A proteomics approach to identify predictive blood biomarkers for pleural mesothelioma in prospective cohorts.

Background Bicuspid aortic valve (BAV) is a common congenital heart defect. Patients with BAV are at risk for long-term complications such as arrhythmias and reinterventions. Purpose This study aimed to investigate (1) sex differences in blood and imaging biomarkers and (2) the role of blood and echocardiographic biomarkers in the long-term risk prediction of patients with BAV. Methods In this multicenter prospective observational study, all included adult BAV patients underwent venous blood sampling and transthoracic echocardiography including speckle tracking at the time of inclusion. Analyzed blood biomarkers were: RDW, creatinine, CRP, TroponinT, NT-proBNP and TGF-beta. Sex differences were analyzed at baseline. Associations between blood & echocardiographic biomarkers and arrhythmia-free & intervention-free survival were determined by Cox proportional hazards models. Results A total of 182 patients were included (median age 34 (Interquartile range: 23-46) years, 55.5% male). Significant differences were found in blood biomarkers at baseline between men and women. CRP, NT-proBNP and RDW were higher in women while creatinine, TroponinT and TGF-beta were higher among men (figure 1). After a median follow-up time up of 6.9 (IQR: 6.5- 9.9) years, arrhythmia-free and event-free survival rates were respectively 81.0% and 73.1%. NT-proBNP was the only blood biomarker independently associated with both arrhythmia free and intervention free survival. On echocardiography an increase in LA size, LVEDD, LV mass index and E/E’ratio were associated with arrhythmia free survival. Intervention free survival was associated with increased LA size, LV mass index, aortic valve peak velocity and the presence of moderate or severe aortic regurgitation. No associations were found with ejection fraction and global longitudinal strain (figure 2). Conclusion Significant sex-related differences were observed in blood biomarkers between men and women with BAV at baseline. NT-proBNP was the only blood biomarker associated with arrhythmia-and intervention-free survival. The strongest associations of echocardiographic markers were those indicating diastolic function and LV mass index.Sex differences in blood biomarkersForest plot

Bevacizumab was the first molecular-targeted antiangiogenic therapy approved for the treatment of metastatic colorectal cancer. Until now, there are no predictive biomarkers available to decide the prescription of bevacizumab in patients with colorectal cancer. The purposes of this review were to provide a critical appraisal of the evidence and to identify possible predictive genetic biomarkers. A literature search was performed to identify studies that determine different levels of treatment response between patients stratified according to defined biomarkers. Interesting findings were reported between patients stratified according to rs3025039 and rs833061 polymorphisms of the gene VEGFA, with statistically and clinically significant differences for progression-free survival and overall survival. However, another study conducted in a larger sample does not confirm these previous findings, suggesting that well-designed prospective studies are still needed to achieve conclusive results. FLT1 (or VEGFR1) rs9513070 seems to be an interesting candidate as a predictive biomarker, with differences of more than 10 months in OS between different patients groups. In our opinion, possible interesting biomarker candidates for future research could be the polymorphisms rs833061 and rs3025039 of VEGF-A, rs9513070 or haplotype analysis of FLT1, rs2661280 of RGS5, rs444903 and rs6220 of EGF and Ang-2 or LDH plasma levels.

Epidermal growth factor receptor (EGFR) serves as a co-target for dual/pan-EGFR-inhibitors in breast cancer. Findings suggest that EGFR and EGFR-ligands are involved in resistance towards certain breast cancer treatments. The aim is to explore the validity of EGFR and EGFR-ligands in blood as prognostic and predictive biomarkers in breast cancer. The systematic review was conducted in accordance to the PRISMA guidelines. Literature searches were conducted to identify publications exploring correlations between EGFR/EGFR-ligands in serum/plasma of breast cancer patients and prognostic/predictive outcome measures. Sixteen publications were eligible for inclusion. Twelve studies evaluated EGFR, whereas five studies evaluated one or more of the EGFR-ligands. Current evidence indicates associations between low baseline serum-EGFR and shorter survival or reduced response to treatment in patients with advanced breast cancer, especially in patients with estrogen and/or progesterone receptor positive tumors. The prognostic and predictive value of EGFR and EGFR-ligands in blood has only been investigated in highly selected subsets of breast cancer patients and most studies were small. This is the first systematic review evaluating the utility of EGFR and EGFR-ligands as predictive and prognostic biomarkers in blood in breast cancer. Further exploration in large well-designed studies is needed.

