Search Results (13,880)

Background: Local delivery after resection of high-grade glioma, particularly glioblastoma (GBM), aims to increase intratumoral drug exposure while limiting systemic toxicity. The only U.S. Food and Drug Administration (FDA)-approved implantable intracranial chemotherapy is the carmustine (1,3-bis[2-chloroethyl]-1-nitrosourea; BCNU)-impregnated polyanhydride wafer (Gliadel wafer), indicated for newly diagnosed high-grade glioma and recurrent GBM. More than two decades of clinical use and randomized data show that intracavitary chemotherapy is feasible and confers a modest survival benefit in carefully selected patients. Nevertheless, Gliadel wafer has not altered the overall poor prognosis of GBM because of biological resistance to nitrosoureas, constrained brain-parenchymal pharmacokinetics, and device-related adverse effects. Objective: The aim is to synthesize clinical and preclinical evidence defining the current limitations of Gliadel wafer and to outline strategies for next-generation local delivery systems, with emphasis on GBM within the broader high-grade glioma setting. Methods: A narrative review of randomized and observational clinical studies, pharmacokinetic studies, and preclinical investigations evaluating Gliadel wafer and potential next-generation local delivery systems in GBM and other high-grade gliomas was performed. Results: The literature delineates key limitations of Gliadel wafer: short diffusion distances and burst-weighted carmustine release, high tumor cell resistance to carmustine due to heterogeneity, and device-related side effects. Emerging approaches to address these limitations include (i) multidrug systems with synergistic effects against GBM cells; (ii) advanced biomaterials that enable controlled and sustained release; and (iii) targeted agents with minimal off-target effects. Testing newer generations of local drug-delivery systems in more predictive translational models, such as patient-derived organoids and spontaneous large-animal glioma models, is essential to maximize the translatability of preclinical studies to human studies. However, broader adoption of spontaneous large-animal glioma models is constrained by ethical oversight, animal-welfare considerations, cost, and limited availability compared with rodent platforms. Conclusions: Next-generation local drug-delivery systems should include multiple synergistic tumor-selective drugs that can be released in a controlled, sustained manner deep into the residual tumor. Preclinical testing of these systems should be conducted in clinically relevant animal models that are more translatable than those used in early Gliadel wafer studies. Full article

Background/Objectives: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains associated with poor prognosis despite multimodal therapy. Metabolic reprogramming, particularly increased dependence on glutamine, supports GBM bioenergetic, biosynthetic, and redox demands. This study aimed to systematically identify glutamine-associated metabolic regulators with prognostic relevance and biological plausibility in GBM. Methods: Transcriptomic data from TCGA and GTEx were analyzed using GEPIA2, with survival validation performed using the CGGA. Functional pathway enrichment, protein expression assessment, protein–protein interaction network analysis, tumor microenvironment evaluation, epigenetic profiling, and single-cell RNA sequencing validation were integrated to contextualize candidate genes. Pharmacogenomic correlation analysis and structure-based molecular docking were applied as supportive validation layers. Results: Ceruloplasmin (CP), Solute Carrier Family 25 Member 13 (SLC25A13), and Solute Carrier Family 38 Member 2 (SLC38A2) were selectively dysregulated and associated with poor clinical outcomes in GBM. CP was linked to redox regulation and stress-adaptive survival programs, SLC25A13 to mitochondrial metabolite exchange and glutamine-coupled nucleotide biosynthesis, and SLC38A2 to glutamine uptake, nutrient sensing, and mTORC1-MYC-associated growth signaling. Conclusions: CP, SLC25A13, and SLC38A2 emerge as clinically relevant glutamine-associated metabolic regulators in GBM, linking redox regulation, mitochondrial metabolite exchange, and glutamine-driven growth signaling. These findings highlight transport- and exchange-centered metabolic nodes as potential biomarkers and candidates for future metabolic targeting in GBM. Full article

