Predictive Value For Treatment Response Research Articles

Plasma miR-379 can predict treatment response to FOLFIRINOX and gemcitabine-nab-paclitaxel in advanced pancreatic cancer

BackgroundNovel biomarkers, such as plasma microRNAs (miRs), are needed to help guide clinical decision-making for the type of chemotherapy to use in patients with advanced pancreatic ductal adenocarcinoma (PDAC). This study assessed the ability of plasma miRs to predict optimal treatment response from FOLFIRINOX or gemcitabine-nab-paclitaxel in these patients. MethodsNext-generation sequencing (NGS) was performed for biomarker discovery in pre-treatment plasma samples from advanced PDAC patients subsequently treated with FOLFIRINOX (n = 12) or gemcitabine-nab-paclitaxel (n = 12). Selected candidate biomarkers were validated in 40 patients with advanced PDAC using RT-qPCR. Cox regression was then used to assess the predictive value of plasma miRs for either FOLFIRINOX or gemcitabine-nab-paclitaxel. ResultsIn the validation cohort, high plasma miR-379 expression was strongly predictive of treatment response (Pinteraction = 0.0004). Overall survival (OS) was significantly better with FOLFIRINOX vs. gemcitabine-nab-paclitaxel in those patients with lower plasma miR-379 expression (hazard ratio, 0.32 [95% confidence interval, 0.08 to 0.98]; P = 0.046). However, gemcitabine-nab-paclitaxel was associated with superior OS in patients with higher plasma miR-379 (hazard ratio, 0.28 [0.10 to 0.86]; P = 0.027). In contrast, miR-127, miR-155, and miR-200 showed no predictive value for treatment response for either chemotherapy regimen (Pinteraction = 0.12, Pinteraction = 0.83 and Pinteraction = 0.12, respectively). ConclusionsPlasma miR-379 appears clinically useful as a predictive biomarker to identify which patients with advanced PDAC benefit most from treatment with FOLFIRINOX or gemcitabine-nab-paclitaxel. Further validation in larger studies and clinical trials is now warranted.

Dynamic Contrast-enhanced MRI Quantification of Altered Vascular Permeability in Autoimmune Encephalitis.

Background Blood-brain barrier (BBB) permeability change is a possible pathologic mechanism of autoimmune encephalitis. Purpose To evaluate the change in BBB permeability in patients with autoimmune encephalitis as compared with healthy controls by using dynamic contrast-enhanced (DCE) MRI and to explore its predictive value for treatment response in patients. Materials and Methods This single-center retrospective study included consecutive patients with probable or possible autoimmune encephalitis and healthy controls who underwent DCE MRI between April 2020 and May 2021. Automatic volumetric segmentation was performed on three-dimensional T1-weighted images, and volume transfer constant (Ktrans) values were calculated at encephalitis-associated brain regions. Ktrans values were compared between the patients and controls, with adjustment for age and sex with use of a nonparametric approach. The Wilcoxon rank sum test was performed to compare Ktrans values of the good (improvement in modified Rankin Scale [mRS] score of at least two points or achievement of an mRS score of ≤2) and poor (improvement in mRS score of less than two points and achievement of an mRS score >2) treatment response groups among the patients. Results Thirty-eight patients with autoimmune encephalitis (median age, 38 years [IQR, 29-59 years]; 20 [53%] female) and 17 controls (median age, 71 years [IQR, 63-77 years]; 12 [71%] female) were included. All brain regions showed higher Ktrans values in patients as compared with controls (P < .001). The median difference in Ktrans between the patients and controls was largest in the right parahippocampal gyrus (25.1 × 10-4 min-1 [95% CI: 17.6, 43.4]). Among patients, the poor treatment response group had higher baseline Ktrans values in both cerebellar cortices (P = .03), the left cerebellar cortex (P = .02), right cerebellar cortex (P = .045), left cerebral cortex (P = .045), and left postcentral gyrus (P = .03) than the good treatment response group. Conclusion DCE MRI demonstrated that BBB permeability was increased in all brain regions in patients with autoimmune encephalitis as compared with controls, and baseline Ktrans values were higher in patients with poor treatment response in the cerebellar cortex, left cerebral cortex, and left postcentral gyrus as compared with the good response group. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Filippi and Rocca in this issue.

Primary bladder neck obstruction in men: The importance of urodynamic assessment and cystourethrography in measuring its severity.

