Early Indicator Of Response Research Articles

Reduced blood flow by laser speckle flowgraphy after 125I-plaque brachytherapy for uveal melanoma

BackgroundTo determine whether reductions in retinal and choroidal blood flow measured by laser speckle flowgraphy are detected after 125I-plaque brachytherapy for uveal melanoma.MethodsIn a cross-sectional study, retinal and choroidal blood flow were measured using laser speckle flowgraphy in 25 patients after treatment with 125I-plaque brachytherapy for uveal melanoma. Flow was analyzed in the peripapillary region by mean blur rate as well as in the entire image area with a novel superpixel-based method. Relationships between measures were determined by Spearman correlation.ResultsSignificant decreases in laser speckle blood flow were observed in both the retinal and choroidal vascular beds of irradiated, but not fellow, eyes. Overall, 24 of 25 patients had decreased blood flow compared to their fellow eye, including 5 of the 6 patients imaged within the first 6 months following brachytherapy. A significant negative correlation between blood flow and time from therapy was present.ConclusionsDecreases in retinal and choroidal blood flow by laser speckle flowgraphy were detected within the first 6 months following brachytherapy. Reduced retinal and choroidal blood flow may be an early indicator of microangiographic response to radiation therapy.

Abstract 5748: Longitudinal evaluation of ctDNA molecular response for monitoring clinical benefit and investigating treatment related impacts in metastatic colorectal cancer patients treated with different drug regimens

Abstract Introduction: The patient-centric liquid biopsy approach to detect changes in ctDNA provides an early indication of treatment response to therapies and is an emerging tool to aid clinicians in treatment decision making. We investigated this approach in the mCRC palliative treatment setting by exploring the potential clinical utility of the validated Guardant Health Molecular Response (MR) algorithm. Methods: Longitudinal plasma samples (70) were collected from 14 patients with mCRC and treated using chemotherapy alone or combined with one or more targeting agents. All patients were clinically stable or had clinical benefit over the course of plasma collection. 6 patients had radiological response by RECISTv1.1 and 10 had tumor RAS/RAF mutation status. Baseline and longitudinal plasma samples (27-276 days post treatment) were tested by GuardantOMNI® 500-gene liquid biopsy assay. Selection of qualifying alterations and generation of MR scores were pursued using the Guardant Health MR algorithm. Results: Thirteen patients were evaluable for MR by having somatic alterations at each timepoint that exceeded the molecule threshold required for reliable MR score calculation. Mean variant allele fraction (mVAF) of all plasma samples outside the 4-10 week on-treatment window trended in the same direction as the early on-treatment plasma samples when compared to baseline. Eleven patients experienced a consistent reduction in mVAF compared to baseline. One outlier showed a mVAF increase at the earliest on-treatment timepoint, followed by molecular clearance at all subsequent timepoints. GuardantOMNI® detected a frameshift APC alteration at the baseline of this patient, which may have limited the tumor response to the chemotherapy. The second outlier patient was originally diagnosed as RAS/RAF wild-type and treated with anti-EGFR and anti-PD-L1. MR scores for this patient across all timepoints reflected an increase in mVAF compared to baseline. Notably, GuardantOMNI® detected a low level KRAS alteration in the baseline plasma sample of this patient, indicating this patient’s disease had elements of KRAS alteration that were not detected by tissue-based testing. All 6 patients with RECIST 1.1 information had partial responses (PR) and 5 showed a decrease in the MR score. The one patient whose MR score did not align with radiographic assessment was the mis-genotyped KRAS mutation-positive patient, who is under further investigation. Conclusions: We demonstrate that ctDNA analysis of plasma samples taken at early timepoints (4-10 weeks) after treatment initiation are sufficient to support MR assessments and highlight the advantage of the patient-centric liquid biopsy approach over genetic testing of diagnostic tumor samples in detecting potential resistance mutations prior to therapy. Citation Format: Neil R. Smith, Jean-Christophe Pignon, Scott A. Shell, Arialle Yablonovitch, Juergen Scheuenpflug, Zheng Feng. Longitudinal evaluation of ctDNA molecular response for monitoring clinical benefit and investigating treatment related impacts in metastatic colorectal cancer patients treated with different drug regimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5748.

