Diseases (Basel, Switzerland)最新文献

Background: The efficacy of upadacitinib in patients with Crohn's disease (CD) has been shown in pivotal randomized controlled trials. However, real-world data is needed to assess its effectiveness and safety in routine clinical care with biologic-experienced patients. This study aimed to evaluate the clinical and endoscopic efficacy, patient-reported outcomes (PROs), and safety of upadacitinib in biologic-experienced patients with CD in a real-world setting.

Methods: This prospective bi-centric real-world study enrolled 28 anti-TNF-experienced patients with CD receiving upadacitinib 45 mg daily for 12 weeks (induction), followed by 30 mg daily maintenance through week 52. Primary endpoints included endoscopic response (≥50% SES-CD reduction or ≥2-point decrease from baseline for baseline SES-CD ≤ 4) and clinical remission (Harvey-Bradshaw Index [HBI] ≤ 4). Secondary endpoints included endoscopic remission, clinical response (HBI decrease ≥ 3 points), and quality of life (IBD-Disk). Statistical analysis used the Wilcoxon signed-rank test with 95% confidence intervals (CIs).

Results: Median patient age was 37 years; 75% had ≥3 prior biologic failures. Clinical remission rates (HBI) were 59% (95% CI: 41-75%) at week 12, 44% (95% CI: 27-63%) at week 26, and 53% (95% CI: 29-76%) at week 52. Endoscopic response rates were 48% (95% CI: 44-52%) at week 26 and 46% (95% CI: 21-72%) at week 52. Endoscopic remission was achieved in 43% (95% CI: 40-48%) at week 26 and 27% (95% CI: 10-57%) at week 52. Clinical response (HBI) improved progressively from 65% at week 2 to 71% at week 52. Quality of life, as assessed by the IBD-Disk, showed significant improvement: Reduced Disease Burden (defined as a decrease of 70% or a CED-Disk Score of ≤15) was observed in 33% of patients at week 12 and 35% at week 52. Median SES-CD decreased from 9 points (IQR: 6-17) at baseline to 5 points (IQR: 1-12, p = 0.005) at week 52. Adverse events occurred in 11% of patients (4% lymphopenia, 7% skin disease), with no serious adverse events or deaths.

Conclusions: Upadacitinib demonstrates significant clinical and endoscopic efficacy in biologic-experienced, anti-TNF-pretreated patients with CD, achieving remission rates comparable to or exceeding those of the pivotal trials despite a highly refractory population (75% with ≥3 prior biologic failures). The favorable safety profile supports upadacitinib as an important therapeutic option in sequential treatment of refractory CD.

Palmitoylethanolamide (PEA) among N-acylethanolamides displays a noteworthy impact on different inflammatory conditions and promises to become a valuable anti-inflammatory tool that does not interfere with the cyclooxygenase pathway. Mounting evidence confirms the multi-dimensional PEA-mediated crosstalk between microglia and mast cells, which would open new therapeutic opportunities targeting a neuroimmune axis and influencing both health and disease. In particular, PEA acts as a preserver of cellular homeostasis by regulating microglia cell activity and inhibiting mast cell activation in the central nervous system. The improved bioavailability and efficacy of ultramicronized formulations of PEA reflect its ultimate usefulness for different clinical applications, including significantly relieving inflammation but also reducing the pro-inflammatory burden of complex patients with either neuropathies or non-neurologic afflictions. This review aims to comprehensively delineate the therapeutic potential of PEA beyond its mere indication for acute inflammation and to highlight PEA activity as a broad-spectrum pan-tissue protective agent through the results of different preclinical and also some clinical studies. Much more remains to be learned about further PEA mechanisms of action that regulate neuroinflammation, and additional studies will have to investigate the exact role of microglia and mast cells in inflammatory diseases.

