Prognostic Implications Research Articles

Prognostic and immunological implications of protein kinases in gastric cancer: a focus on hub gene ABL2 and its impact on the polarization of M2 macrophages

BackgroundProtein kinases are essential cellular signal modulators involved in tumorigenesis, metastasis, immune response, and drug resistance. However, the comprehensive features and clinical significance of protein kinases in gastric cancer (GC) remain inconclusive.MethodsWe analyzed the transcriptional profiles of protein kinases in GC patients from the GEO and TCGA databases. Based on differentially expressed kinase genes (DE-KGs), a novel cluster was identified to assess its association with patient survival and the tumor microenvironment (TME) in GC. Subsequently, an optimal DE-KGs-based model (DE-KGsM) was determined using 101 machine-learning algorithm combinations. This model was evaluated using multi-omics data to investigate its associations with patient prognosis, clinical features, tumor microenvironment, tumor-infiltrating immune cells (TIICs), and immunotherapy response. Furthermore, scRNA-seq analysis and TIMER algorithm were applied to determine the correlation between the hub gene (ABL2) in the DE-KGsM and Macrophages. Finally, in vitro experiments were performed to explore the immune-related mechanisms of ABL2 in GC.ResultsWe identified two molecular subtypes of GC patients based on 64 DE-KGs expression. Significant differences were observed in overall survival and TIIC characteristics between Cluster 1 and Cluster 2. Among these 64 DE-KGs, we identified an optimal DE-KGsM that could be a prognostic indicator in GC. TIICs and TIDE analyses exhibited that GC patients in the high-DE-KGsM score group had a higher proportion of M2 macrophages and lower response rates to ICI treatment. scRNA-seq analysis indicated that ABL2 might play an indispensable role in tumor immunity. Furthermore, in vitro experiments demonstrated that ABL2 accelerated the proliferation, migration, and invasion of GC cells, as well as the polarization of M2 macrophages.ConclusionsThe DE-KGsM could be a powerful predictor of GC patients’ survival and might facilitate the development of personalized therapy. Furthermore, as a hub gene in the DE-KGsM, ABL2 could be an immunological biomarker that modulates the polarization of M2 macrophages, thereby promoting GC progression.Clinical trial numberNot applicable.

Prognosis prediction in non-Hodgkin lymphoma by assessing lymphoid organs uptake patterns using baseline 18F-FDG PET/CT.

The prognostic implications of lymphoid organs (LOs) involvement in untreated non-Hodgkin lymphoma (NHL) patients remain underexplored. This study aims to explore the significance of LOs metabolic activity, assessed via 18F-FDG PET/CT, in predicting the early treatment response and prognosis of NHL patients. A retrospective analysis was conducted on 18F-FDG PET/CT imaging data of untreated NHL patients from March 2016 to December 2023. Metabolic activity levels of LOs were evaluated and scored. Prognostic parameters included the international prognostic index (IPI), progression-free survival (PFS), overall survival (OS), and the interim efficacy evaluation. The median follow-up time was 15 months. The survival analysis was conducted using Kaplan-Meier and Cox regression methods. We included a total of 125 NHL patients (63 ± 12 years) with baseline 18F-FDG PET/CT scans. Based on the metabolic scores of LOs, patients were divided into three groups: 36 (28.8%) in the low metabolism group, 64 (51.2%) in the intermediate metabolism group, and 25 (20.0%) in the high metabolism group. LOs metabolic scores emerged as an independent prognostic factor. Patients with high metabolic activity in LOs had significantly shorter PFS and OS compared to those with lower activity (OS HR = 4.56; PFS HR = 3.87; p <0.01). The combination of LOs metabolism and extra-LOs tumor burden can further stratify the risk in NHL patients. Metabolic activity in LOs in 18F-FDG is a vital prognostic indicator and may predict early treatment response in NHL patients. The incorporation of LOs metabolic assessment into clinical practice could enable more accurate prognosis and tailored treatment strategies.

Molecular Alterations in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS Pathways in Gastric Cancer Among Ethnically Heterogeneous Cohorts.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08) and APC mutations being significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta, and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients. This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta, and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations.

Epilepsy syndromes classification.

