Current therapeutic outcomes for advanced colorectal cancer (CRC) remain suboptimal, and chemotherapy-based regimens continue to be the mainstay of treatment. Circular RNAs (circRNAs) can serve as templates for translating short peptides or proteins, and the resulting products actively regulate malignant tumour progression, making them attractive therapeutic targets.

Brain metastasis (BM) is a leading cause of cancer-related mortality, particularly in patients with lung cancer. Traditional diagnostic methods, such as tissue biopsies, are often impractical, and there are currently no reliable biomarkers for early detection in clinical practice. In this context, liquid biopsy has emerged as a valuable non-invasive diagnostic tool for cancer patients with BM. This review summarizes the advantages and current limitations (such as the low sensitivity in early-stage disease and the potential for false positives from non-cancer sources) of liquid biopsy samples, specifically focusing on peripheral blood and cerebrospinal fluid (CSF). We discuss key biomarkers, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and tumor-derived platelets (TEPs), and current technologies for their detection, highlighting their potential clinical applications. Additionally, we explore the role of liquid biopsy in patients with epidermal growth factor receptor-mutated (EGFR-mutant) non-small cell lung cancer (NSCLC), a group that experiences a high incidence of BM. Finally, we address emerging biomarkers and innovative detection methods, offering recommendations for enhancing the application of liquid biopsy in clinical settings. Our review aims to underscore the significance of liquid biopsy in improving the detection and management of BM.

Transgelin is an actin-binding protein that promotes cancer progression via activation of cancer-associated fibroblasts and has been identified as a prognostic marker. However, its distribution and functional role in colon cancer remain unclear. In this study, we aimed to elucidate the mechanistic role of transgelin in colon cancer progression by focusing on its functional impact in cancer-associated fibroblasts. Tissue microarrays from 359 human colon cancer tissues were investigated to elucidate the clinical importance of transgelin expression in cancer stroma. We focused on transgelin in fibroblasts and investigated its functional role in stromal activation using in vitro knockdown experiments and in vivo co-transplantation models. Primary cultures of human colon fibroblasts were evaluated for their biological function. Our data showed that transgelin expression is predominant in activated cancer-associated fibroblasts in colon cancer tissues. Stimulation by cancer-cell-conditioned medium (CM) significantly upregulated transgelin, ACTA2, COL1A1, and TNC expression in colonic fibroblasts. Additionally, transgelin knockdown (KD) in fibroblasts did not influence the upregulation except for transgelin itself. Transgelin KD in fibroblasts did not result in drastic alterations in gene expression profiles. Transgelin KD suppressed collagen gel contractility. Furthermore, co-transplantation experiments of cancer cells and colonic fibroblasts into immunodeficient mice revealed that transgelin KD inhibited tumor growth in fibroblasts. In conclusion, stromal transgelin expression in colon cancer strongly correlated with distant metastasis and served as a prognostic factor for colon cancer. Mechanistically, transgelin in cancer-associated fibroblasts promotes tumor growth by regulating stromal contractility, suggesting transgelin as a potential therapeutic target.

Ovarian clear cell carcinoma (OCCC) is an endometriosis-associated ovarian cancer subtype. Somatic mutations in OCCC are reported in ARID1A, PIK3CA, and the TERT promoter (TERTp), as well as less commonly in KRAS and TP53 among other genes. OCCC is typically resistant to standard-of-care chemotherapy, especially after relapse. While recent studies have seen favourable responses to immunotherapy, patients with OCCC face limited therapeutic options.

BRAF p.V600E-mutant gliomas and glioneuronal tumors comprise a wide clinicopathological spectrum, yet the relationship between genomic alteration burden and histological grade remains incompletely defined. We analyzed 15 BRAF p.V600E-mutant gliomas and glioneuronal tumors across histological grades using the PleSSision Rapid sequencing platform. Single-nucleotide variants (SNVs) and copy-number alterations were assessed in parallel to characterize genomic alteration profiles. Low-grade tumors generally exhibited limited genomic alterations; however, a subset of low-grade tumors showed increased numbers of SNVs. High-grade tumors demonstrated more extensive genomic alterations, characterized predominantly by copy-number gains. A trend toward increased copy-number gains with higher WHO grade was observed. Homozygous deletion of CDKN2A was observed in pleomorphic xanthoastrocytoma, including both CNS WHO grade 2 and grade 3 tumors, and epithelioid glioblastoma. These findings indicate substantial genomic heterogeneity among BRAF p.V600E-mutant gliomas and glioneuronal tumors. While low-grade tumors are generally genomically quiet, a subset shows increased alterations, and high-grade tumors tend to acquire copy-number changes, highlighting the limitations of genomic event counts alone as a surrogate for malignant potential.