Abstract LB057: Bevacizumab leaves a photoacoustic fingerprint in breast cancer mouse models

Abstract Background: Photoacoustic tomography (PAT) provides a direct readout of tumor haemoglobin (Hb) concentration and oxygenation. This readout could be used to provide an early indication of response to anti-angiogenic drugs, thus optimizing the management of these therapies. Experimental Procedures: Two cohorts of nude Balb/c were inoculated with either estrogen-dependent MCF-7 (n=7) or estrogen-independent MDA-MB-231 (n=19) cells. Mice were randomly split into Control (Ctrl) and Bevacizumab (Bev,10 mg/Kg, IP, weekly) groups. PAT was performed weekly, starting just before enrolment. Oxy- and deoxy-Hb were quantified in the tumour and reference areas. Total Hb (THb) and O2 saturation (SO2) were calculated. Blood samples and tissues were collected after imaging. Hypoxia (Hypoxyprobe and CA-IX) and vascular density/maturity (CD31 and ASMA) were analyzed by immunohistochemistry. Circulating levels of human and mouse vascular endothelial growth factor (hVEGF and mVEGF) and Hb were measured. Summary of New Data: Reflecting clinical observations, the MCF-7 Bev group and most of the mice from the MDA-MB-231 Bev group (8/11) showed no improvement in survival with Bev treatment. All resistant tumours (Bev MCF-7 and Bev MDA-MB-231 non-responders (Bev-NR)) showed an increase in hVEGF production (Ctrl vs Bev; 73.0513.06 vs. 497103.9 for MCF-7; 247.984.81 vs. 330.4 85.97 for Bev NR). MDA-MB-231 responders (Bev-R) showed a significant decrease in hVEGF (247.984.81 vs. 80.53 26.13). These results indicate that VEGF was only successfully sequestered in a small subset of animals (3/11) and that VEGF overload might be a resistance mechanism. At the final time point, PAT showed no difference between Ctrl and Bev-NR in THb for either group (THbMDA-MB-231 7.2±1.3 vs. 5.5±1.2). THb was found significantly increased in the Bev-R group by PAT (13.9±3.3 p-valuevs.Crtl=0.0339; p-valuevs.Bev=0.0072) and biochemical measurements. SO2 showed a slight but significant decrease between Ctrl and Bev-NR (0.58±0.03 vs. 0.48±0.01). A dramatic decrease was seen in the Bev-R group (0.31±0.07) and significantly different from Ctrl and Bev-NR. SO2 was sensitive to early changes, SO2 values increased in Ctrl and Bev-NR 48h after enrolment (p-values paired t-test pCtrl= 0.0134; pNR=0.0268) while Bev-R shows a trend (p=0.0649). Analysis of SO2MSOT over time shows a significant (p<0.0001) change in slope at 3 weeks after enrolment in the Bev-R group compared to either of the Ctrl or Bev-NR groups. Our results indicate that PAT SO2 can differentiate responders at very early stages of the treatment. Histologically, we observed fewer blood vessels but better structured in Bev-NR than in Bev-R, which showed higher vascular density and also higher levels of hypoxia makers. Statement of the Conclusions: Our results postulates PAT as a low-cost, label-free and non-invasive candidate to monitor response to Bevacizumab over time. Our results also indicate that tumours with functional vasculature may be resistant to Bevacizumab treatment. Citation Format: Isabel Quiros-Gonzalez, Michal R. Tomaszewski, Monika A. Golinska, Emma Brown, Laura Ansel-Bollepalli, Lina Hacker, Dominique-Laurent Couturier, Rosa M. Sainz, Sarah E. Bohndiek. Bevacizumab leaves a photoacoustic fingerprint in breast cancer mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB057.

