Citations

Abstract OBJECTIVE Despite advancements in therapy and improved survival rates for patients with primary central nervous system lymphoma (PCNSL), the optimal management strategy for recurrent or refractory PCNSL (r/r PCNSL) remains undefined. In such cases, repeat brain biopsy is often performed to confirm disease recurrence, though its diagnostic and therapeutic value is uncertain. This study evaluates whether repeat brain biopsy provides new, actionable diagnostic insights that influence treatment decisions. METHODS A retrospective analysis was conducted on patients with a confirmed diagnosis of PCNSL who underwent repeat brain biopsy for suspected recurrent or refractory disease between 2005 and 2023. Patients with a history of other CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. RESULTS Twenty patients met inclusion criteria (55% female), with a mean age at biopsy of 56 years in the PCNSL group and 61 years in the r/r PCNSL group. While the overall distribution of presenting symptoms did not significantly differ (p = 0.2), gait instability, weakness, and cognitive decline were more common in r/r PCNSL. PCNSL more often presented with single lesions, while r/r PCNSL had predominantly multiple lesions (p < 0.05). Periventricular enhancement was significantly more frequent in r/r PCNSL (p < 0.05), though other radiologic features were comparable. Repeat biopsy confirmed DLBCL in 90% of cases; no infections or alternate malignancies were identified. Diagnostic clarification was the primary indication for repeat biopsy. Chemotherapy regimens were altered in 50% of post-biopsy cases, without a corresponding difference in overall survival (p = 0.79). Procedure-related morbidity was observed in three patients (15%). CONCLUSIONS The second biopsy in most cases reaffirmed the original diagnosis of diffuse large B cell lymphoma. Although biopsy results led to treatment adjustments; these changes did not affect overall survival.

Abstract Brain metastases significantly impact neurocognitive function and overall survival. Stereotactic radiosurgery (SRS) is a cornerstone of treatment for patients with limited metastases and expected survival beyond three months. Despite current guidelines, up to 20% of patients with brain metastases undergoing SRS have been reported to die within 90 days. This study retrospectively evaluates prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. We retrospectively analyzed a cohort of 1,546 patients who underwent Gamma Knife SRS for brain metastases at our institution between 2015 and 2023. One hundred seventy patients who survived fewer than 90 days post-SRS were identified and case-matched to 170 patients who survived over 90 days. Measured variables included patient demographics, tumor characteristics, treatment history, functional status, and control of the primary cancer. We modeled post-SRS 90-day survival using binomial and multivariate logistic regression. Multivariate analysis highlighted Karnofsky Performance Status (KPS) < 70 (OR: 17.4, p < 0.001), prior whole brain radiation (OR: 6, p = 0.004), and focal neurological deficits (OR: 3.02, p = 0.003) as significant predictors of early deaths, while CNS progression before SRS (OR: 0.22, p < 0.001) and control of systemic cancer (OR: 0.556, p = 0.002) were associated with a less than 90-day survival. The predictive model demonstrated acceptable performance with an area under the curve (AUC) of 0.85, accuracy of 80%, sensitivity of 87%, and specificity of 71%. Key predictors of 90-day survival following SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurologic deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.

Background and aims To validate the applicability of the new histological criteria for autoimmune hepatitis (AIH) proposed by the International AIH Pathology Group (IAIH‐PG) among Chinese patients with AIH and drug‐induced liver injury (DILI). Methods The gold standard for diagnosis relied on clinical response: discontinuing treatment without relapse supported DILI, while relapse or ongoing immunosuppressive treatment confirmed AIH. This two‐centre retrospective cohort study included inpatients with DILI or AIH from January 2002 to March 2023. Cases that underwent liver biopsy were selected according to inclusion and exclusion criteria. The diagnostic performance of the criteria was assessed by an area under the receiver operating characteristic curve (AUROC). Results Out of 69 patients: AIH (41, 59%) and DILI (28, 41%). The accuracy, sensitivity and specificity of the new histological criteria for likely and possible AIH were 70%, 98% and 29%, respectively, with an AUROC of 0.8236 [95% confidence interval (CI): 0.7533–0.8938]. For likely AIH, the accuracy, sensitivity and specificity were 73%, 61% and 89%, respectively, with an AUROC of 0.9177 [95% CI: 0.8757–0.9596]. Moreover, for possible AIH, significant differences were found in serum alanine aminotransferase levels [178.4 (87.0, 435.0) versus 536.5 (206.9, 930.4) U/L] and antinuclear antibody (ANA) ≥1:160 [10 (67%) versus 1 (6%)], as well as in lobular lymphoplasmacytic infiltrate [15 (100%) versus 12 (71%)] and more than mild inflammation [13 (87%)versus 6 (35%)] between AIH and DILI (all P values were <0.05). Conclusion The new histological criteria exhibit good diagnostic efficacy in distinguishing AIH from DILI in China, with high AUROC. Key discriminators include low aminotransferase, ANA ≥1:160, lobular lymphoplasmacytic infiltrate and more than mild inflammation, which may further improve diagnostic accuracy for AIH.

