High-risk Subgroups Research Articles

Prediction of relapse-free survival in stage III gastric cancer patients treated with postoperative adjuvant chemotherapy: Random survival forest analysis from the START-2 trial.

446 Background: The START-2 trial demonstrated that docetaxel plus S-1 (DS) was superior to S-1 alone (S-1) in terms of recurrence-free survival (RFS) and overall survival (OS) as the adjuvant chemotherapy for stage III gastric cancer (GC) patients (pts) (J Clin Oncol 2019, Gastric Cancer 2022). We conducted the START-2 AR study as a retrospective analysis using data from the START-2 trial to develop a prognostic model for stage III GC pts treated with postoperative chemotherapy. Methods: Among 912 pts in the START-2 trial, 599 pts signed the consent form to participate in the START-2 AR study. There were 542 pts (265 pts in DS group and 277 pts in S-1 group) without missing values of prognostic candidates. Pts were randomly divided into a training set and a validation set with a ratio of 7:3. Prognostic model for RFS was developed using random survival forest (RSF) with the training set. The RSF model was applied to the validation set to assess its performance, evaluated using Harrell's C-index. We calculated tertiles of risk scores from the RSF model to divide the training set into low-, middle-, and high-risk subgroups. These cut-off values were used to classify the validation set. A Cox proportional hazard model was applied to compare the prognosis among the risk groups. Results: There were no statistically significant differences in patient characteristicsbetween the 599 pts in the START-2 AR study and the 912 pts in the STRAT-2 trial. RFS was comparable between the two groups. The RSF model for the training set (n = 380) yielded a C-index of 0.873, identifying the number of metastatic lymph nodes, serum albumin, CEA, tumor diameter, the primary tumor location, platelet count, age as prognostic factors in order of importance. In the validation set (n = 162), the C-index was 0.648. Both the low-risk group (n = 35) (hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.17 – 0.68, p < 0.01) and the middle-risk group (n = 74) (HR: 0.55, 95% CI: 0.33 – 0.89, p = 0.02) in the validation set had significantly better RFS compared to the high-risk group (n = 53). Among the 76 pts in the low-risk group treated with DS, 44 were categorized into the low-risk group when assuming they had been treated with S-1 alone. The analysis of 599 pts after multiple imputation yielded results consistent with those from the complete data. Conclusions: We developed the RSF-based predictive model for stage III GC pts, which demonstrated good performance. The number of metastatic lymph modes was identified as the most important prognostic factor. Risk stratification based on this model effectively differentiated prognostic outcomes. Future external validation of the model is required. Clinical trial information: UMIN000011438.

Risk of peritoneal recurrence following laparoscopic versus open surgery for stage II or III colorectal cancer (JCOG2310A): An integrated analysis of three phase III randomized controlled trials.

161 Background: Peritoneal recurrence in colorectal cancer (CRC) has long been a concern. Although studies have examined the higher risk of peritoneal recurrence following laparoscopic (LAP) compared with open (OP) surgery, the issue remains unresolved, largely due to the heterogeneity of existing data and the limited number of observed peritoneal recurrence events, preventing any definitive conclusions. This study aimed to evaluate whether LAP for pStage II/III CRC presents a potential risk factor for peritoneal recurrence compared with OP. Methods: Data from three phase III trials (JCOG0404, JCOG0910, JCOG1006) were extracted from an ancillary research database (JCOG2310A). From this cohort, patients with pStage II or III CRC who underwent curative surgery were included, and the incidence of peritoneal recurrence was compared between LAP and OP. A multivariate analysis was conducted to adjust covariates between the two groups. The primary outcome was the cumulative incidence of peritoneal recurrence, and the secondary outcome was recurrence in specific high-risk subgroups identified through a univariate analysis. Results: From 3061 patients (OP: 1734; LAP: 1327), pT4 (25% vs. 17%), pStage III (65% vs. 83%), and right-sided tumor (63% vs. 70%) were different between OP and LAP, respectively. With a median follow-up for peritoneal recurrence of 6.2 years, the 5-year cumulative incidence of peritoneal recurrence was 2.8% in the OP group and 2.9% in the LAP group (hazard ratio (HR): 0.940, 95% confidence interval (CI): 0.621-1.425 in the univariate analysis, and HR: 1.086, 95% CI: 0.683-1.727 in the multivariate analysis. The univariate analysis identified pT4, pN2, pStage III, right-sided tumor, poorly differentiated (por/sig/muc), and ECOG-PS 1 as risk factors for peritoneal recurrence. No significant difference was observed in the subgroups (see table). An exploratory propensity score matching analysis with 1066 patients in each group also showed no difference between the groups (the 5-year cumulative incidence of peritoneal recurrence was 2.8% in the OP group and 3.0% in the LAP group [HR: 1.002, 95% CI: 0.625-1.607]). Conclusions: This study revealed that LAP was not a risk factor regarding peritoneal recurrence following curative surgery for Stage II/III CRC. Subgroup analysis of cumulative incidence of peritoneal recurrence. OutcomeMeasures Subgroups pT4 pN2 pStage III Right-sided Poorly differentiated ECOG PS 1 N(OP vs. LAP) 428 vs. 229 274 vs. 184 1133 vs. 1105 635 vs. 403 122 vs. 66 56 vs. 25 Event(OP vs. LAP) 31 vs. 23 13 vs. 10 45 vs. 32 28 vs. 18 10 vs. 2 7 vs. 2 5-year peritoneal recurrence rate (OP vs. LAP)(%) 6.8 vs. 10.1 4.8 vs. 5.4 3.6 vs. 2.9 4.1 vs. 4.5 7.5 vs. 3.0 9.1 vs. 8.0 HR (95% CI) 1.403(0.819-2.402) 1.144(0.503-2.603) 0.725(0.461-1.139) 1.014(0.562-1.829) 0.372(0.081-1.699) 0.609(0.130-2.862)