Serum thymidine kinase 1 and its kinetics in HER2-positive breast cancer: Results from the Swedish phase II PREDIX HER2 trial.

e12598 Background: Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in HER2-negative early and metastatic breast cancer (BC). Here we present the first report of TK1 in HER2-postitive BC. Methods: In the PREDIX HER2 trial, 202 patients with HER2-positive BC were randomized to 6 cycles of neoadjuvant trastuzumab, pertuzumab and docetaxel or trastuzumab emtansine every three weeks followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum was prospectively collected from all participants at multiple timepoints: At baseline, after cycles 2, 4 and 6, at end of adjuvant therapy and then annually for 5 years and in case of recurrence. TK1 activity was measured by DiviTum assay (Biovica, Sweden), blinded to treatment allocation, patient characteristics and outcome. TK1 activity was correlated with baseline characteristics, pathologic complete response (pCR) and event-free survival (EFS). Results: Baseline TK1 activity as categorical variable was not associated with tumor size or hormone receptor expression. An increase of TK1 activity was seen in the majority of cases after treatment (mean TK1 at baseline = 111.7, after cycle 2 = 1257.0, after cycle 4 = 1157.0, after cycle 6 = 1178.0). Neither baseline TK1, on-treatment TK1 nor its change from baseline to cycle 2 were significantly associated with pCR in multivariable logistic regression analysis (Table). Baseline TK1 activity was not predictive for differential benefit to the study treatments ( pinteraction = 0.19). After a median follow-up of 52.5 months, 21 patients had EFS events. There was no significant correlation between baseline TK1 activity and EFS in multivariable Cox regression analysis. Conclusions: Serum TK1 activity in HER2-positive BC increased following treatment with neoadjuvant therapy but was not correlated to pCR rates or EFS. [Table: see text]

Symptom Improvement of ulceRative colitis after an Induction dose of UStekinumab in Japanese clinical practice (SIRIUS), measured using patient-reported outcomes: a prospective observational study

IntroductionUlcerative colitis (UC) is an idiopathic, chronic inflammatory disease of the large intestine. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12 and interleukin-23 and has proven efficacy...

A prediction study of IL-18 and IFN-γ in glucocorticoid treatment response in infants and young children with severe Mycoplasma pneumoniae pneumonia.

BackgroundIn infants and young children, the clinical decision to apply glucocorticoids to severe Mycoplasma pneumoniae pneumonia (SMPP) is more an empirical choice with reference to clinical symptoms, but the effect is not satisfying. We aimed to explore and identify early predictive indicators of ideal response to glucocorticoids treatment in SMPP in infants and young children.MethodsWe retrospectively reviewed the data of 59 patients, which met the age range and diagnostic criteria, admitted to Department of Pediatrics, the Sixth People’s Hospital Affiliated to Shanghai Jiaotong University, from January to December 2017. Patients were divided into a glucocorticoid treatment group and a normal treatment group according to whether glucocorticoid treatment was used, and the difference in therapeutic effectiveness was compared between two groups. The glucocorticoid treatment group was further subdivided into effective versus ineffective treatment groups dependent on the difference of glucocorticoid treatment effect in main clinical symptoms improvement. We obtained the test value of biomarkers by ELISA, and identified several specific indicators with significantly different expressions in the early stage by independent sample t-tests and calculated their cut-off values by ROC curve.ResultsThirty-one SMPP patients who received glucocorticoid treatment were divided into effective and ineffective treatment groups according to the clinical improvements shown on different days of glucocorticoid use. The expression of two markers, interleukin-18 (IL-18) and interferon-γ (IFN-γ), were significantly different in cases showing improvement in the early stage of SMPP (P<0.05), and the cut-off values for IL-18 (218.19 pg/mL, AUC =0.581, sensitivity =0.909, 1-specificity =0.786) and IFN-γ (11.24 pg/mL, AUC =0.566, sensitivity =0.905, 1-specificity =0.795) were identified.ConclusionsThe expressions of IL-18 and IFN-γ in the early stage of SMPP might suggest their predictive effect of early application of glucocorticoid for effective treatment of SMPP in infants and young children. Further study with larger sample size will be carried on in the future.

Photoacoustic Tomography Detects Response and Resistance to Bevacizumab in Breast Cancer Mouse Models.

Photoacoustic assessment of tumor oxygenation is a noninvasive early indicator of response to bevacizumab therapy, clearly distinguishing between control, responding, and resistant tumors within just a few weeks of treatment.