Epilepsy syndromes are distinct electroclinical entities which have been recently defined by the International League Against Epilepsy Nosology and Definitions Task Force. Each syndrome is associated with "a characteristic cluster of clinical and EEG features, often supported by specific etiologic findings". Syndromes often present in an age-dependent manner, carry both prognostic and treatment implications, and are associated with a specific range of comorbidities. Syndromes are most commonly identified in young children and are less frequent in adults. Syndrome identification assists clinicians in selecting the highest yield investigations, the most effective therapies, and allows them to give more accurate prognoses both with regards to seizure control and potential remission as well as expected, associated comorbidities. This review outlines how syndromes are organized and defined, highlighting the characteristic features of the more common entities. PLAIN LANGUAGE SUMMARY: Epilepsy syndromes are identifiable entities that are characterized by specific seizure type(s) and EEG findings. Identification of an epilepsy syndrome often provides a clue to the underlying cause, helps clinicians select the most effective treatments, and provides information on the likely outcome.

Exploring the Clinical Utility of Cardiorespiratory Optimal Point in Heart Failure Patients: Creating a New Research Gap

The cardiorespiratory optimal point (COP) is an emerging submaximal parameter from cardiopulmonary exercise testing (CPET) that reflects the optimal balance between cardiac workload and pulmonary ventilation. Recent studies have explored the clinical utility and prognostic value of the COP in various populations, particularly in patients with heart failure (HF). This comprehensive literature review evaluated the current evidence on the COP and its potential as an independent risk factor for cardiovascular disease and mortality. The COP has been identified as a predictor of all-cause and cardiovascular mortality, with elevated values being significantly associated with an increased risk. Studies have demonstrated that higher COP values correlate with greater mortality risk independent of traditional risk factors, with significant sex-based differences. Evidence suggests that COP values greater than 26 significantly influence mortality rates and lead to a worse prognosis in patients with HF. For example, individuals with a COP &gt; 30 had an approximately six-fold higher mortality risk (17.1%) than those with a COP &lt; 22, and the combination of a high COP (&gt;30) + low VO2max leads to a significant increase in the risks of adverse effects (30.9%). This underscores the importance of the COP in the clinical management and risk stratification of HF patients. While the COP shows promise as a valuable submaximal marker with significant prognostic implications, further research is needed to establish its superiority over other established prognostic markers and elucidate the underlying mechanisms linking the COP to health outcomes. Nonetheless, the ability of the COP to predict mortality and enhance risk stratification in diverse populations makes it a promising tool in clinical practice.

Evaluation of the clinical management of Graves' Orbitopathy according to severity: a real-life Analysis.

Due to the clinical and prognostic implications of Graves' Orbitopathy (GO), clinical care needs to be tailored to current recommendations, but real-life information is scarce. We aim to describe GO management in a real-life setting for health care improvement. This is a retrospective cohort study evaluating the clinical performance of clinicians attending patients diagnosed with GO. All cases with GO from 2018 to 2021 were included in the analysis, with no exclusion criteria. We performed an evaluation of the healthcare provided to these patients, with clinical performance evaluated from diagnostic and therapeutic viewpoints. A backwards stepwise multivariate binomial logistic regression analysis was run to assess the variables associated with severity. This was a cohort of 151 cases, predominantly of women in the fifth decade of life, most of whom had hyperthyroidism. There were 50 (33.1%) cases with moderate-severe GO, but none of them with sight-threatening disease. Total annualized visits were more frequent to endocrinologists than ophthalmologists, except for moderate-severe cases. Active smoking (57 cases; 37.7%), unstable hyperthyroidism (59 cases; 39.1%), and elevated maximum TSI levels (136; 90.1%) conditioned clinical care. Altogether, the performance of an imaging technique, the use of systemic corticosteroid therapy and eyelid surgery were significantly different in those with more severe GO. Clinical care provided to patients with GO is variable and influenced by several variables. Both endocrinologists and ophthalmologists must coordinate to ensure a unified patient-tailored protocol that covers all these patients' needs.

