Search Results (5,407)

Background: Breast cancer remains one of the most prevalent and lethal malignancies worldwide. Although doxorubicin (DOX) is widely used as a first-line chemotherapeutic agent, its clinical utility is constrained by dose-limiting cardiotoxicity and systemic adverse effects. Nanoparticulate drug delivery systems have therefore attracted attention for improving DOX stability, biocompatibility, and tumor selectivity. In this study, we explored sterosomes—simple non-phospholipid nanocarriers composed of cholesterol and palmitic acid—as an alternative DOX delivery platform with pH-responsive properties. Methods: DOX-loaded sterosomes (DOX-STs) were prepared using cholesterol and palmitic acid to impart acid-sensitive behavior. The nanocarriers were systematically evaluated through particle characterization, physicochemical stability assessment, in vitro pH-dependent drug release, and cellular uptake studies. Furthermore, therapeutic efficacy and systemic safety were investigated in an MDA-MB-231 breast cancer xenograft mouse model. Results: DOX-STs exhibited particle sizes below 100 nm, high encapsulation efficiency, and excellent colloidal stability for 28 days. The sterosomes demonstrated accelerated DOX release under acidic conditions relative to physiological pH, consistent with their pH-responsive design. Enhanced cellular uptake was observed in both MCF-7 and MDA-MB-231 cells. In vivo, DOX-ST treatment resulted in significant tumor growth suppression and prolonged survival without notable body weight loss, indicating reduced systemic toxicity compared to free DOX. Conclusions: This study presents a simple sterosome-based nanocarrier system that achieves pH-responsive DOX release and enhanced antitumor efficacy while minimizing toxicity. These findings highlight the potential of sterosomes as a translatable nanomedicine platform for breast cancer therapy. Full article

Background: Obstructive sleep apnea (OSA) is a highly prevalent disorder associated with increased morbidity and mortality. Continuous positive airway pressure (CPAP) remains the first-line therapy, but its long-term effectiveness is limited by suboptimal adherence, with only 50–60% of patients achieving the recommended use. Evidence on adherence with alternative modalities, such as bilevel positive airway pressure (BiPAP) or oxygen therapy, is even more limited. Furthermore, few studies have directly compared these treatments with each other, particularly in relation to survival outcomes. Objective: Evaluate 5-year survival in patients with OSA treated with CPAP, BIPAP, or oxygen therapy. Methods: A retrospective cohort study with survival analysis was conducted in subjects with OSA followed at a tertiary-level institution in Colombia between January 2005 and December 2021. Results: Among 3039 patients with OSA (mean age 59.6 years; 59.8% male), the five-year mortality rate was 5.8%. Deceased patients presented a higher prevalence of comorbidities, including hypertension, diabetes, and cardiovascular disease (all p < 0.001). Adherence to CPAP was significantly lower in deceased patients. Survival analysis showed the highest five-year survival among adherent CPAP/Auto-CPAP users (95.6%), followed by non-adherent CPAP (95%) and adherent BiPAP users (94.1%). Lower survival was observed in non-adherent BiPAP users (91.7%) and oxygen therapy patients (80.6%). In multivariable analysis, treatment type, older age, congestive heart failure, chronic lung disease, and metastatic cancer were independently associated with increased mortality risk. Conclusions: Five-year survival in patients with obstructive sleep apnea was significantly associated with the treatment modality and adherence level. Full article

