Responder Group Research Articles

Longitudinal FDG-PET Radiomics for Early Prediction of Treatment Response to Chemoradiation in Locally Advanced Cervical Cancer: A Pilot Study

Objectives: This study aimed to assess the capacity of longitudinal FDG-PET radiomics for early distinguishing between locally advanced cervical cancer (LACC) patients who responded to treatment and those who did not. Methods: FDG-PET scans were obtained before and midway through concurrent chemoradiation for a study cohort of patients with LACC. Radiomics features related to image textures were extracted from the primary tumor volumes and stratified for relevance to treatment response status with the aid of random forest recursive feature elimination. Predictive models based on the k-nearest neighbors time series classifier were developed using the top-selected features to differentiate between responders and non-responders. The performance of the developed models was evaluated using receiver operating characteristic (ROC) curve analysis and n-fold cross-validation. Results: The top radiomics features extracted from scans taken midway through treatment showed significant differences between the two responder groups (p-values < 0.0005). In contrast, those from pretreatment scans did not exhibit significant differences. The AUC of the mean ROC curve for the predictive model based on the top features from pretreatment scans was 0.8529, while it reached 0.9420 for those derived midway through treatment scans. Conclusions: The study highlights the potential of longitudinal FDG-PET radiomics extracted midway through treatment for predicting response to chemoradiation in LACC patients and emphasizes that interim PET scans could be crucial in personalized medicine, ultimately enhancing therapeutic outcomes for LACC.

Abstract B050: Frequent monitoring of NSCLC immunotherapy using an mDETECT liquid biopsy reveals unexpected complexity and opportunities

Abstract We have developed a version of our "methylation DETection of Circulating Tumour" DNA (mDETECT) assay that is able to sensitively and quantitatively monitor Non-Small Cell Lung Cancer (NSCLC). We used this assay to frequently assess the tumour burden of a small cohort (17 individuals) of patients undergoing first line monotherapy with pembrolizumab for metastatic disease. Patients were tested weekly or biweekly in the period immediately after initiation of treatment with radiological assessment being done at approximately 3 months. Radiologically non-responding patients showed constant or increased mDETECT levels over the 3 month time frame. Responding patients showed 2 different patterns, with some showing dramatically increasing mDETECT levels for a short period of time followed by a rapid decrease. Other responders showed an immediate decrease within the first few week of treatment. In both responder groups these decreases were associated with a longer term response. Continued monitoring did reveal eventual progression in some of these patients with increasing mDETECT levels being seen 4 to 6 months before radiological changes. In some non-responding patients complex responses were seen, with mDETECT levels varying significantly over time. In one non-responding patient the addition of carboplatin to their treatment regime did produce a temporary improvement in their mDETECT levels. Frequent assessment of tumour burden by a liquid biopsy such as mDETECT offers the opportunity to rapidly determine a patient's response to therapy and potentially modify treatments to improve responses. Citation Format: Christopher R Mueller, Keira Parr, Mihaela Mates, Andrew Robinson, Harriet Feilotter, Keira Frosst. Frequent monitoring of NSCLC immunotherapy using an mDETECT liquid biopsy reveals unexpected complexity and opportunities [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B050.

Plasma essential amino acid levels in first episode psychosis at baseline and after antipsychotic treatment

This study assessed plasma levels of essential amino acids (EAA) in drug-naïve first episode psychosis (FEP) patients at diagnosis and after 10 weeks of antipsychotic treatment. Forty FEP patients were enrolled at baseline, with blood samples collected before and after a 10-week antipsychotic treatment period. Plasma EAA levels were measured using an LC/MS/MS method. Psychotic symptoms were evaluated using standardized inventories before and after treatment. A decrease in BPRS score of more than 40% was used to indicate treatment response. Thirty-five healthy volunteers served as the control group. Baseline plasma levels of Thr, Met, Leu, Lys, His, and Tyr were higher in FEP patients than in healthy controls. After 10 weeks of treatment, Leu, His, and Tyr increased further, primarily in treatment-responsive patients. Conversely, Val level was lower than controls in patients at baseline and remained unchanged after treatment. Increased EAA levels were correlated with lower (less severe) scores in positive symptom scales. Treatment non-responders had persistently low Tyr/large neutral amino acid (LNAA) ratio. Tyr/LNAA ratio increased after treatment, specifically in treatment-responders. Phe/Tyr ratio decreased post-treatment in both responder and non-responder groups. Elevated EAA levels in FEP patients may signify compensatory responses to increased physiological demand for neurotransmitters or energy. Combining specific EAA supplementation with antipsychotic treatment may enhance treatment response in these patients.