Primary bladder neck obstruction (PBNO) is a condition primarily affecting young men, characterized by obstruction at the bladder neck, leading to lower urinary tract symptoms. The aim of this study was to identify a correlation between the severity of bladder neck opening impairment and urinary symptoms by means of urodynamic studies. A retrospective analysis was conducted in adult males diagnosed with PBNO at a university neurourology department between 2015 and 2022 who underwent voiding cystourethrography (VCUG) and pressure-flow studies. The cohort was divided into two groups: absence of bladder neck opening on VCUG (Group A) and incomplete bladder neck opening (Group B). Out of the 82 patients with PBNO screened, 53 were included in the analysis. Nocturia was the only symptom more prevalent in Group A (65% in Group A vs. 30% in Group B, p = 0.02) but scores and subscores of the Urinary Symptom Profile questionnaire were not different between groups. In addition, the detrusor pressure at a maximum flow rate (PdetQmax), bladder outlet obstruction index (BOOI), and bladder contractility index (BCI) were higher in Group A than in Group B [PdetQmax (A = 93.7 ± 53.7 cmH2O vs. B = 65.7 ± 26.4 cmH2O; p = 0.01)-BOOI (A = 77 ± 58.3 vs. B = 48 ± 25.7; p = 0.03)-BCI (A = 136 ± 51.3 vs. B = 110 ± 41.7; p = 0.04)]. This study demonstrates a significant association between the extent of bladder neck opening impairment observed on VCUG and obstruction and contraction urodynamic parameters, but no association with the severity of urinary symptoms. Future studies should evaluate the predictive value of treatment response and the occurrence of complications based on clinical and urodynamic parameters.

Shared and distinctive neural substrates of generalized anxiety disorder with or without depressive symptoms and their roles in prognostic prediction

BackgroundThe neurophysiological mechanisms underlying generalized anxiety disorder (GAD) with or without depressive symptoms are obscure. This study aimed to uncover them and assess their predictive value for treatment response. MethodsWe enrolled 98 GAD patients [58 (age: 33.22 ± 10.23 years old, males/females: 25/33) with and 40 (age: 33.65 ± 10.49 years old, males/females: 14/26) without depressive symptoms] and 54 healthy controls (HCs, age: 32.28 ± 10.56 years old, males/females: 21/33). Patients underwent clinical assessments and resting-state functional MRI (rs-fMRI) at baseline and after 4-week treatment with paroxetine, while HCs underwent rs-fMRI at baseline only. Regional homogeneity (ReHo) was employed to measure intrinsic brain activity. We compared ReHo in patients to HCs and examined changes in ReHo within the patient groups after treatment. Support vector regression (SVR) analyses were conducted separately for each patient group to predict the patients' treatment response. ResultsBoth patient groups exhibited higher ReHo in the middle/superior frontal gyrus decreased ReHo in different brain regions compared to HCs. Furthermore, differences in ReHo were detected between the two patient groups. After treatment, the patient groups displayed distinct ReHo change patterns. By utilizing SVR based on baseline abnormal ReHo, we effectively predicted treatment response of patients (p-value for correlation < 0.05). LimitationsThe dropout rate was relatively high. ConclusionsThis study identified shared and unique neural substrates in GAD patients with or without depressive symptoms, potentially serving as biomarkers for treatment response prediction. Comorbid depressive symptoms were associated with differences in disease manifestation and treatment response compared to pure GAD cases.

Australasian Leukaemia & Lymphoma Group NHL35-Pacific: An Open Label Phase II Study of Pembrolizumab and Chemo-Immunotherapy As First-Line Therapy for Primary Mediastinal B-Cell Lymphoma - Trial in Progress

