Search Results (359)

Neutrophils are increasingly recognized as key players in the tumor microenvironment (TME), displaying functional plasticity that enables them to either promote or inhibit cancer progression. Depending on environmental cues, tumor-associated neutrophils (TANs) may polarize toward antitumor “N1” or protumor “N2” phenotypes, exerting diverse effects on tumor growth, metastasis, immune modulation, and treatment response. While previous studies have focused on the pathological roles of TANs in cancer, less attention has been given to how cancer therapies themselves influence the behavior of TANs. This review provides a comprehensive synthesis of current knowledge regarding the dynamics of TANs in response to major cancer treatment modalities, including chemotherapy, radiotherapy, cell-based immunotherapies, and oncolytic viral and bacterial therapies. We discuss how these therapies influence TAN recruitment, polarization, and effector functions within the TME, and highlight key molecular regulators involved. By consolidating mechanistic and translational insights, this review emphasizes the potential to therapeutically reprogram TANs to enhance treatment efficacy. A deeper understanding of context-dependent TAN roles will be essential for developing more effective, neutrophil-informed cancer therapies. Full article

Background/Objectives: This study aims to evaluate the additional value of [¹⁸F]F-fluorocholine ([¹⁸F]F-FCH) PET/CT over contrast-enhanced magnetic resonance imaging (CE-MRI) in detecting the recurrence of brain metastases (BMs) after stereotactic radiosurgery (SRS) in patients with lung cancer brain metastases (LCBMs). Methods: Thirty-one patients with suspected recurrence of BM in LCBM after SRS were enrolled in this retrospective study. They underwent both [¹⁸F]F-FCH PET/CT and CE-MRI within 2 weeks. The tumor imaging parameters and clinical features were analyzed. The results of histopathology or radiographic follow-up served as the reference standard for the final diagnosis. Results: In these 31 patients, there were 54 lesions, of which 27 lesions were proven to be BM recurrence, while 27 lesions were non-recurrence. [¹⁸F]F-FCH PET/CT showed high radiotracer uptake in recurrent lesions of BM and identified 24 positive lesions (88.89% of sensitivity), while CE-MRI indicated 23 positive lesions (85.19% of sensitivity). [¹⁸F]F-FCH PET/CT indicated higher specificity (81.48%) and accuracy (85.19%) in detecting recurrence of BM than CE-MRI (40.74% and 62.96%, both p < 0.05), particularly in frontal lobes and cerebella. For lesion sizes, the accuracy of [¹⁸F]F-FCH PET/CT in detecting recurrent lesions was higher than that of CE-MRI for lesions over 1.0 cm but below 2.0 cm (p = 0.016). The detective performance of [¹⁸F]F-FCH PET/CT combined with CE-MRI was higher than [¹⁸F]F-FCH PET/CT or CE-MRI alone (all p < 0.05). Interestingly, TLC (≥4.11) was significantly correlated with poor intracranial PFS (iPFS), meaning it was a significant prognostic factor for iPFS. Conclusions: This study identified that compared with CE-MRI, [¹⁸F]F-FCH PET/CT demonstrated higher specificity and accuracy in diagnosing recurrence of BM in LCBM after SRS. Combining [¹⁸F]F-FCH PET/CT with CE-MRI has the potential to improve diagnostic performance for recurrence of BM and management of patient treatment. TLC was an independent risk factor for iPFS. Full article

