Good Response Group Research Articles

Responsiveness of anti-VEGF treatment for polypoidal choroidal vasculopathy based on aqueous humour proteomics: A preliminary study.

Patients with polypoidal choroidal vasculopathy (PCV) exhibit variability in response to anti-VEGF therapy. This study aimed to analyse the aqueous humour proteomic profiles of PCV patients and provide preliminary insights for the identification of biomarkers associated with anti-VEGF drug responsiveness. PCV patients who were treatment-naïve or untreated for more than 3 months were prospectively recruited from two hospitals in Beijing and Tianjin. Based on the relative changes in central macular thickness (ΔCMT/baseline-CMT) before and after anti-VEGF treatment, the PCV patients were divided into a good response (GR) group (≤-25%) and a poor response (PR) group (>-25%). Aqueous humour proteomics was performed by the Data-independent Acquisition-Mass Spectrometry (DIA-MS) method, and differentially expressed proteins (DEPs) analysis between the different PCV groups and the control group was conducted. Key DEPs were selected for preliminary validation in the aqueous humour using the Luminex method retrospectively. A total of 31 PCV patients (31 eyes) were included, 13 in the GR group and 18 in the PR group. A total of 414 DEPs were identified, including 36 significantly upregulated proteins, such as G protein regulatory factor 10 (RGS10), podocin (PODN) and epidermal growth factor (EGF), and 32 downregulated proteins, including RAB11FIP4 (Rab11 family-interacting protein 4), α-synuclein (SNCA), haemoglobin subunit δ (HBD) and interleukin 6 (IL6). Compared to the cataract control group (10 eyes), 134 proteins were significantly upregulated, and 72 were downregulated. KEGG pathway enrichment analysis revealed that the GR and PR groups differ in terms of cell communication, and cell signal transduction. Protein-protein interaction analysis revealed interactions between EGF and various DEPs. Validation of aqueous humour proteins using the Luminex method revealed that changes in the levels of EGF were associated with the anti-VEGF treatment response in PCV patients. PCV patients with good or poor anti-VEGF responses exhibit distinct aqueous humour proteomic profiles. Aqueous EGF may serve as a biomarker for the 'precise treatment' of PCV.

18F]AlF-NOTA-FAPI-04 PET/CT for Predicting Pathologic Response of Resectable Esophageal Squamous Cell Carcinoma to Neoadjuvant Camrelizumab and Chemotherapy: A Phase II Clinical Trial.

This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of 18F-labeled fibroblast activation protein inhibitor ([18F]AlF-NOTA-FAPI-04, denoted as 18F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent 18F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On 18F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUVmax (area under the curve [AUC], 0.87; P = 0.0026), SUVpeak (AUC, 0.89; P = 0.0017), SUVmean (AUC, 0.88; P = 0.0021), TBRmax (AUC, 0.86; P = 0.0031), and TBRmean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%-81.82% and specificities of 83.33%-100%. Changes in SUVmax (AUC, 0.81; P = 0.0116), SUVpeak (AUC, 0.82; P = 0.0097), SUVmean (AUC, 0.81; P = 0.0116), and TBRmean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: 18F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants.

Significant drop in serum C-reactive protein in patients with solid neoplasia and bacterial infection is associated with a better prognosis and identifies candidates for short-course antibiotic therapy

