Search Results (14,383)

Background: SCLC remains an aggressive malignancy with limited therapeutic progress over the past few decades. It remains unclear how the sequence of immunotherapy initiation influences overall survival (OS) in SCLC; we performed a population-based analysis using NCDB to evaluate its association with survival. Methods: SCLC patients in NCDB from 2016 to 2021 were identified to evaluate the impact of immunotherapy on OS. Among ES-SCLC patients, we conducted subsequent analyses to clarify the relationship between the sequence of immunotherapy initiation and OS in the context of chemotherapy and CRT. Results: Among 69,820 eligible patients, 9242 received CRT plus immunotherapy (CRT + IO), and 11,755 received chemotherapy plus immunotherapy (Chemo + IO). In the overall population, adding immunotherapy to chemotherapy or CRT was associated with modestly improved survival. In ES-SCLC, immunotherapy was associated with longer survival in both the Chemo and CRT cohort, while the addition of immunotherapy did not confer benefits in limited-stage SCLC (LS-SCLC). Within the ES-SCLC Chemo + IO cohort, altering the initiated immunotherapy interval (0–90 days) did not show any meaningful difference in survival. By contrast, in the CRT + IO cohort, survival showed benefit in a time-dependent pattern: patients who initiated immunotherapy within 4–7 days after CRT had a trend of survival, which was consistent with the proposed immune activation window. Conclusions: This real-world analysis suggests that immunotherapy was associated with longer survival in ES-SCLC, CRT + IO is associated with improved OS, with a more obvious survival benefit when immunotherapy is initiated within 4–7 days after CRT. These findings hint at the potential importance of immunotherapy initiation sequence and warrant further prospective validation. Full article

Osteosarcoma remains a highly aggressive malignancy with limited therapeutic progress and poor outcomes, particularly in metastatic or recurrent cases. Conventional treatment approaches, primarily based on surgery and high-dose chemotherapy, are hindered by significant drawbacks, including severe toxicity, high relapse rates, and drug resistance, underscoring the inadequacy of current standard approaches. This review examines emerging advances in precision medicine and drug discovery, including targeted inhibitors, immunomodulatory agents, combination treatments, and advanced biomaterials, that promise to transform osteosarcoma care. Recent advances, such as combinations of immune checkpoint inhibitors with novel agents or nanoparticle-based drug delivery systems, as well as CRISPR-Cas9 gene-editing applications, offer new strategies to overcome the inherent challenges of conventional therapies. In addition, cutting-edge research leveraging multi-omics analyses and digital pathology is refining our understanding of the tumour microenvironment, paving the way for more individualised treatment strategies. Full article

Background and aims: Liver transplantation is effective against hepatocellular carcinoma (HCC), but recurrence remains a challenge. Traditional criteria based on tumor size, nodule number, and AFP levels have had limited success in predicting aggressiveness. [18F]FDG PET/CT has shown promise in identifying high-risk tumor features, including microvascular invasion (MVI), which is a key predictor of recurrence. Methods: In this retrospective, single-center study, all consecutive patients who underwent LT for HCC between 2010 and 2019 were included. Prior to listing, the patients underwent [18F]FDG PET/CT, and explant pathology was analyzed for MVI and other histological features. The primary objective was to identify the predictors of early HCC recurrence (within 24 months after LT). Secondary objectives included identifying predictors of high-risk histological features of the explant, describing recurrence patterns, and assessing post-recurrence survival. Results: The study included 143 patients (median age 59 years [IQR 54–64], 85% males, median MELD 10 [IQR 8–14], median AFP value 8.5 [IQR 4–39] ng/mL) and 40 (28%) with intra-hepatic [18F]FDG PET/CT positivity. HCC recurred post-LT in 25 patients (17%) (median post-LT follow-up 49 months [IQR 28.5–77]) and within 24 months in 12 patients (48%). MVI at the explant stage was independently associated with early recurrence (HR: 7.20, 95% CI 1.82–28.45, p = 0.005), while intra-hepatic [18F]FDG PET/CT positivity before LT independently predicted MVI in explants (OR 3.90, 95% CI 1.30–11.71, p = 0.01). Conclusions: [18F]FDG PET/CT may offer a valuable tool for pre-transplant risk assessment by identifying MVI, which is an independent predictor of early cancer recurrence. Its incorporation into the selection criteria for LT may enhance patient stratification and post-transplant outcomes. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with limited response to conventional chemotherapies such as paclitaxel (PTX) due to poor solubility, low bioavailability, and systemic toxicity. To address these limitations, this study explores mesenchymal stem cell (MSC)-derived exosomes as biocompatible, tumor-homing nanocarriers for PTX delivery. Exosomes were isolated from MSC-conditioned media using ultracentrifugation and tangential flow filtration (TFF), with TFF yielding 8 to 9-fold higher exosome recovery. Flow cytometry confirmed the presence of exosomal (CD63, CD81) and MSC (CD90) surface markers, while transmission electron microscopy and dynamic light scattering revealed spherical vesicles averaging ~160 nm in diameter with a zeta potential of approximately −28 mV. PTX was loaded into exosomes using ultrasonication, achieving an encapsulation efficiency of 31.3 ± 2.0%, and release studies showed an initial burst within 24 h followed by sustained release over 7 days. Blank exosomes exhibited no cytotoxicity toward PANC-1, BxPC-3, and HPNE cells, confirming their excellent biocompatibility. In contrast, PTX-loaded exosomes significantly enhanced cytotoxicity compared to free PTX, reducing IC₅₀ values from 12.48 nM to 7.55 nM in BxPC-3 cells and from 22.44 nM to 19.29 nM in PANC-1 cells and suppressed colony formation and spheroid growth more effectively. These findings demonstrate that MSC-derived exosomes can efficiently encapsulate and deliver PTX, enhancing its antitumor efficacy. This exosome-based platform offers a promising strategy to overcome pharmacological barriers and improve therapeutic outcomes in PDAC. Full article

