BIOM-24. PROTEIN SURFACE SIGNATURE ON SERUM EXTRACELLULAR VESICLES FOR NON-INVASIVE DETECTION OF TUMOR PROGRESSION IN GLIOBLASTOMA PATIENTS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi15-vi16
Author(s):  
Theophilos Tzaridis ◽  
Johannes Weller ◽  
Daniel Bachurski ◽  
Farhad Shakheri ◽  
Christina Schaub ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Healthy Volunteers ◽  
Extracellular Vesicles ◽  
Clinical Decision Making ◽  
Histone H3 ◽  
Clinical Decision ◽  
Size Exclusion ◽  
Phase Iii ◽  
Multivariable Logistic Regression Analysis ◽  
Rano Criteria

Abstract INTRODUCTION Detection of tumor progression in glioblastoma patients remains a major challenge for clinicians due to equivocal MRI results. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of tumor patients. In this study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as a marker for tumor progression in adjunction with MRI assessment. METHODS Glioblastoma patients from two independent cohorts, one from the multicenter Phase III CeTeG/NOA-09 trial (n=36) and the other from patients treated at the University of Bonn (n=31), were included in this study. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. RESULTS EVs from the serum of glioblastoma patients (n=67) showed an upregulation of CD29 (p=0.08), CD44 (p< 0.0001), CD81 (p< 0.0001), CD146 (p< 0.0001), C1QA (p=0.003), and histone H3 (p< 0.0001) as compared to serum EVs from healthy volunteers. For both independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44, and histone H3 upon tumor progression, but not in patients with stable disease. Notably, six patients with worse survival compared to the median survival of the cohort did not fulfill RANO criteria at the time of suspected progression, yet showed an elevation of at least one out of these three markers. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA, and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. CONCLUSION Measurement of CD29, CD44, CD81, C1QA, and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, could improve detection of true tumor progression and thus be a useful tool for clinical decision making.

scholarly journals Single-inhaler triple therapy in symptomatic COPD patients: FULFIL subgroup analyses

2018 ◽  
Vol 4 (2) ◽  
pp. 00119-2017 ◽  
Author(s):  
David M.G. Halpin ◽  
Ruby Birk ◽  
Noushin Brealey ◽  
Gerard J. Criner ◽  
Mark T. Dransfield ◽  
...  
Keyword(s):  
Disease Severity ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Forced Expiratory Volume ◽  
Phase Iii ◽  
Chronic Obstructive ◽  
Double Blind Study ◽  
Double Blind ◽  
Subgroup Analyses ◽  
Long Acting

Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD) and at risk of exacerbations. However, the benefits versus side-effects of triple inhaled therapy for COPD, based on distinct patient clinical profiles, are unclear.FULFIL, a phase III, randomised, double-blind study, compared 24 weeks of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg using the Ellipta inhaler with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg using the Turbuhaler. Subgroup analyses of forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) Total score and exacerbation rates were carried out. Subgroups were defined by COPD medication at screening (ICS+LABA, BUD+FOR, ICS+LABA+LAMA, LAMA alone, tiotropium alone and LAMA+LABA), by disease severity (lung function and exacerbations) and by exacerbation history (exacerbation severity and frequency).In the intent-to-treat population (n=1810) at week 24, FF/UMEC/VI (n=911) versus BUD/FOR (n=899) improved FEV1 and SGRQ Total score and reduced mean annual exacerbation rates in all disease severity and exacerbation history subgroups. FF/UMEC/VI versus BUD/FOR improved FEV1 and SGRQ Total score in all medication subgroups and reduced mean annual exacerbation rates in all medication subgroups, except LAMA+LABA. Adverse events were similar across subgroups.These findings support the benefit of FF/UMEC/VI compared with dual ICS/LABA therapy in patients with symptomatic COPD regardless of disease severity or prior treatment and may help to inform clinical decision making.

State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012

2012 ◽  
pp. 289-291 ◽  
Author(s):  
Oliver Sartor
Keyword(s):  
Prostate Cancer ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Optimal Sequence ◽  
Molecular Stratification ◽  
Castration Resistant ◽  
Radium 223 ◽  
Phase Iii Trials

Overview: Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future, we will develop molecular “stratification systems” to better guide therapeutic choices in CRPC.

