Non-response Patients Research Articles

Multi-omics analysis and response prediction of PD-1 monoclonal antibody containing regimens in patients with relapsed/refractory diffuse large B-cell lymphoma

Patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) show varied responses to PD-1 monoclonal antibody (mAb) containing regimens. The mechanisms and predictive biomarkers for the efficacy of this regimen are unclear. This study retrospectively collected r/r DLBCL patients who received PD-1 mAb and rituximab regimens as salvage therapy. Clinical and genomic features were collected, and mechanisms were explored by multiplex immunofluorescence and digital spatial profiling. An artificial neural network (ANN) model was constructed to predict the response. Between October 16th, 2018 and May 4th, 2023, 50 r/r DLBCL patients were collected, 29 were response patients and 21 were non-response patients. CREBBP (p = 0.029) and TP53 (p = 0.015) alterations were statistically higher in non-response patients. Patients with PD-L1 CPS ≥ 5 were correlated with a longer overall survival (OS) than those with PD-L1 CPS < 5 (median OS: not reached vs. 9.7 months, hazard ratio [HR]: 3.8, 95% confidence interval [CI] 0.64–22.44, p = 0.016). Immune-related pathways were activated in response patients. The proportion and spatial organization of tumor-infiltrating immune cells affect the response. PD-L1 CPS level, age, and alterations of TP53, MYD88, CREBBP, EP300, GNA13 were used to build an ANN predictive model that showed high prediction efficiency (training set area under curve [AUC] of 0.97 and test set AUC of 0.94). The proportion and spatial distribution of tumor-infiltrating immune cells may be related to the function of immune-related pathways, thereby influencing the efficacy of PD-1 mAb containing regimens. The ANN predictive model showed potential value in predicting the responses of r/r DLBCL patients received PD-1 mAb and rituximab regimens.

Intestinal mRNA expression profiles associated with mucosal healing in ustekinumab-treated Crohn's disease patients: bioinformatics analysis and prospective cohort validation

BackgroundVariations exist in the response of patients with Crohn’s disease (CD) to ustekinumab (UST) treatment, but the underlying cause remains unknown. Our objective was to investigate the involvement of immune cells and identify potential biomarkers that could predict the response to interleukin (IL) 12/23 inhibitors in patients with CD.MethodsThe GSE207022 dataset, which consisted of 54 non-responders and 9 responders to UST in a CD cohort, was analyzed. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the most powerful hub genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performances of these genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to estimate the proportions of immune cell types. These significantly altered genes were subjected to cluster analysis into immune cell-related infiltration. To validate the reliability of the candidates, patients prescribed UST as a first-line biologic in a prospective cohort were included as an independent validation dataset.ResultsA total of 99 DEGs were identified in the integrated dataset. GO and KEGG analyses revealed significant enrichment of immune response pathways in patients with CD. Thirteen genes (SOCS3, CD55, KDM5D, IGFBP5, LCN2, SLC15A1, XPNPEP2, HLA-DQA2, HMGCS2, DDX3Y, ITGB2, CDKN2B and HLA-DQA1), which were primarily associated with the response versus nonresponse patients, were identified and included in the LASSO analysis. These genes accurately predicted treatment response, with an area under the curve (AUC) of 0.938. T helper cell type 1 (Th1) cell polarization was comparatively strong in nonresponse individuals. Positive connections were observed between Th1 cells and the LCN2 and KDM5D genes. Furthermore, we employed an independent validation dataset and early experimental verification to validate the LCN2 and KDM5D genes as effective predictive markers.ConclusionsTh1 cell polarization is an important cause of nonresponse to UST therapy in patients with CD. LCN2 and KDM5D can be used as predictive markers to effectively identify nonresponse patients.Trial registration: Trial registration number: NCT05542459; Date of registration: 2022-09-14; URL: https://www.clinicaltrials.gov.

Gastric cancer immune microenvironment score predicts neoadjuvant chemotherapy efficacy and prognosis.

The efficacy of neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (GC) varies greatly. Thus, we aimed to verify the predictive value of tumor-infiltrating immune cells (TIICs) on the treatment response to NACT and the prognosis of patients with advanced GC, and to explore the impact of NACT on the tumor immune microenvironment (TIME). Paired tumor tissues (pre- and post-NACT) from patients with advanced GC were collected for this study. TIICs were assessed using immunohistochemistry staining and analyzed using logistic regression to establish an immune microenvironment score for GC (ISGC score) and predict NACT efficacy. Kaplan-Meier curves were used to evaluate the survival outcome of patients. The results showed that TIME was dramatically heterogeneous between NACT response and nonresponse patients. In the validation cohort, the ISGC score demonstrated good predictive performance for treatment response to NACT. Moreover, high ISGC indicated better long-term survival in patients with advanced GC. Furthermore, tumor-infiltrated T cells (CD3+ and CD8+) and CD11c+ macrophages were significantly increased in the response group, while CD163+ macrophages and FOXP3+ Treg cells were decreased after NACT. However, opposite results were exhibited in the nonresponse group. Finally, we found that the percentage of programmed cell death ligand 1 (PD-L1)-positive tumors was 31% (32/104) pre-NACT and 49% (51/104) post-NACT, and almost all patients with elevated PD-L1 were in the NACT response group. The ISGC model accurately predicted NACT efficacy and classified patients with GC into different survival groups. NACT regulates the TIME in GC, which may provide strategies for personalized immunotherapy.