Antiangiogenic combination therapy-antiangiogenic agents combined with immune checkpoint inhibitors and/or chemotherapy-has become an important treatment strategy for advanced driver-negative non-small cell lung cancer (NSCLC). We conducted a network meta-analysis to compare efficacy and safety and identify optimal antiangiogenic combinations.

Glioblastoma (GBM) is a lethal brain tumor where diffuse invasion and a mesenchymal phenotype drive therapy resistance. Maintaining proteostasis through ubiquitin editing is a crucial stress-adaptive mechanism in cancer, but its role in GBM invasiveness is unclear. We analyzed JOSD1 expression in clinical samples and assessed its correlation with patient survival. Gain- and loss-of-function studies in GBM cell lines were performed to evaluate the role of JOSD1 in invasion, migration, proliferation, and the regulation of epithelial-to-mesenchymal transition (EMT) markers. Protein-protein interaction, deubiquitination, and cycloheximide chase assays were used to define the mechanistic relationship between JOSD1 and Twist1. Rescue experiments with Twist1 re-expression were conducted to confirm the functional axis. JOSD1 was markedly upregulated in GBM and high expression correlated with poor patient survival. JOSD1 overexpression promoted invasion, migration, proliferation, and an EMT-like shift (decreased E-cadherin, increased N-cadherin and Vimentin), while its silencing had opposite effects. Mechanistically, JOSD1 directly bound to and deubiquitinated Twist1, preventing its proteasomal degradation and extending its protein half-life. JOSD1 depletion accelerated Twist1 turnover, and re-expression of Twist1 rescued the impaired invasiveness and growth in JOSD1-deficient cells. Conversely, Twist1 knockdown abrogated the pro-invasive effects of JOSD1 overexpression. Our findings define a JOSD1-Twist1 axis that sustains a mesenchymal, invasive phenotype in GBM by regulating Twist1 protein stability. This links ubiquitin-dependent proteostasis to GBM pathogenicity, suggesting that targeting JOSD1 may represent a therapeutic strategy for aggressive, mesenchymal GBM. Glioblastoma remains one of the most lethal human cancers, and effective strategies to block its diffuse invasion are urgently needed. Here we identify the deubiquitinase JOSD1 as a previously unrecognized driver of epithelial-mesenchymal transition and invasion in glioblastoma. JOSD1 directly binds and deubiquitinates the transcription factor Twist1, preventing its proteasomal degradation and sustaining a mesenchymal, highly motile phenotype. Genetic depletion inhibition of JOSD1 destabilizes Twist1, suppresses invasion, and attenuates tumor growth in preclinical models. Clinically, JOSD1 is markedly upregulated in glioma tissues and its high expression predicts poor patient survival. Our findings nominate the JOSD1-Twist1 axis as a druggable vulnerability for invasive glioblastoma and support future development of JOSD1-targeted therapies.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor with a poor prognosis. Magnetic resonance imaging (MRI) is widely used for the clinical diagnosis and prognostic evaluation of GBM. This study aimed to investigate the relationship between MRI semantic features and overall survival, and to explore the underlying biological mechanisms by transcriptomic analysis. In this study, we reviewed the MRI images of 171 patients with GBM from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases and evaluated twelve MRI semantic features. Cox regression model and Kaplan-Meier survival curve were used to assess the prognostic value of the imaging features. Additionally, we investigated the relationship between imaging features and gene expression using differential gene expression and enrichment analysis in the cohort of 68 tumor samples with RNA-seq data. 171patients with GBM were included in the imaging-prognostic cohort (median age was 60.0 years and 59.6% were male). In the multivariate analyses, age (HR: 1.04, 95% CI: 1.03-1.06, P < 0.001), ependymal extension (HR:1.88, 95% CI:1.32-2.69, P < 0.001), contrast-enhancing tumor (CET) crossing midline (HR:2.38, 95% CI:1.16-4.91, P = 0.018) were significantly associated with shorter overall survival (OS). Gene set enrichment analysis (GSEA) showed that these features were significantly associated with pathways involved in inflammatory responses and tumor invasiveness, such as TNF-α signaling via NF-κB and epithelial-to-mesenchymal transition. Our study demonstrated that MRI semantic features, including ependymal extension and CET crossing the midline, can serve as prognostic indicators for patients with GBM. Additionally, several selected MRI features were found to be associated with specific biological pathways, potentially informing treatment decisions based on these distinctive semantic characteristics of GBM.