Combination chemotherapy versus temozolomide (TMZ) for patients with MGMT methylated (m-MGMT) glioblastoma (GBM): Results of cellworks omics biosimulation—MyCare-015.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Michael Castro ◽  
Nirjhar Mundkur ◽  
Anusha Pampana ◽  
Aftab Alam ◽  
Aktar Alam ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clinical Decision Making ◽  
Drug Effects ◽  
Standard Of Care ◽  
Clinical Decision ◽  
Phase Iii ◽  
Patient Specific ◽  
Experimental Therapy ◽  
Newly Diagnosed ◽  
Current Standard

e14501 Background: UKT-03 evaluated TMZ plus Lomustine in a single arm phase II trial in newly diagnosed GBM patients. An overall survival of 23 months was a substantial improvement over historical experience. Patients with m-MGMT v. unmethylated tumors had a 2-yr survival of 75% and median survival not reached compared to 20% and 12.5 months, respectively. These data formed the basis for NOA-9, a randomized phase III trial in newly diagnosed, m-MGMT GBM which randomized 141 patients to standard therapy or experimental therapy with Lomustine and TMZ every 6 weeks. A superiority for the combination was observed: 48.1 v. 31.4 months for the standard arm in the ITT analysis. Nevertheless, many neurooncologists are reluctant to adopt this approach. The current standard of care uses single biomarker, m-MGMT, in contrast to comprehensive pathway analysis (CPA). We sought to determine if CPA could discriminate more effectively among each patient’s likelihood of benefiting from combination treatment. Methods: Cellworks Singula employs a novel Cellworks Omics Biology Model (CBM) to predict patient-specific biomarker and phenotype response of personalized GBM avatars to drug agents, radiation, and targeted therapies. The CBM was developed and validated using PubMed to generate protein network maps of patient-specific activated and inactivated disease pathways. CBM was used to simulate the TMZ and TMZ-Lomustine therapies for each patient in a TCGA cohort of 368 GBM patients. Omics data including methylation, whole exome sequencing, and copy number alterations were input into CBM. The Singula Composite Inhibition Score (CIS) was calculated based on the measured quantitative drug effects. Results: Though incremental gain from the combination was seen in all patients, CIS varied across the population with relative scores ranging from 32-82, with best responders have more than twice the benefit. Conclusions: CPA shows that m-MGMT is an excellent biomarker for determining the likelihood of benefit from TMZ and lomustine, with the caveat that CBM identifies 18% could be spared from TMZ exposure and would benefit from Lomustine alone. Otherwise, these data lend support for evolving the standard of care with combination therapy for patients with m-MGMT GBM and should help overcome a reluctance to employing combination therapy. Additionally, CBM has utility to individualize clinical decision making. [Table: see text]

scholarly journals Effect of Hemifacial Spasm on Intraocular Pressure Measurement

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Erdogan Cicik ◽  
Rengin Yildirim ◽  
Ceyhun Arici ◽  
Funda Dikkaya ◽  
Osman Sevki Arslan
Keyword(s):  
Intraocular Pressure ◽  
Healthy Volunteers ◽  
Hemifacial Spasm ◽  
Clinical Decision Making ◽  
Corneal Thickness ◽  
Clinical Decision ◽  
Age And Gender ◽  
Applanation Tonometer ◽  
Iop Measurement ◽  
And Gender

Purpose. To evaluate the effect of hemifacial spasm (HFS) on intraocular pressure (IOP) measurement. Methods. Twenty-four consecutive patients with HFS and 25 age- and gender-matched randomly selected eyes of healthy volunteers underwent corneal pachymetry and IOP measurements using Goldmann applanation tonometer (GAT) and noncontact tonometer (NCT). IOP measurements were performed before (during HFS) and 2 weeks after Botox injections in HFS patients and in healthy volunteers without Botox injections. Results. There was no statistical difference between involved eye side and uninvolved eye side of HFS patients in measured central corneal thickness. Similarly, no difference was found between involved eye side of HFS patients and controls. There were no statistically significant differences comparing IOP values before treatment and levels measured at 2 weeks of Botox injections, either with GAT (p=0.33, 0.11) or NCT (p=0.80, 0.43) devices in the involved eyes and uninvolved eyes of patients with HFS, respectively. There were also no significant differences in these parameters (GAT (p=0.63) and NCT (p=0.54)) in controls. Conclusions. Contractions in facial muscles may not lead to significant increase in IOP in HFS patients. This result may help clinical decision making in the treatment of glaucoma patients with HFS. This trial is registered with NCT03390803.

