Onco

Cancer metastasis is the leading cause of cancer-related mortality, accounting for more than 90% of cancer deaths worldwide. However, the epigenetic mechanisms governing the metastatic cascade remain incompletely understood. Epigenetic reprogramming, including reversible changes in histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA (ncRNA)-mediated regulation, enables tumor cells to acquire invasive, migratory, stem-like, and immune-evasive characteristics. During epithelial-to-mesenchymal transition (EMT), key epigenetic regulators such as histone deacetylases (HDACs), the Polycomb repressive complex 2 (PRC2) subunit EZH2, lysine-specific demethylase 1 (LSD1/KDM1A), and bromodomain and extraterminal (BET) proteins repress epithelial gene expression while activating mesenchymal transcriptional programs, promoting invasion and dissemination. At distant sites, epigenetic plasticity facilitates metastatic colonization through mesenchymal-to-epithelial transition (MET) and adaptive chromatin remodeling. Because these changes are reversible, they represent attractive therapeutic targets. HDAC, EZH2, LSD1/KDM1A, BET, and DNA methyltransferase (DNMT) inhibitors have shown promise in preclinical models of metastasis, with several advancing through clinical trials. Long non-coding RNAs, particularly HOTAIR, function as epigenetic scaffolds that reinforce metastatic programs, while reciprocal interactions between tumor cells and the tumor microenvironment (TME) drive epigenetic adaptations that promote immune evasion and metastatic progression. In addition, circulating tumor DNA (ctDNA) methylation signatures are emerging as minimally invasive biomarkers for assessing metastatic risk and monitoring treatment. This review summarizes current insights into the epigenetic regulation of cancer metastasis, evaluates emerging epigenetic therapies, and highlights translational opportunities to advance precision anti-metastatic strategies and improve patient outcomes. Full article

Background/Objectives: Cutaneous adverse events (cAEs) are among the most common toxicities associated with modern anticancer therapies and can significantly affect quality of life, treatment adherence, and therapeutic outcomes. This narrative review aims to provide an updated overview of the mechanisms, clinical manifestations, prognostic implications, and management strategies of cancer therapy-related cutaneous toxicities, with a particular focus on precision oncodermatology. Methods: A narrative review of the recent literature was performed, integrating evidence from clinical studies, meta-analyses, pharmacovigilance investigations, consensus guidelines, and translational research. The review examines cutaneous toxicities associated with immune checkpoint inhibitors, targeted therapies, antibody–drug conjugates, and other emerging anticancer treatments. Results: Four major axes were identified: immune disinhibition, epithelial signaling inhibition, cytotoxic epithelial injury, and cytokine-driven immune activation. Cutaneous immune-related adverse events (cirAEs) emerged as potential biomarkers of treatment efficacy, particularly vitiligo, lichenoid, and psoriasiform eruptions. Increasing evidence supports the use of steroid-sparing biologic therapies, including dupilumab, omalizumab, anti-IL-17 agents, and Janus kinase inhibitors, although prospective validation remains limited. Recent advances in immunologic endotyping have identified distinct inflammatory pathways that may enable personalized therapeutic approaches. Antibody–drug conjugates represent an expanding source of unique dermatologic toxicities requiring dedicated management strategies. Emerging biomarkers, including cytokine signatures and microRNAs, may further refine risk stratification and treatment selection. Conclusions: The management of cancer therapy-related cutaneous toxicities is evolving toward a precision medicine model integrating clinical phenotype, immunologic endotype, and biomarker profiling. Early multidisciplinary intervention and mechanism-based therapeutic strategies may improve patient outcomes while preserving anticancer efficacy. Prospective studies are needed to validate biomarker-guided and steroid-sparing approaches in oncodermatology. Full article

