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12 pages, 463 KiB  
Article
Association Between BRAF V600E Allele Frequency and Aggressive Behavior in Papillary Thyroid Microcarcinoma
by Luiza Tatar, Saruchi Bandargal, Marc P. Pusztaszeri, Véronique-Isabelle Forest, Michael P. Hier, Jasmine Kouz, Raisa Chowdhury and Richard J. Payne
Cancers 2025, 17(15), 2553; https://doi.org/10.3390/cancers17152553 (registering DOI) - 1 Aug 2025
Abstract
Background/Objectives: Papillary thyroid microcarcinoma (MPTC), a subset of papillary thyroid carcinoma (PTC), is increasingly detected with advanced imaging. While most MPTCs are indolent, some exhibit aggressive behavior, complicating clinical management. The BRAF V600E mutation, common in PTC, is linked to aggressive features, [...] Read more.
Background/Objectives: Papillary thyroid microcarcinoma (MPTC), a subset of papillary thyroid carcinoma (PTC), is increasingly detected with advanced imaging. While most MPTCs are indolent, some exhibit aggressive behavior, complicating clinical management. The BRAF V600E mutation, common in PTC, is linked to aggressive features, and its allele frequency (AF) may serve as a biomarker for tumor aggressiveness. This study explored the association between BRAF V600E AF and aggressive histopathological features in MPTC. Methods: Data from 1 January 2016 to 23 December 2023 were retrieved from two McGill University teaching hospitals. Inclusion criteria comprised patients aged ≥ 18 years with thyroid nodules ≤ 1 cm, documented BRAF V600E mutation and AF results, and available surgical pathology reports. Tumor aggressiveness was defined as the presence of lymph node metastasis, aggressive histological subtype (tall cell, hobnail, columnar, solid/trabecular or diffuse sclerosing), extra thyroidal extension, or extensive lymphovascular extension. Associations were explored using t-tests. Results: Among 1564 records, 34 met the inclusion criteria and were included in analyses. The mean BRAF V600E AF was significantly higher in aggressive tumors (23.58) compared to non-aggressive tumors (13.73) (95% CI: −18.53 to −1.16, p = 0.03). Although not statistically significant, trends were observed for higher BRAF V600E AF in tumors with lymph node metastasis (mean AF: 25.4) compared to those without (mean AF: 16.67, p = 0.08). No significant difference was noted in BRAF V600E AF by histological subtype (mean AF for aggressive: 19.57; non-aggressive: 19.15, p = 0.94). Conclusions: Elevated BRAF V600E AF is associated with aggressive behavior in MPTC, highlighting its potential as a biomarker to inform treatment strategies. Larger studies are warranted to validate these findings and enhance clinical management of MPTC patients. Full article
(This article belongs to the Special Issue Thyroid Cancer: Diagnosis, Prognosis and Treatment (2nd Edition))
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8 pages, 2841 KiB  
Case Report
Melanotrichoblastoma: A Histopathological Case Report of a Rare Pigmented Variant of Trichoblastoma
by George S. Stoyanov, Ivaylo Balabanov, Svetoslava Zhivkova and Hristo Popov
Reports 2025, 8(3), 130; https://doi.org/10.3390/reports8030130 (registering DOI) - 1 Aug 2025
Abstract
Background and clinical significance: Trichoblastomas are rare, mixed epithelial tumors with a mesenchymal component and hair follicle differentiation. Case presentation: Herein, we present a case report of a 51-year-old female patient presenting to the obstetrics and gynecology department with complaints of edema and [...] Read more.
