Predictive Value For Response Research Articles

On sensitivity analysis of the fundamental frequency of cracked fiber metal laminated (FML) beams using experimental survey and finite element method

PurposeIn this research, the free vibration sensitivity analysis of cracked fiber metal laminated (FML) beams is investigated numerically and experimentally. The effects of single and double cracks on the frequency of the cantilever beams are simulated using the finite element method (FEM) and compared to the experimental results.Design/methodology/approachIn FEM analysis, the crack defect is simulated by the contour integral technique without considering the crack growth. The specimens are fabricated with an aluminum sheet, woven carbon fiber and epoxy resin. The FML specimens are constructed by bonding five layers as [carbon fiber-epoxy/Al/carbon fiber-epoxy/Al/carbon fiber-epoxy]. First, the location and length of cracks are considered input factors for the frequency sensitivity analysis. Then, the design of the experiment is produced in the cases of single and double cracks to compute the frequency of the beams in the first and second modes using the FEM. The mechanical shaker is used to determine the natural frequency of the specimens. In addition, the predicted response values of the frequency for the beam are used to compare with the experimental results.FindingsConsequently, the results of the sensitivity analysis demonstrate that the location and length of the crack have significant effects on the modes.Originality/valueEffective interaction diagrams are introduced to investigate crack detection for input factors, including the location and length of cracks in the cases of single and double cracks.

26 Applying single cell RNA sequencing of sarcomatoid renal cell carcinoma for the development of a novel transcriptomic biomarker to predict immunotherapy response

Abstract Background Renal cell carcinoma with sarcomatoid features (sRCC) is a unique kidney cancer subtype associated with aggressive biology and poor clinical outcomes. Intriguingly, sRCC has recently exhibited preferential responsiveness to immune checkpoint blockade (ICB) therapies. Within the RCC population, however, there currently is a paucity of biomarkers predictive for ICB response, representing a critical unmet clinical need for optimal therapy selection. Therefore, we sought to derive a transcriptomic signature from sRCC samples encapsulating this paradoxical hyper-aggression and ICB-responsiveness to identify RCC patients most likely to benefit from ICB irrespective of sarcomatoid feature presence. Methods Nephrectomy specimens from patients with RCC were processed for single cell RNA sequencing (scRNAseq). Clustering was performed and annotated tumor cells were computationally isolated. Tumor cell counts were aggregated and differential expression between sRCC and non-sRCC cases was performed. Genes significantly upregulated in sRCC were next filtered against differential gene expression data of sRCC vs non-sRCC from three clinical RCC datasets (TCGA, CheckMate, & Javelin101) to identify genes enriched in sRCC across scRNAseq and bulk RNA sequencing. The prognostic and predictive features of this gene signature were then assessed in cohorts of patients with RCC receiving ICB. Results In total, 73,123 unique cells from 18 RCC patients (10 sRCC; 8 clear cell RCC) were analyzed by scRNAseq, including 5,386 tumor cells. Differential gene expression of tumor clones revealed 20 genes significantly enriched in sRCC relative to ccRCC. Filtering against public differential gene expression data resulted in 10 genes included within the final Sarcomatoid Signature (SS). SS expression scores for clinical specimens were calculated by single-sample gene set enrichment analysis. SS scores were significantly enriched in sRCC patient tumors across TCGA KIRC, CheckMate, and IMmotion151 datasets (p<0.001 for all cohorts). Within TCGA KIRC, SS scores were significantly increased in patients with nuclear grade 4 (p<0.001) and metastatic (p<0.001) disease, while stratification by median SS score revealed worsened overall (HR=2.19, p<0.001) and disease-free (HR=2.08, p<0.001) survival among SS-high patients. Amongst the CheckMate cohort (including patient samples from the CheckMate-010 & CheckMate-025 trials), SS-high patients experienced improved progression free survival (PFS) when treated with nivolumab relative to everolimus (HR=0.70, p=0.055), whereas no difference was seen between therapies in the SS-low patient population (HR=0.98, p=0.9). In the IMmotion151 trial, which was not utilized for gene filtering and signature refinement and thus represents an independent validation cohort, SS-high patients experienced reduced PFS duration (HR=1.39, p<0.001) irrespective of treatment arm. However, SS-high patients experienced improved objective response rates with the ICB-containing atezolizumab/bevacizumab regimen compared to sunitinib (p<0.001) and relative to SS-low patients receiving atezolizumab/bevacizumab (p=0.028) (Figure 1). Within the SS-high population, patients experienced prolonged PFS with atezolizumab/bevacizumab (HR=0.70, p=0.003) relative to sunitinib whereas no PFS difference between arms was seen in the SS-low population (HR=1.01, p>0.99). Conclusions This novel SS derived from scRNAseq demonstrates negative prognostic yet positive predictive value for ICB response. In a domain currently void of efficacious biomarkers, the SS, upon prospective validation, may assist in optimal therapy selection for patients with RCC.

