Search Results (417)

Glioblastoma (GBM) recurs predominantly from infiltrative disease that persists beyond the contrast-enhancing tumor (CET). This structured narrative review aims to define the invasive margin and peritumoral brain zone (PBZ) as a spatially organized molecular ecosystem, summarize the approaches used to interrogate this compartment, and evaluate how malignant-cell plasticity, host niches, and treatment-induced remodeling contribute to minimal residual disease and recurrence. A structured literature search of PubMed/MEDLINE, Scopus, and Web of Science identified the clinical, translational, preclinical, and review literature available through July 2026; evidence was synthesized qualitatively, with priority given to human tissue studies and single-cell or spatially resolved analyses. Across studies, the margin differs from both tumor core and normal brain and contains heterogeneous malignant states interacting with neural, vascular, immune, hypoxic, and extracellular-matrix-supported niches. Surgery, radiotherapy, and systemic treatment further reshape these interactions through inflammation, vascular injury, senescence, hypoxia, and fibrosis. The main translational challenge is therefore not simply to control the CET, but to identify biologically high-risk non-enhancing tissue and demonstrate that therapy reaches and modifies it. We propose three priorities: image-registered characterization of residual compartments, regional measurement of drug exposure and target engagement, and integration of local margin control with distributed and niche-directed treatment. Prospective validation is required before spatial PBZ biomarkers can guide routine care. Full article

Objectives: Tenascin-C (TNC) is an extracellular matrix protein associated with tissue remodeling, tumor progression, and poor prognosis in breast cancer. Although TNC has attracted interest as a potential stromal biomarker, its baseline histopathological distribution in untreated breast cancer has not been fully characterized. This exploratory pilot study aimed to characterize the immunohistochemical distribution of TNC in representative treatment-naïve breast cancer tissues. Methods: Immunohistochemical staining for TNC was performed in representative breast cancer tissue specimens obtained from 16 treatment-naïve patients encompassing major histological and molecular subtypes. Tumor and non-tumor areas were evaluated descriptively by two board-certified pathologists using consensus assessment. Results: Heterogeneous TNC expression was observed in the stroma surrounding invasive tumors in all cases. In most specimens, TNC staining was predominantly localized to the peritumoral stroma, whereas occasional staining was observed around non-invasive lesions. Non-tumor breast stroma was largely negative, although positive staining was observed in biopsy scars and sclerotic areas. No consistent subtype-specific pattern of TNC distribution or staining intensity was identified. Conclusions: TNC showed heterogeneous stromal expression in treatment-naïve breast cancer and was also detected in biopsy scars and areas of stromal remodeling. These findings provide baseline histopathological information regarding TNC localization in untreated breast cancer. Further studies are required to determine the potential clinical utility of TNC as a stromal biomarker, including its application in the post-neoadjuvant setting. Full article

Background: Glioblastoma (GBM) shows marked heterogeneity in overall survival (OS), yet robust radiological prognostic markers remain limited. The prognostic value of peritumoral edema and tumor location remains uncertain. Objective: To evaluate whether peritumoral edema, tumor burden, and spatial tumor distribution predict OS using automated MRI analysis and Brain-Grid-based topographical mapping. Methods: In this retrospective study, preoperative T1-contrast-enhanced and T2-FLAIR MRI sequences from 271 patients with IDH-wildtype GBM were analyzed using automated segmentation (Raidionics). Tumor and edema volumes, edema-to-tumor ratio (ETR), and voxel-wise infiltration patterns were extracted. Location was mapped using the Brain-Grid system. Survival was assessed using Kaplan–Meier and multivariable Cox regression adjusted for age and tumor volume, with correction for multiple testing. Results: In multivariable analysis, only age remained a conventional independent predictor of OS (HR 1.03, p < 0.001). Tumor volume, edema volume, and ETR were not associated with survival. In contrast, Brain-Grid analysis identified two centrally located subcortical voxel regions that remained significantly associated with shorter OS after full adjustment and multiple testing correction. Total number of infiltrated voxels showed no prognostic value. Conclusions: Spatially defined subcortical infiltration patterns, rather than global tumor or edema burden, independently stratify survival in GBM. These findings highlight the prognostic relevance of voxel-level tumor topography and support further validation of Brain-Grid-based imaging biomarkers. Full article