Background: Surgical resection (SR) and liver transplantation (LT) are the main curative options for non-hepatocellular carcinoma (non-HCC) liver malignancies, including colorectal liver metastases (CRLMs), intrahepatic cholangiocarcinoma (iCCA), hilar cholangiocarcinoma (hCCA), and neuroendocrine tumor liver metastases (NETLMs). Resection aims for negative margins and adequate hepatic reserve, while LT offers treatment for unresectable disease but is limited by donor scarcity, immunosuppression, and ethical constraints. Methods: A targeted literature search (2005–2025) was conducted using PubMed and Google Scholar with predefined MeSH terms combining “liver resection,” “hepatectomy,” and “liver transplantation” across non-HCC malignancies. Relevant studies, reviews, and guidelines were included. Results: For CRLMs, SR remains standard with 5-year overall survival (OS) up to 58%, while LT offers 60–83% in highly selected unresectable cases. In iCCA, resection achieves median survival around 40 months, and LT yields OS up to 69% in very early or neoadjuvant-controlled disease. For hCCA, the Mayo protocol combining neoadjuvant therapy with LT provides 5-year OS of 65–80%. In NETLMs, LT achieves 63–97% OS under strict criteria. Conclusions: SR remains first-line for resectable non-HCC malignancies, while LT provides superior outcomes in unresectable yet biologically favorable disease, emphasizing careful selection and organ allocation. Full article

Background/Objectives: Immune checkpoint inhibitor (ICI)-based combinations are the standard first-line therapy for unresectable hepatocellular carcinoma (HCC). A major challenge is the early identification of patients with primary progression (1st-PD) and those who experience early progression despite initial disease control (2nd-PD). This study evaluated whether very early treatment changes in alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) could serve as predictors of treatment response during atezolizumab plus bevacizumab (Atz + Bev) therapy. Methods: A total of 147 patients treated with Atz + Bev were retrospectively analyzed. Serum tumor markers were measured approximately every 3 weeks, and radiologic responses were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 at week 6 (first evaluation) and again at a median of 14.8 weeks (second evaluation). Results: At the first evaluation, 32 patients achieved a partial response, 81 showed stable disease, and 25 had progression. In the week 3 landmark analysis, early increases in AFP (ratio ≥ 1.4) or DCP (ratio ≥ 1.0) identified patients who would experience primary radiologic progression, with a clear separation in landmark progression-free survival (PFS) (3.4 vs. 13.1 months; p < 0.001). Among the 109 patients with disease control at week 6, 92 maintained control and 17 progressed at the second evaluation. In the week 9 landmark cohort, modest rises in AFP (ratio ≥ 1.1) or DCP (ratio ≥ 1.5) identified individuals at risk for early secondary progression, again showing marked differences in landmark PFS (3.8 vs. 14.0 months; p < 0.001). Conclusions: The dynamic monitoring of AFP and DCP provides a simple framework for biomarker-based responder selection and adaptive treatment optimization during Atz + Bev therapy. Clinically actionable thresholds at weeks 3 and 9 may support timely treatment switching and the integration of locoregional strategies, enabling personalized, biomarker-guided management to improve outcomes in unresectable HCC. Full article

Hepatocellular carcinoma (HCC) remains a prevalent form of cancer with a poor prognosis and requires systemic therapies for most advanced cases. In this review, we summarize considerations for selecting treatment options for HCC, particularly with regard to immune checkpoint inhibitors (ICIs). Traditional chemotherapy has been surpassed by molecular-targeted therapies and ICIs, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors, which enhance the immune response against tumors. The European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) guidelines recommend atezolizumab/bevacizumab (Atez/Bev) and tremelimumab/durvalumab (Dur/Tre) as first-line treatments for unresectable HCC, along with alternatives, such as sorafenib and lenvatinib. Atezolizumab and bevacizumab have demonstrated superior efficacy but require the monitoring of bleeding risk and adverse events, such as proteinuria. Tremelimumab and durvalumab offer alternatives for patients at high risk of anti-Vascular Endothelial Growth Factor (anti-VEGF)-related complications. In cases where ICIs are contraindicated, lenvatinib and sorafenib serve as additional options, with lenvatinib demonstrating longer progression free survival (PFS) in clinical trials. It is important to consider that each treatment has specific side effects or contraindications, and the choice of medication should be based not only on the therapeutic efficacy of the drug, but also on the patient’s health status, liver function, and tumor characteristics. Full article