e15235 Background: Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with likelihood of response to specific checkpoint inhibitors, prediction of response is rather imperfect and, thus, more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B, a DNA-repair gene, as candidate predictive biomarker for efficacy of anti-PD-1 therapy in patients with non-small cell lung cancer (NSCLC), correlating with patients’ outcome. Methods: PD-L1 immunoexpression and RAD51Bme levels were analysed in samples of NSCLC obtained from patients not treated with anti-PD-1 blockade (testing cohort) and patients treated with anti-PD-1 (validation cohort). Results: Of a total of 127 patients assessed, 58.3% depicted positivity for PD-L1 (PD-L1+). RAD51Bme levels significantly associated with PD-L1 immunoexpression. Patients with clinical benefit from immunotherapy disclosed higher RAD51Bme levels (p = 0.04) and significantly higher median progression free survival (PFS) (p = 0.02). PD-L1+ was also associated with longer overall survival (p = 0.03). Conclusions: We demonstrated that RAD51Bme levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51Bme should be confirmed in prospective studies.

Delayed cerebral ischemia (DCI) is a severe complication of subarachnoid hemorrhage (SAH). Clinical and radiographic features of SAH may be helpful in identification of individuals prone to DCI. The aim of this systematic review was to analyze the present evidence on predictive value of blood and cerebrospinal fluid (CSF) biomarkers of DCI after SAH. We systematically searched in PubMed, Scopus, Web of Science, and Cochrane Library databases for publications before July 15, 2018, reporting correlations between blood/CSF biomarkers and occurrence of DCI and/or vasospasm in SAH patients. Included studies underwent quality assessment according to QUIPS and STARD guidelines. Level of evidence (I-IV) for each of tested biomarkers was assessed according to GRADE guidelines. Of 2181 unique records identified in four databases, 270 original articles and 5 meta-analyses were included to this review. Of 257 blood and CSF parameters analyzed in 16.914 SAH patients, there was no biomarker with positive association with DCI/vasospasm showing level I evidence. Twenty-one biomarkers achieved level II evidence and could be confirmed as predictive biomarkers. In this review, six single nucleotide polymorphisms (for EET metabolic pathways, COMT, HMGB1, ACE, PAI-1 promoter, and Hp genes) and 15 non-genetic biomarkers (pNF-H, ADAMTS13, NPY, Copeptin, HMGB1, GFAP, periostin, Tau, BNP, NT pro-BNP, hs-TnT, PA-TEGMA, MPV:PLT, NLR, and PLR) were selected as predictive DCI biomarkers. We propose that a panel analysis of the selected genetic and protein biomarker candidates would be needed for further validation in a large SAH cohort.