Vitiligo-specific soluble biomarkers as early indicators of response to immune checkpoint inhibitors in metastatic melanoma patients

Immunotherapy with checkpoint inhibitors (CPIs) strongly improved the outcome of metastatic melanoma patients. However, not all the patients respond to treatment and identification of prognostic biomarkers able to select responding patients is currently of outmost importance. Considering that development of vitiligo-like depigmentation in melanoma patients represents both an adverse event of CPIs and a favorable prognostic factor, we analyzed soluble biomarkers of vitiligo to validate them as early indicators of response to CPIs. Fifty-seven metastatic melanoma patients receiving CPIs were enrolled and divided according to the best overall response to treatment. Patient sera were evaluated at pre-treatment and after 1 and 3 months of therapy. We found that basal CD25 serum levels were higher in stable and responding patients and remained higher during the first 3 months of CPI therapy compared to non-responders. CXCL9 was absent in non-responding patients before therapy beginning. Moreover, an increase of CXCL9 levels was observed at 1 and 3 months of therapy for all patients, although higher CXCL9 amounts were present in stable and responding compared to non-responding patients. Variations in circulating immune cell subsets was also analyzed, revealing a reduced number of regulatory T lymphocytes in responding patients. Altogether, our data indicate that a pre-existing and maintained activation of the immune system could be an indication of response to CPI treatment in melanoma patients.

The Predictive Role of Serum Levels of Soluble Cell Adhesion Molecules (sCAMs) in the Therapy of Advanced Breast Cancer-A Single-Centre Study.

Background and Objectives: Soluble cell adhesion molecules (sCAMs) play a significant role in the metastatic potential of breast cancer (BC). They might block lymphocytes and promote angiogenesis and migration of cancer cells. We assessed the usefulness of sCAMs in the prognosis and monitoring of the progression of advanced BC. Materials and Methods: We assessed soluble E-selectin, P-selectin, VCAM-1, ICAM-1, EpCAM, IL-6Ra, TNF-R1, and TNF-R2 in 39 women with aBC. Blood samples were obtained at the beginning of the treatment and after 2 months. Results: The median progression-free survival (PFS) was 9 months, and overall survival (OS) was 27 months. The higher levels of sICAM-1 (HR = 2.60, p = 0.06) and lower levels of sEpCAM (HR = 2.72, p < 0.05) were associated with faster progression of aBC. High levels of sEpCAM through the follow-up period were significantly associated with a lower risk of progression (HR = 0.40, p < 0.01). We found the independent predictive value of higher than median sICAM-1 levels for PFS (HR = 2.07, p = 0.08) and of sVCAM-1 levels for OS (HR = 2.59, p < 0.05). Conclusions: Our data support the predictive value of sICAM-1 and sVCAM-1 and suggest that they could become markers for tailoring new therapies in aBC. sEpCAM level could be used as an early indicator of response to the therapy.

Hyperpolarized Micro-NMR Platform for Sensitive Analysis of In Vitro Metabolic Flux in Living Cells.

Metabolism represents an ensemble of cellular biochemical reactions, and thus metabolic analyses can shed light on the state of cells. Metabolic changes in response to external cues, such as drug treatment, for example, can be rapid and potentially an early indicator of therapeutic response. Unfortunately, conventional techniques to study metabolism, such as optical microscopy or mass spectrometry, have functional limitations in specificity and sensitivity. To address this technical need, we developed a sensitive analytical tool based on nuclear magnetic resonance (NMR) technology, termed hyperpolarized micro-NMR, that enables rapid quantification of multiple metabolic fluxes in a small number of cells, down to 10,000 cells, nondestructively. This analytical capability was achieved by miniaturization of an NMR detection coil along with hyperpolarization of endogenous metabolites. Using this tool, we were able to quantify pyruvate-to-lactate flux in cancer stem cells nondestructively within 2min, which has not been possible with other techniques. With further optimization, we envision that this novel device could be a powerful analytical platform for sensitive analysis of metabolism in mass-limited samples.

Feasibility and First Results of Heart Failure Monitoring Using the Wearable Cardioverter-Defibrillator in Newly Diagnosed Heart Failure with Reduced Ejection Fraction.