Background and clinical significance: Trichoblastomas are rare, mixed epithelial tumors with a mesenchymal component and hair follicle differentiation. Case presentation: Herein, we present a case report of a 51-year-old female patient presenting to the obstetrics and gynecology department with complaints of edema and erythema of the right Bartholin gland, and a lesion measuring 2 cm on the right lateral edge of the mons pubis, towards the inguinal fold. Marsupialization of the Bartholin gland was performed, as well as an incision into the pubo-inguinal lesion, which the patient depicted as grossly resembling an ingrown hair. Upon incision into the pubic–inguinal lesion, it was dark brown in color and spontaneously popped out of the subcutis, without an attempt at enucleation. Histology and subsequent immunohistochemistry of the lesion showed a blue basaloid tumor with an extensive pigment component located deep in the dermis that was sharply demarcated from the surrounding tissues. Conclusion: Immunohistochemistry was diffusely and strongly positive for epithelial markers; melanocytic markers were positive only in dendritic melanocytes dispersed within the tumors, and the proliferative index was low. As such, the tumor was identified as melanotrichoblastoma. Full article
(This article belongs to the Section Dermatology)
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10 pages, 1246 KiB  
Case Report
Synchronous Ovarian Sertoli–Leydig Cell and Clear Cell Papillary Renal Cell Tumors: A Rare Case Without Mutations in Cancer-Associated Genes
by Manuela Macera, Simone Morra, Mario Ascione, Daniela Terracciano, Monica Ianniello, Giovanni Savarese, Carlo Alviggi, Giuseppe Bifulco, Nicola Longo, Annamaria Colao, Paola Ungaro and Paolo Emidio Macchia
Curr. Oncol. 2025, 32(8), 429; https://doi.org/10.3390/curroncol32080429 - 30 Jul 2025
Viewed by 31
Abstract
(1) Background: Sertoli–Leydig cell tumors (SLCTs) are rare ovarian neoplasms that account for less than 0.5% of all ovarian tumors. They usually affect young women and often present with androgenic symptoms. We report a unique case of a 40-year-old woman diagnosed with both [...] Read more.
(1) Background: Sertoli–Leydig cell tumors (SLCTs) are rare ovarian neoplasms that account for less than 0.5% of all ovarian tumors. They usually affect young women and often present with androgenic symptoms. We report a unique case of a 40-year-old woman diagnosed with both SLCT and clear cell papillary renal cell carcinoma (CCP-RCC), a rare tumor association with unclear pathogenesis. (2) Methods: Both tumors were treated surgically. The diagnostic workup included hormonal testing, imaging studies, and extensive genetic testing, including DICER1 mutation analysis and multiplex ligation-dependent probe amplification (MLPA), as well as the examination of a next-generation sequencing (NGS) panel covering ~280 cancer-related genes. (3) Results: Histopathologic examination confirmed a well-differentiated SLCT and CCP-RCC. No pathogenic variants in DICER1 were identified by WES or MLPA. No clinically relevant changes were found in the extended NGS panel either, so a known hereditary predisposition could be ruled out. The synchronous occurrence of both tumors without genomic alterations could indicate a sporadic event or as yet unidentified mechanisms. (4) Conclusions: This case highlights the importance of a multidisciplinary approach in the management of rare tumor compounds. The exclusion of DICER1 mutations and the absence of genetic findings adds new evidence to the limited literature and underscores the importance of long-term surveillance and further research into potential shared oncogenic pathways. Full article
(This article belongs to the Section Gynecologic Oncology)
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26 pages, 4256 KiB  
Review
Progress in Pharmacokinetics, Pharmacological Effects, and Molecular Mechanisms of Swertiamarin: A Comprehensive Review
by Hao-Xin Yang, Ying-Yue Hu, Rui Liang, Hong Zheng and Xuan Zhang
Cells 2025, 14(15), 1173; https://doi.org/10.3390/cells14151173 - 30 Jul 2025
Viewed by 155
Abstract
Swertiamarin (SW), a natural iridoid glycoside primarily isolated from the genus Swertia, Gentianaceae family, has been extensively utilized in traditional medicine systems, including Ayurveda, Traditional Chinese Medicine, and Tibetan medicine, for treating fever, diabetes, liver disorders, and inflammatory conditions. Pharmacokinetic studies reveal [...] Read more.