Background and Objectives: Systemic inflammation and renal dysfunction play a central role in the progression and prognosis of type A aortic dissection (TAAD). This study evaluated the SCr score, a composite index combining the systemic inflammation response index (SIRI) and serum creatinine, to assess its prognostic value postoperatively. Materials and Methods: Clinical data from 299 surgically treated TAAD patients were retrospectively analyzed. SCr scores were stratified into three levels using optimal cutoffs. Survival differences were examined using Kaplan–Meier curves. Independent predictors of overall survival (OS) and in-hospital mortality (IHM) were identified through multivariable Cox and logistic regression, respectively. A prognostic nomogram integrating SCr and significant clinical variables was developed, and model performance was evaluated and compared with previously published models. Results: Higher SCr scores were associated with a progressively increased mortality risk. In multivariable Cox analysis, both SCr scores of 1 and 2 emerged as independent predictors of worse long-term survival, with SCr = 2 demonstrating a particularly strong association (hazard ratio (HR) = 4.408, 95% confidence interval (CI): 1.786–10.881; p = 0.001). In logistic regression analysis, SCr scores remained an independent predictor of IHM (SCr = 1: odds ratio (OR) = 3.066, 95% CI: 1.032–9.102; SCr = 2: OR = 4.811, 95% CI: 1.081–21.409; p < 0.05 for both). A prognostic nomogram based on the SCr score and other clinical variables achieved strong discrimination for OS (area under the curve [AUC]: 0.845) and IHM (AUC: 0.821). Conclusions: The SCr score was independently associated with preoperative risk in patients with TAAD. An SCr-incorporating nomogram demonstrated favorable discriminative performance for predicting overall survival and in-hospital mortality. These findings suggest that SCr-based assessment may provide complementary information and assist in the identification of high-risk patients within established clinical assessment frameworks. Full article

Background: Medicaid-insured patients experience higher rates of late-stage cancer diagnosis and worse survival than non-Medicaid patients. The impact of Medicaid enrollment timing on cancer outcomes is less clear. This study examines the association between Medicaid enrollment and timing with tumor stage and cancer-specific survival for breast, colorectal, and lung cancers. Methods: We analyzed SEER-Medicaid linked data for 276,755 breast, 104,784 colorectal, and 101,058 lung cancer patients < 65 years of age. Patients were categorized as non-Medicaid enrollees, pre-diagnosis enrollees (≥12 months before), or post-diagnosis enrollees (≤12 months after). Multivariable logistic regression estimated odds ratios of late-stage diagnosis, and cause-specific Cox proportional hazards models were used to assess cancer-specific survival, adjusting for demographic and socioeconomic factors. Results: Compared to non-Medicaid enrollees, post-diagnosis enrollees had the highest odds of late-stage diagnosis (breast cancer: OR: 3.41; colorectal cancer: OR: 3.78; lung cancer: OR: 1.87). Pre-diagnosis enrollees also had increased odds, but the association was weaker than post-diagnosis enrollees. Cancer-specific mortality was higher for both pre- and post-diagnosis enrollees compared to non-Medicaid enrollees for each cancer examined across tumor stage at diagnosis. Among Medicaid enrollees, those enrolled post-diagnosis had higher cancer-specific mortality than those enrolled pre-diagnosis for localized-stage colorectal (HR: 1.82) and lung cancer (HR: 1.30). In contrast, those enrolled post-diagnosis had lower mortality than those enrolled pre diagnosis for distant-stage breast cancer (HR: 0.91). Conclusions: Compared with cancer patients not insured by Medicaid, post-diagnosis Medicaid enrollment was associated with a greater likelihood of late-stage cancer and worse cancer-specific survival across each cancer type examined. Future research is warranted to examine the role of Medicaid enrollment timing in cancer care to better understand its impact on cancer outcomes. Full article

