Vulvar squamous cell carcinoma and its precursors are heterogeneous and classified into 3 biologically distinct subgroups: human papillomavirus (HPV)-associated, HPV-independent TP53-mutated, and HPV-independent TP53-wild type. Although nomenclature is established for HPV-associated high-grade squamous intraepithelial lesion and TP53-mutated differentiated vulvar intraepithelial neoplasia lesions, terminology for precursors in the TP53-wild-type subgroup is evolving. Accurate classification is essential, as prognosis, progression risk, and recurrence rates differ among subgroups. Diagnosis relies on integrated assessment of clinical presentation, histopathology, and immunophenotype, particularly p16 and p53 expression.

This article highlights current advances in melanocytic lesions and their impact on histopathologic diagnosis and patient management. Special emphasis is given to the concept of melanocytoma and the study of dysplastic nevi. Finally, the article describes the current status and possible future applications of immunohistochemistry, digital analysis, and artificial/augmented intelligence.

In the past 2 decades, several molecular methods have been developed as an adjunct for the assessment of melanocytic neoplasms. Some tests can assist in the diagnostic workup of neoplasms with ambiguous histopathologic findings. Others can optimize the selection of patients for targeted therapy. Some tests also aim to provide prognostic information. Scenarios when ordering these tests may be appropriate and helpful are discussed in this article as well as pitfalls in the interpretation of test results. Due to the inherent limitations in sensitivity and specificity of various tests, correlation with the histopathologic findings is paramount.

This study aimed to systematically review the literature regarding topical therapies for reducing the risk of cervical intra-epithelial neoplasia (CIN) grade 2 or higher (CIN II+) lesions among women with high-risk human papillomavirus (HPV) infection and histologically confirmed CIN I or either no cervical lesions.

Carcinoembryonic antigen (CEA) is commonly raised in patients with colorectal carcinoma (CRC) and has an established role in postoperative monitoring to detect early recurrence. CEA is not recommended as a screening tool for CRC; however, a de novo raised level mandates further investigation with a colonoscopy. This report describes a patient referred from primary care with a raised CEA and functional bowel symptomatology who went on to have a normal colonoscopy. The persistently rising CEA prompted a repeat colonoscopy, upper gastrointestinal and small bowel investigation and a CT of the abdomen and pelvis, without any cause being found. Finally, a CT-positron emission tomography scan revealed localised uptake in the thyroid gland, with a fine-needle aspiration confirming a diagnosis of medullary cell thyroid carcinoma with regional lymph node involvement.

Breast cancer is the most common invasive malignancy among women and represents the second leading cause of cancer-related mortality in this population, following lung cancer. While metastases typically involve the bones, liver and lungs, less common metastatic sites have also been documented. Metastatic involvement of the pancreas or duodenum from an extrapancreatic primary tumour is rare, accounting for less than 3% of all pancreatic and periampullary malignancies. We report a case of isolated ampullary metastasis originating from invasive lobular breast carcinoma in a female patient in her late 50s, more than a decade after the initial diagnosis, accompanied by a review of the relevant literature.Given the limited number of published cases, this report underscores the importance of considering metastatic breast cancer in the differential diagnosis of women presenting with obstructive jaundice, particularly in the presence of a relevant clinical history.

Focal treatment has emerged as a precision-oriented alternative to whole-gland treatment approaches for localized prostate cancer. It aims to selectively destroy clinically significant tumor foci while preserving surrounding structures that are essential for urinary continence and sexual function. Irreversible electroporation (IRE) is a relatively new and increasingly investigated focal treatment modality. By delivering short high-voltage pulses, IRE creates permanent nanopores in cell membranes and induces cell death predominantly through non-thermal mechanisms.This theoretical advantage - tissue ablation with relative preservation of the collagen-rich extracellular matrix - has heightened interest in IRE, particularly for tumors located near sensitive structures such as the neurovascular bundles, the urethral sphincter complex, and the rectal wall.In this review, we outline key procedural and technical aspects and summarize the clinical evidence for IRE in localized prostate cancer. Data from both prospective and retrospective case series demonstrate encouraging early and intermediate-term oncologic outcomes, although patterns of recurrence and the need for retreatment vary between cohorts and depend on the respective follow-up protocols. Functional outcomes are consistently excellent: continence is preserved in the vast majority of patients, and potency preservation is often high, typically ranging from approximately 75 to 95% among men who were potent prior to treatment.Despite these promising findings, widespread adoption in routine clinical practice is limited by the lack of robust long-term endpoints and the absence of randomized comparisons with established standards such as radical prostatectomy, radiotherapy, or risk-adapted active surveillance. While prospective comparative studies are highly challenging as they require large sample sizes, long follow-up periods, and careful endpoint definition, they are essential to clarify the role of irreversible electroporation within treatment algorithms, optimize patient selection, standardize follow-up and salvage strategies, and ultimately confirm durable tumor control with a sustained functional benefit.

