Perturbation of macropinocytosis triggers methuosis, a non-apoptotic cell death characterized by cytoplasmic vacuolization. However, the regulatory mechanisms of methuosis remain poorly defined. Lipid metabolism dysregulation is implicated in various cell death pathways, while its role in methuosis has remained elusive. Herein, LXX-8250, an isopropanolamine derivative of β-elemene, induced a vacuolization-associated cell death in breast and liver cancer cell lines. This process was accompanied by massive macropinocytosis, thereby confirming the occurrence of methuosis. Mechanistically, hypoxia-inducible lipid droplet-associated protein (HILPDA), a key regulator that promotes intracellular triacylglycerol (TAG) accumulation, was identified as the direct target of LXX-8250. By suppressing HILPDA, LXX-8250 inhibited diacylglycerol O-acyltransferase 1 (DGAT1) and activated adipose triglyceride lipase (ATGL). Consequently, lipid droplets and cellular TAG levels were reduced, while the subsequent increased diacylglycerol (DAG) stimulated macropinosome formation, leading to methuosis in these cells. In this study, we discover a novel methuosis agonist LXX-8250, and elucidate the critical role of HILPDA repression-dysregulated lipid metabolism in methuosis. Our study highlighted the potential of targeting this pathway as a therapeutic strategy to trigger cancer cell death.

Epignathus, a teratoma arising from the palate or pharynx, is extremely rare and palatal fetus-in-fetu represents an even rarer anomaly. We report a prenatally diagnosed palatal fetus-in-fetu successfully managed with ex utero intrapartum treatment (EXIT). A 4 cm oral mass detected at 23 weeks caused polyhydramnios and gastric shrinkage, suggesting impaired swallowing and potential airway obstruction. Multidisciplinary evaluation determined the need for EXIT to secure the airway under placental circulation. At 34+5 weeks of gestation, caesarean delivery with EXIT was performed; a 14 cm tumour was delivered and tracheostomy followed by staged resection was undertaken. Histopathology revealed multiple differentiated tissues-including nerve, gastrointestinal tract, adrenal gland, skin, bone and teeth-meeting Spencer's criteria for fetus-in-fetu. The infant recovered well and was discharged 96 days postnatally. EXIT proved invaluable for airway management in high-risk epignathus, and fetus-in-fetu differs from teratoma by its lower malignant potential, emphasising individualised prenatal planning and team collaboration.

The urethral caruncle is the most common lesion arising from the posterior lip of the urethral meatus in women; however, various benign and malignant tumours may mimic this condition. We report a case of a solitary fibrous tumour (SFT) presenting as a urethral caruncle. A woman in her late 60s presented with a progressively enlarging urethral mass that was accompanied by urinary spraying. Physical examination revealed a smooth spherical mass measuring 1.2 cm at the posterior urethral meatus. The lesion was completely excised under local anaesthesia. Histologically, the tumour consisted of spindle cells within collagenous stroma. Immunohistochemically, the tumour cells showed nuclear expression of STAT6 with focal CD34 positivity, supporting the diagnosis of SFT. No recurrence was observed during the 9-month follow-up period. This case highlights that lesions clinically resembling urethral caruncle may include mesenchymal tumours such as SFT, underscoring the importance of histopathological evaluation.

Metabolic reprogramming through enhanced glycolysis is a hallmark of cancer that supports tumor progression and promotes protumor immune responses. Methylglyoxal (MG), a reactive by-product of glycolysis, has recently emerged as an oncometabolite implicated in cancer progression and therapy resistance. Our previous work demonstrated that an imbalance between MG production and detoxification by the glyoxalase system, referred to as MG stress, contributes to progression and metastatic dissemination in triple-negative breast cancer (TNBC). However, the impact of MG stress on the tumor immune microenvironment remains poorly understood.

Immunotherapeutic approaches for cutaneous squamous cell carcinoma (cSCC) remain limited to programmed cell death protein 1 (PD-1) blockade. Although genomics studies have characterized key driver mutations in cSCC, preclinical models that faithfully recapitulate both the genetic landscape and immune microenvironment of the human disease, that could drive the development of novel, effective therapies, are lacking.

This study aims to elucidate the molecular mechanisms by which Polyphyllin I (PPI), a potent steroidal saponin, attenuates non-small cell lung cancer (NSCLC) progression via mechanistic reprogramming of an autophagy-dependent immunogenic response.