Background: The development of brain metastases (BM) is a relatively uncommon but significantly adverse event in the spread of colorectal cancer (CRC). Although management of CRC BM has improved with advances in imaging and systemic therapies, clinical outcomes remain poor. Methods: This retrospective cohort study used the U.S. National Cancer Database to evaluate survival outcomes, treatment patterns, and prognostic factors in CRC patients diagnosed with BM between 2010 and 2020. Patients with isolated brain-only metastases formed the primary analytic cohort, while those with additional extracranial metastases were included for descriptive comparison. Multivariable Cox proportional hazards and logistic regression models were used to assess factors associated with of survival. Proportional hazards assumptions were tested using Schoenfeld residuals. Accelerated failure time models were also employed. Results: From a cohort of 1,040,877 individuals with CRC, 795 had metastatic disease present along with relevant data, of which 296 had isolated BM. Median overall survival (mOS) in BM-only metastatic disease group was 7.82 months (95% CI: 5.82–9.66). The longest survival was observed among patients treated with stereotactic radiosurgery combined with systemic therapy (SRS+Sys), with a median OS of 23.26 months (95% CI: 17.51–41.95) and a 3-year survival rate of 35.8%. In adjusted Cox models, SRS, systemic therapy, and definitive surgery of the primary site were each independently associated with reduced hazard of death. Rectal cancer patients had longer survival than those with colon primaries (mOS: 10.35 vs. 6.08 months). Age, comorbidity burden, and insurance status were not associated with survival in adjusted analyses. Conclusions: SRS+Sys was associated with longer survival compared to other treatment strategies. However, treatment selection is highly dependent on individual clinical factors such as performance status, comorbidities, and disease extent; therefore, these findings must be interpreted with caution Future prospective studies incorporating molecular and biomarker data are warranted to better guide care in this rare and high-risk group. Full article

Objectives: Circulating tumor DNA (ctDNA) has emerged as a reliable prognostic biomarker in both early- and late-stage non-small cell lung cancer (NSCLC) patients. However, its role in NSCLC with pleural dissemination (M1a), a subset of disease with indolent biology, remains to be elucidated. Methods: We collected 41 M1a patients with serial ctDNA and CEA monitoring. Progression-free survival (PFS) was assessed between patients with different levels of ctDNA and CEA. An independent cohort of 61 M1a patients was included for validation. Results: At the diagnostic landmark, the detection rates for ctDNA and CEA were 22% and 55%, respectively. Among patients who experienced disease progression with pleural metastases, only ten had detectable ctDNA in longitudinal timepoints, resulting in a sensitivity of 50%. Moreover, there was no significant difference in PFS between patients with longitudinally detectable and undetectable ctDNA (HR: 0.86, 95% CI 0.33–2.23, p = 0.76). In contrast, patients with a decreasing CEA trend within 3 months after diagnosis were associated with an improved PFS (HR: 0.22; 95% CI, 0.03–1.48, p = 0.004). This finding is confirmed in an independent M1a patient cohort. Conclusions: Together, our findings suggest that M1a NSCLC with isolated pleural dissemination may represent a “non-shedding” tumor type, where ctDNA shows limited diagnostic and prognostic value. Monitoring early changes in CEA could be a more cost-effective predictor of disease progression. Full article

Colorectal liver metastasis (CRLM) poses a significant challenge in oncology due to its high incidence and poor prognosis in unresectable cases. Current treatments, including surgical resection, systemic chemotherapy, and liver-directed therapies, often fail to effectively target hypoxic tumor regions, which are inherently more resistant to these interventions. This review examines the potential of a novel therapeutic strategy combining irreversible electroporation (IRE) ablation and Clostridium novyi-nontoxic (C. novyi-NT) bacterial therapy. IRE is a non-thermal tumor ablation technique that uses high-voltage electric pulses to create permanent nanopores in cell membranes, leading to cell death while preserving surrounding structures, and is often associated with temporary tumor hypoxia due to disrupted perfusion. C. novyi-NT is an attenuated, anaerobic bacterium engineered to selectively germinate and proliferate in hypoxic tumor regions, resulting in localized tumor cell lysis while sparing healthy, oxygenated tissue. The synergy between IRE-induced hypoxia and hypoxia-sensitive C. novyi-NT may enhance tumor destruction and stimulate systemic antitumor immunity. Furthermore, the integration of advanced imaging and artificial intelligence can support precise treatment planning and real-time monitoring. This integrated approach holds promise for improving outcomes in patients with CRLM, though further preclinical and clinical validation is needed. Full article