The wearable cardioverter–defibrillator (WCD) is used in patients with newly diagnosed heart failure and reduced ejection fraction (HFrEF). In addition to arrhythmic events, the WCD provides near-continuous telemetric heart failure monitoring. The purpose of this study was to evaluate the clinical relevance of additionally recorded parameters, such as heart rate or step count. We included patients with newly diagnosed HFrEF prescribed with a WCD. Via the WCD, step count and heart rate were acquired, and an approximate for heart rate variability (HRV5) was calculated. Multivariate analysis was performed to analyze predictors for an improvement in left ventricular ejection fraction (LVEF). Two hundred and seventy-six patients (31.9% female) were included. Mean LVEF was 25.3 ± 8.5%. Between the first and last seven days of usage, median heart rate fell significantly (p < 0.001), while median step count and HRV5 significantly increased (p < 0.001). In a multivariate analysis, a delta of HRV5 > 23 ms was an independent predictor for LVEF improvement of ≥10% between prescription and 3-month follow-up. Patients with newly diagnosed HFrEF showed significant changes in heart rate, step count, and HRV5 between the beginning and end of WCD prescription time. HRV5 was an independent predictor for LVEF improvement and could serve as an early indicator of treatment response.

Tumor mutation burden is correlated with response and prognosis in microsatellite-stable (MSS) gastric cancer patients undergoing neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NACT) before radical gastrectomy is preferred for locally advanced gastric cancer (GC). However, clinical practices demonstrate that a considerable proportion of GC patients do not benefit from NACT, largely due to the lack of biomarkers for patient selection and prognosis prediction. A recent study revealed that patients with microsatellite instability-high (MSI-H) may be resistant to NACT, however, most tumors in Chinese GC patients (~ 95%) are characterized by microsatellite stability (MSS). Here, we aimed to discover new molecular biomarkers for this larger population. We performed whole-exome sequencing on 46 clinical samples (pre- and post-treatment) from 30 stage II/III MSS GC patients whose response to NACT was rigorously defined. Serum tumor markers (TMs), including AFP, CEA, CA199, CA724 and CA242 were measured during the course. High tumor mutation burden (TMB-H) and 19q12 amplification (19q12 +) were positively associated with the NACT response. When TMB and 19q12 amplification were jointly analyzed, those with TMB-H or 19q12 + showed favorable response to NACT (p = 0.035). Further, TMB-H was negatively correlated with ypN stage, lymph node metastasis, and macrophage infiltration. Patients with TMB-H showed better disease-free survival (DFS) than those with TMB-L (P = 0.025, HR = 0.1331), and this was further validated using two larger GC datasets: TCGA-STAD (p = 0.004) and ICGC-CN (p = 0.045). The combination of TMB-H and 19q12 + can serve as an early indicator of response to NACT. Superior to traditional clinical indicators, TMB-H is a robust and easily accessible candidate biomarker associated withbetter DFS, and can be evaluated at the time of diagnosis.

Machine Learning Establishes Single-Cell Calcium Dynamics as an Early Indicator of Antibiotic Response.

Changes in bacterial physiology necessarily precede cell death in response to antibiotics. Herein we investigate the early disruption of Ca2+ homeostasis as a marker for antibiotic response. Using a machine learning framework, we quantify the temporal information encoded in single-cell Ca2+ dynamics. We find Ca2+ dynamics distinguish kanamycin sensitive and resistant cells before changes in gross cell phenotypes such as cell growth or protein stability. The onset time (pharmacokinetics) and probability (pharmacodynamics) of these aberrant Ca2+ dynamics are dose and time-dependent, even at the resolution of single-cells. Of the compounds profiled, we find Ca2+ dynamics are also an indicator of Polymyxin B activity. In Polymyxin B treated cells, we find aberrant Ca2+ dynamics precedes the entry of propidium iodide marking membrane permeabilization. Additionally, we find modifying membrane voltage and external Ca2+ concentration alters the time between these aberrant dynamics and membrane breakdown suggesting a previously unappreciated role of Ca2+ in the membrane destabilization during Polymyxin B treatment. In conclusion, leveraging live, single-cell, Ca2+ imaging coupled with machine learning, we have demonstrated the discriminative capacity of Ca2+ dynamics in identifying antibiotic-resistant bacteria.