Impact of glycemic control metrics on short- and long-term mortality in transcatheter aortic valve replacement patients: a retrospective cohort study from the MIMIC-IV database

BackgroundGlycemic control is critical for managing transcatheter aortic valve replacement (TAVR) patients, especially those in intensive care units (ICUs). Emerging metrics such as the hemoglobin glycation index (HGI), stress hyperglycemia ratio (SHR), and glycemic variability (GV) offer advanced insights into glucose metabolism. However, their prognostic implications for short- and long-term outcomes post-TAVR remain underexplored.MethodsThis retrospective cohort study analyzed 3342 ICU-admitted TAVR patients via the MIMIC-IV database. Patients were stratified into tertiles for HGI, SHR, and GV levels. Survival analyses, including Kaplan‒Meier curves, Cox proportional hazards models and restricted cubic splines (RCSs), were used to assess associations between glycemic control metrics and 30-day and 365-day all-cause mortality in these patients. Sensitivity analyses, subgroup assessments, and external validation were also performed to verify the study findings.ResultsDuring follow-up, 1.6% and 6.9% of patients experienced 30-day and 365-day mortality after TAVR, respectively. In the fully adjusted cox regression model, lower HGI (HR 1.48, 95% CI 1.05–2.09, P = 0.025) and higher SHR (HR 1.63, 95% CI 1.15–2.32, P = 0.006) were most significantly associated with an increased risk of 365-day mortality. Higher SHR was also significantly associated with an increased risk of 30-day mortality in patients (HR 2.92, 95% CI 1.32–6.45, P = 0.008). Both lower (HR 0.59, 95% CI 0.38–0.92, P = 0.019) and higher GV levels (HR 1.43, 95% CI 1.06–1.93, P = 0.020) were associated with the risk of 365-day mortality.ConclusionsIn critically ill TAVR patients, glycemic control metrics are closely associated with long-term all-cause mortality. The HGI, SHR, and GV provide prognostic insights into clinical outcomes that surpass conventional glucose measurements. These findings highlight the importance of personalized glycemic management strategies in improving TAVR patient outcomes.

Gastrointestinal tumors of the small bowel: prognostic roles of tumor stage and inflammatory markers

Aims: Small bowel tumors are a heterogeneous group of malignancies, including gastrointestinal stromal tumors (GISTs), adenocarcinomas, neuroendocrine tumors (NETs), and myofibroblastic tumors, each with distinct prognostic implications. While tumor stage is a well-established prognostic factor, patient survival outcomes and systemic inflammatory markers also play a crucial role in disease progression. This study evaluates these factors comprehensively to enhance prognostic assessment in small bowel malignancies. Methods: This retrospective study analyzed 25 patients diagnosed with small bowel tumors, including various histological subtypes. The prognostic significance of tumor stage (T and N classification), systemic inflammatory markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], albumin, and C-reactive protein [CRP]), and overall survival was assessed. Kaplan-Meier survival analysis was conducted to evaluate the association between tumor stage, inflammatory markers, and patient outcomes. Statistical analyses included independent sample t-tests, Mann-Whitney U tests, and Chi-square tests. Results: The median age of the cohort was 63 years (range: 47–81). The most common histological subtype was GIST (52%), followed by adenocarcinoma (24%), NET (20%), and myofibroblastic tumors (4%). Kaplan-Meier survival analysis revealed a significant association between tumor stage and patient survival (p=0.036), with advanced-stage tumors (T3–T4) demonstrating significantly lower survival rates compared to early-stage tumors (T2). Lymph node involvement (N stage) was also a significant predictor of reduced survival (p=0.013). Although inflammatory markers such as NLR, PLR, albumin, and CRP were assessed, they did not show statistically significant associations with survival outcomes (p&gt;0.05). Conclusion: This study highlights the importance of evaluating both tumor stage and patient survival when determining prognosis in small bowel tumors. The Kaplan-Meier analysis underscores the strong prognostic impact of tumor staging and lymph node involvement on survival outcomes. Although systemic inflammatory markers did not show significant prognostic value in this cohort, their role in risk stratification warrants further investigation in larger studies. These findings contribute to a broader understanding of small bowel tumor prognosis beyond staging alone, supporting the need for a multidimensional approach in clinical assessment and treatment planning.

Macular microvascular and structural changes on optical coherence tomography angiography in atypical optic neuritis.