Background: Primary Mediastinal B-cell Lymphoma (PMBL) comprises 10% of Diffuse large B-cell lymphoma (DLBCL), primarily affecting young adults. Combination chemoimmunotherapy with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) is effective, however up to 10-20% of patients may have either refractory disease or experience relapse within 12 months of completing treatment. Consolidative radiotherapy has often been used following R-CHOP, with retrospective data suggesting a survival benefit compared with R-CHOP alone. However, mediastinal radiotherapy increases risk of breast cancer and cardiovascular disease and the recently reported randomised IELSG37 study demonstrated no improvement in progression free survival (PFS) with the use of consolidative radiotherapy following chemoimmunotherapy. Dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (DA-EPOCH-R) without radiotherapy has demonstrated excellent activity in a small phase II study but with increased chemotherapy toxicity. In IELSG37, PFS was inferior for patients treated with R-CHOP-21 compared with other chemoimmunotherapy regimens, supporting intensification of therapy beyond R-CHOP-21 in this entity. The outcome for patients with relapsed/refractory PMBL is poor, with response rates of around 25% to second line therapy, and a 2-year overall survival of 15%. Therefore, there remains a need to improve initial therapy for patients with PMBL. Programmed-Death-1 (PD-1) ligands PD-L1/PD-L2 are commonly upregulated in PMBL. The PD-1 inhibitor Pembrolizumab blocks the interaction of PD-1 and PD-L1/2, and subsequent signalling, and has encouraging activity in relapsed/refractory PMBL, with an overall response rate of 43% (complete response 23%) and modest toxicity in a phase II study. ‘Window’ induction treatment involving delivery of checkpoint inhibitor therapy to patients with lymphoma, prior to initiation of chemotherapy has been investigated in phase II studies, showing encouraging efficacy and no safety concerns with this ‘chemotherapy-free’ initial treatment approach. The combination of Pembrolizumab and Rituximab is predicted to be synergistic, and in non-randomised trials in other B-cell lymphoma histologies, has demonstrated superior response rates to those expected with Rituximab monotherapy, suggesting synergism of the combination. There is therefore compelling rationale for combining R-CHOP and Pembrolizumab as first-line therapy for PMBL. This study investigates the efficacy and safety of this novel, time-limited, radiotherapy sparing regimen. Methods ALLG-PACIFIC (ANZCTR- ACTRN12621001529831) is a phase II, single arm, open-label study of R-CHOP in combination with Pembrolizumab. The trial is open to recruitment across Australia. Approximately 35 patients with newly diagnosed PMBL, will be enrolled to receive two cycles of Rituximab (375mg/m 2) plus Pembrolizumab (200mg) once every 21 days ('window phase') followed by six cycles of R-CHOP plus Pembrolizumab once every 21 days ('induction phase') followed by five cycles of Pembrolizumab 400mg once every 42 days ('consolidation phase') (Figure 1). Adults (≥18 years) with treatment naïve histologically confirmed PMBL and adequate organ function are eligible. Key exclusion criteria are the presence of active autoimmune disease, requiring recent immunosuppressive therapy, life-threatening or organ-compromising lymphoma symptoms requiring urgent cytoreductive therapy, and other medically significant conditions that preclude eligibility to receive R-CHOP. Patients who require urgent cytoreductive therapy following initiation of window phase treatment may proceed immediately to induction phase chemotherapy. The primary endpoint is 18-month event free survival. Key secondary endpoints include response to window phase treatment, overall survival, requirement for radiotherapy and safety of treatment including rates of early discontinuation due to treatment toxicity. Several biomarkers are also being investigated for their predictive value for treatment response including minimal residual disease status (measured by Adaptive Immunoseq and CAPP-Seq), PET-CT parameters (e.g., Metabolic tumour volume), and PD-1/PD-L1 expression and 9q24 alterations.

Cutaneous allodynia as predictor for treatment response in chronic migraine: a cohort study

BackgroundCentral sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an analogous spatial distribution of cutaneous allodynia with cephalic and extracephalic symptoms. We investigated whether allodynia, and its subtypes based on spatial distribution and type of stimulus, predict response to treatment in chronic migraine patients.MethodsThis study was conducted as part of the CHARM study (NTR3440), a randomized, double-blind, placebo-controlled trial in chronic migraine patients with medication overuse. We included 173 patients. The presence of cutaneous allodynia at baseline was established with the Allodynia Symptom Checklist. Primary endpoint was reversion from chronic to episodic migraine.ResultsOf all patients, 74.6% reported cutaneous allodynia. Absence of allodynia compared to presence of allodynia was predictive for reversion from chronic to episodic migraine, odds ratio (OR): 2.45 (95% CI: 1.03–5.84), p = 0.042. The predictive value was more pronounced when subdivided for spatial distribution, for participants without allodynia versus cephalic (OR: 4.16 (95% CI: 1.21–14.30), p = 0.024) and extracephalic (OR: 7.32 (95% CI: 1.98- 27.11), p = 0.003) allodynia. Mechanical, but not thermal, allodynia, was associated with outcome.ConclusionsCutaneous allodynia, an important marker for central sensitization, likely has predictive value for treatment response in chronic migraine.Graphical

The Association of Urinary MCP-1 with Disease Activity of Lupus Nephritis

Background: The association of urinary MCP-1 (Monocyte Chemoattractant Protein-1) with disease activity in lupus nephritis (LN) has been a subject of significant interest. MCP-1 is a chemokine involved in the recruitment and activation of monocytes, which play a critical role in the pathogenesis of LN. Objective: To assess association of Urinary MCP-1 with disease activity of lupus nephritis. Method: This cross sectional study was conducted in the Department of Nephrology, Dhaka Medical College Hospital, Dhaka from January, 2017 to June, 2018. This cross sectional study was performed on 60 biopsy proven lupus nephritis patients and 30 age and sex matched apparently healthy control subjects. All the patients were recruited as per inclusion and exclusion criteria. Diagnosed SLE patients who had renal involvement and undergone renal biopsy for standard clinical indications were recruited by purposive sampling and divided into two groups of active and inactive LN as per operational definition. Results: During the study, The urinary MCP-1 was higher in active LN patients compared to the inactive group and both were higher than the level in the control. Plus, highest Sensitivity and specificity of uMCP-1 observed at cutoff value 433 pg/ml, where sensitivity was 0.967 and specificity was 0.900. Among 30 active lupus nephritis cases raised uMCP-1 was found in 29 cases and among 30 inactive lupus nephritis cases raised uMCP-1 was found in 3 cases. uMCP-1 showed very good agreement in diagnosis of lupus nephritis activity according to Kappa statistics. uMCP-1 in diagnosis of lupus nephritis activity showed accuracy, sensitivity, specificity, PPV and NPV were 0.933, 0.967, 0.900, 0.906 and 0.964 respectively. Conclusion: In conclusion, urinary MCP-1 holds great promise as a useful biomarker for the determination of lupus nephritis activity. Its association with disease activity, predictive value for treatment response and renal outcomes, and non-invasive nature make it an ...