Background and Objectives: Helicobacter pylori (H. pylori) infection remains one of the most common chronic bacterial infections worldwide and is associated with a wide range of gastrointestinal disorders, including gastritis, peptic ulcer disease, and gastric cancer. Increasing rates of antibiotic resistance, particularly to clarithromycin and fluoroquinolones, represent a major therapeutic challenge. The objective of this study was to determine the prevalence of resistance-associated mutations in H. pylori-positive gastric biopsy samples from western Romania. Materials and Methods: We conducted a prospective study from January to December 2024, enrolling 138 patients undergoing gastroscopy. Biopsies were collected from the gastric antrum, and H. pylori infection was confirmed using the rapid urease test (RUT). Positive samples were further analyzed with the GenoType HelicoDR assay to detect mutations in the 23S rRNA gene (clarithromycin resistance) and gyrA gene (fluoroquinolone resistance). Clinical, demographic, and endoscopic data were also collected. Results:H. pylori infection was confirmed in 41.3% of the patients (57), of whom 63.2% (36) were treatment-naïve and 36.8% (21) had prior eradication therapy. Among treatment-naïve patients, clarithromycin resistance was identified in 19.4%, whereas previously treated patients showed a markedly higher resistance rate of 47.6% (p = 0.018). All clarithromycin-resistant cases carried the A2147G (23S MUT3) mutation. Fluoroquinolone resistance was present in 13.9% of naïve patients and increased to 23.8% in those with prior eradication therapy, with resistance linked to gyrA mutations at codons 87 (N87K) and 91 (D91 variants). Combined resistance to both antibiotics was observed only in a subset of previously treated patients. Conclusions: Primary resistance to clarithromycin in western Romania exceeds the 15% threshold defined by international guidelines, making clarithromycin-based triple therapy unsuitable as an empirical first-line option. The findings support the use of bismuth quadruple therapy as the preferred empirical regimen in this region. Also, molecular testing proved effective for rapid identification of resistance-associated mutations. Full article

Amphotericin: B (AmpB)-resistant Candida (C.) species, such as C. parapsilosis, are among the most common causes of invasive fungal infections, posing significant challenges in hospital settings. Although AmpB is considered the first-line treatment owing to its broad-spectrum fungicidal activity, its use is hampered by severe side effects and the emergence of acquired resistance, particularly in C. parapsilosis, which exhibits reduced susceptibility to polyene, azole, and echinocandin-based antifungal drugs. Here, we present findings on photodynamic therapy (PDT) that targets the opportunistic fungal pathogens C. parapsilosis and C. albicans via the use of photosensitizers from the iodocyanine and newly developed iodinated Methylene blue families. These compounds contain heavy iodine atoms that increase the production of reactive oxygen species (ROS), the agents responsible for oxidative cellular damage, via the heavy-atom effect, which promotes intersystem crossing (ISC) and triplet-state formation. A strong antifungal effect was observed against AmpB-resistant C. parapsilosis, indicating a correlation between the quantum yield of ROS generation and the photosensitizing efficacy under near-infrared (NIR) light irradiation. The combination of efficient cellular uptake and enhanced ROS generation positions iodinated photosensitizers as promising candidates for the treatment of drug-resistant Candida strains. Full article

Primary biliary cholangitis (PBC) is a heterogeneous autoimmune liver disease in which clinical presentation, disease progression, and response to therapy vary markedly from patient to patient. This heterogeneity reflects its complex, multifactorial, and not-completely elucidated pathogenesis. Currently, serological markers are available to non-invasively diagnose PBC, reserving liver biopsy for selected cases with atypical presentations or diagnostic uncertainty. Anyway, the accurate non-invasive prediction of liver-related and non-liver-related (i.e., extra-hepatic, including pruritus) outcomes remains an open challenge, as well as an urgent need, considering the great variability in clinical course and prognosis reported in PBC patients. Moreover, although ursodeoxycholic acid (UDCA) remains the standard first-line treatment, not all individuals respond equally, either in terms of therapeutic efficacy or timing of biochemical improvement. This further variability in treatment response underscores the inadequacy of uniform management approaches and reinforces the urgent need for personalized medicine, where treatment decisions are guided by patient-specific biological and clinical parameters. In this scenario, the identification and validation of non-invasive predictive biomarkers capable of detecting early therapeutic responsiveness are pivotal for optimizing care pathways. Finally, a growing portion of patients show an insufficient UDCA response or are UDCA intolerant, making the identification of novel strategies of care an urgent need. Concerning this, very recently, new therapeutic options beyond UDCA targeting, among the other pathways, bile acid metabolism (including the modern Peroxisome Proliferator-Activated Receptor agonists), immune regulation, and fibrogenesis, have expanded the treatment landscape. In the Era of Precision Medicine, these diagnostic, prognostic, and therapeutic innovations, by reflecting the complexity of PBC pathogenesis, underline the cruciality of a patient-tailored strategy to improve outcomes and mitigate disease progression. The present review reports recent advances, highlights ongoing challenges, and outlines future perspectives in the management of PBC. Full article