Statistical noise in PD-(L)1 inhibitor trials: Unravelling the durable-responder effect

BackgroundProgrammed-death-1/ligand-1 inhibitors (PD-1/L1i’s) have emerged as pivotal treatments for many cancers. A notable feature of this class of medicines is the dichotomous response pattern: A small (but clinically-relevant) percentage of patients (5% - 20%) benefit from deep and durable responses resembling functional cures (durable responders), while most patients experience only a modest or negligible response. Accurately predicting durable responders remains elusive due to the lack of a reliable biomarker. Another notable feature of these medicines is that different PD-1/L1’s have obtained statistically significant results, leading to marketing approval, for some cancer indications, but not for others, with no discernible pattern. These puzzling inconsistencies have generated extensive discussions among oncologists. Proposed (but not entirely convincing) explanations include true underlying differences in efficacy for some types of cancer, but not others; or subtle differences in trial design. ObjectiveTo investigate a less-explored hypothesis—the durable-responder effect: An initially unidentified group of durable responders generates more statistical noise than anticipated, leading to low-powered randomised controlled trials (RCTs) that report randomly variable results. Study designEmploying simulation, this investigation divides participants in PD-(L)1i RCTs into two groups: durable responders and patients with a more modest response. Drawing on published data for melanoma, lung and urothelial cancers, multiple pre-specified scenarios are replicated 50,000 times, systematically varying the durable-responder percentage from 5% to 20% and the modest-response hazard ratio for overall survival [HR(OS)] from 0.8 to 1.0. This allowed evaluation of the effect of durable responders on power, point estimates of the treatment effect for OS, and the probability of a misleading signal for harm. ResultsWhen the treatment effect for the modest responders is similar to the comparator arm, statistical power remains below 80%, limiting the ability to reliably detect durable responders. Conversely, there is a material probability of obtaining a statistically significant result that exaggerates the treatment effect by chance. For instance, with an average HR(OS) of 0.93 (corresponding to 5% durable responders), statistically significant trials (7.2%) show an average HR(OS) of 0.77. Additionally, when 5% are durable responders, there is a 20% probability that the HR(OS) will exceed 1.0—suggesting potential harm, when none exists. ConclusionThis paper adds to the possible explanations for the puzzlingly inconsistent results from PD-(L)1i RCTs. Initially unidentified durable responders introduce features typical of imprecise, low-powered studies: a propensity for false-negative results; estimates of benefit that might not replicate; and misleading signals for harm.

Assessment of Acceptability, Usage, and Impact on Caregivers of Children With Autism's Stress and Mindfulness: Multiple-Method Feasibility Study of the 5Minutes4Myself App's Mindfulness Module.

Caregiver wellness programs need to be easily accessible to address caregivers' constraints to participation. We aimed to assess the feasibility of 5Minutes4Myself app's mindfulness module (usability, usage, and impact on caregivers' levels of mindfulness and perceived stress). Before and after participation in the 5Minutes4Myself program, 15 participants were asked to complete the Perceived Stress Scale (PSS) and Five Facet Mindfulness Questionnaire (FFMQ). Data on the usage of app-delivered meditations were collected electronically via the app, and app usability was rated on the Modified System Usability Scale. Analyses assessed participants' frequency of use of app-delivered meditations, app usability, and changes in participants' stress and mindfulness post intervention. Overall, participants completed 10.9 minutes of mindfulness meditations per week and rated the app 76.7, indicating above-average usability. Related samples t tests (2-tailed) found that group PSS (t10=1.20, P=.26) and FFMQ (t10=-1.57, P=.15) pre- or postintervention mean scores were not significantly different. However, a visualization of pre- and post-PSS and mindfulness scores suggested there was a group of responders who had decreased stress with increased mindfulness. This was confirmed via an individual change analysis. The effect size of the FFMQ scores (d=0.47) suggests there may be treatment effects with a larger sample. A hierarchical multiple regression analysis examined the degree mindfulness impacted perceived stress; 20% of the variance in participants' perceived stress could be attributed to increases in self-rated mindfulness (P=.04) when controlling for preintervention stress levels. Caregivers found the app highly usable and on average used low-dose levels of mindfulness meditations (10 min/wk). For responders, increased mindfulness was related to stress reduction to population-based levels.