Atypical optic neuritis, consisting of neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody disease (MOGAD), has a very similar presentation but different prognostic implications and long-term management strategies. Vascular and metabolic factors are being thought to play a role in such autoimmune neuro-inflammatory disorders, apart from the obvious immune mediated damage. With the advent of optical coherence tomography angiography (OCTA), it is easy to pick up on these subclinical macular microvascular and structural changes. To study the macular microvascular and structural changes on OCTA in atypical optic neuritis. This observational cross-sectional study involved 8 NMOSD and 17 MOGAD patients, diagnosed serologically, as well as 10 healthy controls. Macular vascular density (MVD) and ganglion cell + inner plexiform layer thickness (GCIPL) were studied using OCTA. There was a significant reduction in MVD in NMOSD and MOGAD affected as well as unaffected eyes when compared with healthy controls. NMOSD and MOGAD affected eyes had significant GCIPL thinning compared with healthy controls. NMOSD unaffected eyes did not show significant GCIPL thinning compared to healthy controls in contrast to MOGAD unaffected eyes. On comparing NMOSD with MOGAD, there was no significant difference in terms of MVD or GCIPL in the affected or unaffected eyes. Although significant microvascular and structural changes are present on OCTA between atypical optic neuritis and normal patients, they could not help in differentiating between NMOSD and MOGAD cases.

Mast Cells and Microbiome in Health and Disease.

Inter-kingdom communication between human microbiota and mast cells (MCs), as sentinels of innate immunity, is crucial in determining health and disease. This complex signaling hub involves micro-organisms and, more importantly, their metabolic products. Gut microbiota is the host's largest symbiotic ecosystem and, under physiological conditions, it plays a vital role in mediating MCs tolerogenic priming, thus ensuring immune homeostasis across organs. Conversely, intestinal dysbiosis of various etiologies promotes MC-oriented inflammation along major body axes, including gut-skin, gut-lung, gut-liver, and gut-brain. This review of international scientific literature provides a comprehensive overview of the cross-talk under investigation. This process is a key biological event involved in disease development across clinical fields, with significant prognostic and therapeutic implications for future research.

Modulation of the tumor immune microenvironment by Interferon Regulatory Factor 8 enhances immunotherapy in lung adenocarcinoma

Interferon regulatory factors (IRFs) are integral in governing the expression of Type I interferon (IFN) genes. However, the precise role of IRFs in lung adenocarcinoma remains elusive. Our objective is to elucidate the prognostic implications of IRFs and their potential influence on the immunotherapeutic response in patients with lung adenocarcinoma (LUAD). The association between IRFs expression and clinical as well as prognostic features was evaluated utilizing the TCGA database. Prognostic determinants for LUAD were pinpointed via univariate and multivariate analyses. Nomogram to evaluate prognosis predicated on IRF expression levels. Gene enrichments were conducted to elucidate the mechanisms of action. The degree of immune infiltration was using bioinformatics methods and was validated through a single-cell dataset. We compiled our unique cohort of LUAD patients who underwent anti-PD-1 therapy for subsequent immunohistochemistry and multicolor immunofluorescence staining to gauge the conclusion above. Our findings revealed that IRF8 serves as an independent risk factor for overall survival (OS) in patients with LUAD. An analysis of patients undergoing immunotherapy revealed a positive association between the expression of IRF8 and the response to the treatment. In our specific cohort treated with anti-PD-1, high IRF8 expression was observed to enhance immunotherapy response and prolong OS by modulating immune cell infiltration. Our retrospective analysis suggests that elevated IRF8 expression correlates with improved prognosis in LUAD, with higher IRF8 expression being predictive of a more robust immunotherapy response. Mechanistically, IRF8 expression is associated with a modulated tumor immune microenvironment and improved immunotherapeutic response.

Pan-cancer analysis unveils the role and mechanisms of neddylation modifications in tumorigenesis.

This study explores the roles of ubiquitin-like modification genes in pan-cancer, focusing on their regulatory mechanisms, prognostic implications, and drug sensitivity. Data on five key neddylation pathway genes (RBX1, NEDD8, NAE1, UBA3, UBE2M) were collected from TCGA and GTEx databases, covering mRNA expression, DNA methylation, SNVs, and CNVs. Gene expression differences between normal and cancer tissues, along with associations with genetic alterations, methylation, and cancer-related pathways, were analyzed. Drug sensitivity correlations were assessed using GDSC and CTRP databases. Neddylation pathway genes exhibit hypomethylation and overexpression across various cancers, correlating with poor prognosis. SNVs are predominantly missense mutations, while CNVs are mostly heterozygous deletions and amplifications. These genes regulate several key cancer-related pathways, such as DNA damage repair, cell cycle modulation, and inhibition of RTK/RAS/MAPK pathways. Ubiquitin-like modification genes are associated with poor prognosis due to their low methylation and high expression in cancers. Their genetic alterations impact cancer pathways, underscoring their potential as therapeutic targets and prognostic biomarkers.