scholarly journals Prolactin ≤1 ng/mL predicts macroprolactinoma reduction after cabergoline therapy

2020 ◽  
Vol 182 (2) ◽  
pp. 177-183
Author(s):  
Daham Kim ◽  
Cheol Ryong Ku ◽  
Kyungwon Kim ◽  
Hyein Jung ◽  
Eun Jig Lee
Keyword(s):  
Tumor Size ◽  
Prolactin Level ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Post Treatment ◽  
Size Reduction ◽  
Multivariable Logistic Regression Analysis ◽  
High Dose ◽  
Pituitary Hormone ◽  
Level 1

Objective The association between prolactin level variation and prolactinoma size reduction remains unclear. This study aimed to determine the prolactin level cut-off predictive of a tumor size reduction. Design Retrospective cohort study. Methods We reviewed medical records of patients with prolactinoma who received primary cabergoline therapy and for whom complete data on pituitary hormone assays and sellar MRI at baseline and 3 months post treatment were available. We tested whether the certain prolactin level after 3 months post treatment predicted better response. Results Prolactin levels normalized in 109 (88.6%) of 123 included macroprolactinoma patients. The mean tumor size reduction was 22.9%, and patients in the lowest prolactin tertile (≤0.7) had the highest frequency of tumor size reductions of ≥20% (73.7 vs 52.9% and 45.9% in tertiles 2 (>0.7 to 2.6) and 3 (>2.6 to 20), P = 0.015). Patients with prolactin levels ≤1 ng/mL exhibited larger tumor size reductions vs those with prolactin levels of 1–20 (27.2 ± 18.3% vs 19.5 ± 13.9%, P = 0.014), 1–10 (19.3 ± 13.7%, P = 0.017) and 1–5 ng/mL (19.2 ± 14.3%, P = 0.039). A multivariable logistic regression analysis revealed that a prolactin level ≤1 ng/mL at 3 months and high-dose cabergoline therapy were significantly associated with tumor size reductions of ≥20% (odds ratio (OR): 2.8, 95% confidence interval (CI): 1.2–6.7, P = 0.017; OR: 2.0, 95% CI: 1.0–3.9, P = 0.043). Conclusions A prolactin level ≤1 ng/mL at 3 months after cabergoline treatment was correlated with a significant tumor size reduction in patients with macroprolactinoma. This finding may help clinical decision making when treating macroprolactinoma patients.

scholarly journals Isolation and Characterization of Urine Microvesicles from Prostate Cancer Patients: Different Approaches, Different Visions

2021 ◽  
Author(s):  
María García-Flores ◽  
Christian M. Sánchez-López ◽  
Marta Ramírez-Calvo ◽  
Antonio Fernández-Serra ◽  
Antonio Marcilla ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Protein Quantification ◽  
Size Exclusion ◽  
Biologically Relevant ◽  
Isolation And Characterization ◽  
Isolation Methods ◽  
Exclusion Chromatography ◽  
Significant Enrichment

Abstract BackgroundBecause of their specific and biologically relevant cargo, urine extracellular vesicles (EVs) constitute a valuable source of potential non-invasive biomarkers that could support the clinical decision-making to improve the management of prostate cancer (PCa) patients. Different EV isolation methods differ in terms of complexity and yield, conditioning, as consequence, the analytical result. MethodsThe aim of this study was to compare three different isolation methods for urine EVs: ultracentrifugation (UC), size exclusion chromatography (SEC), and a commercial kit (Exolute® Urine Kit). Urine samples were collected from 6 PCa patients and 4 healthy donors (HDs). After filtered through 0.22 µm filters, urine was divided in 3 equal volumes to perform EVs isolation with each of the three approaches. Isolated EVs were characterized by spectrophotometric protein quantification, nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), AlphaScreen Technology, and whole miRNA Transcriptome. ResultsOur results showed that UC and SEC provided better results in terms of EVs yield and purity than Exolute®, non-significant differences were observed in terms of EV-size. Interestingly, luminescent AlphaScreen assay demonstrated a significant enrichment of CD9 and CD63 positive microvesicles in SEC and UC methods compared with Exolute®. This heterogeneity was also demonstrated in terms of miRNA content indicating that the best correlation was observed between UC and SEC. ConclusionsOur study highlights the importance of standardizing the urine EV isolation methods to guaranty the analytical reproducibility necessary for their implementation in a clinical setting.

