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PubMed2026

Genomic Characterization of ETV6::RUNX1-Positive Childhood B-ALL in a Chinese Cohort: Novel Fusion Partners, Co-Occurring Mutations, and Risk-Stratifying Biomarkers.

BACKGROUND: ETV6::RUNX1 is the most common genetic abnormality in pediatric B-cell acute lymphoblastic leukemia (ALL; ∼25%), yet the comprehensive genetic architecture and molecular predictors of intermediate-risk (IR) stratification remain incompletely characterized. METHODS: We performed whole-transcriptome sequencing (Illumina NovaSeq 6000, rRNA depletion, 41.70 Gb/sample) on bone marrow samples from 93 pediatric ETV6::RUNX1-positive B-ALL patients. Bioinformatics analysis included STAR alignment, MuTect2 variant calling, FusionCatcher fusion detection, and VEP annotation. The Jaccard index with permutation testing assessed mutation co-occurrence; logistic regression identified independent predictors of IR classification. RESULTS: Beyond ETV6::RUNX1, we identified 51 distinct fusion genes across the cohort, including the reciprocal RUNX1-ETV6 (73.1%), chr8::KLF1210 (38.7%), and KLF12-chr8 (34.4%). Somatic mutations in 249 genes were detected; the most frequent were KIAA1715 (17.2%), KRAS (11.8%), and NSD2 (10.8%). Network analysis revealed significant chromatin modifier co-occurrence (KIAA1715-KMT2C: J = 0.136, p = 0.015) and KRAS-NRAS mutual exclusivity (J = 0.000, p = 0.042). PTCH1 (OR = 3.50, 95% CI 0.21-58.49, p = 0.41) and GNB1 (OR = 6.5, 95% CI 1.2-34.8, p = 0.029) mutations independently predicted IR classification. chr8::KLF1210 fusion correlated with higher Day-19 MRD levels (p = 0.038). CONCLUSIONS: GNB1 mutation represents a novel independent predictor of IR stratification in ETV6::RUNX1-positive B-ALL. The chromatin modifier co-occurrence module and extensive fusion architecture reveal biological heterogeneity within this favorable-risk subtype, with potential implications for risk-adapted therapeutic strategies.

B‐ALL↗
PubMed1998

The prognostic significance of the biomarkers p21WAF1/CIP1, p53, and bcl-2 in laryngeal squamous cell carcinoma.

BACKGROUND: The clinical course of laryngeal squamous cell carcinoma (LSCC) varies considerably among patients. New biologic markers are needed to facilitate the stratification of individual patients within the conventional clinicopathologic stages of LSCC. METHODS: Eighty-three LSCCs from an equal number of patients who received at least 10 years of follow-up were investigated for p53, p21WAF1/CIP1, and bcl-2 protein expression by immunohistochemical techniques. The results were correlated with various clinicopathologic parameters, DNA content, and patient outcome by univariate and multivariate statistical analyses. RESULTS: Stage IV disease, large tumor size (>3 cm), positive lymph node status, extranodal extension, and p53 overexpression (in > 75% of cells) correlated significantly with prognosis in univariate analysis. There was no correlation between patient outcome and age, gender, race, histologic differentiation, or expression of bcl-2 or p21WAF1/CIP1. In multivariate analysis, lymph node status and p53 overexpression were the only factors significantly associated with survival. CONCLUSIONS: High p53 expression and positive lymph node status were independent predictors of the outcomes of patients with LSCC. These factors may assist in prognostication and better classification of patients for treatment.

Adult↗
PubMed2003

Biomarkers in Barrett's esophagus.

This article provides a framework for clinicians who are attempting the difficult task of interpreting the Barrett's biomarker literature with the goal of improving care for their patients. Although many articles. including more that 60 proposed biomarkers, have been published on this subject, only a few describe phase 3 and 4 studies that are of interest to the clinical gastroenterologist (Table 1). For year, dysplasia grade has been the sole means of risk stratification for patients with BE, and it likely will continue to be used in the foreseeable future. The current authors believe that dysplasia classification can be valuable using the team management approach and quality controls described previously. Significant problems, however, have emerged in phase 2 through 4 studies of dysplasia that make it imperative for the Barrett's field to incorporate additional biomarkers as they are validated. These problems include poor reproducibility of dysplasia interpretations, poor predictive value for negative, indefinite, and low-grade dysplasia, and inconsistent results for HGD in different centers, all of which makes it virtually impossible to develop national guidelines for surveillance. Some studies have even suggested that endoscopic biopsy surveillance using dysplasia may not be worthwhile. Currently, flow cytometric tetraploidy and aneuploidy have progressed furthest in biomarker validation (see Table 1). With proper handling, endoscopic biopsy specimens can be shipped to reference laboratories that have the instruments, computer analytic methods, and expertise to reproducibly detect tetraploidy and aneuploidy. The results of phase 4 studies indicate that flow cytometry appears to be useful in detecting a subset of patients who do not have HGD and yet have an increased risk of progression to cancer that cannot be identified by dysplasia grade. For many reasons, the authors anticipate that the number of validated biomarkers will increase substantially in the future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.