Field cancerization describes molecular alterations occurring in histologically normal tissues surrounding tumors that may contribute to cancer initiation and progression. In prostate cancer (PCa), the molecular characteristics of peritumoral tissue (PTT) remain incompletely understood. Because microRNAs (miRNAs) play key roles in gene regulation, tumor progression, and microenvironmental remodeling, we investigated miRNA expression patterns and regulatory networks across benign tissue (BT), PTT, and tumor tissue (TT). Small RNA sequencing was performed on matched formalin-fixed paraffin-embedded samples from 40 patients with PCa. Differential expression analysis was conducted using DESeq2, adjusting for age and Gleason grade, while functional enrichment analysis and weighted gene co-expression network analysis (WGCNA) were used to identify dysregulated pathways and conserved miRNA modules. PTT exhibited a molecular profile intermediate between BT and TT, consistent with a field cancerization effect. Compared with BT, 102 miRNAs were differentially expressed in TT and 57 in PTT, with 39 miRNAs (68% of the PTT-associated miRNAs) overlapping the tumor signature. Shared dysregulated pathways included PI3K–Akt, p53, and HIF-1 signaling; whereas, PTT showed additional enrichment in pathways related to epigenetic regulation (Polycomb Repressive Complex) and cellular stress responses (mitophagy, protein processing in ER) exclusively through up-regulated miRNAs; no pathways were uniquely enriched from down-regulated miRNAs in PTT. WGCNA identified conserved miRNA modules enriched for members of the let-7, miR-200, miR-103/107, and miR-106a~363 families, which have established roles in epithelial–mesenchymal transition, tumor progression, and microenvironmental remodeling. Collectively, these findings demonstrate that histologically benign peritumoral tissues harbor tumor-associated miRNA programs and regulatory networks that closely resemble those observed in prostate tumors, providing molecular evidence of field cancerization in PCa and identifying potential miRNA-mediated mechanisms relevant to disease progression and biomarker development. Full article

Sentinel lymph node (SLN) mapping plays a pivotal role in oncological staging in veterinary medicine. However, conventional techniques often depend on radioactive tracers or specialized imaging equipment that is unavailable in many clinical settings. This brief report describes the use of indirect radiographic lymphography with the non-ionic iodinated contrast agent iohexol for SLN identification in a dog with auricular melanoma. A 12-year-old spayed female mixed-breed dog presented with an ulcerated cutaneous mass affecting the left auricle. Cytological evaluation was consistent with a melanocytic neoplasm. Immediately before surgery, iohexol was administered intradermally at four peritumoral sites (0.75 mL per cm²). Radiographic images acquired 3 and 4.5 min after injection demonstrated lymphatic drainage to the superficial ventral and superficial dorsal cervical lymph nodes, which were identified as sentinel lymph nodes. The patient underwent vertical ear canal ablation, conchectomy, partial auriculectomy, and excision of the mapped sentinel lymph nodes. Histopathological examination confirmed a mixed-type cutaneous melanoma with macrometastatic involvement of the superficial ventral cervical sentinel node and micrometastatic deposits in both the superficial dorsal cervical and left parotid lymph nodes. Although the parotid lymph node was not enlarged radiographically, afferent lymphatic channels indicated contrast uptake, and histopathology confirmed metastatic involvement. This finding supports considering elective regional lymphadenectomy alongside sentinel lymph node biopsy in similar cases. An incidental cutaneous hemangiosarcoma was identified at a distant abdominal site, excised with complete margins, and was unrelated to the primary tumor. No systemic adverse effects associated with iohexol administration were observed, and only transient mild-to-moderate localized edema developed at the injection site, resolving spontaneously without treatment. These findings suggest that iohexol-based indirect radiographic lymphography is a practical, safe, and accessible technique for sentinel lymph node identification and may represent a promising, though not yet validated, alternative for lymphatic staging in veterinary oncology, although further prospective studies are needed to establish its diagnostic accuracy. Full article