Predicting blood pressure response to renal denervation based on a new approach

Background: Identifying predictors of blood pressure (BP) response to renal denervation (RDN) is crucial for patient selection. According to Wilder's principle, baseline BP predicts BP change after any antihypertensive intervention. Thus, any observed BP change after RDN is the sum of the BP change depending on the baseline BP and the specific BP reduction due to RDN. Based on this concept, we propose a new definition of BP responders. Methods: In our center, 148 patients with uncontrolled hypertension underwent RDN, and 24-h ambulatory BP (ABP) was measured at baseline, and 6 months after the procedure. The decrease in 24-h systolic BP (SBP) correlated with baseline SBP (P = <0.001, r = −0.374). We determined the RDN-specific effect by subtracting the predicted SBP decrease from the observed SBP decrease. The cohort was divided into RDN responders, neutral responders, and nonresponders. Results: Our study population had a mean age of 59 ± 10.4 years and was 74% male. The RDN-specific (residual) 24-h ABP decreased by −14.9 ± 6.3/−8.2 ± 3.8 mmHg (responder group), 1.0 ± 3.2/0.2 ± 1.9 mmHg (neutral group), and 14.2 ± 10.4/8.3 ± 3.9 mmHg (nonresponder group) 6 months after RDN. Responders had fewer antihypertensive medications (P = 0.018), higher baseline office heart rate (HR) (P = 0.019), higher 24-h ambulatory HR (P = 0.003), lower BMI (P < 0.038), and absence of type 2 diabetes (T2D) (P = 0.020). Conclusion: Our definition of BP responders to RDN separates baseline BP-related changes from RDN-specific changes. Positive predictors for BP response to RDN include low BMI, fewer antihypertensive medications, high baseline office HR, high 24-h ambulatory HR, and absence of T2D.

Comparative analysis of muscle sympathetic nerve activity in patients afflicted with orthostatic hypertension versus conventional hypertension

Abstract Introduction Standing places a significant hemodynamic burden on the cardiovascular system. In healthy individuals, neurohumoral reflex mechanisms, particularly the arterial baroreflex, maintain blood pressure during standing. However, in some cases, the counterregulatory response can be excessive, resulting in a condition known as orthostatic hypertension (OrthoHT), which appears to be linked to an increased cardiovascular risk. Epidemiologically, orthostatic hypertension has been reported in 5-30% of hypertensive patients. Furthermore, in recent years, it has garnered attention as a responder group in renal denervation therapy. Purpose In hypertensive patients, sympathetic hyperactivity is expected to exacerbate cardiovascular risk. However, the relationship between OrthoHT and sympathetic nerve activity remains poorly understood. This study aims to assess the differences in sympathetic nerve activity between OrthoHT and conventional hypertensive patients using muscle sympathetic nerve activity (MSNA) measurements. Methods We conducted an examination of hypertensive patients undergoing drug treatment at our clinic between April 1, 2023, and June 30, 2023, to identify cases of OrthoHT. Only patients with essential HT were included in the HT group; patients diagnosed with secondary HT were excluded. HT patients with other active CV diseases (i.e., symptomatic cerebral/coronary artery diseases or heart failure) and/or severe renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m2) were also excluded. OrthoHT was defined as a sustained increase in systolic blood pressure ≥20 mmHg and/or diastolic blood pressure ≥10 mmHg within 3 minutes of standing. MSNA was recorded from the left peroneal nerve using a tungsten microelectrode at supine position. We measured MSNA in the cases for which consent was obtained. Statistical analyses were performed using SPSS software. Results Among the 183 cases, 31 were diagnosed with OrthoHT, and 7 of them consented to MSNA measurement. Of the 11 cases of hypertensive patients who consented, two groups were well age-matched. We assessed body mass index, resting systolic blood pressure, diastolic blood pressure, heart rate, blood glucose level, creatinine, cholesterol, brain natriuretic hormone, and ejection fraction measured by echocardiography, but found no significant differences between the two groups. OrthoHT patients exhibited elevated MSNA burst frequency (28.3 +/- 5.7 vs. 38.4 +/- 12.2 bursts/min, P < 0.05) and burst incidence (44.6 +/- 11.1 vs. 61.1 +/- 21.3 bursts/100 heartbeats, P < 0.05) at rest. Conclusions OrthoHT is associated with sympathetic hyperactivity compared to normal hypertensive patients, contributing to an increased cardiovascular risk.