Background: Muscular dystrophies (MDs) may cause heart failure (HF), but outcomes specific to MD-related HF are not well characterized. Research Question: Do the outcomes of HF hospitalizations differ between patients with underlying MDs (MD-HF) vs. patients without MDs (non-MD-HF) in the United States? Methods: Discharge data from HF hospitalizations were abstracted from the Nationwide Readmissions Database (2016-2022) and stratified by the presence or absence of MD (MD-HF vs. non-MD-HF). Logistic regression and lognormal models were estimated to assess differences in inpatient mortality, length of stay (LOS), total costs, complications, and 30-day and 90-day all-cause readmissions. Propensity-score matching (PSM) was used to control baseline differences between the MD-HF and non-MD-HF cohorts. Odds ratios (OR) with associated 95% Confidence intervals (CI) and p-values were reported. Analyses were conducted via SAS v. 9.4, with statistical significance indicated by two-tailed p<.05. Results: 8,466,806 HF hospitalizations were included in the analysis, of which 3688 (0.04%) involved patients with MD. MD-HF hospitalizations involved younger patients (mean age 55.3 vs. 71.3 years, p<0.001) with higher rates of HF with reduced ejection fraction (HFrEF) compared to non-MD-HF hospitalizations (48.1% vs. 34.9%, p<0.001). Compared to non-MD-HF hospitalizations (2.01%), MD-HF hospitalizations (5.82%) were associated with significantly higher odds of inpatient mortality (OR 3.01, 95% CI: 2.03, 4.45); higher complications rate (OR 2.11, 95% CI, 1.77, 2.52) including cardiogenic shock (OR 2.61, 95% CI, 1.90, 3.59), cardiac arrest (OR 2.27, 95% CI, 1.17, 4.41), use of mechanical ventilation (OR 2.23, 95% CI, 1.82, 2.73); higher palliative care consultation (OR 4.52, 95% CI, 3.21, 6.36); as well as more extended hospital LOS (OR 1.18, 95% CI, 1.09, 1.29), higher total costs (OR 1.32, 95% CI, 1.24, 1.41), and higher odds of discharge to rehab facility (OR 2.46, 95% CI, 1.99, 3.03) and home healthcare (OR 1.85, 95% CI, 1.55, 2.21) (all p<0.001). MD was not associated with a significant difference in 30-day (OR 0.94, 95% CI, 0.78, 1.12) and 90-day (OR 0.98, 95% CI, 0.82, 1.17) all-cause readmission rates. Conclusion: MD-HF hospitalizations were associated with higher inpatient mortality, complication rates, resource utilization, discharge to rehab facility and home healthcare, and no difference in readmission rates compared to non-MD-HF hospitalizations.

Background: Heart failure (HF) continues to be a major cause of morbidity and mortality worldwide, placing a significant burden on healthcare systems. Differences in the outcomes of HF hospitalizations for adults in teaching vs. non-teaching hospitals in urban settings are uncertain. Research Question: Do outcomes of HF hospitalizations differ between patients hospitalized in urban teaching vs. non-teaching hospitals in the United States? Methods: HF hospitalizations were abstracted from the 2016 through 2022 Nationwide Readmissions Database and stratified into urban teaching vs. urban non-teaching hospital settings. Propensity-score matching was used to control for baseline differences between teaching and non-teaching hospital cohorts. Logistic regression and lognormal models were estimated to assess differences in inpatient mortality, length of stay (LOS), total costs, complications, and 30-day and 90-day all-cause readmissions. Odds ratios (OR) with associated 95% Confidence intervals (CI) and p-values were reported. Analyses were conducted via SAS v. 9.4. Results: A total of 7,558,299 weighted HF hospitalizations were included in the analysis, of which 76.3% involved urban teaching hospitalizations. Compared to urban non-teaching, HF hospitalizations in urban teaching hospitals were associated with higher odds of in-hospital mortality (OR 1.24, 95% CI:1.21-1.27); had higher complications, including cardiogenic shock (OR 2.58, 95% CI, 2.46, 2.70), cardiac arrest (OR 1.31, 95% CI, 1.27, 1.36), CPR (OR 1.28, 95% CI, 1.22, 1.34), and use of extracorporeal membrane oxygenation (OR 20.13, 95% CI, 13.0, 31.2), intra-aortic balloon pump (OR 4.46, 95% CI, 3.90, 5.10) and mechanical ventilation (OR 1.27, 95% CI, 1.23, 1.33); higher hospitalization cost (Ratio 1.18, 95% CI: 1.17,1.20), longer length of stay (OR 1.16, 95% CI: 1.15, 1.17) and a greater palliative care consultation rate (Ratio 1.35 (95% CI 1.30, 1.40) (all p<0.001) ( Figure 1 ). 30-day (OR 1.03, 95% CI: 1.02, 1.04) and 90-day (OR 1.05, 95% CI: 1.02, 1.07) all-cause readmission rates were also statistically higher (p<0.001), though the difference was clinically non-significant ( Figure 2 ). The home discharge rate was similar for teaching and non-teaching hospitals ( Figure 2 ). Conclusion: HF hospitalizations in urban teaching hospitals were associated with higher inpatient mortality, complication rates, resource utilization, and palliative care consult rates than urban non-teaching hospitals.