Glioblastoma recurrence remains nearly inevitable despite maximal resection and adjuvant therapy, with most relapses occurring within or adjacent to the original tumor site. Conventional MRI underestimates tumor infiltration beyond contrast-enhancing margins, limiting preoperative identification of peritumoral regions at higher risk of recurrence. We developed a radiomics-based machine-learning framework to generate preoperative spatial recurrence risk maps from routine MRI. Preoperative T1-weighted contrast-enhanced and FLAIR images from 79 patients with glioblastoma were analyzed. The cohort was divided at the patient level into a training set (n = 63) and an independent test set (n = 16). Using a balanced spatial ROI sampling strategy, local radiomic features were extracted from tumor and peritumoral regions and linked to recurrence sites identified on follow-up MRI acquired after at least 12 months after surgery. A CatBoost classifier achieved an AUC of 0.743 and a recall of 0.856 on an independent test set. The framework also generated preoperative probability maps that showed qualitative spatial correspondence with observed recurrence locations. These findings indicate that radiomic patterns from standard preoperative MRI may contain spatially localized information associated with future relapse. The proposed approach supports the feasibility of preoperative spatial risk stratification and may provide useful information for surgical planning and subsequent treatment strategies. Full article

Nasal transitional carcinoma (TC) is one of the most common epithelial nasal tumors in dogs, but systematic descriptions of its clinical and computed tomographic (CT) features are limited. This multicenter retrospective study characterized the clinical and CT features of histopathologically confirmed nasal TC in 16 dogs examined at four animal hospitals between July 2014 and January 2024. Signalment, clinical signs, CT findings, and follow-up information were summarized descriptively. Epistaxis was the most common clinical sign (12/16, 75%). All tumors involved the caudal nasal cavity, and extension to adjacent structures or most commonly affected the maxillary recess (14/16, 88%), orbit (11/16, 69%), and nasal choanae (10/16, 63%). Most tumors exhibited destructive growth (15/16, 94%) with frequent cribriform plate lysis (12/16, 75%). Cranial vault invasion was identified in 12 dogs (75%), whereas CT-detected brain parenchymal involvement was present in only 2 dogs (13%). Intralesional non-enhancing fluid-attenuating regions consistent with necrosis or cystic change and peritumoral fluid accumulation were observed in 12 (75%) and 10 dogs (63%), respectively, and intralesional calcification was absent in all dogs. These results provide a frequency-based CT reference pattern for canine nasal TC; however, the findings are not specific for this tumor type, and histopathological examination remains necessary for definitive diagnosis. Full article

Headache is a frequent and clinically relevant symptom in patients undergoing cranial radiotherapy, most often reflecting treatment-induced structural and inflammatory changes such as cerebral edema or radiation-related brain injury. Differentiating secondary headache from primary disorders, particularly migraine, is essential for appropriate management. This review aims to examine the pathophysiological mechanisms underlying headache following cranial radiotherapy, evaluate current pharmacological and complementary treatment strategies and highlight key aspects of differential diagnosis with migraine. Unlike existing literature that focuses primarily on radiological findings of radiation injury, this review adopts a symptom-driven approach, reframing headache as a critical clinical gateway for the early detection of structural complications. A structured narrative review of the literature was conducted using PubMed/MEDLINE, Scopus and Google Scholar to identify studies published between 2020 and 2025, focusing on cerebral edema, radiation-related complications, therapeutic approaches and migraine. Relevant clinical trials, systematic reviews and guidelines were included. Cerebral edema consistently emerges as the main mechanism of acute and subacute post-radiotherapy headache, whereas late-onset symptoms are most often linked to radiation necrosis. Corticosteroids remain first-line therapy, while bevacizumab has demonstrated benefit in steroid-refractory cerebral edema and radiation necrosis through inhibition of vascular endothelial growth factor (VEGF), thereby reducing vascular permeability and attenuating peritumoral edema. Its use in the context of cranial radiotherapy requires careful consideration, as the safety of concomitant administration with radiation has not been formally established, and headache itself is among its recognized adverse effects. Evidence for complementary therapies, including Boswellia serrata and plant-based compounds, remains limited. Migraine constitutes a distinct neurovascular disorder requiring careful differentiation from secondary headache in oncological patients. The review emphasizes headache as a clinically relevant indicator of underlying structural complications rather than an isolated symptom. Post-radiotherapy headache should be interpreted as a manifestation of underlying structural pathology. Accurate etiological diagnosis and individualized management are essential. Further research is needed to refine treatment strategies and clarify the role of complementary therapies. Full article