Background/Objectives: Primary renal NETs are exceptionally rare neoplasms that occur disproportionately in horseshoe kidneys. Their rarity and non-specific clinical and radiological features make preoperative diagnosis particularly challenging. Methods: Herein, we report the case of a 60-year-old woman presenting with a painful left lumbar mass associated with dysuria and pollakiuria. Results: Computed tomography revealed a large heterogeneous tumor arising from the left moiety of a horseshoe kidney. Histopathological examination of the resected specimen demonstrated a 14 cm well-differentiated NET (grade 1) with diffuse chromogranin A and synaptophysin expression, a mitotic count of 1 per 2 mm², and a Ki-67 proliferation index of <1%. The histopathological and immunohistochemical findings, together with the absence of an extrarenal primary site on staging investigations, supported the diagnosis of a primary renal NET. The postoperative course was uneventful, and the patient remained disease-free after two years of follow-up. Conclusions: This case highlights the diagnostic challenges posed by this rare entity and underscores the importance of including primary renal neuroendocrine tumors in the differential diagnosis of renal masses arising in horseshoe kidneys. Full article

Head and neck squamous cell carcinoma (HNSCC) remains a significant global health burden with limited survival improvement in locally advanced disease despite multimodal therapy. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have demonstrated substantial clinical benefit in recurrent or metastatic HNSCC, establishing PD-1 blockade as a standard of care. Similar approaches in locally advanced disease, including concurrent administration with chemoradiotherapy or use in the adjuvant setting, have not demonstrated improvement in survival outcomes across multiple randomized trials. Perioperative strategies incorporating neoadjuvant and adjuvant checkpoint inhibition have shown improved event-free and disease-free survival in resectable disease. Meta-analyses of concurrent and adjuvant approaches confirm limited benefit in unselected populations, with modest improvements restricted to biologically defined subgroups. Trial outcomes across disease settings demonstrate a consistent pattern in which therapeutic efficacy varies despite the use of similar agents. Rather than simply summarizing these clinical findings, this review integrates evidence across recurrent/metatstatic, unresected locally advanced and perioperative disease settings into a biologically focused framework to help explain the varying efficacies of immune checkpoint inhibition in HNSCC. Current evidence indicates that the effectiveness of immunotherapy in HNSCC is determined by the biologic context of treatment, including tumor antigen availability, host immune competence, and timing of immune activation. Administration of checkpoint blockade in the presence of intact tumor antigen and preserved immune function is associated with improved outcomes, whereas treatment delivered during or after cytotoxic therapy is limited by lymphopenia and reduced antigen exposure. By synthesizing randomized clinical evidence through this biologic framework, the review provides a conceptual perspective that may help explain previous trial outcomes and inform future biomarker-driven patient selection and treatment sequencing. Optimization of immunotherapy in HNSCC will depend on the integration of immune activation with disease context rather than an escalation of therapeutic intensity. Full article

Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, accounting for 15% of lung cancer cases worldwide. In recent years, the histological transformation from non-small-cell lung cancer (NSCLC) to SCLC has become a significant mechanism of acquired resistance, especially in patients undergoing treatment with tyrosine kinase inhibitors (TKIs) or immunotherapy. Although there is growing clinical understanding, the crucial biological mechanisms that drive this phenotypic switch are still not fully understood. Transformed SCLC (T-SCLC) seems to exhibit differences from de novo SCLC regarding molecular characteristics and tumor microenvironment, indicating unique evolutionary paths. While traditional chemotherapy has been the main treatment method after transformation, patient outcomes continue to be unsatisfactory, highlighting the necessity for a more profound mechanistic insight and the development of more effective treatments. Full article

Background/Objectives: Irinotecan is a key late-line agent in metastatic gastric cancer, but its dose-limiting toxicities—severe neutropenia and diarrhea—are strongly influenced by UGT1A1 promoter polymorphisms. Commercial genotyping kits in Japan routinely interrogate only the common *6 and *28 alleles and may fail to resolve rarer TATA-box variants. We report a case in which an indeterminate commercial result unmasked an extremely rare loss-of-function genotype. Methods: A Japanese man in his 60s with HER2-negative, microsatellite-stable metastatic gastric cancer progressing after four prior lines underwent pretreatment UGT1A1 genotyping with a commercial DNA chip in anticipation of irinotecan. When the *28 result returned as indeterminate owing to a TA-ratio error, reflex Sanger sequencing of the UGT1A1 promoter TATA box was performed. Results: The chip reported *6 as wild-type but could not resolve *28. Sanger sequencing identified one allele with seven TA repeats (*28) and one with eight TA repeats (*37), with no wild-type six-repeat allele—a *28/*37 compound heterozygote. The *37 allele is exceptionally rare in Japanese individuals (ToMMo 61KJPN allele frequency 0.000294) and has historically been reported almost exclusively in individuals of African ancestry. This genotype has previously caused fatal neutropenic colitis despite preemptive dose reduction. Given the patient’s frailty and limited expected benefit, irinotecan was withheld entirely. Conclusions: Indeterminate commercial UGT1A1 results may conceal rare loss-of-function alleles with divergent functional consequences. Such results should trigger confirmatory sequencing rather than empiric dose reduction, and institutions should establish reflex pathways in advance to support biomarker-informed, frailty-adapted treatment selection. Full article