Robot-assisted radical nephroureterectomy (RANU) is increasingly used for upper tract urothelial carcinoma (UTUC), yet most published series are selected and real-world data from consecutive, unselected practice are scarce. We reviewed 100 consecutive RANU performed at a single institution between April 2022 and March 2026, including six cases with a concomitant procedure. Median age was 77 years and 39 patients had pT3-4 disease. Median estimated blood loss was 29 mL, operative time 200 min, and console time 141 min; three patients required transfusion. Clavien-Dindo grade II or higher complications occurred within 90 days in 13 patients, with only one grade III event. At a median follow-up of 15.5 months, the cumulative incidence of intravesical and of distant or local recurrence was approximately 17% and 18% at 12 months, and overall survival was approximately 86% at 24 months. RANU was feasible with favorable perioperative outcomes in this elderly, frequently advanced cohort.

Rectal cancer with mesorectal fascia involvement (MRF+) requires neoadjuvant downstaging and/or induction therapy, followed by (beyond) total mesorectal excision and/or multivisceral resection (MVR) depending on response. Decisions on the need for MVR and plane of dissection vary. This nationwide cross-sectional study aimed to evaluate treatment and oncological outcomes in MRF+ primary rectal cancer and the impact of MVR types.

HLA-G is a non-classical MHC class I molecule with potent immunoregulatory functions that is aberrantly expressed in multiple malignancies, yet its tumor-intrinsic role remains poorly defined. To characterize this potential oncogenic role of HLA-G in clear cell renal cell carcinoma (ccRCC), we utilized integrated transcriptomic, in vitro, and in vivo approaches. Analysis of the Cancer Genome Atlas (TCGA) ccRCC cohort revealed that elevated HLA-G expression was associated with immunosuppressive programs and cell populations. Interrogation of a publicly available ccRCC single-cell RNA sequencing dataset revealed that HLA-G expression within tumor epithelial clusters is associated with hypoxia-driven, metabolic transcriptional programs. Multiplex immunofluorescence of human ccRCC specimens confirmed the presence of tumor cell-intrinsic HLA-G expression in advanced disease. Functional studies using RCC7 cells expressing the full-length canonical HLA-G isoform (RCC7/HLA-G1) demonstrated increased proliferation, migration, clonogenicity, cell-cycle progression, and resistance to apoptosis compared with HLA-G-negative RCC7wt cells. RCC7/HLA-G1 xenografts exhibited accelerated tumor growth accompanied by the activation of proliferative, stemness-related, and metabolic programs. Multi-omics analyses further revealed enhanced mitochondrial activity and redox metabolic adaptation in HLA-G-expressing tumors. Mechanistically, HLA-G expression was associated with increased VEGF-C expression and enhanced VEGFR3 signaling, suggesting the activation of a VEGF-C/VEGFR3-associated pro-survival pathway. In three-dimensional tumor spheroid immune cell co-culture models, HLA-G expression reduced CD8⁺ T-cell-mediated cytotoxicity while promoting regulatory T-cell expansion and macrophage polarization toward an immunosuppressive M2-like phenotype. Collectively, these findings establish HLA-G as a key contributor to tumor progression and immune suppression in ccRCC and support HLA-G as a promising therapeutic target.

Primary breast neuroendocrine carcinomas (NECs) are rare, high-grade malignancies that are frequently grouped with invasive breast carcinomas with neuroendocrine differentiation (IBC-NED), despite uncertain biological equivalence. We sought to define the clinicopathologic, immunophenotypic, and genomic features of breast NEC and to determine whether they represent a biologically distinct entity.

Diffuse midline gliomas (DMGs) are highly aggressive, WHO grade 4 glial tumors that arise in midline central nervous system structures and are defined by K27M mutations in histone H3 genes. These K27M mutations shape intratumoral myeloid cell composition in DMG. In H3.1K27M DMGs, genetic ablation of monocyte recruitment reshapes the tumor microenvironment (TME) by reducing monocyte-derived macrophages (MDMs) and increasing microglia and neutrophil presence, with overall survival remaining unchanged, indicating compensatory myeloid remodeling is occurring. Here, by using CRISPR/Cas9-based genome editing, we generated a mouse model deficient for CCR1/CCR2/CCR3/CCR5 (Δ1235). Using this strain, we effectively abolished monocyte and MDM infiltration and reversed compensatory recruitment of CCR1+ neutrophils. Abolishing MDMs in tumors skewed remaining neutrophils and microglia toward a homeostatic state, reduced expression of immune checkpoint molecules on T cells, and extended the survival of H3.1K27M DMG-bearing mice. In contrast, H3.3K27M DMG showed independence from MDM recruitment, suggesting reliance on other TME-driven signaling. Last, H3.1K27M DMGs exhibited reduced microglia presence and a dose-dependent increase in MDM infiltration postirradiation. MDM depletion did not further enhance radiation efficacy, potentially due to compensatory recruitment of classical neutrophils. Collectively, these data reveal histone mutation-specific myeloid dependencies in DMG, highlighting MDM-independent mechanisms in H3.3K27M tumors and MDM-dependent pathways in H3.1K27M tumors.