Swertiamarin (SW), a natural iridoid glycoside primarily isolated from the genus Swertia, Gentianaceae family, has been extensively utilized in traditional medicine systems, including Ayurveda, Traditional Chinese Medicine, and Tibetan medicine, for treating fever, diabetes, liver disorders, and inflammatory conditions. Pharmacokinetic studies reveal that SW exhibits rapid absorption but demonstrates low oral bioavailability due to the first-pass effect. Pharmacological studies have demonstrated that SW possesses a wide range of pharmacological activities, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and neuroprotective activities. Our analysis demonstrates that SW exerts remarkable therapeutic potential across multiple pathological conditions through coordinated modulation of key signaling cascades, including Nrf2/HO-1, NF-κB, MAPK, PI3K/Akt, and PPAR pathways. This comprehensive review systematically consolidates current knowledge on SW’s pharmacokinetic characteristics, toxicity, diverse biological activities, and underlying molecular mechanisms based on extensive preclinical evidence, establishing a scientific foundation for future drug development strategies and potential clinical applications of the potential natural lead compound. Full article
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22 pages, 1703 KiB  
Article
Towards Personalized Precision Oncology: A Feasibility Study of NGS-Based Variant Analysis of FFPE CRC Samples in a Chilean Public Health System Laboratory
by Eduardo Durán-Jara, Iván Ponce, Marcelo Rojas-Herrera, Jessica Toro, Paulo Covarrubias, Evelin González, Natalia T. Santis-Alay, Mario E. Soto-Marchant, Katherine Marcelain, Bárbara Parra and Jorge Fernández
Curr. Issues Mol. Biol. 2025, 47(8), 599; https://doi.org/10.3390/cimb47080599 - 30 Jul 2025
Viewed by 84
Abstract
Massively parallel or next-generation sequencing (NGS) has enabled the genetic characterization of cancer patients, allowing the identification of somatic and germline variants associated with their diagnosis, tumor classification, and therapy response. Despite its benefits, NGS testing is not yet available in the Chilean [...] Read more.
Massively parallel or next-generation sequencing (NGS) has enabled the genetic characterization of cancer patients, allowing the identification of somatic and germline variants associated with their diagnosis, tumor classification, and therapy response. Despite its benefits, NGS testing is not yet available in the Chilean public health system, rendering it both costly and time-consuming for patients and clinicians. Using a retrospective cohort of 67 formalin-fixed, paraffin-embedded (FFPE) colorectal cancer (CRC) samples, we aimed to implement the identification, annotation, and prioritization of relevant actionable tumor somatic variants in our laboratory, as part of the public health system. We compared two different library preparation methodologies (amplicon-based and capture-based) and different bioinformatics pipelines for sequencing analysis to assess advantages and disadvantages of each one. We obtained 80.5% concordance between actionable variants detected in our analysis and those obtained in the Cancer Genomics Laboratory from the Universidad de Chile (62 out of 77 variants), a validated laboratory for this methodology. Notably, 98.4% (61 out of 62) of variants detected previously by the validated laboratory were also identified in our analysis. Then, comparing the hybridization capture-based library preparation methodology with the amplicon-based strategy, we found ~94% concordance between identified actionable variants across the 15 shared genes, analyzed by the TumorSecTM bioinformatics pipeline, developed by the Cancer Genomics Laboratory. Our results demonstrate that it is entirely viable to implement an NGS-based analysis of actionable variant identification and prioritization in cancer samples in our laboratory, being part of the Chilean public health system and paving the way to improve the access to such analyses. Considering the economic realities of most Latin American countries, using a small NGS panel, such as TumorSecTM, focused on relevant variants of the Chilean and Latin American population is a cost-effective approach to extensive global NGS panels. Furthermore, the incorporation of automated bioinformatics analysis in this streamlined assay holds the potential of facilitating the implementation of precision medicine in this geographic region, which aims to greatly support personalized treatment of cancer patients in Chile. Full article
(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era, 2nd Edition)
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13 pages, 596 KiB  
Review
Drug Repurposing of New Treatments for Neuroendocrine Tumors
by Stefania Bellino, Daniela Lucente and Anna La Salvia
Cancers 2025, 17(15), 2488; https://doi.org/10.3390/cancers17152488 - 28 Jul 2025
Viewed by 218
Abstract
Drug repurposing or drug repositioning is the process of identifying new therapeutic uses for approved or investigational drugs beyond the original treatment indication. The discovery of new drugs for cancer therapy needs this cost-effective and time-saving alternative strategy to traditional drug development for [...] Read more.