The potential for Safewards to reduce restrictive interventions for people arriving to the emergency Department with police for a mental health assessment.

A retrospective file audit was conducted using pre and post measures on the use of restrictive interventions following the implementation of Safewards. Demographic and restrictive interventions data were extracted from the hospital databases 12 months before and 6 months after Safewards was implemented. All patients transported to the ED by police for a mental health assessment were included in two regional emergency departments in Victoria, Australia, with over 122,000 presentations per year accredited by the Australasian College for Emergency Medicine. There were 1379 pre and 543 post attendances accompanied by police. Of these, 85.5% pre and 99.1% post were transported to the hospital under Section 351 of the MHA (2014). Post implementation, there were fewer code grey events (clinical and security responses to unarmed threat) that required restrictive interventions including mechanical or chemical restraint. The number of code grey events in which no restrictive intervention was applied increased from 76.7% to 86.6%. Staff assigned higher triage ratings following the introduction of Safewards. There was a significant reduction in code grey events that used one restrictive intervention after implementing Safewards ED interventions (15.6% versus 7.2%; p=<0.001). Significantly fewer sedative medications were administered to manage behaviour on arrival (20.6% pre versus 9.8% post, p=<0.001). The Safewards ED adaptation may have contributed to a reduction in the use of restrictive interventions in this high-risk subgroup of patients frequently subject to restrictive interventions in the ED. Further research is required to validate the findings from this subgroup analysis.

Predictive methylation signature for gemcitabine sensitivity in pancreatic ductal adenocarcinoma: A pathway to personalized treatment.

768 Background: Gemcitabine (Gem) is a key drug used in chemotherapy regimens for treating pancreatic ductal adenocarcinoma (PDA). Identifying a biomarker to predict patient response to Gem could be crucial in personalizing treatment selection between Gemcitabine and fluorouracil (5-FU)-based therapies, thereby improving patient outcomes. We hypothesize that DNA methylation changes in genes linked to Gem resistance may serve as surrogates for the expression of corresponding proteins, thereby predicting treatment outcomes in patients with PDA receiving this therapy. Methods: We curated a 93-gene panel through a literature review spanning from January 1970 to April 2024. The proteins encoded by these genes have demonstrated either preclinical evidence (from cell line or mouse models) or clinical evidence (from tissue-based studies) of affecting the response to Gem in PDA. We evaluated the prognostic significance of methylation at specific CpG (cytosine-phosphate-guanine) sites within these genes using data from The Cancer Genome Atlas (TCGA) database, focusing on patients who had received Gem (106 /184 patients). We utilized elastic net multivariate analysis to analyze survival and created Kaplan-Meier plots based on our gene panel to estimate overall survival (OS). We compared RNA and gene expression levels for the clinically significant gene signatures between normal (NT) and PDA tissues using TNMplot.com, a web-based tool developed from data in the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO), TCGA, Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories. This tool employs Mann-Whitney or Kruskal-Wallis tests to determine statistical significance. Results: We identified an 8-CpG site methylation signature across eight genes, distinguishing a high-risk subgroup within the Gem-treated cohort in the TCGA database. Patients exhibiting methylation at specific CpG sites in this signature experienced significantly worse OS, with median survival times of 20.35 months compared to 49.38 months (p=0.0068). Additionally, the RNA expression (fold change: 2.11, p=2.12e-55) and gene expression (fold change: 1.42, p=3.14e-18) of these genes were markedly higher in PDA tissues compared to normal tissues. Notably, the candidate genes in our signature do not overlap with those used to classify PDA into classical versus basal subtypes. In an ongoing study, we are also investigating methylation changes of these candidate genes in the blood (cell-free DNA) of PDA patients. Conclusions: We present a signature that can predict Gem sensitivity or resistance in patients with PDA. This signature serves as a critical first step toward personalizing treatment strategies.