Reduced skeletal muscle mass may impair outcomes of immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma. We evaluated whether temporal muscle thickness (TMT) on routine head computed tomography was associated with treatment response and survival.

Smoking cessation decreases lung cancer progression; however, its effects on precancerous lesions and the underlying mechanisms remain unclear. This study established a mouse model of precancerous pulmonary nodules and employed single-cell RNA sequencing (scRNA-seq) and immune repertoire sequencing (IR-seq) to elucidate the regulatory mechanisms by which smoking cessation influences the development of lung precancerous lesions.

Myelosuppression is common during chemoradiotherapy for nasopharyngeal carcinoma (NPC), but the prognostic impact of multilineage cytopenia remains unclear. This retrospective study evaluated a three-lineage cytopenia score in 576 patients with locally advanced NPC. The score (0-3) was defined as the number of lineages (leukocytes, hemoglobin, platelets) below normal limits. During a median follow-up of 74 months, higher cytopenia grades were significantly associated with worse overall survival, locoregional relapse-free survival, and distant metastasis-free survival (all P < 0.001). The score was an independent prognostic factor. Compared with score 0, score 3 was associated with a 7.55-fold increased risk of death (HR = 7.545, 95%CI: 3.158-18.028) and a 21.33-fold increased risk of distant metastasis (HR = 21.333, 95%CI: 5.076-89.655). The model incorporating the three-lineage cytopenia score yielded an area under the curve (AUC) of 0.593 (95% CI: 0.533-0.652, P = 0.001), indicating modest discriminatory ability. The three-lineage cytopenia score is a simple, independent prognostic indicator for locally advanced NPC with strong predictive value for distant metastasis. It may serve as a useful adjunct to traditional staging for risk stratification.

Pediatric supratentorial tumors are almost always primary brain tumors. They are defined by a relatively short list of diagnoses that can be broadly divided into tumors with high-grade and low-grade features, intraventricular lesions, and other rare tumors. The differential diagnosis can be further narrowed depending on age at presentation and particular imaging features. Treatment in most cases is surgical resection and may be followed by adjuvant therapy. Many tumors, such as high-grade glioma, ependymoma, and atypical teratoid rhabdoid tumor, are associated with specific genetic mutations that determine diagnosis and prognosis. ©RSNA, 2026 Supplemental material is available for this article.

Breast biopsy markers have evolved from simple metallic markers to sophisticated multimaterial devices that serve critical purposes throughout the breast cancer care continuum. This evolution began at The University of Texas MD Anderson Cancer Center in the 1960s for gynecologic and head and neck tumors. After the MicroMark (Biopsys) clip was approved by the U.S. Food and Drug Administration in 1995, markers were subsequently adapted for patients with breast cancer in 1999. By 2003, markers had become the standard of care. Modern markers serve multiple clinical functions: marking biopsy sites, facilitating cross-modality imaging correlation, guiding surgical planning and radiation therapy targeting, and ensuring continuity of care across health care facilities. Long-term studies demonstrate excellent safety profiles with minimal adverse events and significant cost-effectiveness through improved surgical precision and reduced re-excision rates. Despite the widespread adoption of these markers, contemporary challenges persist, including marker migration, allergic reactions to metallic components or embedding materials, and visibility limitations on US images. However, recent technological advances address these concerns through improved marker designs, nonmetallic alternatives, and innovative detection methods. Current best practices emphasize optimal placement timing, appropriate marker selection based on patient-specific factors, migration prevention techniques, and use of Doppler US "twinkling" artifacts for enhanced US visualization. © The Author(s) 2026. Published by the Radiological Society of North America under a CC BY 4.0 license. Supplemental material is available for this article.

