of 1 or 2). Among 170 comatose OHCA survivors with median electroencephalography time of 22 h, a 6-month favourable neurologic outcome was observed in 34.1% (58/170). After adjusting other clinical characteristics, an electroencephalography background with dominant alpha and theta waves had the highest odds ratio of 13.03 (95% confidence interval, 4.69–36.22) in multivariable logistic analysis. A combination of other clinical features (age < 65 years, initial shockable rhythm, resuscitation duration < 20 min) with an electroencephalography background with dominant alpha and theta waves increased predictive performance for favourable neurologic outcomes with a high specificity of up to 100%. A background with dominant alpha and theta waves in standard electroencephalography during TTM could be a simple and early favourable prognostic finding in comatose OHCA survivors.

Cancer Liquid Biopsy Using Integrated Microfluidic Exosome Analysis Platforms.

Liquid biopsies serve as both powerful noninvasive diagnostic tools for early cancer screening and prognostic tools for monitoring cancer progression and treatment efficacy. Exosomes are promising biomarkers for liquid biopsies, since these nano-sized extracellular vesicles (EVs) enrich proteins, lipids, mRNAs, and miRNAs from cells of origin, including cancer cells. Although exosomes are abundantly present in various bodily fluids, conventional exosome isolation and detection methods that rely on benchtop equipment are time-consuming, expensive, and involve complicated non-portable procedures. As an alternative, recently developed microfluidic platforms can perform effective exosome separation and detection for liquid biopsies using a single device. Such methods offer advantages of integrity, speed, cost-efficiency, and portability over conventional benchtop and early microfluidic-based single-functional methods which can only separate or detect exosomes separately. These advances have made exosome-based point-of-care (POC) applications possible. This review outlines recent integrated microfluidic-based exosomal detection strategies to guide future development of such devices for use in liquid biopsies for early cancer screening, prognostic monitoring, and other potential POC applications.

Liquid Biopsy: A New, Non-Invasive Early Diagnostic and Prognostic Tool in Oncology

Cancer is essentially a genetic disease. Neoplastic progression consists of a subsequent series of genetic alterations that cumulate. In the bloodstream of an affected subject, circulating tumor cells (CTC) and/or small deoxy-ribonucleic acid (DNA) fragments, known as circulating tumor DNA (ctDNA), can be found as a consequence of cancer cells death. Cell-free circulating DNA (cfDNA) consists of small fragments of DNA that are found free in plasma or serum, but also in other body fluids. The term liquid biopsy (LB) describes a highly sensitive method (based on a simple sampling of peripheral blood) for the isolation and analysis of cfDNA, which can also contain ctDNA and CTC. Its purpose is to look for cancer cells or portions of their DNA that are circulating in the blood. LB can be used to help find cancer in an early stage. It also has the additional advantage of being largely non-invasive and, therefore, being done more frequently, allowing better tumor and genetic mutations tracking. It can also be used to validate the efficacy of a drug for cancer treatment by taking multiple samples of LB within a few weeks. This technology can also be beneficial for patients after treatment to control relapse. The aim of this work is to give an overview of this technique, from its history, state-of-the-art, and methodology of execution, to its applications in oncology and with a hint to the gynecological field.

18F-FDG PET-Based Imaging of Myocardial Inflammation Predicts a Functional Outcome Following Transplantation of mESC-Derived Cardiac Induced Cells in a Mouse Model of Myocardial Infarction

Cellular inflammation following acute myocardial infarction has gained increasing importance as a target mechanism for therapeutic approaches. We sought to investigate the effect of syngeneic cardiac induced cells (CiC) on myocardial inflammation using 18F-FDG PET (Positron emission tomography)-based imaging and the resulting effect on cardiac pump function using cardiac magnetic resonance (CMR) imaging in a mouse model of myocardial infarction. Mice underwent permanent left anterior descending coronary artery (LAD) ligation inducing an acute inflammatory response. The therapy group received an intramyocardial injection of 106 CiC into the border zone of the infarction. Five days after myocardial infarction, 18F-FDG PET was performed under anaesthesia with ketamine and xylazine (KX) to image the inflammatory response in the heart. Flow cytometry of the mononuclear cells in the heart was performed to analyze the inflammatory response. The effect of CiC therapy on cardiac function was determined after three weeks by CMR. The 18F-FDG PET imaging of the heart five days after myocardial infarction (MI) revealed high focal tracer accumulation in the border zone of the infarcted myocardium, whereas no difference was observed in the tracer uptake between infarct and remote myocardium. The CiC transplantation induced a shift in 18F-FDG uptake pattern, leading to significantly higher 18F-FDG uptake in the whole heart, as well as the remote area of the heart. Correspondingly, high numbers of CD11+ cells could be measured by flow cytometry in this region. The CiC transplantation significantly improved the left ventricular ejection function (LVEF) three weeks after myocardial infarction. The CiC transplantation after myocardial infarction leads to an improvement in pump function through modulation of the cellular inflammatory response five days after myocardial infarction. By combining CiC transplantation and the cardiac glucose uptake suppression protocol with KX in a mouse model, we show for the first time, that imaging of cellular inflammation after myocardial infarction using 18F-FDG PET can be used as an early prognostic tool for assessing the efficacy of cardiac stem cell therapies.

Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p&lt;0.0001), IHP (Χ2=49.078, p&lt;0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Unequivocal Biomarker for Parkinson's Disease: A Hunt that Remains a Pester.

Devastating motor features, lack of early prognostic tools, and absence of undeviating therapies call for an endeavor to develop biomarkers for Parkinson's disease (PD). A biomarker is anticipated to help in timely and selective diagnosis as well as to hunt for an appropriate treatment option. Peripheral fingerprints can be used to assess the progression, distinguish PD from other related disorders, and monitor the efficacy of therapeutic options. From the last two decades, peripheral blood is constantly targeted in search of an appropriate marker owing to minimal invasive procedure for collection, highly dynamic nature, and insignificant ethical concern. Besides, cerebrospinal fluid (CSF) is also preferred because of its close proximity to the brain. Employing conventional and contemporary sophisticated devices, a number of protein and non-protein entities, mainly metallic elements, have been shown to hold adequate potential to be used as biomarkers for monitoring progression and assessing treatment options for such a distressing neurodegenerative disorder. Classical strategies and relatively newer sophisticated tools, such as proteomics, deciphered the presence of an altered level of highly specific blood- and CSF-specific proteins, free metals, metal-binding proteins, common inflammatory proteins, and overexpressed/modified α-synuclein in PD patients. While several chemical entities are shown to be associated, not even a single protein or metal is converted into unambiguous disease fingerprint. The article provides an update on proteins and metals that are shown to possess enormous potential in the course of biomarker exploration but are unable to deliver a reliable indicator. The review also sheds light on the reasons of ineffective hit to hunt for an authentic fingerprint and proposes the doable ways to translate the output into reality.

Congenital Cytomegalovirus Infection Alters Olfaction Before Hearing Deterioration In Mice.

In developed countries, cytomegalovirus (CMV)-infected newborns are at high risk of developing sensorineural handicaps such as hearing loss, requiring extensive follow-up. However, early prognostic tools for auditory damage in children are not yet available. In the fetus, CMV infection leads to early olfactory bulb (OB) damage, suggesting that olfaction might represent a valuable prognosis for neurological outcome of this viral infection. Here, we demonstrate that in utero CMV inoculation causes fetal infection and growth retardation in mice of both sexes. It disrupts OB normal development, leading to disproportionate OB cell layers and rapid major olfactory deficits. Olfaction is impaired as early as day 6 after birth in both sexes, long before the emergence of auditory deficits. Olfactometry in males reveals a long-lasting alteration in olfactory perception and discrimination, particularly in binary mixtures of monomolecular odorants. Although sensory inputs to the OB remain unchanged, hallmarks of autophagy are increased in the OB of 3-postnatal week-old mice, leading to local neuroinflammation and loss of neurons expressing tyrosine hydroxylase and calbindin. At the cellular level, we found CMV-infected cells and an increased number of apoptotic cells scattered throughout the OB layers, whereas cell proliferation in the neurogenic subventricular zone was decreased. These cellular observations were long-lasting, persisting up to 16 weeks after birth in both males and females and thus providing a mechanism supporting olfactory loss. Despite obvious differences in neurogenesis between human and mouse, these findings offer new strategies aimed at early detection of neurological dysfunctions caused by congenital infections.SIGNIFICANCE STATEMENT In developed countries, congenital cytomegalovirus (CMV)-infected newborns are at high risk of developing sensory handicaps such as hearing loss, thus requiring prolonged follow-up. In this study, we describe for the first time the functional impact of congenital CMV infection on the olfactory system and its associated sense of smell. We demonstrate that a mouse model of congenital CMV infection shows defects in olfactory bulb (OB) normal development and pronounced olfactory deficits affecting acuity and discrimination of odorants. These major olfactory deficits occur long before the emergence of auditory deficits through the upregulation of OB autophagy inducing local neuroinflammation and altered neuron content. Our findings provide new opportunities for designing olfactory means to monitor the possible neurological outcome during congenital CMV infection.