Search Results (19,120)

Patient-derived organoids (PDOs) have rapidly transitioned from research tools into promising platforms for clinical translation. In this review, we analyze 139 PDO-related clinical trials registered between 2023 and 2025 and contrast them with recent advances in disease modelling. Our analysis revealed a predominance of oncology-focused studies, with translational maturity spanning from foundational research to studies in which PDOs directly informed clinical decision-making. In contrast, non-oncology areas show extensive preclinical progress but remain trial-poor. We found that trial registration is geographically concentrated in a small number of countries, reflecting uneven global adoption. We then explored advances in disease modeling, mainly confined to preclinical studies, including immune-competent PDOs, complex organ-on-a-chip systems, synthetic matrices, AI-enabled platforms, and therapeutic transplantation. Based on these findings, we propose a conceptual framework outlining the trajectory of PDO adoption in clinical trials. This trajectory can be understood as three overlapping waves of translation: the first wave, focusing on oncology, has already demonstrated impacts on patient care; the second, targeting non-oncology diseases, is scientifically advanced but has not achieved widespread clinical application; and the third, involving frontier technologies, remains in the preclinical stage. Understanding these trajectories underscores the promise and challenges of PDOs that must be addressed for broader clinical adoption. Full article

Background: Lymphocyte-activation gene 3 (LAG3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) are immune checkpoint receptors and inhibitory regulators of T-cells. Methods: Here, we analyzed the prevalence and potential impact of the LAG3 gene variant rs870849 and the CTLA4 gene variant rs231775 in AML patients eligible for autologous stem cell transplantation. Results: While CTLA4 rs231775 was prevalent at reduced minor allele frequencies (MAF 0.33), LAG3 rs870849 was prevalent at elevated minor allele frequencies (MAF 0.58) in AML patients, compared to the allele frequencies in the European population (MAF 0.37 and MAF 0.39). The gene risk analysis indicated a dose-dependent risk of AML disease associated with LAG3 rs870849, but no risk associated with CTLA4 rs231775. Baseline blood count profiles differed across LAG3 genotypes, suggesting a link between LAG3 rs870849 and disease-associated levels of anemia, thrombocytopenia and peripheral blast percentage. Conslusions: The germline LAG3 variant rs870849 may be associated with AML disease risk and specific hematological disease features. Full article

Multiple myeloma (MM) is a biologically heterogeneous plasma cell malignancy in which prognosis is strongly influenced by cytogenetic abnormalities. Recent updates from the International Myeloma Working Group (IMWG), along with the European Hematology Association (EHA) and European Myeloma Network (EMN), have refined the definition of high-risk (HR) disease by integrating TP53 alterations, chromosome 1 abnormalities, and specific combinations of cytogenetic lesions. However, validation of these criteria in real-world patient populations remains limited. We conducted a retrospective, single-center study including 738 patients diagnosed with MM between 2017 and 2025, of whom 408 had available fluorescence in situ hybridization (FISH) data at diagnosis. Patients were reclassified according to the latest IMWG/IMS high-risk criteria proposed in international literature. Cytogenetic abnormalities, treatment patterns, and clinical outcomes, including overall survival (OS), progression-free survival (PFS), response rates, and relapse, were analyzed. Survival was estimated using the Kaplan–Meier method. A total of 103 patients (25%) were reclassified as high-risk according to IMWG/IMS high-risk criteria. Cytogenetic HR abnormalities were identified in 17.2% of cases, with del(17p) being the most frequent (14.7%). Median OS and PFS in HR patients were 52.4 months and 16 months, respectively, compared with 68.4 months and 28 months in standard-risk patients (log-rank test p values of 0.0197 and 0.0004, respectively). Although overall response rates were high (83% in HR vs. 91% in standard-risk), relapse remained frequent in HR patients. Outcomes varied significantly according to cytogenetic complexity. Isolated del(17p) was associated with improved survival compared with cases harboring additional abnormalities, while double-hit and triple-hit profiles demonstrated inferior outcomes. The presence of chromosome 1 abnormalities, particularly in combination with IGH translocations, further worsened prognosis. Among HR patients, 44% underwent autologous stem cell transplantation (ASCT), including 10 cases of TANDEM ASCT. No survival benefit was observed for TANDEM compared with single ASCT, with median OS of 52.9 vs. 78.3 months, respectively (log-rank test p values of 0.2516). Our real-world analysis supports the prognostic relevance of the updated IMS/IMWG high-risk criteria in MM. Cytogenetic complexity, rather than individual abnormalities alone, is a key determinant of outcome. Despite high response rates achieved with modern therapies, survival remains inferior in HR patients. TANDEM ASCT did not confer additional benefit in this cohort, supporting a more individualized approach to treatment intensification. Full article