Purpose: Neuroendocrine carcinomas (NECs) are aggressive tumors treated with cisplatin-based chemotherapy, though responses vary. As DNA damage response (DDR) pathways influence cisplatin sensitivity, this single-center retrospective study evaluates the efficacy of first-line cisplatin in recurrent or metastatic NEC based on DDR mutation status. Materials and Methods: This study analyzed patients with grade 3 recurrent or metastatic NEC treated with first-line etoposide plus cisplatin at Samsung Medical Center between January 2019 and September 2023. All patients underwent next-generation sequencing to determine DDR mutation status, defined by pathogenic alterations in major DNA repair pathways. Clinical outcomes were assessed per RECIST v1.1. Survival analyses were conducted using Kaplan–Meier methods and Cox regression models, with significance set at p ≤ 0.05. Results: A total of 40 patients with NEC were included in this study. There were 16 patients with DDR wild-type (WT) and 24 patients with DDR mutant type (MT). The most common primary tumor sites were the pancreas (25.0%), stomach (20.0%), and gallbladder/duct (12.5%). Among 40 patients, those with DDR mutations (n = 24) showed significantly higher objective response (58.3% vs. 12.5%) and disease control rates (91.7% vs. 50.0%) compared to patients with DDR WT (n = 16). The median progression-free survival (PFS) showed the favorable trend in the DDR mutant group (8.0 vs. 4.3 months; p = 0.15), with similar trends observed across homologous recombination repair (HRR), Fanconi anemia (FA), and mismatch repair (MMR) subgroups. Conclusions: This study revealed that patients with DDR mutations had significantly higher response to first-line etoposide–cisplatin, suggesting DDR mutation status as a potential predictive marker to guide treatment and improve outcomes in recurrent or metastatic NEC. Full article

REG3A, a prominent member of the human regenerating islet-derived (REG) lectin family, plays a pivotal and multifaceted role in immune defense, inflammation, and cancer biology. Primarily expressed in gastrointestinal epithelial cells, REG3A reinforces barrier integrity, orchestrates mucosal immune responses, and regulates host–microbiota interactions. It also functions as a potent non-enzymatic antioxidant, protecting tissues from oxidative stress. REG3A expression is tightly regulated by inflammatory stimuli and is robustly induced during immune activation, where it limits microbial invasion, dampens tissue injury, and promotes epithelial repair. Beyond its antimicrobial and immunomodulatory properties, REG3A contributes to the resolution of inflammation and the maintenance of tissue homeostasis. However, its role in cancer is highly context-dependent. In some tumor types, REG3A fosters malignant progression by enhancing cell survival, proliferation, and invasiveness. In others, it acts as a tumor suppressor, inhibiting growth and metastatic potential. These opposing effects are likely dictated by a combination of factors, including the tissue of origin, the composition and dynamics of the tumor microenvironment, and the stage of disease progression. Additionally, the secreted nature of REG3A implies both local and systemic effects, further modulated by organ-specific physiology. Experimental variability may also reflect differences in methodologies, analytical tools, and model systems used. This review synthesizes current knowledge on the pleiotropic functions of REG3A, emphasizing its roles in epithelial defense, immune regulation, redox homeostasis, and oncogenesis. A deeper understanding of REG3A’s pleiotropic effects could open up new therapeutic avenues in both inflammatory disorders and cancer. Full article