Peripheral Blood Inflammation Indicators as Predictive Factors for Treatment Response Assessed by MRI in Cervical Cancer Patients Referred for Radiotherapy

Backgroud: Radiotherapy (RT) with or without concurrent chemotherapy is regarded as the standard therapy for locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IB2 and above). However, markedly different responses to RT are seen among patients with similar FIGO stages.The study aimed to evaluate the peripheral blood inflammation indicators that may have predictive value for treatment response in cervical cancer patients referred for RT. Methods: This was a retrospective study that enrolled 75 patients who had stages IB2 to IVA cervical cancer, and who underwent RT alone or concurrent chemoradiation therapy (CCRT). All patients were treated at the department of Clinical Oncology of the University of Hong Kong-Shenzhen hospital between November 2015 and April 2020. The endpoint was treatment response assessed by magnetic resonance imaging (MRI) according to the Response EvaluationCriteria in Solid Tumors (RECIST). Multivariate logistic regression models were used to identify predicting values of peripheral blood inflammation indicators, including the systemic immune-inflammation index (SII), neutrophil/lymphocyte ratio (NLR), tumor-related leukocytosis (TRL), platelet/lymphocyte ratio (PLR) and monocyte/lymphocyte ratio (MLR). Results: The percentage of complete response (CR) was significantly different between different groups of peripheral blood inflammation indicators. The percentage of CR was 64.3%, 57.9%, 81.8% and 48.3% respectively in low SII, NLR, PLR and MLR groups, which was significantly higher than in the high SII group (34.0%), high NLR group (32.4%), high PLR group (30.2%) and high MLR group (35.3%). Multivariate logistic regression revealed that the TRL and PLR were significant prognostic factors for treatment response with an odds ratio of 0.18 (95% confidence interval [95% CI] 0.04–0.77) for TRL and 16.36 (95% CI 3.67–73.04) for PLR. Conclusions: The result revealed that a TRL-negative or lower PLR tumor was associated with radiosensitivity, which may provide important information for the prediction of treatment response in cervical cancer patients referred for RT.

Incorporating knowledge of disease-defining hub genes and regulatory network into a machine learning-based model for predicting treatment response in lupus nephritis after the first renal flare

BackgroundIdentifying candidates responsive to treatment is important in lupus nephritis (LN) at the renal flare (RF) because an effective treatment can lower the risk of progression to end-stage kidney disease. However, machine learning (ML)-based models that address this issue are lacking.MethodsTranscriptomic profiles based on DNA microarray data were extracted from the GSE32591 and GSE112943 datasets. Comprehensive bioinformatics analyses were performed to identify disease-defining genes (DDGs). Peripheral blood samples (GSE81622, GSE99967, and GSE72326) were used to evaluate the effect of DDGs. Single-sample gene set enrichment analysis (ssGSEA) scores of the DDGs were calculated and correlated with specific immunology genes listed in the nCounter panel. GSE60681 and GSE69438 were used to examine the ability of the DDGs to discriminate LN from other renal diseases. K-means clustering was used to obtain the separate gene sets. The clustering results were extended to data derived using the nCounter technique. The least absolute shrinkage and selection operator (LASSO) algorithm was used to identify genes with high predictive value for treatment response after the first RF in each cluster. LASSO models with tenfold validation were built in GSE200306 and assessed by receiver operating characteristic (ROC) analysis with area under curve (AUC). The models were validated by using an independent dataset (GSE113342).ResultsForty-five hub genes specific to LN were identified. Eight optimal disease-defining clusters (DDCs) were identified in this study. Th1 and Th2 cell differentiation pathway was significantly enriched in DDC-6. LCK in DDC-6, whose expression positively correlated with various subsets of T cell infiltrations, was found to be differentially expressed between responders and non-responders and was ranked high in regulatory network analysis. Based on DDC-6, the prediction model had the best performance (AUC: 0.75; 95% confidence interval: 0.44–1 in the testing set) and high precision (0.83), recall (0.71), and F1 score (0.77) in the validation dataset.ConclusionsOur study demonstrates that incorporating knowledge of biological phenotypes into the ML model is feasible for evaluating treatment response after the first RF in LN. This knowledge-based incorporation improves the model's transparency and performance. In addition, LCK may serve as a biomarker for T-cell infiltration and a therapeutic target in LN.