Background/Objectives: Sister Mary Joseph’s nodule (SMJN) is classified as FIGO stage IVb in ovarian cancer. While traditionally considered an indicator of poor prognosis, emerging evidence suggests variable outcomes. This study aimed to describe overall survival (OS) and recurrence-free survival (RFS) in ovarian cancer patients presenting with SMJN and to explore outcome patterns relative to other FIGO IVb presentations. Methods: We conducted a retrospective multicenter cohort study including patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma diagnosed between 2010 and 2023 at four academic centers in Switzerland, Italy, and Israel. Eligible patients had FIGO IV disease at diagnosis and complete clinical data. Patients were grouped according to metastatic pattern: SMJN or other distant sites. Survival outcomes were analyzed using Kaplan–Meier curves and Cox proportional hazards models. Results: Eighty-seven patients met inclusion criteria, including 23 (26.4%) with SMJN and 64 (73.6%) with other FIGO IV metastases. Median age and histologic subtype distribution were similar between groups. Complete cytoreduction was achieved in 65.2% of SMJN patients. Median OS was not reached in the SMJN group versus 47.2 months in controls (HR 0.44; 95% CI 0.17–1.12; p = 0.084). Median RFS was 42.6 vs. 23.2 months, respectively (HR 0.68; 95% CI 0.35–1.32; p = 0.25). Conclusions: Patients presenting with SMJN may represent a potentially resectable manifestation within the heterogeneous spectrum of FIGO stage IV ovarian cancer, with a non-significant trend toward more favorable survival outcomes compared with other stage IV presentations. Full article

This study focuses on parameter estimation and reliability analysis for the two-parameter Rayleigh distribution under random censoring. It is shown that directly fitting the standard Rayleigh distribution can lead to substantial estimation errors, especially when the dataset contains a markedly high minimum value. To overcome the limitation of the conventional single-parameter Rayleigh distribution, which lacks a threshold parameter in practical applications, a two-parameter Rayleigh distribution model is proposed. The main research contents include the following: establishing a randomly censored data model; deriving classical inference methods based on maximum likelihood estimation along with several other classical estimation techniques; and constructing a Bayesian estimation framework. We also analyze several reliability and experimental characteristics by deriving their corresponding estimates. A Monte Carlo simulation study is carried out to assess the performance of the proposed estimators. Finally, the practicality and superiority of the two-parameter model are validated using real strength datasets. The results demonstrate that the two-parameter Rayleigh distribution can more accurately describe survival data with threshold characteristics and outperforms the single-parameter model in terms of model fit and reliability estimation. Full article

Background: Metastatic squamous cell carcinoma of the anus (SCCA) carries a poor prognosis, with systemic therapy remaining the standard of care. While metastasis-directed therapy improves outcomes in select gastrointestinal malignancies, the role of liver-directed intervention in metastatic SCCA remains undefined. We evaluated clinicopathologic features and oncologic outcomes of patients with liver-limited metastatic SCCA treated with curative-intent hepatic local therapy at a tertiary academic center. Methods: We conducted a retrospective cohort study of adults with histologically confirmed SCCA and liver-only metastatic disease who underwent curative-intent hepatic resection or ablation at Mayo Clinic between 1993 and 2023. Patients with extrahepatic disease or incomplete records were excluded. Demographic, tumor, treatment, and outcomes data were abstracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method. Prognostic factors were assessed using univariate Cox proportional hazards models. Results: Twenty-five patients met inclusion criteria. Median age was 56.7 years, and 92% were female. Most patients had metachronous metastases (76%), a single hepatic lesion (56%), and unilobar disease (76%). Pre-intervention systemic therapy was administered in 52% of patients, with radiographic complete or partial responses observed in all treated patients. Liver-directed therapy consisted of surgical resection in 80% and thermal ablation in 20%. Among surgical patients, 90% achieved microscopically negative margins. With a median follow-up of 22 months, disease recurrence occurred in 80% of patients, most commonly within the liver. Median DFS was 7.27 months. Median OS from the date of liver-directed therapy was 51.3 months. On univariate analysis, poorly differentiated tumor histology was associated with inferior OS (hazard ratio 4.67, p = 0.018). No other clinicopathologic variables were significantly associated with DFS or OS. Conclusions: In this single-institution experience, carefully selected patients with liver-limited metastatic SCCA undergoing curative-intent hepatic-directed therapy achieved prolonged overall survival, substantially exceeding historical outcomes with systemic therapy alone. Despite frequent recurrence, the observed median OS exceeding four years supports consideration of liver-directed therapy within a multidisciplinary framework for patients demonstrating favorable disease biology and response to systemic treatment. Prospective studies are needed to better define patient selection and optimal integration of local and systemic therapies in the modern treatment era. Full article