Serum interα-trypsin inhibitor heavy chain H4 may be an anti-inflammatory marker reflecting disease risk, activity and treatment outcome of ankylosing spondylitis

Interα-trypsin inhibitor heavy chain H4 (ITIH4) modulates inflammation and immunity, which take part in the pathogenesis of ankylosing spondylitis (AS). The current research intended to discover the clinical value of serum ITIH4 quantification for AS management. Serum ITIH4 among 80 AS patients before current treatment initiation (baseline) at weeks (W) 4, 8 and 12 after treatment was detected by ELISA. Serum ITIH4 from 20 disease controls (DCs) and 20 healthy controls (HCs) was detected. ITIH4 expression was lower in AS patients than in DCs (p = 0.002) and HCs (p < 0.001). Among AS patients, ITIH4 was negatively associated with C-reactive protein (CRP) (r = −0.311, p = 0.005), bath AS disease activity index (BASDAI) (r = −0.223, p = 0.047), total pack pain (r = −0.273, p = 0.014) and AS disease activity score (ASDAS) (CRP) (r = −0.265, p = 0.018). Meanwhile, ITIH4 was negatively related to tumor necrosis factor (TNF)-α (r = −0.364, p = 0.001), interleukin (IL)-1β (r = −0.251, p = 0.025), IL-6 (r = −0.292, p = 0.009) and IL-17A (r = −0.254, p = 0.023). After treatment, the assessment of the spondylitis arthritis international society 40 response rate was 28.7% at W4, 46.3% at W8 and 55.0% at W12; ITIH4 showed an increasing trend from baseline to W12 (p < 0.001). Furthermore, ITIH4 at W8 (p = 0.020) and W12 (p = 0.035), but not at baseline or W4 (both p > 0.05), was enhanced in response patients vs. nonresponse patients. Additionally, ITIH4 at W12 was increased in AS patients receiving TNF inhibitors vs. those receiving nonsteroidal anti-inflammatory drugs (NSAIDs) (p = 0.024). Serum ITIH4 increases after treatment, and its augmentation is correlated with lower disease activity, decreased inflammation and enhanced treatment response in AS patients.

Significant participation bias and suboptimal cardiovascular risk management in learning healthcare systems due to non-consent

Abstract Background Computer-aided clinical decision support algorithms require continuous adjustments (learning) to account for changes in patient-characteristics, treatment(s), and outcomes, also referred to as a "Learning Healthcare System" (LHS). A LHS’s accuracy depends on adequate reflection of all patients, and participation bias may distort its effectiveness substantially. Therefore, we studied participation bias in a single center cardiovascular cohort study. Methods The cardiovascular cohort was set up as a LHS aiming for guideline-based treatment according to the individual risk profile for all cardiovascular disease patients in routine clinical care. Patients visiting an outpatient clinic for first time evaluation of a cardiovascular disease or risk factor received information on the cardiovascular cohort prior to their visit. During visit, cardiovascular risk management (CVRM) data was collected in the electronic health record (EHR) and informed consent was asked. We studied differences in characteristics between consenting, non-consenting and non-responding patients, and used multivariable logistic regression to identify determinants of non-consent. Multinomial regression was used for exploratory analyses of non-response determinants. A waiver (19/641) was obtained from the institutional review board for this study. Results In total, 2378 patients were consenting, 1907 non-consenting, and 1445 non-responding. In short, non-consent was related to higher cardiovascular risk (e.g., a cardiovascular disease history (OR 1.43, 95%CI 1.23-1.66)) and lower education (OR 0.76, 95%CI 0.60-0.97) than consent (Figure 1). Non-response, in contrast, was associated with higher physical activity (OR 1.04, 95%CI 1.01-1.08) and education level (OR 1.43, 95%CI 1.04-1.98) compared to consent. Non-consent and non-response patients were, respectively, younger and older. Presence of CVRM indicators in the EHR was 5-30% lower in non-consenting and 37-69% lower in non-responding patients compared to consenting patients. Conclusion A traditional informed consent procedure leads to participation bias in a LHS. Furthermore, it affects structured registration of CVRM indicators in the EHR, which is detrimental for the LHS feedback loop, and potentially leads to suboptimal cardiovascular risk management in patients not willing to participate. This study underlines the importance of reassessing the need of a traditional informed consent procedure for the use of routine care data in learning healthcare systems.

Outcomes of Upgrading to LBBP in CRT Nonresponders: A Prospective, Multicenter, Nonrandomized, Case-Control Study

