Predictors Of Clinical Response Research Articles

Clinical Predictors of Good/Poor Response to Growth Hormone Treatment in Children with Idiopathic Short Stature.

Children with idiopathic short stature (ISS) are known to have varying responses to growth hormone (GH) treatment (GHT). We conducted a post hoc analysis to identify clinical characteristics predictive of good and poor response during year 1 of GHT. Data from the NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905) were used. Patients were grouped according to their response to GHT; good, middle, and poor responders had a change in HSDS of >1.0, 0.4-1.0, and <0.4, respectively. Patients were also grouped according to their responsiveness to GH dose. Logistic regression modelling was performed to identify clinical characteristics predictive of response to GHT. The response analysis set included 207 patients. Patients were 3-11 years old (males) or 3-10 years old (females) at treatment start and were prepubertal throughout year 1 of treatment. Age at treatment start (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.5;0.9, p = 0.0169) and distance from target HSDS (OR 2.05, 95% CI 1.1;3.9, p = 0.0259) were found to be significant independent predictors of being in the good- versus poor-response groups. When patients were grouped according to their responsiveness to GH dose, a positive correlation between GH dose and change in HSDS was observed. We identified younger age and further distance from target HSDS as clinical predictors of response to GHT in a heterogenous population of children with ISS. Future studies, designed to identify the genetic determinants of response to GHT could further facilitate individualisation of GHT. .

Prediction of Clinical Response to Dupilumab for CRSwNP Based on the Amsterdam Classification of Completeness of Endoscopic Sinus Surgery (ACCESS) Score.

Although the effectiveness of molecular antibodies has been established, evidence is still lacking on objective predictors of response. The aim of this study was to assess whether the extent of previous endoscopic sinus surgeries, assessed by means of the Amsterdam Classification of Completeness of Endoscopic Sinus Surgery (ACCESS) score, may influence clinical outcomes in refractory CRSwNP patients treated with dupilumab. A consecutive sample of patients treated with dupilumab for previously operated recalcitrant CRSwNP were enrolled in the study. Every patient was required to undergo a CT scan at baseline (T0), at 3 (T1), and 12 (T2) months after treatment start. ACCESS score was calculated at baseline, whilst at every timepoint patients underwent assessment of Nasal-Polyp-Score (NPS), Lund-Kennedy-Score (LKS), and had to fill in the 22-item Sinonasal-Outcome-Test (SNOT-22) and Visual-Analog-Scales (VAS) for sinonasal symptoms. Favorable outcome was considered based on EUFOREA guidelines, namely improving at least 3 of the followings: (i) NPS; (ii) SNOT-22; (iii) VAS-olfaction; and (iv) need for systemic corticosteroids. Overall favorable outcome was achieved in 69.1% (n = 38/55) of cases at T1, while in 89.1% (n = 49/55) at T2. There were no differences in baseline characteristics between responders and non-responders at both timepoints. At T1, out of all the included variables, no statistically significant predictor of favorable outcome was observed. Conversely, at T2, ACCESS score was the only confirmed independent predictive factor of response to dupilumab treatment (OR = 0.81 [95% CI = 0.67-0.92], P = .010). Our findings suggest that the extent of previous endoscopic sinus surgeries may have a role in influencing clinical outcomes in patients with refractory CRSwNP undergoing treatment with dupilumab.

The relationship between lung MIBG uptake and clinical response to renal denervation

