The aim of this study was to analyze the survival outcomes in different time periods (recent, 2016-2024; earlier, 2007-2015; historical, before 2007) for patients with brain metastasis managed with surgical resection and postoperative radiotherapy. Major changes in systemic therapy over time were hypothesized to translate into better survival. A retrospective analysis was performed that included 174 patients, largely with single brain metastasis and Karnofsky performance status (KPS) 80-100. Uni- and multivariate analyses of actuarial overall survival were performed. Three significant prognostic factors for survival emerged: KPS, primary tumor control, and administration of systemic therapy after treatment of brain metastasis. In all patients, and also those who received systemic therapy after treatment for brain metastasis, survival remained similar (median of 16 months) for all three time periods (recent, earlier, historical). In patients with controlled primary tumor, survival increased from 17.5 (historical) to 35.8 months, p=0.01. Patients with resected and postoperatively irradiated brain metastasis benefited from additional systemic therapy. Only one subgroup experienced major survival prolongation in more recent years: those with controlled primary tumor. Therefore, efforts to optimize primary tumor control, such as surgery and radical radiotherapy, may play an important role in multimodal treatment paradigms.

Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase known to function as a tumor suppressor by promoting ubiquitination and degradation of the Myc protein. In this study, we investigated the role of cyclin-dependent kinase 5 (CDK5) in regulating GSK-3β kinase activity, as well as Myc phosphorylation and ubiquitination. Four Ewing sarcoma cell lines were used in this study. Cells were transfected with a CDK5 expression vector, and cell proliferation, cell-cycle progression, and apoptosis were analyzed. We examined whether CDK5 alters the phosphorylation status of GSK-3β. In addition, siRNA-mediated knockdown and expression vectors were used to modulate CDK5 and GSK-3β expression, and the effects on Myc ubiquitination were evaluated. Compared with control cells, CDK5-overexpressing Ewing sarcoma cells showed increased proliferative capacity and enhanced cell-cycle progression. Under these conditions, dephosphorylation of GSK-3β at Tyr216 and phosphorylation at Ser9 as well as Ser389 - patterns consistent with the inactive form of GSK-3β - were observed. Concomitantly, ubiquitination of the Myc protein was reduced. In contrast, cells transfected with a GSK-3β expression vector exhibited increased Myc phosphorylation and ubiquitination. These findings suggest that functional impairment of GSK-3β and subsequent upregulation of Myc may promote the proliferation of Ewing sarcoma cells. Myc is normally phosphorylated by GSK-3β, which triggers its ubiquitination and proteasomal degradation. Although CDK5 is recognized as a cell-cycle-related kinase, our results demonstrate that CDK5 is associated with increased inhibitory phosphorylation of GSK-3β, resulting in functional suppression of its activity. As a result, GSK-3β-mediated phosphorylation of Myc is attenuated, leading to reduced ubiquitination and accumulation of Myc. Regulation of Myc expression through CDK5-mediated modulation of GSK-3β plays a critical role in controlling Ewing sarcoma cell proliferation and may represent a promising therapeutic target.

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. However, patient prognosis remains poor despite advances in our understanding of its molecular cytogenetics and pathogenesis. Differentiation therapy aims to overcome the characteristic differentiation blockade observed in leukemia cells, but its efficacy is limited to specific AML subtypes. Therefore, there is an urgent need to develop novel therapeutic agents for AML. To identify potential therapeutic candidates, we screened 100 US Food and Drug Administration-approved drugs by measuring CD11b expression. The anti-leukemia effects of tenofovir alafenamide (TAF) were evaluated using flow cytometry, MTS assays, cell proliferation assays, and trypan blue staining in U937 and THP-1 AML cells. Real-time polymerase chain reaction was performed to assess the expression of differentiation-associated genes and relative telomere length. Western blotting was used to detect proteins involved in the DNA-damage response. Through chemical screening, TAF was identified as a drug with significant differentiation-inducing activity in AML cells. TAF promoted differentiation while simultaneously reducing cell viability and inhibiting cell proliferation. Moreover, TAF exhibited synergistic effects when combined with cytarabine. TAF also suppressed cell proliferation in primary AML patient samples harboring various mutations. Mechanistically, TAF inhibited telomerase reverse transcriptase activity and increased generation of reactive oxygen species, thereby activating the DNA-damage response. TAF may serve as a promising novel therapeutic agent for the treatment of AML.