Gynecologic Cancer InterGroup CA125 response has a high negative predictive value for CHK1 inhibitor RECIST response in recurrent ovarian cancer

We investigated the association of CA125 response with prognosis and RECIST response/progressive disease (PD) criteria in recurrent high grade serous ovarian cancer (HGSOC) patients treated with a cell cycle checkpoint kinase 1 inhibitor (CHK1i), prexasertib. 81 patients had measurable disease per RECISTv1.1, of which 72 and 70 were measurable by Gynecologic Cancer InterGroup (GCIG) CA125 response and PD criteria, respectively. Univariate and multivariate analyses showed that GCIG CA125 response (n = 32) is associated with improved progression-free survival (PFS) and overall survival (OS) compared to no GCIG CA125 response (n = 40) (median PFS 8.0 vs. 3.5 months [HR: 0.30, 95% CI: 0.18–0.51, p < 0.0001]; median OS 19.8 vs. 10.0 months [HR: 0.38, 95% CI: 0.23–0.64, p < 0.001]) independent of BRCA mutation status, platinum-sensitivity, previous PARP inhibitor therapy, ECOG performance status, and FIGO stage. Notably, GCIG CA125 response had a high negative predictive value (NPV: 93%, 95% CI: 80–98), but poor positive predictive value (PPV: 53%, 95% CI: 35–71) in predicting RECIST response. CA125 PD criteria also showed poor concordance with RECIST PD (PPV 56%, 95% CI: 40–71; NPV 33%, 95% CI: 17–54). Therefore, serum CA125 may be useful as a highly accessible prognostic and predictive biomarker to CHK1i therapy in recurrent HGSOC.

Siderophore-harboring gut bacteria and fecal siderophore genes for predicting the responsiveness of fecal microbiota transplantation for active ulcerative colitis

BackgroundPredictive markers for fecal microbiota transplantation (FMT) outcomes in patients with active ulcerative colitis (UC) are poorly defined. We aimed to investigate changes in gut microbiota pre- and post-FMT and to assess the potential value in determining the total copy number of fecal bacterial siderophore genes in predicting FMT responsiveness.MethodsPatients with active UC (Mayo score ≥ 3) who had undergone two FMT procedures were enrolled. Fecal samples were collected before and 8 weeks after each FMT session. Patients were classified into clinical response and non-response groups, based on their Mayo scores. The fecal microbiota profile was accessed using metagenomic sequencing, and the total siderophore genes copy number via quantitative real-time polymerase chain reaction. Additionally, we examined the association between the total siderophore genes copy number and FMT efficacy.ResultsSeventy patients with UC had undergone FMT. The clinical response and remission rates were 50% and 10% after the first FMT procedure, increasing to 72.41% and 27.59% after the second FMT. The cumulative clinical response and clinical remission rates were 72.86% and 25.71%. Compared with baseline, the response group showed a significant increase in Faecalibacterium, and decrease in Enterobacteriaceae, consisted with the changes of the total bacterial siderophore genes copy number after the second FMT (1889.14 vs. 98.73 copies/ng, P < 0.01). Virulence factor analysis showed an enriched iron uptake system, especially bacterial siderophores, in the pre-FMT response group, with a greater contribution from Escherichia coli. The total baseline copy number was significantly higher in the response group than non-response group (1889.14 vs. 94.86 copies/ng, P < 0.01). A total baseline copy number cutoff value of 755.88 copies/ng showed 94.7% specificity and 72.5% sensitivity in predicting FMT responsiveness.ConclusionsA significant increase in Faecalibacterium, and decrease in Enterobacteriaceae and the total fecal siderophore genes copy number were observed in responders after FMT. The siderophore genes and its encoding bacteria may be of predictive value for the clinical responsiveness of FMT to active ulcerative colitis.

Machine Learning in Electroconvulsive Therapy

Abstract Despite years of research, we are still not able to reliably predict who might benefit from electroconvulsive therapy (ECT) treatment. As we exhaust what is possible using traditional statistical analysis, ECT remains a good candidate for machine learning approaches due to the large data sets with data captured through electroencephalography (EEG) and other objective measures. A systematic review of 6 databases led to the full-text examination of 26 articles using machine learning approaches in examining data predicting response to ECT treatment. The identified articles used a wide variety of data types covering structural and functional imaging data (n = 15), clinical data (n = 5), a combination of clinical and imaging data (n = 2), EEG (n = 3), and social media posts (n = 1). The clinical indications in which response prediction was assessed were depression (n = 21) and psychosis (n = 4). Changes in multiple anatomical regions in the brain were identified as holding a predictive value for response to ECT. These primarily centered on the limbic system and associated networks. Clinical features predicting good response to ECT in depression included shorter duration, lower severity, higher medication dose, psychotic features, low cortisol levels, and positive family history. It has also been possible to predict the likelihood of relapse of readmission with psychosis after ECT treatment, including a better response if higher transfer entropy was calculated from EEG signals. A transdisciplinary approach with an international consortium collecting a wide range of retrospective and prospective data may help to refine and extend these outcomes and translate them into clinical practice.