IntroductionThe greater predisposition to infections, as well as the possibility of a worse response to treatment, can lead to the excessive use of antimicrobials among cancer patients. C-reactive protein (CRP) has gained prominence as a tool for monitoring therapeutic responses and reducing the duration of antibiotic therapy; however, few studies have analyzed this protein in cancer patient populations. We hypothesize that cancer patients with a good response to antibiotic therapy show a faster decline in serum CRP levels, which would allow us to identify candidates for short-course treatments.ObjectiveTo evaluate the behavior of serum CRP levels among adult cancer patients using antibiotic therapy, and its association with the duration of this treatment, therapeutic response, and clinical recurrence.MethodsThis work consisted of a retrospective study with cancer patients admitted to a university hospital between September 2018 and December 2019. Adults (age ≥ 18 years) who underwent at least one course of antibiotic therapy were included. CRP behavior over the first 7 days of treatment was classified as: i) good response: when the CRP value on the fifth day of therapy reached 50% or less of the peak value detected in the first 48 h of treatment, and ii) poor response: Maintenance, within the same interval, of a CRP value > 50% of the peak value in the first 48 h. The duration of antibiotic therapy was categorized as up to seven full days or more. Outcomes were assessed by events that occurred during the 30 days of hospitalization or until hospital discharge. Primary outcome: Clinical recurrence of the index infection. Secondary outcomes: i) Death from any cause; ii) microbiological recurrence; iii) therapeutic response; iv) colitis associated with Clostridioides difficile; and v) isolation of multi-resistant bacteria, whether in clinical or surveillance samples.ResultsThe final analysis consisted of 212 patients, with a median age (IQ) of 59.2 (48 – 67) years old and a predominance of females (65%), who were hypertensive (35%), smokers (21%), and diabetics (17.8%). There was no difference in clinical recurrence between the two groups (8.1% vs. 12.2%; p = 0.364), with a lower 30-day mortality in the good CRP response group (32.2% vs. 14.5%; p = 0.002). Despite the tendency towards a lower occurrence of other secondary outcomes in the good response group, these differences were not statistically significant. In the poor CRP response group, outcomes like clinical recurrence, mortality, and therapeutic response were significantly worse, regardless of the duration of antibiotic treatment.ConclusionIn this study, cancer patients with a good CRP response during antibiotic therapy presented lower mortality and a higher proportion of satisfactory therapeutic responses. CRP can be a useful tool when combined with other clinical information in optimizing the duration of antimicrobial treatment in a hospitalized cancer population.

Prediction on the chin advancement of the twin block functional appliance in growing Chinese patients using the cephalometric markers: a retrospective study.

In spite of the widespread use of functional appliances, broad variations were applied the treatment response. The aim of this study is to investigate the pre-treatment cephalometric predictors on the chin advancement of twin-block in growing Chinese patients with class II malocclusion. After screening, 90 patients treated by twin-block were included in the study. The treatment outcome was assessed by the alterations in the distance of skeletal pogonion (Pog) to the vertical reference plane perpendicular to the Frankfurt plane (ΔPog-VRP). Moreover, ΔPog-VRP was divided by the cranial growth indicated by the Nasion to Basion changes (ΔN-Ba) to minimize the growth discrepancy among individuals (adjΔPog-VRP). Patients with ΔPog-VRP/adjΔPog-VRP above the median value were categorized into good response group (GRG/adjGRG, N = 45), while the rest were poor response group (PRG/adjPRG, N = 45). Independent t-test was used to compare the pre-treatment cephalometric measurements between GRG/adjGRG and PRG/adjPRG. Stepwise multivariate regression models were used to determine the pre-treatment cephalometric predictors for the chin advancement. Generally, there were not any significant differences between GRG/adjGRG and PRG/adjPRG regarding age, gender and cervical stage before twin-block treatment. Patients from GRG had significantly reduced cephalometric measurements in the vertical dimensions, including ∠N-Go-Me, ∠Mandibular plane-Occlusal plane (∠MP-OP) and the sum of angles (p < 0.05) in comparison to PRG. When the individual growth was taken account, similar findings were observed. The patients from adjGRG had a significantly lower ∠Sella Nasion line-MP (∠SN-MP), ∠Ar-Go-Me and ∠N-Go-Me, as well as an increased Posterior facial height (PFH)/Anterior facial height (AFH) (p < 0.05) compared with their counterparts. ∠N-Go-Me variable was the independent predictor on Pog advancement with (β = -0.26, 95% CI: -0.06 to -0.01, p = 0.01) and without (β = -0.29, 95% CI: -0.06 to -0.01, p < 0.01) adjustments on individual growth. The results of this study showed that patients with a reduced N-Go-Me angle are more likely to experience a greater chin advancement following twin-block treatment.

Alterations in functional brain connectivity following treatment for restless legs syndrome: The role of symptom improvement in restoring functional connectivity.