Bone metastasis is a devastating complication of advanced osteotropic malignancies, notably breast, prostate, lung carcinomas, and malignant melanoma, and remains a primary driver of mortality. Historical paradigms have conceptualized skeletal dissemination almost exclusively as a hematogenous process wherein circulating tumor cells colonize receptive bone marrow niches. However, this model fails to reconcile why lymph node metastasis consistently serves as a potent predictor of bone involvement even though therapeutic lymphadenectomy rarely prevents distant spread. This discordance suggests that lymph nodes function not merely as passive reservoirs but as active ‘evolutionary gateways’ that sculpt bone-tropic metastatic clones. In this review, we introduce the Lymphatic–Bone Axis, a framework integrating lymphatic biology into models of bone metastasis. We synthesize emerging evidence elucidating how the lymph node microenvironment primes tumor cells through CCR7-CXCR4 switching, induction of osteomimicry programs, and metabolic reprogramming that favors survival within the bone marrow. We also discuss preclinical data demonstrating direct intranodal intravasation via high endothelial venules (HEVs), providing a rapid route into the systemic circulation that bypasses the thoracic duct. Beyond consolidating current knowledge, we outline a research agenda for dissecting this axis, including longitudinal single-cell transcriptomic mapping and functional assessments of lymph node-derived tumor cells. Finally, we consider translational implications, highlighting why bone-targeted agents alone may prove insufficient once cells are conditioned within lymphatic niches. By mechanistically linking lymphatic priming to skeletal colonization, this review informs the rational design of multimodal therapeutic approaches that jointly target lymphatic transit and the bone microenvironment. Full article

Background and Objectives: Reliable tools for evaluating tumor biology and forecasting clinical outcomes in recurrent hepatocellular carcinoma (HCC) remain scarce, and molecular characterization through genetic profiling is equally limited in this setting. This investigation explores whether serum tumor marker expression patterns correlate with genomic mutation profiles, and whether such correlations may facilitate more accurate prediction of tumor biology and patient prognosis in recurrent HCC. Materials and Methods: We analyzed a cohort of 20 patients who underwent curative-intent resection for both primary and recurrent HCC. Tumor specimens collected at the time of each operation were subjected to targeted next-generation sequencing for mutation profiling. Based on pre-operative serum levels of AFP (alpha-fetoprotein) and PIVKA-II (Protein Induced by Vitamin K Absence or Antagonist-II) measured before each surgery, patients were stratified into four biomarker subgroups. Those who maintained the same biomarker subgroup at both operations were designated the ‘serum concordant group’, whereas those who transitioned between subgroups were classified as the ‘serum discordant group’. Clinical characteristics and mutation data were subsequently compared between these two classifications. Results: The interval from primary surgery to disease recurrence was significantly shorter in the serum concordant group relative to the serum discordant group (mean 11.16 ± 1.86 vs. 44.8 ± 9.45 months, p < 0.001). Additionally, disease-free survival following reoperation was significantly inferior in the concordant group compared with the discordant group (p = 0.039). Regarding mutational patterns, the concordant group demonstrated shared gene mutations between primary and recurrent lesions, while the discordant group exhibited divergent mutational landscapes across both timepoints. Conclusions: The concordance or discordance of serum tumor marker profiles between primary and recurrent HCC lesions may serve as a clinically accessible surrogate for underlying tumor biology and prognostic stratification. These results are preliminary and hypothesis-generating. Further studies in larger, independent cohorts are warranted to confirm the observed associations. Full article

Clostridioides difficile infection (CDI) remains a major cause of healthcare-associated morbidity and mortality, particularly among older adults and patients with recent healthcare exposure, underscoring the need for early risk stratification and accurate prognostic assessment. This retrospective observational study evaluated clinical, laboratory, and therapeutic factors associated with disease severity and in-hospital mortality, and assessed the predictive performance of the ATLAS score and the Charlson comorbidity index. A total of 101 adult inpatients with laboratory-confirmed CDI admitted to a Portuguese tertiary care hospital were included. Data were extracted from clinical records and analysed using comparative statistics, multivariable logistic regression, and Kaplan–Meier survival analysis. Advanced age, elevated white blood cell count, renal dysfunction, and prior exposure to multiple antibiotic classes were independently associated with increased disease severity and mortality. The ATLAS score demonstrated good discriminative ability, particularly for short-term mortality, and showed higher sensitivity compared with the Charlson comorbidity index. These findings provide additional evidence on clinical and laboratory factors associated with severe CDI and in-hospital mortality, while supporting the utility of the ATLAS score as a practical tool for early risk stratification in hospitalised patients. Full article