Background: Acute myocardial infarction (AMI) represents a significant component of cardiovascular disease (CVD) mortality among the young and middle-aged populations of the United States (US). Research Question: To analyze the long-term trends and the impact of the COVID-19 pandemic on AMI-related mortality among the young and middle-aged populations of the US. Methods: Data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) multiple causes of death database were used to analyze death certificates from 1999 to 2023 for AMI-related deaths among the young and middle-aged population (aged 25-64) of the US. Age-adjusted mortality rates (AAMRs) per 100,000 people and associated annual percent changes (APCs) and average APC (AAPCs) were analyzed using Joinpoint regression analysis. Mortality trends were stratified by sex, race/ethnicity, and census region. Results: From 1999 to 2023, there were 970,454 AMI-related deaths among U.S. adults aged 25-64 years. The annual number of AMI-related deaths decreased from 44,040 in 1999 to 31,522 in 2023. The overall AAMR per 100,000 decreased from 31.02 deaths (95% CI, 30.73 to 31.31) in 1999 to 15.29 (95% CI, 15.11 to 15.46) in 2023 (AAPC -2.92%, 95% CI -3.22 to -2.75). The AAMR per 100,000 declined at a faster rate from 31.02 in 1999 to 19.57 in 2010 (1999-2010, APC -4.26), followed by a slower rate from 19.57 in 2010 to 16.67 in 2019 (2010-2019, APC -1.41), The declining trend was disrupted by a transient increase during the COVID-19 pandemic, with a peak AAMR of 19.73 (95% CI, 19.53 to 19.93) in 2021 (2019-2021, APC 8.52). The declining trend resumed from 2021 to 2023, with AAMR decreasing to the lowest levels of 15.29 in 2023 (2021-2023, APC -12.58). Heterogeneity across demographic and regional groups has narrowed during these 25 years. However, they are still prevalent, with men ( figure 1 ), non-Hispanic (NH) Black or African American, NH American Indian or Alaska Native ( figure 2 ), and the residents of the Southern United States ( figure 3 ) having higher mortality rates. Conclusion: Over the past 25 years, AMI-related mortality has declined in the young and middle-aged population of the US, although rates spiked during the COVID-19 pandemic before resuming their decline in 2022. While disparities among demographic and regional groups have narrowed, they still exist, necessitating comprehensive efforts to improve cardiovascular health outcomes.