The pathophysiology of restless legs syndrome (RLS) remains incompletely understood. Although several studies have investigated the alterations of brain connectivity as one of the pathophysiological mechanisms of RLS, there are only few reports on functional connectivity changes after RLS treatment. Forty-nine patients with newly diagnosed RLS and 50 healthy controls were prospectively enrolled. The patients underwent resting-state functional magnetic resonance imaging (rs-fMRI) at baseline, and 39 patients underwent follow-up rs-fMRI, 3 months after treatment with pramipexole or pregabalin. Patients were divided into good or poor medication response groups. Functional brain connectivity was analysed using rs-fMRI and graph theoretical analysis. Significant differences in functional connectivity were observed between the RLS patients and healthy controls. The average path length, clustering coefficient, transitivity, and local efficiency were lower (2.02 vs. 2.30, p < 0.001; 0.45 vs. 0.56, p < 0.001; 3.08 vs. 4.21, p < 0.001; and 0.71 vs. 0.76, p < 0.001, respectively) and the global efficiency was higher (0.53 vs. 0.50, p < 0.001) in patients with RLS than in healthy controls. Differences in functional connectivity at the global level were also observed between post- and pre-treatment RLS patients who showed a good medication response. Transitivity in the post-treatment group was higher than that in the pre-treatment group (3.22 vs. 3.04, p = 0.007). Global efficiency was positively correlated with RLS severity (r = 0.377, p = 0.007). This study demonstrates that RLS is associated with distinct alterations in brain connectivity, which can be partially normalised following symptom management. These findings suggest that therapeutic interventions for RLS modulate brain function, emphasising the importance of symptom-focussed treatment in managing RLS.

Multi-parametric MRI radiomics for predicting response to neoadjuvant therapy in patients with locally advanced rectal cancer.

This study aims to evaluate the application value of multi-parametric magnetic resonance imaging (MRI) radiomics in predicting the response of patients with locally advanced rectal cancer (LARC) to neoadjuvant chemoradiotherapy(nCRT), aiming to provide non-invasive biomarkers for clinical decision-making in personalized treatment. A retrospective analysis was conducted on the clinical data and imaging records of patients with LARC who received nCRT and total mesorectal excision (TME) in two medical centers from 2017 to 2023. The patients were divided into a training group and a test group in a 7:3 ratio. Through radiomics analysis, radiomics features of tumor volume and mesorectal fat at baseline, before and after neoadjuvant therapy were extracted. Radiomics models based on single sequences (T2WI, DWI) and multi-sequence fusion were constructed, and the logistic regression classifier model was used to evaluate the prediction performance. A total of 82 patients were included, with 30 in the good response group and 52 in the poor response group. Through the selection of radiomics features, radiomics models based on baseline MRI of tumor volume, mesorectal fat, and differences before and after treatment (Delta) were constructed. The area under the receiver operating characteristic curve (AUC) of the multi-parametric radiomics fusion model in the training and test groups was 0.852 and 0.848, respectively, showing high prediction performance and good calibration. This study demonstrates that the multi-parametric MRI radiomics model can effectively predict the response of patients with locally advanced rectal cancer to neoadjuvant chemoradiotherapy. Especially, the fusion model provides high accuracy and good calibration. This result is conducive to the formulation of personalized treatment plans and optimization of treatment strategies.

Switching to Intravitreal Brolucizumab after Ranibizumab or Aflibercept Using Treat and Extend Regimen for Neovascular Age-Related Macular Degeneration in Japanese Patients: 1-Year Results and Factors Associated with Treatment Responsiveness.

Objective: To purpose of this study was to retrospectively evaluate the 1-year outcomes and factors associated with the treatment responsiveness of switching to intravitreal brolucizumab (IVBR) for neovascular age-related macular degeneration (nAMD) in Japanese patients refractory to ranibizumab or aflibercept using a treat and extend (TAE) regimen. Methods: A total of 48 eyes of 47 nAMD patients were switched to IVBR, and 36 eyes of 35 patients (27 males and 8 females) underwent 1-year treatment after the switch. Results: The rate of dry macula was significantly higher 12 months after the switch to IVBR (p < 0.001), with a significant decrease in the mean central macular thickness (CMT) and the mean central choroidal thickness (CCT) (p < 0.01 and p < 0.01, respectively). The injection interval was significantly extended from 7.0 ± 1.7 weeks to 10.3 ± 2.5 weeks 12 months after the switch (p < 0.001). In the multivariate analysis, a smaller number of prior anti-VEGF injections (p = 0.025; odds ratio: 0.947; 95% confidence interval: 0.903-0.994) and a pre-switching CCT of less than 250 µm (p = 0.023; odds ratio: 0.099; 95% confidence interval: 0.013-0.731) were associated with the good response group. Conclusions: These results suggest that IVBR may suppress disease activity and prolong the injection interval by switching for AMD patients with an insufficient response to treatment with ranibizumab and aflibercept.

Evaluation of pathological response to neoadjuvant chemotherapy in locally advanced cervical cancer

Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.