Drug repurposing or drug repositioning is the process of identifying new therapeutic uses for approved or investigational drugs beyond the original treatment indication. The discovery of new drugs for cancer therapy needs this cost-effective and time-saving alternative strategy to traditional drug development for a rapid clinical translation in Phase II/III studies, especially for unmet medical needs and rare diseases. Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms arising from cells of the neuroendocrine system that, though often indolent, can be aggressive and metastatic. In this context, drug repurposing has emerged as a promising strategy to improve treatment options due to the limited number of effective treatments and the heterogeneity of the disease. Indeed, a large number of non-oncology drugs have the potential to address more than one target that could be therapeutic for cancer patients. Although many repurposed drugs are used off-label, efficacy for the new use must be demonstrated in clinical trials. Within regulatory frameworks, both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have procedures to reduce the need for extensive new studies and to expedite the review of drugs for serious conditions when preliminary evidence indicates substantial clinical improvement over available therapy. In spite of several advantages, including reduced development time, lower costs, known safety profiles, and faster regulatory approval, difficulty in obtaining new patents for old drugs with limited protection for intellectual property may reduce commercial returns and disincentivize investments. This review aims to provide comprehensive information on some marketed drugs currently under investigation to be repurposed or used in clinical practice for NETs and to discuss the major clinical challenges. Although drug repurposing is a useful strategy for early access to medicines, the monitoring of the clinical benefit of oncologic drugs during the post-marketing authorization is crucial to support the safety and effectiveness of treatments. Full article
(This article belongs to the Special Issue Advances in Drug Repurposing to Overcome Cancers)
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32 pages, 1740 KiB  
Review
Cancer-Associated Fibroblasts: Immunosuppressive Crosstalk with Tumor-Infiltrating Immune Cells and Implications for Therapeutic Resistance
by Jogendra Singh Pawar, Md. Abdus Salam, Md. Shalman Uddin Dipto, Md. Yusuf Al-Amin, Moushumi Tabassoom Salam, Sagnik Sengupta, Smita Kumari, Lohitha Gujjari and Ganesh Yadagiri
Cancers 2025, 17(15), 2484; https://doi.org/10.3390/cancers17152484 - 28 Jul 2025
Viewed by 345
Abstract
Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within [...] Read more.
Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within the complex ecosystem of TME, with significant heterogeneity and plasticity in origin and functional phenotypes. Very enigmatic cells, CAFs determine the progress and outcomes of tumors through extensive reciprocal signaling with different tumors infiltrating immune cells in the TME. In their biological drive, CAFs release numerous chemical mediators and utilize various signaling pathways to recruit and modulate tumor-infiltrating immune cells. The CAF-induced secretome and exosomes render immune cells ineffective for their antitumor activities. Moreover, by upregulating immune inhibitory checkpoints, CAFs create an immunosuppressive TME that impedes the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs). Further, by depositing and remodeling extracellular matrix (ECM), CAFs reshape the TME, which enhances tumor growth, invasion, metastasis, and chemoresistance. Understanding of CAF biology and its crosstalk with tumor-infiltrating immune cells is crucial not only to gain insight in tumorigenesis but to optimize the potential of novel targeted immunotherapies for cancers. The complex relationships between CAFs and tumor-infiltrating immune cells remain unclear and need further study. Herein, in this narrative review we have focused on updates of CAF biology and its interactions with tumor-infiltrating immune cells in generating immunosuppressive TME and resistance to cell death. Full article
(This article belongs to the Section Tumor Microenvironment)
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10 pages, 1034 KiB  
Article
Infratemporal Fossa Approach with Preservation of the Posterior Bony Wall of External Auditory Canal: Case Series and the Outcome
by Hye Ah Joo, Na-Kyum Park and Jong Woo Chung
J. Clin. Med. 2025, 14(15), 5294; https://doi.org/10.3390/jcm14155294 - 26 Jul 2025
Viewed by 324
Abstract
Objective: To evaluate the outcomes of a modified infratemporal fossa approach (ITFA) that preserves the posterior external auditory canal (EAC) in patients with tumors in the infratemporal fossa and skull base, focusing on postoperative hearing and facial nerve function. Methods: This retrospective study [...] Read more.