Development of Composite Indicators of Cyclical Response in Business Surveys

The article proposes a new set of composite indicators-predictors in business tendency surveys, which allow identifying early information signals of a cyclical nature in the economic behavior of business agents. The main criterion for the efficiency of such indicators is their sensitivity to a cyclical pattern and changes in the dynamics of statistical referents. Property such as a statistically significant lead in time series or earlier publication allows them to be combined into indicators of early response. The composite Business Activity Indicator (BAI) in the basic sectors of the Russian economy is calculated by the authors for the first time based on the results of regular (monthly and quarterly) business surveys of Rosstat for 1998–2020 with a large-scale coverage of sampling units. In 2020, the number of survey respondents averaged about 20,000 organizations of all sizes. The index reflects the «common» profile in the dynamics of short-term fluctuations of the key parameters of the economic environment, which consists of the «balances of opinions» of respondents to the questions unified for all sectoral surveys and connected with the reference quantitative statistics with cross-correlation coefficients that are statistically significantly different from zero, with a lead at least one quarter. This is its main difference from the well-known indices of economic sentiment and entrepreneurial confidence. The main components of the BAI are the new composite indices of real demand, current output, real employment, total profits and economic situation. They aggregate the relevant «order» statistics for the basic sectors of the national economy, including the main kinds of industrial activities, retail trade, construction, and services.The article provides a methodological substantiation and an extended procedure for identifying the BAI components; their composition is formed for the entire set of retrospective results of business tendency monitoring in Russia. A new Aggregate Economic Vulnerability Indicator with a counterdirectional profile and varying degrees of symmetry of its dynamics relative to the short-term movement of the BAI is being introduced as the main limitation of business activity. Proactive monitoring of emerging vulnerabilities in the business environment is necessary to warn their large-scale accumulation, prevent the risks of economic downturns and ensure the highest possible macroeconomic stability. This integrated approach makes it possible to determine the novelty of the proposed measurements of short-term cyclical fluctuations in economic development.

O07 The increase in erythrocyte mean corpuscular volume by methotrexate is potentiated by hydroxychloroquine and is an early indicator of clinical response in rheumatoid arthritis

Background/Aims Rheumatologists are facing a significant challenge in the management of early rheumatoid arthritis (RA) due to limitations placed on outpatient visits during the COVID-19 pandemic. Frequent clinical assessments of disease activity are recommended during implementation of the treat to target strategy to achieve remission. A biomarker indicating response to methotrexate during the early phase of therapy could complement clinical examination. Methotrexate increases erythrocyte mean corpuscular volume (MCV), which is measured routinely, prompting us to investigate whether changes in MCV could act as an early indicator of response. Methods Patients with early RA who were started on methotrexate therapy were included from two independent cohorts. The larger cohort (discovery cohort, n = 655) was used to build the model and the second cohort (validation cohort, n = 225) was applied to test the prediction of the model. Conventional statistical, and machine learning approaches were adopted to identify key determinants that influence the potential relationship between MCV and clinical response, defined as attainment of remission or low disease activity, at six months after starting methotrexate. Results A LASSO penalised logistic regression model was built with the discovery cohort [area under the receiver operating characteristics (AUROC) curve = 0.76], where change of MCV from three months [Odds ratio (OR) 1.53 (95% CI 1.38-1.70)], concomitant use of hydroxychloroquine [OR 2.16 (95% CI 1.52 - 3.07, p < 0.001)], and seropositivity [OR 1.83 (95% CI 1.12 - 3.03, p = 0.02)] were associated with favourable methotrexate response [accuracy 81% (95% CI 76%-86%) of the model testing against discovery model]. Different machine learning classification methods were applied. Random forest exhibited the maximum accuracy and AUROC (89%, and 86%, respectively), confirming the above three predictors as the most significant. Two latent classes (class 1: smaller MCV increase and class 2: greater MCV increase) were identified based on the MCV changes over six months. Class 1 had fewer responders and a lower number of patients on hydroxychloroquine compared to class 2. The earliest time point of significant difference of MCV between responders and non-responders was three months [mean difference 1.43 (95% CI 0.57-2.3)]. Combination hydroxychloroquine and methotrexate caused the greatest increase in MCV with a difference between responders and non-responders at 2 months. Change of MCV at three months showed AUROC of 0.75 to predict treatment response to the combination of methotrexate and hydroxychloroquine at six months with an optimal cut-point of MCV 3.5 fL (95% CI 3.5-3.6) with 71% sensitivity and 75%, specificity. Conclusion Our data provides mechanistic insight into the synergistic clinical benefit of concomitant hydroxychloroquine with methotrexate, boosting the rise in erythrocyte MCV which could serve as an early biomarker of treatment response. Disclosure M.R. Shipa: Grants/research support; Versus arthritis. S. Yeoh: Grants/research support; Royal College of Physicians, Rosetrees Trust, NIHR University College London Hospitals Biomedical Research Centre, UCLH Charities. A. Embleton-Thirsk: None. D. Mukerjee: None. M.R. Ehrenstein: Grants/research support; University College London Hospital Biomedical Research Centre.