Background and Aim: Iron deficiency (ID) is a common condition worldwide, affecting about one-third of the population, and is particularly prevalent in heart failure (HF) patients. In HF, ID worsens symptoms such as fatigue and shortness of breath, contributing to higher hospitalization rates and mortality. Intravenous (IV) iron therapies like Ferric Carboxymaltose (FCM) and Ferric Derisomaltose (FDI) have effectively enhanced symptoms and improved quality of life. This meta-analysis examines the safety and efficacy of these iron treatments. Methods: A comprehensive literature search was conducted using PubMed, Clinical Trial.gov, and Cochrane Library databases from inception to May 2024 to identify relevant studies. All statistical analyses were conducted using R statistical software version 4.1.2. Our protocol was registered with PROSPERO (CRD#CRD42023469246). Our study included Randomized Controlled Trials (RCTs). The primary outcomes of our study includes major adverse events such as Cardiovascular Mortality, All-Cause Death, heart failure hospitalization rate, KCCQ, LVEF, MLHFQ3, and Peak Oxygen Consumption (pVO2). Results: Twenty-four RCTs with 11,333 participants were analyzed. The pooled analysis indicated that All-cause mortality risk reduction was observed with FCM [RR=0.89; 95% CI: 0.75–1.04] and FDI [RR=0.95; 95% CI: 0.81–1.12]. FCM significantly reduced composite outcomes of hospitalization for HF or cardiovascular mortality [HR=0.74; 95% CI: 0.59–0.93], while FDI showed modest effects [HR=0.86; 95% CI: 0.56–1.26]. Kansas City Cardiomyopathy Questionnaire scores improved notably with FCM [MD=5.21; 95% CI: 2.22–8.19]. Left Ventricular Ejection Fraction improvement was highest with Iron Sucrose [MD=2.92; 95% CI: 1.61–4.21]. For the Minnesota Living with Heart Failure Questionnaire (MLHFQ), Iron Sucrose also showed the most improvement [MD = -18.00; 95% CI: -38.52 to 2.52], followed by FCM and FDI. In peak oxygen consumption (pVO2), FCM exhibited modest benefits [MD = 1.25; 95% CI: -2.34 to 4.84]. The six-minute walk test (6MWT) results identified Ferrous Sulphate as the most effective [MD = 53; 95% CI: -18.85 to 124.85], followed by FCM. Conclusion: This highlights Ferric Carboxymaltose as a promising iron therapy for heart failure patients with iron deficiency. However, clinical decisions should consider patient factors, tolerability, and cost-effectiveness. Further long-term studies are needed to optimize treatment and prevent hospitalization.

With rapid industrial expansion, air pollution’s adverse neurological effects have gained increasing attention. Children face a greater risk of neurological damage because of their higher breathing rates, developing brains, and limited ability to detoxify harmful substances. Fine particulate matter has been identified as a primary neurotoxic contributor affecting developing brains. Strong evidence connects environmental pollutant exposure to the prevalence of Autism Spectrum Disorder (ASD), a neurodevelopmental condition marked by lasting difficulties with social communication and interaction. This study explores the association between long-term PM2.5 exposure and ASD symptom exacerbation, investigating underlying mechanisms. We hypothesize that long-term PM2.5 exposure exacerbates ASD symptoms through neuroinflammatory activation, leading to neuronal damage and impaired synaptic plasticity. Our investigation employs three complementary approaches: First, integrated analysis combining Global Burden of Disease data with Mendelian randomization demonstrates a significant association between PM2.5 exposure and increased ASD severity risk. Second, utilizing the China High-Resolution Air Pollution Database in conjunction with cohort studies, we provide evidence that ambient air pollution substantially influences autism severity, with PM2.5 identified as the predominant environmental determinant. Third, through network toxicology, single-cell transcriptomics, and animal experimentation, we demonstrate that chronic PM2.5 exposure exacerbates valproic acid-induced autism-like behaviors in murine models, identifying CTNNB1, PTEN, CCR2, AKT1, and mTOR as potential core mediating genes. Importantly, these findings represent preliminary results. Several potential confounding factors such as co-exposure to other pollutants and socioeconomic variables have not been fully addressed. While our multi-modal approach provides converging lines of evidence, further validation in larger, more diverse populations with refined control of confounders will be essential to establish causality and elucidate mechanisms. Nonetheless, these early insights advance our understanding of PM2.5-induced neurotoxicity in the context of ASD and offer timely, albeit preliminary, evidence to inform public health policy.

Prostate cancer (PCa) progression is driven by intricate molecular mechanisms involving dysregulated signaling networks and posttranslational modifications of key regulatory proteins. In this study, we identify a novel oncogenic pathway wherein cyclin-dependent kinase 12 (CDK12) physically interacts with and phosphorylates forkhead box A1 (FOXA1) at serine 234 (S234). Phosphorylation at this residue markedly enhances FOXA1 transcriptional activity, leading to up-regulation of downstream targets including murine double minute 2 (MDM2), a critical negative regulator of the p53 tumor suppressor. Mechanistically, this CDK12–FOXA1–MDM2 axis destabilizes p53, attenuates apoptotic signaling, and promotes PCa cell survival and proliferation. Therapeutic targeting of CDK12 using the small-molecule inhibitor THZ531 or RNA interference effectively abrogates FOXA1 phosphorylation, restores p53 stability, reactivates apoptotic pathways, and suppresses tumor growth. Notably, the identification of S234 as a functional phosphorylation site in FOXA1 reveals a previously uncharacterized posttranslational regulatory mechanism in PCa biology. These findings establish the CDK12–FOXA1–MDM2 axis as a pivotal driver of PCa progression and underscore the therapeutic potential of targeting FOXA1 phosphorylation to restore tumor suppressor function and induce apoptosis in PCa. Our work provides a mechanistic framework for developing precision therapies aimed at disrupting this oncogenic cascade in PCa.