Introduction: Patients with major burn injuries are highly susceptible to hypothermia due to extensive skin loss, aggressive fluid resuscitation, repeated surgical procedures, and exposure during wound care. Hypothermia is associated with coagulation disorders, increased blood loss, impaired immune response, prolonged hospitalization, and increased mortality. When conventional warming strategies fail, intravascular temperature management systems may be employed, although they carry risks inherent to central venous catheters. Case Report: We report the case of a 26-year-old male with 66% total body surface area flame burns and inhalational injury, admitted to the Burns Intensive Care Unit with persistent hypothermia despite standard warming measures. An intravascular temperature management catheter was inserted via the femoral vein and successfully restored normothermia. Due to clinical instability, the catheter remained in situ beyond the recommended duration. During attempted catheter removal, significant resistance was encountered, raising concern for mechanical malfunction. Imaging confirmed catheter entrapment without fracture. Multidisciplinary management involving vascular surgery and interventional radiology enabled successful removal using endovascular snare techniques. A detached balloon fragment was identified and secured with venous stenting. Conclusions: This report describes the first documented case of complicated removal of an intravascular warming catheter due to balloon detachment in burn patients. Physicians using these devices should be aware of this possible complication and be prepared for its management. Full article

Background and Clinical Significance: Fatal attacks by domestic dogs, particularly against familiar owners, are rare but represent a significant forensic and public health concern. Understanding the dynamics and forensic features distinguishing predatory aggression from postmortem scavenging is essential, especially when cases involve large breeds and vulnerable individuals, such as the elderly. Case Presentation: An 82-year-old man was found dead in his home, presenting extensive mutilation of the head and neck. He lived with his daughter and her four-year-old male German Shepherd. The dog exhibited blood and tissue residues on its mouth, forelimbs, and abdomen. Autopsy findings indicated death due to hemorrhagic shock from deep cervical and facial vessel lacerations. There were no defense wounds or classic bite marks; however, massive excision of musculocutaneous tissue from the neck to the scalp suggested active predation rather than postmortem scavenging. The facial and cervical soft tissues were completely avulsed, exposing deep anatomical structures and causing the loss of the right eye and dental elements. No signs of third-party involvement, intrusion, or external aggression were identified, and the dog appeared healthy and unrestrained. Conclusions: The findings support the theory of a fatal attack by the household German Shepherd occurring shortly after the victim’s meal. This case underscores the potential for lethal aggression in domestic dogs toward familiar humans, even in the absence of provocation or prior behavioral concerns. It highlights the importance of awareness and preventive measures when managing large, powerful dog breeds in environments with elderly or otherwise vulnerable individuals. Full article