Evidence-based psychopharmacotherapy. A valid and reliable approach?

2012 ◽  
Vol 09 (04) ◽  
pp. 231-238
Author(s):  
H.-J. Möller
Keyword(s):  
Decision Making ◽  
Clinical Experience ◽  
Clinical Decision Making ◽  
Positive Impact ◽  
Belief Systems ◽  
Clinical Decision ◽  
Clinical Situation ◽  
Phase Iii ◽  
Evidence Based ◽  
Oriented Phase

Summary Objective: Psychopharmacotherapy should now be regulated in the sense of evidence-based medicine (EBM), as is the case in other areas of clinical treatment in medicine. Methods: Descriptive overview of limitations and problems of EBM in pharmacopsychiatry. Results: In general this is a meaningful development, which principally will have a positive impact on routine health care in psychiatry. But several related problems should not be ignored. So far consensus on an internationally accepted evidence graduation could not be reached, due to several difficulties related to this. For example, to focus on the results of meta-analyses instead of considering relevant single studies results in a decision-making logic which is in conflict with the rationale applied by drug authorities in the licensing process. Attempts to regulate psychopharmacotherapy in the sense of EBM come closer to their limits the more complex the clinical situation and the respective decision-making logic are. Conclusion: EBM has severe problems and limitations. Even in times of EBM a large part of complex clinical decision-making in psychopharmacotherapy still relies more on clinical experience and a consensus about clinical experience, traditions and belief systems than on results of efficacy oriented phase-III and effectiveness-oriented phase-IV clinical studies.

scholarly journals In silico learning of tumor evolution through mutational time series

2019 ◽  
Vol 116 (19) ◽  
pp. 9501-9510 ◽  
Author(s):  
Noam Auslander ◽  
Yuri I. Wolf ◽  
Eugene V. Koonin
Keyword(s):  
Time Series ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Clinical Decision Making ◽  
Short Term Memory ◽  
Complex Dynamics ◽  
Clinical Decision ◽  
Tumor Evolution ◽  
Cancer Evolution ◽  
Driver Genes

Cancer arises through the accumulation of somatic mutations over time. Understanding the sequence of mutation occurrence during cancer progression can assist early and accurate diagnosis and improve clinical decision-making. Here we employ long short-term memory (LSTM) networks, a class of recurrent neural network, to learn the evolution of a tumor through an ordered sequence of mutations. We demonstrate the capacity of LSTMs to learn complex dynamics of the mutational time series governing tumor progression, allowing accurate prediction of the mutational burden and the occurrence of mutations in the sequence. Using the probabilities learned by the LSTM, we simulate mutational data and show that the simulation results are statistically indistinguishable from the empirical data. We identify passenger mutations that are significantly associated with established cancer drivers in the sequence and demonstrate that the genes carrying these mutations are substantially enriched in interactions with the corresponding driver genes. Breaking the network into modules consisting of driver genes and their interactors, we show that these interactions are associated with poor patient prognosis, thus likely conferring growth advantage for tumor progression. Thus, application of LSTM provides for prediction of numerous additional conditional drivers and reveals hitherto unknown aspects of cancer evolution.

scholarly journals The role of natalizumab in the treatment of multiple sclerosis: benefits and risks

2017 ◽  
Vol 10 (9) ◽  
pp. 327-336 ◽  
Author(s):  
Barry A. Singer
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Decision Making ◽  
Opportunistic Infections ◽  
Clinical Decision ◽  
Phase Iii ◽  
Effective Option ◽  
Natalizumab Treatment ◽  
The Central Nervous System ◽  
Infusion Reactions ◽  
Post Hoc