Time trend analysis of osteoporosis prevalence among adults 50years of age and older in the USA, 2005-2018.

This is the first study to assess osteoporosis prevalence trends over time and the proportion of undiagnosed osteoporosis across gender, ethnicity/race, and age groups. Observational time trend analyses were conducted using the 2005-2006, 2007-2008, 2009-2010, 2013-2014, and 2017-2018 National Health and Nutrition Examination Survey (NHANES) datasets, along with a descriptive analysis using the 2017-2018 NHANES dataset to capture the proportion of undiagnosed osteoporosis. The findings showed a statistically significant increase in osteoporosis prevalence among women, non-Hispanic Whites, and all age groups (except for individuals 80years of age and older) during the study period. A subsequent analysis examining individuals by both gender and ethnicity/race demonstrated a statistically significant increase among Other Hispanic men and non-Hispanic White women. Additional descriptive analyses found that 69.12% of individuals with osteoporosis went undiagnosed. Specifically, 86.88% of men and 84.77% of individuals 50-59years of age with osteoporosis went undiagnosed, representing the two highest groups. The substantial and increasing prevalence among certain groups and sub-groups, along with the lack of diagnostic capture of osteoporosis, highlights existing gaps in public health efforts and care delivery infrastructure. This paper highlights high-risk groups and sub-groups that may benefit most from accelerated initiatives to reduce the burden of illness associated with osteoporosis.

The Rise of Syphilis Infections and Reinfections over a Decade (2009–2019) in the Bolognese Area: A Retrospective Analysis

Syphilis has resurged globally, especially in urban areas of developed countries. This study analyses syphilis cases over a decade at an STD centre in Bologna, Italy, examining new diagnoses, reinfections, and impacts on high-risk subgroups, compared with national and European data. Data from 2009–2019 were retrospectively reviewed, including primary, secondary, early latent, late latent, and indeterminate syphilis cases, as per WHO guidelines. Cases of tertiary syphilis and serological-only diagnoses were excluded. Statistical analysis was conducted using IBM SPSS Statistics 26 with logistic regression and chi-square tests. A total of 1086 syphilis cases were identified, rising from 43 cases in 2009 to 157 in 2019—a 265% increase over the decade. In 2019, reinfections accounted for 23.7% of cases, primarily among men who have sex with men (MSM, 82.1%), with an HIV co-infection rate of 37.6%. The most affected age group was over 45 years. Bologna’s syphilis rates consistently exceeded European averages, with a higher median age, indicating unique transmission patterns and public health challenges. The high reinfection rate among MSM and older individuals emphasises the need for targeted public health initiatives. The sharp rise in cases highlights potential influences such as Bologna’s population dynamics and the increased use of Pre-Exposure Prophylaxis (PrEP). Focused public health efforts, particularly on high-risk groups, are critical to address this challenge effectively.

Persistent depressive symptom trajectory is associated with cognitive impairment: a population-based longitudinal study of aging in Taiwan

BackgroundTo investigate the associations between five depressive symptom trajectories and cognitive impairment in Taiwan’s older population. In addition, we investigated the moderating factors influencing these associations.MethodsThis population-based, longitudinal, cohort study was conducted on the basis of the Taiwan Longitudinal Study on Aging. Data corresponding to the fifth (2003), sixth (2007), and seventh (2011) survey waves were analyzed, focusing on individuals aged ≥ 65 years. Depressive symptom trajectories were analyzed using the 10-item Centre for Epidemiological Studies Depression scale, and cognitive function was assessed using the Short Portable Mental State Questionnaire. Logistic regression models were adjusted for various covariates such as sociodemographic, lifestyle, and health-related variables. We also investigated moderating effects of sex, age, type 2 diabetes mellitus, hypertension, and coronary heart disease.ResultsFive trajectories of depressive symptoms included 1,549 older individuals were identified. Approximately 36.09%, 47.13%, 5.68%, 6.20%, and 4.91% exhibited no, mild, decreasing, increasing, and persistent depressive symptom trajectories, respectively. The odds ratios for cognitive impairment were 3.17 (95% confidence interval [CI]: 1.41–7.15) in Model 1; 3.24 (95% CI: 1.42–7.41) in Model 2; and 2.95 (95% CI: 1.24–7.00) in Model 3 in individuals with persistent depressive symptom trajectory. Only persistent depressive symptom trajectory reached statistical significance in all three models. Cognitive decline was evident across all trajectories. The rate of cognitive decline was more rapidly in the persistent depressive symptom trajectory, nearly twofold to no depressive symptom trajectory, which the corresponding β values (score/year) were − 0.0862, − 0.1020, − 0.1192, − 0.1206, and − 0.1683 for the no, mild, decreasing, increasing, and persistent depressive symptom trajectories, respectively. Female sex, older age, type 2 diabetes mellitus, and coronary heart disease were significant moderators on the risk of cognitive impairment.DiscussionPersistent depressive symptoms is associated with cognitive impairment in older adults. Identifying high-risk subgroups is crucial for targeted assistance. Policymakers and health-care professionals should be informed accordingly.