Cancer is a leading health issue worldwide, affecting approximately 20 million people annually. Developing efficient chemotherapy agents for cancer treatment is a challenging, costly, and time-consuming process. Drug repurposing for cancer treatment provides an optimal alternative, as the pharmacokinetic properties and the safety of these drugs have been previously tested. It also offers a faster and more cost-effective path to novel cancer therapies, which is especially valuable when conventional treatments face resistance or toxicity limitations. Antipsychotic drugs, which are primarily used for treating psychiatric disorders, including schizophrenia and bipolar disorder, have recently been investigated for their potential anticancer effects through drug repurposing strategies. While covering preliminary data and providing an overview of their mechanisms of action, this review highlights the latest research on antipsychotic medications’ emerging potential in oncology in experimental models, emphasizing their observed anticancer effects in preclinical studies, safety profile and capacity to enhance the effectiveness of conventional therapies. Despite growing interest, a research gap remains in translating these findings to clinical oncology, an issue this review addresses by proposing future investigative directions. Full article

(1) Background: Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies due to late diagnosis, aggressive tumor biology, and limited therapeutic options. Artificial intelligence has emerged as a promising tool to improve detection, risk stratification, and treatment planning. This study aims to review the current clinical applications of artificial intelligence in the management of pancreatic cancer and evaluate its translational potential. (2) Methods: A comprehensive literature search was conducted across major databases (PubMed/MEDLINE, Scopus, Web of science and Cochrane) for studies published between 2015 and 2026. Eligible studies included clinical investigations and systematic reviews reporting quantifiable outcomes related to diagnosis, staging, prognostication, and treatment response using artificial intelligence methods. (3) Results: A total of 24 studies were included, most of which were retrospective and utilized imaging, histopathology, and clinical datasets. Artificial intelligence demonstrated high diagnostic performance, particularly in imaging-based detection and lesion characterization, with several models achieving excellent accuracy. Applications in staging, surgical planning, and prognostication also showed promising results, although external validation and prospective data were limited. (4) Conclusions: Artificial intelligence has significant potential to enhance the management of pancreatic cancer, particularly as a decision-support tool. However, further prospective validation and integration into clinical workflows are required before widespread adoption. Full article

Genomic instability is a defining feature of cancer progression and therapeutic resistance, yet contemporary oncology interprets it largely through tumor-intrinsic genetic alterations, with less attention to the evolving host physiological context in which DNA damage accumulates and genome maintenance operates. In this perspective, we propose a longitudinal host-transfer-state framework that treats host physiology not as a static background but as a continuously evolving adaptive system. Gut microbial ecology, micronutrient physiology, inflammatory signaling, circadian organization, hydration, environmental exposures, and chronic stress are framed as interacting biologic transfer systems that shape DNA repair fidelity, oxidative buffering, immune coordination, and adaptive tumor behavior over time. These influences are proposed to vary by tumor type, treatment context, and individual physiologic reserve, and clinically observable disease may lag behind deeper latent biologic dynamics. We further outline how longitudinal multi-omic integration and constrained, bounded artificial intelligence—used for longitudinal data integration, normalization, contextualization, and bounded analytical support rather than autonomous decision-making—could identify patient-specific constraints on genome maintenance and treatment tolerance. Host-directed strategies are presented as complementary to, not replacements for, established tumor-directed therapies. Full article