Although immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) have transformed the treatment of non-small cell lung cancer (NSCLC) across disease stages, real-world access remains highly unequal worldwide. Persistent cost barriers, fragmented reimbursement frameworks, and heterogeneous regulatory pathways limit equitable availability. The rapid proliferation of me-too agents has been proposed to counter monopolies; yet, this expansion has not consistently improved affordability. Heterogeneous evidentiary requirements-along with differences in clinical end points, comparator selection, crossover policies, and treatment duration-fragment therapeutic markets and complicate assessment of incremental clinical benefit. Divergent regulatory decisions, particularly between the US Food and Drug Administration and European Medicines Agency, underscore how trial design and geographic representation influence drug availability, especially when approvals rely on single-country data sets. These challenges are amplified in perioperative treatment strategies and rare oncogene-defined subgroups, where feasibility constraints and limited clinical equipoise hinder large randomized trials. As a result, an increasingly crowded therapeutic landscape makes cross-trial comparisons difficult and allows disparities in patient access to persist despite multiple approved therapies. Dose selection has historically followed maximum tolerated dose principles, even when preclinical and pharmacologic data suggest activity plateaus at lower exposure of ICI and TT. Dose and schedule optimization-through reduced dosing, extended intervals, or other deintensified strategies-therefore represents a rational and ethically grounded approach with a meaningful clinical impact. Such strategies may preserve efficacy while improving tolerability, reducing treatment burden, and mitigating financial toxicity, particularly in resource-limited settings. Aligning regulatory frameworks with dose optimization could promote more scalable, equitable, and sustainable NSCLC innovation.

Reviewing pathology reports requires physicians to integrate complex histopathologic, immunohistochemical, and molecular findings from multiple reports and institutions, often under time constraints that increase the risk of error and fatigue. Large language models (LLMs) offer a potential solution by generating concise, coherent summaries from complex pathology data.

Immune checkpoint inhibitors (ICIs) can essentially treat cancer but only in a small subset of patients. Treatment strategies capable of effectively and robustly sensitizing refractory patients to ICIs represent a highly coveted yet unmet clinical need. In this study, we identified DJ-1 as a negative T cell regulator. DJ-1 knockout boosts antitumor immunity and significantly potentiates PD-1 and TIM-3 blockades in murine cancer models. Single-cell sequencing of tumor-infiltrating CD45+ cells revealed that DJ-1 deficiency indirectly activates T cells by reprogramming macrophages. Mechanistically, loss of DJ-1 increases reactive oxygen species (ROS) in macrophages, activating NF-κB/STAT3 signaling to promote differentiation into Cxcl9+ immune-stimulatory phenotypes while reducing immune-suppressive Spp1+ macrophages. Notably, this reprogramming may be stable across tumor microenvironments because the transplanted DJ-1-deficient macrophages maintain T cell-activating capacity. Pharmacological inhibition of DJ-1 by disulfiram markedly potentiated antitumor efficacy of PD-1 blockade. This designates DJ-1 as a promising target for overcoming immune checkpoint resistance and optimize combination therapies.

Metabolic reprogramming is a hallmark of cancer, while tricarboxylic acid cycle is increasingly recognized as a multifaceted hub driving tumor metabolism and progression. Integrated analysis of solute carrier (SLC) transporters revealed consistent down-regulation of SLC13A2 in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and mouse models. Adeno-associated virus-mediated liver-specific knockout or overexpression of SLC13A2 (SLC13A2-OE) promoted or ameliorated HCC progression, indicating its protective role. SLC13A2 inhibited HCC proliferation by decreasing mitochondrial function via suppressed glycolysis, respiration, and adenosine 5'-triphosphate production. Flux analysis showed that SLC13A2 imported citrate to generate acetyl-coenzyme A for pyruvate kinase isozyme type M2 acetylation, triggering its degradation. Reduced pyruvate kinase activity limited pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. Moreover, SLC13A2-imported citrate induced intracellular protein acetylation, particularly histone proteins, which provided an epigenetic basis for transcriptional regulation and contributed to tumor suppression. Thus, SLC13A2 perturbs metabolic and transcriptional programs to suppress tumor growth, highlighting potential drug targets for HCC therapy.