Primary urethral cancer is an extremely rare malignancy, accounting for less than 1% of all cancers. Due to its rarity, evidence-based treatment recommendations are lacking. We report the case of a 44-year-old woman with metastatic squamous cell urethral carcinoma and paraneoplastic Sweet syndrome. The tumor was p16-positive with strong PD-L1 expression (CPS > 50%). Following surgery and adjuvant chemoradiotherapy, the patient developed hepatic and lymph node metastases. Pembrolizumab was initiated as first-line systemic therapy because of prior hematologic toxicity with cisplatin. After four cycles, complete radiologic remission of metastases and full resolution of the Sweet syndrome were achieved. This case highlights the potential benefit of immune checkpoint inhibitors in metastatic urethral SCC, particularly in p16-positive and PD-L1-high tumors, suggesting an inflamed and immunogenic microenvironment. To our knowledge, this is the first reported case of paraneoplastic Sweet syndrome successfully treated with pembrolizumab. These findings underscore the need for further investigation of immunotherapy in this rare and challenging malignancy. Full article

Background: Cefiderocol (CFD) is a novel cephalosporin targeting multidrug-resistant Gram-negative bacterial (GNB) infections. It mimics siderophores to enter into GNB through iron transport receptors. However, evidence on its use in Hospital at Home (HaH) and outpatient parenteral antibiotic therapy (OPAT) programs remains scarce. Objectives: The primary objective was to evaluate feasibility and efficacy of CFD in HaH setting. The secondary objective was to assess its safety. Methods: A retrospective, observational study was conducted across six Spanish centers between January 2023 and December 2024. Adult patients with documented GNB infections treated with CFD in HaH units were included. Demographic, clinical and microbiological data, treatment characteristics, and outcomes were collected. Statistical analysis was descriptive; no inferential or correlation tests were performed. Results: 27 patients were included; 70.4% were male, with a median age of 69 years. Most infections were nosocomial (65.4%), particularly skin and soft tissue (37%). Septic shock occurred in 14.8% of patients. Pseudomonas aeruginosa (66.7%) and Klebsiella pneumoniae (14.8%) were the most frequent pathogens involved, with Verona Integron-encoded metallo-B-lactamase (VIM, 50%) being the predominant resistance mechanism. CFD was used as a first-line therapy in 63% of cases and in combination with other antibiotics in 40.7%. Median treatment duration was 21.7 days. Administration was mainly via peripherally inserted central catheters (PICC, 33.3%) and electronic pumps (52%). Adverse effects occurred in 7.4% of patients, leading to discontinuation in one case. A total of 88.8% of patients achieved clinical success, with 7.7% recurrence within a month. Escalation of care occurred in 7.7% and 19.2% were readmitted within a month after HaH discharge. No infection-related deaths were reported. Conclusions: CFD is a feasible, safe, and effective treatment for difficult-to-treat GNB infections in HaH settings. Full article