Serum GM-CSF level is a predictor of treatment response to tocilizumab in rheumatoid arthritis patients: a prospective observational cohort study

BackgroundThe aim of this prospective observational cohort study was to unveil the predictors of treatment response to tocilizumab (TCZ) therapy in rheumatoid arthritis (RA) patients, in terms of clinical characteristics and serum proinflammatory cytokines, especially to explore the predictive value of granulocyte macrophage-colony stimulating factor (GM-CSF).MethodsActive adult RA patients with inadequate response to MTX intending to receive TCZ therapy were recruited prospectively in the study. A total of 174 severe RA patients were included for the identification of the associations between treatment response and the following characteristic features: demographics, medications, disease activity, serum proinflammatory cytokines and so on.ResultsDisease duration (OR = 0.996), tender joint count (TJC)/68 (OR = 0.943), neutrophil ratio (W4/baseline) (OR = 0.224), the high level of GM-CSF > 5 ng/ml (OR = 0.414) at baseline were the independent adverse predictors of good response assessed by clinical disease activity index (CDAI) at week 24 (W24) for TCZ therapy in RA patients. Moreover, DAS28-ESR (OR = 2.951, P = 0.002) and the high level of GM-CSF > 10 ng/ml at baseline (OR = 5.419, P = 0.002) were independent predictors of poor response, but not the high level of GM-CSF > 5 ng/ml (OR = 2.713, P = 0.054). The patients in the high GM-CSF group had significantly higher DAS28-ESR and serum levels of cytokines (IL-17A, IL-1β, IL-6, TNF-α) at baseline, as well as significantly higher rate of non-good response (62.8% vs. 39.4%, P = 0.010) and poor response (27.9% vs. 9.1%, P = 0.004) than the low GM-CSF group at W24. In addition, poor responders had significantly higher levels of GM-CSF with concomitant increase in the serum levels of IL-17A and IL-1β at baseline than those in moderate and good response groups, while serum levels of IL-6 and TNF-α at baseline were not significantly different in three response groups.ConclusionThe high levels of GM-CSF (> 5 ng/ml and > 10 ng/ml) at baseline were the independent predictors of non-good response and poor response to TCZ at W24 respectively. The high level of GM-CSF at baseline is a marker of high disease activity and a predictor of poor response to TCZ in severe RA patients, which may facilitate the development of individualized treatment strategies for refractory RA.

Predictive value of circulating lymphocyte subsets and inflammatory indexes for neoadjuvant chemoradiotherapy response in rectal mucinous adenocarcinoma patients: A machine learning approach.

In this study, we aimed to evaluate the predictive value of circulating lymphocyte subsets and inflammatory indexes in response to neoadjuvant chemoradiotherapy (NCRT) in patients with rectal mucinous adenocarcinomas (MACs). Rectal MAC patients who underwent NCRT and curative resection at Fujian Medical University Union Hospital's Department of Colorectal Surgery between 2016 and 2020 were included in the study. Patients were categorized into good and poor response groups based on their pathological response to NCRT. An independent risk factor-based nomogram model was constructed by utilizing multivariate logistic regression analysis. Additionally, the extreme gradient boosting (XGB) algorithm was applied to build a machine learning (ML)-based predictive model. Feature importance was quantified using the Shapley additive explanations method. Out of the 283 participants involved in this research, 190 (67.1%) experienced an unfavorable outcome. To identify the independent risk factors, logistic regression analysis was performed, considering variables such as tumor length, pretreatment clinical T stage, PNI, and Th/Tc ratio. Subsequently, a nomogram model was constructed, achieving a C-index of 0.756. The ML model exhibited higher prediction accuracy than the nomogram model, achieving an AUROC of 0.824 in the training set and 0.762 in the tuning set. The top five important parameters of the ML model were identified as the Th/Tc ratio, neutrophil to lymphocyte, Th lymphocytes, Gross type, and T lymphocytes. Radiochemotherapy sensitivity is markedly influenced by systemic inflammation and lymphocyte-mediated immune responses in rectal MAC patients. Our ML model integrating clinical characteristics, circulating lymphocyte subsets, and inflammatory indexes is a potential assessment tool that can provide a reference for individualized treatment for rectal MAC patients.