Baseline characteristics and seven-year follow-up of patients with coronary slow flow: A cohort study in northeastern Iran

Introduction: An angiographic finding known as "coronary slow flow phenomenon" (CSFP) occurs when there is no discernible stenosis but the contrast flow is slower than usual. Although the prognosis for the majority of CSFP cases is favorable, frequent angina significantly lowers their quality of life. Therefore, this study aimed to explore the potential contributing risk factors and prognostic implications of CSFP on long-term cardiovascular outcomes. Methods: This retrospective, cohort study was conducted between years 2014-2022 and included a total of 65 CSFP patients and 65 controls with normal coronary flow, as evidenced by coronary angiography. These two groups were examined in terms of future cardiovascular consequences due to this phenomenon, baseline demographic characteristics, and laboratory findings. A P value&lt;0.05 was considered significant. Results: In this study 130 people including 73 men and 57 women, who because of the typical chest pain and at least a noninvasive test took angiography, were explored. The median triglyceride (200.80±48.51 vs 131.79±34.22, P&lt;0.001), total cholesterol (189.46±10.84 vs 103.43±8.13, P&lt;0.001), and low-density lipoprotein (153.28±34.28 vs 103.34±19.70, P=0.01) were significantly higher in the affected people. During clinical follow-up, a higher number of major adverse cardiac events (8.97±2.95 vs 4.52±2.12, P&lt;0.001) was observed in the CSFP cases. Moreover, a one-unit increase in body mass index raised the probability of adverse cardiac events by 0.912 in CSFP cases. Conclusion: Our research indicated that individuals with CSFP were more likely to develop cardiac events including unstable angina. Furthermore, obesity and dyslipidemia could provoke this phenomenon.

The Prognostic, Predictive and Clinicopathological Implications of KRT81/HNF1A- and GATA6-Based Transcriptional Subtyping in Pancreatic Cancer.

Transcriptional subtypes of pancreatic ductal adenocarcinoma (PDAC) based on the expression of hallmark genes may have prognostic implications and potential predictive functions. The two most employed subtyping markers assess the combined expression of KRT81 and HNF1A or of GATA6 alone, which can be detected by immunohistochemistry (IHC). This study aimed to determine the prognostic or predictive impact of both subtyping marker panels in two large cohorts of advanced and resected pancreatic ductal adenocarcinoma (PDAC) patients. Transcriptional subtypes were determined by combining the expression of KRT81/HNF1A or assessing GATA6 expression alone by IHC in samples of two independent PDAC patient cohorts (advanced PDAC n = 139 and resected PDAC n = 411) as well as in 57 matched primary tumors and their corresponding metastases. RNAseq-based expression data of 316 resected PDAC patients was analyzed for validation. Transcriptional subtypes widely overlapped in both marker panels (χ2p < 0.001) but switched during disease progression in up to 31.6% of patients. They had a modest impact on the patients' prognosis in both cohorts, with longer overall survival (OS) for patients with KRT81-/HNF1A+ or GATA6+ tumors but better progression-free survival (PFS) and disease-free survival (DFS) in patients with KRT81+/GATA6- tumors treated with palliative or adjuvant gemcitabine-based chemotherapy. RNAseq expression data confirmed the findings. Transcriptional subtypes have differential responses to palliative and adjuvant gemcitabine-based chemotherapy and may change during disease progression. Both employed subtyping marker panels are equivalent and may be used to inform clinical therapy decisions.

Clinical use of measurable residual disease in adult ALL: recommendations from a panel of US experts.