Abstract Background Renal denervation (RDN) reduces the sympathetic overdrive and can optimize blood pressure control in patients with difficult-to-treat hypertension (DTH). However, a substantial proportion of patients undergoing RDN do not show a clinical response to the procedure, making it critical to identify novel and more accurate predictors. The metaiodobenzylguanidine (MIBG) scintigraphy allows non-invasive assessment of sympathetic nerve activity. Yet, studies evaluating the heart and kidney MIBG uptake as predictors of clinical response to RDN provided conflicting results, and a comprehensive evaluation of the MIBG uptake in different organs of DTH patients undergoing RDN is lacking. Purpose To explore if a more comprehensive evaluation of MBG uptake in the kidneys, heart and lungs can predict the clinical response to RDN. Methods Eighteen patients with DTH underwent evaluation of their clinical and pharmacological history, office and ambulatory BP values and levels of cardiovascular risk factors. A rest echocardiography, carotid vascular ultrasound and MIBG scintigraphy were also performed before RDN. The patient’s pharmacological history and office and ambulatory BP values were re-evaluated after 3 months from RDN. We considered responders (R) those subjects with a significant reduction of the office BP values on stable BP-lowering treatment or a reduced burden of BP-lowering medications while maintaining optimal control of the office BP. Results Ten patients could be classified as R (1 woman, mean age 49±10 years), while 7 were non-responders (NR, 2 women, mean age 53±8 years). The reduction in office systolic and diastolic BP (baseline vs 3 months) was significantly larger in R vs NR (p=0.01 for both). The burden of BP-lowering medications after the procedure was reduced by 39% in R, compared to 2% in NR (p&amp;lt;0.01). Responders had a higher baseline HR and prevalence of carotid atherosclerosis than NR (p&amp;lt;0.05 for both). In early MIBG acquisitions, the lung/mediastinum ratio on both sides showed higher MIBG uptake in R vs NR (p&amp;lt;0.05). There was a higher MIBG uptake in the right vs. left lung in the whole population and in R vs NR. In late acquisitions, only the left side showed a significant difference between R and NR (p&amp;lt;0.05). The associations between the lung/mediastinum ratio MIBG uptake and response to RDN remained significant after adjusting for the baseline clinical predictors of the RDN response. All other MIBG scintigraphy parameters were similar between groups. Conclusions Our results suggest that RDN might be less effective in patients with an advanced burden of hypertension-mediated target organ damage and confirm a higher HR as a reliable predictor of the clinical response to the procedure. We also document a novel association between the lung/mediastinum ratio MIBG uptake and response to RDN that, if confirmed in future studies, might provide a novel marker to improve the selection of patients undergoing RDN.

Utility of Lymph Node Ratio in Predicting Biochemical Incomplete Clinical Response in Patients with Papillary Ca thyroid with Positive Neck Node.

with the requirement of aggressive follow-up in patients with biochemically incomplete response in patients of papillary ca. thyroid with neck node, a predictor for clinical response would be of great help for better treatment and follow-up planning. To determine the utility of lymph-node ratio (central and lateral) as predictors for clinical response post total thyroidectomy and neck dissection. 51 patients of papillary carcinoma thyroid with neck node were treated with surgery and RAI as per ATA guidelines and were analyzed for a median of 3 years. (Retrospective cohort analysis). We did response evaluation, correlated clinical response with lymph-node ratios. We found a statistically significant relationship of lymph-node ratio with around a sensitivity and specificity of approximately 90% in predicting the biochemically incomplete response. we conclude that lateral and central compartment ratios can be used in predicting the occurrence of biochemically incomplete response.

Response predictors of a topical corticosteroid-based regimen for dry eyes: A real-life study.

To examine the effectiveness and identify clinical response predictors of a short corticosteroid-based regimen consisting of topical preservative-free 0.1% dexamethasone (Monopex®, Théa Laboratories) in conjunction with artificial tears (AT) for dry eyes in a real-life clinical setting. Patients were recruited from the Norwegian Dry Eye Clinic and were allowed to use ATs of their own choice in addition to the prescribed 14-day topical dexamethasone course. Ocular Surface Disease Index (OSDI), Dry Eye Questionnaire (DEQ-5), Schirmer test (ST), fluorescein tear film break-up time (FBUT), ocular surface staining (OSS), meibum expressibility (ME), meibum quality (MQ), number of expressible meibomian glands among the central eight glands in the lower lids (NMG) and intraocular pressure (IOP) were measured at baseline and at 1-month follow-up. The average values of clinical parameters from both eyes were used for analyses. A paired t-test and a significance value of p < 0.05 were used for statistical analyses. Associations between sex, age, baseline values and the changes after the intervention (Δ) were explored using linear regression. A total of 167 patients (124 women, mean age 54 years ±17 (standard deviation)) were included. One month after initiation of intervention, OSDI and DEQ5 scores improved from 39.5 ± 22.1 to 31.4 ± 21.3 (p < 0.001) and from 12.6 ± 4.2 to 11.0 ± 4.6 (p < 0.001), respectively. OSS improved from 2.2 ± 1.4 to 1.8 ± 1.5 (p < 0.001), NMG increased from 4.8 ± 2.2 to 5.1 ± 2.2 (p < 0.05), while IOP decreased from 12.9 ± 3.3 to 12.4 ± 3.5 mmHg (p < 0.05). Significant associations were found between the change in symptoms and objective measures of DED (ΔOSDI, ΔDEQ5, ΔOSS, ΔFBUT, ΔNMG, ΔMQ) and their respective baseline values (OSDI, DEQ5, OSS, FBUT, NMG, MQ). The remaining tests did not show statistically significant changes. Improvement in dry eye symptoms and signs were observed following a short course of topical, preservative-free 0.1% dexamethasone treatment in combination with AT. Individuals exhibiting more pronounced symptoms and signs witnessed the most profound improvements with the treatment regimen, suggesting that poor baseline parameters may serve as response predictors of the treatment regimen. While the real-life data presented herein are valuable, the conclusions are limited by the inherent biases of a non-controlled study.