QEEG Predictors of Treatment Response in Major Depressive Disorder- A Replication Study from Northwest India.

Background: Predicting treatment response with antidepressant is a challenging task for clinicians and researchers. An important limitation of an antidepressant trial is the increased time spent before an adequacy of trial can be decided. Quantitative Electroencephalography has shown some evidence in identifying early changes seen with antidepressants. No data has been reported from Indian population on its predictive capabilities. Aim: To examine whether early changes in frontal and prefrontal theta value in QEEG could predict antidepressant treatment response. Methods: Structured clinical assessments were conducted at baseline and after one week in a sample of treatment-seeking adults with major depressive disorder (n = 50). Patients were started on SSRI (Escitalopram, fluoxetine, paroxetine or sertraline) and followed for 8 weeks. QEEG recordings were carried out at baseline and week 1 and its parameters (relative theta power and cordance) were assessed to identify its predictive value for treatment response. Treatment response was assessed using Hamilton depression rating scale with 50% reduction after 8 weeks being considered as response. Results: Mean age of the sample was 39 ± 10 years and majority of them were females (64%). A significant reduction was found in relative frontal theta value (p = 0.021) from baseline to one week in responders. However, linear regression revealed that this change could not predict the treatment response (p = 0.37). Conclusions: QEEG changes are observed in initial phase of antidepressant treatment but these changes can't predict the treatment response.

Systematic review of the use of CRP in clinical trials for psoriatic arthritis: a concern for clinical practice?

BackgroundC reactive protein (CRP) levels are suggested as serum biomarkers in the diagnosis and prognosis of psoriatic arthritis (PsA). However, increased CRP levels are found in less than 50% of...

P13.22 Menglia: an innovative approach to liquid biopsies in glioma patients

Abstract BACKGROUND Gliomas are the second most frequent primary brain tumor. Since 2016 gliomas are classified according to histological, and molecular features such as IDH status and 1p19q codeletion. Recently oncological research has focused on liquid biopsies to reduce the need for invasive diagnostic tests. Cerebrospinal fluid (CSF) is the principal source of brain tumor biomarkers. Modern technologies currently allow us to analyze proteomic and metabolomic tumor profiles, in order to find new biomarkers without being constrained by a priori hypothesis. Several data from the literature also suggests that inflammatory cells and cytokines in tumors contribute to tumor growth, progression and immunosuppression. The possibility of simultaneously testing different inflammatory molecules on the biological fluids could lead to the identification of new biological markers with prognostic and predictive value for treatment response. STUDY OBJECTIVES - Identification of protein and/or lipid biomarkers specific to the glioma subgroup among those under analysis. - Identification of tumor group- and subgroup-specific CSF and/or serum inflammatory biomarkers among those tested. - Correlation of biomarkers with Progression Free Survival (PFS), Overall Survival (OS). ELIGIBILITY CRITERIA - Patients with a radiological suspected diagnosis of glioma eligible for surgery. - Age ≥ 18 years. - Availability of histological samples, CSF, blood and urine. - Patients with unconfirmed histological diagnosis of glioma will be excluded. - Patients who have never received any systemic or local treatment for CNS diseases. STUDY DESIGN This is a prospective monocentric study involving mass spectrometry analysis for characterization of proteins and metabolites and ELISA analysis for the characterization of different cytokines in parallel anonymized biological samples consisting of tumor tissue, CSF, blood and urine from glioma patients, divided into three different molecular subtypes: 1p19q codelet/IDH mutated, 1p19q non-codelet/IDH mutated and 1p19q non-codelet/IDH wt. Biological samples will be taken at surgery, at 24–48 h after surgery and every 3 months up to 1 year. The control group will include patients with subarachnoid hemorrhage or hydrocephalus, either undergoing external ventricular shunting or undergoing ventricular catheter placement/revision surgery. STUDY ANALYSIS Data interpretation will be based on a statistical analysis of the data, applying tools such as Principal Component Analysis (PCA) Weighted Correlation Network Analysis (WGNCA), Multiple Venn Diagram, T-Test, ANOVA, Clustering and Gene Ontology Enrichment, non-parametric Mann-Whitney test. For the assessment of clinical outcome, survival curves will be compared between different groups of patients who share a similar protein/metabolomic/inflammatory profile.

Can treatment response to SGLT2-inhibitors in syndrome of inappropriate antidiuresis be predicted by copeptin, natriuretic peptides and inflammatory markers?