BackgroundCardiac resynchronization therapy (CRT) nonresponders account for nearly 30% of CRT candidates. Left-bundle branch pacing (LBBP) is an alternative to CRT. ObjectivesThis study aimed to evaluate the feasibility, clinical efficacy, and outcomes of upgrading to LBBP in CRT nonresponders, using propensity-score matching (PSM) analysis. MethodsCRT nonresponders were defined as those with an implantable CRT-pacemaker or CRT-defibrillator for more than 12 months who remained nonresponsive (a decrease in left ventricular end-systolic volume of <15% or a left ventricular ejection fraction [LVEF] absolute increase of <5%) after optimal medical therapy and device optimization compared with baseline. In total, 145 CRT nonresponders were prospectively enrolled and randomly divided into 2 groups: upgraded to LBBP (n = 48), and continuing biventricular pacing (BVP) (control; n = 97). PSM was performed at a 1:1 ratio, and clinical evaluation and echocardiographic assessments were compared at baseline and follow-up in paired cohorts. The primary composite endpoint for clinical outcomes (heart failure-related rehospitalization events, all-cause death, or heart transplantation) was analyzed. ResultsSuccessful upgrading to LBBP was achieved in 48/49 patients (97.96%), with a significant decrease in QRS duration (P < 0.001). In the paired LBBP group, LVEF significantly increased (baseline: 29.75% ± 7.79%; 6 months: 37.78% ± 9.25% [P < 0.001]; 12 months: 38.84% ± 12.13% [P < 0.001]) with 21/44 patients (47.73%) classified as echocardiographically responsive, whereas in the BVP control group, no significant improvement was observed (29.55% ± 6.74% vs 29.22% ± 8.10%; P = 0.840). In a multivariate logistic regression model, LV end-diastolic volume and baseline LBBB QRS morphology were independent predictors of echocardiographic response after upgrading to LBBP. At a median 24 months, the primary composite endpoint was significantly lower in the LBBP group (HR: 0.31; 95% CI: 0.14-0.72; log-rank P = 0.007). ConclusionsUpgrading to LBBP is feasible and effective in achieving significant heart function improvement and better clinical outcomes in CRT nonresponders, making it a reasonable and promising pacing strategy. (LBBP in CRT Non-Response patients; ChiCTR1900028131)

Predictive Partition Dosimetry and Outcomes after Yttrium-90 Resin Microsphere Radioembolization of Colorectal Cancer Metastatic to the Liver: A Retrospective Analysis

PurposeTo characterize estimated absorbed tumor dose (ADT), objective response (OR), and estimated target dose of liver metastatic colorectal cancer (mCRC) after resin microsphere yttrium-90 (90Y) radioembolization using partition dosimetry. Materials and MethodsIn this retrospective, single-center study, multicompartment dosimetry of index tumors undergoing 90Y radioembolization from October 2013 to July 2022 was performed using MIM SurePlan and pretreatment technetium-99m macroaggregated albumin infusion data. Thirty-eight patients with mCRC underwent treatments for 59 index tumors. Patients were imaged every 2–3 months after treatment and then every 3–6 months after disease control to determine the best response per Response Evaluation Criteria in Solid Tumors 1.1. Responses were categorized as OR or nonresponse (NR). A Cox proportional hazards model evaluated the probability of tumor OR and local progression–free survival (LPFS) based on ADT. ResultsPatients had a median follow-up of 116 days (interquartile range [IQR], 69–231 days). The ADT was higher for OR patients than for NR patients (median, 130.8 [IQR, 85.6–239.0] vs 40.6 [IQR, 26.0–66.3] Gy; P < .001). A greater percentage of OR than NR patients were treated with activities calculated by partition modeling (54% vs 12%; P = .005). Only ADT predicted response (P = .032). At 6 months, an ADT of 120 Gy predicted a 55% (95% CI, 0.0%–89%) probability of OR. Only ADT (P = .010) and female sex (P = .014) predicted LPFS. At 1 year, an ADT of 120 Gy predicted a 70% (95% CI, 35%–100%) probability of LPFS. ConclusionsTumor dose was the strongest predictor of OR for mCRC. Administration of an estimated 120 Gy to mCRC predicted 55% OR with 90Y resin microspheres at 6 months.

Abstract 1250: Aberrant polyunsaturated fatty acids desaturation impairs survival and anti-tumor immunity of tumor resident memory CD8+ T cell in hepatocellular carcinoma

Abstract Background &amp; Aim: Aberrant polyunsaturated fatty acids (PUFAs) metabolism is closely associated with the immunosuppressive tumor microenvironment (TME). Tissue-resident memory T cell (Trm) plays a central role against solid tumors, including HCC, depending on the uptake of exogenous fatty acids to maintain survival and anti-tumor immunity. Here we aimed to explore the potential interaction in TME between HCC-derived PUFAs and Trm function in a series of integrated clinical, basic and translational studies. Methods: Tissue interstitial fluids (TIFs) were isolated and analyzed from fresh paired adjacent tissues and HCC for detecting the PUFAs alterations in the HCC TME. Integrated analyses were performed in multiple public databases and local cohorts. Fatty acid desaturase 1 (FADS1) knockdown (KD) HCC cell line was generated to observe the tumor biology and metabolic function. The effects of FADS1 knockout (KO) or overexpression were investigated in multiple spontaneous HCC mouse models via hydrodynamic tail vein injection (HTVI) in vivo. Mutation landscape analysis was used to explore the mechanism of FADS1 transcription. Therapeutic interventions by downregulating FADS1 were also evaluated in vivo. Results: Clinically, we found that the arachidonic acid (ARA) level was enriched in HCC TIFs. A rate-limiting enzyme controlling PUFA biosynthesis, especially ARA production from dihomo-γ-linolenic acid (DGLA), FADS1, was overexpressed in HCC patients. High expression of FADS1 predicted poor survival and was negatively correlated with CD8+CD103+Trm infiltration. Moreover, in the local clinical trial, we noticed that the expression of FADS1 was upregulated in non-response patients with anti-PD-1 mAb treatment. Functionally, we demonstrated that the ARA level was decreased in the conditioned medium (CM) from FADS1 KD cells. Applying CM prolonged the survival of CD8+CD103+Trm ex vivo. FADS1 KO inhibited tumor development by increasing intratumor infiltration and function of CD8+CD103+Trm. In contrast, overexpression of FADS1 promoted HCC progression by restraining immune surveillance in vivo. Mechanistically, we found that the expression of FADS1 was upregulated in the TP53 mutation group by analyzing the mutation landscape of HCC. Mutant P53 protein could bind to the promoter region of FADS1. Therapeutically, recombinant adeno-associated 8 (rAAV8)-shRNAs delivery and anti-PD-1 mAb administration inhibited the tumor growth of anti-PD-1 mAb treatment-resistant HCC model driven by CTNNB1N90 and MYC. Conclusions: We demonstrated that mutant P53 protein directly promoted FADS1 transcription, increasing ARA accumulation in HCC TME. FADS1 remodeling the metabolic patterns of PUFAs impaired CD8+CD103+Trm anti-tumor immunity, possibly leading to HCC progression. Citation Format: Tao Ding, Li Pang, Runying Long, Shinuan Zeng, Kevin TP Ng, Qingmei Zhang, Zhiwei Chen, Kwan Man. Aberrant polyunsaturated fatty acids desaturation impairs survival and anti-tumor immunity of tumor resident memory CD8+ T cell in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1250.