Management of inflammatory bowel disease-associated gastrointestinal cancers, including Crohn's disease-associated cancer and ulcerative colitis-associated cancer, remains challenging because of concerns regarding treatment-related toxicity and limited clinical data. We aimed to investigate the safety of chemotherapy in patients with inflammatory bowel disease-associated gastrointestinal cancer. This retrospective study analyzed 21 patients with inflammatory bowel disease-associated gastrointestinal cancer (Crohn's disease-associated cancer: 10; ulcerative colitis-associated cancer: 11) who received chemotherapy or chemoradiotherapy between 2010 and 2024. Chemotherapy regimens, adverse events, treatment completion rates, and residual small intestinal lengths in patients with Crohn's disease were evaluated. Oxaliplatin-based chemotherapy was the most commonly used chemotherapeutic regimen. Dose reduction was required in all patients with Crohn's disease-associated cancer and in 64% of those with ulcerative colitis-associated cancer, primarily because of diarrhea or neurotoxicity. In the Crohn's disease-associated cancer group, diarrhea occurred in all patients and was significantly more severe in those with shorter residual small intestines (p=0.02). Despite these toxicities, 80% of patients with Crohn's disease-associated cancer and 55% of those with ulcerative colitis-associated cancer completed the planned chemotherapy regimen. No inflammatory bowel disease flares or need for corticosteroids or biologics occurred during treatment. Chemoradiotherapy was administered to five patients with Crohn's disease-associated cancer and locally advanced anorectal cancer, with no major safety concerns. Chemotherapy, including chemoradiotherapy, can be safely administered to patients with inflammatory bowel disease-associated gastrointestinal cancer with careful management. In Crohn's disease-associated cancer, residual small intestinal length is a key factor in predicting gastrointestinal toxicity severity, particularly diarrhea. Individualized dose adjustments and close monitoring are essential to balance cancer treatment efficacy with the unique risks associated with inflammatory bowel disease.

This study investigated the effectiveness of a protocol-based pharmacotherapy management (PBPM) system in preventing hepatitis B virus (HBV) reactivation induced by chemotherapy. This protocol requires pharmacists to verify orders for hepatitis B (HB) surface antigen (HBsAg), anti-HB core antibody (HBcAb), anti-HBs antibody (HBsAb), and HBV-deoxyribonucleic acid (DNA) tests before the start of chemotherapy. Pharmacists are also required to enter any missing test orders after confirming them with physicians. We retrospectively compared the implementation rates of HBsAg, HBcAb, HBsAb, and HBV-DNA tests using the chi-squared test across the following three periods: the pre-PBPM system implementation (pre-PBPM) period (July to September 2021; n=203), the ≤6 month post-PBPM system implementation (≤6M post-PBPM) period (November 2021 to April 2022; n=453), and the >6 month post-implementation (>6M post-PBPM) period (May to July 2022; n=245). The implementation rate of HBsAg tests remained at 100% throughout the entire study period. The overall HBsAg positivity rate was 2.0% (18/901). The implementation rates of HBcAb/HBsAb tests increased significantly, from 59.6% (121/203; pre-PBPM period) to 91.2% (413/453; ≤6M post-PBPM period, p<0.001) and to 98.0% (240/245; >6M post-PBPM period, p<0.001). The HBcAb/HBsAb positivity rates and HBV-DNA implementation rates in the respective periods were 33.1% (40/121), 26.9% (111/413), and 23.8% (57/240), and 90.0% (36/40), 89.2% (99/111), and 91.2% (52/57), with no statistically significant differences observed. No cases of HBV reactivation were observed during the study period. Introduction of the PBPM system significantly contributed to the improvement in the implementation rates of HBsAb/HBcAb testing.

Cancer has been described as the perennial second leading cause of death, despite advances in detection and treatment. Considering this disease remains a major public health crisis across the world, scientists have been looking for additional anticancer drugs options. In this context, the privileged scaffold quinoline appears to be an interesting chemical structure to develop new anticancer drugs, especially when more efficient synthetic routes to form these compounds are proposed. A total of five quinoline derivatives were obtained by applying the adapted methodology of Skraup and Doebner-von Miller and Heck-Mizoroki. The anticancer profile was investigated on cervical cancer (HeLa and Me-180) and chronic myeloid leukemia (K562) cell lines, by using the MTT or FACSVerse flow cytometer assays. Treatment of Vero cells was performed to assess the Selectivity Index, followed by the type of cell death assessment (apoptosis and necrosis) for the most active and safe derivative. ADMET profile was investigated by using SwissADME platform and DataWarrior® software. The most promising result was achieved with derivative 3, with best antiproliferative activity especially against cervical cancer cell lines (HeLa: IC50 15.13 μM and Me-180: IC50 46.90 μM) and safe profile compared to Vero cells and in silico prediction. The type of cell death was mostly related to late apoptosis. All quinoline derivatives demonstrated druglikeness in agreement with Lipinski and Veber rules. Our findings provide quinoline derivatives with anticancer activity, which may pave the way for new alternatives for anticancer drug development.