Objectives: Glioblastoma multiforme (GBM) is considered the most aggressive primary brain tumor, which often exhibits tumor heterogeneity. Hypoxia is a key aspect of intratumoral heterogeneity that contributes to poor prognosis in GBM. In this study, we aimed to develop machine learning (ML) models using radiomics and clinical features for the prediction of one-year survival for GBM. Methods: Data from 35 patients in the ACRIN 6684 trial, including fluoromisonidazole (FMISO)-positron emission tomography (PET), magnetic resonance (MR) (T1, T2, and fluid-attenuated inversion recovery (FLAIR)) images, and clinical information, were retrieved from The Cancer Imaging Archive (TCIA). Three ML algorithms, namely, support vector machine (SVM), random forest (RF), and linear regression (LR), were utilized to analyze selected features. Receiver-operating characteristic (ROC) curves were utilized to evaluate the predictive performance of the models. Several statistical analyses, namely, the permutation test, the permutation importance of selected features, Fisher's exact test, and the unpaired t-test, were performed to analyze the models and features. Results: FMISO achieved the best performance in radiomics models, with an area under the curve (AUC) of 0.870. The clinical data model achieved the best performance of all models, with an AUC of 0.921, outperforming the combined all sequential forward selection (SFS) model (AUC: 0.862). Female sex (p = 0.030) and younger age (p = 0.0043) were significantly associated with better prognosis. Conclusions: Our proposed models have the potential to predict the one-year survival of GBM and facilitate personalized therapy. Future studies with a larger sample size are needed to confirm the generalizability of the models. Full article

Cellular senescence has been traditionally viewed as a tumor-suppressive program that halts its proliferation in response to oncogenic stress or DNA damage. However, recent studies have highlighted a paradoxical role for senescence in glioblastoma (GBM), IDH-wildtype, the most aggressive primary brain tumor in adults. Accumulating evidence indicates that senescence represents a “frequent and durable” cell fate in GBM, particularly following standard therapies such as temozolomide and radiotherapy. Senescent cells frequently persist after temozolomide or radiotherapy and acquire a senescence-associated secretory phenotype (SASP) composed of inflammatory cytokines, growth factors and matrix-remodeling enzymes. These factors not only promote tumor cell survival with stemness-induction but also reshape the pro-tumorigenic microenvironment with metabolic rewiring and immune evasion. Notably, senescence also arises in non-malignant cells—including astrocytes, endothelial cells, microglia, and infiltrating immune cells—creating a multicellular senescent niche that fuels recurrence. Here, we describe a recent advance in our understanding of senescence and SASP in the pathobiology of GBM. We further focus on a state-of-the-art, challenging exploration of the idea that single-cell and spatial profiling, capable of identifying senescence- and SASP-associated morphologic and heterogeneous states, will further refine patient selection and therapeutic timing. By reframing senescence as a modifiable determinant of GBM evolution, this review underscores its emerging significance as both a cancer hallmark and a therapeutic vulnerability. Full article

Indonesia’s long-term climate strategy targets net-zero emissions by 2060. In this context, this paper develops a simulation for the Java–Madura–Bali (Jamali) grid to quantify the joint impact of electric vehicle (EV) uptake and rooftop photovoltaic (PV) integration on system performance from 2025 to 2060. Historical statistics and national planning projections were used to calibrate annual capacity, peak load, and energy trajectories, which were downscaled to hourly resolutions. EV charging demand, generated using state-of-charge-dependent Alternating Current (AC) and Direct Current (DC) load profiles, and PV output were modeled across a 36-year span under a 5 × 5 policy matrix, producing a 900-scenario-year. These scenarios range from Business-as-usual (BAU) to aggressive interventions (including subsidies, regulation, and smart management). The scenarios were evaluated using a min–max composite index weighting supply–demand balance, production–consumption balance, and policy cost. Based on this simulation inputs, results indicate that the scenario combining regulated EV growth with BAU PV adoption achieves the highest average composite score. While charge-time management strategies provided the best adequacy, highly interventionist EV–PV packages were the most expensive without delivering proportional benefits. The study concludes that, with this current parameter input, moderate and regulation-driven strategies outperform aggressive interventions when adequacy, balance, and cost are jointly considered. Full article

Youth with neurodevelopmental disorders (NDDs) face an increased risk of trauma compared to their peers without NDDs, often leading to challenging behaviors such as self-injury, aggression, and property destruction. However, limited research exists on the behavioral profiles and treatment outcomes of youth with both NDDs and trauma. This study examines a sample of 21 youth with NDDs and trauma admitted to a specialized psychiatric unit in the Rocky Mountain region of the United States. A retrospective review of health records and admission data identified the most common target behaviors: negative vocalizations (95%), property destruction (62%), elopement (52%), and aggression (43%). Functional analyses indicated that escape was the most prevalent behavior function identified (43%), while 29% of the analyses yielded undifferentiated outcomes. Behavior analytic treatment packages incorporating differential reinforcement resulted in an average of 72% reduction from the baseline target behaviors. The average Pediatric ACEs score was 5 out of 10. The findings highlight the key behavioral patterns in this population and underscore the need for further research on effective interventions. Full article