Off-pump versus on-pump coronary artery bypass grafting in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Off-pump coronary artery bypass graft surgery (OPCAB) has been suggested as superior to on-pump coronary artery bypass graft surgery (ONCAB) in certain high-risk subgroups, but its benefit in patients with chronic obstructive pulmonary disease (COPD) remains controversial. This meta-analysis aimed to evaluate OPCAB versus ONCAB outcomes in COPD patients. We followed PRISMA guidelines and searched PubMed, Embase, and the Cochrane Library in August 2024 for studies comparing OPCAB and ONCAB in COPD patients. Statistical analysis was conducted using Review Manager 5.4.1 and Rstudio with a fixed orrandom effects model. Six studies with a total of 1,687 patients were included, of which 1,062 (62.95%) underwent OPCAB. The mean patient age was 63.6years. OPCAB did not significantly affect all-cause mortality compared to ONCAB (OR 1.14; 95% CI 0.65-1.99). There were no significant differences in reintubation (OR 0.81; 95% CI 0.53-1.23), prolonged ventilation (OR 0.54; 95% CI 0.24-1.22), post-operative atrial fibrillation (OR 0.90; 95% CI 0.70-1.15), or ARDS (OR 0.43; 95% CI 0.14-1.33). However, ventilation time was significantly shorter in the OPCAB group (MD - 5.30h; 95% CI - 7.22 to - 3.38). OPCAB is associated with reduced ventilation time in COPD patients though it shows no significant difference in all-cause mortality or other post-operative complications compared to ONCAB.

Refining prognostic assessment of diffuse large B-cell lymphoma: insights from multi-omics and single-cell analysis unveil SRM as a key target for regulating immunotherapy

PurposesPrevious studies have demonstrated that proliferation, stroma or immunity strongly influence the prognosis and therapeutic resistance of diffuse large B-cell lymphoma (DLBCL). Herein, we aimed to integrate proliferation, stromal, and immune (PSI) features to systematically evaluate the risk stratification and explore novel therapeutic targets in DLBCL.MethodsUsing data from multiple researches, we comprehensively evaluated the characteristics and prognostic impact of PSI features in DLBCL, and developed a novel risk stratification model (PSI score) with a consistent cutoff value to stratify the risk of 3,229 DLBCL patients from different cohorts. Mechanisms underlying adverse prognosis in the high-risk DLBCLs were investigated through transcriptomic (n = 3,229), genomic (n = 576), and scRNA-seq (n = 20) analyses.ResultsWe identified a high-risk DLBCL subgroup (HPSI, 36.1% of DLBCL). HPSI was characterized by upregulation of spermidine synthase (SRM) and cold tumor microenvironment (TME). Compared to low-risk group, HPSI exhibited poorer prognosis, with lower 3-year OS (51.7% vs. 78.1%, P < 0.0001) and PFS (48.9% vs. 72.6%, P < 0.0001) rates. HPSI shared malignant proliferative phenotype resembling Burkitt lymphoma. Genomic analysis revealed extensive copy-number loss in the chemokine and interleukin coding regions within HPSI. Bulk and scRNA-seq analyses indicated that upregulation of SRM might mediate cold TME in DLBCL, potentially through suppressing immune activation pathways, promoting dendritic cells (DCs) transformation into tolerogenic DCs, and facilitating M2 polarization of macrophages. Finally, for eventual clinical translation, we integrated the model with other clinical features to develop a comprehensive database for DLBCL.ConclusionOur study effectively simplifies risk stratification of DLBCL, revealing that immune microenvironment and SRM jointly shape a subgroup of DLBCL with extremely poor prognosis. Targeting SRM may become a potential strategy for modulating immunotherapy in DLBCL, providing new insight for immunotherapy.