Association of Clinical Response of ITP Patients to Eltrombopag with the Regulation of Platelet Binding to Lymphocytes

Introduction Primary immune thrombocytopenia (ITP) is caused by the destruction of platelets (PLT) and megakaryocytes by autoantibodies, cellular cytotoxicity, or/and impairment in PLT production. Thrombopoietin-receptor agonists (TPO-RA) are a commonly used therapy in ITP that activate JAK/STAT pathways, stimulating megakaryocyte growth and PLT production. TPO-RAs, which include eltrombopag (EPAG), are effective in restoring PLT count in 70-80% of cases with chronic ITP. Recently, it has been observed that PLTs have an immunoregulatory role and their binding to lymphocytes and monocytes can modulate leukocyte inflammatory profile. Our aim was to determine the percentage of lymphocytes with bound PLTs before and after EPAG treatment, analyzing factors associated with this binding and with response. Methods For this purpose, peripheral whole blood was collected from 43 ITP patients relapsed/refractory to corticosteroids (at baseline and 2, 4, 12, and 18 w after the initiation of EPAG) and 15 healthy donors (HD). The percentage of T CD4+, T CD8+, and B lymphocytes with bound PLTs (CD41a+) were analyzed by flow cytometry and plasma levels of cytokines (IFN-γ, TNF-α, IL-10 and IL-17) by ELISA. Results In comparison with HD, the absolute number of PLTs was lower and the percentage of free activated PLTs was higher in ITP patients at baseline. Additionally, the percentage of T and B lymphocytes with bound PLTs in ITP patients was lower than in HD. After 2w of EPAG treatment, the percentages of T and B lymphocytes with bound PLTs were normalized and IFN-g levels were reduced. However, no significant changes were observed in the percentage of free-activated PLTs and in the percentage of T and B lymphocytes with bound activated PLTs. The percentages of T and B lymphocytes with bound PLTs were higher in ITP patients that reached complete response (>100 x 109 PLT/L without bleeding) compared with partial response (30-100 x 109 PLT/L) and non-response (<30x 109 PLT/L) patients in each time point of the study after EPAG treatment (Figure 1). Conclusions Our results suggest that the increase of PLTs after EPAG treatment is not only mediated through the platelet production stimulation, but also through the increase of PLT binding to lymphocytes which may influence the inflammatory profile of ITP patients. This newly mechanism of action could explain the persistent response of ITP patients after EPAG treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prediction and evaluation of high-risk patients with primary biliary cholangitis receiving ursodeoxycholic acid therapy: an early criterion

Background and aimsCurrent treatment guidelines recommend ursodeoxycholic acid (UDCA) as the first-line treatment for new-diagnosed primary biliary cholangitis (PBC) patients. However, up to 40% patients are insensitive to UDCA monotherapy, and evaluation of UDCA response at 12 months may result in long period of ineffective treatment. We aimed to develop a new criterion to reliably identify non-response patients much earlier.MethodsFive hundred sixty-nine patients with an average of 59 months (Median: 53; IQR:32–79) follow-up periods were randomly divided into either the training (70%) or the validation cohort (30%). The efficiency of different combinations of total bilirubin (TBIL), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcomes was assessed at 1, 3 or 6 month after the initiation of UDCA therapy. The endpoints were defined as adverse outcomes, including liver-related death, liver transplantation and complications of cirrhosis. Adverse outcome-free survival was compared using various published criteria and a proposed new criterion.ResultsA new criterion of evaluating UDCA responses at 1 month was established as: ALP ≤ 2.5 × upper limit of normal (ULN) and AST ≤ 2 × ULN, and TBIL ≤ 1 × ULN (Xi’an criterion). The 5 year adverse outcome-free survival rate of UDCA responders, defined by Xi’an criterion, was 97%, which was significantly higher than that of those non-responders (64%). An accurate distinguishing high-risk patients’ capacity of Xi’an criterion was confirmed in both early and late-stage PBC.ConclusionsXi’an criterion has a similar or even higher ability to distinguish high-risk PBC patients than other published criteria. Xi’an criterion can facilitate early identification of patients requiring new therapeutic approaches.

Correlation of renal cortical blood perfusion and BP response after renal artery stenting.