FAS/FAS-ligand (FAS-L) complex is implicated in critical cell functions including programmed cell death (apoptosis) and immune response regulation. FAS and FAS-ligand are members of the tumor necrosis factor (TNF) superfamily. Their activation triggers the caspase-mediated apoptotic cataract. The aim of this study was to investigate the role of their altered co-expression in a series of laryngeal squamous cell carcinomas (LSCCs). A set of fifty (n=50) LSCC archival tissue sections was analyzed by performing a combination of immunohistochemistry (IHC) and digital image analysis (DIA) assays for determining the expression of FAS/FAS-L expression. A broad spectrum of FAS/FAS-L expression values were detected across the examined cases. A significant negative correlation was found between FAS and FAS-L overall expression (p<0.001) indicating that higher FAS expression is associated with lower FAS-L expression. Furthermore, the expression of FAS was highest in stage IV carcinomas, whereas FAS-L was higher in stage III tumors, however, the differences were not statistically significant (p=0.260, p=0.101, respectively). Concerning the size of the examined malignancies (max diameter), the FAS/FAS-L expression showed a statistically significant difference in both (p=0.001, p=0.011, respectively). According to their expression status, larger tumors tend to demonstrate higher levels of FAS protein, whereas smaller tumors exhibit overexpression of FAS-L. FAS/FAS-L apoptotic system deregulation is a relatively frequent event in LSCCs. Dysregulation of the system - due to altered FAS and FAS-L co-expression levels - negatively affects the normal apoptotic mechanism. Additionally, this abnormality is clearly observed in aggressive phenotypes (advanced stage, enlarged tumor volume).

Repetitive magnetic stimulation (rMS) is used to treat neurological conditions. Understanding its modulatory effects requires investigating cellular processes and molecular pathways in vitro. This study aimed to standardize a prototype rMS stimulator-based cell culture method and evaluate tumorigenesis-related cellular and molecular parameters. Active (75-, 150-, and 300-sec exposure) or sham rMS was administered daily (4 days/300mT-1Hz) to two neuronal [SK-N-BE(2) and SH-SY5Y] and one non-neuronal (HOS) tumor line. Cell viability, cell death, and gene expression of BDNF, NGF, and their receptors, TRKB and TRKA, were evaluated immediately (0 h) and 24 h post-stimulation. Data were analyzed using Kruskal-Wallis/Dunn, one-way ANOVA/Bonferroni, or t-test. Both neuroblastoma cell lines, SH-SY5Y (150-sec) and SK-N-BE(2) (75-sec), exhibited increased viability compared to the 300-sec group immediately after treatment; however, none of the stimulated groups was different from sham. rMS increased BDNF, TRKB, NGF, and TRKA gene expression in the 75- and 300-sec groups across both neuroblastoma lines immediately after stimulation. Twenty-four h after rMS, a cell-line and stimulation-time specific reduction in gene expression was observed. Neither cell viability in the three cell lines under investigation, nor cell death in the SK-N-BE(2) were affected by rMS. Twenty-four h after sham or active rMS, all groups demonstrated increased cell viability compared to immediately post-stimulation. rMS did not affect cell viability or death in these in vitro models. In the 75- and 300-sec groups, increased neurotrophic gene expression was observed immediately after rMS exposure in both neuroblastoma cell lines, subsequently reducing after 24 h. These data demonstrate molecular effects that are specific to exposure time and cell line, validating this specific in vitro rMS prototype and stimulation protocol.

Chemotherapy-induced nausea and vomiting (CINV) remain major challenges during concurrent chemoradiotherapy (CCRT) for cervical cancer. Mannitol and furosemide are agents widely used to prevent cisplatin-induced nephrotoxicity; however, the differences in their effect on CINV have not been characterized. This study aimed to evaluate the impact of concomitant diuretic administration (mannitol versus furosemide) on the incidence and timing of vomiting in patients with cervical cancer undergoing CCRT. This multicenter, retrospective study evaluated the impact of concomitant diuretic administration on CINV in 485 patients receiving weekly, cisplatin-based CCRT between 2016 and 2024, including 206 who received mannitol and 279 who received furosemide. Vomiting occurred more frequently in the mannitol group than in the furosemide group (18.4% vs. 10.4%). Time-to-event analysis found that vomiting occurred earlier with mannitol during the entire CCRT course. These findings may reflect mannitol's osmotic properties and the increased, intestinal permeability associated with CCRT-related mucosal injury. To the best of our knowledge, this study is the largest investigation to date comparing diuretic agents in this setting. The results suggested that furosemide may be a more appropriate option for patients with a high risk of CINV.

Recent advances in cancer biology have revolutionized the development of targeted and combination therapies, offering new avenues for improving cancer management. Among the central molecular regulators, the mammalian target of rapamycin (mTOR) plays a pivotal role in orchestrating cell growth, metabolism, and survival. Aberrant activation of mTOR signaling driven by genetic mutations or dysregulation of upstream pathways such as phosphoinositide 3-kinase (PI3K)/AKT has been strongly implicated in cancer progression, metastasis, and therapeutic resistance. Consequently, mTOR has emerged as a promising target for anticancer drug development. Although synthetic mTOR inhibitors, including rapamycin and its analogs (rapalogs), have shown clinical benefits, their limited efficacy and the emergence of resistance have highlighted the need for novel strategies. Natural product-derived mTOR modulators have gained increasing attention due to their multi-targeted mechanisms of action, simultaneously modulating mTOR and its upstream or parallel signaling networks. These compounds exhibit potent anticancer properties, including suppression of tumor growth, induction of apoptosis, and reversal of drug resistance. This review elucidates the biological functions of mTOR in tumorigenesis and delineates its regulatory mechanisms underlying malignant phenotypes. Furthermore, it emphasizes the therapeutic promise of natural products as a rich source of mTOR inhibitors, providing insights for the rational design of innovative cancer therapies and combination regimens.