Adenocarcinoma↗
PubMed2005

Usefulness of biomarkers for predicting long-term mortality in patients with diabetes mellitus and non-ST-elevation acute coronary syndromes (a GUSTO IV substudy).

The present study evaluated whether biomarkers of ischemia, inflammation, myocardial damage, and dysfunction are equally useful in patients who have diabetes mellitus (DM) for prediction of cardiac events in non-ST-elevation acute coronary syndrome (ACS). DM was present in 1,677 of 7,800 patients (21.5%) who had non-ST-elevation ACS and were included in the Fourth Global Utilization of Strategies To Open Occluded Arteries (GUSTO IV) trial. Creatinine, N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), troponin T, C-reactive protein, and interleukin-6 were analyzed in serum samples that were obtained at a median of 9.5 hours from symptom onset. One-year mortality rates were 13.5% among patients who had DM (n = 227) and 6.9% among those who did not (n = 418, p < 0.001). The median level of NT-pro-BNP was 2 times as high in patients who had DM, whereas troponin T levels did not differ by DM status. Mortality increased with ascending quartiles of NT-pro-BNP, with 1-year mortality rates of 3.9% (n = 11) in the bottom quartile and 29% (n = 103) in the top quartile. In multivariable analyses, factors that were predictive of 1-year mortality in patients who did not have DM were also significant for those who did. Presence of ST depression > 0.5 mm had the highest odds ratio of 2.3 (95% confidence interval 1.2 to 4.6). NT-pro-BNP levels > 669 ng/L (odds ratio 2.0, 95% confidence interval 1.1 to 3.6) and interleukin-6 levels > 10 ng/L (odds ratio 1.9, 95% confidence interval 1.2 to 3.0) were significant biomarker predictors. In conclusion, DM confers a high long-term mortality in non-ST-elevation ACS. Despite a larger proportion of ST depression and increased levels of NT-pro-BNP and interleukin-6 at admission, these factors provide independent prognostic information that may improve risk stratification and guidance of treatment.

Aged↗
PubMed2000

[Prospective multicenter observational study of early rheumatoid arthritis--prognostic factors and predictors of disease course].

The aim of a new prospective, multicenter trial on early rheumatoid arthritis is to evaluate parameters of potential relevance for the prediction of an erosive disease course. The integration of general practitioners, rheumatologists, arthritis care units and experimental research groups in a network structure is intended to improve the cooperation between basic and clinical research as well as the treatment of the patients. The final goal is to identify new parameters that may improve an early stratification of patients into the appropriate treatment areas.

Adult↗
PubMed2025

Methylation Signatures Identify Two Distinct Clusters of Uterine Leiomyosarcoma With Unique Histologic and Clinical Behaviors.

Uterine leiomyosarcoma (uLMS) is a rare and deadly gynecologic malignancy. uLMS is histologically heterogeneous and presents with a wide spectrum of tumor differentiation, with a broad range of genomic DNA instability, which can make the diagnosis and prognosis of uLMS challenging. Methylation has emerged as a useful molecular tool in tumor classification and diagnosis in certain neoplasms. We initiated this study to investigate the role of global methylation in the differential diagnosis of uLMS from its mimics in correlation with pathologic characteristics and clinical outcomes. In this study, we performed array-based global methylation profiling analysis in a total of 71 uLMS and compared the methylation signatures of uLMS with several other uterine mesenchymal tumors and soft tissue leiomyosarcoma. We found that uLMS demonstrated distinct methylation patterns differing from all other tumor types. Notably, methylation profiling defines 2 distinct subgroups of uLMS with differing copy number alterations, resulting in unique histologic and clinical behaviors, further emphasized by differences in methylation pathway analysis. This study is the first to report methylation profiling as a useful diagnostic tool in differentiating uLMS from mimics and defines 2 subtypes of uLMS based on methylation signatures.