BackgroundThis study aimed to observe the correlation between renal cortical blood perfusion (CBP) parameters and BP response in patients with severe renal artery stenosis (RAS) who underwent stenting.MethodsThis was a single-center retrospective cohort study. A total of 164 patients with unilateral severe RAS after successful percutaneous transluminal renal artery stenting in Beijing Hospital from October 2017 to December 2020 were included. According to the results of BP evaluated at 12 months, all patients were divided into the BP response group (n = 98) and BP nonresponse group (n = 66). The baseline clinical and imaging characteristics and follow-up data about 24 h ABPM and CBP were recorded and analyzed. Pearson correlation analysis was used to evaluate the relationship between CBP parameters and 24 h average SBP. Univariate and multivariate logistic regression analysis was used to evaluate the risk factors for BP response.ResultsAmong 164 patients with severe RAS, there were 100 males (61.0%), aged 37–75 years, with an average of 56.8 ± 18.4 years, and average artery stenosis of 84.0 ± 12.5%. The BP nonresponse patients had a longer duration of hypertension, more current smoking subjects and diabetic patients, lower eGFR, increased number of hypertensive agents, and rate of insulin compared with the BP response group (P < 0.05). After PTRAS, patients in the BP response group were associated with significantly lower BP and improved CPB, characterized by increased levels of maximum intensity (IMAX), area under ascending curve (AUC1), area under the descending curve (AUC2), shortened rising time (RT), mean transit time (mTT), and prolonged time to peak intensity (TTP; P < 0.05). However, the BP nonresponse group was only associated with significantly reduced RT (P < 0.05) compared with baseline data. During an average follow-up of 11.5 ± 1.7 months, the BP response group was associated with significantly lower levels of SBP, DBP, 24 h average SBP, and 24 h average DBP compared with the nonresponse group (P < 0.05). Pearson correlation analysis showed that the the pre-operative CBP parameters, including IMAX (r = 0.317), RT (r = 0.249), AUC1 (r = 0.614), AUC2 (r = 0.558), and postoperative CBP parameters, including RT (r = 0.283), AUC1 (r = 0.659), and AUC2 (r = 0.674) were significantly positively correlated with the 24 h average SBP, while the postoperative TTP (r = −0.413) and mTT (r = −0.472) were negatively correlated with 24 h average SBP (P < 0.05). Multivariate Logistic regression analysis found that diabetes (OR = 1.294), NT-proBNP (OR = 1.395), number of antihypertensive agents (OR = 2.135), pre-operation IMAX (OR = 1.534), post-operation AUC2 (OR = 2.417), and baseline dDBP (OR = 2.038) were related factors for BP response (all P < 0.05).ConclusionPatients in the BP nonresponse group often have diabetes, a longer duration of hypertension, significantly reduced glomerular filtration rate, and heavier renal artery stenosis. CBP parameters are closely related to 24 h average SBP, and pre-operation IMAX and post-operation AUC2 are markers for a positive BP response.

Meshless Electrophysiological Modeling of Cardiac Resynchronization Therapy—Benchmark Analysis with Finite-Element Methods in Experimental Data

Computational models of cardiac electrophysiology are promising tools for reducing the rates of non-response patients suitable for cardiac resynchronization therapy (CRT) by optimizing electrode placement. The majority of computational models in the literature are mesh-based, primarily using the finite element method (FEM). The generation of patient-specific cardiac meshes has traditionally been a tedious task requiring manual intervention and hindering the modeling of a large number of cases. Meshless models can be a valid alternative due to their mesh quality independence. The organization of challenges such as the CRT-EPiggy19, providing unique experimental data as open access, enables benchmarking analysis of different cardiac computational modeling solutions with quantitative metrics. We present a benchmark analysis of a meshless-based method with finite-element methods for the prediction of cardiac electrical patterns in CRT, based on a subset of the CRT-EPiggy19 dataset. A data assimilation strategy was designed to personalize the most relevant parameters of the electrophysiological simulations and identify the optimal CRT lead configuration. The simulation results obtained with the meshless model were equivalent to FEM, with the most relevant aspect for accurate CRT predictions being the parameter personalization strategy (e.g., regional conduction velocity distribution, including the Purkinje system and CRT lead distribution).

Abstract 6106: The effect of neoadjuvant chemotherapy on tumor immune microenvironment in ovarian cancer

Abstract Background: Ovarian cancer (OC) is a highly lethal gynecologic malignancy, neoadjuvant chemotherapy (NACT) with interval de-bulking surgery (IDS) is an established strategy for woman with advanced epithelial ovarian cancer (EOC). Tumor infiltrating lymphocytes (TILs) play an important role in the pathogenesis of OC. However, the effect of NACT on tumor immune microenvironment (TIME) has not been evaluated. Methods: All patients underwent NACT with IDS. Formalin-fixed paraffin-embedded tissue samples were collected from biopsy specimens and the corresponding post-NACT surgical specimens. The densities and percentage of specific TILs [CD8+, CD3+, CD4+, CD20+, tumor associated macrophages (TAMs), dim CD56+NK, bright CD56+NK, PD-1+ etc.] within the TIME were analyzed by multiplex immunohistochemistry (3DMedcines Inc.). Serum CA 125 was measured 3-weekly per protocol and evaluated the response to NACT using GCIG CA125 response criteria. Results: A total of 28 patients were enrolled in this study with planned IDS after NACT. Of 25 patients evaluated by GCIG CA125 response criteria, 76% (19/25) had a CA125 response. In CA125 response patients, we observed significant recruitments of the densities and percentage of CD8+ in tumor, percentage of PD-1+ cell in tumor after-NACT vs before-NACT (34.85/mm3 vs 110.54/mm3, p=0.0258; 0.50% vs 1.73%, p=0.0132; 0.53% vs 2.66%, p=0.0576, respectively), while no significant change was found in TAMs, NK cells and CD20+ cells. However, in CA125 non-response patients, the TILs in tumor did not change significantly. Conclusion: NACT could release the tumor associated antigen by killing tumor cells for uptake by tumor-infiltrating dendritic cells and promote the infiltration of CD8+ and PD-1+ T lymphocyte in CA125 response OC patients. Given the limited clinical prognostic information and the number of patients in this study, the results of this study will need confirmation in larger studies in the future. Citation Format: Guangming Cao, Dingchao Hua, Lina Cui, Xiaochen Zhao, Shuzhen Wang, Lei Zhu. The effect of neoadjuvant chemotherapy on tumor immune microenvironment in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6106.