Circulating tumor DNA as a predictor of treatment response to neoadjuvant chemotherapy in stage 2/3 rectal cancer without high risks: Subset analysis from the COPEC trial.

e15623 Background: Circulating tumor DNA (ctDNA) serves as a valuable tool for minimal residual disease (MRD) assessment. It has been reported as a promising noninvasive biomarker for the dynamic monitoring of treatment response of metastatic colorectal cancers to chemotherapy and locally advanced rectal cancers (LARC) to neoadjuvant chemoradiotherapy. However, the potential role of ctDNA in neoadjuvant chemotherapy (NCT) in LARC remains unexplored. The present study aims to investigate the value of ctDNA in NCT based on a prospective, multicentered, non-inferior, randomized, controlled trial (ClinicalTrials.gov ID, NCT04922853). The COPEC trial enrolls stage 2/3 LARC with low or intermediate and is designed to determine the optimal time (after 2 or 4 cycles of CAPOX) to evaluate treatment response based on pathological regression grades. Methods: Colonoscopy biopsy was taken before neoadjuvant therapy. Peripheral blood samples were collected before neoadjuvant (baseline, BL), one cycle (C1) and two cycles (4-cycle group, C2) after NCT, before surgery (BS), and within one month after surgery (postoperative, OP). All tissue biopsy and plasma specimens were analyzed by NGS assays using the MinerVA platform (Genecast Biotechnology Co., Ltd). MRI tumor regression grade (mrTRG) was assessed after 2 and 4 cycles (4-cycle group) of NCT. The primary outcome was the accuracy of ctDNA in the prediction of pathological tumor regression grade (pTRG). Results: A total of 151 LARC patients were enrolled, including 82 in the 2-cycle group and 69 in the 4-cycle group. The ctDNA was detectable in 87.4% (132/151), 39.6% (55/139), 29.0% (18/62), 38.4% (58/151), and 4.4% (6/138) at BL, C1, C2, BS and OP, respectively. The ctDNApositivity rates were significantly lower in good responders determined by mrTRG (mrTRG 1-3) compared to mrTRG 4-5 group at C1 (29% vs. 63.89%, p &lt; 0.001), C2 (20% vs.56.25%, p = 0.011), and BS time points (23.85% vs. 74.36%, p &lt; 0.001). Furthermore, the ctDNA-positivity rates at C1 in the good response group determined by TRG (pTRG 0-1) were 6.25%, significantly lower than that in the pTRG 2-3 group (49.53%). At neither C2 nor BS time point, patients in the pTRG 0-1 subgroup were detected as ctDNA positive while the ctDNA positivity rates for patients in pTRG 2-3 subgroup were 39.13% and 50%, respectively. Additionally, the mean of hGE/ml was 0.045 in pTRG 0-1 group at C1, significantly lower comparing to 1.337 in pTRG 2-3 group (p &lt; 0.001). Conclusions: We find that dynamic monitoring of ctDNA status was a useful tool in early predicting the effect of (treatment response to) NCT in LARC patients with low/intermediate risks. The monitoring of ctDNA status can supplement MRI in determining the NCT response and could potentially help identify poor responders to discontinue the treatment with inadequate efficacy. Clinical trial information: NCT04922853 .

Machine learning–based response assessment in patients with rectal cancer after neoadjuvant chemoradiotherapy: radiomics analysis for assessing tumor regression grade using T2-weighted magnetic resonance images

PurposeThis study aimed to assess tumor regression grade (TRG) in patients with rectal cancer after neoadjuvant chemoradiotherapy (NCRT) through a machine learning–based radiomics analysis using baseline T2-weighted magnetic resonance (MR) images.Materials and methodsIn total, 148 patients with locally advanced rectal cancer(T2-4 or N+) who underwent MR imaging at baseline and after chemoradiotherapy between January 2010 and May 2021 were included. A region of interest for each tumor mass was drawn by a radiologist on oblique axial T2-weighted images, and main features were selected using principal component analysis after dimension reduction among 116 radiomics and three clinical features. Among eight learning models that were used for prediction model development, the model showing best performance was selected. Treatment responses were classified as either good or poor based on the MR-assessed TRG (mrTRG) and pathologic TRG (pTRG). The model performance was assessed using the area under the receiver operating curve (AUROC) to classify the response group.ResultsApproximately 49% of the patients were in the good response (GR) group based on mrTRG (73/148) and 26.9% based on pTRG (28/104). The AUCs of clinical data, radiomics models, and combined radiomics with clinical data model for predicting mrTRG were 0.80 (95% confidence interval [CI] 0.73, 0.87), 0.74 (95% CI 0.66, 0.81), and 0.75(95% CI 0.68, 0.82), and those for predicting pTRG was 0.62 (95% CI 0.52, 0.71), 0.74 (95% CI 0.65, 0.82), and 0.79 (95% CI 0.71, 0.87).ConclusionRadiomics combined with clinical data model using baseline T2-weighted MR images demonstrated feasible diagnostic performance in predicting both MR-assessed and pathologic treatment response in patients with rectal cancer after NCRT.

