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Background/aim: The impact of enfortumab vedotin (EV) dose reduction and/or interruption on its efficacy for advanced urothelial carcinoma (UC) is unclear.

Patients and methods: We retrospectively analyzed consecutive patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to June 2024. Patients were categorized into three groups based on the calculated relative dose intensity (RDI): RDI<50%, RDI ≥50 to <80%, and RDI ≥80%.

Results: A total of 26 patients (male, n=15; median age, 72 years) were enrolled. The RDI was categorized as follows: ≥80% (n=13; 50.0%), ≥50 to <80% (n=7; 26.9%), and <50% (n=6; 23.1%). There were no marked differences in the overall response (p=0.921) or disease control rates (p=0.859) among the three groups categorized by the RDI. A log-rank test revealed no significant differences in either the progression-free survival (p=0.309) or the overall survival (p=0.704) according to RDI. There were no marked differences in the incidence of any-grade adverse events (AEs) (p=0.405) or grade ≥3 AEs (p=0.018) according to RDI. There were significant differences in the incidence of any-grade cutaneous AEs (p=0.038) and grade ≥3 cutaneous AEs (p=0.007) according to RDI. A multivariate analysis revealed that ECOG PS≥2 (p=0.009) and mixed UC (p=0.011) were independently associated with the prognosis.

Conclusion: Despite frequent dose reductions and interruptions required to manage treatment-emergent AEs during EV therapy, these adjustments did not significantly impair the drug's efficacy in patients with advanced UC.

Background/aim: Autologous stem cell transplantation (ASCT) is the standard strategy after induction therapy for newly diagnosed transplant-eligible multiple myeloma. High-dose melphalan (HDM) conditioning has been the recommended treatment regimen for a long time. No other conditioning regimen has been proven safer and more effective. Because bortezomib has a synergistic effect with melphalan, bortezomib with HDM (Bor-HDM) as a conditioning regimen has shown favorable outcomes, improved complete response rates after ASCT, and no prolonged hematological toxicities. However, few studies have reported long-term follow-up data. This study aimed to evaluate the long-term progression-free survival (PFS) and overall survival (OS) of patients receiving Bor-HDM conditioning, compared to those treated with HDM alone.

Patients and methods: This single-center retrospective study included 36 patients newly diagnosed with transplant-eligible myeloma from 2008 to 2020. In total, 15 patients received a Bor-HDM regimen, while 21 patients received HDM as a conditioning regimen. The probabilities of PFS and OS were plotted using the Kaplan-Meier method. All statistical analyses were performed using EZR software.

Results: After a median follow up of 77 months, no severe hematological toxicities were observed. The PFS and OS rates in the Bor-HDM group as compared with the HDM group were 0.762 vs. 0.60 (p=0.409) and 0.80 vs. 0.904 (p=0.476) respectively. No significant differences were observed between the two groups.

Conclusion: These long-term results show that Bor-HDM is a safe and effective option for ASCT conditioning regimens.

Background/aim: Enhanced recovery after surgery (ERAS) protocol is adopted in clinical practice worldwide, but a lack of evidence for measurable benefits after upper gastrointestinal (GI) surgeries can be detected especially regarding early oral feeding.

Patients and methods: A propensity score-matching study was conducted at the Department of Surgery of the University of Pécs between January 2020 and December 2023. The study included patients who underwent upper GI cancer surgery and were treated according to an early oral feeding protocol (EOF). Investigational and control groups were analyzed and compared from prospectively collected datasets.

Results: We enrolled 72 patients, 36 in the EOF group, and 36 case-matched patients in the traditional late oral feeding (LOF) group. Oral feeding in the EOF group started on an average of 1.94 days postoperatively, while in the LOF group, it began on an average of 5.72 days postoperatively. EOF could reduce the average length of hospital stay. Statistically significant decreases were observed in the EOF group concerning the time until the first bowel movements, and the length of postoperative intravenous fluid therapy. No significant differences were detected regarding mortality, anastomosis insufficiency, inflammation and stricture or seroma formation.

Conclusion: Early oral nutritional support positively impacts the recovery of patients following upper GI surgery without increasing mortality or anastomosis insufficiency rates compared to traditional protocols. Significant improvements were observed in quality of life indicators for patients in the early oral feeding group. This approach aligns with ERAS goals and suggests a valuable strategy for postoperative care in upper GI cancer surgeries.