HLA-C Peptide Repertoires as Predictors of Clinical Response during Early SARS-CoV-2 Infection.

The human leukocyte antigen (HLA) system plays a pivotal role in the immune response to viral infections, mediating the presentation of viral peptides to T cells and influencing both the strength and specificity of the host immune response. Variations in HLA genotypes across individuals lead to differences in susceptibility to viral infection and severity of illness. This study uses observations from the early phase of the COVID-19 pandemic to explore how specific HLA class I molecules affect clinical responses to SARS-CoV-2 infection. By analyzing paired high-resolution HLA types and viral genomic sequences from 60 patients, we assess the relationship between predicted HLA class I peptide binding repertoires and infection severity as measured by the sequential organ failure assessment score. This approach leverages functional convergence across HLA-C alleles to identify relationships that may otherwise be inaccessible due to allelic diversity and limitations in sample size. Surprisingly, our findings show that severely symptomatic infection in this cohort is associated with disproportionately abundant binding of SARS-CoV-2 structural and non-structural protein epitopes by patient HLA-C molecules. In addition, the extent of overlap between a given patient's predicted HLA-C and HLA-A peptide binding repertoires correlates with worse prognoses in this cohort. The findings highlight immunologic mechanisms linking HLA-C molecules with the human response to viral pathogens that warrant further investigation.

Predictors of response to accelerated rTMS in the treatment of treatment-resistant depression.

Accelerated repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for treatment-resistant depression (TRD). We aimed to investigate the existence of clinical predictive factors in response to accelerated rTMS in the treatment of TRD. In total, 119 TRD patients who received accelerated rTMS were included in this study. The stimulation protocol was 15Hz stimulation over the the left dorsolateral prefrontal cortex. The protocol consisted of 25 sessions, each session lasting 30min for a total of 3000 pulses. Five sessions were applied per day for 5 consecutive days. At baseline (T0), day 5 (immediately after treatment) (T1), 4 weeks after treatment (T2), depression severity was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD-17), cognitive function was evaluated using Wisconsin Card Sorting Test (WCST), the intensity of suicidal ideation was evaluated using the Columbia-Suicide Severity Rating Scale (C-SSRS). Systemic immune-inflammation index (SII) was calculated at T0 and T2. The HAMD-17 scores, WCST performance, the C-SSRS scores at T1 and T2 were improved from T0 (P < 0.01). The SII at T2 was lower than at T0 (P < 0.01). The response rates at T1 and T2 were 57.98% (69/119) and 48.74% (58/119), respectively. The results of binary logistic analysis showed that shorter course of depression, two failed antidepressant trials, no history of ECT treatment, and lower levels of SII were predictive factors for accelerated rTMS treatment response at T1 and T2 (P < 0.05), while not having a history of hospitalization was a predictive factor for response at T2 (P < 0.05) but not at T1 (P > 0.05). Based on ROC curve analysis, the optimal cut-off values of SII for discriminating responders from non-responders at T1 and T2 were < 478.56 and < 485.03, respectively. The AUC of SII at T0 predicting response for T1 and T2 were 0.729 and 0.797. We found several clinical predictors of better responses to the accelerated rTMS. Identifying clinical predictors of response is relevant to personalize and adapt rTMS protocols in TRD patients.