Humans↗
PubMed2004

Risk assessment in chronic myelomonocytic leukemia (CMML).

The clinical course of chronic myelomonocytic leukemia (CMML) is extremely variable, and disease progression can occur at any time from diagnosis. Median survival is about 20 months. About 20% of patients develop acute myeloid leukaemia (AML). Multivariate analyses performed by several groups showed that elevated medullary blast count, low haemoglobin, elevated serum lactate dehydrogenase (LDH), and perhaps an increased lymphocyte count, are the most important independent prognostic parameters, whereas karyotype analysis was not consistently shown to yield additional prognostic information. Applying different scoring systems to 288 CMML patients included in the Düsseldorf MDS Registry, we found that the International Prognostic Scoring System (IPSS) was not useful for defining risk groups in CMML, while the Spanish Score, the modified Bournemouth Score, the Düsseldorf Score, and probably the MDAP Score, identified patient groups differing significantly in survival. These scores should therefore be employed for clinical decision making and for risk stratification in the context of clinical trials.

Acute Disease↗
PubMed1999

Biochemical markers of thrombolytic success. IFCC Committee on Standardization of Markers of Cardiac Damage.

This paper reviews the clinical criteria necessary for use of thrombolytic drug therapy, the role of monitoring biochemical markers for detection of successful reperfusion following thrombolytic therapy, and the role of monitoring markers following percutaneous intervention to assess risk. Review of several studies demonstrates that early monitoring of myoglobin, cardiac troponin I, cardiac troponin T, and CK MB mass provides greater than 80% sensitivity and specificity for detecting reperfusion within 90 minutes following the initiation of therapy. However, the number of acute myocardial infarction patients studied are small. Since no prospective studies are reported, additional studies are necessary prior to clinical acceptance of routine monitoring of markers for detection of reperfusion. Most important, TIMI 3 flow patients cannot be differentiated from TIMI 2 flow patients. Monitoring markers after PTCA does appear to assist in short term (30 day) risk stratification. However, more studies are needed to assess the use of cardiac troponins.

Biomarkers↗
PubMed2025

Circulating Trimethylamine N-Oxide and Growth Rate of Abdominal Aortic Aneurysms and Surgical Risk.

IMPORTANCE: Plasma levels of the gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) are associated with prevalent abdominal aortic aneurysms (AAA) in humans and fostering of AAA progression in animal models; therapeutic targeting of TMAO production blocks AAA progression and rupture in multiple mouse models. A blood biomarker that identifies individuals at risk for incident AAA development, accelerated AAA expansion, or recommendation for surgical AAA repair could be an asset for risk stratification. OBJECTIVE: To determine whether TMAO is associated with risk for AAA development, rapid AAA expansion, and risk for recommended surgical intervention. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study using 2 independent clinical cohorts undergoing aorta imaging surveillance: a European cohort and a US cohort. Included in this study were patients undergoing serial imaging surveillance of the aorta and long-term outcome monitoring. Patients were recruited from single-center studies in Uppsala, Sweden, and Cleveland, Ohio. Study data were analyzed from October 2023 to May 2025. EXPOSURES: Plasma TMAO concentrations measured by stable isotope dilution liquid chromatography with tandem mass spectrometry. MAIN OUTCOMES AND MEASURES: The association of TMAO levels with AAA risk, fast-growing AAA (&#x2265;4.0 mm per year), and recommended surgical intervention (&#x2265;4.0 mm per year or &#x2265;5.5 cm diameter). RESULTS: The European cohort included 237 individuals (median [IQR] age, 65 [65-73] years; 211 male [89.0%]), and the US cohort included 658 individuals (median [IQR] age, 63 [57-70] years; 523 male [79.5%]). In the European cohort, elevated circulating TMAO was significantly associated with AAA risk independent of traditional risk factors and kidney function. Moreover, elevated TMAO predicted both greater risk for fast-growing AAA (adjusted odds ratio [aOR], 2.75; 95% CI, 1.20-6.79) and recommended surgical intervention (aOR, 2.67; 95% CI, 1.24-6.09). Similar patterns were observed in the US cohort and the combined European and US cohort, with heightened circulating TMAO corresponding with significantly increased adjusted risk for fast-growing AAA (US cohort: aOR, 2.71; 95% CI, 1.53-4.80; combined cohort: aOR, 2.30; 95% CI, 1.47-3.62) and recommended surgical intervention (US cohort: aOR, 2.73; 95% CI, 1.56-4.80; combined cohort: aOR, 2.41; 95% CI, 1.55-3.74). Addition of TMAO to base models containing traditional cardiovascular risk factors resulted in significant improvement in both risk estimation for fast-growing AAA and predicting recommended surgical intervention. CONCLUSION AND RELEVANCE: Results of this cohort study suggest that elevated circulating TMAO levels were associated with increased risk of AAA and identified patients at heightened risk for fast-growing AAA and recommended surgical intervention. TMAO may help identify individuals who may benefit from more frequent surveillance imaging and early surgical intervention to prevent aortic dissection or rupture.