Myocardial single photon emission computed tomography imaging to identify non-responders to cardiac resynchronization therapy in patients with non-left bundle branch block

Abstract Background Non-response to cardiac resynchronization therapy (CRT) is an important issue in the treatment of heart failure with reduced ejection fraction (HFrEF) and non-left bundle branch block (LBBB). Although the QRS duration and morphology are crucial parameters for selecting CRT candidates, electrocardiogram (ECG) markers may inadequately represent the mechanical activation patterns within the heart. Owing to limitations associated with the ECG criteria, there is increasing interest in advanced multimodality imaging to improve patient selection. Recently, myocardial single-photon emission computed tomography imaging (G-MPI) is used for assessing left ventricular (LV) dyssynchrony. This technique is mostly automatic and has high intra- and inter-observer reproducibility and repeatability. Objectives This study aimed to examine whether preoperative G-MPI evaluation could predict non-responsiveness to CRT in patients with HFrEF with non-LBBB. Methods Between January 2021 and December 2022, 128 patients underwent CRT, of whom 73 with pre-operative evaluation using G-MPI were selected. Forty-three patients with non-LBBB (21 and 22 CRT responders and non-responders, respectively) were assessed. These patients were divided into CRT responder and non-responder groups. We evaluated the cut-off and clinical impact of pre-operative G-MPI parameters in predicting non-responsiveness to CRT. In addition, 30 patients with LBBB were analyzed. Results Among patients with non-LBBB, CRT responders and non-responders showed no significant differences in baseline characteristics, except for the LV dimension. A receiver operating characteristic curve analysis identified 108° and 27.7° as the optimal cut-offs for the bandwidth and phase standard deviation (SD), respectively, to predict non-responsiveness to CRT (area under the curve [AUC]=0.762; 95% confidence interval [CI]: 0.601–0.923 and AUC=0.742; 95% CI: 0.576–0.909, respectively). A multivariate analysis revealed that a cut-off bandwidth of ≥108° and phase SD of ≥27.7° are independent predictors of non-responsiveness to CRT in patients with non-LBBB (hazard ratios 5.65; 95% CI: 1.53–20.9; P=0.009). In contrast, there were no relationships between G-MPI parameters and non-responsiveness to CRT in patients with LBBB. Conclusions Pre-operative G-MPI findings were associated with non-responsiveness to CRT in patients with non-LBBB. The identification of potentially nonresponsive patients could influence patient management and alter outcomes.

Investigation of Blood Count-Based Inflammatory Biomarkers as Predictors of Response to Dupilumab Treatment in Patients with Chronic Rhinosinusitis with Nasal Polyps

Background/Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease often resistant to standard treatments. Dupilumab, a monoclonal antibody targeting the IL-4α receptor, has shown efficacy in CRSwNP, but a significant subset of patients do not respond to this therapy. This study aims to investigate pretreatment complete blood count (CBC)-based inflammatory biomarkers as predictors of response to dupilumab in patients with CRSwNP. Methods: This mono-centric, retrospective, single-arm longitudinal cohort study included 80 patients with uncontrolled CRSwNP who received dupilumab treatment at the Medical University of Graz. Patients were classified into responder and non-responder groups based on a reduction of >1 in nasal polyp score (NPS) and a sinonasal outcome test-22 (SNOT-22) score <40 points at six months. Pretreatment CBC-derived biomarkers, including eosinophil count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation indices including the aggregate inflammation systemic index (AISI), systemic inflammation index (SII), and systemic inflammation response index (SIRI), were analyzed for their predictive value. Results: Of the 80 patients, 72.5% were classified as responders, while 27.5% were non-responders. A significant positive correlation was found between baseline eosinophil count and NPS reduction (p = 0.027), suggesting that higher eosinophil levels may predict higher NPS reduction in dupilumab treatment. However, no significant associations were observed between NLR, PLR, and systemic inflammation indices with treatment outcomes. Conclusions: Pretreatment eosinophil count may serve as a potential biomarker for predicting nasal polyp reduction in dupilumab treatment of CRSwNP. Other CBC-based inflammatory markers did not show significant predictive value. Further prospective studies are needed to validate these findings and explore additional, reliable biomarkers to optimize treatment outcomes for CRSwNP patients.

Preventive treatment effects on brain structures and functions in patients with chronic migraine: A multimodel magnetic resonance imaging study.

Patients with chronic migraine (CM) often exhibit structural and functional alterations in pain-matrix regions, but it remains unclear how preventive treatment affects these changes. Therefore, this study aimed to investigate the structural and functional changes in pain-matrix regions in CM patients after 6-month treatment. A total of 24 patients with CM and 15 healthy controls were recruited for this study. Patients were divided into responder group (N = 9) and non-responder group (N = 15). After completing the Migraine Disability Assessment (MIDAS) questionnaire, all patients underwent whole-brain high-resolution T1-weighted images, diffusion-weighted imaging, and resting-state functional magnetic resonance imaging at baseline and 6-month follow-up. Whole brain gray matter volume and white matter diffusion indices were analyzed using voxel-based analysis. Structural and functional connectivity analyses were performed to understand brain changes in patients after 6-month preventive treatment. The responder group exhibited significantly higher MIDAS scores than the non-responder group at baseline, but no significant difference between the two groups at follow-up. No significant interval change was noted in gray matter volume, white matter diffusion indices, and structural connectivity in CM patients after 6-month treatment. Nonetheless, the functional connectivity was significantly increased between occipital, temporal lobes and cerebellum, and was significantly decreased between parietal and temporal lobes after 6-month preventive treatment. We concluded that resting-state functional connectivity was suitable for investigating the preventive treatment effect on CM patients.