The human bowel is exposed to numerous biotic and abiotic external noxious agents. Accordingly, the digestive tract is frequently involved in malfunctions within the organism. Together with the commensal intestinal flora, it regulates the immunological balance between inflammatory defense processes and immune tolerance. Pathological changes in this system often cause chronic inflammatory bowel diseases including Crohn's disease and ulcerative colitis. This review article highlights the complex interaction between commensal microorganisms, the intestinal microbiome, and the intestinal epithelium-localized local immune system. The main functions of the human intestinal microbiome include (i) protection against pathogenic microbial colonization, (ii) maintenance of the barrier function of the intestinal epithelium, (iii) degradation and absorption of nutrients and (iv) active regulation of the intestinal immunity. The local intestinal immune system consists primarily of macrophages, antigen-presenting cells, and natural killer cells. These cells regulate the commensal intestinal microbiome and are in turn regulated by signaling factors of the epithelial cells and the microbiome. Deregulated immune responses play an important role and can lead to both reduced activity of the commensal microbiome and pathologically increased activity of harmful microorganisms. These aspects of chronic inflammatory bowel disease have become the focus of attention in recent years. It is therefore important to consider the immunological-microbial context in both the diagnosis and treatment of inflammatory bowel diseases. A promising holistic approach would include the most comprehensive possible diagnosis of the immune and microbiome status of the patient, both at the time of diagnostics and during therapy.

Microbiome and radiotherapy represent bidirectionally interacting entities. The human microbiome has emerged as a pivotal modulator of the efficacy and toxicity of radiotherapy; however, a reciprocal effect of radiotherapy on microbiome composition alterations has also been observed. This review explores the relationship between the microbiome and extracranial solid tumors, particularly focusing on the bidirectional impact of radiotherapy on organ-specific microbiome. This article aims to provide a systematic review on the radiotherapy-induced microbial alteration in-field as well as in distant microbiomes. In this review, particular focus is directed to the oral and gut microbiome, its role in the development and progression of cancer, and how it is altered throughout radiotherapy. This review concludes with recommendations for future research, such as exploring microbiome modification to optimize radiotherapy-induced toxicities or enhance its anti-cancer effects.

Background/aim: Alzheimer's disease is a complex, incurable to date, multifactorial disease, which suggests the need for continued development of pharmacotherapy.

Materials and methods: A comprehensive literature search was conducted to identify known ligands with anticholinesterase activity, resulting in the discovery of over 100 alkaloids that are also available in the PubChem database. Subsequently, the ligands underwent molecular docking to evaluate their affinity for the target enzyme. The ligands with the greatest affinity were selected for ligand-based virtual screening.

Results: Three potential compounds were identified for further investigation: ZINC000055042508, ZINC000096316348, and ZINC000067 446933. Computational models of absorption, distribution, metabolism, and excretion (ADME) properties prediction using SwissADME suggested that ZINC000055042508 and ZINC000067446933 can permeate the blood-brain barrier and exhibit non-substrate behavior with respect to P-glycoprotein. In contrast, the ProTox-III prediction indicated the potential for all three compounds to penetrate the blood-brain barrier.

Conclusion: These alkaloid derivatives warrant further investigation as potential acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

Background/aim: Silicosis, the most severe type of occupational pneumoconiosis, leads to diffuse pulmonary fibrosis without specific therapy. Ferroptosis is triggered by reactive oxygen species (ROS) and Fe²⁺ overload-induced lipid peroxidation, which is involved in the progression of pulmonary fibrosis. As an important coenzyme in the process of aerobic respiration, Coenzyme Q10 (CoQ10) can enhance mitochondrial function and energy supply and reduce malondialdehyde (MDA) to limit the risk of fibrosis. We aimed to clarify whether ferroptosis is involved in the process of coenzyme CoQ10-treated silicosis fibrosis.

Materials and methods: C57BL/6J mice were divided in 3 groups (n=6 in each group). In the normal group, mice underwent sham operation; in the silicosis group, mice were tracheally instilled with SiO₂ suspension; in CoQ10 group, mice with silicosis were treated with CoQ10 solution. Histological analyses were performed to assess the lung injury level. Iron content was measured by colorimetry in lung tissue. The levels of MDA in lung tissue were characterized by immunofluorescence staining. The level of alpha smooth muscle actin (α-SMA), Collagen I, GPX4, p53 expression was analyzed by qRT-PCR and western blotting.

Results: CoQ10 significantly reduced the mRNA and protein expression levels of α-SMA and collagen I in silicosis lung tissues. It is worth noting that CoQ10 significantly inhibited the accumulation of lipid peroxidation and Fe²⁺ level by increasing the expression of ferroptosis regulatory core enzyme GPX4 and reducing its upstream regulator p53 in silicosis lung tissues.