Obesity is increasingly recognized as a complex systemic disorder rather than a simple consequence of excess energy intake and fat accumulation. This review presents a systems biology framework that examines how obesity-driven disruption of inter-organ communication networks contributes to chronic disease susceptibility, with particular emphasis on colorectal cancer (CRC). Disrupted signaling among the brain, adipose tissue, liver, skeletal muscle, gut, and immune system generates maladaptive feedback loops that promote chronic metabolic inflammation (metaflammation), loss of physiological resilience, and progressive metabolic dysfunction. Within this framework, obesity is redefined as a network disease characterized by neuroendocrine dysregulation, adipose tissue remodeling, immune dysfunction, impaired organ crosstalk, and alterations in the gut microbiome. A central feature of this dysregulation is persistent low-grade inflammation driven by immune-metabolic reprogramming and sustained activation of inflammatory pathways. Obesity-associated metaflammation is further linked to accelerated biological aging through mechanisms involving cellular senescence, mitochondrial dysfunction, oxidative stress, and impaired metabolic resilience. These interconnected processes create a tumor-promoting environment by enhancing oncogenic signaling, disrupting intestinal barrier integrity, altering microbial and metabolic signaling, impairing immune surveillance, and promoting epithelial dysfunction, thereby increasing susceptibility to CRC. The review also examines how behavioral, circadian, environmental, and socioeconomic factors influence metabolic health and cancer risk. Finally, emerging translational opportunities, including biomarker-guided risk stratification, precision prevention, metabolic network restoration, and integrative lifestyle and pharmacological interventions, are discussed. Collectively, this review reframes obesity as a whole-body regulatory disorder and provides an integrated conceptual framework linking metabolism, inflammation, aging, and colorectal carcinogenesis to inform future prevention and therapeutic strategies. Full article

The family of uterine mesenchymal neoplasms is diverse in etiology and clinical impact. While histomorphology remains central to diagnostic classification, numerous biomarkers have been developed to aid in refining diagnoses and informing optimal treatment strategies. Indeed, a growing number of neoplasms are being primarily classified on the basis of key pathognomonic genetic events, and this number is expected to continue expanding as access to next-generation sequencing rapidly democratizes. Moreover, several quantitative biomarker tests have been developed to aid in the prognostic stratification of tumours with ambiguous morphologic features, providing critical insights to clinicians seeking optimal oncologic management while minimizing unnecessary treatment morbidity. In this review, we discuss key advances in the utilization of biomarkers for diagnostic classification, prognostication, and the prediction of response to targeted therapeutics in uterine mesenchymal neoplasms, with the aim of highlighting the most clinically impactful biomarkers used by pathologists to enhance the clinical care of patients. Full article

Background/Objectives: Pelvic radiotherapy (RT) for mid–low rectal and anal cancers frequently causes acute and late vaginal toxicity, including dryness, irritation, and dyspareunia, with a substantial impact on quality of life. Evidence supporting targeted interventions for radiation-induced vaginal mucosal changes remains limited. This exploratory retrospective study evaluated the association between daily use of Colpofix^® Ovules and temporal changes in patient-reported vaginal symptoms and Vaginal Health Index (VHI) scores in women undergoing pelvic RT. Methods: Twenty women treated with pelvic RT or chemoradiotherapy between 2024 and 2025 were included. Vaginal symptoms were assessed using a Numerical Rating Scale (NRS 0–10), and mucosal status was evaluated using the VHI (5–25). Assessments were performed at baseline (T0), end of RT (T1), 3 months (T2), and 6 months (T3). Due to the retrospective nature of the dataset, only aggregated summary values were available; analyses were therefore descriptive and aimed at characterizing temporal trends. Results: A clear and progressive reduction in vaginal dryness, irritation, reduced lubrication, and dyspareunia was observed from T0 to T3, with improvements already evident at T1 and further consolidation at T2–T3. VHI scores increased from a mean of 10.8 at baseline to 21.0 at 6 months, reflecting a consistent trend toward mucosal recovery across all domains. In the anal cancer subgroup, the trend toward improvement in dysuria did not meet conventional thresholds for statistical significance (p = 0.073). At T3, 90% of patients reported perceived benefit (55% marked, 35% mild). No adverse events attributable to Colpofix^® were documented. Conclusions: In this small retrospective cohort, daily use of Colpofix^® Ovules was associated with favorable temporal trends in both vaginal symptoms and VHI scores up to 6 months after pelvic RT. These exploratory findings support further prospective controlled studies to better define the potential role of Colpofix^® in managing vaginal mucosal changes during pelvic radiotherapy. Full article