Effects of vagal nerve stimulation parameters on heart rate variability in epilepsy patients.

Vagal nerve stimulation (VNS) is used as an alternative treatment in drug-resistant epilepsy patients. Effects of VNS on the cardiac autonomic system are controversial. In this study, we aimed to investigate the relationship between VNS parameters and heart rate variability (HRV) in epilepsy patients who underwent VNS treatment. Our study included 31 patients who underwent VNS for drug-resistant epilepsy. Patients were divided into groups according to response to VNS and VNS parameters. All patients underwent 24-h Holter ECG. The mean age of 31 VNS-treated epilepsy patients included in the study was 33.87 ± 7.6 years. When patients were grouped according to VNS response, 25 patients were in the VNS responder group and six patients were in the VNS-nonresponder group. When comparing Holter parameters in the VNS responder and non-responder groups, the median HF was significantly lower in the VNS responder group. VNS duration and signal frequency had a positive effect on LF/HF, while output and off time had a negative effect on LF/HF. When ROC analysis was performed to determine the cut-off values of the parameters for the VNS-responsive state, the AUC value of the HF parameter was 0.780, which was statistically significant. The cut-off value to distinguish response to VNS was 156.9. In conclusion, the effects of VNS parameters on HRV parameters are quite complex. However, the conclusion is that VNS is a neuromodulation method that affects the autonomic system in a complex way. Different levels of VNS parameters may also contribute to this effect. Furthermore, HRV parameters can be used as biomarkers to predict the patient population that may benefit from VNS.

Predictive biomarkers for low-dose IL-2 therapy efficacy in systemic lupus erythematosus: a clinical analysis

BackgroundLow-dose IL-2 (Ld-IL2) has shown favorable therapeutic effects in systemic lupus erythematosus (SLE) therapy. However, previous clinical trials reported an SLE Responder Index-4 (SRI-4) response rate of 65.52%-68%, with approximately half failing to achieve the primary endpoint by week 24. Our study aims to determine the real-world use of Ld-IL2 and to identify determinants of its effectiveness in SLE.MethodsWe pooled data from 342 SLE patients undergoing sequential Ld-IL2 treatment, with 314 persisting for over 3 months were included in effectiveness and prediction analyses. All patients were categorized into responder (n = 136) and non-responder group (n = 178) according to SRI-4. Lupus Low Disease Activity State (LLDAS) was also analyzed to validate our results.ResultsRash, lower complement 3 (C3), and renal involvement including urine protein, urine occult blood and urine casts emerged as prominent predictors of achieving SRI-4. Adjusting for baseline values using the ratio of change to baseline revealed significant differences in CD4 + T cell immune profiles between responders and non-responders. ROC analysis confirmed a satisfactory performance of rash, renal involvement, percentage change of CD4 + T cells, and C3 in predicting SRI-4, yielding an AUC of 0.933. LLDAS analysis showed that hematological involvements and lower CLA + Treg were potent predictive markers in LLDAS attainment. Conversely, renal involvement failed to have significant association in achieving LLDAS. The analysis of background therapy in SLE patients showed that MMF was more likely to reach the SRI-4 response with the combination of Ld-IL2.ConclusionsThese findings uncovered the predictors of Ld-IL2 treatment efficacy in SLE patients and provided guidance to physicians for rational utilization.

Comparison of the Gut Microbiota of Patients Who Improve with Antibiotic Combination Therapy for Ulcerative Colitis and Those Who Do Not: Investigation by Fecal Metagenomic Analyses.