Human herpesvirus 8 (HHV-8) is the etiologic agent of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and KS-associated immune reconstitution inflammatory syndrome (IRIS-KS). Quantifying HHV-8 DNA in whole blood is clinically relevant, yet laboratory practices remain heterogeneous. Here, we developed and validated an in-house quantitative PCR (qPCR) assay targeting ORF26, optimized for whole blood. Assay calibration used plasmid, BCBL-1 cell–derived, and commercial HHV-8 DNA standards. Analytical validation was performed following the Clinical and Laboratory Standards Institute (CLSI) guidelines and the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines and showed a 95% limit of detection of 65.7 copies/reaction, efficiencies of 90–101% (R² > 0.99), and intra/inter-assay coefficients of variation < 6.5%. Strong correlations were observed among the three calibrators (R² > 0.97).Clinical validation against a composite reference yielded 100% sensitivity, specificity, PPV, and NPV. Viral loads (log₁₀ copies/mL) varied by clinical condition: classic KS and transplant-associated KS showed the lowest medians (2.30–2.23), MCD HIV− and PEL intermediate values (2.83–3.72), and epidemic KS, MCD HIV+, and IRIS-KS the highest (4.12, 4.86, and 5.03, respectively). Viremia > 5 log₁₀ copies/mL was associated with uncontrolled E-KS, MCD HIV+, and IRIS-KS. Longitudinal follow-up revealed viral load decline paralleled clinical improvement. This validated assay provides a robust, affordable tool for HHV-8 quantification in whole blood and supports its integration into diagnostic workflows and patient monitoring. Full article

Background: The optimal ¹³C-urea breath test (UBT) dosage for diagnosing Helicobacter pylori remains debated. We compared the accuracy and agreement of a low-dose 45 mg tablet (without citric acid) versus the standard 75 mg granule (with citric acid) protocol. Methods: In this prospective, randomized crossover trial, adults underwent both a 45 mg and a 75 mg ¹³C-UBT on the same day. Breath samples were collected at 15 and 30 min. The primary outcome was diagnostic agreement at 30 min. Secondary outcomes included diagnostic performance against a composite reference standard, wherein concordant 45 mg and 75 mg UBT results were presumed to represent true H. pylori status, while discordant cases underwent endoscopic reference testing (rapid urease test and histology, with immunohistochemistry where required), stratified by age and BMI. Results: For the 431 participants included, the 45 mg and 75 mg tests showed substantial agreement at 30 min (90.3%; κ = 0.766). The 30 min sampling time yielded significantly better accuracy than 15 min for both doses. The 45 mg protocol achieved excellent accuracy (AUC 0.953), statistically non-inferior to the 75 mg protocol (AUC 0.966; p = 0.50). Notably, in participants aged <40 years or with BMI < 25.0 kg/m², the 45 mg protocol demonstrated robust performance (AUC 0.977 and 0.966, respectively), comparable to the 75 mg standard (p > 0.05). No adverse events occurred. Conclusions: The low-dose 45 mg ¹³C-UBT provides high diagnostic agreement and comparable clinical performance to the standard 75 mg protocol without requiring citric acid acidification. Its robust performance in younger, lower-BMI individuals shows clinical promise. However, because diagnostic accuracy analyses partly relied on a composite reference assumption, further externally validated studies are required before broad screening-policy claims can be made. Full article

Background: Relapse is the leading cause of treatment failure in patients with myeloid hematologic malignancies undergoing allogeneic hematopoietic cell transplantation. Clonal genomic evolution may contribute to post-transplant relapse, yet its determinants and prognostic impact remain incompletely characterized. Methods: In this retrospective study, we analyzed 63 patients with myeloid neoplasms who underwent cytogenetic evaluation both at diagnosis and at relapse after allogeneic hematopoietic stem cell transplantation. Cytogenetic changes (CGE), including evolution, devolution, or combined patterns, were assessed and correlated with clinical characteristics, prior treatment exposure, and survival outcomes. Results: Cytogenetic changes were observed in 46.1% of patients. The presence of cytogenetic changes (CGE) was strongly associated with the presence and complexity of cytogenetic abnormalities at initial diagnosis, whereas prior chemotherapy exposure, conditioning intensity, and donor type showed no significant association. Patients with cytogenetic changes had a lower complete remission rate at day 30 after transplantation; however, relapse-free survival and post-relapse survival did not differ significantly between groups. Conclusions: These findings suggest a potential association between post-transplant cytogenetic changes and intrinsic genomic instability, although treatment-related effects cannot be excluded. Larger, disease-stratified studies integrating cytogenetic and molecular analyses are warranted to further clarify the biological and prognostic relevance of clonal evolution following transplantation. Full article