Humans↗
PubMed2026

From standardization to precision medicine: Evolution of European Leukemianet recommendations in Philadelphia-negative myeloproliferative neoplasms.

The European LeukemiaNet (ELN) recommendations have been instrumental in shaping the diagnosis, risk stratification, and management of Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Over the past two decades, these recommendations have evolved from consensus-based frameworks focused on response standardization to increasingly sophisticated, evidence-based and biologically informed approaches. Early efforts primarily aimed to harmonize response criteria across clinical studies, establishing a foundation for consistent therapeutic evaluation. Subsequent updates introduced risk-adapted treatment strategies centered on thrombotic risk, reflecting the major determinants of morbidity and mortality in these disorders. However, the limitations of surrogate endpoints prompted a shift toward clinically meaningful outcomes, including symptom burden, vascular events, and disease progression. More recent advances have been driven by the integration of molecular genetics and the adoption of structured evidence-based methodologies, enabling refined diagnostic classification and more accurate prognostic assessment. Contemporary ELN frameworks increasingly incorporate dynamic clinical parameters, genomic profiling, and emerging biomarkers, supporting a transition toward individualized, risk-adapted therapeutic strategies. Beyond their role in standardizing MPN management, ELN recommendations have also influenced clinical trial design, endpoint selection, risk stratification, and therapeutic decision-making. Evidence from prospective studies and real-world cohorts supports the clinical applicability of these frameworks, although their implementation remains heterogeneous across healthcare settings. This review provides a comprehensive and critical overview of the evolution and implementation of ELN recommendations, highlighting their impact on clinical research and routine practice, current limitations, and future directions toward precision medicine in Philadelphia-negative MPNs.

Essential thrombocythemia↗
PubMed2006

Circulating levels of pro-atrial natriuretic peptide in lower respiratory tract infections.

OBJECTIVE: To analyse the mid region of plasma N-terminal pro-atrial natriuretic peptide (MR-proANP) levels in patients with lower respiratory tract infections to evaluate its prognostic use for the severity of disease and outcome. DESIGN: Prospective observational study. Setting. Emergency department of a university hospital. SUBJECTS: A total of 545 consecutive patients with lower respiratory tract infections and 50 healthy controls. Interventions. MR-proANP was measured in serum from all patients using a new sandwich immunoassay. RESULTS: MR-proANP levels (median [IQR], in pmol L(-1)) were significantly higher in patients with lower respiratory tract infections when compared with controls (138.0 [74.1-279.0] vs. 72.7 [62.5-89.5], P < 0.001), with highest levels in patients with community-acquired pneumonia (CAP). MR-proANP, but not C-reactive protein (CRP) levels, gradually increased with increasing severity of CAP, classified according to the pneumonia severity index (PSI) score (P < 0.001). On admission, MR-proANP levels were significantly higher in nonsurvivors when compared with survivors (293.0 [154.0-633.0] vs. 129.0 [71.4-255.0], P < 0.001). In a receiver operating characteristic (ROC) analysis for the prediction of survival of patients with CAP the area under the ROC curve (AUC) for MR-proANP was 0.69, similar when compared with the PSI (AUC 0.74, P = 0.31), and better when compared with other biomarkers, i.e. procalcitonin (AUC 0.57, P = 0.08), CRP (AUC 0.52, P = 0.02), and leucocyte count (AUC 0.56, P = 0.07). CONCLUSIONS: MR-proANP levels are increased in lower respiratory tract infections, especially in CAP. Together with other clinical, radiographic and laboratory findings, MR-proANP levels might be helpful for the risk stratification in CAP.