Purpose The syndrome of inappropriate antidiuresis (SIAD) is the main cause of hyponatremia and the SGLT2-inhibitor empagliflozin is a promising new treatment option. A biomarker predicting treatment response could optimize treatment success. Materials and methods Secondary analysis of a trial including 84 hospitalized patients with SIAD-induced hyponatremia. Patients were randomized to four days of treatment with empagliflozin 25 mg/d (n = 43) or placebo (n = 41) with both groups receiving fluid restriction <1000 ml/d. Baseline levels of copeptin, the natriuretic peptides MR-proANP and NT-proBNP and C-reactive protein (CRP) were evaluated as predictors for treatment response defined as absolute sodium change, using linear regression models. Additionally, urinary sodium was assessed as predictor for non-response to fluid restriction alone by constructing the receiver-operating characteristic (ROC) curve. Results No clinically relevant predictive value for treatment response to empagliflozin could be found for copeptin, MR-proANP, NT-proBNP or CRP. A urinary sodium cut-off of >76 mmol/l led to a specificity of 91.7% [95% confidence interval (CI): 75%, 100%] and sensitivity of 51.9% [33.3%, 70.4%] to predict non-response to fluid restriction alone. Conclusions Based on our data, no biomarker could be identified as predictor for treatment response to empagliflozin. Urinary sodium was confirmed as a good marker for non-response to fluid restriction in SIAD patients. Clinical trial registration: ClinicalTrials.gov (Number: NCT02874807)

Amino Acid Substitutions Associated with Treatment Failure for Hepatitis C Virus Infection.

Despite the high virological response rates achieved with current directly acting antiviral agents (DAAs) against hepatitis C virus (HCV), around 2% to 5% of treated patients do not achieve a sustained viral response. The identification of amino acid substitutions associated with treatment failure requires analytical designs, such as subtype-specific ultradeep sequencing (UDS) methods, for HCV characterization and patient management. Using this procedure, we have identified six highly represented amino acid substitutions (HRSs) in NS5A and NS5B of HCV, which are not bona fide resistance-associated substitutions (RAS), from 220 patients who failed therapy. They were present frequently in basal and posttreatment virus of patients who failed different DAA-based therapies. Contrary to several RAS, HRSs belong to the acceptable subset of substitutions according to the PAM250 replacement matrix. Their mutant frequency, measured by the number of deep sequencing reads within the HCV quasispecies that encode the relevant substitutions, ranged between 90% and 100% in most cases. They also have limited predicted disruptive effects on the three-dimensional structures of the proteins harboring them. Possible mechanisms of HRS origin and dominance, as well as their potential predictive value for treatment response, are discussed.

A predictive model for treatment response in patients with locally advanced esophageal squamous cell carcinoma after concurrent chemoradiotherapy: based on SUVmean and NLR

BackgroundWe conducted this study to combine the mean standardized uptake value (SUVmean) and neutrophil to lymphocyte ratio (NLR) to establish a strong predictive model for patients with esophageal squamous cell carcinoma (ESCC) after concurrent chemoradiotherapy (CCRT).MethodsWe retrospectively analyzed 163 newly diagnosed ESCC patients treated with CCRT. Eighty patients (training set) were randomly selected to generate cut-off SUVmean and NLR values by receiver operating characteristic (ROC) curve analysis and to establish a predictive model by using the independent predictors of treatment outcomes. Then, we evaluated the performance of the prediction model regarding treatment outcomes in the testing set (n = 83) and in all sets.ResultsA high SUVmean (> 5.81) and high NLR (> 2.42) at diagnosis were associated with unfavorable treatment outcomes in patients with ESCC. The prediction model had a better performance than the simple parameters (p < 0.05). With a cut-off value of 0.77, the prediction model significantly improved the specificity and positive predictive value for treatment response (88.9 and 92.1% in the training set, 95.8 and 97.1% in the testing set, and 92.2 and 91.8% in all sets, respectively).ConclusionsThe pretreatment SUVmean and NLR were independent predictors of treatment response in ESCC patients treated with CCRT. The predictive model was constructed based on these two parameters and provides a highly accurate tool for predicting patient outcomes.