SIRPG expression positively associates with an inflamed tumor microenvironment and response to PD-1 blockade

BackgroundThis study aimed to investigate the relationship between signal regulatory protein gamma (SIRPG) and tumor immune microenvironment phenotypes or T cell mediated-adaptive antitumor immunity, and its predictive value for response to PD-1 blockade in cancers.MethodsPan-cancer analysis of SIRPG expression and immune deconvolution was performed using transcriptomic data across 33 tumor types. Transcriptomic and clinical data from 157 patients with non-small-cell lung cancer (NSCLC) and melanoma received PD-1 blockade were analyzed. Expression characteristics of SIRPG were investigated using single-cell RNA sequencing (scRNA-seq) data of 103,599 cells. The effect of SIRPG expression was evaluated via SIRPG knockdown or overexpression in Jurkat T cells.ResultsThe results showed that most cancers with high SIRPG expression had significantly higher abundance of T cells, B cells, NK cells, M1 macrophages and cytotoxic lymphocytes and increased expression level of immunomodulatory factors regulating immune cell recruitment, antigen presentation, T cell activation and cytotoxicity, but markedly lower abundance of neutrophils, M2 macrophages, and myeloid-derived suppressor cells. High SIRPG expression was associated with favorable response to PD-1 blockade in both NSCLC and melanoma. scRNA-seq data suggested SIRPG was mainly expressed in CD8+ exhausted T and CD4+ regulatory T cells, and positively associated with immune checkpoint expression including PDCD1 and CTLA4. In vitro test showed SIRPG expression in T cells could facilitate expression of PDCD1 and CTLA4.ConclusionHigh SIRPG expression is associated with an inflamed immune phenotype in cancers and favorable response to PD-1 blockade, suggesting it would be a promising predictive biomarker for PD-1 blockade and novel immunotherapeutic target.

A molecular subtyping associated with the cGAS-STING pathway provides novel perspectives on the treatment of ulcerative colitis

Ulcerative colitis (UC) is characterized by an abnormal immune response, and the pathogenesis lacks clear understanding. The cGAS-STING pathway is an innate immune signaling pathway that plays a significant role in various pathophysiological processes. However, the role of the cGAS-STING pathway in UC remains largely unclear. In this study, we obtained transcriptome sequencing data from multiple publicly available databases. cGAS-STING related genes were obtained through literature search, and differentially expressed genes (DEGs) were analyzed using R package limma. Hub genes were identified through protein–protein interaction (PPI) network analysis and module construction. The ConsensuClusterPlus package was utilized to identify molecular subtypes based on hub genes. The therapeutic response, immune microenvironment, and biological pathways of subtypes were further investigated. A total of 18 DEGs were found in UC patients. We further identified IFI16, MB21D1 (CGAS), TMEM173 (STING) and TBK1 as the hub genes. These genes are highly expressed in UC. IFI16 exhibited the highest diagnostic value and predictive value for response to anti-TNF therapy. The expression level of IFI16 was higher in non-responders to anti-TNF therapy. Furthermore, a cluster analysis based on genes related to the cGAS-STING pathway revealed that patients with higher gene expression exhibited elevated immune burden and inflammation levels. This study is a pioneering analysis of cGAS-STING pathway-related genes in UC. These findings provide new insights for the diagnosis of UC and the prediction of therapeutic response.

Penentuan Setting Optimal Mesin Injection Moulding Menggunakan Metode Response Surface

PT. Medion Farma Jaya is a company that produces livestock equipment, parts, and plastic packaging. One of the products produced by PT. Medion Farma Jaya is a 5-CC measuring spoon. This mass production process is based on what the company needs to package it with other products, or that can be from customer orders. This research is focused on the 5 CC measuring spoon product (SEN5CC) because, according to the company's 2021 historical data, there is a large percentage of rejected or defective products. Because of these problems, things can be done. The effect on the response to defective products is the setting of the injection Moulding machine by trial and error. Therefore, this research aims to find optimal settings for the machine for injection molding so that it can improve the quality of the product. To find out the optimal settings in this research, the response surface method was used. Based on this method is useful for getting the optimal level of factors or parameters that are significant to the response results. Based on research results, the factors used significantly influence optimal results, namely the melting temperature factor of 260 °C, holding pressure of 30 bar, and injection pressure of 62 bar. Therefore, the predicted response value was -25.1667, which meets the minimum target for the rejected product.

Pan-cancer analysis of LRRC59 with a focus on prognostic and immunological roles in hepatocellular carcinoma.

LRRC59 is a leucine-rich repeats-containing protein located in the endoplasmic reticulum (ER), it serves as a prognostic marker in several cancers. However, there has been no systematic analysis of its role in the tumor immune microenvironment, nor its predictive value of prognosis and immunotherapy response in different cancers. A comprehensive pan-cancer analysis of LRRC59 was conducted from various databases to elucidate the associations between its expression and the prognosis of cancer, genetic alterations, tumor metabolism, and tumor immunity. Additionally, further functional assays were performed in hepatocellular carcinoma (HCC) to study its biological role in regulating cell proliferation, migration, apoptosis, cell cycle arrest, and sensitivity to immunotherapy. The pan-cancer analysis reveals a significant upregulation of LRRC59 in pan-cancer, and its overexpression is correlated with unfavorable prognosis in cancer patients. LRRC59 is negatively correlated with immune cell infiltration, tumor purity estimation, and immune checkpoint genes. Finally, the validation in HCC demonstrates LRRC59 is significantly overexpressed in cancer tissue and cell lines, and its knockdown inhibits cell proliferation and migration, promotes cell apoptosis, induces cell cycle arrest, and enhances the sensitivity to immunotherapy in HCC cells. LRRC59 emerges as a novel potential prognostic biomarker across malignancies, offering promise for anti-cancer drugs and immunotherapy.