Genomic characterization of Chinese locally advanced or metastatic gastric cancer.

e16085 Background: The comprehensive molecular characterization of gastric cancer has been uncovered by The Cancer Genome Atlas (TCGA) research work. However, the genomic feature of Chinese locally advanced or metastatic gastric cancer has been seldom reported. This study aims to explore the genomic landscape of Chinese locally advanced or metastatic gastric cancer. Methods: 556 locally advanced or metastatic gastric cancer patients were enrolled in this study and 245 eligible patients with adequate clinicopathological data were analyzed. The baseline tumor tissues and corresponding blood were collected and target-captured sequencing were applied. Both tumor fragments and fragmented genomic DNA were subjected to the NGS platform aiming a panel covering exon regions of 599 genes. Genetic alterations were analyzed to investigate the mutational profile of Chinese locally advanced or metastatic gastric cancer. Results: The top 10 common tumor driver gene alterations among all cases were TP53, ARID1A, CDH1, ARID1B, NOTCH1, ATRX, AR, RAD50, SMAD4 and ZFHX3. TP53 mutation was detected in 70% of all cases, which was significantly higher than that in the TCGA non-Asian (44%) and Asian (46%) advanced gastric cancer patients. 90% (20/22) MSI-H patients had high TMB values, and 32.7% (20/61) high TMB patients were MSI-H. Neither TMB values nor MSI scores was statistically different between patients with response (CR+PR) and without response (PD+SD) to chemotherapy (p = 0.366, 0.436). While the combination of SPTA1 and TP53 mutation was significantly more frequent in response (CR+PR) than non-response (PD+SD) patients. Conclusions: The mutated driver genes of Chinese locally advanced or metastatic gastric cancer were different from the TCGA advanced gastric cancer. The combination of TP53 and and SPTA1 could identify the patients’ response to chemotherapy.

Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 in rheumatoid arthritis: Longitudinal change after treatment and correlation with treatment efficacy of tumor necrosis factor inhibitors

BackgroundMucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) correlates with treatment outcomes in inflammatory bowel disease and rheumatoid arthritis (RA). This study aimed to further evaluate the MALT1 longitudinal change and its relationship with tumor necrosis factor inhibitors (TNFi) response in RA patients.MethodsSeventy‐one RA patients receiving TNFi [etanercept (n = 42) or adalimumab (n = 29)] were enrolled. MALT1 was detected by RT‐qPCR in peripheral blood samples of RA patients before treatment (W0), at week (W)4, W12, and W24 after treatment. RA patients were divided into response/non‐response, remission/non‐remission patients according to their treatment outcome at W24. Meanwhile, MALT1 was also detected by RT‐qPCR in 30 osteoarthritis patients and 30 healthy controls (HCs).ResultsMucosa‐associated lymphoid tissue lymphoma translocation protein 1 was elevated in RA patients compared with HCs (Z=−6.392, p < 0.001) and osteoarthritis patients (Z = −5.020, p < 0.001). In RA patients, MALT1 was positively correlated with C‐reactive protein (rs = 0.347, p = 0.003), but not other clinical characteristics, treatment history, or current TNFi category. Meanwhile, MALT1 decreased from W0 to W12 in total RA patients (x2 = 86.455, p < 0.001), etanercept subgroup (x2 = 46.636, p < 0.001), and adalimumab subgroup (x2 = 41.291, p < 0.001). Moreover, MALT1 at W24 (p = 0.012) was decreased in response patients compared with non‐response patients; MALT1 at W12 (p = 0.027) and W24 (p = 0.010) were reduced in remission patients than non‐remission patients. In etanercept subgroup, MALT1 at W24 (p = 0.013) was decreased in response patients compared with non‐response patients. In adalimumab subgroup, MALT1 at W24 (p = 0.015) was lower in remission patients than non‐remission patients.ConclusionMucosa‐associated lymphoid tissue lymphoma translocation protein 1 reduction after treatment is associated with response and remission to TNFi in RA patients.

Clinical evaluation of Elecsys PIVKA-II for patients with advanced hepatocellular carcinoma.