AR-V7 Protein Expression in Circulating Tumour Cells Is Not Predictive of Treatment Response in mCRPC

Introduction: Androgen receptor variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC) and has shown potential as a predictive biomarker in circulating tumour cells (CTCs) isolated from the bloodstream in terms of a liquid biopsy. Studies have shown that AR-V7 is a potential surrogate for selecting drug classes for systemic treatment by detecting nuclear AR-V7 by immunofluorescence or measuring AR-V7 messenger RNA by quantitative PCR. Here, we assessed the predictive value of AR-V7 detected by classical immunohistochemistry (IHC) for treatment response. Methods: CTCs were isolated by cell separation by density gradient centrifugation from patients with metastatic CRPC (n = 26) before, while, and after undergoing a new therapy with chemotherapy (cabazitaxel or docetaxel) or antiandrogen (enzalutamide or abiraterone). CTCs were sequentially cytospun on object slides, and AR-V7 status was then detected by IHC based on a staining regime established on a 22Rv1 cell line with antibodies against CK8/18 und AR-V7. Results: AR-V7 status detected by IHC showed no predictive value for progression-free survival (PFS). Kaplan-Meier analysis revealed that there was no difference in PFS between patients found positive or negative for AR-V7. Discussion/Conclusion: AR-V7 detected by classical IHC has no predictive value for treatment response in the described setting. The future role of AR-V7 in CTCs as a biomarker in clinical routine remains elusive.

Albumin-bilirubin score is associated with response to pegylated interferon and nucleos(t)ide analogues in chronic hepatitis B patients

Background and aimRecently, the role of albumin-bilirubin (ALBI) score in chronic hepatitis B (CHB) has not been well-understood. We aimed to investigate the association of ALBI score with natural history of chronic HBV infection and treatment response of CHB patients. MethodsThe ALBI score in a cohort of 849 individuals including 721 chronic HBV-infected patients naïve to anti-HBV treatment in different phases and 128 healthy controls were estimated. Additionally, the dynamic changes of ALBI score of 243 hepatitis B e antigen (HBeAg)-positive CHB patients treated with pegylated interferon-alpha (PEG-IFN-α) or nucleos(t)ide analogues (NAs) were tested for 72 weeks. ResultsALBI score differed among phases, with the highest score in HBeAg-positive CHB patients, followed by HBeAg-negative CHB patients, HBeAg-positive chronic HBV infection, and HBeAg-negative chronic HBV infection. Besides, CHB patients harbouring high baseline ALBI score exhibited a relatively stronger therapeutic response to PEG-IFN-α or NAs. Moreover, the rate of HBeAg and HBsAg loss in patients with ALBI grade 2 was persistently higher than that in patients with ALBI grade 1 throughout the course of treatment. Furthermore, ALBI score was an independent predictor of sustained response achievement. The combined use of ALBI score, HBeAg and ALT could enhance the predictive value of treatment response. ConclusionsALBI score differed significantly across the natural course of chronic HBV infection and was correlated with PEG-IFN-α and NAs treatment response in HBeAg-positive CHB patients, which suggested that ALBI score could be useful as an auxiliary clinical factor to determine the initiation of therapy and predict stronger antiviral treatment response.

CXCR4-Targeted Positron Emission Tomography Imaging of Central Nervous System B-Cell Lymphoma

Introduction Central nervous system lymphoma (CNSL) is a rare neoplasia and arises as primary (PCNSL) or secondary CNSL (SCNSL) and most commonly occurs as diffuse large B-cell lymphoma. Although prognosis of this disease has significantly improved due to advantages in diagnostic procedures and intensification of treatment over the last decade there remain major challenges in the clinical management. Magnetic resonance imaging (MRI) - as the standard imaging modality - has difficulties to discriminate CNSL from other brain-derived tumors or metastasis. Moreover, prognostic scores in CNSL lack the ability to reliable define patients with high relapse risk 1. Therefore, novel strategies to facilitate diagnosis and to select patients that profit from intense treatment protocols are urgently needed. The C-X-C chemokine receptor 4 (CXCR4) is a transmembrane chemokine receptor with pivotal roles in cell homing and is often overexpressed in hematologic malignancies. CXCR4-directed positron emission tomography (PET) imaging with the tracer [68Ga]Pentixafor has been proven to be a suitable in vivo imaging modality for CXCR4 expression in lymphoid malignancies 2. To evaluate the feasibility of CXCR4-directed PET and the prognostic value of this imaging modality this retrospective proof-of-concept study evaluated [68Ga]Pentixafor PET imaging in patients with CNSL. Methods 11 patients with lymphoma of the CNS (n=8 PCNSL, n=3 SCNSL) were imaged with the CXCR4-directed PET tracer [68Ga]Pentixafor in this retrospective proof-of-concept study after signing inform consent. Lymphoma tissue was assessed for CXCR4 expression ex vivo by immunohistochemistry. The prognostic value of CXCR4-directed PET imaging was evaluated in a computed analysis in 7 patients with follow-up MRI. Treatment response calculated as treatment efficiency η by sequential MRI was correlated with [68Ga]Pentixafor PET derived parameters at diagnosis such as volume of PET positive lymphoma lesion V(PET), maximal PET uptake value within the lesion max(PET) or integrated uptake values over the lymphoma lesion ∫(PET). Analysis was performed in a lesion- and patient-based manner. Results [68Ga]Pentixafor PET imaging was positive in all patients with active disease (10/11 patients) with excellent contrast characteristics to the surrounding brain parenchyma. PET positive lesions correlated well with lymphoma lesions in MRI-T1c sequences. The surrounding edema depicted in MRI-FLAIR sequences was evaluated as PET negative (Figure 1). Semi-quantitative analysis revealed maximum standard uptake values of [68Ga]Pentixafor-derived PET from 4.2 to 23.3 within the lesions with a high tumor-to-background-ratio ranging from 13.2 to 83.0. The computed analysis revealed that CXCR4-directed PET parameters at diagnosis given by max(PET) and ∫(PET) significantly correlated with treatment response in the lesion-based as well as in the patient-based analysis. Specifically, ∫(PET) was the most significant prognostic factor in the present study (Figure 2 C, D, F). On the other hand tumor volume at diagnosis measured either by MRI or by [68Ga]Pentixafor PET did not denote a predictive marker for treatment response (Figure 2 A, B, E). Conclusion/Outlook CXCR4-directed PET imaging represents a novel imaging modality for CNSL. Due to its excellent contrast properties it might help to facilitate diagnosis and refine response assessment. Moreover, owing the predictive value for treatment response, CXCR4-directed PET could serve as a biomarker for the selection of patients profiting from intense treatment protocols. Furthermore, the feasibility of endoradiotherapeutic approaches targeting CXCR4 with Pentixather - the therapeutic twin of the imaging peptide Pentixafor - has been shown in hematologic malignancies and could be incorporated in the treatment of CNSL.