Acute Disease↗
PubMed2006

Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.

CONTEXT: Controversy exists as to whether lipoprotein(a), a lipoprotein with homology to plasminogen, is a clinically meaningful cardiovascular risk marker in women. There is also poor agreement among lipoprotein(a) levels obtained by different assays. OBJECTIVE: To determine the association of lipoprotein(a) levels, measured with an assay independent of apolipoprotein(a) isoform size, with the incidence of future cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 27,791 initially healthy women in the Women's Health Study, enrolled between November 1992 and July 1995 and followed up for 10 years. Lipoprotein(a) level was measured in blood samples obtained at baseline with an assay independent of apolipoprotein(a) isoform size. MAIN OUTCOME MEASURE: Hazard ratios (HRs) for first-ever major cardiovascular events (nonfatal myocardial infarction, nonfatal cerebrovascular event, coronary revascularization, or cardiovascular deaths). RESULTS: During follow-up, there were 899 incident cardiovascular events. After adjusting for age, smoking, blood pressure, body mass index, total cholesterol, high-density lipoprotein cholesterol, diabetes, hormone use, C-reactive protein, and randomization treatment groups, women in the highest quintile of lipoprotein(a) (> or =44.0 mg/dL) were 1.47 times more likely (95% CI, 1.21-1.79; P for trend <.001) to develop cardiovascular events than women in the lowest quintile (< or =3.4 mg/dL). This association, however, was due almost entirely to a threshold effect among those with the highest lipoprotein(a) levels. After adjusting for all of the variables listed above, the HR associated with lipoprotein(a) levels exceeding the 90th percentile (> or =65.5 mg/dL) was 1.66 (95% CI, 1.38-1.99); 95th percentile (> or =83 mg/dL), 1.87 (95% CI, 1.50-2.34); and 99th percentile (> or =130.7 mg/dL), 1.99 (95% CI, 1.32-3.00), with almost no risk gradient at lower levels. Associations were strongest among women with low-density lipoprotein cholesterol (LDL-C) above the median level. In this subgroup, the adjusted HR associated with lipoprotein(a) levels exceeding the 90th percentile was 1.81 (95% CI, 1.48-2.23); 95th percentile, 1.93 (95% CI, 1.51-2.48); and 99th percentile, 1.93 (95% CI, 1.21-3.05) (P value for interaction with LDL-C = .001). CONCLUSIONS: In this cohort of initially healthy women, extremely high levels of lipoprotein(a) (> or =90th percentile), measured with an assay independent of apolipoprotein(a) isoform size, were associated with increased cardiovascular risk, particularly in women with high levels of LDL-C. However, the threshold and interaction effects observed do not support routine measurement of lipoprotein(a) for cardiovascular stratification in women.

Apolipoproteins↗
PubMed2006

[Minimal residual tumor in gastrointestinal carcinoma. Relevance to prognosis and oncologic surgical consequences].

Isolated tumor cells as a consequence of minimal residual disease are often not detectable by routine diagnostic procedures. However, before or after surgery, isolated tumor cells in lymph nodes, the peritoneal cavity, blood, or bone marrow can frequently be identified by immunohistochemical or molecular methods. Failure to reveal the presence of such cells results in under-staging of tumor patients and may constitute the source of unexpected tumor recurrence after radical surgery. These facts emphasize the importance of isolated tumor cells at least as a surrogate marker. The frequency of appearance of isolated tumor cells in different organ systems also depends on the type of primary tumor. Developments in modern detection methods have led to increasing sensitivity but at the expense of specificity. Isolated tumor cells demonstrate remarkable heterogeneity with respect to proliferative potential and tumorigenicity. This characteristic is also reflected by a striking variability in the expression of various genes conditioning the aforementioned biological behavior. Unfortunately there is also remarkable heterogeneity in methods used for sampling and processing patient material as well as for the enrichment and detection of isolated tumor cells. Despite the ongoing controversies concerning detection methods and biological significance of isolated tumor cells, several clinical trials providing data supporting the prognostic relevance of minimal residual disease should also be considered for gastrointestinal carcinoma. In future this finding should be integrated in the planning of trials in surgical oncology, and "minimal residual disease" should receive stronger attention as a stratification criterion in such clinical studies.

Biomarkers, Tumor↗