Correlation of High-Grade Osteosarcoma Response to Chemotherapy with Enhanced Tissue Immunological Response: Analysis of CD95R, IFN-γ, Catalase, Hsp70, and VEGF

High-grade osteosarcoma, a primary malignant bone tumour, is experiencing a global increase in reported incidence with varied prevalence. Despite advances in management, which include surgery and neoadjuvant chemotherapy often an unsatisfactory outcome is found due to poor or heterogeneous response to chemotherapy. Our study delved into chemotherapy responses in osteosarcoma patients and associated molecular expressions, focusing on CD95 receptor (CD95R), interferon (IFN)-γ, catalase, heat-shock protein (Hsp)70, and vascular endothelial growth factor (VEGF). Employing immunohistochemistry and Huvos grading of post-chemo specimens, we analysed formalin-fixed paraffin-embedded (FFPE) osteosarcoma tissue of resected post-chemotherapy specimens from Dr. Soetomo General Academic Hospital in Surabaya, Indonesia (DSGAH), spanning from 2016 to 2020. Results revealed varied responses (poor 40.38%, moderate 48.08%, good 11.54%) and distinct patterns in CD95R, IFN-γ, catalase, Hsp70, and VEGF expression. Significant differences among response groups were observed in CD95R and IFN-γ expression in tumour-infiltrating lymphocytes. The trend of diminishing CD95R expression from poor to good responses, accompanied by an increase in IFN-γ, implied a reduction in the count of viable osteosarcoma cells with the progression of Huvos grading. Catalase expression in osteosarcoma cells was consistently elevated in the poor response group, while Hsp70 expression was highest. VEGF expression in macrophages was significantly higher in the good response group. In conclusion, this study enhances our understanding of immune-chemotherapy interactions in osteosarcoma and identifies potential biomarkers for targeted interventions.

Evaluation of inflammatory biomarkers and the ratio of hemoglobin-red cell distribution width in patients with rheumatoid arthritis treated with tumor necrosis factor-alpha inhibitors.

The aim of this study was to examine pre-treatment and post-treatment hemogram-derived inflammatory biomarkers in patients with rheumatoid arthritis (RA) who received anti-tumor necrosis factor (TNF)-α treatment. The data of 1182 patients with RA were screened. Among them, 207 patients who met the eligibility criteria were included in the retrospective study. Demographic parameters, disease activity, and blood cell-derived indexes were evaluated. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and hemoglobin-red cell distribution width (Hb/RDW) rates were evaluated before treatment and at the third month of treatment in patients with RA who received anti-TNF-α treatment. According to the EULAR response criteria, 12.6% of the 207 patients responded to anti-TNF-α treatment as none, 21.3% as good, and 66.2% as moderate, respectively. Post-treatment NLR and PLR values were significantly lower than pre-treatment values (p < 0.001), whereas post-treatment LMR and Hb/RDW values were significantly higher than pre-treatment values (respectively, p = 0.001 and p = 0.012). The difference between pre-treatment and post-treatment values of LMR and Hb/RDW was significantly higher when compared to the moderate + good response groups than the none-response group (p = 0.002 and p = 0.014, respectively). However, in the receiver operating characteristic curve analysis, these parameters were not found to be significant in predicting treatment response. Significant changes were detected in hemogram-derived inflammatory markers of the groups responding to anti-TNF-α treatment. They can be used as a guide during treatment follow-up. Yet, they do not predict treatment response. Key Points • RA may manifest with periods of remission and activation, and regular follow-up is essential. • There is a demand for readily available, reproducible, and cost-effective parameters to assess treatment response. • Hemogram-derived inflammatory markers differ in relation to anti-TNF-α treatment response in RA. • None of those markers demonstrate an acceptable predictive performance in distinguishing patients based on their response to TNF-α inhibitors.

