Therapeutic Decisions In Patients Research Articles

Development and Validation of a Predictive Model for Metastatic Melanoma Patients Treated with Pembrolizumab Based on Automated Analysis of Whole-Body [18F]FDG PET/CT Imaging and Clinical Features.

Antibodies that inhibit the programmed cell death protein 1 (PD-1) receptor offer a significant survival benefit, potentially cure (i.e., durable disease-free survival following treatment discontinuation), a substantial proportion of patients with advanced melanoma. Most patients however fail to respond to such treatment or acquire resistance. Previously, we reported that baseline total metabolic tumour volume (TMTV) determined by whole-body [18F]FDG PET/CT was independently correlated with survival and able to predict the futility of treatment. Manual delineation of [18F]FDG-avid lesions is however labour intensive and not suitable for routine use. A predictive survival model is proposed based on automated analysis of baseline, whole-body [18F]FDG images. Lesions were segmented on [18F]FDG PET/CT using a deep-learning approach and derived features were investigated through Kaplan-Meier survival estimates with univariate logrank test and Cox regression analyses. Selected parameters were evaluated in multivariate Cox survival regressors. In the development set of 69 patients, overall survival prediction based on TMTV, lactate dehydrogenase levels and presence of brain metastases achieved an area under the curve of 0.78 at one year, 0.70 at two years. No statistically significant difference was observed with respect to using manually segmented lesions. Internal validation on 31 patients yielded scores of 0.76 for one year and 0.74 for two years. Automatically extracted TMTV based on whole-body [18F]FDG PET/CT can aid in building predictive models that can support therapeutic decisions in patients treated with immune-checkpoint blockade.

Association between primary tumor characteristics and histopathological growth pattern of liver metastases in colorectal cancer.

The microarchitecture of liver metastases (LMs), or histopathological growth pattern (HGP), has been demonstrated to be a significant prognostic factor in patients undergoing resection of colorectal liver metastases (CRLMs). Currently, however, HGP can be only determined on the operative specimen. Therefore, the development of new tools to predict the HGP of CRLMs before surgery and to understand the mechanisms that drive these patterns is important for improving individualization of therapeutic management. In this study, we analyzed data from a retrospective series of patients who underwent surgery for CRLMs to compare primary tumor characteristics, including markers of local aggressiveness and migratory capacity, and HGP of liver metastases. Data from a retrospective series of 167 patients who underwent curative-intent resection of CRLMs and in whom pathological samples from both primary tumor and liver metastases were available were reviewed. At the primary tumor level, KRAS mutational status, grade of differentiation, and tumor budding were assessed. HGP was scored in each resected CRLM, according to consensus guidelines, and classified as desmoplastic (dHGP) or non-desmoplastic (non-dHGP). Associations between primary tumor characteristics and HGP of CRLMs were evaluated using a binary logistic regression model. Overall survival and disease-free survival were evaluated using Kaplan-Meier and multivariable Cox regression analyses. CRLMs were classified as dHGP in 36% of the patients and as non-dHGP in 64%. Higher rates of moderately or poorly differentiated primary tumors were observed in the non-dHGP CRLM group (80%), as compared with the dHGP group (60%) (OR = 3.6; 95%CI: 1.6-7.05; p = 0.001). Higher rates of tumor budding were observed in the non-dHGP CRLM group, with a median tumor budding value of 4 as compared with 2.5 in the dHGP group (p = 0.042). In the entire series, 5-year overall and disease-free survival were 43% and 32.5%, respectively. The non-dHGP CRLM group had worse post-hepatectomy survival, with 5-year overall and disease-free survival of 32.2% and 24.6%, respectively, as compared with 60.8% and 45.9%, respectively, for the dHGP group (p = 0.02). Colorectal tumors with moderate or poor differentiation and those with high tumor budding are more frequently associated with CRLMs with a non-dHGP. This suggests that primary tumor characteristics of local aggressiveness and migratory capacity could preferentially promote the development of CRLMs with an infiltrating pattern and that these parameters should be considered as part of new scores for predicting HGP before surgery. This finding may stimulate new lines of research for more individualized therapeutic decision in patients with CRLM candidate to surgery.

Artificial intelligence and radiation effects on brain tissue in glioblastoma patient: preliminary data using a quantitative tool.