Background/Objectives: The primary objective of this study was to assess the symptom profile and changes observed at discharge of lung cancer (LC) patients following comprehensive palliative care. The secondary objective was to evaluate potential differences between LCr patients and those with other cancer (OC) diagnoses. Methods: A consecutive sample of LC patients admitted to the acute palliative care unit (APCU) was prospectively assessed and compared with a random sample of patients with OC. All patients underwent comprehensive palliative care treatment. Demographic data, Karnofsky, referral sources, recent oncological treatments, and patient status at admission and discharge (on-treatment, off-treatment, or uncertain) were collected. At admission (T0) and at the time of discharge (TX), symptom burden was assessed using the Edmonton Symptom Assessment Scale (ESAS). Lastly, there was subsequent referral to next care settings (discharge home, home palliative care, hospice, other units). Results: A total of 159 patients with LC were compared with a similar sample of OC. In all patients a significant decrease in the number of “on therapy” patients were reported at discharge, and concomitantly the number of “off-therapy” patients increased (p < 0.0005) in comparison with the data recorded at admission. Dyspnea intensity was higher in group LC at T0 and TX (p < 0.0005), as well as pain intensity, which was significant at TX (p < 0.0005). A statistical difference in MDAS was also observed at TX (p = 0.034). LC patients had a lower overall survival (p = 0.034). Conclusions: Comprehensive palliative care in APCU provided relevant changes in symptom burden, with the potential to prevent inappropriate admissions to other hospital units and to reduce costs associated with non-specialist interventions. Full article

This critical integrative review reassesses the lipid paradigm by systematically mapping 380 influential trials and cohort studies on cholesterol, saturated fats, and statins in relation to cardiovascular and cognitive outcomes. The evidence base reveals a nearly even split between studies supporting and challenging LDL-centric causality, alongside pervasive methodological flaws, including reliance on surrogate lipid markers, ecological inferences, residual confounding, and industry-related reporting biases. Trial-generation comparisons and structured risk-of-bias assessment (ROB 2, ROBINS-I) repeatedly show that substantial pharmacological LDL reductions do not consistently yield proportional reductions in myocardial infarction, stroke, or all-cause mortality. Integrating Mendelian randomization with clinical and metabolomic data, the review advances a Critical Window Hypothesis in which LDL is necessary but not sufficient for atherogenesis, exerting dominant causal influence during early and midlife plaque initiation, while inflammatory, oxidative, and hemodynamic factors become primary drivers in advanced disease. Metabolomic studies of extreme longevity and late-life cohorts demonstrate that bile acids, steroid metabolites, and low-glycemic metabolic profiles—not total cholesterol—better predict survival and cognitive preservation, and that higher LDL in the oldest-old often associates with lower mortality and dementia risk. These findings challenge universal LDL-centric policies and support lifestyle medicine strategies prioritizing systemic metabolic optimization over isolated cholesterol targets. Full article

Introduction & Objective: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with limited treatment options for steroid-resistant cases. Ruxolitinib, a JAK1/2 inhibitor, has shown promise in treating steroid-resistant acute (aGVHD), chronic (cGVHD), and overlap GVHD (oGVHD), but real-world data remain limited. This study evaluated the real-world efficacy and safety of ruxolitinib in allo-HSCT patients with steroid-resistant GVHD. Materials & Methods: This retrospective, multicenter study included adult patients treated with ruxolitinib for Grade II or higher aGVHD or moderate-to-severe cGVHD at nine centers in Turkey (2017–2024). Clinical characteristics, treatment responses, and adverse events were recorded. Primary outcomes were overall response rate (ORR) and overall survival (OS). Results: Among 80 patients (mean age: 39.3 ± 13.3 years; 60 males), 39 had aGVHD, 68 cGVHD, and 15 oGVHD. The ORR was 72 of 80 patients (90.0%) (complete response: 37 of 80 [46.3%], partial response: 35 of 80 [43.8%]). The 1-year and 2-year OS rates were 91.3% and 82.5%. Severe cGVHD (p < 0.001) and lack of response to ruxolitinib (p = 0.018) were associated with reduced OS. Adverse events included infections in 40 of 80 patients (50.0%), cytopenias in 23 of 80 (28.7%), and cytomegalovirus reactivation in 20 of 80 (25.0%). Conclusion: In this retrospective multicenter cohort, ruxolitinib was associated with high response rates in steroid-refractory GVHD, while disease severity remained a key determinant of survival, and findings should be interpreted as exploratory. Full article