Background/Objectives: The metastatic patterns of apical lymph node (ALN) in rectal and sigmoid colon cancer are currently unclear, and there is no consensus on the indications for dissection of ALN. This study aimed to analyze the impact of ALN metastasis on prognosis, determine the metastatic patterns of ALN and provide evidence for indications of ALN dissection in rectal and sigmoid colon cancer. Methods: In this multicenter, retrospective cohort study, patients from five centers with stage I-III rectal or sigmoid colon cancer who underwent laparoscopic radical surgery with ALN dissection without neoadjuvant treatment from January 2015 to December 2019 were enrolled. Results: Among 2809 patients, the positive rate of ALN was 1.9%. The 5-year overall survival and cancer-specific survival rate for patients with metastatic ALN were 37.5% and 41.0%, respectively. ALN metastasis was the independent risk factor for poor prognosis. Tumor size ≥5 cm (OR = 2.32, 95% CI: 1.30–4.13, p = 0.004), signet ring cell cancer/mucinous adenocarcinoma (vs. poor differentiated adenocarcinoma, OR = 0.19, 95% CI: 0.08–0.45, p < 0.001; vs. moderate to well differentiated adenocarcinoma, OR = 0.22, 95% CI: 0.11–0.42, p < 0.001), T4 stage (OR = 1.93, 95% CI: 1.05–3.55, p = 0.034), N2 stage (OR = 8.86, 95% CI: 4.45–17.65, p < 0.001) and radiologic evidence of extramural venous invasion (OR = 1.88, 95% CI: 1.03–3.42, p = 0.040) were independent risk factors for ALN metastasis. The nomogram model developed by these factors achieved a good predictive performance. Conclusions: This research offered insights into the incidence, risk factors, and prognostic significance of apical lymph node metastasis in cases of rectal and sigmoid colon cancer. Additionally, the study furnished empirical support for the criteria guiding ALN dissection. Furthermore, a pragmatic risk assessment model was developed to predict ALN metastasis. Full article

As tumor research has deepened, the deregulation of cellular metabolism has emerged as yet another recognized hallmark of cancer. Tumor cells adapt different biochemical pathways to support their rapid growth, proliferation, and invasion, resulting in distinct anabolic and catabolic activities compared with healthy tissues. Certain metabolic shifts, such as altered glucose and glutamine utilization and increased de novo fatty acid synthesis, are critical early on, while others may become essential only during metastasis. These metabolic adaptations are closely shaped by, and in turn remodel, the tumor microenvironment, creating favorable conditions for their spread. Anticancer metabolic strategies should integrate pharmacological approaches aimed at inhibiting specific biochemical pathways with well-defined dietary interventions as adjunctive therapies, considering also the role of gut microbiota in modulating diet and treatment responses. Given the established link between the consumption of foods rich in saturated fatty acids and sugars and an increased cancer risk, the effects of diet cannot be ignored. However, current evidence from controlled and multicenter clinical trials remains insufficient to provide definitive clinical recommendations. Further research using modern omics methods, such as metabolomics, proteomics, and lipidomics, is necessary to understand the changes in the metabolic profiles of various cancers at different stages of their development and to determine the potential for modifying these profiles through pharmacological agents and dietary modifications. Therefore, clinical trials should combine standard treatments with novel approaches targeting metabolic reprogramming, such as inhibition of specific enzymes and transporters or binding proteins, alongside the implementation of dietary restrictions that limit nutrient availability for tumor growth. However, to optimize therapeutic efficacy, a precision medicine approach should be adopted that balances the destruction of cancer cells with the protection of healthy ones. This approach, among others, should be based on cell type-specific metabolic profiling, which is crucial for personalizing oncology treatment. Full article

Background: Treatment of metastatic cancer remains a challenge, because cancer cells acquire resistance even to the most contemporary therapies. This study analyzed the role of the phosphoprotein Stathmin 1 (STMN1) in regulating cancer cell growth and metastatic potential. Methods: Public datasets with metastatic castration-resistant prostate cancer (mCRPC) and breast cancer (BC) were analyzed to determine the interrelationship between STMN1, hepatocyte growth factor (HGF) and MET proto-oncogene (MET) expression, overall survival, and response to chemotherapy. Site-directed mutagenesis, cell cycle analysis, proliferation, and migration and invasion assays determined the impact of STMN1 phosphorylation on proliferation and metastatic potential. Results: Increased STMN1 associates with HGF and MET gene expression in mCRPC, and taxane chemotherapy further increases HGF expression. STMN1 and HGF are highest, and overall survival is poorest in mCRPC in the liver compared to other sites, implying the metastatic site influences their expression levels and potentially the pattern of metastatic spread. Increased STMN1 and MET also predict taxane responsiveness in BC patients. Analysis of STMN1 serine (S)16, 25, 38, and 63 determined that total (t) STMN1 and STMN1 S16 phosphorylation (pSTMN1^S16) are co-regulated by HGF/MET during cell cycle progression, pSTMN1^S16 alone can promote cell proliferation, and pSTMN1^S16 shortens the cell cycle similar to HGF treatment, while STMN1^S16 dephosphorylation lengthens the cell cycle to arrest cell growth in G2/M, similar to HGF plus the MET inhibitor AMG337. Importantly, STMN1^S16 does not promote metastasis. Conclusions: Selectively inhibiting STMN1^S16 phosphorylation may provide an alternative strategy for inhibiting MET-mediated cell growth to eliminate metastatic cancer cells and inhibit further metastasis. Full article