Background/Objectives: The cause of ulcerative colitis (UC) may be related to commensal bacteria in genetically susceptible patients. We previously demonstrated that triple antibiotic combination therapy induces remission in patients with active UC in randomized controlled trials (RCTs). Now, we investigate changes in the gut microbiota of patients who responded to the antibiotic combination therapy. Methods: Thirty-one patients with UC given ATM/AFM (amoxicillin, metronidazole, and tetracycline or fosfomycin) therapy for two weeks were enrolled in this study. The clinical conditions of these UC patients were evaluated by the partial Mayo score. The gut microbiota was compared via the metagenomic shot gun analysis of fecal samples. Results: Of the 31 patients, 16 and 8 experienced complete and partial remission, respectively, over three months in response to ATM/AFM therapy, whereas ATM/AFM showed no efficacy in 7 patients. The dysbiosis before treatment in the active stage could be associated with increased populations of Bacteroides, Parabacteroides, Rickenella, Clostridium, Flavonifractor, Pelagibacter, Bordetella, Massilia, and Piscrickettsia species. Metagenomic analysis revealed dramatic changes in the gut microbiota at an early stage, that is, just two weeks after starting ATM/AFM therapy. After treatment in the responder group, the populations of bifidobacterium and lactobacilli species were significantly increased, while the population of bacteroides decreased. Conclusions: These results suggest that metagenomic analysis demonstrated a marked change in the gut microbiota after antibiotic combination treatment. In the triple antibiotic combination therapy, remission was associated with an increase in bifidobacterium and lactobacilli species.

Assessing the Tumor Immune Landscape Across Multiple Spatial Scales to Differentiate Immunotherapy Response in Metastatic Non-Small Cell Lung Cancer

Although immune checkpoint inhibitor-based therapy has shown promising results in non-small cell lung cancer patients with high programmed death-ligand 1 expression, not all patients respond to therapy. The tumor microenvironment (TME) is complex and heterogeneous, making it challenging to understand the key agents and features that influence response to therapies. In this study, we leverage multiplex fluorescent immunohistochemistry to quantitatively assess interactions between tumor and immune cells in an effort to identify patterns occurring at multiple spatial levels of the TME. To do so, we introduce several computational methods novel to a data set of 1,269 multiplex fluorescent immunohistochemistry images from a cohort of 52 patients with metastatic non-small cell lung cancer. With the spatial G-cross function, we quantify the degree of cell interaction at an entire image level, where we see significantly increased activity of cytotoxic T cells and helper T cells with epithelial tumor cells in responders to immune checkpoint inhibitor-based (P = .022 and P < .001, respectively) and decreased activity of T-regulatory cells with epithelial tumor cells compared with nonresponders (P = .010). By leveraging spatial overlap methods, we define tumor subregions (which we call the tumor “periphery,” “edge.” and “center”) and discover more localized immune-immune interactions influencing positive response, including those between cytotoxic T cells and helper T cells with antigen presenting cells in these subregions specifically. Finally, we trained an interpretable deep learning model that identified key cellular regions of interest that most influenced response classification (area under the curve = 0.71 ± 0.02). Assessing spatial interactions within these subregions further revealed new insights that were not significant at the whole image level, particularly the elevated association of antigen presenting cells and T-regulatory cells with one another in responder groups (P = .024). Altogether, we demonstrate that elucidating patterns of cell composition and interplay across multiple levels of spatial analyses can improve our understanding of the TME and better differentiate patient responses to immunotherapy.

Texture analysis can predict response to etoposide-doxorubicin-cisplatin in patients with adrenocortical carcinoma.

The adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy originating from the adrenal cortex. These patients usually undergo chemotherapy with etoposide, doxorubicin, cisplatin and mitotane (EDP-M) in case of locally advanced or metastatic ACC. Computed tomography (CT) radiomics showed to be useful in adrenal pathologies. The study aimed to analyze the association between response to EDP-M treatment and CT textural features at diagnosis in patients with locally advanced or metastatic ACCs. We enrolled 17 patients with advanced or metastatic ACC who underwent CT before and after EDP-M therapy. The response to treatment was evaluated according to RECIST 1.1, Choi, and volumetric criteria. Based on the aforementioned criteria, the patients were classified as responders and not responders. Textural features were extracted from the biggest lesion in contrast-enhanced CT images with LifeX software. ROC curves were drawn for the variables that were significantly different (p < 0.05) between the two groups. Long-run high grey level emphasis (LRHGLE_GLRLM) and histogram kurtosis were significantly different between responder and not responder groups (p = 0.04) and the multivariate ROC curve combining the two features showed a very good AUC (0.900; 95%IC: 0.724-1.000) in discriminating responders from not responders. More heterogeneous tissue texture of initial staging CT in locally advanced or metastatic ACC could predict the positive response to EDP-M treatment. Adrenal texture is able to predict the response to EDP-M therapy in patients with advanced ACC.