Background: Muscle-invasive bladder cancer (MIBC) is an aggressive disease with heterogeneous responses to neoadjuvant chemotherapy and emerging chemo-immunotherapy combinations. Reliable biomarkers to predict treatment responsiveness before therapy initiation are needed to guide patient selection. Objective: The objective of this study was to identify genomic and immune-related features associated with immune-active tumor phenotypes in MIBC using The Cancer Genome Atlas bladder cancer cohort (TCGA-BLCA). Methods: A retrospective bioinformatics analysis of TCGA-BLCA data was performed, evaluating gene expression, somatic mutations, tumor mutational burden (TMB), DNA damage response (DDR) gene status, and immune infiltration signatures. Immune enrichment metrics were derived from transcriptomic data. In the absence of direct treatment response data, a surrogate immune response classification was applied. Associations were analyzed using descriptive statistics and Firth’s penalized logistic regression. Results: Tumors classified as immune-high phenotype group based on immune-related features exhibited significantly higher global immune infiltration, including increased ImmuneScore and enrichment of cytotoxic and innate immune cells. In multivariable analysis, ImmuneScore was the only independent predictor of inferred responsiveness (p = 0.003). Conclusions: Global immune infiltration showed the strongest association with immune-active tumor phenotypes among the features examined in this TCGA-based analysis. These exploratory findings suggest that immune profiling may warrant further investigation as a component of tumor characterization in MIBC, pending validation in cohorts with clinical treatment and outcome data. Full article

Intercellular mitochondrial trafficking has emerged as an important mechanism influencing tumor progression, metabolic adaptability, and cancer cell plasticity. Beyond their classical bioenergetic functions, mitochondria act as central regulators of redox homeostasis, signaling pathways, and epigenetic remodeling. Increasing evidence suggests that mitochondria can be transferred between tumor, stromal, and immune cells through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and cell fusion within the tumor microenvironment. This dynamic excshange enables metabolically compromised cancer cells to restore oxidative phosphorylation, optimize energy production, and survive under hypoxia and therapeutic stress. Mitochondrial transfer has been increasingly associated with enhanced cellular plasticity and adaptive phenotypic transitions, including the acquisition of stem-like features that contribute to tumor heterogeneity, metastasis, and treatment resistance. In addition to bioenergetic restoration, transferred mitochondrial DNA and metabolites participate in retrograde signaling, linking metabolic state to epigenetic regulation and transcriptional reprogramming. This metabolic epigenetic interplay supports tumor cell adaptation to environmental stress and therapeutic pressure. Although significant progress has been made, the precise mechanisms governing mitochondrial integration and their long-term impact on cellular phenotypes remain incompletely understood. A deeper understanding of these processes may reveal novel therapeutic strategies to disrupt tumor adaptability and progression. Specifically, targeting intercellular mitochondrial trafficking and its associated metabolic and epigenetic effects could help limit tumor plasticity, overcome treatment resistance, reduce disease recurrence, and improve overall clinical outcomes in cancer patients. Full article