Abstract PO1-16-04: Targeting PKMYT1 Kinase as a Therapeutic Strategy for Treatment of Triple Negative Breast Cancer with Low Molecular Weight Cyclin E (LMW-E) Expression

Abstract Purpose: Low molecular weight isoforms of cyclin E (LMW-E) have been implicated in various human cancers, including triple negative breast cancer (TNBC), and are associated with a poor prognosis. However, targeted therapies for TNBC based on biomarkers are currently lacking. This study aims to investigate LMW-E as a potential therapeutic target in TNBC and evaluate the efficacy of RP-6306, a selective inhibitor of the Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1), in LMW-E-positive breast tumors. Experimental Design: Immunohistochemical (IHC) analysis was performed on pre-treatment tumor specimens from TNBC patients (n=36) to assess the correlation between LMW-E expression, CDK1 phosphorylation at Threonine 14 (pT14), and pathologic complete response to neoadjuvant chemotherapy. LMW-E inducible human mammary epithelial cells (hMEC) and breast cancer cell lines were used to investigate the regulatory effect of LMW-E on PKMYT1, the kinase responsible for CDK1 phosphorylation at T14, and the response to RP-6306, a first in-class and selective inhibitor of PKMYT1. Patient-derived xenograft (PDX) models and transgenic mouse mammary tumor virus (MMTV) models of TNBC expressing human LMW-E (hLMW-E) were also utilized to assess LMW-E as a biomarker for predicting response to RP-6306. Results. Analysis of TNBC tumor biopsies revealed a significant positive correlation between LMW-E expression and CDK1 pT14, and both biomarkers were associated with a lack of pathological complete response to neoadjuvant chemotherapy. In vitro results using LMW-E inducible hMECs and breast cancer cell lines demonstrated that LMW-E up-regulates PKMYT1 and CDK1 pT14, acting as a PKMYT1 binding protein and enhancing PKMYT1 protein stability. High LMW-E protein levels predicted a favorable response to RP-6306, resulting in the accumulation of sub-G1 and polyploid cells, decreased tolerance to replication stress, increased DNA damage, chromosomal breakage, and apoptosis. In vivo treatment of TNBC PDX models and hLMW-E transgenic tumors with RP-6306 resulted in a significant reduction in tumor volume only in mice harboring high LMW-E tumors, while low cyclin E models showed no response. Immunohistochemical analysis confirmed increased γ-H2AX and decreased CDK1-pT14 and Ki67 levels, indicating the efficacy of RP-6306 in both PDX and transgenic models. Conclusion: This study highlights the regulatory axis from LMW-E to PKMYT1 and its predictive value for pathological complete response in TNBC patients receiving neoadjuvant chemotherapy. The selective PKMYT1 kinase inhibitor RP-6306 consistently induced DNA damage and inhibited tumor growth in in vitro and in vivo pre-clinical breast tumor models. Co-expression of LMW-E and CDK1-pT14 in TNBC can be used to stratify patients whose tumors are likely to respond to RP-6306, emphasizing its therapeutic significance. Citation Format: Mi Li, Amriti Lulla, Cansu Karakas, Spiridon Tsavaschidis, Yan Wang, Tuyen Nguyun, Tuyen Bui, Gary Marshall, Kelly Hunt, Khandan Keyomarsi. Targeting PKMYT1 Kinase as a Therapeutic Strategy for Treatment of Triple Negative Breast Cancer with Low Molecular Weight Cyclin E (LMW-E) Expression [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-04.

Abstract PO3-15-11: Soluble sFas, sFasL, sPD1, and sPD-L1 analyses in the blood peripheral of locally advanced breast cancer women before and after neoadjuvant chemotherapy

Abstract Assess soluble sFAS, sFASL, sPD1, and sPD-L1 levels in patients with HER2 or triple-negative (TN) breast cancer submitted to neoadjuvant chemotherapy. A prospective cohort study was performed with TN and HER2+ breast cancer patients between 2015 and 2018. Soluble levels of sFasL, sFas, sPD-L1, and sPD1 were collected before and after neoadjuvant chemotherapy (NAC). NAC regimens included a dense dose of Adriablastin and cyclophosphamide during four cycles, followed by Paclitaxel for 12 weeks. No clinical evidence of tumor in the breast and axillary lymph nodes was defined as a pathological complete response (pCR). Twenty-one women with TN (56,7%) and 16 (43,3%) HER2+ breast cancer were included. Twenty-one women (56.7%) presented complete pathological response (pCR) after neoadjuvant chemotherapy (NAC), defined as the absence of invasive disease in the breast and lymph nodes. High sPD1 and sFas levels in the TN and HER2+ patients compared to the control group (P&amp;lt; 0.05). In paired analysis, statistical differences of sFas and sFasL levels in TN and HER2+ patients before and after NAC (P&amp;lt; 0.05). Low levels of sPDL1 in HER2+ patients with pCR compared to non-pCR (P&amp;lt; 0.05). High sFasL levels in TN patients with pCR compared to the non-pCR group (P&amp;lt; 0.05). Conclusion: soluble sFas, sFas-L, sPD1, and sPD-L1 levels were apoptosis-related markers with potential predictive value of neoadjuvant chemotherapy response in TN and HER2+ breast cancer. Keywords: breast cancer; FAS receptor; Programmed death 1, HER2+, Triple negative Citation Format: Carolina Vasconcelos, Marcelo Salgado, Carlos Eduardo Anunciação, Denise Viana, Leuridan Torres, Nathália Valois Montarroyos de Moraes. Soluble sFas, sFasL, sPD1, and sPD-L1 analyses in the blood peripheral of locally advanced breast cancer women before and after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-11.