Hypertriglyceridaemia is the third most common aetiology of acute pancreatitis and a leading cause of recurrence in specialized lipid clinics. The risk of acute pancreatitis rises steeply once triglycerides exceed approximately 10 mmol/L (≈885 mg/dL). Still, clinically meaningful risk may occur at lower levels in the presence of chylomicronaemia, metabolic stress, or pregnancy. This mini-review synthesizes contemporary evidence on epidemiology, mechanistic links between triglyceride-rich lipoproteins and pancreatic injury, and the practical distinction between secondary (acquired) and genetic drivers of severe hypertriglyceridaemia. We summarize acute management strategies aimed at rapid triglyceride reduction (including insulin-based approaches and therapeutic plasma exchange in selected scenarios) and focus on long-term prevention of recurrence through lifestyle interventions, correction of secondary contributors, and triglyceride-lowering pharmacotherapy. Finally, we discuss emerging RNA-targeted therapies against apolipoprotein C-III and angiopoietin-like 3, which are reshaping prevention strategies for familial and persistent chylomicronaemia and may reduce pancreatitis burden in the highest-risk phenotypes.

Triple-negative breast cancer (TNBC) is an aggressive malignancy that disproportionately affects young women. The integration of immune checkpoint inhibitors (ICIs) has significantly improved outcomes in both early-stage and metastatic TNBC, shifting attention toward long-term survivorship issues, particularly endocrine function and fertility. However, the reproductive safety profile of ICIs remains insufficiently characterized. This narrative review synthesizes current preclinical and clinical evidence on ICI-associated reproductive toxicity, focusing on both direct immune-mediated gonadal injury and indirect disruption of the hypothalamic-pituitary-gonadal axis. Experimental models consistently demonstrate immune cell infiltration of ovarian and testicular tissue, cytokine-driven inflammatory cascades, follicular atresia, impaired spermatogenesis, and altered steroidogenesis following PD-1/PD-L1 and CTLA-4 blockade. Emerging clinical data report cases of immune-related orchitis, azoospermia, testosterone deficiency, diminished ovarian reserve, and premature ovarian insufficiency. Secondary hypogonadism due to immune-mediated hypophysitis represents an additional and frequently underdiagnosed mechanism. We further discuss the oncofertility challenges faced by young patients with TNBC treated with chemoimmunotherapy, emphasizing the uncertainty of fertility risk stratification and the importance of early fertility counseling and individualized fertility preservation strategies. To illustrate the potential clinical impact, we present the case of a 34-year-old nulliparous woman who developed premature ovarian insufficiency two years after neoadjuvant chemoimmunotherapy including atezolizumab, despite ovarian suppression. In conclusion, while ICIs have transformed the therapeutic landscape of TNBC, their potential long-term impact on reproductive and endocrine health represents a clinically significant concern. A precautionary, multidisciplinary oncofertility approach and prospective clinical registries are essential to define the true incidence and mechanisms of ICI-associated reproductive toxicity.

Acute myeloid leukemia (AML) continues to pose significant therapeutic challenges, with high relapse rates driven largely by leukemic stem cells (LSCs), a rare, therapy-resistant population with self-renewal capacity, niche adaptation, and the ability to re-initiate disease. In this state-of-the-art review, we synthesize recent advances in LSC biology, addressing (i) how LSCs differ functionally and phenotypically from normal hematopoietic stem cells (HSCs), (ii) practical approaches for LSC quantification using multiparameter flow cytometry and LSC-enriched marker panels, (iii) the dysregulated signaling, metabolic and epigenetic programs that enable LSC persistence under chemotherapy and contribute to measurable residual disease, and (iv) current therapeutic strategies targeting LSC eradication, including antibody-based therapies, apoptosis and metabolic inhibitors, and emerging epigenetic agents. We also examine the key translational barriers, particularly antigen overlap with normal progenitors, microenvironmental protection, and the need for assay harmonization, while proposing a practical framework for integrating LSC assessment into risk stratification and therapeutic development.