173 Background: Higher levels of vascular endothelial growth factor-D (VEGF-D) is a potential predictive biomarker for ramucirumab (Ram) efficacy on overall survival and progression-free survival (PFS) in Ram+FOLFIRI vs Placebo+FOLFIRI for bevacizumab (Bev) refractory metastatic colorectal cancer (mCRC). However, it is not clear whether VEGF-D acts as a predictive biomarker in pts who pretreated without Bev. RAINCLOUD showed the clinical benefit of FOLFIRI+ plus Ram for pts with recurrent CRC refractory to adjuvant chemotherapy (median PFS was 6.2 months (M); ESMO-GI 2022). RAINCLOUD-TR was designed as a prospective biomarker study estimating the association of biomarkers with Ram efficacy. Methods: Plasma sample collections were done at time points of pre-/ post-treatments in pts receiving FOLFIRI+Ram. Measurements of 17 factors (including VEGF-A, VEGF-D and PlGF) were performed by multiplex assay with Luminex technology. The high/ low groups were defined bases on the median plasma level at the baseline. Results: From September 2017 to September 2021, 81 plasma samples were collected from 48 pts and 32 pts in both pre/ and post treatment. Level of VEGF-A, VEGF-D, PlGF and TSP-2 were all significantly higher in post vs pre-treatment [Table]. The ORR analyses were as follows; VEGF-A, VEGF-D and PlGF in low vs high were 50.0%/33.3% (p=0.35, HR 1.97), 55.0% /33.3% (p=0.22, HR 2.39), and 60.0%/28.6% (p=0.35, HR 1.95). The PFS analyses were as follows; VEGF-A, VEGF-D, and PlGF in low vs high were 6.1M/6.0M (p=0.815, HR 0.92), 7.6M /5.6M (p=0.095, HR 0.56), and 8.0M/4.2M (p=0.014, HR 0.40). In other factors, low TSP-2 were better ORR (low vs high: 66.7%/20.0% (p=0.004, HR 7.54) and PFS 7.5M/4.3M (p=0.022, HR 0.45). Conclusions: In this exploratory study, PFS was numerically greater for pts with low vs high VEGF-D for Ram in pts with mCRC pretreated without Bev. VEGF-D may not be predictive biomarker, but TSP-2 may be a potential prognostic biomarker, further studies in larger cohorts are needed to confirm our results. Clinical trial information: UMIN000028678 . [Table: see text]

Objectives: Allograft rejection is the most common event that occurs posttransplant and the current diagnostic tools like the measurement of serum creatinine or core kidney biopsy could not serve as a predictive tool and have certain drawbacks. Thus, our target was to find potential, non-invasive, and predictive biomarkers which could identify recipients at the risk of post-transplant allograft rejection. Methods: It is a prospective longitudinal cohort study comprising of 40 live-related kidney transplant recipients whose peripheral blood was collected at three time points viz pre, one and threemonths post-transplant to assess the plasma cytokine levels of FOXP3, IL- 6, IL-17 and TGF-b using Enzyme linked immunosorbent assay (ELISA). The patients were clinically followed for period of two years to determine their posttransplant outcome. Findings: 13 of our recipients had biopsy proven allograft rejection at the end of follow-up period. The pre-transplant concentration of FOXP3 were less in the rejection group whereas the concentration of IL-6, IL- 17 and TGF- b were more in the rejection group (p<0.05). The classification accuracy of the markers FOXP3, TGF- b , IL-17 and IL-6 were assessed and they had an AUC of 1.0, 1.0, 0.96 and 0.84 respectively with high sensitivity, specificity, and statistical significance. Novelty: Pre-transplant levels of plasma cytokines were able to predict recipients at the risk of allograft rejection. Thus, our study confirms the predictive power of our cytokine biomarkers FOXP3, IL- 6, IL-17 and TGF-b and further paves way for personalized immunosuppressive regimen. Keywords: Predictive Biomarkers; Allograft Rejection; FOXP3; IL6; IL17; TGFb

415 Background: Clinical trials support the efficacy of immune checkpoint blockades (ICBs) plus chemotherapy in a subset of patients with metastatic gastric cancer (mGC). With the aim of identifying determinants of response, we developed a TMEscore assay (PCR assay with 30 genes) to assess tumor microenvironment, which was previously proved to be a robust predictive biomarker for patients treated with ICBs. Methods: Advanced GC patients treated with ICB combined with chemotherapy as first-line regimen were included in this multi-center prospective clinical trial (NCT#04850716). 65 tumor specimens obtained from 8 medical centers before treatment were applied to estimate TMEscore, PD-L1(CPS) and mismatch repair deficiency (MMR). Of 65 patients, 43 patients with treatment response and 34 patients with progression-free survival (PFS) were used to compare the predictiveness of biomarkers. Results: Theoverall response rate (ORR) and median PFS of this cohort were 39.9% and 4.67 months.Enhanced ORR was observed in TMEscore-high mGC patients (ORR = 61%), but only 16.7% in the low group. Regressive tumors (partial response, PR) had markedly higher TMEscore than stable and progressive tumors (stable disease, SD; progressive disease, PD, P = 0.001). By applying ROC curve analysis, the TMEscore was found to be an encouraging predictive biomarker that surpassed MMR and CPS statistically (AUC = 0.863, 0.525, and 0.519, respectively; Delong test, P = 0.003). Importantly, the Kaplan-Meier survival analysis demonstrated that a high TMEscore was significantly related to a more favorable PFS ( P = 0.0026, HR=0.18, 95%CI 0.06-0.55). Compared to TMEscoreA (immune score), TMEscoreB (stromal score) presented a dramatically higher hazard ratio for PFS (HR = 12.25, P = 0.0001), implicating stromal activation as a critical mechanism of intrinsic resistance to ICB plus chemotherapy. Meanwhile, PD-L1 (CPS) was not statistically associated with PFS, whether 1 or 5 were used as a cutoff to divide patients ( P = 1 and 0.22). Conclusions: This prospective clinical study indicated that the TMEscore assay is a robust biomarker for screening mGC patients who may derive survival benefit from ICB plus chemotherapy. Our data also suggest that TMEscore may be a more accurate predictive biomarker than MSI and CPS (PD-L1) for mGC patients, which warrants additional investigations in larger cohorts. Clinical trial information: NCT#04850716 .