The quantification of radiotherapy (RT)-induced functional and morphological brain alterations is fundamental to guide therapeutic decisions in patients with brain tumors. The magnetic resonance imaging (MRI) allows to define structural RT-brain changes, but it is unable to evaluate early injuries and to objectively quantify the volume tissue loss. Artificial intelligence (AI) tools extract accurate measurements that permit an objective brain different region quantification. In this study, we assessed the consistency between an AI software (Quibim Precision® 2.9) and qualitative neruroradiologist evaluation, and its ability to quantify the brain tissue changes during RT treatment in patients with glioblastoma multiforme (GBM). GBM patients treated with RT and subjected to MRI assessment were enrolled. Each patient, pre- and post-RT, undergoes to a qualitative evaluation with global cerebral atrophy (GCA) and medial temporal lobe atrophy (MTA) and a quantitative assessment with Quibim Brain screening and hippocampal atrophy and asymmetry modules on 19 extracted brain structures features. A statistically significant strong negative association between the percentage value of the left temporal lobe and the GCA score and the left temporal lobe and the MTA score was found, while a moderate negative association between the percentage value of the right hippocampus and the GCA score and the right hippocampus and the MTA score was assessed. A statistically significant strong positive association between the CSF percentage value and the GCA score and a moderate positive association between the CSF percentage value and the MTA score was found. Finally, quantitative feature values showed that the percentage value of the cerebro-spinal fluid (CSF) statistically differences between pre- and post-RT. AI tools can support a correct evaluation of RT-induced brain injuries, allowing an objective and earlier assessment of the brain tissue modifications.

Implications of left atrial volume index in patients with three-vessel coronary disease: A 6.6-year follow-up cohort study.

Risk assessment and treatment stratification for three-vessel coronary disease (TVD) remain challenging. This study aimed to investigate the prognostic value of left atrial volume index (LAVI) with the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score II, and its association with the long-term prognosis after three strategies (percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], and medical therapy [MT]) in patients with TVD. This study was a post hoc analysis of a large, prospective cohort of patients with TVD in China, that aimed to determine the long-term outcomes after PCI, CABG, or optimal MT alone. A total of 8943 patients with TVD were consecutively enrolled between 2004 and 2011 at Fuwai Hospital. A total of 7818 patients with available baseline LAVI data were included in the study. Baseline, procedural, and follow-up data were collected. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which was a composite of all-cause death, myocardial infarction (MI), and stroke. Secondary endpoints included all-cause death, cardiac death, MI, revascularization, and stroke. Long-term outcomes were evaluated among LAVI quartile groups. During a median follow-up of 6.6 years, a higher LAVI was strongly associated with increased risk of MACCE (Q3: hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.06-1.37, P = 0.005; Q4: HR 1.85, 95%CI 1.64-2.09, P <0.001), all-cause death (Q3: HR 1.41, 95% CI 1.17-1.69, P <0.001; Q4: HR 2.54, 95%CI 2.16-3.00, P <0.001), and cardiac death (Q3: HR 1.81, 95% CI 1.39-2.37, P <0.001; Q4: HR 3.47, 95%CI 2.71-4.43, P <0.001). Moreover, LAVI significantly improved discrimination and reclassification of the SYNTAX score II. Notably, there was a significant interaction between LAVI quartiles and treatment strategies for MACCE. CABG was associated with lower risk of MACCE than MT alone, regardless of LAVI quartiles. Among patients in the fourth quartile, PCI was associated with significantly increased risk of cardiac death compared with CABG (HR: 5.25, 95% CI: 1.97-14.03, P = 0.001). LAVI is a potential index for risk stratification and therapeutic decision-making in patients with three-vessel coronary disease. CABG is associated with improved long-term outcomes compared with MT alone, regardless of LAVI quartiles. When LAVI is severely elevated, PCI is associated with higher risk of cardiac death than CABG.

Predicting Long-term Outcomes in Deceased Donor Kidney Transplant Recipients Using Three Short-term Graft Characteristics.

Delayed graft function (DGF) in kidney transplant recipients is used to determine graft prognosis, make organ utilization decisions, and as an important end-point in clinical trials. However, DGF is not an ideal measure of graft function. We aimed to develop and validate a model that provides incremental risk assessment for inferior patient and graft outcomes. We included adult kidney-only deceased donor transplant recipients from 1996 to 2016. In addition to DGF, two short-term measures were used to assess risk: renal function recovery<100% (attaining half the donor's eGFR) and recipient's 90-day eGFR<30. Recipients were at no-, low-, moderate- or high-risk if they met zero, one, two, or all criteria, respectively. Cox proportional hazards models were used to assess the independent relationship between the exposure and death-censored graft failure (DCGF) and mortality. Of the 792 eligible recipients, 24.5% experienced DGF, 40.5% had renal function recovery<100% and 6.9% had eGFR<30. Over a median follow-up of 7.3 years, the rate of DCGF was 18.7% and mortality was 25.1%. When compared with recipients at no risk, those at low-, moderate- and high-risk were noted to have an incremental increase in risk of DCGF (aHR=1.53, 95%CI:1.03-2.27; aHR=2.84, 95%CI:1.68-4.79; aHR=15.46, 95%CI:8.04-29.71) and mortality (aHR=1.16, 95%CI:0.84-1.58; aHR=1.85, 95%CI:1.13-3.07; aHR=2.66 (95%CI:1.19-5.97). When using a hierarchical approach, each additional exposure predicted the risk of DCGF better than DGF alone and 100 random bootstrap replications supported the internal validity of the risk model. In an external validation cohort deemed to be at lower risk for DCGF, similar non-significant trends were noted. We propose a risk model that provides an incremental assessment of recipients at higher risk of adverse long-term outcomes than DGF alone. This can help advance the field of risk assessment in transplantation and inform therapeutic decision-making in patients at the highest spectrum of inferior outcomes.