Objective: To evaluate the outcomes of a modified infratemporal fossa approach (ITFA) that preserves the posterior external auditory canal (EAC) in patients with tumors in the infratemporal fossa and skull base, focusing on postoperative hearing and facial nerve function. Methods: This retrospective study included nine patients who underwent ITFA with posterior EAC preservation for tumor removal while minimizing facial nerve rerouting. All surgeries were performed by a single surgeon. Preoperative and postoperative hearing levels, facial nerve function, tumor characteristics, and surgical outcomes were analyzed. Air-bone gaps (ABG) were assessed using pure tone audiometry, and facial nerve function was assessed using the House–Brackmann grading system. Results: The cohort consisted of eight female patients and one male patient, with a mean tumor size of 3.0 cm. Surgical outcomes were promising, with no statistically significant increase in postoperative ABG and well-preserved facial nerve function. Only one patient developed postoperative grade II facial palsy. A residual tumor was identified in one case with extensive meningioma, which has remained stable, and no recurrence or regrowth was noted during the follow-up period (mean: 3.7 years). The modified approach minimized complications related to conductive hearing loss and facial nerve dysfunction. Conclusions: The modified ITFA with posterior EAC preservation provides a promising alternative to conventional ITFA for managing deep-seated tumors. It preserves both hearing and facial nerve function while ensuring adequate tumor resection. Full article
(This article belongs to the Section Otolaryngology)
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33 pages, 1777 KiB  
Review
Immunomodulatory Natural Products in Cancer Organoid-Immune Co-Cultures: Bridging the Research Gap for Precision Immunotherapy
by Chang-Eui Hong and Su-Yun Lyu
Int. J. Mol. Sci. 2025, 26(15), 7247; https://doi.org/10.3390/ijms26157247 - 26 Jul 2025
Viewed by 502
Abstract
Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We [...] Read more.
Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We conducted a comprehensive literature analysis examining natural products tested in cancer organoids, immunomodulatory mechanisms from traditional models, technical advances in organoid-immune co-cultures, and standardization requirements for clinical translation. Our analysis reveals a critical research gap: no published studies have investigated natural product-mediated immunomodulation using organoid-immune co-culture systems. Even though compounds like curcumin, resveratrol, and medicinal mushroom polysaccharides show extensive immunomodulatory effects in two-dimensional (2D) cultures, and organoid technology achieves high clinical correlation for drug response prediction, all existing organoid studies focus exclusively on direct cytotoxicity. Technical challenges include compound stability, limited matrix penetration requiring substantially higher concentrations than 2D cultures, and maintaining functional immune populations in three-dimensional (3D) systems. The convergence of validated organoid-immune co-culture platforms, Food and Drug Administration (FDA) regulatory support through the Modernization Act 2.0, and extensive natural product knowledge creates unprecedented opportunities. Priority research directions include systematic screening of immunomodulatory natural products in organoid-immune co-cultures, development of 3D-optimized delivery systems, and clinical validation trials. Success requires moving beyond cytotoxicity-focused studies to investigate immunomodulatory mechanisms in physiologically relevant 3D systems, potentially unlocking new precision cancer immunotherapy approaches. Full article
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16 pages, 2936 KiB  
Article
Bioinformatics Screening of Tumor-Derived Neuropeptides Mediating Neuroimmune Axis of Head and Neck Cancer
by Ravi Kishan, Gao Zhang, Weifa Yang and Yuxiong Su
Cancers 2025, 17(15), 2464; https://doi.org/10.3390/cancers17152464 - 25 Jul 2025
Viewed by 129
Abstract
Background/Objectives: Emerging studies have indicated the importance of intra-tumoral neuronal signals in tumor progression and immune modulation. However, there is limited insight into neuroimmune crosstalk, and the molecules involved are largely unknown. This study investigates the relationship between tumor-derived neuropeptides and immune modulation [...] Read more.