Measurable residual disease (MRD) is a powerful predictor of clinical outcomes in acute lymphoblastic leukemia (ALL). In addition to its clear prognostic importance, MRD information is increasingly used in clinical decision algorithms to guide therapeutic interventions. Although it is well established that achievement of MRD-negative remission is an important end point of ALL therapy, the prognostic and therapeutic implications of MRD in an individual patient are influenced by both disease-related factors (eg, cytomolecular risk) and assay-related factors (eg, sensitivity, specimen source, and timing of assessment), which add complexity to MRD-guided treatment decisions. In this review, we discuss the data supporting the use of MRD assessment in adult ALL and how this information can rationally inform clinical decisions, including selection of patients for MRD-directed therapies or allogeneic hematopoietic stem cell transplantation. We also discuss important interpretative challenges related to novel high sensitivity next-generation sequencing-based MRD assays, which are becoming increasingly used in clinical practice.

Expression and Clinical Significance of CXCR5 and LAG-3 on Peripheral Blood CD8+ T Cells in Patients With Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) exhibits substantial biological and clinical heterogeneity. This study investigated the expression and prognostic implications of C-X-C chemokine receptor type 5 (CXCR5) and lymphocyte activation gene-3 (LAG-3) on peripheral blood CD8+ T cells in patients with DLBCL. A total of 71 DLBCL patients and 71 healthy controls were enrolled. The expression levels of CXCR5 and LAG-3 on peripheral blood CD8+ T cells were assessed and analyzed for their impact on 5-year progression-free survival (PFS) and overall survival (OS). Results revealed significantly elevated CXCR5 and LAG-3 expression levels in DLBCL patients compared to controls. CXCR5 expression correlated with lactate dehydrogenase (LDH) levels, extranodal involvement, Ann Arbor stage, and International Prognostic Index (IPI) scores, while LAG-3 expression was associated with Eastern Cooperative Oncology Group (ECOG) scores, number of extranodal sites, bone marrow involvement, Ann Arbor stage, and IPI scores. Multivariate analysis identified advanced age, Ann Arbor stage III-IV, and elevated CXCR5 and LAG-3 expression as independent risk factors for poorer 5-year PFS and OS. Furthermore, patients with higher CXCR5 and LAG-3 expression levels demonstrated significantly reduced 5-year PFS and OS rates. In conclusion, elevated CXCR5 and LAG-3 expression on peripheral blood CD8+ T cells plays a pivotal role in DLBCL progression and prognosis, making these markers potential therapeutic targets or prognostic indicators.

Comparison of Tricuspid Annular Plane Systolic Excursion to Pulmonary Artery Systolic Pressure Ratio Measured by Transthoracic Echocardiography and Right Heart Catheterization in Pulmonary Arterial Hypertension: Prognostic Implications.

Background/Objectives: Ventricular-arterial (VA) coupling, assessed via the TAPSE/PASP ratio, is a well-established prognostic marker in pulmonary arterial hypertension (PAH). However, transthoracic echocardiography (TTE) often fails to estimate the pulmonary artery systolic pressure (PASP). This study evaluated the prognostic value of TAPSE/PASP when PSAP was obtained both via TEE and RHC and their correlation. Methods: A prospective registry included 90 PAH patients (April 2021-May 2024). TTE and RHC were performed according to clinical guidelines. The correlation and agreement between both techniques were assessed using Spearman's rank correlation and a Bland-Altman analysis. The prognostic utility of TAPSE/PASP for clinical worsening (CW) (death or lung transplantation) was evaluated using Cox models, Harrell's c-statistics, and ROC curve analysis. Results: The median interval between TTE and RHC was 1.5 days (range -3 to +43). TAPSE/PASP showed a strong correlation between both techniques (rho = 0.74, p < 0.001), though TTE slightly overestimated values due to PASP underestimation. The PASP correlation was moderate (rho = 0.56, p < 0.001). CW occurred in 17.8% of patients. According to cut-off points established based on ESC/ERS guidelines, VA coupling via TTE effectively stratified the risk of CW (HR 7.0, p = 0.076 and HR 34.8, p = 0.002 for intermediate and high risk, respectively), whereas VA coupling with PASP measured via RHC showed no association with CW. TAPSE/PASP based on TTE demonstrated superior prognostic performance (C-index = 0.81) over RHC-derived parameters (C-index = 0.58). Conclusions: The TAPSE/PASP ratio showed a strong correlation between TTE and RHC. However, while RHC remains the gold standard for hemodynamic assessments, echocardiographic measurements demonstrated superior performance in risk stratification, supporting its role as a valuable non-invasive tool in PAH.