STANDARDIZATION ISSUES FOR FECAL CALPROTECTIN MEASUREMENT IN INFLAMMATORY BOWEL DISEASE

Fecal calprotectin (FC) is a non-invasive marker of intestinal inflammation that is often used to guide therapeutic decisions in patients with inflammatory bowel disease (IBD). Each step in FC measurement can influence the results, leading to misinterpretation and potentially affecting the management of patients with IBD. To date, FC measurements are highly heterogeneous, and none of the existing methods is generally accepted as a standard. &lt;b&gt;Aim:&lt;/b&gt; to provide a clear position on the preanalytical and analytical steps of FC measurement and to minimize the risk of misinterpretation. &lt;b&gt;Materials and methods.&lt;/b&gt; A systematic search of the scientific literature was carried out in the PubMed/MEDLINE, EMBASE and Cochrane databases until June 2021 to identify all studies reporting data on FC measurement (for the key phrases "fecal markers of inflammation", "calprotectin", "inflammatory bowel diseases"). &lt;b&gt;Results.&lt;/b&gt; Based on available data, quantitative tests should be preferred to measure FC; FC measurements should always be performed using the same method, and factors affecting his levels should be taken into account when interpreting results. &lt;b&gt;Conclusion.&lt;/b&gt; FC concentrations determine treatment decisions by physicians. Although FC is playing an increasingly important role in the management of IBD patients, large multicenter studies should be conducted to determine the reproducibility and to confirm the diagnostic accuracy of the available FC tests.

Predicting Response of Triple-Negative Breast Cancer to Neoadjuvant Chemotherapy Using a Deep Convolutional Neural Network-Based Artificial Intelligence Tool.

Achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved patient outcomes in triple-negative breast cancer (TNBC). Currently, there are no validated predictive biomarkers for the response to NAC in TNBC. We developed and validated a deep convolutional neural network-based artificial intelligence (AI) model to predict the response of TNBC to NAC. Whole-slide images (WSIs) of hematoxylin and eosin-stained core biopsies from 165 (pCR in 60 and non-pCR in 105) and 78 (pCR in 31 and non-pCR in 47) patients with TNBC were used to train and validate the model. The model extracts morphometric features from WSIs in an unsupervised manner, thereby generating clusters of morphologically similar patterns. Downstream ranking of clusters provided regions of interest and morphometric scores; a low score close to zero and a high score close to one represented a high or low probability of response to NAC. The predictive ability of AI score for the entire cohort of 78 patients with TNBC ascertained by receiver operating characteristic analysis demonstrated an area under the curve (AUC) of 0.75. The AUC for stages I, II, and III disease were 0.88, 0.73, and 0.74, respectively. Using a cutoff value of 0.35, the positive predictive value of the AI score for pCR was 73.7%, and the negative predictive value was 76.2% for non-pCR patients. To our knowledge, this study is the first to demonstrate the use of an AI tool on digitized hematoxylin and eosin-stained tissue images to predict the response to NAC in patients with TNBC with high accuracy. If validated in subsequent studies, these results may serve as an ancillary aid for individualized therapeutic decisions in patients with TNBC.

Deciphering the role of monocyte and monocyte distribution width (MDW) in COVID-19: an updated systematic review and meta-analysis.