Background: Current murine glioblastoma (GBM) models do not incorporate tumor resection and thus do not allow study of recurrent GBM after surgery, including postsurgical changes in the tumor microenvironment (TME), thereby limiting translational relevance. Methods: In phase 1 of a three-phase study, we compared tumor cell implantation into a cavity created using conventional microdissection techniques or the Myriad Research Laboratory System (MRLS) versus direct implantation into the brain without a cavity, and assessed morbidity using the neurological severity score (NSS). In phase 2, we developed a new surgical resection model, the Surgical murine GBM resection model (Sur-rGBM), and examined the effects of tumor resection on the tumor microenvironment (TME) and on overall survival. In phase 3, we compared the therapeutic response to temozolomide (TMZ) with or without anti-VEGF antibody, after resection (Sur-rGBM) or no resection. Tumor growth was confirmed before and after resection by ultrasound. Animals were euthanized for immunohistochemical assessment at maximal tumor growth. Results: Creating a cavity for tumor cell implantation using MRLS improved survival compared to direct cell injection with no cavity. Tumor resection increased survival, and TMZ combined with an anti-VEGF antibody after tumor resection improved survival compared with surgery or TMZ alone. Resection induced significant changes in biomarker expression within the TME. Conclusions: Our novel murine GBM surgical resection model (Sur-rGBM) provides reliable, controlled tumor growth and a standardized resection technique to facilitate studies on TME changes and therapeutic response after tumor resection. Full article

Immunotherapy with immune checkpoint inhibitors (ICIs) has profoundly transformed the therapeutic landscape of lung cancer. Although ICIs are generally associated with a more favorable toxicity profile compared with traditional chemotherapy, rare and potentially severe immune-related adverse events (irAEs) may occur, sometimes posing significant diagnostic challenges. We report a case of macrophage activation syndrome (MAS) following a single administration of the anti-PD-L1 antibody atezolizumab in a patient with advanced non-small-cell lung cancer (NSCLC). A 62-year-old woman was diagnosed in February 2024 with stage IIIB NSCLC according to the 8th TNM classification. The patient was deemed ineligible for radiotherapy because of previous thoracic irradiation for breast cancer. First-line therapy with carboplatin plus pemetrexed was administered from March to June 2024, resulting in stable disease; this was followed by pemetrexed maintenance from July to October 2024, at which time thoracic disease progression was documented. Second-line treatment with atezolizumab was initiated in November 2024. Ten days after the first infusion, the patient was admitted to the emergency department for fever and confusion. Laboratory investigations revealed markedly elevated C-reactive protein and hyperferritinemia. Despite empirical antibiotic therapy, fever and thrombocytopenia persisted. Bone marrow biopsy demonstrated findings consistent with MAS. Corticosteroid therapy with prednisone at 1 mg/kg was promptly initiated under rheumatologic supervision, leading to a rapid clinical and biochemical improvement. During tapering, inflammatory markers relapsed when prednisone was reduced to below 12.5 mg/day. Given the occurrence of a grade 4 (CTCAE v5.0) immune-related adverse event, atezolizumab was permanently discontinued. The patient remains in follow-up without radiological evidence of disease progression. This case highlights the diagnostic challenge of MAS secondary to ICIs, which may initially present with nonspecific symptoms such as fever, confusion, and elevated inflammatory markers. Early recognition and timely initiation of high-dose corticosteroids were essential for effective management and full recovery. Clinicians should maintain a high index of suspicion for MAS among rare but severe hematologic irAEs during immunotherapy. Full article

Background/Objectives: Brain tumors, particularly gliomas, have high mortality and are limited in treatment options, often complicated by severe conditions, which can be fatal. Given the increasing incidence and adverse effects of current drugs, an in silico drug repurposing approach using hub gene clusters to streamline and accelerate the search for new therapies. Methods: The GSE66354, GSE68848, GSE74195, and GSE43290 datasets were used to identify DEGs using GEO2R. A gene co-expression network was constructed using the STRING PPI database. Preserved clusters revealed hub genes, which were used for GO and KEGG pathway enrichment analyses. Drug repurposing screening was performed through drug–gene interactions in DGIdb. Suggestive drugs were then validated through GSEA-CMAP and BOILED-Egg. Results: The study identified three key gene clusters that serve a role in synaptic transmission and transmembrane transport, synaptic vesicle neurotransmission, and extracellular matrix formation. Five drugs passed the drug screening, which are Gabapentin, Pyrantel, Resveratrol, Trifluoperazine, and Valproic acid. Conclusions: Valproic acid and Gabapentin are highly suggestive as candidate repurposed drugs. This study enhances our understanding of brain tumor genetics and supports the development of new immunotherapeutic strategies. Full article