Olfactory ensheathing cell (OEC) transplantation has been widely shown to support axonal regeneration, remyelination, and functional recovery after central nervous system injury; however, autologous approaches are limited by low cell yields from patient biopsies, which may be insufficient for large spinal cord lesions. This study evaluated whether cryopreservation could provide a scalable alternative by preserving the therapeutic potential of mucosa-derived OECs. Using a rat dorsal root injury model, cryopreserved mucosa-derived OECs (CmOECs) were thawed and assessed for viability, phenotype, and efficacy following transplantation. Although total viable cell yield was reduced compared with primary cultures, the relative proportion of OECs remained stable, and cells retained characteristic morphology and marker expression in vitro. In vivo, transplantation of CmOECs resulted in significant functional recovery in climbing and forepaw fault tasks compared with injured controls, with outcomes comparable to primary mucosal OEC transplantation. Immunohistochemical analysis confirmed the survival and integration of transplanted cells at the dorsal root entry zone, alongside evidence of axonal regeneration and astrocytic remodeling. These findings demonstrate that mucosa-derived OECs retain therapeutic efficacy following cryopreservation and support the development of standardized OEC biobanks as a scalable strategy for spinal cord repair. Full article

(1) Background: The role of baseline humoral immunization in bone regeneration remains unclear. This study assessed the relationship between baseline serological immunization, graft type, photobiomodulation (PBM), and histological outcomes after maxillary sinus floor augmentation. (2) Methods: This exploratory secondary analysis included 20 adults undergoing lateral maxillary sinus lifting. Patients were allocated according to graft type (allogeneic or xenogeneic) and postoperative protocol (with or without adjunctive PBM). Before surgery, serum samples were analyzed for anti-HLA class I, anti-HLA class II, and anti-MICA antibodies. After approximately 6 months, bone core biopsies were collected. Histological evaluation focused on inflammatory cell infiltrates (ICI). (3) Results: Baseline antibody positivity was detected in 35.0% of patients for anti-HLA class I, 55.0% for anti-HLA class II, and 45.0% for anti-MICA. Histological findings were generally favorable. ICI scores were low, with 65.0% of samples scoring 0 and 35.0% scoring 1. A nominal positive correlation was observed between anti-HLA class I NBG ratio and ICI; however, this finding did not remain statistically significant after correction for multiple comparisons. Exploratory PBM subgroup estimates were directionally different but were based on very small subgroups and should not be interpreted as evidence of effect modification. (4) Conclusions: The findings suggest a possible hypothesis-generating link between baseline humoral sensitization and mild local inflammatory infiltrates, which requires validation in larger, prospectively powered studies with predefined histological and immunological endpoints. Full article

Sickle cell disease (SCD) is a monogenic disorder responsible for recurrent vaso-occlusive crises, progressive organ damage, and shortened life expectancy. For decades, allogeneic hematopoietic stem cell transplantation from a matched sibling donor has been the only established cure, but its reach remains limited by donor availability and transplant-related toxicity. The approval of two autologous gene therapy products in 2023, exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel), marked a turning point for the SCD population and the gene therapy field in general. This review proposes a molecular rationale for fetal hemoglobin reactivation and β-globin gene addition, describes the engineering of lentiviral and CRISPR-based platforms, and highlights the clinical evidence accumulated to date that demonstrated durable disease modification with acceptable short-term toxicity. We then assess the clinical positioning of gene therapy within the broader spectrum of curative options compared to current available treatments and address the financial, ethical and psychosocial barriers that limit access to gene therapy both within high-income countries and globally. Critical research priorities include long-term safety surveillance, comparative effectiveness studies, pediatric trials below 12 years, and validated patient-reported outcome instruments. Base editing, non-genotoxic conditioning, and in vivo delivery represent the most promising avenues to broaden access and reduce treatment burden. Full article

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes—PTPN11, NRAS, KRAS, NF1, or CBL—establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention. Full article

Background/Objectives: Chronic Kidney Disease (CKD) is a prevalent condition requiring ongoing patient counseling and engagement, yet little is known about how physicians communicate with patients about CKD in routine clinical practice. We conducted a qualitative study to examine physician communication approaches related to CKD and to assess how these approaches align with Picker’s principles of patient-centered care framework. Methods: Semi-structured interviews were conducted with primary care physicians and nephrologists practicing in community and safety-net settings. Using directed content analysis, we identified patterns in how clinicians describe educating patients, contextualizing clinical information, and deferring aspects of counseling to other providers. Results: Physicians predominantly emphasized information-giving and the use of laboratory data to explain disease status. In contrast, practices such as explicit patient preference elicitation, addressing fear, anxiety, or physical comfort, and involving family or support persons were infrequently described. Mapping these communication behaviors to patient-centered care principles highlighted specific elements that are routinely enacted and others that remain underutilized in everyday CKD counseling. Conclusions: These findings identify concrete, feasible opportunities to strengthen patient-centered communication through brief, practice-ready strategies such as plain-language explanations, teach-back, values checks, and shared decision-making prompts. Enhancing these communication practices represents a pragmatic opportunity to improve the quality and patient-centeredness of CKD care. Full article