The SARS-CoV-2 infection is characterized by both systemic and organ hyper-thromboinflammation, with a clinical course ranging from mild up-to critical systemic dysfunction and death. In patients with coronavirus disease 2019 (COVID-19) the monocyte/macrophage population is deeply involved as both trigger and target, assuming the value of useful diagnostic/prognostic marker of innate cellular immunity. Several studies correlated morphological and immunophenotypic alterations of circulating monocytes with clinical outcomes in COVID-19 patients, concluding that monocyte distribution width (MDW) may retain clinical value in stratifying the risk ofdisease worsening. Through an electronic search in Medline and Scopus we performed an updated literature review and meta-analysis aimed to explore the association between increased MDW levels and illness severity in COVID-19 patients, deciphering role(s) and function(s) of monocytes in the harmful network underlining SARS-CoV-2 infection. We found that significantly elevated MDW values were frequently present in COVID-19 patients who developed unfavorable clinical outcomes, compounded by a significant association between monocyte anisocytosis and SARS-CoV-2 outcomes. These findings suggest that blood MDW index and its scatter plot could represent useful routine laboratory tools for early identification of patients at higher risk of unfavorable COVID-19 and for monitoring the progression of viral infection, clinical outcomes, and therapeutic efficacy throughout hospitalization. According to this evidence, therapeutic decisions in patients with SARS-CoV-2 infection could benefit from monitoring MDW value, with administration of drugs limiting thrombo-inflammation due to monocyte hyper-activation in patients with severe/critical COVID-19 disease.

The relationship between prognosis of patients with traumatic brain injury and microRNA biogenesis proteins.

This study aims to investigate whether the expression levels of proteins involved in microRNA (miRNA) biogenesis vary in early- and late-stage traumatic brain injury (TBI) patients and to evaluate its effect on prognosis. Dicer, Drosha, DiGeorge Syndrome Critical Region eight (DGCR8), Exportin5 (XPO5), and Argonaute2 (AGO2) levels were measured in the blood samples of severe TBI patients collected 4-6 h and 72 h after the trauma and compared with the control group. Prognostic follow-up of the patients was performed using the Glasgow Coma Scale score. There were no statistically significant changes in the expression of the miRNA biogenesis proteins Dicer, Drosha, DGCR8, XPO5, and AGO2 in patients with severe TBI. However, the expression of Dicer increased in the patients who improved from the severe TBI grade to the mild TBI grade, and the expression of AGO2 decreased in most of these patients. The Dicer expression profile was found to increase in patients discharged from the intensive care unit in a short time. MicroRNAs and their biogenesis proteins may guide prognostic and therapeutic decisions for patients with TBI in the future.

Baseline Glucocorticoid-Related Toxicity Scores in Giant Cell Arteritis: A Post Hoc Analysis of the GiACTA Trial.

Giant cell arteritis (GCA) requires treatment with high-dose, long-term glucocorticoids (GCs). A score assessing and quantifying patients' baseline GC-related toxicity may be important to risk stratification and therapeutic decision-making in patients initiating immunosuppression. We analyzed patients with GCA enrolled in the Tocilizumab in Giant Cell Arteritis (GiACTA) trial. Baseline GC-related toxicity scores for 12 domains were derived from the Glucocorticoid Toxicity Index using baseline medications, medical history, vital signs, and laboratory values. The 12 domains examined were body mass index, glucose tolerance, blood pressure, lipid metabolism, bone and/or tendon, GC myopathy, skin toxicity, neuropsychiatric effects, infection, ocular toxicity, gastrointestinal injury, and adrenal function. Potential scores ranged from 0 to 538. We compared differences between those with newly diagnosed versus relapsing disease at baseline. A total of 250 patients were included (75% female, mean age 69 years). The mean ± SD baseline GC-related toxicity score among all patients was 111.3 ± 53.2. The domains that contributed most to the overall scores were blood pressure (24.0% of the overall score), followed by glucose tolerance (22.6%) and neuropsychiatric effects (15.9%). Baseline GC-related toxicity scores were higher in patients with relapsing disease compared with those with newly diagnosed disease (mean of 122.5 vs. 98.9; P < 0.001). The body mass index and neuropsychiatric domain scores were significantly higher in patients with relapsing disease. This approach to the assessment of baseline GC-related toxicity distinguished patients with relapsing GCA from those with newly diagnosed disease. Baseline GC-related toxicity scores may be useful in therapeutic decision-making for patients beginning immunosuppressive treatment.

Association of Kidney Function With Risk of Adverse Effects of Therapies for Atrial Fibrillation