Predicting response to immunotherapy in oral squamous cell carcinoma via a CT-based radiomics model

BackgroundTo investigate whether radiomics models derived from pretreatment CT could help to predict response to immunotherapy in oral squamous cell carcinoma (OSCC).MethodsRetrospectively, a total of 40 patients with measurable OSCC were included. The patients were divided into responder group and non-responder group according to the comparison of pre-treatment and post-treatment CT findings. Radiomics features were extracted from pre-treatment CT images, and optimal features were selected by univariate analysis and the least absolute shrinkage and selection operator (LASSO) regression analysis. Neural network, support vector machine, random forest and logistic regression models were used to predict response to immunotherapy in OSCC, and leave-one-out cross validation was employed to assess the performance of the classifiers. The area under the curve (AUC), accuracy, sensitivity and specificity were calculated to quantify the predictive efficacy.ResultsA total of 7 features were selected to build models upon machine learning methods. By comparing different machine learning based models, the neural network model achieved the best predictive ability, with an AUC of 0.864, an accuracy of 82.5%, a sensitivity of 82.5%, and a specificity of 82.5%.ConclusionsThe pretreatment CT-based radiomics model showed good performance in predicting response to immunotherapy in OSCC. Pretreatment CT-based radiomics model might provide an alternative approach for the selection of patients who benefit from immunotherapy.

Gut microbiota as a prognostic biomarker for unresectable hepatocellular carcinoma treated with anti-PD-1 therapy.

To investigate the relationship between the gut microbiome and the response to anti-PD-1-based combination therapy in unresectable hepatocellular carcinoma (HCC). We aimed to identify potential non-invasive biomarkers and new strategies to modulate immunotherapy in HCC. In this study, fresh stool samples and clinical data were collected from unresectable HCC patients treated with anti-PD-1-based combination therapy at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2020 and December 2021. The patients were divided into two groups based on their response to treatment: the treatment responder group (R group) and the treatment non-responder group (NR group). The composition and diversity of the gut microbiome were bioinformatically analyzed by using the Whole Genome Shotgun strategy, including taxonomic composition analysis, Alpha diversity analysis, Beta diversity analysis, and differentially enriched bacterial taxa analysis. Differentially enriched bacterial taxa between R and NR groups were identified based on the magnitude of the linear discriminant analysis effect size (LEfSe) and analyzed for their impact on the survival of the patient. A total of 45 eligible patients with unresectable HCC treated with anti-PD-1-based combination therapy participated in this study. The gut microbiological composition and Alpha diversity of patients were not statistically different, but there was a statistically significant difference in Beta diversity between the R and NR groups. (PERMANOVA tests, P = 0.006). We further identified 56 enriched bacterial taxa in the R group and 44 enriched bacterial taxa in the NR group based on the LEfSe analysis (LDA >2.66, P< 0.05). Patients with a high abundance of Collinsella genus, Ruminococcus_AM4211, and Ruminococcus_AF25_28AC had a longer median PFS and median OS compared to those with low abundance (P < 0.05). On the contrary, the median PFS and OS of patients with a high abundance of Bacteroides_AF20_13LB and Veillonella_atypica were significantly shorter than those of patients with low abundance (P < 0.05). The multivariate analysis showed that the abundance of Bacteroides_AF20_13LB and Ruminococcus_ AF25_28AC was independent related factors for PFS, and the abundance of Bacteroides_AF20_13LB was an independent related factor of OS. The enrichment of specific gut microbiota affected clinical efficacy and survival benefits in HCC treated with anti-PD-1 therapy and may be a promising non-invasive gut microbial biomarker and a new strategy for modulating immunotherapy in HCC.

Evaluating the predictive efficacy of real-time 3D echocardiography in cardiac resynchronization therapy

BackgroundThe aim of this study is to assess the predictive efficacy of real-time three-dimensional echocardiography (RT-3DE) and QRS wave duration in determining the response to cardiac resynchronization therapy (CRT) and assessing left ventricular systolic function pre- and post-CRT device implantation.MethodA total of 51 patients with heart failure undergoing CRT at the Second Affiliated Hospital of Nantong University between January 1, 2013, and October 31, 2020, were enrolled in this study. Traditional two-dimensional echocardiography and RT-3DE were performed pre and post-CRT, with QRS wave width data from electrocardiograms and additional clinical information collected. Patients were categorized into CRT responder (n = 36) and CRT non-responder (n = 15) groups based on their response to CRT device implantation. Comparative analyses were conducted on the general characteristics of both groups, as well as the predictive efficacy of RT-3DE and QRS wave width for CRT responsiveness and left ventricular systolic function. Data on the standard deviation (Tmsv16-SD, Tmsv12-SD, Tmsv6-SD) and maximum difference (Tmsv16-Dif, Tmsv12-Dif, Tmsv6-Dif) of left ventricular end-systolic volume (LVESV) at segments 16, 12, and 6, as well as QRS wave width, were collected and analyzed.ResultsThe indicators Tmsv6-Dif, Tmsv12-Dif, Tmsv16-Dif, Tmsv6-SD, Tmsv12-SD, Tmsv16-SD, and QRS wave width exhibited significantly higher values in the CRT responder group when compared to the CRT non-responder group (P < 0.05). Among these, Tmsv16-SD demonstrated superior predictive performance for post-CRT response, with a sensitivity of 88.9%, specificity of 80.0%, and a diagnostic cut-off value of 6.19%. This predictive capability exceeded that of the conventional indicator, QRS wave width.ConclusionRT-3DE enables accurate prediction of post-CRT patient response and significantly facilitates quantitative assessment of CRT therapy efficacy.