High-density lipoprotein cholesterol as a prognostic marker for 90-day transplant-free mortality in hepatitis B virus-related acute-on-chronic liver failure

BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is linked to dyslipidemia and inflammatory responses. This study aimed to investigate the correlation between high-density lipoprotein cholesterol (HDL-C) levels and 90-day transplant-free (TF) mortality in patients with HBV-ACLF.MethodsA prospective cohort of 287 patients with HBV-ACLF from Beijing Ditan Hospital was enrolled between January 2016 and December 2019. The prognostic accuracy of lipid profile parameters was evaluated by the area under the receiver operating characteristic curve (AUC), and the association between HDL-C levels and mortality was assessed using a restricted cubic spline analysis. Correlations between lipid profile parameters and inflammatory factors were analyzed. Kaplan–Meier curves were used to assess 90-day TF mortality, and log-rank tests were used for comparison analysis. These results were internally validated between January 2020 and December 2023 (n=125).ResultsPatients with lower HDL-C levels exhibited higher mortality rates (adjusted hazard ratio for HDL-C &amp;lt; 0.13 mmol/L: 4.04, 95% confidence interval: 1.35–11.85) compared with those in the reference group (with HDL-C levels above 0.36 mmol/L). An “L-shaped” association was observed between HDL-C levels and TF mortality. The prognostic value of HDL-C (AUC at day 90: 0.732) was comparable to the model for end-stage liver disease score of 0.729. Additionally, HDL-C levels were inversely correlated with interleukin (IL)-4, IL-6, and tumor necrosis factor-α (all P&amp;lt;0.05). In the training cohort, the 90-day TF mortality rates were 8.3%, 15.2%, 24.0%, and 43.2% for the extremely low, low, medium, and high-risk subgroups, respectively, while in the validation cohort, they were 4.5%, 18.5%, 31.2%, and 44.7%, respectively.ConclusionsHDL-C levels &amp;lt; 0.13 mmol/L were associated with increased 90-day transplant-free mortality in patients with HBV-ACLF. An inverse correlation was found between HDL-C levels and inflammatory markers.

Computational pathology identifies a low B-cell content in the tumour microenvironment as a predictor of adverse outcome in patients with classic Hodgkin lymphoma treated with ABVD

AimsThe prognostic impact of B lymphocytes surrounding Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) and pathogenic variants in genes associated with apoptosis regulation remains undefined.MethodsWe have...

Inflammatory Markers and Severity in COVID-19 Patients with Clostridioides Difficile Co-Infection: A Retrospective Analysis Including Subgroups with Diabetes, Cancer, and Elderly.

The interplay of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and Clostridioides difficile infection (CDI) poses a critical clinical challenge. The resultant inflammatory milieu and its impact on outcomes remain incompletely understood, especially among vulnerable subgroups such as elderly patients, those with diabetes, and individuals with cancer. This study aimed to characterize inflammatory markers and composite inflammatory severity scores-such as Acute Physiology and Chronic Health Evaluation II (APACHE II), Confusion, Urea, Respiratory rate, Blood pressure, and age ≥ 65 years (CURB-65), National Early Warning Score (NEWS), and the Systemic Immune-Inflammation Index (SII)-in hospitalized Coronavirus Disease 2019 (COVID-19) patients with and without CDI, and to evaluate their prognostic implications across key clinical subgroups. We conducted a retrospective, single-center study of 240 hospitalized adults with Reverse Transcription Polymerase Chain Reaction (RT-PCR)-confirmed COVID-19 between February 2021 and March 2023. Of these, 98 had concurrent CDI. We collected baseline demographics, comorbidities, and laboratory parameters including C-reactive protein (CRP), Interleukin-6 (IL-6), ferritin, neutrophil and lymphocyte counts, albumin, platelet counts, and calculated indices (C-reactive protein to Albumin Ratio (CAR), Neutrophil-to-Lymphocyte Ratio (NLR), Prognostic Nutritional Index (PNI), SII). Patients were stratified by CDI status and analyzed for inflammatory marker distributions, severity scores (APACHE II, CURB-65, NEWS), and outcomes (Intensive Care Unit (ICU) admission, mechanical ventilation, mortality). Subgroup analyses included diabetes, elderly (≥65 years), and cancer patients. Statistical comparisons employed t-tests, chi-square tests, and logistic regression models. Patients with CDI demonstrated significantly higher CRP, IL-6, SII, and CAR, coupled with lower albumin and PNI (p < 0.05). They also had elevated APACHE II, CURB-65, and NEWS scores. CDI-positive patients experienced increased ICU admission (38.8% vs. 20.5%), mechanical ventilation (24.5% vs. 12.9%), and mortality (22.4% vs. 10.6%, all p < 0.05). Subgroup analyses revealed more pronounced inflammatory derangements and worse outcomes in elderly, diabetic, and cancer patients with CDI. Concurrent CDI intensifies systemic inflammation and adverse clinical trajectories in hospitalized COVID-19 patients. Elevations in inflammatory markers and severity scores predict worse outcomes, especially in high-risk subgroups. Early recognition and targeted interventions, including infection control and supportive measures, may attenuate disease severity and improve patient survival.