Abstract PO3-25-07: Characterization of tertiary lymphoid structures and its association with response to immune checkpoint inhibitors in triple negative breast cancer using spatial transcriptomics

Abstract Background Tertiary lymphoid structures (TLS) are ectopic lymphoid organs playing a role in adaptive antitumor immune response. They were shown to be associated with favorable outcome and appears to be a promising biomarker for response to immune checkpoint inhibitors (ICI). Yet, there is no consensus for their detection and quantification. Here we aimed to derive a specific TLS signature using high resolution spatial transcriptomics data from a large series of triple negative breast cancer (TNBC) samples and to assess its clinical relevance including response to ICI. Methods Spatial transcriptomics (ST) was performed on a series of 94 early-stage TNBC surgical samples with detailed clinicopathological and outcome data. TLS and tumor infiltrating lymphocytes (TILs) were scored using hematoxylin and eosin and double immunohistochemistry (CD3/CD20) stained slides by a dedicated breast pathologist. Regression based on morphological annotations and deconvolution methods estimated the fraction of gene expression related to TLS in each ST spot allowing to derive specific TLS signature. Its prognostic and predictive value of response to ICI was assessed using publicly available breast cancer (METABRIC, SCAN-B, and I-SPY2) and other tumor type datasets treated with ICI (Bareche et al. Ann Oncol, 2022) from bulk gene expression data. Results Deconvolution of the TLS compartments using the ST gene expression data showed that TLS are enriched in all B cell subsets, CD4+ (central) memory and naïve T cells, as well as mast cells. A functional analysis showed an enrichment of ‘vascular endothelial cell proliferation’, ‘mitotic G2/M transition checkpoint’, ‘V/D/J recombination’ and ‘regulation of cell chemotaxis to fibroblast growth factor’ suggesting that TLS aggregates are associated with angiogenesis, immune cell proliferation, adaptative humoral response and tissue remodeling. A comparison of gene expression data between TLS and non-aggregated TILs led to the development of a specific TLS gene signature comprising B and T cell-specific genes, immunoglobulin genes as well as genes associated with TLS initiation. Its projection on tumor slides overlapped with the regions annotated as TLS by the pathologist, demonstrating its specificity for TLS detection. As expected, the highest levels of the TLS signature were observed in the immunomodulatory TNBC molecular subtype and fully inflamed tumors, whereas the lowest levels were observed in the mesenchymal molecular subtype and immune desert tumors (p&amp;lt; 0.05). Of note, high levels of the TLS signature were associated with better prognosis in TNBC patients from METABRIC (p=6.5 10−5) and SCAN-B datasets (p=1.6 10−3) as well as with higher pathological complete response rates in all breast cancer patients treated with neoadjuvant pembrolizumab in the I-SPY2 study (p=0.026). Similar results were found in other tumor types treated with immunotherapy in the metastatic setting including metastatic melanoma, pancreatic and bladder cancers (PFS, p=6 10−6). Of interest, the TLS signature outperformed the predictive value of other immune-related signatures including TILs suggesting a key role of TLS in obtaining a sustainable, adaptive antitumor immune response in the vicinity of the tumor area. Conclusion By leveraging the potential of spatial transcriptomics, we have successfully developed a unique TLS gene signature that demonstrates a strong correlation with the response to ICI in breast cancer and various other tumor types. This TLS gene signature outperforms other immune biomarkers, underscoring the pivotal role of TLS in eliciting a robust antitumor immune response. The universality of this TLS signature makes it a potent biomarker capable of identifying patients who would benefit from immunotherapy, pending further validation. Citation Format: Xiaoxiao Wang, David Venet, Frédéric Lifrange, Denis Larsimont, Mattia Rediti, Linnea Stenbeck, Floriane Dupont, Ghizlane Rouas, Andrea Joaquin Garcia, David Gacquer, Ligia Craciun, Laurence Buisseret, Nayanika Bhalla, Yuvarani Masarapu, Kim Thrane, Eva Gracia Villacampa, Lovisa Franzén, Sami Saarenpää, Linda Kvastad, Joakim Lundeberg, Françoise Rothé, Christos Sotiriou. Characterization of tertiary lymphoid structures and its association with response to immune checkpoint inhibitors in triple negative breast cancer using spatial transcriptomics [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-07.

Nomograms Predict PFS and OS for SCLC Patients After Standardized Treatment: A Real-World Study.