Enhanced network synchronization connectivity following transcranial direct current stimulation (tDCS) in bipolar depression: Effects on EEG oscillations and deep learning-based predictors of clinical remission

AimTo investigate oscillatory networks in bipolar depression, effects of a home-based tDCS treatment protocol, and potential predictors of clinical response. Methods20 participants (14 women) with bipolar disorder, mean age 50.75 ± 10.46 years, in a depressive episode of severe severity (mean Montgomery-Åsberg Rating Scale (MADRS) score 24.60 ± 2.87) received home-based transcranial direct current stimulation (tDCS) treatment for 6 weeks. Clinical remission defined as MADRS score < 10. Resting-state EEG data were acquired at baseline, prior to the start of treatment, and at the end of treatment, using a portable 4-channel EEG device (electrode positions: AF7, AF8, TP9, TP10). EEG band power was extracted for each electrode and phase locking value (PLV) was computed as a functional connectivity measure of phase synchronization. Deep learning was applied to pre-treatment PLV features to examine potential predictors of clinical remission. ResultsFollowing treatment, 11 participants (9 women) attained clinical remission. A significant positive correlation was observed with improvements in depressive symptoms and delta band PLV in frontal and temporoparietal regional channel pairs. An interaction effect in network synchronization was observed in beta band PLV in temporoparietal regions, in which participants who attained clinical remission showed increased synchronization following tDCS treatment, which was decreased in participants who did not achieve clinical remission. Main effects of clinical remission status were observed in several PLV bands: clinical remission following tDCS treatment was associated with increased PLV in frontal and temporal regions and in several frequency bands, including delta, theta, alpha and beta, as compared to participants who did not achieve clinical remission. The highest deep learning prediction accuracy 69.45 % (sensitivity 71.68 %, specificity 66.72 %) was obtained from PLV features combined from theta, beta, and gamma bands. ConclusionstDCS treatment enhances network synchronization, potentially increasing inhibitory control, which underscores improvement in depressive symptoms. Baseline EEG-based measures might aid predicting clinical response.

HLA-C peptide repertoires as predictors of clinical response during early SARS-CoV-2 infection

HLA-C peptide repertoires as predictors of clinical response during early SARS-CoV-2 infection

Efficacy and Clinical Predictors of Response to Repetitive Transcranial Magnetic Stimulation Treatment in Resistant Obsessive-compulsive Disorder

Deep transcranial magnetic stimulation has been effectively used as a therapy for refractory obsessive compulsive disorder (OCD). Number of sessions approved by FDA is 20. Here, we report the case of 59 year old female with treatment refractory obsessive compulsive disorder (OCD) whose symptoms markedly improved only after 10 sessions of deep TMS over Dorso Medial Prefrontal Cortex. Our case report shows that, even with fewer sessions than indicated, significant symptoms remission can be achieved with deeper penetration of magnetic field with marked reduction in distress of patient and significant improvement in socio-occupational domain. Her Y-BOCS score reduced by 66% at the end of 10 completed sessions.

Adjunctive cenobamate in people with focal onset seizures: Insights from the Italian Expanded Access Program.

This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses. A total of 236 subjects with a median age of 38 (Q1-Q3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1-Q3 = 2.50-4.47) at baseline to 2.50 (Q1-Q3 = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel. Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam.

Do antro-duodenal manometry parameters predict clinical response after gastric peroral endoscopic pyloromyotomy in refractory gastroparesis?