Circulating miRNAs as early indicators of diet and physical activity response in women with metastatic breast cancer.

Treatments for metastatic breast cancer (MBC) improve survival but often impose prolonged symptom burden. We performed molecular characterization of 84 miRNAs in the circulating serum of women with MBC to explore possible early indicators of intervention response. Expression levels of miR-10a-5p and miR-211-5p were downregulated in nonresponders, but upregulated in responders (miR-10a-5p: 0.40-fold and eightfold; miR 211-5p: 0.47-fold and fourfold). miR-205-5p expression was upregulated in both nonresponders and responders, but to a greater extent in responders (1.8-fold and sixfold). Additionally, levels of miR-10a-5p were negatively correlated with expression levels of IL-6 (r = -0.412). Exploration of these pathways may reveal mechanisms of action in lifestyle interventions aimed at improving quality of life and impacting disease progression for women with MBC.

Response of the Cardiac Autonomic Control to Exposure to Nanoparticles and Noise: A Cross-Sectional Study of Airport Ground Staff.

Airport activity causes the emission of particulate matter and noise, two environmental contaminants and potential health hazards, particularly for the personnel operating nearby taxiways. We explored the association between exposure to fine/ultrafine particles (UFPs) and noise with heart rate variability (HRV), an early indicator of cardiovascular autonomic response, among a sample of airport ground staff. Between May and June 2018, thirty-four male operators (mean age = 43 years and SD = 6.7) underwent personal monitoring of exposure to nanoparticles and noise, and HRV during their work activity. We conducted univariate and multivariate analysis to test the effect of UFP and noise exposure HRV. Total Lung Deposition Surface Area (LDSA) was significantly associated with a decrease in HRV Total Power and Triangular index (β = −0.038 p = 0.016 and β = −7.8 × 10−5, p = 0.042, respectively). Noise peak level showed an opposite effect, which was significant for Total Power (β = 153.03, p = 0.027), and for Triangular index (β = 0.362, p = 0.035). Further investigation is warranted to clarify the effect of the concurrent exposure to UFPs and noise on early changes of cardiac autonomic regulation.

Evaluating foliar characteristics as early indicators of plant response to biochar amendments