This study aims to investigate the process of small cell lung cancer (SCLC) patients from achieving optimal efficacy to experiencing disease progression until death. It examines the predictive value of the treatment response on progression free survival (PFS) and overall survival (OS) of SCLC patients. We conducted a retrospective analysis on 136 SCLC patients diagnosed from 1992 to 2018. Important prognostic factors were identified to construct nomogram models. The predictive performance of the models was evaluated using the receiver operating characteristic curves and calibration curves. Survival differences between groups were compared using Kaplan-Meier survival curves. Subsequently, an independent cohort consisting of 106 SCLC patients diagnosed from 2014 to 2021 was used for validation. We constructed two nomograms to predict first-line PFS (PFS1) and OS of SCLC. The area under the receiver operating characteristic curves for the PFS1 nomogram predicting PFS at 3-, 6-, and 12-months were 0.919 (95% CI: 0.867-0.970), 0.908 (95% CI: 0.860-0.956) and 0.878 (95% CI: 0.798-0.958), and for the OS nomogram predicting OS at 6-, 12-, and 24-months were 0.814 (95% CI: 0.736-0.892), 0.819 (95% CI: 0.749-0.889) and 0.809 (95% CI: 0.678-0.941), indicating those two models with a high discriminative ability. The calibration curves demonstrated the models had a high degree of consistency between predicted and observed values. According to the risk scores, patients were divided into high-risk and low-risk groups, showing a significant difference in survival rate. And these findings were validated in another independent validation cohort. Based on the patients' treatment response after standardized treatment, we developed and validated two nomogram models to predict PFS1 and OS of SCLC. The models demonstrated good accuracy, reliability and clinical applicability by validating in an independent cohort.

Non–small cell lung cancer and immune checkpoint inhibitor therapy: does non-alcoholic fatty liver disease have an effect?

BackgroundImmunotherapy based on the application of immune checkpoint inhibitors (ICIs) is one of the standard treatments for advanced non-small cell lung cancer (NSCLC). Non-alcoholic fatty liver Disease (NAFLD) has demonstrated predictive value for response to immunotherapy in non-lung cancer types. Our study investigated the effect of NAFLD on the efficacy of real-life use of ICIs for patients with stage III / IV NSCLC.MethodsThe clinical and imaging data of patients with stage III / IV NSCLC who were first admitted to Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from March 2020 to July 2022 were retrospectively collected to ensure that they underwent at least one CT scan before treatment. A total of 479 patients were divided into the NAFLD group (Liver/Spleen density ratio ≤ 1) and the non-NAFLD group (Liver/Spleen density ratio > 1) by measuring the baseline liver and spleen CT value. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) of the patients were obtained.ResultsA total of 118 patients with NAFLD and 361 patients without NAFLD were included in the study. Patients with NAFLD tended to have higher BMI and higher total bilirubin compared to patients without NAFLD. The median duration of follow-up in the study was 22 m (IQR, 17–29 m). Both of 2 groups had a higher DCR (94% vs. 92%, p = 0.199) and ORR (38.1% vs. 44.9%, p = 0.452) respectively. There was no difference in efficacy between the two groups. In univariate analysis, NAFLD had no significant effect on PFS (p = 0.785) and OS (p = 0.851). Surprisingly, the presence of hypertension was observed to be associated with a higher OS (HR 1.471 95%CI 1.018–2.127, p = 0.040). Besides, based on multivariate analysis, lactic dehydrogenase was associated with PFS (HR 1.001 95%CI 1.000,1.002, p = 0.037) and OS (HR 1.002, 95%CI 1.001–1.003, p < 0.001).ConclusionsAmong patients with NSCLC, NAFLD did not result in changes in survival or disease progression after immune checkpoint inhibitor therapy.

Octamer-binding transcription factor 4-positive circulating tumor cell predicts worse treatment response and survival in advanced cholangiocarcinoma patients who receive immune checkpoint inhibitors treatment

BackgroundOctamer-binding transcription factor 4-positive circulating tumor cell (OCT4+CTC) exhibits high stemness and invasive potential, which may influence the efficacy of immune checkpoint inhibitors (ICI). This study aimed to assess the prognostic role of OCT4+CTC in advanced cholangiocarcinoma (CCA) patients who received ICI treatment.MethodsIn total, 40 advanced CCA patients who received ICI treatment were included, and CTC and OCT4 counts were detected via a Canpatrol system and an RNA in situ hybridization method before ICI treatment. Patients were subsequently divided into none CTC, OCT4−CTC, and OCT4+CTC groups. Patients were followed up for a median of 10.4 months.ResultsThe percentages of patients in none CTC, OCT4−CTC, and OCT4+CTC groups were 25.0%, 30.0%, and 45.0%, respectively. The proportion of patients with lymph node metastasis was highest in OCT4+CTC group, followed by none CTC group, and lowest in OCT4−CTC group (P = 0.025). The objective response rate (ORR) was lowest in OCT4+CTC group, moderate in OCT4−CTC group, and highest in none CTC group (P = 0.009), while disease control rate was not different among three groups (P = 0.293). In addition, progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.001) were shorter in the OCT4+CTC group than in none CTC & OCT4−CTC group. Moreover, OCT4+CTC (versus none CTC) was independently linked with poorer PFS [hazard ratio (HR) = 6.752, P = 0.001] and OS (HR = 6.674, P = 0.003) in advanced CCA patients.ConclusionOCT4+CTC relates to lymph node metastasis and shows a good predictive value for poor treatment response and survival in advanced CCA patients who receive ICI treatment.