Gastric peroral endoscopic pyloromyotomy (G-POEM) is a promising therapeutic modality for refractory gastroparesis (GP). However, as characteristics of suitable patients for G-POEM remain unclear, antro-duodenal manometry (ADM) has been suggested to provide objective parameters for patient selection. The aim of the present study was to identify ADM parameters as predictors for treatment response after G-POEM in refractory GP. Refractory GP patients who underwent a G-POEM between 2017 and 2022 were included. The following ADM parameters were mainly scored: antral hypomotility, pylorospasm, and the presence of neuropathic enteric patterns. Treatment response was defined as a GCSI-score decrease of ≥1 point 12 months after G-POEM. Explorative analyses were performed on potential predictors of response using logistic regression analysis. Sixty patients (52 women, mean age 52 ± 14 years.) with refractory GP (33 idiopathic, 16 diabetic, 11 postsurgical) were included. Clinical response data were available for 52 patients. In 8 out of 60 patients, it was not feasible to advance the catheter beyond the pylorus. Abnormal ADM was found in 46/60 patients (77%). Antral hypomotility and pylorospasm were found in respectively 33% and 12% of patients. At least one neuropathic enteric dysmotility pattern was found in 58% of patients. No differences were found when comparing baseline ADM parameters between clinical response groups at 12 months follow-up. Following explorative analyses, no ADM parameters were identified to predict clinical response 12 months after G-POEM. No ADM parameters were identified as predictors of clinical response after G-POEM in refractory GP patients. Additionally, a high percentage of abnormal ADM tracings was found, in particular with relation to enteric dysmotility, while only a low percentage of patients showed antral hypomotility or pylorospasm.

Identifying cell type-specific transcription factor-mediated activity immune modules reveal implications for immunotherapy and molecular classification of pan-cancer.

Systematic investigation of tumor-infiltrating immune (TII) cells is important to the development of immunotherapies, and the clinical response prediction in cancers. There exists complex transcriptional regulation within TII cells, and different immune cell types display specific regulation patterns. To dissect transcriptional regulation in TII cells, we first integrated the gene expression profiles from single-cell datasets, and proposed a computational pipeline to identify TII cell type-specific transcription factor (TF) mediated activity immune modules (TF-AIMs). Our analysis revealed key TFs, such as BACH2 and NFKB1 play important roles in B and NK cells, respectively. We also found some of these TF-AIMs may contribute to tumor pathogenesis. Based on TII cell type-specific TF-AIMs, we identified eight CD8+ T cell subtypes. In particular, we found the PD1 + CD8+ T cell subset and its specific TF-AIMs associated with immunotherapy response. Furthermore, the TII cell type-specific TF-AIMs displayed the potential to be used as predictive markers for immunotherapy response of cancer patients. At the pan-cancer level, we also identified and characterized six molecular subtypes across 9680 samples based on the activation status of TII cell type-specific TF-AIMs. Finally, we constructed a user-friendly web interface CellTF-AIMs (http://bio-bigdata.hrbmu.edu.cn/CellTF-AIMs/) for exploring transcriptional regulatory pattern in various TII cell types. Our study provides valuable implications and a rich resource for understanding the mechanisms involved in cancer microenvironment and immunotherapy.

Baseline hepatobiliary MRI for predicting chemotherapeutic response and prognosis in initially unresectable colorectal cancer liver metastases

PurposeTo evaluate the performance of hepatobiliary MRI parameters as predictors of clinical response to chemotherapy in patients with initially unresectable colorectal cancer liver metastases (CRLM).MethodsEighty-five patients with initially unresectable CRLM were retrospectively enrolled from two hospitals and scanned using gadobenate dimeglumine-enhanced MRI before treatment. Therapy response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Conventional parameters (i.e., signal intensity [SI]) and radiomics features of portal venous phase (PVP) and hepatobiliary phase (HBP) images were analyzed between the responders and non-responders. Next, the combined model was constructed, and the area under the receiver operating characteristic (ROC) curve (AUC) was calculated. The relationship between the combined model and progression-free survival (PFS) was analyzed using Cox regression.ResultsOf the 85 patients from two hospitals, 42 were in the response group, and 43 were in the non-response group. Upon conducting five-fold cross-validation, the normalized relative enhancement (NRE) of CRLM during the PVP yielded an AUC of 0.625. Additionally, a radiomics feature derived from the tumor area in the HBP achieved an AUC of 0.698, while a separate feature extracted from the peritumoral region in the HBP recorded an AUC of 0.709. The model that integrated these three features outperformed the individual features, achieving an AUC of 0.818. Furthermore, the combined model exhibited a significant correlation with PFS (P < 0.001).ConclusionThe combined model, based on baseline hepatobiliary MRI, aids in predicting chemotherapeutic response and PFS in patients with initially unresectable CRLM.

Vitamin D as a predictor of clinical response among patients with cardiac resynchronization therapy (CRT).