Predictive asthma scores and biomarkers are important tools that help many physicians in the identification of infants and preschool children at high risk for asthma. Our objective was to review recent data regarding this subject. Recently, two new predictive asthma scores were developed with some innovative features, such as the definition of scales of asthma risk. In a systematic review, 12 asthma-predictive models were identified with heterogeneous performance. Prospective studies have shown that elevated fractional concentration of nitric oxide (FeNO) is a strong risk factor for latter asthma among early wheezers, and a predictive asthma score with FeNO values has been proposed. Plasma cytokines and exhaled volatile organic compounds were also identified as potential asthma predictors. Predictive scores are simple, practical, and inexpensive tools to identify children at high risk for asthma at school age. Whereas some scores are better at identifying asthmatic children, others are better at excluding the diagnosis of asthma. Although promising, clear evidence for FeNO as a robust asthma predictor in comparison to clinical scores is still lacking. Specific IgE and eosinophil counts remain the most consistent biomarkers for the identification of children at risk for asthma, and further studies are necessary to clarify the role of other biomarkers.

BackgroundConcurrent platinum-based chemoradiotherapy (CRT) followed by durvalumab maintenance treatment represents the new standard of care in unresectable stage III non-small cell lung cancer (NSCLC). In this prospective hypothesis-generating single-center study, we aim to identify a framework of prognostic and predictive biomarkers by longitudinal characterization of tumor- and patient (host)-related parameters over all phases of multimodal treatment.MethodsThis study will enroll 40 patients (≥18 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2, with a diagnosis of PD-L1 positive (≥1%), inoperable stage III NSCLC) with an indication for CRT followed by maintenance treatment with durvalumab according to European Medicines Agency (EMA) approval. Comprehensive analysis will include peripheral blood cellular and humoral immunophenotyping and circulating tumor DNA as well as gut/saliva microbiota analyses. Additional morphological analysis with 18F-FDG-PET/computed tomography (CT) before, 6 weeks, 6 and 12 months after the end of CRT is included. Statistical analysis using multiple testing will be used to examine the impact of different parameters on progression-free survival (PFS) and overall survival (OS) as well as tumor response and response duration.DiscussionThis protocol describes the methodology of a comprehensive biomarker study in order to identify a framework of prognostic and predictive markers for unresectable stage III NSCLC in a real-world setting.Trial RegistrationClinicalTrials.gov identifier (NCT05027165), data registered on August 2021.

Transplantomics and Biomarkers in Organ Transplantation: A Report From the First International Conference