Despite recent therapeutic advances, treatment options for advanced, therapy-resistant, and metastatic prostate cancer (PCa) remain limited. Here, we developed and prospectively validated an integrated chemoinformatics and machine learning (ML) workflow with ligand-based similarity filtering. Validation on independent external data sets showed that this applicability-domain-guided integration strategy can reduce false positives and improve virtual screening performance. Screening of DrugBank identified five repurposing candidates with confirmed antiproliferative activity in both 2D and 3D PCa models. Among them, the antifungal agent chlormidazole emerged as the most promising candidate, displaying tumor-selective and predominantly cytostatic activity associated with p57 upregulation, reduced Rb phosphorylation, and G1 arrest. Chlormidazole also enhanced the antiproliferative activity of docetaxel in both models, achieving comparable efficacy at substantially lower docetaxel concentrations. These findings identify chlormidazole as a promising repurposing candidate for PCa and demonstrate the value of integrating chemoinformatics with ML for drug repurposing and virtual screening.

Microtubules are core cytoskeletal components for cellular activities. Their interaction with microtubule-associated protein 7 (MAP7) is crucial for cell proliferation, cellular component transport, and morphological regulation. The conserved microtubule surface region binds tightly to MAP7's microtubule-binding domain (MTBD). Its function relates closely to tumorigenesis and progression. Using structure-based drug design, we first designed peptides 1-3, peptide inhibitors targeting microtubule-MAP7 interaction. These peptides disrupt microtubule-MAP7 interaction by specifically binding to microtubules. After multiple optimizations, peptide-3's binding affinity to microtubules reaches 0.12 μM. Further studies show that it effectively inhibits the proliferation, migration, and invasion of colorectal cancer cells (HCT116 and SW480) and enhances cell damage. Animal experiments confirm its potent in vivo antitumor activity with no obvious toxicity. In summary, peptide-3 specifically disrupts microtubule-MAP7 interaction, acting as a promising lead compound for inhibiting colon cancer cell proliferation.

Resistance to monotherapy remains a major challenge in the treatment of nonsmall cell lung cancer (NSCLC), highlighting the need for innovative therapeutic strategies. To address this issue, we developed a dual-targeting strategy aimed at simultaneously inhibiting the oncogenic protein-protein interaction (PPI) between UBE2M and DCN1─which is critical for neddylation-dependent activation of cullin-RING ligases (CRLs)─and histone deacetylase (HDAC) activity. Inspired by the synergistic antitumor effects observed with combined inhibition of UBE2M-DCN1 and HDAC, we designed hybrid molecules integrating pharmacophores targeting both pathways. Our preferred compound JN210 effectively disrupts the UBE2M-DCN1 interaction and inhibits HDAC, demonstrating significantly enhanced cytotoxicity compared to the parent compounds in vitro and potent tumor growth suppression in vivo. Mechanistic studies revealed dual blockade of CRL neddylation and induction of histone hyperacetylation, resulting in impaired DNA damage repair and synergistic apoptosis. As a novel DCN1/HDAC dual inhibitor, JN210 represents a promising therapeutic candidate for NSCLC.

Two copper(II) complexes, (1) [CuCl2(tmp-terpy)] and (2) {[CuCl(tmp-terpy)]·PF6}n, (tmp-terpy-4'-(3,4,5-trimethoxy-phenyl)-2,2':6',2″-terpyridine) were designed, characterized, and evaluated for cytotoxicity in 2D human cell models (HCT116, HCT116-DoxR, and in normal primary fibroblasts), and 3D colorectal cancer (CRC) spheroids and patient-derived organoids (PDOs). Both complexes demonstrated potent antiproliferative effects, alone and in combination with the FOLFOX (FF), across all 3D models. Importantly, the cytotoxic effects of complex 1 were significantly more pronounced in tumor-derived PDOs than in normal tissue-derived PDOs. Complex 1 induced reactive oxygen species (ROS) production, triggering intrinsic apoptosis and autophagy, consistent with a multimodal anticancer mechanism. It also exerted a cytostatic effect, as shown by delayed cell-cycle progression, and antiangiogenic activity in vivo without systemic toxicity. Notably, cotreatment of complex 1 with FF significantly potentiated cytotoxicity in 3D tumor spheroids and PDOs tumor-derived-PDOs. [CuCl2(tmp-terpy)] alone or in combination with the FF regimen warrants further evaluation in advanced preclinical models.