BackgroundProthrombin induced by vitamin K absence-II (PIVKA-II) was reported as a diagnosis and prognosis marker for hepatocellular carcinoma (HCC). Although the development of systemic therapies for advanced HCC has been remarkable, the role of PIVKA-II is unclear. This prospective study aimed to verify Elecsys PIVKA-II compared with Lumipulse PIVKA-II in a cohort with advanced HCC undergoing systemic therapy.MethodsA total of 62 HCC patients who were treated with atezolizumab and bevacizumab (ATZ+BEV) and molecular targeted agents (MTAs) were prospectively enrolled at Musashino Red Cross Hospital from January 2020 to December 2020. A total of 208 serum samples from 52 patients were tested using Elecsys PIVKA-II and Lumipulse PIVKA-II assays. Furthermore, the relationship of Elecsys PIVKA-II and progression-free survival (PFS) was investigated with 48 patients (24 ATZ+BEV and 24 MTAs) whose Lumipulse PIVKA-II levels were >40 mAU/mL.ResultsIn the test accuracy analysis, the Elecsys assay has a correlation coefficient (R) of 0.92 compared with that of the Lumipulse assay (ATZ+BEV, 0.95; MTAs, 0.91). In the PFS analysis, the number of patients who received ATZ+BEV and MTAs as first- and late-line therapy were 9 and 13, and 15 and 11, respectively. The PIVKA-II response was defined for patients who had a reduction in the Elecsys PIVKA-II level on the first month of treatment evaluation. The PFS of patients with Elecsys PIVKA-II response was significantly longer than that of nonresponse patients (5.8 months vs 3.8 months, p = 0.0205).ConclusionThe Elecsys PIVKA-II was not only as useful as the Lumipulse PIVKA-II but also for stratifying the PFS of patients with advanced HCC.

Abstract P1-16-02: A randomized phase II study investigating oral metronomic vinorelbine versus conventional dosage of vinorelbine in HER2-negative metastatic breast cancer previously treated with anthracycline or taxane:clinical results and biomarker analysis

Abstract Background: Metronomic chemotherapy, defined as frequent administration of. chemotherapeutic agents at a non-toxic dose without extended rest periods, can overcome drug resistance and achieve disease control with reduced toxicity compared to conventional chemotherapy in maximum tolerated dose by shifting the therapeutic target from tumor cells to tumor endothelial cells. Some of the previous studies of oral vinorelbine have shown good data in efficacy and safety in advanced breast cancer. Methods: The multicenter, open-label, non-inferiority, randomized phase 2 study (NCT03854617) aimed to evaluate the efficacy and safety of oral metronomic vinorelbine in 13 hospitals in China. Eligible HER2-negative breast cancer patients previously treated with anthracycline or taxane regimens were randomized (1:1) to receive metronomic dosage of oral vinorelbine (50mg/3 times a week) or conventional dosage of oral vinorelbine (60mg/m2 weekly for cycle 1 and 80mg/m2 weekly for subsequent cycles in the absence of grade 3 or 4 toxicity) for first-line/second-line chemotherapy. The primary end point was Disease Control Rate (DCR) and a non-inferiority margin of 6% was defined for DCR. Patient characteristics, progression-free survival (PFS), overall survival (OS) and safety/adverse events (AEs) were among the parameters assessed. The expression of 27 cytokines was profiled longitudinally in these patients at baseline and at regular intervals during therapy. Results: Between February 2019 and September 2020, a total of 171 patients were enrolled and randomized to metronomic dosage group (86 patients) and conventional dosage group (85 patients). 136 patients were hormone receptor(HR)positive and 117 patients (68.4%) had visceral metastases. The DCR was 59.3% (95% CI:48.17% to 69.78%) in the metronomic dosage group and 67.1% (95% CI:56.02% to 76.87%) in the conventional dosage group. Whereas, the 18-month survival rate was higher in the metronomic dosage group than that in the conventional dosage group (68.7% vs 43.0%).The median progression-free survival in the metronomic dosage group was 2.8 months (95% CI:1.40 to 3.50) compared with 4.1 months (95% CI:2.80 to 6.20) in the conventional dosage group. Grade 3 or higher adverse events were significantly less frequent in patients in the metronomic dosage group than patients in the conventional dosage group (19.8% vs 48.2%, P&amp;lt;0.001). By comparing the variation of cytokine profiles at baseline and after 6-week treatment in 122 patients, multilevel partial least squares discriminant analysis (PLS-DA) suggested the variation of VEGF, MIP-1α, IL-1B, IL-17, MCP-1, IL-13, PDGF-BB, IL-4 and RANTES were significantly different between the metronomic dosage group and the conventional dosage group during the treatment (all VIP values &amp;gt; 1.2). As for the patients in the metronomic dosage group, GM-CSF, MCP-1, TNF-α, IL-10, IL-13 and MIP-1α were potential biomarkers between the response patients and non-response patients (all VIP values &amp;gt; 1.2). Conclusions: Oral metronomic vinorelbine decreased the risk of severe toxicity significantly and may be an option for older patients and for those intolerable to standard chemotherapy with proper predictive biomarkers, though this study couldn’t prove to show the non-inferiority of oral metronomic vinorelbine for first-line or second-line chemotherapy previously treated with anthracycline or taxane in HER2-negative metastatic breast cancer. Citation Format: Fei Ma, Xinlan Liu, Yanxia Shi, Xiuwen Guan, Huihui Li, Xiaojia Wang, Yuee Teng, Qiang Liu, Jin Yang, Man Li, Qingyuan Zhang, Weihong Zhao, Caiwen Du, Lili Sheng, Binghe Xu. A randomized phase II study investigating oral metronomic vinorelbine versus conventional dosage of vinorelbine in HER2-negative metastatic breast cancer previously treated with anthracycline or taxane:clinical results and biomarker analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-02.

PBMC CDC42 reveals the disease activity and treatment efficacy of TNF inhibitor in patients with ankylosing spondylitis.