Emerging importance of HER3 in tumorigenesis and cancer therapy.

HER3 is a member of the HER/ErbB family of receptor tyrosine kinases, together with EGFR (HER1), HER2 and HER4. Despite having only weak intrinsic kinase activity, HER3 can contribute to oncogenic signalling via ligand-induced heterodimerization with other HER family members. Evidence indicates that HER3 is altered or aberrantly expressed across a variety of tumour types and can be associated with poor clinical outcomes. Whereas anticancer agents targeting EGFR and HER2 have been approved for decades, no drug targeting HER3 had been approved until very recently. Initial targeting of HER3 with monoclonal antibodies as single agents or in combination with other therapeutics produced disappointing clinical results. Subsequently, efforts have been made to target HER3 with novel agents such as antibody-drug conjugates and bispecific antibodies, with promising efficacy observed in several trials encompassing various tumour types. In December 2024, the HER3 × HER2 bispecific antibody zenocutuzumab was granted FDA Accelerated Approval for the treatment of non-small-cell lung cancers or pancreatic cancers harbouring fusions involving NRG1, the gene encoding the high-affinity HER3 ligand neuregulin 1. In this Review, we provide an essential guide to HER3 signalling and oncogenesis, HER3 expression in cancer and its prognostic implications, oncogenic HER3 somatic mutations as well as rare NRG1 fusions that might depend on HER3 signalling, and the roles of HER3 in resistance to cancer therapies. We also highlight efforts to target HER3 with diverse therapeutic strategies and the potential interplay between HER3 and the antitumour immune response.

Mortality associated with moderate and severe mitral regurgitation in 608 570 men and women undergoing echocardiography

BackgroundAlthough the prognostic implications of severe mitral regurgitation (MR) are well recognised, they are less clear in moderate MR. We therefore explored the prognostic impact of both moderate and severe...

Clinical and prognostic implications of pituitary macroadenomas (PitNets) grading: a monocentric experience.

Pituitary neuroendocrine tumors (PitNets), also known as pituitary adenomas, are aggressive in 20% of cases, with local invasion, relapse/scarce response to conventional treatment, in the absence of reliable predictive parameters. In 2018, Trouillas et al. proposed a 5-tier clinicopathological classification, not widely validated yet. In the present study we investigated, in a PitNets monocentric series, the correlation between this classification system and features at diagnosis and medium-term clinical and biochemical outcomes. we retrospectively evaluated 88 consecutive patients (51M, 50.5±14.7 yrs) with functioning (FPA) or non-functioning pituitary macroadenomas (NFPA), referred to the Endocrine Unit of Messina University Hospital, and operated by the same neurosurgeon in the period 2015-2020. Of each patient we reviewed recorded demographic, clinical, radiological, biochemical data and visual field, both at diagnosis/last follow-up (median 3 ± 1.5 yrs), therapeutical history, and pathological data. Once classified PitNets according to Trouillas et al. grading system, we correlated it to clinico-pathological and hormonal features at diagnosis, and to clinical, biochemical and ophthalmological outcomes at 6 months after surgery and at last follow-up. According to Trouillas grading system, 38.6% of patients were assigned the 1a grade, 7.9% the 1b, 48.9% and 4.5% the 2a and 2b, respectively. At diagnosis, panhypopituitarism and visual field alterations were more frequent among 2a grade tumors. GH-omas were significantly prevalent among 1a tumors, NFPA among 2a. PitNets with 1a and 2a grade had a better response to single surgery (p < 0.01), while cyberknife stereotactic radiotherapy was needed more frequently in 2a and 2b tumors. Panhypopituitarism/visual field alterations were more frequent among 2a PitNets even after surgery. Ki-67 was positively associated to persistent disease in FPA, while radiological invasion was associated to remnant presence among NFPA. Invasive and not-proliferating PitNets (2a) were more frequently associated to impaired pituitary function/visual field before and after surgery. Less proliferating tumors (1a and 2a) were more responsive to surgery. Ki-67 correlated to disease persistence in FPA, while adiuvant radiotherapy was more needed among invasive tumors. Thus, among ≥ 1cm PitNets, tumor invasion seems to impact on clinico-biochemical outcomes, while Ki-67 proliferation index influences surgical outcomes.