Immune exclusion refers to the phenomenon in which immune cells are restricted to the peritumoral stroma. This phenomenon arises from complex interactions within the tumor microenvironment (TME) that limit immune cell infiltration. Consequently, immune exclusion represents a major barrier to effective antitumor immunity and a key obstacle to the success of immunotherapy. The principal components of the TME that orchestrate immune exclusion are (i) the tumor vasculature, (ii) the extracellular matrix (ECM), and (iii) stromal cells and their chemokine-mediated signaling. Understanding immune exclusion is critical for designing therapies that enhance the efficacy of immunotherapy and improve clinical outcomes. This review synthesizes current knowledge of the molecular and cellular mechanisms underlying immune exclusion and discusses emerging therapeutic strategies aimed at overcoming this phenomenon. Full article

Objectives: The histologic grade is an important prognostic factor in hepatocellular carcinoma (HCC). A Gd-EOB-DTPA-enhanced MRI may provide noninvasive imaging markers related to tumour differentiation. This study aimed to evaluate the association of Gd-EOB-DTPA-enhanced MRI features, together with the albumin–bilirubin (ALBI) score and alpha-fetoprotein (AFP), with the HCC histologic grade and to assess the performance of combined predictive models. Methods: In this prospective cross-sectional study, 75 patients (mean age, 56.4 years; 66 men) with 88 histopathologically confirmed HCC lesions were enrolled. Patients were classified into well-differentiated (grades I–II, n = 24) and poorly differentiated (grades III–IV, n = 51) groups according to the Edmondson–Steiner system. The MRIs were performed on a 1.5-T scanner and included T1-weighted in-phase/opposed-phase imaging; T2-weighted imaging; diffusion-weighted imaging; and dynamic Gd-EOB-DTPA-enhanced sequences, including arterial, portal venous, transitional, and 20 min hepatobiliary phases. Two radiologists, blinded to the pathology, assessed predefined imaging features, and the lesion-to-liver ratio (LLR) was measured. Group comparisons were performed using Student’s t-test, a Mann–Whitney U test, and a chi-square or Fisher’s exact test, followed by a multivariable logistic regression and ROC analysis with bootstrap resampling. Results: Compared with well-differentiated HCC, poorly differentiated HCC showed a higher frequency of peritumoral hepatobiliary phase (HBP) hypointensity (62.7% vs. 4.2%, p < 0.001) and peritumoral arterial hyperintensity (39.2% vs. 0%, p < 0.001). In the multivariable analysis, peritumoral HBP hypointensity remained independently associated with poorly differentiated HCC (OR = 30.89, p = 0.002). The two-parameter MRI model, including peritumoral HBP hypointensity and HBP tumour signal, yielded an AUC of 0.84. The combined MRI + ALBI + AFP model yielded an AUC of 0.87 and an accuracy of 78.7%, representing only a small exploratory improvement over the two-parameter MRI model (AUC = 0.84) in this cohort. Conclusions: Gd-EOB-DTPA-enhanced MRI features, particularly peritumoral HBP hypointensity, were associated with a high histologic grade in HCC. In this surgically treated, predominantly HBV-related cohort with mostly preserved liver function, these findings provide a preliminary basis for preoperative histologic risk stratification; however, they remain exploratory and require external validation in larger, more diverse cohorts before broader clinical application. Full article