Lipid keratopathy is an uncommon corneal disorder characterized by stromal lipid deposition that may cause progressive corneal opacity and visual impairment. We report a case of advanced bilateral lipid keratopathy with severe visual-axis involvement. At presentation, best-corrected visual acuity (BCVA) was counting fingers in the right eye and 0.1 Snellen (1.0 logMAR) in the left eye. Slit-lamp examination and anterior segment optical coherence tomography (AS-OCT) demonstrated dense stromal lipid deposits involving the visual axis in both eyes. The patient underwent staged bilateral penetrating keratoplasty, with procedures performed three months apart. Postoperatively, corneal transparency improved in both eyes. At 6 months, BCVA was 0.5 Snellen (0.3 logMAR) in the right eye and 0.7 Snellen (0.15 logMAR) in the left eye. Residual visual limitation was attributed mainly to coexisting cataract, and sequential cataract surgery was planned. Together, the clinical photographs and AS-OCT scans illustrate an uncommon presentation of visually disabling bilateral lipid keratopathy, characterized by dense central stromal lipid deposition involving both visual axes and profound preoperative visual loss. The case is clinically noteworthy because it combines severe bilateral disease, close clinical–tomographic correlation, and sequential penetrating keratoplasty performed as a staged visual rehabilitation strategy, resulting in restoration of graft clarity and meaningful visual improvement during postoperative follow-up. Full article

There is a bidirectional relationship between chronic kidney disease (CKD) and an altered gut microbiome, with gut-derived uremic toxins contributing to cardiovascular-kidney-metabolic effects. In this review, we summarize the interplay between diet, the intestinal microbiota and systemic sequelae including CKD progression, cardiovascular morbidity and cognitive decline. We discuss the current state of knowledge regarding microbiota-modulating therapies that have the potential to delay CKD complications such as plant-dominant diets, oral adsorbents, prebiotics/probiotics, fecal microbiota transplantation and exercise. Full article

Background and Objectives: This study evaluated the effect of two wound closure methods—polypropylene sutures and a butyl-2-cyanoacrylate tissue adhesive—on the rate of soft tissue regeneration following palatal donor site harvesting. A bovine collagen sponge, used as a secondary-intention dressing, was evaluated descriptively. Materials and Methods: Data from 300 patients (n = 100/group) with palatal donor sites were analyzed. Primary analysis compared suture vs. adhesive using Early Wound Healing Score (EHS) at days 7 and 14. Secondary outcomes were granulation tissue (day 7) and complications. Statistical methods: Mann–Whitney U test for between-group comparison (suture vs. adhesive); Kruskal–Wallis with Dunn’s post hoc for granulation across all three groups; Spearman’s correlation and logistic regression for the relationship between granulation tissue and EHS within primary healing groups. Results: At day 7, median EHS was similar between suture and adhesive groups (7.0 [interquartile range (IQR) 5.0–9.0] vs. 7.0 [IQR 7.0–9.0]; p = 0.31). By day 14, both groups achieved excellent healing (median 10.0, IQR 9.0–10.0 in both; p = 0.82). The collagen sponge group showed slower healing (median EHS day 7 = 4.0 [IQR 3.0–5.0], day 14 = 6.0 [IQR 5.0–7.0]), reported descriptively as expected for secondary intention. Granulation tissue on day 7 was highest in the adhesive group (p < 0.001 vs. collagen; p = 0.024 vs. suture). A strong positive correlation between day-7 granulation tissue and day-14 EHS was found in the primary-healing groups (ρ = 0.78, p < 0.001). Receiver operating characteristic (ROC) analysis established a granulation score ≥ 2 as the optimal cut-off for predicting successful healing (EHS ≥ 9) by day 14 (sensitivity 89.4%, specificity 76.0%, area under the curve (AUC) = 0.80), pending external validation. Conclusions: Surgical adhesive may be considered a viable alternative to sutures for palatal donor sites closed by primary intention, offering comparable healing by day 14. Collagen sponges result in slower healing and should be considered only when secondary intention is specifically desired. Early assessment of granulation tissue may serve as a simple prognostic indicator, but external validation is needed before clinical application. Full article