Localized scleroderma (LSc), or morphea, is an autoimmune connective tissue disease causing inflammation and fibrosis of the skin and underlying tissues. While distinct from systemic sclerosis, its clinical presentation is highly diverse. This review summarizes recent advances in the understanding and management of LSc. Pathophysiological insights have evolved significantly; the somatic mosaicism hypothesis is now supported by the observation of all six of Happle’s classic lesion patterns in LSc. Furthermore, recent single-cell RNA sequencing has elucidated key cellular mechanisms, revealing an IFN-γ-driven pro-fibrotic crosstalk between T cells, dendritic cells, and specific inflammatory fibroblast subpopulations. The discovery of a rare monogenic form of LSc caused by a STAT4 gain-of-function mutation provides a powerful human model, solidifying the critical role of the JAK-STAT pathway. Clinically, LSc is classified into subtypes such as circumscribed, linear, and generalized morphea. Extracutaneous manifestations are common, particularly in juvenile LSc, and are associated with higher disease activity and reduced quality of life, necessitating a multidisciplinary approach. Management is becoming standardized, with methotrexate as the first-line systemic therapy for severe disease. For refractory cases, targeted treatments including abatacept, tocilizumab, and JAK inhibitors are emerging as promising options. In addition, reconstructive therapies like autologous fat grafting are crucial for managing atrophic sequelae. These recent advances are paving the way for more effective, targeted therapies to improve outcomes for patients with this complex disease. Full article

Oxygen–ozone (O₂–O₃) therapy is widely used for treating lumbar disc herniation. However, controversy remains regarding the safest and most effective route of administration. While intradiscal injection is purported to show clinical efficacy, it has also been associated with serious complications. In contrast, the intramuscular route can exhibit a more favourable safety profile and comparable pain outcomes, suggesting its potential as a safer alternative in selected patient populations. This mixed-method study combined computed tomography (CT) imaging, biophysical diffusion modelling, and a meta-analysis of clinical trials to evaluate whether intramuscular O₂–O₃ therapy can achieve disc penetration and therapeutic efficacy comparable to intradiscal nucleolysis, while minimizing procedural risk. Literature searches across PubMed, Scopus, and Cochrane databases identified seven eligible studies (four randomized controlled trials and three cohort studies), encompassing a total of 120 patients. Statistical analyses included Hedges’ g, odds ratios, and number needed to harm (NNH). CT imaging demonstrated gas migration into the intervertebral disc within minutes after intramuscular injection, confirming the plausibility of diffusion through annular micro-fissures. The meta-analysis revealed substantial pain reduction with intramuscular therapy (Hedges’ g = −1.55) and very high efficacy with intradiscal treatment (g = 2.87), though the latter was associated with significantly greater heterogeneity and higher complication rates. The relative risk of severe adverse events was 6.57 times higher for intradiscal procedures (NNH ≈ 1180). O₂–O₃ therapy offers a biologically plausible, safer, and effective alternative to intradiscal injection, supporting its adoption as a first-line, minimally invasive strategy for managing lumbar disc herniation. Full article

Background/Objectives: Granzyme B (GZB) PET Imaging is a non-invasive tool that can determine tumoral and systemic effects in immunotherapy. We aim to evaluate ⁶⁸Ga-NOTA-CYT-200 PET Imaging as a molecular imaging approach to determine CAR T-cell therapy response in a human melanoma mouse model. Our goal is to provide a method to monitor CAR T-cell therapy for patients with melanoma and other solid tumors. Methods: A human melanoma mouse model was generated by implanting naïve NSG mice (n = 28) with a human melanoma cell line (A375) subcutaneously (s.c.). After tumor implantation, mice were randomly assigned to receive either the treatment (CAR T) or vehicle solution (controls). After treatment, tumor sizes were measured every other day up to 35 days after cell implantation. ⁶⁸Ga-NOTA-CYT-200 PET Imaging was performed on days 2, 7, and 14 after CAR T-cell administration to assess T-cell activity within the tumors and organs. The PET Imaging results were correlated with IHC and immunofluorescent staining and cytokine assessment of tumor samples. Results: Tracer uptake within tumors of the CAR T group was significantly greater on days 2 (3.1 ± 1.2 vs. 1.1 ± 0.4, p = 0.002) and 7 (2.0 ± 1.1 vs. 1.1 ± 0.1, p = 0.01) after treatment, even before the CAR T group first presented with significantly lower tumor volumes on day 11 after treatment (61.8 mm³ ± 8.7 vs. 287.1 mm³ ± 157.6, p = 0.05). GZB (p = 0.03) and CAR T (p = 0.001) staining were also significantly greater in tumors of CAR T-cell-treated mice. Inflammatory cytokines such as IFN gamma (p = 0.03), CXCL10 (p = 0.004), and CCL5 (p = 0.02) concentrations were also significantly greater in CAR T-cell-treated tumors. Conclusions: CAR-T-treated tumors show significantly elevated ⁶⁸Ga-NOTA-CYT-200 uptake compared with controls, consistent with enhanced effector activity. Full article