Fluid therapy in ICU – A review

The most common indications of fluid resuscitation in critical care settings are severe hypovolemia, sepsis, trauma, burns, and perioperative fluid loss. Evaluation of intravascular volume status and the ability for identifying patients who might profit from volume expansion is vital. Traditional markers such as central venous pressure and pulmonary capillary wedge pressure have poor predictive value for fluid responsiveness. Dynamic indices such as pulse pressure variation, stroke volume variation, tidal volume challenge, and passive leg raise test are recommended to predict fluid responsiveness over static markers. The next perplexing part of fluid therapy is the choice of fluid resuscitation. The simplest answer is to provide crystalloids and avoid synthetic colloids (hydroxyethyl startch, gelatin, and dextran). Among the colloids, albumin has a role in certain clinical conditions in critical care settings. Between normal saline and buffered solutions, buffered solutions have the advantage of reducing acid–base disturbances, and chloride burden, and are likely to prevent renal failure. However, the advantage of buffered solutions did not consistently show up in large randomized controlled trials. Although administering fluids is a common therapeutic approach in critical care settings, administering fluids excessively has been linked to fatal outcomes. The resuscitation, optimization, stabilization, and evacuation concept describes the use of a dynamic fluid strategy to optimize benefits and prevent the negative effects of fluid overload. After receiving a patient in an emergency room or intensive care unit with hemodynamic instability, the first thing that comes to mind is whether or not the patient would benefit from fluid administration. How to predict fluid responsiveness? What type of fluids should be administered? When to stop administering fluids and start evacuation are vital questions confronted in day-to-day practice. In this article, we would like to discuss these issues and provide recommendations for current practices.

Predictive value of immediate early response 5 like (IER5L) in the prognosis and immune checkpoint blockade therapy of non-small cell lung cancer patients

BackgroundNon-small cell lung cancer (NSCLC) is a malignancy with high mortality. Immediate early response 5 like (IER5L) has been found to associate with worse prognosis in colorectal cancer patients. However, its role in the prognosis prediction of NSCLC has remained largely unknown. MethodsThe IER5L expression in NSCLC and normal tissues was analyzed in two public cohorts: TCGA-LUAD-LUSC and GSE159857. Additionally, functional enrichment, survival analysis, CIBERSORT and tumor mutation burden (TMB) were investigated between low- and high-IER5L level groups. The in vitro IER5L mRNA and protein levels were determined using RT-qPCR and western blot, respectively. ResultsThe data from TCGA-LUAD-LUSC and GSE159857 cohorts showed a high IER5L mRNA expression in NSCLC tissue samples compared to normal controls. The increased expression of IER5L in NSCLC cells were also validated by RT-qPCR and western blot analysis. Additionally, NSCLC patients with high-IER5L level had significantly worse prognosis and IER5L could be used as an independent prognostic factor for NSCLC patients. Meanwhile, patients in the high-IER5L group had higher TMB level. IER5L expression was negatively correlated with the proportion of Monocytes and T cells CD4 memory resting, and was positively related to the proportion of Tregs and M0 macrophages in tumor tissues. Besides, transcription factors TFAP4 and ZNF692 may bind to the promoter region of IER5L, and then modulate IER5L gene transcription, thereby affecting IER5L gene expression. Furthermore, GSEA results showed that IER5L gene was closely related to MAPK, PI3K-Akt, NF-kappaB signaling pathways in NSCLC. ConclusionCollectively, high IER5L expression may be a promising unfavorable prognostic biomarker and therapeutic target for NSCLC patients.

Pan-cancer and single-cell analyses identify CD44 as an immunotherapy response predictor and regulating macrophage polarization and tumor progression in colorectal cancer.

Cluster of differentiation (CD) 44 is a non-kinase cell surface transmembrane glycoprotein critical for tumor maintenance and progression. We conducted a systematic analysis of the expression profile and genomic alteration profile of CD44 in 33 types of cancer. The immune characteristics of CD44 were comprehensively explored by TIMER2.0 and CIBERSORT. In addition, the CD44 transcriptional landscape was examined at the single-cell level. Then, Pseudotime trajectory analysis of CD44 gene expression was performed using Monocle 2, and CellChat was utilized to compare the crosstalk differences between CD44+monocytes and CD44- monocytes. Tumor immune dysfunction and exclusion (TIDE) was used to evaluate the predictive ability of CD44 for immune checkpoint blockade (ICB) responses. The effects of CD44 on colorectal cancer (CRC) and macrophage polarization were investigated by knocking down the expression of CD44 in HCT-116 cell and macrophages in vitro. The expression of CD44 elevated in most cancers, predicting unfavorable prognosis. In addditon, CD44 was correlation with immune cell infiltration and key immune regulators. CD44+ monocytes had a higher information flow intensity than CD44- monocytes. CD44 had good predictive ability for immune checkpoint blockade responses. Knockdown of CD44 inhibited the proliferation, migration, and invasion of HCT-116 cell in vitro. Knockdown of CD44 inhibited M2 macrophage polarization. These findings suggest that CD44 is involved in regulating tumor development, macrophage polarization, and has certain predictive value for patient clinical prognosis and response to immunotherapy.