Cardiovascular and noncardiovascular comorbidities have been recognized as predictors of clinical response in patients receiving cardiac resynchronization therapy (CRT). However, data on vitamin D as a predictor of CRT response are conflicting. We identified studies from MEDLINE and Embase databases, searching from inception to May 2024, to investigate the association between 25-OH vitamin D levels before CRT implantation and outcomes. Studies had to report 25-OH vitamin D levels or the proportion of patients with vitamin D insufficiency and categorize outcomes as CRT responders or nonresponders. We extracted mean 25-OH vitamin D and standard deviations for both groups from each study and calculated the pooled mean difference (MD). We also retrieved risk ratios, and 95% confidence intervals (CIs) for the association between vitamin D insufficiency and lack of CRT response, combining them using the generic inverse variance method. Our meta-analysis included four studies. CRT responders had higher levels of 25-OH vitamin D than nonresponders, with a pooled MD of 8.04 ng/mL (95% CI: 3.16-12.93; I 2 = 48%, p < .001). Patients with vitamin D insufficiency before implantation had higher odds of lacking response to CRT, with a pooled RR of 3.28 (95% CI: 1.43-7.50; I 2 = 0%, p = .005) compared to those with normal vitamin D. CRT responders had higher 25-OH vitamin D levels compared to nonresponders. Vitamin D insufficiency was associated with a higher risk of nonresponse to CRT. These findings highlight the importance of monitoring and managing vitamin D levels in these patients.

Anti‑CGRP monoclonal antibodies in resistant migraine: preliminary real-world effectiveness and clinical predictors of response at twoyears.

Monoclonal antibodies targeting calcitonin gene-related peptide (anti-CGRP mAbs) have shown clinical effectiveness and safety in randomized clinical studies. However, long-term studies in clinical practice remain limited. To assess the long-term effectiveness, clinical predictors and safety of three anti-CGRP mAbs (erenumab, galcanezumab, fremanezumab) in resistant migraine patients. A single-center retrospective study was conducted from December 2019 to June 2023 involving 120 resistant migraine patients who received at least a month of anti-CGRP mAbs treatment. Patients completed a headache diary that included monthly acute medication intake (MAM), monthly migraine days (MMD), adverse events as well as completed Patient-Reported Outcome questionnaires (MIDAS [Migraine Disability Assessment] and Headache Impact Test 6 [HIT-6]). The number of patients achieving a ≥ 50% reduction in monthly migraine days was determined and classified as ≥ 50% responders, and baseline parameters and logistic regression between responders and non-responders were analyzed to identify potential predictors of response. Adverse events were registered in every follow-up. Treatment with anti-CGRP mAbs led to reductions in MIDAS, HIT-6, MMD and MAM from baseline to 6-24months. At 6-12months, responders (61% and 57%, respectively) exhibited lower baseline MMD and MAM. Medication overuse was associated with non-responders from 6 to 24months and it was identified as a negative predictor of treatment effectiveness (OR 0.23, 95% CI 0.07-0.74; p = 0.014). Anti-CGRP mAbs prove effectiveness and safety over a 24-month period in a RM population. Patients with no medication overuse and lower basal MMDs and MAM may respond better to anti-CGRP mAbs.

S100 proteins as potential predictive biomarkers of abatacept response in polyarticular juvenile idiopathic arthritis

BackgroundJuvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA).MethodsData from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months.ResultsAt baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25–5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48–9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03–8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02–5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57–5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23–5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46–9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76–7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07–3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10–4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15–8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders.ConclusionLower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.

Early symptom improvement and other clinical predictors of response to repetitive transcranial magnetic stimulation for depression