Background/Objectives: Early recurrence after curative-intent resection is a major determinant of poor prognosis in hepatocellular carcinoma (HCC). Artificial intelligence (AI)-driven predictive models have emerged to identify patients at high risk of recurrence but remain incompletely synthesized for early recurrence specifically. This review aimed to identify and appraise AI-driven models predicting early recurrence after surgical resection. Methods: PubMed/MEDLINE, Scopus and Web of Science were searched from inception to November 2025. Eligible studies developed and evaluated AI-driven models predicting early recurrence (≤24 months) after curative-intent hepatectomy as first-line treatment for HCC. Risk of bias and applicability were assessed using PROBAST+AI, and findings were synthesized narratively due to methodological heterogeneity. The review was registered in PROSPERO. Results: Thirty-six studies involving 14,716 patients were included. Most studies originated from China (33/36, 91.7%), were single-center (27/36, 75%), and retrospective (35/36, 97.2%). Magnetic resonance imaging (MRI) was the predominant imaging modality (15/36, 41.7%), followed by computed tomography (CT) (11/36, 30.6%) and ultrasound (US)/contrast-enhanced ultrasound (CEUS) (6/36, 16.7%). Three studies developed non-imaging models, and one combined CT and MRI. In within-study comparisons, multimodal models generally showed better discrimination than unimodal approaches. Peritumoral, habitat-based, and multiphasic strategies appeared promising. However, external validation was reported in only 6/36 studies (16.7%), calibration and decision-curve analysis were inconsistently reported, and most studies had high risk of bias. Conclusions: AI-driven models show potential to predict early recurrence of HCC after curative-intent resection. Nevertheless, evidence remains limited by methodological heterogeneity and restricted geographical diversity, while clinical utility remains inconsistently evaluated, and no model has yet been generalized in clinical practice. Prospective multicenter studies with standardized outcomes, transparent reporting, and external validation are needed for clinical implementation. Full article

Systemic administration of antibodies that target immune checkpoint inhibitor pathways is a highly effective approach to cancer immunotherapy, but systemic toxicity can limit clinical utility. In preclinical testing, a peri-tumor injection of a low dose of hydrogel-encapsulated cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody was shown to selectively activate T cells in tumor-draining lymph nodes, induce tumor infiltration by cytotoxic T cells, and result in tumor regression, protective immunity, and long-term survival. In contrast to systemic therapy, there was limited systemic exposure or risk for autoimmune toxicity. The current study focuses on translating this platform into a biocompatible human therapeutic. The hydrogel matrix was reformulated using a low-molecular-weight hyaluronic acid. A recombinant human hyaluronidase (rHuPH20) was incorporated to promote lymph node targeting and self-resorbing features. Formulations were optimized to operate at neutral pH and with gelation kinetics allowing a 5 to 10 min administration window. Performance features were assessed including the capacity to encapsulate human IgG or ipilimumab antibody at proposed therapeutic doses (1–15 mg/mL), impact of rHuPH20 and antibody on rheologic properties and three-dimensional microstructure, and payload delivery profiles in vitro and in vivo. Results confirm the capacity for this unique hydrogel platform to be adapted for human testing. Full article

Background: Wilms tumor (WT) rupture is a serious complication that upstages the disease and requires treatment intensification. This study evaluates clinical characteristics, radiological-pathological concordance, and survival outcomes of ruptured versus non-ruptured WT at a major Middle Eastern tertiary center. Methods: We conducted a retrospective cohort study of 111 pediatric patients with unilateral WT treated at King Hussein Cancer Center, Jordan, between October 2014 and December 2023 (follow-up to December 2025). Tumor rupture was defined by preoperative CT findings (peritumoral effusion, hemorrhage, or peritoneal nodules), intraoperative capsular breach/spillage, or pathological confirmation. Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan–Meier methods and compared with the log-rank test. Multivariable Cox regression identified independent prognostic factors. Results: Tumor rupture occurred in 17 patients (15.3%). Ruptured cases were older (median 4.2 vs. 3.5 years, p = 0.03), had larger tumors (13.7 vs. 11.7 cm, p = 0.01), and presented with lower hemoglobin (7.9 vs. 10.4 g/dL, p < 0.001). All ruptured cases were stage III/IV, with 41% having distant metastases at diagnosis. Five-year EFS was 44.1% vs. 75.8% (p = 0.025) and OS was 58.2% vs. 81.4% (p = 0.002) for ruptured vs. non-ruptured groups. On multivariable analysis, rupture independently predicted death (HR 17.62, 95% CI 2.69–115.48, p = 0.003) and relapse (HR 8.1, 95% CI 1.66–39.57, p = 0.01). Conclusion: WT rupture is associated with advanced disease at presentation and significantly inferior survival. Substantial discordance between preoperative radiological/intraoperative findings and post-chemotherapy pathology highlights the “masking effect” of neoadjuvant chemotherapy. A multidisciplinary approach integrating initial imaging, surgical notes, and histology is essential to avoid undertreatment in SIOP-based protocols. Full article