Background: Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare pediatric central nervous system tumors, first recognized in the 2016 WHO classification. Their clinical course is highly heterogeneous, and no international consensus treatment guidelines are currently available. This study aims to describe clinical characteristics, disease evolution, and management strategies for pediatric DLGNT patients, with a focus on aggressive forms. Methods: This retrospective, multicenter, international study (Belgium and France) included pediatric patients diagnosed with DLGNT between 1 February 2016 and 31 December 2024. Clinical, radiological, histopathological, molecular, and therapeutic data were collected. Findings were analyzed and contextualized through an extensive literature review. Results: Eleven patients were enrolled (median age: 8.2 years; median follow-up: 52 months). The median delay between the first MRI and definitive diagnosis was 6.5 months. Symptoms of intracranially elevated pressure were present in 55% of patients. Two-thirds of the patients presented with leptomeningeal dissemination at diagnosis. The primary tumor site could not be identified in two patients. A KIAA1549::BRAF transcript fusion was detected in 82% of cases, and chromosome 1q gain in 38%. All patients underwent surgery at diagnosis. The median number of therapeutic lines was four: 82% received chemotherapy (weekly vinblastine in 55%, vincristine/carboplatin regimen in 45%), 64% received MAPK pathway-targeted therapy, and 18% underwent radiotherapy. Five-year overall survival (OS) was 68.5%, and median progression-free survival (PFS) was 5.3 months after first-line therapy and 16.5 months after the second line. At the end of follow-up, only one patient achieved complete remission, and 78% of survivors presented with persistent neurological deficits. Conclusions: This study underscores the significant diagnostic delay, clinical heterogeneity, and absence of standardized therapeutic approaches in pediatric DLGNT patients. Conventional low-grade glioma chemotherapy constitutes the current treatment backbone, while MAPK pathway-targeted therapies show promising potential. Further studies and the establishment of an international registry are crucial to better characterize aggressive subtypes and optimize management strategies. Full article

Several immediate and distal social environmental factors work directly and indirectly with one another to contribute to multiple forms of peer victimization. Bullying is the most prevalent form of peer victimization during adolescence; however, peer victimization typically takes the form of indirect aggression during young adulthood. Therefore, we examined how perceptions of school and neighborhood income inequality worked through perceptions of school climate, neighborhood violence, and neighborhood distrust to predict retrospective adolescent bullying victimization and current young adulthood indirect peer victimization. In a cross-sectional sample of 460 young adults (M_age = 20.2, SD_age = 2.18; 59.6% women; 40.4% men; 51.6% White), path analyses revealed that higher school income inequality indirectly predicted higher levels of bullying and indirect peer victimization through lower school climate. Higher neighborhood income inequality also indirectly predicted higher levels indirect peer victimization through higher neighborhood violence. Our findings highlight the importance of targeting adverse environmental risk factors to prevent and intervene in multiple forms of peer victimization across development. Full article