Background/Objectives: Emerging studies have indicated the importance of intra-tumoral neuronal signals in tumor progression and immune modulation. However, there is limited insight into neuroimmune crosstalk, and the molecules involved are largely unknown. This study investigates the relationship between tumor-derived neuropeptides and immune modulation in head and neck squamous cell carcinoma (HNSC). Methods: By utilizing neuropeptide databases and web tools leveraging TCGA data, neuropeptides’ expression and their associations with neurotrophic factors, immune cell infiltration, and immune checkpoints were analyzed, followed by survival analysis. Results: Over half of the neuropeptides were expressed in HNSC, with 16% exhibiting differential expression compared to normal counterparts. Notably, differentially expressed neuropeptides showed significant correlations with neurotrophic factors, immune cell infiltration, and checkpoint genes. Further, their expression was significantly different in responder and non-responder patient samples subjected to immune checkpoint therapy. Neuropeptide genes—PTHLH, NMB, GAST, APLN, and LYNX1—were identified and emerged as crucial mediators in neuroimmune crosstalk. Additionally, the neurotrophic gene NTRK1 exhibited extensive correlation with immune checkpoint genes, underscoring the prevalence of neuroimmune crosstalk in HNSC. Conclusions: These findings shed light on the role of tumor-derived neuropeptides in neuroimmune regulation in HNSC, offering valuable insights for future studies to decode the cancer neuroscience of HNSC progression and therapy. Full article
(This article belongs to the Section Cancer Biomarkers)
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20 pages, 12384 KiB  
Article
Oxidative Stress Model of Lipopolysaccharide-Challenge in Piglets of Wuzhishan Miniature Pig
by Ruiying Bao, Pingfei Qiu, Yanrong Hu, Junpu Chen, Xiaochun Li, Qin Wang, Yongqiang Li, Huiyu Shi, Haiwen Zhang and Xuemei Wang
Vet. Sci. 2025, 12(8), 694; https://doi.org/10.3390/vetsci12080694 - 24 Jul 2025
Viewed by 174
Abstract
Oxidative stress (OS) is a major concern in young poultry and livestock, prompting extensive research on OS models. This study aimed to systematically investigate the dynamic effects and temporal trends of OS induced with lipopolysaccharide (LPS) over time. Twenty-eight piglets were randomly divided [...] Read more.
Oxidative stress (OS) is a major concern in young poultry and livestock, prompting extensive research on OS models. This study aimed to systematically investigate the dynamic effects and temporal trends of OS induced with lipopolysaccharide (LPS) over time. Twenty-eight piglets were randomly divided into four groups and equally intraperitoneally injected with LPS at doses of 0 μg/kg (control), 50 μg/kg (L-LPS), 100 μg/kg (M-LPS) and 150 μg/kg (H-LPS) body weight, respectively. The results showed that total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), and catalase (CAT) were decreased, while malondialdehyde (MDA), nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), diamine oxidase (DAO) and D-lactic acid (D-LA) were increased in the M-LPS and H-LPS group on day 1 in comparison with the control group, but no differences were found among treatments on day 7. However, LPS treatments gave rise to varying degrees of pathological injury in the intestines, livers and spleens on day 7. Metabolomics analysis indicated that compared with the control group, glycyl-valine, histamine and lepidine F were decreased in the M-LPS group. Most differentially expressed metabolites were enriched in amino acid-related metabolism pathways on both day 1 and day 7. Microbiome analysis identified that Oscillibacter_sp._CAG:241 was decreased in the M-LPS group compared with the control group on day 1, while Bacteroides_thetaiotaomicron and Lactobacillus_amylovorus were reduced in the M-LPS group on day 7. Collectively, an LPS dose of 100 μg/kg body weight is optimal for inducing acute inflammation in Wuzhishan miniature pigs. These findings highlight the importance of considering both the duration of OS induction and the specific research objectives when establishing OS models. Full article
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15 pages, 4111 KiB  
Article
Impact of Tumor Budding in Head and Neck Cancers on Neck Lymph Node Metastasis and Prognosis
by Oğuz Gül, Özlem Çelebi Erdivanlı, Mehmet Birinci, Suat Terzi, Metin Çeliker, Oğuzhan Okçu, Çiğdem Öztürk, Tuğba Yemiş, Fatma Beyazal Çeliker, Zerrin Özergin Coşkun and Engin Dursun
J. Clin. Med. 2025, 14(15), 5224; https://doi.org/10.3390/jcm14155224 - 23 Jul 2025
Viewed by 321
Abstract
Background/Objectives: Tumor budding (TB)—clusters of one to five tumor cells at the invasive front—has emerged as a prognostic marker in various cancers. Its prognostic value in head and neck squamous cell carcinoma (HNSCC) is unclear. Methods: We retrospectively analyzed 98 HNSCC patients. The [...] Read more.