ObjectiveCell division cycle 42 (CDC42) regulates the polarization of M2 macrophage and maintains the T cell homeostasis, to participate in multiple autoimmune diseases, while its clinical involvement in ankylosing spondylitis (AS) remains unclear. Hence, the current study aimed to investigate the correlation of CDC42 with clinical characteristics and treatment outcome in AS patients receiving tumor necrosis factor (TNF) inhibitor therapy.MethodsPeripheral blood mononuclear cell (PBMC) CDC42 expression was detected at baseline, week (W) 4, W8, and W12 after TNF inhibitor treatment in 91 AS patients and in 50 HCs after enrollment. Furthermore, serum TNF‐α, interferon‐γ (IFN‐γ), interleukin‐10 (IL‐10), and interleukin‐17A (IL‐17A) from AS patients were detected at baseline.ResultsBlood CDC42 was lower in AS patients compared with HCs (p < 0.001). Additionally, blood CDC42 was negatively linked with CRP (r = −0.349, p = 0.001), BASDAI score (r = −0.243, p = 0.020), and ASDASCRP score (r = −0.238, p = 0.023) in AS patients; however, blood CDC42 was not correlated with other clinical characteristics. Besides, CDC42 was negatively correlated with TNF‐α (r = −0.237, p = 0.024) and IL‐17A (r = −0.339, p = 0.001) but not with IFN‐γ (p = 0.083) or IL‐10 (p = 0.280). Moreover, blood CDC42 was elevated after TNF inhibitor treatment (p < 0.001). Meanwhile, blood CDC42 was not varied at baseline and W4 between response patients and non‐response patients, while it was higher at W8 (p = 0.019) and W12 (p = 0.002) in response patients than in non‐response patients after treatment.ConclusionBlood CDC42 deficiency links with elevated pro‐inflammatory cytokines, disease activity and unsatisfying response to TNF inhibitor in AS patients.

Clinical Features and Corrected Factors with Neurosyphilis in HIV/Syphilis Co-Infected Patients Based on Stage of Syphilis

Abstract Objective: Neurosyphilis is challenging to diagnose, especially in patients with human immunodeficiency virus (HIV)/syphilis co-infection. The aim of this study was to profile the clinical features of neurosyphilis and evaluate the correlation between neurosyphilis and clinical or laboratory factors among patients with HIV/syphilis co-infection. Methods: We retrospectively analyzed the data of 479 HIV/syphilis co-infected patients examined between August 2009 and September 2018. A multivariate logistic regression model was used to identify factors correlated with neurosyphilis. Results: The overall prevalence of neurosyphilis was 21.7%. The prevalence of neurosyphilis differed among patients with primary (11.1%), secondary (20.1%), and latent syphilis (29.1%). The prevalences of neurosyphilis in patients with serological non-response and serofast patients were 26.1% and 6.3%, respectively, while 12.5% of patients with serological relapse had neurosyphilis. Patients with secondary and latent syphilis had serum rapid plasma reagin (RPR) titers (per unit) of 1.44-fold [95% confidence interval (CI): 1.08–1.93, P = 0.014] and 2.73-fold (95% CI: 1.49–5.00, P = 0.001), respectively, which increased the risk of confirmed neurosyphilis. Among patients with latent syphilis, a serum RPR titer of ≥1:32 and peripheral blood CD4 cell count of ≤350/mL were significantly associated with neurosyphilis, with adjusted odds ratios of 9.45 (95% CI: 1.86–48.03, P = 0.007) and 3.75 (95% CI: 1.11–12.66, P = 0.033), respectively. Conclusion: A serum RPR titer of ≥1:32 and a peripheral blood CD4 cell count of ≤350/mL have predictive value in screening for neurosyphilis among HIV-positive patients with latent syphilis.

Deep learning radiomics of ultrasonography can predict response to neoadjuvant chemotherapy in breast cancer at an early stage of treatment: a prospective study.

Breast cancer (BC) is the most common cancer in women worldwide, and neoadjuvant chemotherapy (NAC) is considered the standard of treatment for most patients with BC. However, response rates to NAC vary among patients, which leads to delays in appropriate treatment and affects the prognosis for patients who ineffectively respond to NAC. This study aimed to investigate the feasibility of deep learning radiomics (DLR) in the prediction of NAC response at an early stage. In total, 168 patients with clinicopathologically confirmed BC were enrolled in this prospective study, from March 2016 to December 2020. All patients completed NAC treatment and underwent ultrasonography (US) at three time points (before NAC, after the second course, and after the fourth course). We developed two DLR models, DLR-2 and DLR-4, for predicting responses after the second and fourth courses of NAC. Furthermore, a novel deep learning radiomics pipeline (DLRP) was proposed for stepwise prediction of response at different time points of NAC administration. In the validation cohort, DLR-2 achieved an AUC of 0.812 (95% CI: 0.770-0.851) with an NPV of 83.3% (95% CI: 76.5-89.6). DLR-4 achieved an AUC of 0.937 (95% CI: 0.913-0.955) with a specificity of 90.5% (95% CI: 86.3-94.2). Moreover, 19 of 21 non-response patients were successfully identified by DLRP, suggesting that they could benefit from treatment strategy adjustment at an early stage of NAC. The proposed DLRP strategy holds promise for effectively predicting NAC response at its early stage for BC patients. • We proposed two novel deep learning radiomics (DLR) models to predict response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients based on US images at different NAC time points. • Combining two DLR models, a deep learning radiomics pipeline (DLRP) was proposed for stepwise prediction of response to NAC. • The DLRP may provide BC patients and physicians with an effective and feasible tool to predict response to NAC at an early stage and to determine further personalized treatment options.