Background: Melanoma management has been revolutionized by the use of immune checkpoint inhibitors (ICIs). However, ICIs are associated with immune-related adverse events (irAEs), including rhinosinusitis, which remains underexplored. This study evaluated the incidence, characteristics, management, and prognostic implications of rhinosinusitis in patients with melanoma under ICIs. Methods: A retrospective analysis was conducted on adult patients with melanoma treated with ICIs. Demographic, clinical, laboratory, treatment, and survival data were collected. Rhinosinusitis was defined radiographically and graded using the Harvard scoring system. Associations between rhinosinusitis and survival outcomes were analyzed. Results: Among 304 patients, 64 (21.1%) developed imaging-confirmed rhinosinusitis during ICI treatment, with 9.4% symptomatic cases. Rhinosinusitis was the sole irAE in 11.8% of patients, and 9.2% experienced it alongside other irAEs. A significant correlation with eosinophilia was observed: 39.6% of eosinophilic patients developed rhinosinusitis versus 17.1% without eosinophilia (p < 0.001). Most cases occurred during the first ICI line (86.4%), particularly with nivolumab monotherapy (32.8%). Importantly, in metastatic melanoma, rhinosinusitis was associated with significantly longer overall survival since ICI initiation (OS_ICI) compared to patients without rhinosinusitis (33.3 vs. 15.4 months, p = 0.025). No survival benefit was observed in the adjuvant setting. The condition was predominantly aseptic, and corticosteroids were used in 7.8%. Conclusions: This study highlights rhinosinusitis as an irAE associated with improved OS in metastatic melanoma. Further research is required to elucidate the underlying mechanisms and assess the resolution of rhinosinusitis after ICI discontinuation. Additionally, rhinosinusitis may serve as a marker of favorable prognosis in metastatic melanoma patients receiving ICIs. Full article

Recent advances in technology and pharmacologic agents have significantly improved both local and systemic therapies, making the treatment of non-small cell lung cancer (NSCLC) more effective and less invasive. However, recurrence after radical resection remains a major clinical challenge. Among the various recurrence patterns, oligo-recurrence—particularly metachronous oligo-recurrence, characterized by a limited number of metastatic lesions appearing after a disease-free interval—has gained attention due to its potential for long-term survival and even cure through local therapy. Concurrently, systemic treatments have advanced with the development of molecularly targeted therapies and immune checkpoint inhibitors. Numerous studies have demonstrated their clinical efficacy, resulting in significant improvements in patient prognosis. Therefore, selecting an appropriate treatment strategy for recurrent NSCLC involves a broad spectrum of therapeutic options, including targeted therapies, immune checkpoint inhibitors, and conventional chemotherapy. Treatment decisions are particularly complex in cases of oligo-recurrence, where local therapy is feasible, making it challenging to choose the best approach from the available options. This narrative review summarizes current evidence from retrospective and ongoing prospective trials and discusses the clinical characteristics and treatment strategies for oligo-recurrent NSCLC. Full article