Background/Objectives: Tumor budding (TB)—clusters of one to five tumor cells at the invasive front—has emerged as a prognostic marker in various cancers. Its prognostic value in head and neck squamous cell carcinoma (HNSCC) is unclear. Methods: We retrospectively analyzed 98 HNSCC patients. The tumor buds were counted on hematoxylin–eosin-stained sections as per the 2016 International Tumor Budding Consensus Conference (ITBCC) guidelines. An optimal cutoff was determined by ROC analysis using excisional lymph nodes and five-year overall survival (OS) as the endpoint, stratifying patients into low- (≤4 buds) and high-risk (>4 buds) groups. The associations with clinicopathological features, OS, and disease-free survival (DFS) were assessed using Kaplan–Meier curves and Cox regression. Results: Among the 98 patients (median follow-up 58 months, range 18–108), 32 (32.7%) died. The optimal TB cutoff was 4.5 (AUC 0.85, 95% CI 0.76–0.93). High TB was associated with poorer five-year OS (26.4% vs. 85.3%). Multivariate Cox regression identified TB and extranodal extension as independent predictors of OS (TB HR: 3.4, 95% CI 1.3–9.2, p = 0.013). In the laryngeal cancer subgroup, TB was associated with worse survival in the univariate analysis (HR 7.5, 95% CI 1.6–35.6, p = 0.011), though this was not significant in the multivariate modeling. High TB independently predicted neck lymph node metastasis (multivariate OR 4.9, 95% CI 1.2–20.5, p = 0.029), which was present in 65.8% of the high-TB vs. 31.7% of the low-TB patients. High TB correlated with advanced AJCC stage and lymphovascular invasion. No clinicopathological factors, including TB, independently predicted DFS, in either the full cohort or the laryngeal subgroup. Conclusions: High tumor budding denotes an aggressive HNSCC phenotype and may guide decisions on elective neck dissection. Its assessment is simple, cost-effective, and potentially valuable for routine pathology, pending external validation. Full article
(This article belongs to the Section Otolaryngology)
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14 pages, 1088 KiB  
Article
Management and Outcomes of Urinary Tract Involvement in Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC): A Retrospective Cohort Study
by Feza Karakayali, Melik Kagan Aktas, Erman Aytac, Ugur Sungurtekin, Sezai Demirbas, Mustafa Oncel, Ersin Ozturk, Tahsin Colak, Mehmet Ince, Mustafa Haksal, Safak Coskun and Selman Sokmen
Medicina 2025, 61(8), 1331; https://doi.org/10.3390/medicina61081331 - 23 Jul 2025
Viewed by 202
Abstract
Background and Objectives: The combined use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is employed for the treatment of peritoneal carcinomatosis (PC). To achieve optimal cytoreduction, there may be a need for extensive resection and subsequent reconstruction of urologic structures. [...] Read more.