In the digital era, even the most remote communities are increasingly connected to global networks. However, a critical question persists: how can such connectivity translate into tangible economic growth and sustainable development for isolated mountainous villages? Guided by the sustainable livelihood framework, this study investigates how digital capital—specifically the use of social media to showcase a village’s natural and cultural assets—drives tourism development and improves local livelihoods. Focusing on Dazhai Village in China, a rural community that gained substantial online attention and tourism inflow through social media promotion, this research employs qualitative methods, including 17 semi-structured interviews. Data were analysed using thematic analysis and matrix coding techniques via NVivo 12 Plus. Findings reveal that the introduction of digital capital enhances village visibility, stimulates tourist interest, and initiates a development trajectory describe as “going live.” In contrast, “going alive” refers to the process of revitalizing a once abandoned, impoverished mountain village, enabling it to survive and thrive once more. However, the sustainability of this trajectory is fragile as the departure of influential digital promoters can deplete digital capital, undermining diminishing online engagement and risking renewed marginalization. To transform “going live” into “going alive,” remote communities must continuously adapt and reinforce their online presence to secure long-term stakeholders’ engagement and resilient tourism flows. An interesting finding of this study is that the village achieved regenerative tourism, whereby its environmental conditions improved as a result of tourism development. This unexpected outcome was facilitated by sustained visibility, both online and offline, which prompted residents to place greater emphasis on environmental protection. This study enriches the sustainable livelihoods framework by integrating digital capital and regenerative tourism into the understanding of livelihood assets and outcomes in remote settings. Ultimately, it underscores the transformative potential of digital capital in revitalizing “hollowed-out” villages, offering a strategic pathway for remote communities to reclaim their developmental agency and achieve sustainable rural revitalization. Full article

Background: Continuity of care for rheumatoid arthritis patients within regional networks enables stable long-term clinical data collection, despite chronic rheumatologist shortages in Japan. We determined 5-year drug survival and discontinuation reasons for eight biological disease-modifying antirheumatic drugs (bDMARDs) using a regional multicenter registry. Methods: We retrospectively analyzed 1182 patients initiating their first (naïve, n = 784) or subsequent (switch, n = 398) bDMARD between May 2001 and August 2022 across five institutions. The primary endpoint (5-year drug survival) and secondary endpoints (discontinuation risk factors and cumulative incidence of reasons) were evaluated using Kaplan–Meier curves, Cox proportional hazards, and Fine & Gray models. Results: Baseline characteristics varied significantly among bDMARDs. Five-year drug survival in the naïve cohort ranged from tocilizumab (50.8%) to golimumab (22.6%); in the switch cohort, from abatacept (42.6%) to infliximab (10.0%). In multivariable Cox analysis of naïve patients, male sex (hazard ratio [HR] = 1.49, 95% confidence interval [CI] = 1.09–2.02), lower baseline 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) (HR = 0.90, 95% CI = 0.82–0.99), and absence of methotrexate co-therapy (HR = 0.73, 95% CI = 0.55–0.97) predicted discontinuation. The lower baseline DAS28-ESR association potentially reflects successful courses toward intentional cessation following remission. Discontinuations were attributed to inadequate response (27.1%), non-adverse events (25.3%), and adverse events (17.3%). Conclusions: Tocilizumab and abatacept demonstrated the highest retention rates in biologic-naïve and switch cohorts, respectively. Early, individualized drug selection and dose optimization are crucial to maximizing long-term bDMARD effectiveness before switching. Full article