Both primary and metastatic brain malignancies are fatal and highly infiltrated with tumor-associated macrophages (TAMs). Enhancing the phagocytosis of neoplastic cells by TAMs is pivotal for slowing tumor growth. Great endeavors have been made to develop tyrosine kinase inhibitors (TKIs) for brain malignancies, yet whether tumor-targeting TKIs affect the phagocytic capacity of TAMs remains largely unknown. In this preclinical study, we report that repurposing ibrutinib, a blood-brain barrier-penetrable TKI, effectively suppresses the growth of several primary and metastatic brain tumors highly expressing Bruton's tyrosine kinase (BTK) or bone marrow X-linked nonreceptor tyrosine kinase (BMX) but concurrently dampens the TAM phagocytic function. Mechanistically, BTK, which is activated in TAMs, interacts with and phosphorylates Wiskott-Aldrich syndrome protein (WASp) to organize the actin cytoskeleton, which is imperative for phagocytosis. Ibrutinib treatment disrupts BTK-mediated WASp activation, thereby compromising TAM phagocytic efficacy. Pharmacological activation of WASp by its selective small-molecular activator EG-011 restores the ibrutinib-impaired TAM engulfment of tumor cells and effectively improves ibrutinib efficacy in mice bearing glioblastomas, primary central nervous system lymphomas, and lung carcinoma brain metastases. Furthermore, elevated expression of phosphorylated BTK or phosphorylated WASp in TAMs correlates with an increased phagocytic TAM subset identified by single-cell RNA sequencing and correlates with prolonged patient survival in a cohort with glioblastoma. Our preclinical study highlights the necessity of evaluating the on-target, off-tumor attack of TAMs during TKI administration and provides a proof of concept for reinvigorating the TAM phagocytic function to achieve additional clinical benefit.

In this article, we propose a deep reinforcement learning based chemotherapy regulation framework to realize personalized and dynamic optimization of cancer treatment. We use a nonlinear dynamic system to model the dynamic evolution of the tumor microenvironment including tumor cell, normal cell and immune cell interactions, with drug concentration serving as the control input variable. The Deep Deterministic Policy Gradient (DDPG) algorithm makes agents can study optimal dosing strategy in a continuous space of movement to inhibit tumor growth effectively and minimize damage to normal tissues. To make the strategy more stable, Gauss noise is added to the model to simulate physiological oscillations and uncertainties in the treatment reaction. Experimental results show that it can control the growth of tumor in various initial scenarios and the accumulation of the drug concentration with high flexibility and safety. Our technique provides a feasible technical way for precision, low toxicity adaptive chemotherapy.

Tumor-derived exosomes play critical roles in pancreatic ductal adenocarcinoma (PDAC) progression by mediating intercellular communication within the tumor microenvironment. This study identifies the long non-coding RNA PLBD1-AS1 as a functional oncogenic lncRNA enriched in PDAC exosomes. We demonstrate that PLBD1-AS1 promotes tumor cell proliferation, migration, and invasion by interacting with the glycolytic enzyme ALDOA and enhancing glycolytic flux. Furthermore, tumor exosomes deliver PLBD1-AS1 to pancreatic stellate cells (PSC), augmenting their glycolysis and facilitating their activation into cancer-associated fibroblasts, thereby shaping a pro-tumorigenic microenvironment. To target it, we developed an engineered exosome system modified with the tumor-penetrating peptide iRGD for specific delivery of siPLBD1-AS1 to both tumor and stromal cells. The resulting iRGD-exo-siPLBD1-AS1 construct demonstrated enhanced cellular uptake and effectively suppressed PLBD1-AS1 expression, inhibited glycolysis, impaired PSC activation, and significantly attenuated tumor growth. Our findings reveal a novel mechanism of exosome-mediated metabolic crosstalk in PDAC and establish a promising RNAi-based therapeutic strategy targeting this lethal malignancy.

Bladder cancer remains a significant therapeutic challenge due to its marked heterogeneity and capacity for immune evasion. Here, we employ spatial metabolomics and spatial transcriptomics to systematically characterize and visualize the metabolic and transcriptional landscapes of bladder cancer. Our findings identify distinct metabolic and transcriptional profiles across different tumor regions, highlighting heterogeneity and immune-associated metabolic reprogramming in BLCA. Further investigation identifies zinc finger protein 36 (ZFP36) as a potential immunotherapeutic target. Utilizing Zfp36 whole-body knockout and T cell-specific Zfp36 conditional knockout mice, we validated that Zfp36 knockout decreases the activation threshold for T cells and increases T cell infiltration in tumors. Moreover, we found that elevated ZFP36 expression is dramatically linked to worse patient outcomes. Mechanistically, ZFP36 facilitates mRNA degradation of key immune regulators, including C1QBP, thereby inhibiting T cell activation and cytotoxicity. Notably, combining Zfp36 knockout with anti-PD-1 therapy produced synergistic antitumor effects, suggesting that ZFP36 inhibition could be a promising therapeutic strategy. This integrated multiomics approach collectively uncovers immune-metabolic regulatory pathways in BLCA and points to critical molecular targets for immunotherapy.