Atrial fibrillation (AF) is common in chronic kidney disease (CKD) and is treated with rate control medications, antiarrhythmic medications, as well as anticoagulation and procedures, each of which have associated risks. We aimed to evaluate the association of CKD status with the risks of adverse effects after initiation of AF therapies. This was a cohort study of community-based adults who newly initiated rate control medications, antiarrhythmic medications, warfarin, direct oral anticoagulants (DOACs) or received AF procedures in the 1 year after diagnosis of AF. Baseline estimated glomerular filtration rate (eGFR) was calculated using outpatient serum creatinine measures. Adverse effects within 1 year related to each AF therapy or within 1 month of an AF procedure were ascertained from vital sign databases, electrocardiograms (ECGs), and administrative codes. Fine-Gray hazard models were used to study the association of eGFR categories with risk of adverse effects for each AF therapy. Among 115,564 patients with incident AF, lower eGFR (vs. eGFR≥60 ml/min per 1.73 m2) was significantly associated with higher adjusted risk of adverse effects after initiation of rate control therapies (most commonly hypotension and bradycardia) as follows: eGFR 45-59 (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.07-1.22), 30-44 (HR 1.15, 95% CI 1.06-1.25), and 15-29 (HR 1.29, 95% CI: 1.12-1.47) ml/min per 1.73 m2. Lower eGFR was associated with higher adjusted risk of adverse effects (most commonly prolonged QRS and QTc intervals) after initiation of an antiarrhythmic medication (vs. eGFR >60 ml/min per 1.73 m2) as follows: eGFR 45-59 (HR 1.12, 95% CI 1.01-1.23) and eGFR<15 (HR 1.43, 95% CI 1.01-2.01) ml/min per 1.73 m2. There was a graded association between lower eGFR and risk of major bleeding with warfarin use, with the greatest risk among those with eGFR<15 ml/min per 1.73 m2 (HR of 2.93, 95% CI 1.99-4.30). There was no association of eGFR with major bleeding in patients receiving DOACs. Rates of adverse effects within 1 month of an AF procedure were low among patients with (n= 18) and without (n= 41) CKD and was underpowered for further analyses. In conclusion, lower eGFR was associated with significantly higher risks of adverse effects after initiation of commonly used therapies to treat AF. These data may help inform the complex therapeutic decisions in patients with CKD and AF.

Pursuit of Myocardial Ischemia for Therapeutic Decision-Making in Patients With Diabetes and Stable Ischemic Heart Disease: Reconciling Randomized Controlled Trials and Observational Studies.

Pursuit of Myocardial Ischemia for Therapeutic Decision-Making in Patients With Diabetes and Stable Ischemic Heart Disease: Reconciling Randomized Controlled Trials and Observational Studies.

Differences between complex epithelial neoplasms of the ovary and high-grade serous ovarian cancer: a retrospective observational cohort study

BackgroundComplex epithelial neoplasms of the ovary (CENO), an uncommon pathological histotype in ovarian cancer, comprises adenosquamous carcinoma and adenocarcinoma with metaplasia. Owing to the rarity of relevant reports, there are currently no statistics on outcomes based on large samples. Meanwhile high-grade serous ovarian cancer (HGSOC) is the most common histotype in ovarian cancer which has a recognized first-line treatment regimen and poor prognosis. Thus, we aimed to determine the characteristics, prognosis, and independent predictors of survival for CENO, compare them with those of HGSOC and construct prognostic predictive models and nomograms.MethodsWe used the Surveillance, Epidemiology, and End Results (SEER) database to determine patients diagnosed with CENO or HGSOC from 2000 to 2017. Clinical, demographic, and treatment characteristics were compared between these groups. Propensity score matching, Cox risk regression analysis, Kaplan–Meier survival curves, and the Least Absolute Shrinkage and Selection Operator regression analysis were employed for analyzing the data.ResultsHere, 31,567 patients with HGSOC and 216 patients with CENO between 2000 and 2017 in the SEER database were enrolled. Age < 57 years, unmarried, and early-stage diseases were more common in patients with CENO than in those with HGSOC. Women with CENO were less likely to receive adjuvant chemotherapy (65.7% vs. 79.4%) but more likely to receive radiotherapy (6.0% vs. 0.8%; both p < 0.001) than those with HGSOC. Year of diagnosis, surgery status, number of primary tumors, grade, and FIGO stage were independent prognostic factors for overall and cancer-specific survival in CENO. Overall survival rates were significantly lower for CENO than for more malignant HGSOC.ConclusionsIn summary, CENO was rare in ovarian cancer, while the year of diagnosis, surgery status, number of primary tumors, grade, and FIGO stage were independent prognostic factors. Compared with other common malignant ovarian tumors, CENO had a poor prognosis. Prognostic predictive models and nomograms had been determined to predict the individual survival rates of patients with CENO. These methods could improve evaluations of survival and therapeutic decisions for patients.