Conclusion: CoQ10 alleviated silicosis fibrosis via inhibiting ferroptosis in mice. This finding is a new perspective for exploring the pathogenesis and treatment for silicosis.

Background/aim: Gangliosides regulate bone formation and resorption. Bone formation is reduced in mice lacking ganglioside GM2/GD2 synthase due to a decrease in osteoblasts. However, the effects of the loss of complex gangliosides by the deletion of both GM2/GD2 and GD3 synthases are unknown. Therefore, we investigated whether deletion of complex gangliosides in mice affected bone metabolism.

Materials and methods: Twenty-six double-knockout mice lacking both GM2/GD2 and GD3 synthases (dKO) and 30 wild-type (WT) mice as controls were used. The mass of cancellous bone and bone strength in femurs were determined using three-dimensional micro-computed tomography and three-point bending test, respectively. Bone formation and resorption were assessed using histomorphometrical analysis with hematoxylin and eosin, and tartrate-resistant acid phosphatase (TRAP), respectively. Osteoblast proliferation was determined by bromodeoxyuridine assay and the differentiation into osteoclasts by TRAP staining; mRNA levels of osteoclast differentiation markers [nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1); Trap; and cathepsin K (Ctsk)] were also determined.

Results: Bone mass increased in dKO mice, while bone formation and resorption decrease. In terms of bone strength, breaking displacement significantly increased in dKO mice. Furthermore, the proliferation of osteoblasts was suppressed, and the number of TRAP-positive multinucleated cells was reduced in dKO mice. Treatment with receptor activator of NF-[Formula: see text]B ligand significantly reduced Nfatc1, Trap and Ctsk mRNA levels in macrophages from dKO mice.

Conclusion: Bone formation and resorption were reduced by the deletion of genes for complex gangliosides. The slight increase in bone strength in dKO mice may be due to the cancellous bone volume increase in these mice.

Background/aim: Despite the seriousness of lung adverse events (AEs) associated with sorafenib, comprehensive data are limited. This study was conducted to examine the disproportionality, times to onset, incidence rates, and outcomes of sorafenib-associated lung AEs, using the Japanese Adverse Drug Event Report database.

Patients and methods: Data for the period between April 2004 and May 2023 were analyzed. Data on lung AEs were extracted, and the relative disproportionality of AEs was estimated using reporting odds ratios (RORs).

Results: A total of 2,230,863 reports were analyzed, and 8,374 reports of AEs associated with sorafenib, including 381 lung AEs, were identified. Signals were detected for two lung AEs: metastases to the lung and tracheal hemorrhage. Fatal outcomes were observed for both AEs. Histograms of the median times to onset of the two detected lung AE signals showed that AEs occurred from 49 to 275 days after sorafenib administration. Weibull distributions showed that the incidences of these AEs occurred constantly throughout the exposure period (random failure type).

Conclusion: This study focused on lung AEs associated with sorafenib, highlighting serious outcomes such as lung metastases and tracheal hemorrhage. Continuous monitoring for these AEs is crucial from treatment initiation through the entire therapy course.

Background/aim: Acute lung injury (ALI) is an important pathological process in acute respiratory distress syndrome; however, feasible and effective treatment strategies for ALI are limited. Recent studies have suggested that stem cell-derived exosomes can ameliorate ALI; however, there remains no consensus on the protocols used, including the route of administration. This study aimed to identify the appropriate route of administration of canine stem cell-derived exosomes (cSC-Exos) in ALI. Lipopolysaccharides were used to induce ALI.

Materials and methods: Mice with ALI were treated with cSC-Exos by intratracheal instillation or intravenous injection. The efficacy of the route of administration was confirmed by determining the total cell count in the bronchoalveolar lavage fluid and histopathological changes. The treatment mechanism was confirmed by measuring cytokine levels and immune cell changes in M2 macrophages (CD206+ cells) and regulatory T cells (FOXP+ cells).

Results: When cSC-Exos were injected, inflammation was alleviated, pro-inflammatory cytokine levels were reduced, and FOXP3+ and CD206+ cells were activated. Following intratracheal instillation, an enhanced inflammation-relieving response was observed.

Conclusion: This study compared the effects of stem cell-derived exosomes on alleviating lung inflammation according to injection routes in an ALI mouse model. It was confirmed that direct injection of exosomes into the airway had a greater ability to alleviate lung inflammation than intravenous injection by polarizing M2 macrophages and increasing regulatory T cells.