Ewing sarcoma is driven by chromosomal translocations that fuse a FET RNA-binding protein to an ETS transcription factor, most commonly generating the EWS-FLI1 fusion oncoprotein. EWS-FLI1 engages GGAA microsatellite repeats to form de novo enhancers that activate oncogenic transcriptional programs essential for tumorigenesis. In addition to this truncal driver, recurrent loss-of-function alterations in the cohesin subunit STAG2 occur in approximately 10 to 15% of Ewing sarcomas and are associated with adverse clinical outcomes. However, how STAG2 loss reshapes EWS-FLI1 chromatin engagement and transcriptional output remains poorly understood. Here, using genetic STAG2 loss-of-function models combined with integrative multiomic profiling, we demonstrate that STAG2-cohesin deficiency reprograms the EWS-FLI1 chromatin landscape by altering its binding at GGAA-microsatellite enhancers. Despite increased EWS-FLI1 protein abundance, STAG2 loss eliminates over 40% of EWS-FLI1 binding sites, predominantly at enhancers containing short (1-4) GGAA repeats, while concurrently increasing binding at multimeric enhancers with ≥5 GGAA-repeat motifs. These reprogrammed sites show changes in both chromatin accessibility and H3K27ac, leading to selective amplification of EWS-FLI1 activity at multimeric microsatellite enhancers. By integrating Hi-C chromatin interaction maps with altered EWS-FLI1 occupancy, we define distinct monomeric and multimeric GGAA enhancer-driven transcriptional gene signatures and demonstrate that STAG2 loss selectively augments the multimeric transcriptional program. Consistently, the long GGAA microsatellite-activated gene signature is enriched in patient tumors with aggressive clinical features and deleterious STAG2 alterations. Together, these findings reveal that STAG2 loss reprograms, rather than globally attenuates, EWS-FLI1 function, amplifying a high-risk oncogenic transcriptional state in Ewing sarcoma.

Despite the availability of several chemotherapeutic regimens for early-stage breast cancer (BC), the ideal combination and dosing strategy remain to be defined. Thus, we conducted a network meta-analysis (NMA) comparing the current chemotherapeutic regimens used in the treatment of women with early-stage BC.

Progastrin, is over-expressed in human colorectal tumor cells and also directly targets the ß-catenin/Tcf4 oncogenic pathway, The association between Wnt/ß-catenin pathway and cancer is not merely restricted to colorectal cancer as disruption of this pathway results in epithelial mesenchymal transition in oral carcinogenesis. As therole of progastrin in subjects with Oral cancer(OC) is less explored, this study was contemplated to assess the role of plasma progastrin levels in subjects with various stages of oral squamous cell carcinoma.

In Algeria, breast cancer accounts for 37.8% of new cancer cases in women. It is an epithelial cell tumor in most cases. CA15-3 (carbohydrate antigen) is the marker of choice for therapeutic monitoring, although ASCO (the American Society of Clinical Oncology) does not recommend its routine use, preferring CYFRA21.1 (cytokeratin19 fragment) to assess response to treatment. The aim of this study was to estimate the degree of correlation between these two biological markers as a function of tumour histological type and the presence or absence of metastases. In a prospective descriptive study, sera from 110 breast cancer patients (mean age 49 ± 7.23 years) were measured using the electrochemiluminescence (ECL) technique to assess CYFRA 21.1 and CA 15.3 levels. Comparison of CA15.3 and CYFRA21.1 levels between patients and controls (79 controls) showed a highly significant association (p<0.0001) between these two markers and breast cancer. The significant correlation between CA15.3 and CYFRA21.1 (r=0.245; P< 0.0001) suggests that reliance on CYF 21.1 for monitoring breast cancer patients undergoing chemotherapy is possible. The results show a good correlation between the two markers, especially for the two histological types luminal a and luminal b+HER2 (r=0.602 ; p<0.0001, r=0.505 ;p< 0.0001 respectively). This study also assessed the correlation between CA15.3 and CYFRA21.1 levels in patients with and without metastases. A significant correlation was also found between CA15.3 and CYFRA 21.1 in the presence of metastases (r=0.472, p<0.0001). A multi-marker approach could provide a more comprehensive assessment of tumor burden and response to treatment.

Accurately estimating physiological fitness and life expectancy is challenging in older patients with early-stage non-small cell lung cancer (NSCLC) considered for stereotactic body radiotherapy (SBRT). Noninvasive biological age metrics may improve assessment beyond chronological age.