Development and Validation of an Inflammatory Prognostic Index to Predict Outcomes in Advanced/Metastatic Urothelial Cancer Patients Receiving Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) improve overall survival (OS) in advanced/metastatic urothelial cancer (a/mUC) patients. Preliminary evidence suggests a prognostic role of inflammatory biomarkers in this setting. We aimed to develop a disease-specific prognostic inflammatory index for a/mUC patients on ICIs. Fifteen variables were retrospectively correlated with OS and progression-free survival (PFS) in a development (D, n = 264) and a validation (V, n = 132) cohort of platinum-pretreated a/mUC pts receiving ICIs at L2 or further line. A nomogram and inflammatory prognostic index (U-IPI) were developed. The index was also tested in a control cohort of patients treated with chemotherapy only (C, n = 114). The strongest predictors of OS were baseline platelet/lymphocyte (PLR) and neutrophil/lymphocyte (NLR) ratios, and lactate dehydrogenase (LDH), NLR, and albumin changes at 4 weeks. These were used to build the U-IPI, which can distinctly classify patients into good or poor response groups. The nomogram scoring is significant for PFS and OS (p < 0.001 in the D, V, and combined cohorts) for the immunotherapy (IO) cohort, but not for the control cohort. The lack of a baseline systemic inflammatory profile and the absence of early serum inflammatory biomarker changes are associated with significantly better outcomes on ICIs in a/mUC pts. The U-IPI is an easily applicable dynamic prognostic tool for PFS and OS, allowing for the early identification of a sub-group with dismal outcomes that would not benefit from ICIs, while distinguishing another that draws an important benefit.

The quantitative parameters based on marrow metabolism derived from synthetic MRI: A pilot study of prognostic value in participants with newly diagnosed multiple myeloma.

The value of SyMRI-derived parameters from lumbar marrow for predicting early treatment response and optimizing the risk stratification of the Revised International Staging System (R-ISS) in participants with multiple myeloma (MM) is unknown. We prospectively enrolled participants with newly diagnosed MM before treatment. The SyMRI of lumbar marrow was used to calculate T1, T2, and PD values and the clinical features were collected. All participants were divided into good response (≥VGPR) and poor response (<VGPR) groups after four treatment cycles. Univariate, multivariate analyses and ROC were used to identify prognostic significance. Mann-Whitney U-tests were used to compare the SyMRI parameters between genders. The value of optimizing the risk stratification was analyzed by Fisher's exact tests at each R-ISS stage. Fifty-nine participants (good response, n = 33; poor response, n = 26) were evaluated. The bone marrow plasma cell percentage, β2-microglobulin, T1 and T2 value were difference between two groups (all p < 0.05). The T1 (odds ratio 1.003, p = 0.005) and T2 values (odds ratio 0.910, p = 0.002) were independent predictors and the AUC and cut-off values were 0.787, 967.2 ms and 0.784, 75.9 ms, respectively. There were no significant differences in SyMRI parameters between genders. Participants with both T1 value ≥967.2 ms and T2 value ≤75.9 ms in the R-ISS II stage were potentially to get poor response. Synthetic MRI is a promising tool for predicting early treatment response to MM and promoting R-ISS II stage risk stratification.

Prognosis of a Heterogeneous TRG Pathological Response to Neoadjuvant Chemotherapy in Patients who Undergo Resection for Colorectal Liver Metastases.

Optimal management of colorectal liver metastasis (CRLM) is based on a combination of chemotherapy and surgical resection. The tumor regression grade (TRG) score is a histological scoring system to evaluate response to chemotherapy. The prognosis of a heterogeneous response in cases of multiple metastases has not been evaluated according to the TRG score. All patients who underwent liver resection for multiple CRLM after neoadjuvant chemotherapy in two tertiary centers from January 2015 to April 2019 were retrospectively included. Oncological characteristics and outcome between TRG 1-2-3 (good response group), TRG 4-5 (poor response group) and heterogeneous TRG (good and poor TRG among different lesions within the same patient) groups were compared. Among the 327 patients included, 134 (41.0%) had good response (TRG 1-2-3), 120 (36.7%) had poor response (TRG 4-5), and 73 (22.3%) had heterogeneous response. The type and number of cycles of chemotherapy, k-Ras mutational status, and tumor number or size did not differ between the three groups. Use of irinotecan-based and anti-VEGF neoadjuvant therapy was associated with better TRG response [irinotecan-based: hazard ratio (OR) = 1.744; p = 0.045; anti-VEGF neoadjuvant therapy: 2.054; p = 0.005). Overall survival (OS) was higher in the 1-2-3 TRG group than in the heterogeneous TRG group (2-year OS = 81.3% vs. 60.3%, respectively; p = 0.003) and the 4-5 TRG group (2-year OS = 81.3% vs. 55.0%, respectively; p = 0.012) and similar between the heterogeneous and 4-5 TRG groups. The proportion of heterogeneous pathological response according to TRG is 22.3%, and the prognosis is comparable to that of poor pathological response.