Background/Objectives: Synovial sarcoma (SS) is a rare and aggressive soft-tissue malignancy characterized by complex molecular alterations and poor prognosis, highlighting the need for targeted immunotherapeutic strategies. This study aimed to design a rational multi-epitope vaccine targeting the FKBP10 oncoprotein to elicit effective immune responses against SS. Methods: Transcriptomic data from the GEO dataset GSE144190, comprising 10 tumor and 9 normal tissue samples, were analyzed to identify differentially expressed genes (DEGs). Results: Our findings revealed significantly upregulated FKBP10 with a log2 fold change of 3.55, baseMean expression of 1521.84, and adjusted p-value of 8.37 × 10⁻²⁶. Mutational analysis across 7782 sarcoma samples indicated a low alteration frequency of ~1.5%, primarily missense variants. Functional mapping showed FKBP10 as a hub interacting with multiple collagen chains and chaperone proteins, implicating its role in extracellular matrix organization and protein folding. Linear B-cell epitope prediction identified 17 epitopes (6–21 amino acids), while T-cell mapping yielded 10 MHC class I and 9 MHC class II high-affinity epitopes, all antigenic (VaxiJen > 0.5) and non-allergenic. A multi-epitope vaccine was constructed incorporating a 50S ribosomal protein L22 adjuvant, linkers, and a 6× histidine tag. Physicochemical analysis showed a molecular weight of 36.43 kDa, pI 6.97, instability index 31.79, aliphatic index 64.88, and GRAVY −0.509, indicating stability and hydrophilicity. Structural modeling validated 82.5% residues in favored regions. Molecular docking revealed strong binding with TLR4 (−9.7 kcal/mol) and TLR9 (−9.4 kcal/mol), and 200 ns molecular dynamics simulations confirmed stable RMSD trajectories, low RMSF at binding residues (<4 Å), persistent hydrogen bonding, compact radius of gyration (38–42 Å for TLR4; ~20 Å for TLR9), favorable total energy (−1400 to −1500 kcal/mol for TLR4; −650 to −720 kcal/mol for TLR9), and stable SASA (~52,000–54,000 Ų). Conclusions: These findings demonstrate that the FKBP10 multi-epitope vaccine is structurally stable, immunogenic, and capable of engaging key innate immune receptors, supporting its potential as a promising immunotherapeutic candidate for synovial sarcoma. Full article

Background and Objectives: Gastric cancer is an aggressive malignancy characterized by high recurrence rates, even following curative resection. The Albumin–Bilirubin (ALBI) score was originally established to assess hepatic functional reserve in patients with hepatocellular carcinoma (HCC). By reflecting both systemic inflammation and nutritional status, the ALBI score has demonstrated significant prognostic utility across a spectrum of solid malignancies. The present study aimed to evaluate the prognostic significance of the ALBI score in gastric cancer patients receiving adjuvant therapy after curative-intent resection. Materials and Methods: This retrospective study included 168 patients with gastric cancer who underwent curative-intent resection followed by adjuvant therapy between November 2008 and January 2021. ALBI scores were calculated from pre-treatment serum albumin and bilirubin levels. Patients were dichotomized into ALBI Grade 1 and ALBI Grade 2 based on an optimal ROC-derived cut-off value of −2.60. Survival outcomes, including overall survival (OS) and recurrence-free survival (RFS), were estimated using the Kaplan–Meier method and compared via the log-rank test. Independent prognostic factors were identified using univariate and multivariate Cox proportional hazards regression models. Results: Of the 168 patients, 56.5% were classified as ALBI Grade 1 and 43.5% as ALBI Grade 2. ALBI Grade 2 was associated with significantly shorter median RFS (18.7 vs. 72.2 months; p = 0.001) and OS (40.7 vs. 104.3 months; p = 0.003). Multivariable analysis identified ALBI Grade 2 as an independent predictor for both poor OS (HR: 1.699, p = 0.010) and RFS (HR: 1.767, p = 0.004). Pathological stage III disease was also a significant independent prognostic factor for OS (HR: 3.024) and RFS (HR: 3.049) (all p = 0.010). Additionally, elevated CEA correlated with shorter RFS (p = 0.023). Conclusions: The ALBI score is a prognostic marker for both overall and recurrence-free survival in gastric cancer patients receiving adjuvant therapy. A lower ALBI score is associated with longer survival outcomes. The ALBI score may support postoperative risk stratification and individualized follow-up planning. Full article

Glioblastoma (GB) is one of the most aggressive malignant brain tumors. Due to the high invasiveness of this cancer, surgical removal is often not possible, and relapses after surgery are very common, making current treatments ineffective. Developing new therapies or treatment combinations remains a major challenge in managing GB. Metformin (MET), an anti-diabetic medication, has recently gained attention for its potential anticancer effects. To better understand how MET inhibits GB growth at the molecular level, we studied its impact on survivin, a member of the inhibitor of apoptosis (IAP) family that is essential for GB cell survival, resistance to radio- and chemotherapy, and tumor recurrence. Using T98G and U87-MG cell lines, we performed cell viability, migration, and invasion assays, along with Western blot analysis, ChIP assays, and gene silencing experiments to examine key signaling pathways. We found that MET effectively inhibits the growth, viability, and invasiveness of GB cell lines through a molecular mechanism involving activation of the AMPK/FoxO3a/survivin pathway. In vivo studies support these findings, showing increased FoxO3a and decreased survivin in brain tissue sections from metformin-treated mice compared with untreated controls. These results suggest new possibilities for repurposing MET as an adjuvant treatment for GB. Full article