Aims/hypothesisHypoadiponectinaemia and raised C-reactive protein (CRP) level are obesity-related biomarkers associated with glucose dysregulation. We evaluated the combined use of these two biomarkers in predicting the deterioration of glycaemia in a prospective study after a median of 5.4 years.MethodsIn total 1,288 non-diabetic participants from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, with high-sensitivity CRP (hsCRP) and total adiponectin levels measured were included. OGTT was performed in all participants. Two hundred and six participants had deterioration of glycaemia at follow-up, whereas 1,082 participants did not.ResultsBaseline age, hsCRP and adiponectin levels were significant independent predictors of the deterioration of glycaemia in a Cox regression analysis after adjusting for baseline age, sex, BMI, hypertension, triacylglycerols, 2 h post-OGTT glucose and homeostasis model assessment of insulin resistance index (all p < 0.01). The introduction of hsCRP or adiponectin level to a regression model including the other biomarker improved the prediction of glycaemic progression significantly in all participants, especially in women (all p < 0.01). The combined inclusion of the two biomarkers resulted in a modest improvement in model discrimination, compared with the inclusion of either one alone. Among participants with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) at baseline, hsCRP and adiponectin levels were not predictive of progression or improvement of glycaemic status.Conclusions/interpretationAdiponectin and hsCRP levels are independent factors in predicting the deterioration of glycaemia, supporting the role of adiposity-related inflammation in the development of type 2 diabetes. Their combined use as predictive biomarkers is especially useful in women, but not in participants with IFG/IGT.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2227-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

This review summarizes recent studies on the predictive value of molecular markers in adult gliomas, including 1p/19q codeletion, MGMT methylation, IDH mutation and markers identified using omics and next-generation sequencing studies. The long-term results of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer trials in anaplastic oligodendroglial glioma have shown that the 1p/19q codeletion predicts an overall survival benefit from early PCV (procarbazine CCNU vincristine) chemotherapy. This benefit can also be predicted using gene expression-based molecular subtypes of gliomas while the predictive value of the IDH mutation in this context requires further study. In elderly patients with glioblastoma, the analysis of MGMT methylation status in two phase III trials suggests that this alteration may guide treatment decisions; however, this finding still needs confirmation in prospective studies. Omics and next-generation sequencing studies have identified additional potential predictive markers. In particular, IDH mutations, BRAF V600E mutations and FGFR gene fusions might predict efficacy of therapies targeted against these alterations. Currently, the 1p/19q codeletion is the only well established predictive marker with clinical utility. However, it is likely that other molecular markers such as MGMT methylation, IDH mutation and those identified using omics and next-generation sequencing studies will further guide treatment decisions in adult gliomas.

It all began in Weimar, at the Goethe National Museum in Weimar, a magnificent and placid place, redolent in history and culture, where Prof. Richard Baum organized the fourth Mitteldeutsches Neuroendokriner Tumor Symposium, in June 2013 (Fig. 7.1). Richard has always been a pioneer and the first to understand and disseminate the importance of many innovations, including the now popular theranostic concept. Unlike many conservative and “predictable” scientific gatherings, his meetings have always been avant-garde and pivotal in defining the trends for the future. To my delight and pleasure, I was invited to participate in what I knew would be a tour de force of the trailblazers of innovative nuclear medicine. Inspired by such greatness, we subsequently established the LuGenIum Consortium for Independent Research to addressed some of the major challenges in the use of peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs), which are the prediction of efficacy and toxicity and the consequent patient stratification. In the following years, we conducted clinical trials to understand the role of individual predisposition and specific tumor genomic profile in the response and toxicity to PRRT. Our specific aims were to, first, conduct a retrospective analysis of toxicity to PRRT (i.e., define the problem) in a large patient cohort, then to conduct two prospective studies (assess the efficacy of the ideas). To this aim, we firstly identified NETs at a genomic level and assessed the response to PRRT with a PCR-based blood analysis, and, secondly, we analyzed markers of long-term toxicity in patients previously undergone to PRRT, with a PCR-based blood analysis. During our investigations, we identified a new biomarker, the PRRT predictive quotient, or PPQ, which demonstrated 95% accuracy in predicting the response to PRRT in the three prospective series that were studied under the LuGenIum umbrella. These results provide the demonstration that PPQ is a predictive biomarker and a measure of radiosensitivity. We also demonstrated in these patients that the NET identifying circulating transcriptomic signature NETest was able to accurately monitor the course of PRRT during its delivery, as opposed to imaging, which becomes reliable only after treatment completion. The results of these studies opened a new era for treatment individualization and optimization.

Predictive value of serum soluble corin in the risk of hyperglycemia: A population-based prospective cohort study in China