Background and Objectives: The combined use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is employed for the treatment of peritoneal carcinomatosis (PC). To achieve optimal cytoreduction, there may be a need for extensive resection and subsequent reconstruction of urologic structures. This study was designed to evaluate the outcomes of urinary tract resection or repair performed in CRS/HIPEC in terms of operative and oncological outcomes. Materials and Methods: After institutional review board approval, data from 550 consecutive patients who underwent the CRS/HIPEC procedure from January 2007 to July 2018 at six university hospitals was retrieved from prospectively maintained databases. Data from patients who had a concomitant curative resection and reconstruction of the bladder, ureter, or kidney during the CRS/HIPEC procedure were analyzed retrospectively. Results: A total of 50 out of 550 patients had undergone resection with a repair of the urinary tract due to tumor invasion or iatrogenic injury. Postoperative (within 30 days) urologic complications were observed in 9 of the 50 patients. It was found that having a peritoneal cancer index (PCI) equal to or greater than 20 (p < 0.009) was the sole significant risk factor associated with the occurrence of early urinary complications. Survival time post CRS/HIPEC treatment did not significantly differ between patients with and without urologic complications (median overall survival: 23 vs. 27 months, p = 0.683). Conclusions: Despite urinary tract issues during CRS/HIPEC for PC, including a PCI over 20 and potential complications from resection or repair, the procedure still offers significant survival benefits. Full article
(This article belongs to the Section Surgery)
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26 pages, 1310 KiB  
Review
Combination Strategies with HSP90 Inhibitors in Cancer Therapy: Mechanisms, Challenges, and Future Perspectives
by Yeongbeom Kim, Su Yeon Lim, Hyun-Ouk Kim, Suk-Jin Ha, Jeong-Ann Park, Young-Wook Won, Sehyun Chae and Kwang Suk Lim
Pharmaceuticals 2025, 18(8), 1083; https://doi.org/10.3390/ph18081083 - 22 Jul 2025
Viewed by 420
Abstract
Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, [...] Read more.
Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, their therapeutic potential as monotherapies has been limited by suboptimal efficacy, dose-limiting toxicity, and the emergence of drug resistance. Recent studies have demonstrated that combination therapies involving HSP90 inhibitors and other anticancer agents such as chemotherapeutics, targeted therapies, and immune checkpoint inhibitors can enhance anticancer activity, overcome resistance mechanisms, and modulate the tumor microenvironment. These synergistic effects are mediated by the concurrent degradation of client proteins, the disruption of signaling pathways, and the enhancement of antitumor immunity. However, the successful clinical implementation of such combination strategies requires the careful optimization of dosage, administration schedules, toxicity management, and patient selection based on predictive biomarkers. In this review, we provide a comprehensive overview of the mechanistic rationale, preclinical and clinical evidence, and therapeutic challenges associated with HSP90 inhibitor-based combination therapies. We also discuss future directions leveraging emerging technologies including multi-omics profiling, artificial intelligence, and nanoparticle-mediated delivery for the development of personalized and effective combination regimens in oncology. Full article
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22 pages, 1008 KiB  
Review
Ap4A in Cancer: A Multifaceted Regulator and Emerging Therapeutic Target
by Kateryna Tkachenko, Tiziana Bachetti and Camillo Rosano
Molecules 2025, 30(15), 3056; https://doi.org/10.3390/molecules30153056 - 22 Jul 2025
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Abstract
Diadenosine polyphosphates, including diadenosine tetraphosphate (Ap4A), are ubiquitous nucleotides that are present across diverse life forms, gaining considerable interest due to their role as cellular signaling molecules. Ap4A, in particular, has been extensively researched in various biological systems, especially under conditions of environmental [...] Read more.
Diadenosine polyphosphates, including diadenosine tetraphosphate (Ap4A), are ubiquitous nucleotides that are present across diverse life forms, gaining considerable interest due to their role as cellular signaling molecules. Ap4A, in particular, has been extensively researched in various biological systems, especially under conditions of environmental stress. This review provides an in-depth analysis of the current knowledge surrounding Ap4A, focusing on its biosynthesis and degradation pathways, the identification of Ap4A protein targets and the molecular mechanisms underlying its action. Furthermore, this review aims to examine the interplay between the various pathogenetic mechanisms driving tumor development and the potential role of Ap4A which emerges as pivotal signaling molecules orchestrating cellular responses to environmental challenges, positioning them at the nexus of cancer adaptation and progression. Full article
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