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a rapidly emerging treatment for depression, but outcome prediction is still a challenge. This study aimed to identify predictors of response to rTMS among baseline clinical factors and early symptomatic improvements. MethodsThis cohort study comprised 136 patients with a unipolar or bipolar depressive episode referred for clinical intermittent theta-burst stimulation or right-sided 1 Hz rTMS at the Uppsala Brain Stimulation Unit. The co-primary outcomes used for logistic regression were response, defined as ≥50 % reduction of Montgomery and Åsberg Depression Rating Scale Self-assessment (MADRS-S) total score, and 1–2 points on the Clinical Global Impression Improvement (CGI-I) scale. Early improvement was defined as ≥20 % reduction in the MADRS-S total score, or ≥ 1 point reduction in each MADRS-S item, after two weeks of treatment. ResultsThe response rates were 21 % for MADRS-S and 45 % for CGI-I. A depressive episode >24 months had lower odds for MADRS-S response compared to ≤12 months. Early improvement of the MADRS-S total score predicted CGI-I response (95 % CI = 1.35–9.47, p = 0.011), Initiative6 predicted MADRS-S response (95 % CI = 1.08–9.05, p = 0.035), and Emotional involvement7 predicted CGI-I response (95 % CI = 1.03–8.66, p = 0.044). LimitationsNo adjustment for concurrent medication. ConclusionsA depressive episode ≤12 months and early improvement in overall depressive symptoms, as well as the individual items, Initiative6 and Emotional involvement7, predicted subsequent rTMS response in a naturalistic sample of depressed patients. This could facilitate the early identification of patients who will benefit from further rTMS sessions.

The importance of 3D fibre architecture in cancer and implications for biomaterial model design.

The need for improved prediction of clinical response is driving the development of cancer models with enhanced physiological relevance. A new concept of 'precision biomaterials' is emerging, encompassing patient-mimetic biomaterial models that seek to accurately detect, treat and model cancer by faithfully recapitulating key microenvironmental characteristics. Despite recent advances allowing tissue-mimetic stiffness and molecular composition to be replicated in vitro, approaches for reproducing the 3D fibre architectures found in tumour extracellular matrix (ECM) remain relatively unexplored. Although the precise influences of patient-specific fibre architecture are unclear, we summarize the known roles of tumour fibre architecture, underlining their implications in cell-matrix interactions and ultimately clinical outcome. We then explore the challenges in reproducing tissue-specific 3D fibre architecture(s) in vitro, highlighting relevant biomaterial fabrication techniques and their benefits and limitations. Finally, we discuss imaging and image analysis techniques (focussing on collagen I-optimized approaches) that could hold the key to mapping tumour-specific ECM into high-fidelity biomaterial models. We anticipate that an interdisciplinary approach, combining materials science, cancer research and image analysis, will elucidate the role of 3D fibre architecture in tumour development, leading to the next generation of patient-mimetic models for mechanistic studies and drug discovery.

ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages

BackgroundUnderstanding the mechanisms that mediate the interaction between tumor and immune cells may provide therapeutic benefit to patients with cancer. The N6-methyladenosine (m6A) demethylase, ALKBH5 (alkB homolog 5), is overexpressed in non-small cell lung cancer. However, its role in the tumor microenvironment is unknown.MethodsDatasets and tissue samples were used to determine the relationship between ALKBH5 expression and immunotherapy efficacy. Bioinformatic analysis, colorimetric assay to determine m6A RNA methylation, dual luciferase reporter assay, RNA/m6A-modified RNA immunoprecipitation, RNA stability assay, and RNA sequencing were used to investigate the regulatory mechanism of ALKBH5 in non-small cell lung cancer. In vitro and in vivo assays were performed to determine the contribution of ALKBH5 to the development of non-small cell lung cancer.ResultsALKBH5 was upregulated in primary non-small cell lung cancer tissues. ALKBH5 was positively correlated with programmed death-ligand 1 expression and macrophage infiltration and was associated with immunotherapy response. JAK2 was identified as a target of ALKBH5-mediated m6A modification, which activates the JAK2/p-STAT3 pathway to promote non-small cell lung cancer progression. ALKBH5 was found to recruit programmed death-ligand 1-positive tumor-associated macrophages and promote M2 macrophage polarization by inducing the secretion of CCL2 and CXCL10. ALKBH5 and tumor-associated macrophage-secreted IL-6 showed a synergistic effect to activate the JAK2/p-STAT3 pathway in cancer cells.ConclusionsALKBH5 promotes non-small cell lung cancer progression by regulating cancer and tumor-associated macrophage behavior through the JAK2/p-STAT3 pathway and the expression of CCL2 and CXCL10, respectively. These findings suggest that targeting ALKBH5 is a promising strategy of enhancing the anti-tumor immune response in patients with NSCLC and that identifying ALKBH5 status could facilitate prediction of clinical response to anti-PD-L1 immunotherapy.