Background/Objectives: Pregnancy is characterized by complex immunological adaptations that may increase susceptibility to infections, including SARS-CoV-2. Interleukin-6 (IL-6), a key pro-inflammatory cytokine, plays a crucial role in the immune response and has been strongly implicated in the pathogenesis of COVID-19. Genetic variations in the IL6 gene, particularly single-nucleotide polymorphisms (SNPs) in the promoter region, can modulate IL-6 expression and potentially influence individual susceptibility to viral infections. This study aimed to evaluate the relationship between promoter region IL6 gene polymorphisms and COVID-19 susceptibility, as well as the inflammatory response, in pregnant women. Methods: We enrolled in this study 204 pregnant women with evidence of SARS-CoV-2 infection in pregnancy and 134 pregnant women with no evidence of SARS-CoV-2 infection in the past. Genotyping was conducted for the two functional SNPs in the IL6 promoter region, rs1800796 and rs1800797, via Sanger sequencing, and for associations with COVID-19 susceptibility and IL-6 levels were analyzed. Results: No significant association was found between IL6 polymorphisms and COVID-19, IL-6 levels, age, or immunization status. IL-6 levels > 5 pg/mL were more frequent in SARS-CoV-2-negative pregnant women than in SARS-CoV-2-positive pregnant women (p = 0.032). Among vaccinated participants, IL-6 levels were significantly higher in SARS-CoV-2-negative pregnant women (p = 0.044), while no difference was observed in the unvaccinated group. Conclusions:IL6 polymorphisms rs1800797 and rs1800796 were not associated with infection susceptibility or IL-6 levels. These results highlight the complex immunological interplay between pregnancy, infection, and genetic background and support the need for further research in larger cohorts.

Background/objectives: Interleukin-6 (IL-6), a pleiotropic cytokine involved in immune regulation, is consistently detected in human semen, even in the absence of overt infection. Its contribution to sperm dysfunction, oxidative stress, and inflammation remains incompletely understood. This study evaluated the associations between seminal IL-6 concentrations and markers of semen quality, oxidative stress, nuclear integrity, and genital tract inflammation in infertile men.

Methods: A cohort of 204 infertile men was assessed. Seminal IL-6 was quantified by electrochemiluminescence immunoassay. Semen parameters, malondialdehyde (MDA), catalase (CAT) activity, sperm DNA fragmentation index (DFI), sperm chromatin decondensation index (SDI), leukocytospermia, and bacteriospermia were measured. Analyses included correlation testing, IL-6 threshold stratification (<30, 30-60, 60-100, ≥100 pg/mL), and multivariate regression.

Results: IL-6 was detectable in all samples (median: 31.52 pg/mL; range: 1.5-5000 pg/mL). Higher IL-6 levels were significantly associated with reduced sperm concentration, progressive motility, and vitality, and with increased DFI, SDI, MDA, leukocyte counts, and bacteriospermia (p < 0.001). In multivariate models, IL-6 independently predicted reduced progressive motility (β = -0.005; p = 0.032) and elevated leukocyte count (β = 0.0018; p < 0.0001). Logistic regression further showed that IL-6 increased the odds of DFI ≥ 30%, SDI ≥ 30%, and bacteriospermia (p < 0.05).

Conclusions: Seminal IL-6 emerges as a sensitive biomarker of immuno-oxidative stress and sperm dysfunction in infertile men. Its integration into clinical evaluation may improve the assessment of inflammatory and oxidative contributors to male infertility.

Objectives: To synthesize current evidence and emerging data on systemic treatment strategies for early-stage and locally advanced human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), with emphasis on treatment de-escalation and the integration of immunotherapy.

Data sources: We searched PubMed/MEDLINE, Scopus, and EMBASE for English-language studies published from 2010 to 2025 using terms related to HPV-positive disease, oropharyngeal carcinoma, de-escalation, chemoradiation, and immunotherapy.

Review methods: Peer-reviewed clinical trials, meta-analyses, and key translational studies addressing systemic therapy, biomarkers, and immunotherapeutic strategies in HPV-positive OPSCC were included. Emphasis was placed on phase II-III trials evaluating cisplatin-sparing regimens, cetuximab substitution, radiation dose reduction, and early-phase immunotherapy combinations. Evidence was synthesized qualitatively.