Abstract 7209: Overcoming platinum resistance of high-grade serous ovarian cancer targeting the activated JAK/STAT pathways via extracellular vesicles

Abstract High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. While HGSOC usually responds to initial treatment, most cases eventually relapse and develop platinum-resistant ovarian cancer (PROC). The molecular definition of PROC is still unclear, and overcoming PROC has been the biggest challenges. Extracellular vesicles (EVs) have an essential role in cell-to-cell communication within both the primary and distant microenvironments. In this study. we aimed to identify molecular mechanisms of PROC via EVs to suggest novel therapeutic strategies. Platinum responses were categorized by primary treatment-free interval of platinum less than 6 months as PROC, and more than 36 months as platinum good response. Ascites and tumor tissues have been collected prior to initial chemotherapy in patients with HGSOC for analysis according to platinum response. mRNA sequencing in tumor tissues identified significantly upregulated JAK/STAT pathways in PROC. The JAK/STAT family was highly expressed in PROC than the good response group, and also increased than adjusted normal ovaries and fallopian tubes. In addition, PROC cell lines and PROC patient-derived xenograft model tumor tissues showed high JAK expression. Small RNA sequencing for HGSOC tissues and ascites-EVs revealed that miR-135a-5p and miR-221-5p were highly expressed in both PROC tissues and ascites, and the expression of the two miRNAs had a positive correlation between tissues and ascites. Overexpression of the two miRNAs in HGSOC cell lines resulted in higher JAK family expression and resistance to cisplatin. JAK inhibitors (JAKi) had equivalent efficacy for platinum-sensitive/resistant HGSOC cell lines and JAKi highly suppress tumor growth in the PROC mouse model. In addition, suppression of JAK family expression in PROC cell lines significantly increased sensitivity to cisplatin. JAKi also had a synergistic effect with cisplatin for PROC cell lines. IPA analyses in mRNA sequencing in tumor tissues, TGF-β was highly expressed in upstream regulators in PROC, and TGF-β stimulation resulted in the upregulation of the two miRNAs in mesothelial cells, but not in HGSOC cell lines and fibroblasts. In summary, we here demonstrate novel molecular mechanisms of PROC via EVs and provided the rationale for JAK-targeted therapy for PROC. EV-miRNAs can regulate the PROC activated JAK/STAT pathway and can be diagnostic and therapeutic biomarkers for PROC definition or JAKi indications, suggesting that patient stratification in precision medicine for initial treatment of HGSOC. Citation Format: Kazuhiro Suzuki, Akira Yokoi, Kousuke Yoshida, Yusuke Yamamoto, Hiroaki Kajiyama. Overcoming platinum resistance of high-grade serous ovarian cancer targeting the activated JAK/STAT pathways via extracellular vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7209.

Predictive effect of the systemic inflammation response index (SIRI) on the efficacy and prognosis of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer

BackgroundInflammation is a part of tumours, and inflammatory cells can affect the proliferation, invasion, and development of tumour cells. An increasing number of peripheral blood inflammatory markers have been found to play very important roles in the treatment and prognosis of cancer patients. The systemic inflammatory response index (SIRI) is a newer inflammatory marker, and its role in colorectal cancer, especially in locally advanced rectal cancer, is still unclear.MethodsFrom 2015 to 2020, 198 patients with locally advanced rectal cancer (LARC) who underwent surgery following neoadjuvant chemoradiotherapy (Neo-CRT) were analysed. Patients were categorized into good- and poor- response groups according to their pathological results, and clinical characteristics and baseline parameters were compared between the two groups. The optimal cutoff values for inflammatory indicators were determined using receiver operating characteristic (ROC) analysis. Univariate and multivariate analyses were performed using the Cox proportional hazard model. Survival analysis was performed via the Kaplan‒Meier method.ResultsAfter patients were grouped into good and poor response groups, indicator differences were found in CEA, neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and SIRI. According to the ROC analysis, the NLR (P = 0.015), SII (P = 0.001), and SIRI (P = 0.029) were significant prognostic factors. After univariate and multivariate analyses of the Cox proportional hazards regression model, only the SIRI was found to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS). Finally, Kaplan‒Meier survival curves also confirmed the ability of the SIRI to predict survival.ConclusionThe preoperative SIRI can be used to predict the response to Neo-CRT in LARC patients and is an independent predictor of OS and DFS in postoperative patients. A high SIRI was associated with poor radiotherapy response and predicted poor OS and DFS.

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

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