Plasma miR-379 can predict treatment response to FOLFIRINOX and gemcitabine-nab-paclitaxel in advanced pancreatic cancer

BackgroundNovel biomarkers, such as plasma microRNAs (miRs), are needed to help guide clinical decision-making for the type of chemotherapy to use in patients with advanced pancreatic ductal adenocarcinoma (PDAC). This study assessed the ability of plasma miRs to predict optimal treatment response from FOLFIRINOX or gemcitabine-nab-paclitaxel in these patients. MethodsNext-generation sequencing (NGS) was performed for biomarker discovery in pre-treatment plasma samples from advanced PDAC patients subsequently treated with FOLFIRINOX (n = 12) or gemcitabine-nab-paclitaxel (n = 12). Selected candidate biomarkers were validated in 40 patients with advanced PDAC using RT-qPCR. Cox regression was then used to assess the predictive value of plasma miRs for either FOLFIRINOX or gemcitabine-nab-paclitaxel. ResultsIn the validation cohort, high plasma miR-379 expression was strongly predictive of treatment response (Pinteraction = 0.0004). Overall survival (OS) was significantly better with FOLFIRINOX vs. gemcitabine-nab-paclitaxel in those patients with lower plasma miR-379 expression (hazard ratio, 0.32 [95% confidence interval, 0.08 to 0.98]; P = 0.046). However, gemcitabine-nab-paclitaxel was associated with superior OS in patients with higher plasma miR-379 (hazard ratio, 0.28 [0.10 to 0.86]; P = 0.027). In contrast, miR-127, miR-155, and miR-200 showed no predictive value for treatment response for either chemotherapy regimen (Pinteraction = 0.12, Pinteraction = 0.83 and Pinteraction = 0.12, respectively). ConclusionsPlasma miR-379 appears clinically useful as a predictive biomarker to identify which patients with advanced PDAC benefit most from treatment with FOLFIRINOX or gemcitabine-nab-paclitaxel. Further validation in larger studies and clinical trials is now warranted.

Abstract 3904: Multiplexed flow cytometry based immunophenotyping paired with functional ex vivo (MFLEX) drug profiling informs potential efficacy of therapeutic agents in acute myeloid leukemia

Abstract Introduction: Acute Myeloid Leukemia (AML) is a heterogenous hematological malignancy with a complex clonal architecture that requires in-depth immunophenotyping for disease characterization. Conventional AML ex vivo models for preclinical drug screening lack functional readouts that provide single cell level data to identify drug activity in defined AML subsets with unique immune signatures. Here, we present a novel platform that links Multiparameter Flow cytometry with high-throughput EX vivo drug screening (MFLEX) in AML patient-derived cell models to simultaneously detect phenotypic changes and predict cell-subset specific drug responses in AML. Method: We developed a 21-color high-dimensional immune profiling panel that captures AML heterogeneity by delineating primitive and mature AML blasts along with normal hematopoietic lineages. The panel also includes markers for functional measurement of apoptosis, proliferation, differentiation, and expression of BCL2 family proteins in lymphoid and myeloid cell subsets. Ex vivo culture conditions were optimized using physiologically relevant stroma-free cytokine-rich media that supports primary AML cells with minimal phenotypic shift, allowing for high throughput functional drug sensitivity testing. Timepoints and dosing conditions for AML standard of care (SoC) agents were optimized to support combination screens. Multi-parameter datasets were analysed for functional differences and visualized using dimension reduction methods. Results: We tested MFLEX on clinically annotated AML samples to understand sensitivity profiles to venetoclax and combination partners: 5-azacytidine, cytarabine, fludarabine and gilteritinib. We identified distinct drug sensitivity profiles for venetoclax in AML patients with varying leukemic differentiation states where M0/M1 subtypes were more sensitive to therapy than M4/M5. We also observed cell lineage specific sensitivities, with myeloid blast being more sensitive to venetoclax compared to autologous CD4+ and CD8+ T-cells and this observed difference was correlated with higher expression of BCL2. Our platform demonstrated that patients who previously failed venetoclax therapy could benefit from a combination with 5-azacytidine or fludarabine and this was patient-specific. We further evaluated MFLEX’s predictive value for patient clinical response by systematically comparing venetoclax sensitivity in patient-derived xenograft models in vivo vs ex vivo and found a high correlation between drug responses. Conclusion: We have established a unique, immune drug screening platform, MFLEX, that has high translational value and can be implemented in clinical trials to identify drug response patterns, novel combinations, and potential biomarkers of response for patient stratification in AML. Citation Format: Reecha Shah, Heba Wander, Michelle Hsueh, Muskan Floren, Wei Liu, Patricia Cheung, Courtney Andersen, Michael White, Nathan Kingston, Pablo Morentin Gutierrez, Lisa Drew, Giulia Fabbri, Elena Bibikova, Daniel Auclair. Multiplexed flow cytometry based immunophenotyping paired with functional ex vivo (MFLEX) drug profiling informs potential efficacy of therapeutic agents in acute myeloid leukemia [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 3904.