Predictive Value of Slow and Fast EEG Oscillations for Methylphenidate Response in ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder and is characterized by symptoms of inattention and/or hyperactivity and impulsivity. In the current study, we obtained quantitative EEG (QEEG) recordings of 51 children aged between 6 and 12 years before the initiation of methylphenidate treatment. The relationship between changes in the scores of ADHD symptoms and initial QEEG features (power/power ratios values) were assessed. In addition, the children were classified as responder and nonresponder according to the ratio of their response to the medication (>25% improvement after medication). Logistic regression analyses were performed to analyze the accuracy of QEEG features for predicting responders. The findings indicate that patients with increased delta power at F8, theta power at Fz, F4, C3, Cz, T5, and gamma power at T6 and decreased beta powers at F8 and P3 showed more improvement in ADHD hyperactivity symptoms. In addition, increased delta/beta power ratio at F8 and theta/beta power ratio at F8, F3, Fz, F4, C3, Cz, P3, and T5 showed negative correlations with Conners' score difference of hyperactivity as well. This means, those with greater theta/beta and delta/beta powers showed more improvement in hyperactivity following medication. Theta power at Cz and T5 and theta/beta power ratios at C3, Cz, and T5 have significantly classified responders and nonresponders according to the logistic binary regression analysis. The results show that slow and fast oscillations may have predictive value for treatment response in ADHD. Future studies should seek for more sensitive biomarkers.

Long non-coding RNA taurine-upregulated gene 1 correlates with unfavorable prognosis in patients with refractory or relapsed acute myeloid leukemia treated by purine analogue based chemotherapy regimens.

This study aimed to explore the correlation of long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) expression with clinicopathological features and its predictive value for treatment response and survival profiles in refractory or relapsed acute myeloid leukemia (R/R AML) patients. Seventy three R/R AML patients who received cladribine combined with cytarabine and granulocyte colony-stimulating factor (G-CSF) (CLAG) or fludarabine combined with cytarabine and G-CSF (FLAG) based chemotherapy and 37non-malignant controls were recruited. LncRNA TUG1 expression was detected in bone marrow sample obtained before treatment. Complete response (CR), partial response (PR), overall response rate (ORR) and overall survival (OS) were evaluated. LncRNA TUG1 expression was upregulated in R/R AML patients compared to controls. It was also elevated in R/R AML patients with age ⩾ 60 years (vs. age < 60years, P= 0.030) and in patients with secondary AML (vs. primary AML, P= 0.035). R/R AML patients with lncRNA TUG1 high expression achieved numerically lower CR (P= 0.053), decreased ORR (P= 0.028) and shorter OS (P< 0.001) than patients with lncRNA TUG1 low expression. Univariate logistic regression and COX's regression disclosed that lncRNA TUG1 high expression correlated with declined ORR, numerically decreased CR, and reduced OS. Furthermore, multivariate analyses verified that lncRNA TUG1 high expression was an independent predictive factor for decreased ORR and worse OS. In conclusion, lncRNA TUG1 expression was elevated in R/R AML patients, and it might serve as a potential biomarker for poor prognosis in R/R AML patients treated with CLAG or FLAG based chemotherapy.