Results: Cisplatin-based concurrent chemoradiation remains the standard of care for locally advanced HPV-positive OPSCC. De-intensification trials suggest that reduced-intensity regimens may be feasible in carefully selected low-risk patients; however, replacing cisplatin with cetuximab results in inferior survival. PD-1 inhibitors (e.g., pembrolizumab, nivolumab) provide durable responses in recurrent/metastatic disease and are under active evaluation in earlier stages and in combination with therapeutic vaccines, bispecific antibodies, and viral-vector platforms.

Conclusions: Systemic therapy for HPV-positive OPSCC is moving toward biomarker-informed personalization. Cisplatin-based chemoradiation remains the curative backbone, while rational de-escalation and immunotherapy integration may preserve high cure rates while reducing long-term toxicity. Ongoing phase III trials will clarify which patient subsets are most suitable for de-intensified or immunotherapeutic approaches, guiding future standards of care.

Background: Bladder cancer remains a heterogeneous disease, and genetic factors are increasingly recognized as potential contributors to its pathogenesis. CD36, a multifunctional scavenger receptor implicated in lipid metabolism and tumor progression, has not been previously investigated in relation to bladder cancer-associated polymorphisms.

Objectives: This study examined the relationship between the rs1761667 variant and CD36 mRNA expression.

Methods: Our study included 30 patients with bladder cancer and 19 controls. PCR-RFLP genotyping for rs1761667 and RT-qPCR quantification of CD36 mRNA expression, with GAPDH as the reference gene, were performed. Expression levels were analyzed using the 2^-ΔΔCt method, and statistical significance was defined as p < 0.05.

Results: In patients, CD36 expression varied significantly across rs1761667 genotypes with reduced expression in AA carriers compared with GG carriers (post hoc, p = 0.009, with a Holm-adjusted p = 0.03). No significant genotype-related differences were observed among controls. Genotype distributions did not differ significantly between cases and controls (χ², p = 0.053).

Conclusions: These results indicate that rs1761667 may modulate CD36 transcription in a genotype-dependent manner, particularly in the disease context. Overall, our findings point to a potential biological connection between inherited CD36 variation and bladder cancer-related pathways, underscoring the need for further validation in tumor tissues.

Background: Accurate staging of bladder cancer is critical for guiding clinical management, particularly the distinction between non-muscle-invasive (T1) and muscle-invasive (T2-T4) disease. Although MRI offers superior soft-tissue contrast, image interpretation remains opera-tor-dependent and subject to inter-observer variability. This study proposes an automated deep learning framework for MRI-based bladder cancer staging to support standardized radio-logical interpretation.

Methods: A sequential AI-based pipeline was developed, integrating hybrid tumor segmentation using YOLOv11 for lesion detection and DeepLabV3 for boundary refinement, followed by three deep learning classifiers (VGG19, ResNet50, and Vision Transformer) for MRI-based stage prediction. A total of 416 T2-weighted MRI images with radiology-derived stage labels (T1-T4) were included, with data augmentation applied during training. Model performance was evaluated using accuracy, precision, recall, F1-score, and multi-class AUC. Performance un-certainty was characterized using patient-level bootstrap confidence intervals under a fixed training and evaluation pipeline.

Results: All evaluated models demonstrated high and broadly comparable discriminative performance for MRI-based bladder cancer staging within the present dataset, with high point estimates of accuracy and AUC, particularly for differentiating non-muscle-invasive from muscle-invasive disease. Calibration analysis characterized the probabilistic behavior of predicted stage probabilities under the current experimental setting.

Conclusions: The proposed framework demonstrates the feasibility of automated MRI-based bladder cancer staging derived from radiological reference labels and supports the potential of deep learning for stand-ardizing and reproducing MRI-based staging procedures. Rather than serving as an independent clinical decision-support system, the framework is intended as a methodological and work-flow-oriented tool for automated staging consistency. Further validation using multi-center datasets, patient-level data splitting prior to augmentation, pathology-confirmed reference stand-ards, and explainable AI techniques is required to establish generalizability and clinical relevance.