Natalizumab, a monoclonal antibody that blocks lymphocyte infiltration in the central nervous system, is a valuable tool in the treatment of relapsing forms of multiple sclerosis (MS). In a phase III clinical trial comparing natalizumab with placebo over 2 years, natalizumab reduced annualized relapse rate by 68%, 12-week confirmed disability progression by 42%, and reduced contrast-enhancing lesions by 92%. In post hoc analyses, natalizumab treatment was associated with 37% of patients achieving no evidence of disease activity ( versus 7% on placebo) and 30% achieving sustained disability improvement ( versus 19% on placebo). Natalizumab did not achieve a statistically significant primary composite disability outcome in a trial of 887 patients with secondary progressive MS, but it did demonstrate a benefit on a prespecified component of the 9-Hole Peg Test. The greatest risk of natalizumab treatment is progressive multifocal leukoencephalopathy (PML), with a 23% mortality rate. Risk stratification on the basis of immunosuppressant exposure, natalizumab treatment duration and anti-John Cunningham virus (JCV) antibody status and index has greatly improved clinical decision making. Other potential serious natalizumab-associated risks reported in clinical trials and postmarketing settings include infusion reactions, hepatotoxicity and rare, serious opportunistic infections. With more than a decade of continuous postmarketing experience, natalizumab remains a very effective option for patients with relapsing forms of MS. To optimize appropriate selection of natalizumab for patients with relapsing MS, however, a thorough understanding of individual patient risk factors for PML or other adverse events is also required.

Abstract 13609: Predictors of Treatment of Hospitalized Patients With Atrial Fibrillation in the US

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Steven B Deitelzweig ◽  
Amol D Dhamane ◽  
Manuela Di Fusco ◽  
Cristina Russ ◽  
Lisa Rosenblatt ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Outpatient Setting ◽  
Multivariable Logistic Regression Analysis ◽  
Insurance Claims ◽  
Treatment Practices ◽  
The Us ◽  
Comorbidity Index ◽  
Prior Stroke

Introduction: While a few studies have been conducted that evaluated anticoagulant (AC) treatment of patients with atrial fibrillation (AF) in the outpatient setting, little is known regarding inpatient AC treatment practices. Objective: To identify predictors of AC treatment among patients hospitalized with AF in the US Methods: Patients (≥18 years of age) who had a primary or secondary discharge diagnosis code of AF during a hospitalization (without a diagnosis of venous thromboembolism) were selected from the Premier Hospital database (1/1/2016-9/30/2017). Patients were grouped into 2 study cohorts: 1) Patients who received oral AC (OAC) therapy during hospitalization and 2) Patients who did not receive any AC therapy. Demographics, patient clinical characteristics, and hospital characteristics were examined. A multivariable logistic regression analysis was carried out to evaluate potential predictors of not receiving any AC therapy vs. receiving OACs. Results: Of the patients hospitalized with an AF diagnosis, 65.7% (n=205,438; mean age: 74.4 years; 47.1% female) received OAC therapy and 34.3% (n=107,076; mean age: 75.9 years; 46% female) did not receive any AC therapy. The most common OACs received were warfarin (39.4%) and apixaban (34.2%). Key predictors of a greater likelihood of not receiving any AC therapy vs. receiving OACs were greater comorbidity (Charlson Comorbidity Index [CCI] ≥5 vs. 0 odds ratio [OR]: 1.72; 3-4 vs. 0: 1.32; 1-2 vs. 0: 1.11, all p<0.001) and having had prior bleeding (OR: 1.59, p<0.001). Key predictors of receiving OACs, relative to not receiving any AC therapy, were having a AF diagnosis in the first vs. second position on insurance claims (OR: 0.24, p<0.001), chronic (OR: 0.76, p<0.001) or persistent (OR: 0.61, p<0.001) AF vs. paroxysmal, higher stroke risk (CHA 2 DS 2 -VASc=5 vs. 0 OR: 0.48; 3-4 vs. 0: 0.51; 1-2 vs. 0: 0.58, all p<0.001), and a prior stroke (OR: 0.87, p<0.001). Conclusions: A substantial portion of hospitalized AF patients in the study did not receive any AC therapy, particularly those patients with an AF diagnosis in the second position on insurance claims. The predictors of AC treatment that were identified may be helpful in the clinical decision-making process for patients who are hospitalized with AF.

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