Background: Intraoperative ultrasound (IOUS) provides real-time imaging during brain tumor surgery but remains underused in brain metastasis resection. This study evaluates the effectiveness of 2D IOUS in improving the extent of resection compared to standard neuronavigation. Methods: We retrospectively analyzed 55 adult patients with brain metastases treated surgically at a single center. Patients were divided into two groups: IOUS-guided surgery (n = 20) and standard neuronavigation (n = 35). Gross total resection (GTR) was defined as the extent of resection > 96%, assessed volumetrically. Statistical analyses included chi-square tests, logistic regression, and ROC curve analysis. Results: GTR > 96% was achieved in 80% of IOUS-guided cases compared to 42.86% in the control group (p = 0.008). IOUS significantly increased the odds of achieving GTR (OR = 5.33, p = 0.011). Larger tumor volume reduced the likelihood of GTR (OR = 0.469, p = 0.025), but this effect was mitigated by IOUS use (interaction OR = 1.986, p = 0.044). The regression model showed excellent discrimination (AUC = 0.930, p < 0.001). Functional outcomes improved postoperatively in both groups. Conclusions: 2D IOUS significantly enhances the extent of resection in brain metastasis surgery, including that for larger tumors. Its accessibility, real-time feedback, and low cost support its wider adoption in neurosurgical practice, especially in settings with limited resources. Full article

Background: To overcome the limitations of conventional CRC (colorectal cancer) mouse models in replicating metastasis and enabling efficient therapeutic evaluation, we developed a novel implantation method using tissue adhesive to establish reproducible orthotopic and metastatic tumors. Conventional models using injection or suturing techniques often suffer from technical complexity, inconsistent tumor establishment, and limited metastatic reliability. Methods: We developed and validated a novel orthotopic and metastatic CRC model utilizing tissue adhesive for tumor transplantation. Uniform tumor fragments derived from bioluminescent HCT116/Luc xenografts were affixed to the cecum of nude mice. Tumor growth and metastasis were monitored through bioluminescence imaging and confirmed by the results of histological analysis of metastatic lesions. The model’s utility for therapeutic testing was evaluated using MK801, an NMDA receptor antagonist. Results: The biological-based model demonstrated rapid and reproducible tumor implantation (<5 min), consistent primary tumor growth, and robust metastasis to the liver and lungs. The biological-based approach achieved 80% tumor engraftment (4/5), with consistent metastasis to the liver and lungs in all mice, compared with lower and variable metastasis rates in injection (0%, 0/5) and suturing (20%, 1/5) methods. MK801 treatment significantly suppressed both primary tumor growth and metastasis, validating the model’s suitability for preclinical drug evaluation. Conclusions: By enabling rapid, reproducible, and spontaneous formation of metastatic lesions using a minimally invasive tissue adhesive technique, our model represents a significant methodological advancement that supports high-throughput therapeutic screening and bridges the gap between experimental modeling and clinical relevance in colorectal cancer research. Full article

Background/Objectives: Prolonged use of denosumab in patients with metastatic breast cancer has raised concerns about the development of medication-related osteonecrosis of the jaw (MRONJ). However, the threshold at which the risk increases remains unclear. Methods: This retrospective cohort study analyzed patients with breast cancer and bone metastases who received denosumab between May 2012 and August 2024. Associations between cumulative denosumab administration and MRONJ were evaluated using univariate and multivariate logistic regression analyses. A receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff for cumulative doses. Results: MRONJ developed in 101 patients (31.2%). Multivariate analysis identified cumulative denosumab administration (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.03–1.06; p < 0.001) and a history of tooth extraction (OR: 4.40, 95% CI: 2.23–8.71; p < 0.001) as independent risk factors for MRONJ. ROC analysis determined an optimal cutoff of 32 cumulative doses, with an area under the curve of 0.83 (95% CI: 0.78–0.88; p < 0.0001). Conclusions: Cumulative denosumab administration and history of tooth extraction were independent risk factors for MRONJ in patients with breast cancer and bone metastases. The risk of MRONJ increased after 32 cumulative doses, providing a clinically actionable threshold for risk assessment and patient monitoring. Full article