Analysis of novel cardiac biomarkers in diagnosis of decompensated heart failure

Abstract Aims Heart failure (HF) remains a major therapeutic and diagnostic challenge. In this study we aimed to analyze the predictive potential of four novel cardiovascular biomarkers – soluble urokinase-type plasminogen activator receptor (suPAR), vascular cell adhesion molecule (CAM-1), heart-type fatty acid binding Protein (H-FABP) and growth/differentiation factor 15 (GDF-15) in detecting cardiac decompensation in patients with HF. Methods In total, 136 patients (40 decompensated HF, 96 compesated HF) were retrospectively enrolled and the serum biomarker concentrations of GDF-15, suPAR, H-FABP and CAM-1 were analyzed by Enzyme Linked Immunosorbent Assay (ELISA). Biomarker concentrations were correlated with clinical and biochemical parameters of enrolled patients, the predictive value for detecting cardiac decompensation was assessed by ROC-plots, as well as univariate and multivariate logistic regression analysis. Cut-offs for cardiac decompensation were calculated by means of the Youden index. Results A significant increase in the levels of suPAR (1.6-fold change, p&amp;lt;0.0001), CAM-1 (1.6-fold change, p&amp;lt;0.0001), HFABP (2.2-fold change, p=0.0458) and GDF-15 (1.7-fold change, p=0.0009) was detected in all patients with decompensated HF compared to patients with compensated HF. In univariate logistic regression analysis, plasma concentrations of GDF-15, H-FABP, suPAR and CAM-1 were significantly associated with the risk for cardiac decompensation. For GDF-15, suPAR and CAM-1, this association remained significant even after correction for confounders in a multivariate logistic regression analysis. Additionally, AUCs (GDF-15: 0.759, 95% (0.683–0.866), suPAR: 0.838, 95% (0.750–0.926), CAM-1: 0.838, 95% (0.750–0.926)) and optimal cut-offs (GDF-15: 1404.8835 pg/ml, suPAR: 4774.027 pg/ml, CAM-1: 4.74027 ng/ml) of the biomarkers were calculated. Correlation analyses found clinical and biochemical parameters such as creatinine as well as inflammatory marker CRP to be significantly correlated with novel biomarkers (r&amp;gt;0.3, p&amp;lt;0.001. In conjunction with the results for the AUC of NTproBNP (AUC=0.785), suPAR (AUC=0.838) and CAM-1 (AUC=0.838 more accurately prediced cardiac decompensation in heart failure than NTproBNP (Figure 1). Conclusion In conclusion, the investigated novel cardiovascular biomarkers could be a valuable tool to facilitate therapeutic decisions in patients with HF and suspicion of cardiac decompensation. Parameters such as renal function should be taken into account. Funding Acknowledgement Type of funding sources: None.

Evolution and clinical implications of right ventricular dysfunction in ischemic cardiomyopathy with or without coronary artery bypass surgery

Abstract Background The Surgical Treatment of Ischemic Heart Failure (STICH) trial demonstrated that coronary artery bypass grafting (CABG) provides additional survival benefits to patients with ischemic cardiomyopathy. However, it remains unclear whether this benefit is affected by preoperative right ventricular (RV) function and how post-therapeutic evolution of RV function influences long-term outcomes. Purpose We sought to investigate the implications of baseline RV function on therapeutic decision-making in patients with ischemic cardiomyopathy, and to evaluate the prognostic implications of post-therapeutic evolution of RV function. Methods Patients with available baseline echocardiographic RV function assessed by experienced Echocardiography Core Laboratory physicians were included from the hypothesis 1 of the STICH trial. The primary outcome was long-term all-cause mortality. Results A total of 1042 patients were included, among them 757 (72.7%) had normal RV function, 143 (13.7%) mild right ventricular dysfunction (RVD), and 142 (13.6%) moderate to severe RVD. After a median follow-up of 9.8 years, patients with RVD had a higher risk of all-cause mortality compared with patients with normal RV function [mild RVD: adjusted hazard ratio (aHR) 1.32; 95% confidence interval (CI) 1.06–1.64; moderate to severe RVD: aHR, 1.74; 95% CI 1.39–2.18]. Although no significant interaction was detected between RVD degree and treatment allocation (P for interaction = 0.399), a gradually decreasing survival benefit associated with CABG was observed among patients with normal RV function (aHR: 0.79; 95% CI: 0.65–0.96), mild RVD (aHR: 0.85; 95% CI: 0.56–1.29), and moderate to severe RVD (aHR: 0.97; 95% CI: 0.67–1.43). Among 746 patients with available RV function assessed at baseline and post-therapeutic 4-month follow-up, there was a gradient of increasing risk for all-cause mortality across patients with consistent normal RV function, recovery of RVD (aHR: 1.20; 95% CI: 0.88–1.64), newly developed RVD (aHR: 1.59; 95% CI: 1.18–2.14), and consistent RVD (aHR: 2.06; 95% CI: 1.60–2.67). Independent predictors of RVD recovery included baseline left ventricular ejection fraction (per 1-percent increment, adjusted odds ratio: 1.04; 95% CI: 1.00–1.09) and mitral regurgitation ≥ grade 2 (adjusted odds ratio: 0.42; 95% CI: 0.21–0.84). Conclusions Baseline RVD was associated with an increased risk of long-term mortality in patients with ischemic cardiomyopathy, and adding CABG to medical therapy might provide limited survival benefits in patients with moderate to severe RVD. A gradient of increasing risk for mortality was observed across different categories of RV function evolution, which emphasizes the necessity of pre- and post-therapeutic RV assessment for prognostic evaluation. Funding Acknowledgement Type of funding sources: None.