Claudin-low breast cancers (BCs), representing approximately 1.5-14% of all BCs, are characterized by high aggressiveness, enriched cancer stem cell (CSC) population, and poor prognosis. Despite the established role of Notch signaling in mammary gland development and BC progression, its status in claudin-low BCs remains inadequately explored. In this study, Notch pathway activation was evaluated in BC cell lines and 107 patient samples. Claudin-low subtype exhibited elevated Notch activity. Notch1 was observed to be the predominant receptor in the above subtype, whereas Notch3 was predominant in the claudin-high cancers. Notch1 and HES1 expression showed a significant inverse correlation with claudins 3, 4, and 7, and were positively associated with aggressive tumor features including high Ki67 index, higher grade, and increased metastasis. Immunohistochemical analysis further confirmed a correlation between nuclear Notch1 (N1ICD) expression and claudin-low status, supporting its potential as a biomarker for identification of aggressive BC. Combined treatment with celecoxib (10 µM) and doxorubicin (1 µM) in claudin-low cells not only significantly inhibited Notch signaling and claudin expression, but also suppressed viability, proliferation, migration, and BCSC populations. Since Notch signalling may be an essential factor in these latter events, our findings suggest that Notch1/N1ICD can serve as therapeutic targets for the better management of claudin-low BCs. However, validation of the same requires detailed functional studies involving modulation of each type of Notch receptor or other players involved in Notch signaling using more robust approaches.

Hodgkin lymphoma survivors (HLSs) are at risk of developing late effects (LEs), and their knowledge is crucial for prevention and treatment. We explored HLSs' knowledge and experience with LEs, their needs for information about LEs, lifestyle and rehabilitation, their needs for long-term follow-up, and factors associated with these needs.

In PREDIX LumB patients with estrogen receptor positive and human epidermal growth factor receptor negative (ER + /HER2-) breast cancer > 20 mm and/or with lymph node metastasis were randomized 1:1 to receive either paclitaxel weekly for 12 weeks followed by palbociclib and endocrine therapy for 12 weeks (arm A), or the reverse sequence (arm B). Primary endpoint is objective radiologic response at 12 weeks (ORR12), and key secondary endpoints are ORR24, pathologic complete response, event-free survival, safety and correlative studies of tissue and circulating biomarkers. Whole exome sequencing and RNA sequencing were performed on baseline fresh frozen tissue samples. In total, 179 patients comprise the intention-to-treat population. There is no statistically significant difference between the two arms in ORR12 (59% vs 45%, p = 0.058). An exploratory gene expression analysis identified differentially expressed genes and gene sets between responders and non-responders at 12 weeks. A predictive signature, CDKPredX, comprising 31 genes related to proliferation, ER signaling and immune activity was developed to identify patients resistant to chemotherapy but responding to palbociclib plus endocrine therapy (pinteraction=0.03). The predictive signature was independently validated in the CORALLEEN trial (pinteraction=0.048). Clinicaltrials.gov identifier: NCT02603679.

Skin cancer has become a global public health issue. Dermoscopy is a routine diagnostic method; however, to improve accuracy, it is often combined with skin punch biopsy and stained histological slides for microscopic observation. The manual segmentation of the lesion area by doctors involves issues such as high subjectivity and time consumption. Deep learning techniques have become a mainstream solution. Compared to foreground-background segmentation in dermoscopic images, the semantic segmentation task for whole-slide skin cancer images is more complex, requiring precise differentiation of 10 distinct tissue classes (such as tumor, epidermis, dermis, hair follicle, sweat gland, fat, etc.). Among these, various epithelial and dermal tissue types exhibit similar morphological features and are interwoven, which increases segmentation difficulty. To address this, we propose a multi-frequency domain attention-based dual encoder network (MSF-VMDNet), which combines U-Net and Vision Mamba dual encoders for parallel feature extraction. The U-Net encoder incorporates an improved AFNO spectral decomposition module, which uses a frequency domain mechanism to extract high-resolution multi-class semantic information. It further strengthens spatial information through multi-scale feature aggregation, improving segmentation accuracy at class boundaries and making the contours clearer. The Vision Mamba encoder, based on a Linear State Space Model (SSM), optimizes long-range dependency modeling and enhances both global and local feature perception. By utilizing a multi-frequency domain mechanism, this encoder maps subtle class-discriminative features from the skin histological slide into the frequency domain, reinforcing contextual features and reducing misclassification rates. In the decoding phase, the SCConv module fuses features from different frequency domains and spatial levels. Experimental results show that MSF-VMDNet significantly outperforms existing methods in terms of class segmentation performance on skin cancer histological slide datasets, achieving an MIoU of 95.37% and a Dice coefficient of 95.11%. Additionally, the model demonstrates its generalization ability in extended experiments on the ISIC 2018 dermoscopic image, PanNuke pathological cell nucleus image, and Synapse image datasets.

Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTBhigh) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 (p = 0.009; p = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT.

Purpose: We explored the association between metastatic cancer, chemotherapy, and the risk for suicide attempts (suicide injuries) in adult trauma patients.Methods: We conducted a retrospective analysis of the Trauma Quality Program Participant Use File (2017-2019), comprising 27,474 patients from 700 U.S. Trauma Centers. Self-harm/suicide injury (compared to controls) was the dependent variable; presence of metastatic cancer and current chemotherapy were the key independent variables. We adjusted for age, sex, race/ethnicity, method of payment, facility levels, and discharge year (Model 1), and Model 1 plus trauma type, injury location, stay length, comorbidities, Injury Severity Score, and Glasgow Coma Scale (Model 2). We employed chi-square analysis, Fisher's exact test, and unadjusted and adjusted logistic regression using Stata v18, setting statistical significance at P≤0.05.Results: Of 27,474 patients, 249 (0.91%) reported suicide injuries. Significantly higher attempts were noted among patients with metastatic cancer (201 out of 249; 80.72%) and those not receiving chemotherapy (184 out of 249; 73.90%), P<0.001. Metastatic cancer was associated with higher odds of suicide injuries (unadjusted OR:2.252, 95%CI: 1.642-3.089; adjusted OR in Model 1:1.925, 95%CI:1.302-2.848). Chemotherapy was associated with lower odds of suicide injuries (unadjusted OR:0.408, 95%CI:0.307-0.541; adjusted OR in Model 1:0.444, 95%CI:0.311-0.636). However, neither metastatic cancer nor chemotherapy was significantly associated with suicide injuries in adjusted Model 2, suggesting the crucial role of other factors in influencing this risk.Conclusion: Patients with metastatic cancer exhibited notable prevalence of suicide injuries. Findings suggested metastatic cancer was associated with higher odds, and chemotherapy with lower odds, of suicide injuries. Multifaceted factors were associated with suicide risk beyond the presence of metastatic cancer or chemotherapy status, underscoring the importance of mental health assessments and interventions in oncology care, particularly for those with advanced cancer.

Primary cutaneous T-cell and B-cell lymphomas may occur at any age and are defined by specific clinical, histopathologic, and immunophenotypic features. Clinical correlation is critical to differentiate indolent and aggressive entities, such as the lymphomatoid papulosis subtypes, which may have histopathologic and immunophenotypic features that are indistinguishable from aggressive cutaneous T cell lymphomas. Awareness of mycosis fungoides variants that overlap with benign conditions may help prevent misdiagnosis. Lymphoproliferative disorders do not require aggressive treatment or extensive staging. Watchful waiting is often appropriate.

Onychopathology (nail unit pathology) is a niche area in dermatopathology. There is a lack of familiarity with nail unit pathology and basic anatomy in general among pathologists and dermatopathologists, because of the relative rarity of such specimens in practice, and the lack of exposure and teaching regarding these lesions in training. It is however a vibrant area of dermatopathology, with knowledge evolving rapidly. In this article, we explore new information in the analysis of melanocytic and epithelial lesions of the nail unit, as well as nail inflammatory disease.

This article highlights selected cutaneous mesenchymal tumors, emphasizing histopathology, immunophenotype, and molecular alterations. It outlines diagnostic pitfalls, distinguishing features, and clinical behavior of indolent and malignant lesions. Awareness ensures accurate and appropriate treatment, and prevents overtreating benign mimics.

Refinements in histologic criteria, staging systems (American Joint Committee on Cancer 8th edition, Brigham and Women's Hospital), clinical guidelines (National Comprehensive Cancer Network [NCCN]), and molecular tools like gene expression profiling have enhanced the precision of cutaneous squamous cell carcinoma diagnosis and treatment. In Merkel cell carcinoma, recent updates in viral pathogenesis, immunohistochemistry, and emerging biomarkers have aided in better diagnostics. As immunotherapies and precision oncology evolve, dermatopathologists remain essential in guiding patient-specific management strategies for both cutaneous squamous cell carcinoma and Merkel cell carcinoma.

Cutaneous adnexal tumors recapitulate hair follicles, sweat glands, and/or sebaceous glands. These tumors range from benign to malignant and might herald an underlying inherited tumor syndrome. Accurate classification of adnexal tumors is thus critical but can be challenging due to many knowledge gaps in this area. Recent advances have dramatically improved our understanding and diagnosis of adnexal tumors. Here, we review several recently described adnexal carcinomas and summarize new molecular drivers reported in previously established tumor entities. We highlight morphologic, immunohistochemical, and molecular clues helpful for diagnosis of these adnexal tumors.

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.