In Israel, irregular migrants (IMs) living with human immunodeficiency virus (HIV-1) that have no access to regular health insurance are provided with HIV-1-related health coverage under a public–private partnership (PPP) program initiated by the Ministry of Health in 2014. Here we characterized IMs referred to the PPP in 2019–2024 and used a linear mixed-effects model to follow up their CD4 and HIV-1 viral load (VL) counts for a median period of 16 months. Subtypes, resistance mutations and phylogenetic relationships were determined in all cases with viral failure and in selected cases with available blood remains. A total of 231 of 238 referred to the PPP initiated antiretroviral treatment (ART) with nucleoside reverse transcriptase inhibitors (NRTIs) and either non-nucleoside reverse transcriptase inhibitors (NNRTIs, 61.5%, 142/231) or protease inhibitors (PIs, 38.5%, 89/231). Irrespective of the treatment regimen, all these individuals increased their CD4 and decreased their VL trajectories over time (p < 0.001). However, mixed model analysis revealed two classes of CD4 trajectory patterns. Comparison between these two patterns revealed that Class-1 individuals started with lower initial CD4 counts compared to Class-2 individuals (median of 115 cells/mm³, IQR 70–171 compared to median of 312 cells/mm³, IQR 104–510, p < 0.001) and experienced slower recovery compared to Class-2. Most Class-1 individuals originated from Africa (78% vs. 52%, p = 0.016). Treatment failure was observed in 5.6% of all individuals receiving treatment under the program. Sequencing analysis, enabled in 23% of the treated cohort, revealed that the reverse transcriptases (RT) M184V (13%) and K103N (7.4%) were the most prevalent mutations. Conclusively, while treatment was not consistent with current recommendations for first-line therapy, the virological and immunological response of most patients was favorable and the prevalence of cases with resistance mutations was not higher than that identified in people living with HIV-1 who are covered by the national health insurance. Despite the limitations of the PPP, this program may provide a unique therapeutic opportunity for IMs with HIV-1. Full article

Mucormycosis is an uncommon but life-threatening invasive fungal infection caused by molds of the order Mucorales, whose incidence has increased among solid organ transplant (SOT) recipients in recent years. Profound immunosuppression (particularly high-dose corticosteroids), T-cell-depleting therapies, diabetes mellitus, and previous episodes of graft rejection are the main predisposing conditions. This narrative review summarizes the current evidence on epidemiology, pathogenesis, risk factors, clinical presentation, diagnostic strategies, and treatment outcomes of mucormycosis in the SOT population. Pulmonary and rhino-orbital-cerebral infections are the predominant clinical forms, often characterized by rapid angioinvasive progression and mortality rates exceeding 45%. Early diagnosis remains challenging due to nonspecific clinical manifestations and the limited sensitivity of conventional diagnostic tools, although molecular techniques such as the detection of circulating Mucorales DNA in blood and metagenomic next-generation sequencing are promising. Liposomal amphotericin B remains the first-line therapy, ideally associated to surgical debridement and reduction in immunosuppression, while broad-spectrum triazoles (isavuconazole and posaconazole) represent alternative or salvage options. Despite recent advances in diagnostic methods and antifungal therapy, the prognosis of post-transplant mucormycosis remains poor, underscoring the need for multidisciplinary management and collaborative studies to inform the clinical management in this high-risk population. Full article