Classification of expert-level therapeutic decisions for degenerative cervical myelopathy using ensemble machine learning algorithms.

BackgroundTherapeutic decisions for degenerative cervical myelopathy (DCM) are complex and should consider various factors. We aimed to develop machine learning (ML) models for classifying expert-level therapeutic decisions in patients with DCM.MethodsThis retrospective cross-sectional study included patients diagnosed with DCM, and the diagnosis of DCM was confirmed clinically and radiologically. The target outcomes were defined as conservative treatment, anterior surgical approaches (ASA), and posterior surgical approaches (PSA). We performed the following classifications using ML algorithms: multiclass, one-versus-rest, and one-versus-one. Two ensemble ML algorithms were used: random forest (RF) and extreme gradient boosting (XGB). The area under the receiver operating characteristic curve (AUC-ROC) was the primary metric. We also identified the variable importance for each classification.ResultsIn total, 304 patients were included (109 conservative, 66 ASA, 125 PSA, and 4 combined surgeries). For multiclass classification, the AUC-ROC of RF and XGB models were 0.91 and 0.92, respectively. In addition, ML models showed AUC-ROC values of >0.9 for all types of binary classifications. Variable importance analysis revealed that the modified Japanese Orthopaedic Association score and central motor conduction time were the two most important variables for distinguishing between conservative and surgical treatments. When classifying ASA and PSA, the number of involved levels, age, and body mass index were important contributing factors.ConclusionML-based classification of DCM therapeutic options is valid and feasible. This study can be a basis for establishing generalizable ML-based surgical decision models for DCM. Further studies are needed with a large multicenter database.

Lentiviral vector-based xenograft tumors as candidate reference materials for detection of HER2-low breast cancer.

The human epidermal growth factor receptor 2 (HER2) is an important biomarker that plays a pivotal role in therapeutic decision-making for patients with breast cancer (BC). Patients with HER2-low BC can benefit from new HER2 targeted therapy. For ensuring the accurate and reproducible detection of HER2-low cancer, reliable reference materials are required for monitoring the sensitivity and specificity of detection assays. Herein, a lentiviral vector was used to transduce the HER2 gene into MDA-MB-231 cells that exhibited low HER2 density, and the cells were characterized by droplet digital PCR to accurately determine the copy number variation. Then, the formalin-fixed paraffin-embedded (FFPE) samples from xenografts were prepared and evaluated for suitability as candidate reference materials by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The FFPE reference materials were selected on the basis of IHC score of 2+ and negative FISH result to meet the requirement for HER2-low BC detection. Furthermore, the FFPE reference materials exhibited typical histological structures that resembled the clinical BC specimens. These novel FFPE reference materials displayed the high stability and homogeneity, and they were produced in high quantity. In summary, we generated high-quality reference materials for internal quality control and proficiency testing in HER2-low detection.

Integrated multi-omics analyses reveal that BCAM is associated with epigenetic modification and tumor microenvironment subtypes of clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common and highly heterogeneous subtype of renal cell carcinoma. Dysregulated basal cell adhesion molecule (BCAM) gene is associated with poor prognosis in various cancers. However, the dysregulated functions and related multi-omics features of BCAM in ccRCC stay unclear.ResultsBCAM expression was aberrantly downregulated in ccRCC and correlated with adverse pathological parameters and poor prognosis. Low mRNA expression of BCAM was remarkably associated with its CpG methylation levels and BAP1 mutation status. Patients with lower-expressed BCAM concomitant with BAP1 mutation had a worse prognosis. Using RNA-seq data from The cancer genome atlas, we found that compared to the BCAM-high expression subgroup, ccRCC patients in the BCAM-low expression subgroup had significantly higher levels of immune infiltration, higher immune checkpoint expression levels and lower TIDE (tumor immune dysfunction and exclusion) score, indicating potential better response to immunotherapy. Data from the Clinical Proteomic Tumor Analysis Consortium further validated the association between low BCAM expression and CD8 + inflamed phenotype at protein level. Meanwhile, our results suggested that the angiogenesis-related pathways were enriched in the BCAM-high expression subgroup. More importantly, according to the data from the GDSC database, we revealed that the BCAM-high expression subgroup should be more sensitive to anti-angiogenetic therapies, including sorafenib, pazopanib and axitinib.ConclusionsThese results suggest that BCAM could serve as a biomarker distinguishing different tumor microenvironment phenotypes, predicting prognosis and helping therapeutic decision-making for patients with ccRCC.