Biochar amendments are widely promoted for increasing soil nutrient availability and plant yield, and although many plant species show positive growth responses, neutral to negative effects can also occur. Although biochar effects on plant yield may not yet be evident in the first growing season after amendment, foliar characteristics such as nitrogen (N) and chlorophyll concentrations are known to respond to changes in soil fertility and therefore may provide an early indication of plant performance. In this study, we investigated the effects of contrasting biochar treatments on soil nitrogen (N) forms and plant chlorophyll, and the relationships between soil and plant nitrogen status, for two economically important conifer species, Abies balsamea (L.) Mill and Picea pungens Englem., as well as forb and grass weeds. We applied two types of pyrolysis biochars (hereafter, USB and BGR) that differed in feedstock type (pine wood versus mixed forest harvesting residue) at contrasting application rates (low, high, and untreated control) to a fine sandy loam soil. We measured soil water content (SWC), pH, and inorganic nitrogen (NH4+, NO3−, and total inorganic N (TIN)), as well as plant foliar N, and chlorophyll content (Chl-a, -b, -ab), and fluorescence (Fv/Fm). SWC response was variable whereas all treatments except USB low increased pH. All treatments decreased inorganic N concentrations relative to the control, although differences diminished over the study period. USB high decreased Picea foliar N concentration whereas all treatments decreased grass foliar N. BGR decreased Abies Fv/Fm (low) and Picea Chl-a, Chl-ab (both levels), and Chl-b (low), whereas USB increased Abies Chl-ab (high). There was a weak positive relationship between foliar N and soil NH4+ (r2 = 0.14) and NO3− (r2 = 0.11) in Abies seedlings, and between foliar N and TIN (r2 = 0.16, 0.11) in both conifers. Abies foliar N showed a weak positive effect on Chl-a (r2 = 0.22), Chl-b (r2 = 0.10), and Chl-ab (r2 = 0.22). Soil NO3− (r2 = 0.14) and TIN (r2 = 0.14) showed a weak negative correlation with Picea foliar Fv/Fm. This study shows that biochar type and amendment level influence soil and plant nitrogen responses, as well as their relationships, and responses may differ between plant species. Evaluating foliar characteristics shows promise as an early indicator of plant response to biochar, and may provide additional important information for evaluating contrasting biochars as potential sustainable soil amendments.

Optical scattering as an early marker of apoptosis during chemotherapy and antiangiogenic therapy in murine models of prostate and breast cancer

Monitoring of the in vivo tumor state to track therapeutic response in real time may help to evaluate new drug candidates, maximize treatment efficacy, and reduce the burden of overtreatment. Current preclinical tumor imaging methods have largely focused on anatomic imaging (e.g., MRI, ultrasound), functional imaging (e.g., FDG-PET), and molecular imaging with exogenous contrast agents (e.g., fluorescence optical tomography). Here we utalize spatial frequency domain imaging (SFDI), a noninvasive, label-free optical technique, for the wide-field quantification of changes in tissue optical scattering in preclinical tumor models during treatment with chemotherapy and antiangiogenic agents. Optical scattering is particularly sensitive to tissue micro-architectural changes, including those that occur during apoptosis, an early indicator of response to cytotoxicity induced by chemotherapy, thermotherapy, cryotherapy, or radiation therapy. We utilized SFDI to monitor responses of PC3/2G7 prostate tumors and E0771 mammary tumors to treatment with cyclophosphamide or the antiangiogenic agent DC101 for up to 49 days. The SFDI-derived scattering amplitude was highly correlated with cleaved caspase-3, a marker of apoptosis (ρp = 0.75), while the exponent of the scattering wavelength-dependence correlated with the cell proliferation marker PCNA (ρp = 0.69). These optical parameters outperformed tumor volume and several functional parameters (e.g., oxygen saturation and hemoglobin concentration) as an early predictive biomarker of treatment response. Quantitative diffuse optical scattering is thus a promising new early marker of treatment response, which does not require radiation or exogenous contrast agents.

Early Assessment With Gastrointestinal Ultrasound in Patients Hospitalised for a Flare of Ulcerative Colitis and Predicting the Need for Salvage Therapy: A Pilot Study

Approximately 30% of patients hospitalised with severe ulcerative colitis do not respond to corticosteroids, but the decision to introduce salvage therapy is delayed to at least the third day of treatment, according to the widely applied Oxford criteria to assess response. This pilot study aimed to determine if gastrointestinal ultrasound performed on admission can predict steroid-refractory disease. In 10 consecutive patients with severe ulcerative colitis, gastrointestinal ultrasound was performed within 24 h of admission. Six patients failed corticosteroids and required infliximab salvage therapy. Colonic bowel wall thickness was a median of 4.6 mm (range 4.2–5.6 mm) in those responding to steroids compared with 6.2 mm (6–7.9 mm) in those requiring salvage therapy (p = 0.009). Any colonic segment with a bowel wall thickness of >6 mm was associated with the need for salvage therapy (p = 0.033). Gastrointestinal ultrasound may provide an early indication of poor corticosteroid response and enable a timelier introduction of salvage therapy in patients with severe ulcerative colitis.