Evaluating the Effectiveness of Cyclin-Dependent Kinase 4/6 Inhibitors in Early- and Very Early-Onset Metastatic Breast Cancer: A Multicenter Study.

Background and Objectives: Early-onset breast cancer (EOBC), particularly in patients under 40, presents with distinct biological characteristics and worse survival outcomes compared to late-onset cases. Despite intensive treatments, EOBC patients, especially those with hormone receptor-positive, HER2-negative (HR+/HER2-) subtypes, show poorer prognosis. CDK4/6 inhibitors, combined with endocrine therapy (ET) have become the standard for HR+/HER2- metastatic breast cancer, yet younger patients are underrepresented in clinical trials. This study aims to evaluate the efficacy of ribociclib and palbociclib with ET in HR+/HER2- metastatic breast cancer, addressing the critical gap in understanding treatment outcomes in younger patient populations. Materials and Methods: This multicenter, retrospective study evaluated the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, ribociclib, and palbociclib, in combination with endocrine therapy in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer. Results: A total of 198 patients treated between 2019 and 2023 were analyzed for progression-free survival, overall survival, and prognostic factors. Very early-onset breast cancer, which is diagnosed before the age of 35, was identified as an independent prognostic factor for poor progression-free survival. Additional factors associated with poorer outcomes included liver metastasis, progesterone receptor negativity, high tumor grade, and the concurrent use of fulvestrant with CDK4/6 inhibitors. Both ribociclib and palbociclib demonstrated similar efficacy, and dose reductions due to treatment-related adverse events did not compromise therapeutic outcomes. Conclusions: This study is the first to focus specifically on the treatment of early-onset breast cancer with CDK4/6 inhibitors, providing critical insights into the unique challenges faced by this patient population. The findings underscore the urgent need for personalized treatment strategies, routine genetic testing, and dedicated clinical trials designed to address the specific needs of these high-risk subgroups. By advancing our understanding of the clinical and molecular landscape of early-onset breast cancer and very early-onset breast cancer, this study lays the groundwork for improving outcomes in these underserved patients through tailored therapeutic approaches.

Impact of aspirin on biochemical recurrence of prostate cancer after robot assisted radical prostatectomy in a multicenter retrospective cohort study

This study evaluated the impact of aspirin on the biochemical recurrence (BCR) rate following robot-assisted radical prostatectomy (RARP) in patients. A database search identified patients who underwent RARP for pT2-3N0M0 disease at any of 25 centers between 2011 and 2022, categorized into aspirin (n = 350) and control groups (n = 5857). Adjustment by 1:1 propensity score matching (PSM) and Mahalanobis distance matching (MDM) created 350 matched pairs. The effect of aspirin on the BCR rate was evaluated by analysis of BCR-free survival. After PSM and MDM, the 3-year BCR-free rate was significantly better in the aspirin group (85.0%, 95% confidence interval [CI] 80.8–89.4) than in the control group (PSM, 74.5%, 95% CI 66.5–83.5, p = 0.021; MDM, 74.7%, 95% CI 66.3–84.3, p = 0.037). In the analysis of high-risk subgroups, patients in the aspirin group with an ISUP (International Society of Urological Pathology) grade ≥ 4 had a significantly lower recurrence rate in both matched groups (PSM, hazard ratio 0.44, 95% CI 0.22–0.88; MDM, hazard ratio 0.45, 95% CI 0.23–0.90). In conclusion, this study suggests that aspirin could enhance BCR-free survival post-RARP, especially in patients with higher ISUP grades.

Hypertrophic Cardiomyopathy: New Clinical and Therapeutic Perspectives of an "Old" Genetic Myocardial Disease.