What is the impact of circulating histones in COVID-19: a systematic review.

The infectious respiratory condition COVID-19 manifests a clinical course ranging from mild/moderate up-to critical systemic dysfunction and death linked to thromboinflammation. During COVID-19 infection, neutrophil extracellular traps participating in cytokine storm and coagulation dysfunction have emerged as diagnostic/prognostic markers. The characterization of NET identified that mainly histones, have the potential to initiate and propagate inflammatory storm and thrombosis, leading to increased disease severity and decreased patient survival. Baseline assessment and serial monitoring of blood histone concentration may be conceivably useful in COVID-19. We performed a literature review to explore the association among increased circulating levels of histones, disease severity/mortality in COVID-19 patients, and comparison of histone values between COVID-19 and non-COVID-19 patients. We carried out an electronic search in Medline and Scopus, using the keywords "COVID-19" OR "SARS-CoV-2" AND "histone" OR "citrullinated histones" OR "hyperhistonemia", between 2019 and present time (i.e.,June 07th, 2022), which allowed to select 17 studies, totaling 1,846 subjects. We found that substantially elevated histone values were consistently present in all COVID-19 patients who developed unfavorable clinical outcomes. These findings suggest that blood histone monitoring upon admission and throughout hospitalization may be useful for early identification of higher risk of unfavorable COVID-19 progression. Therapeutic decisions in patients with SARS-CoV-2 based on the use of histone cut-off values may be driven by drugs engaging histones, finally leading to the limitation of cytotoxic, inflammatory, and thrombotic effects of circulating histones in viral sepsis.

Somatostatin receptor-directed molecular imaging for therapeutic decision-making in patients with medullary thyroid carcinoma

BackgroundSomatostatin receptor (SSTR) positron emission tomography/computed tomography (PET/CT) is increasingly deployed in the diagnostic algorithm of patients affected with medullary thyroid carcinoma (MTC). We aimed to assess the role of SSTR-PET/CT for therapeutic decision making upon restaging.Methods23 pretreated MTC patients underwent SSTR-PET/CT and were discussed in our interdisciplinary tumor board. Treatment plans were initiated based on scan results. By comparing the therapeutic regimen before and after the scan, we assessed the impact of molecular imaging on therapy decision. SSTR-PET was also compared to CT portion of the SSTR-PET/CT (as part of hybrid imaging).ResultsSSTR-PET/CT was superior in 9/23 (39.1%) subjects when compared to conventional CT and equivalent in 14/23 (60.9%). Those findings were further corroborated on a lesion-based level with 27/73 (37%) metastases identified only by functional imaging (equivalent to CT in the remaining 46/73 (63%)). Investigating therapeutic decision making, no change in treatment was initiated after PET/CT in 7/23 (30.4%) patients (tyrosine kinase inhibitor (TKI), 4/7 (57.2%); surveillance, 3/7 (42.8%)). Imaging altered therapy in the remaining 16/23 (69.6%). Treatment prior to PET/CT included surgery in 6/16 (37.5%) cases, followed by TKI in 4/16 (25%), active surveillance in 4/16 (25%), and radiation therapy (RTx) in 2/16 (12.5%) subjects. After SSTR-PET/CT, the therapeutic regimen was changed as follows: In the surgery group, 4/6 (66.7%) patients underwent additional surgery, and 1/6 (16.7%) underwent surveillance and TKI, respectively. In the TKI group, 3/4 (75%) individuals received another TKI and the remaining subject (1/4, 25%) underwent peptide receptor radionuclide therapy. In the surveillance group, 3/4 (75%) underwent surgery (1/4, (25%), RTx). In the RTx group, one patient was switched to TKI and another individual was actively monitored (1/2, 50%, respectively). Moreover, in the 16 patients in whom treatment was changed by molecular imaging, control disease rate was achieved in 12/16 (75%) during follow-up.ConclusionsIn patients with MTC, SSTR-PET/CT was superior to CT alone and provided relevant support in therapeutic decision-making in more than two thirds of cases, with most patients being switched to surgical interventions or systemic treatment with TKI. As such, SSTR-PET/CT can guide the referring treating physician towards disease-directed treatment in various clinical scenarios.