Background/Objective: Basal cell carcinoma (BCC) is the most common cutaneous malignancy, arising from epidermal basal cells or the outer root sheath of the pilosebaceous unit. Despite its generally indolent clinical behavior, BCC exhibits substantial histopathological heterogeneity, which may reflect underlying biological differences among its subtypes. This study aimed to evaluate the expression of Wnt/β-catenin pathway components and tumor-associated markers—including COX-2, Ki-67, tryptase, CD1a, and WNT3A—across different histopathological subtypes of BCC. Methods: This retrospective cross-sectional study included 100 formalin-fixed paraffin-embedded (FFPE) BCC specimens retrieved between January 2006 and September 2015. After the exclusion of three cases due to inadequate tissue quality, the tumors were classified into nodular (n = 60), infiltrative (n = 16), superficial (n = 9), and other subtypes (n = 12). The immunohistochemical expressions of COX-2, Ki-67, CD1a, intratumoral and peritumoral tryptase, β-catenin, and WNT3A were assessed and compared among the BCC subtypes. Results: No significant differences were observed among the BCC subtypes regarding age or sex distribution. The expression levels of COX-2, Ki-67, CD1a, and mast cell-associated markers (intratumoral and peritumoral tryptase) did not differ significantly among the groups (all p > 0.05). Conversely, β-catenin expression was significantly higher in the infiltrative subtype compared with the other histological variants (p = 0.001). WNT3A immunoexpression was uniformly negative across all evaluated cases. Conclusions: Most of the evaluated immunohistochemical markers did not differentiate among the BCC subtypes. However, the significantly increased β-catenin expression observed in the infiltrative subtype suggests a potential association with tumor growth patterns rather than serving as a specific discriminative marker, thereby highlighting the biological heterogeneity of BCC. Although WNT3A expression was uniformly negative in all cases, this finding should be interpreted cautiously and does not allow for definitive conclusions regarding its role in Wnt pathway activation. Overall, these results support the need for further investigation into the Wnt/β-catenin pathway heterogeneity in BCC. Full article

Background: Hepatocellular carcinoma (HCC) shows a high rate of early recurrence after curative resection, indicating a critical contribution of tumor microenvironment-driven molecular mechanisms. Early recurrence of hepatocellular carcinoma is defined as recurrence within 6 months after curative resection, with a prevalence exceeding 30%. Hypoxia signaling and immune dysregulation have been implicated, yet their compartment-specific relevance remains unclear. Methods: This multicenter nested case–control study included 49 HCC patients to evaluate associations between hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), tumor-infiltrating lymphocytes (TILs), CD4⁺ T cells, CD8⁺ T cells, regulatory T cells (Tregs), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) and early recurrence after resection. TIL density was assessed using hematoxylin and eosin staining, while immunohistochemistry was performed to quantify intratumoral and peritumoral expression of the studied markers. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive performance. Recurrence-free survival (RFS) was analyzed using the Kaplan–Meier, and independent predictors were identified using multivariate Cox proportional hazards regression. Results: Early recurrence occurred in 11 of 49 patients (22.4%) of Child–Pugh A patients. Recurrent tumors were characterized by elevated VEGF expression despite absent HIF-1α, alongside significant depletion of intratumoral TILs (HR 5.02; 95% CI 1.09–23.26), CD4⁺ (HR 7.68; 95% CI 1.66–35.60) and CD8⁺ cells (HR 6.68; 95% CI 1.77–25.23) and reduced peritumoral CD8⁺ infiltration (HR 4.20; 95% CI 1.11–15.91). Multivariable analysis identified low intratumoral CD4⁺ (HR 7.98; 95% CI 1.63–39.07) and reduced peritumoral CD8⁺ expression (HR 4.98; 95% CI 1.14–21.70) as independent predictors, whereas HIF-1α, VEGF, Treg, PD-1, and PD-L1 were not significantly associated. Conclusions: Early HCC recurrence shows HIF-1α-independent angiogenesis alongside spatial immune depletion, supporting integrated immune profiling over single angiogenic markers. Full article