Since its first pathological description over 65 years ago, hypertrophic cardiomyopathy (HCM), with a worldwide prevalence of 1:500, has emerged as the most common genetically determined cardiac disease. Diagnostic work-up has dramatically improved over the last decades, from clinical suspicion and abnormal electrocardiographic findings to hemodynamic studies, echocardiography, contrast-enhanced cardiac magnetic resonance, and genetic testing. The implementation of screening programs and the use of implantable cardioverter defibrillators (ICDs) for high-risk individuals have notably reduced arrhythmic sudden deaths, altering the disease's mortality profile. Therapeutic breakthroughs, including surgical myectomy, alcohol septal ablation, and the novel introduction of "myosin inhibitors", have revolutionized symptom management and reduced progression to advanced heart failure (HF) and death. Despite this progress, refractory HF-both with preserved and reduced systolic function-has become the predominant cause of HCM-related mortality. While most patients with HCM experience a favorable clinical course with low morbidity and mortality, timely identification and targeted treatment of high-risk subgroups progressing toward progressive HF remain a pressing challenge, even for expert clinicians.

Incremental benefit of high dose compared to standard dose influenza vaccine in reducing hospitalizations

Evidence regarding the high-dose (HD) vaccine’s relative vaccine effectiveness (rVE) and absolute benefit in reducing influenza-related hospitalizations compared to the standard-dose (SD) vaccine is warranted. We estimated the adjusted rVE and the number needed to vaccinate (NNV) of the HD vaccine compared to the SD vaccine among Clalit Health Services members aged ≥65 years. Among 418,603 and 393,125 members vaccinated in the 2022–2023 and 2023–2024 influenza seasons, the adjusted rVE was 27% (95% CI: −12% to 61%) for 2022–2023 and 7% (95% CI: −36% to 42%) for 2023–2024, with NNV to prevent one hospitalization event being 2262 (95% CI: 1004 to ∞) and 7662 (95% CI: 1293 to ∞), respectively. Even among the highest-risk subgroup, the NNV was 1289 (95% CI: 571 to ∞) for 2022–2023 and 4719 (95% CI: 797 to ∞) for 2023–2024. The HD vaccine exhibited a limited incremental benefit, even for individuals at the highest risk.

Complex rearrangements fuel ER+ and HER2+ breast tumours.

Breast cancer is a highly heterogeneous disease whose prognosis and treatment as defined by the expression of three receptors-oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2; encoded by ERBB2)-is insufficient to capture the full spectrum of clinical outcomes and therapeutic vulnerabilities. Previously, we demonstrated that transcriptional and genomic profiles define eleven integrative subtypes with distinct clinical outcomes, including four ER+ subtypes with increased risk of relapse decades after diagnosis1,2. Here, to determine whether these subtypes reflect distinct evolutionary histories, interactions with the immune system and pathway dependencies, we established a meta-cohort of 1,828 breast tumours spanning pre-invasive, primary invasive and metastatic disease with whole-genome and transcriptome sequencing. We demonstrate that breast tumours fall along a continuum constrained by three genomic archetypes. The ER+ high-risk integrative subgroup is characterized by complex focal amplifications, similar to HER2+ tumours, including cyclic extrachromosomal DNA amplifications induced by ER through R-loop formation and APOBEC3B-editing, which arise in pre-invasive lesions. By contrast, triple-negative tumours exhibit genome-wide instability and tandem duplications and are enriched for homologous repair deficiency-like signatures, whereas ER+ typical-risk tumours are largely genomically stable. These genomic archetypes, which replicate in an independent cohort of 2,659 primary tumours, are established early during tumorigenesis, sculpt the tumour microenvironment and are conserved in metastatic disease. These complex structural alterations contribute to replication stress and immune evasion, and persist throughout tumour evolution, unveiling potential vulnerabilities.

Exploring the prognostic significance of lactate-mitochondria-related genes in prostate cancer.

Prostate cancer (PCa) is a common and serious health issue among older men globally. Metabolic reprogramming, particularly involving lactate and mitochondria, plays a key role in PCa progression, but studies linking these factors to prognosis are limited. To identify novel prognostic markers of PCa based on lactate-mitochondria-related genes (LMRGs), RNA sequencing data and clinical information of PCa from The Cancer Genome Atlas (TCGA) and the cBioPortal database were used to construct a lactate-mitochondria-related risk signature. Here, we established a novel nine-LMRG risk signature for PCa, and Kaplan-Meier curves confirmed a worse prognosis for high-risk subgroups in the TCGA dataset. Meanwhile, a nomogram that effectively predicts the prognosis of PCa patients was also constructed. Next, close associations between the lactate-mitochondria-related signature and the immune microenvironment were examined to clarify the role of LMRGs in shaping the immune landscape. Furthermore, as the only lactate-related gene among the nine key prognostic risk genes, myeloperoxidase (MPO) was identified as a key factor that mediates lactate production in vitro and in vivo through attenuation of the glycolytic pathway. More importantly, MPO significantly inhibited PCa cell migration, invasion, and epithelial-mesenchymal transition (EMT), indicating its potential as an anticancer gene. Additionally, PCa with high MPO expression is highly sensitive to chemotherapeutic agents and mitochondrial inhibitors, highlighting its potential as an improved therapeutic strategy for PCa management.