Enhancing chronic low back pain management: an initial neuroimaging study of a mobile interoceptive attention training.

Chronic low back pain (cLBP) poses significant challenges, often addressed through avoidance or distraction. Emerging evidence suggests that mind-body interventions, like our novel Mind Your Pain (MyP) smartphone mobile application, may offer relief. We conducted a single-arm, mixed-methods neuroimaging study to assess the degree to which treatment response to our 8-week intervention, as measured by the reduction in the Pain, Enjoyment of Life and General Activity Scale (PEG), was associated with enhanced pain-related insula activation over time. Twenty-nine individuals with cLBP completed patient-reported assessments, qualitative sensory testing (QST) measures, and neuroimaging pre- and post-MyP. Functional MRI data during experimental heat pain on the left forearm were collected and analyzed, comparing responders (≥50% reduction in PEG scores) and non-responders. MyP led to significant decreases in PEG scores overall. Furthermore, MyP responders exhibited increased pain-related activation in key brain regions, including the contralateral posterior insula, bilateral ventral anterior insula, ventral anterior cingulate, dorsolateral prefrontal cortex, and nucleus accumbens. Although baseline behavioral and sensory measures did not differ between the two responder groups, baseline neural differences related to the impact of the endogenous back pain were observed. MyP appears to modify pain response and underlying neural circuitry, suggesting neural changes in interoception may serve as biomarkers for mind-body interventions in cLBP. This study highlights the potential of MyP as a novel approach for cLBP management, warranting further investigation.

Qingchang suppository ameliorates mucosal inflammation in ulcerative colitis by inhibiting the differentiation and effector functions of Th1 and Th17 cells

Ethnopharmacological relevanceQing Chang Suppository (QCS), a traditional Chinese medicine formula, has been shown to effectively alleviate mucosal inflammation in patients with ulcerative colitis (UC). While the mechanism of QCS appears to be related to the regulation of CD4+T cell subset responses, direct evidence demonstrating that QCS inhibits Th1 and Th17 cell activation in UC (particularly based on human data) remains lacking. Additionally, the precise mechanisms through which QCS affects these cells have yet to be fully elucidated. Aim of studyThis study aimed to investigate the effects of QCS on Th1 and Th17 cell responses in UC and to explore the underlying mechanisms. Materials and methodsTwenty-eight patients with mild-to-moderate UC were recruited and treated with QCS for 12 weeks. Symptoms were assessed every two weeks, with sigmoidoscopies performed at baseline and at week 12. Intestinal mucosal biopsies and peripheral blood (PB) were collected at these time points. At the end of the trial, patients were categorized into responder and non-responder groups based on a modified Mayo disease activity index score. Healthy controls (HCs) were defined as subjects without IBD or colorectal carcinoma but with colon polyps. The frequencies of IFN-γ+CD4+T cells and IL-17A+CD4+T cells in PB and colonic mucosa were measured using flow cytometry. The expression levels and localization of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A were determined via immunofluorescence, and JNK signaling activation was assessed through immunoblotting and immunohistochemistry. All parameters were compared across the three groups. ResultsAt week 12, responders showed a significant reduction in colonic mucosal inflammation compared to baseline, accompanied by decreased frequencies of IFN-γ+CD4+T and IL-17A+CD4+ T cells in both PB and the colonic epithelial layer. Notably, Th1 and Th17 cell activity around intestinal epithelial cells (IECs) was nearly undetectable, as evidenced by the diminished expression of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A. Additionally, JNK phosphorylation in these cells was significantly reduced. In contrast, non-responders exhibited no meaningful improvement; colonic pathology remained unchanged, and elevated levels of IFN-γ+CD4+T and IL-17A+CD 4+T cells persisted in both the PB and colonic epithelial layer. The presence of Th1 and Th17 cells and their associated cytokines around IECs remained substantial, and there was no significant change in JNK activation. ConclusionQCS attenuates mucosal inflammation in UC patients by inhibiting the differentiation and effector functions of Th1 and Th17 cells, primarily through the regulation of the JNK signaling pathway.