The landscape of immunogenic cell death-related genes predicts the overall survival and immune infiltration status of non-small-cell lung carcinoma.

Non-small cell lung cancer (NSCLC), which accounts for about 85% of all lung cancers, currently exhibits insensitivity to most treatment regimens. Therefore, the identification of new and effective biomarkers for NSCLC is crucial for the development of treatment strategies. Immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immune responses and generating long-term immune memory, holds promise for enhancing anti-tumor immunity and offering promising prospects for immunotherapy strategies in NSCLC. Clinical information and expressive profiles of NSCLC genes were retrieved from the GEO and TCGA databases. By combining these databases, the researchers were able to identify the appropriate genes for use in forecasting outcomes of patients with this type of cancer. We further performed functional enrichment, gene variants and immune privilege correlation analysis to determine the underlying mechanisms. This was followed by univariate and multivariate Cox regression and LASSO regression analyses, we developed a prognostic risk model based on the TCGA cohort, which included 17 gene labels. The results of the external validation were then used to identify the appropriate genes for use in predicting the survival outcome of patients with this type of cancer. In addition, a nomogram was created to help visualise the clinical presentation of the patients. For the analyses, we performed 50 functional and immunoinfiltration assessments for two risk groups. Using 17 genes (AIRE, APOH, CDKN2A, CEACAM4, COL4A3, CPA, DBH, F10, FCGRB, FGFR4, MMP1, PGLYRP1, SCGB2A2, SLC9A3, UGT2B17 and VIP), The researchers then created a gene signature that could be used to identify patients with an increased risk of contracting cancer. They divided the patients into two groups based on their risk score. The low-risk group exhibited a better prognosis (P<0.01). The survival curve demonstrated that ICD-related models could accurately predict patient prognosis. Conversely, high-risk subgroups were closely associated with immune-related signaling pathways. The analysis of immune infiltration also showed that the infiltration levels of most immune cells were higher in the high risk sub-group than in the low risk sub-group. In comparison to the low-risk group, the high-risk group was more susceptible to the immune-checkpoint blockade (ICB) treatment. Our researchers utilized a gene model to analyze the immune inflammation and prognosis of patients with non-small-cell lung cancer (NSCLC). The discovery of new ICD-related genes could lead to the development of new targeted treatments for this condition.

Association between ambient temperatures and cardiovascular disease: A time series analysis using emergency ambulance dispatches in Chongqing, China, 2019-2021.

Cardiovascular disease (CVD) is one of the leading causes of death globally. Yet, further research is required into the relationship between CVD and extreme environmental temperatures. This study aims to explore the association between the incidence of CVD and extreme temperatures, and also to identify susceptible subgroups within the population. We collected cardiovascular emergency ambulance dispatch (CEAD) records from Chongqing Emergency Dispatch Center in the main urban areas of Chongqing from 2019 to 2021. Then, we used distributed lag nonlinear modeling (DLNM) with a quasi-Poisson distribution to evaluate the association between extreme temperatures and CEADs. Susceptibility subgroups were identified by stratified analysis according to gender, age and initial diagnosis. Finally, the attribution analysis was used to calculate the scores and counts of CEADs caused by low and high temperatures. Compared with the optimal temperature (23°C), the cumulative lagged risk of total CEADs was increased under extreme low-temperature conditions (CRR: 1.732, 95% CI: [1.157, 2.593]), with the lagged effect lasting for 8 days. Under extreme high-temperature conditions, it decreased (CRR: 0.752, 95% CI: [0.611, 0.926]) and a protective effect was observed. Compared to the group under 60, those over 60 were more sensitive to temperature changes, showing a higher risk of disease with cold exposure (RR: 1.087, 95% CI: [1.021, 1.157]). In addition, a reduction in risk of disease was observed just one day after heat exposure. There were also gender differences in the elderly group: males showed longer lagged effects after cold exposure, while females had higher dispatch risk in cold weather and less heat adaptation in hot weather than males. Ambient temperature is significantly associated with the risk of CVD, with elderly patients, especially females, being a high-risk subgroup. Governments need to formulate localized health policies that address regional climate patterns and population vulnerabilities. As one of the famous "Furnace Cities", Chongqing's measures for coping with hot environments can serve as a reference. Nonetheless, improving our understanding and preparation for cold weather is also crucial. Public warning systems should be improved, and local heating strategies for vulnerable groups should be developed to minimize the negative risk of extreme cold temperatures to the public.