Colorectal cancer (CRC) is one of the most common malignancies worldwide. Early and accurate diagnosis remains a clinical priority, yet current biopsy techniques are invasive, spatially limited, and may not capture the molecular heterogeneity of tumors. We evaluated the feasibility and diagnostic potential of electroporation-based biopsy (e-biopsy) as a minimally invasive technique for proteomic sampling of colorectal cancer tissues. We conducted a multicenter, multinational study involving 19 patients undergoing surgical resection for CRC. Paired tumor and adjacent normal tissues were sampled ex vivo using e-biopsy. Proteins extracted from each sample were analyzed via LC-MS/MS. Bioinformatics pipelines, including differential expression, PCA, and pathway analysis, were used to identify CRC-specific signatures. E-biopsy consistently retrieved more proteins from tumor tissues than from adjacent healthy tissues (mean: 1300 vs. 800). Of the 3246 proteins identified, 54% were significantly upregulated in tumor tissues. Notably, proteins such as DLAT, LETM1, RBBP4, PPIB, and BCAP31 emerged as potential CRC biomarkers. Functional analyses revealed dysregulation in RNA processing, immune response, and metabolic pathways, consistent with known CRC biology. The integrated workflow, spanning tissue collection, electroporation, protein isolation, and mass spectrometry analysis across four institutions in two countries, was successfully executed, demonstrating the feasibility of multi-institutional implementation of the e-biopsy protocol while preserving tissue integrity throughout. E-biopsy enables rapid, reproducible, and minimally invasive molecular sampling of CRC tissue. This study demonstrates its potential to complement standard histopathology, aid in early diagnosis, and support molecularly guided treatment strategies in colorectal oncology.

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for therapy-resistant cancers. Glutathione peroxidase 4 and the selenoprotein biosynthesis pathway essential for its translation are key regulators of ferroptosis but lack effective therapeutic targeting. In a drug screening using a selenoprotein translation reporter, here we identify FMS-like tyrosine kinase 3 (FLT3) inhibitors as suppressors of selenoprotein translation that induce ferroptosis in FLT3-mutant acute myeloid leukaemia. Mechanistically, FLT3 inhibition disrupts selenocysteine recoding, in which a UGA stop codon is recoded as selenocysteine via the SECIS element and associated binding proteins. Notably, the antileukemic efficacy of the FLT3 inhibitor gilteritinib was markedly reduced by dietary vitamin E, which attenuated ferroptosis. This study highlights ferroptosis as a vulnerability in FLT3-mutant acute myeloid leukaemia and suggests that high vitamin E intake may compromise tyrosine kinase inhibitor efficacy partly by suppressing ferroptosis.

Sialadenoma papilliferum (SP) is a rare benign salivary gland tumor characterized by a distinctive biphasic architecture and clinical resemblance to other papillary lesions of the oral cavity. Although recent studies have identified alterations in the MAPK pathway, particularly BRAF V600E mutations, the molecular landscape of this rare lesion remains incompletely characterized. We report a case of SP arising in the floor of the mouth of a 25-year-old male patient. Histopathological examination confirmed the diagnosis of SP, while immunohistochemical analysis revealed p63 positivity and negative staining for BRAF V600E and p16. Molecular analysis detected HPV-11 DNA by PCR-RFLP. To the best of the authors' knowledge, this is the first reported case of HPV-11 DNA detection in SP. Further studies are needed to clarify the biological significance of HPV detection and to better characterize the molecular pathways involved in the development of this rare lesion.

Neuroblastoma is the most common extracranial solid tumor in children, with risk stratification guiding therapy and prognosis. Although current risk stratification incorporates imaging-based staging, definitive risk assignment still relies on tissue and molecular characterization, highlighting the need for complementary noninvasive imaging biomarkers. The objectives were to evaluate the classification performance of multiparametric magnetic resonance imaging (MRI) radiomics for risk stratification of pediatric neuroblastoma and to determine how MRI sequences, feature-selection methods, and machine learning classifiers influence classification performance. This retrospective single-center feasibility study included 30 children with histologically confirmed neuroblastoma who underwent pre-treatment T1-, T2-, and diffusion-weighted MRI. From each sequence, 208 radiomic features were extracted from the whole-tumor volume and reduced using six feature-selection methods. Principal components of selected features trained six machine learning classifiers. Performance was assessed using a nested leave-one-out cross-validation framework, with predictions aggregated to one per patient before computing performance metrics, for binary classification of low/intermediate-risk versus high-risk neuroblastoma, using clinical risk classification as the reference standard, with pairwise differences evaluated by DeLong test and Benjamini-Hochberg correction. Among 30 children (mean age ± SD: 38 ± 40 months), the highest discrimination between risk groups was achieved using T2-weighted features and the combined T1w + T2w + ADC features, both with XGB (AUC = 0.88 ± 0.06 and 0.88 ± 0.07, respectively); however, the limited sample size prohibited the detection of significant differences between classifiers after correction for multiple comparisons. Features derived from T2-weighted and diffusion-weighted MRI contributed most to accurate classification. The chi-square feature selection method most frequently contributed to high-performing model configurations (30.8%). Multiparametric MRI radiomics based on whole-tumor volumes showed preliminary evidence of feasibility for noninvasive risk stratification of pediatric neuroblastoma, supporting its potential as a complementary imaging biomarker.

The high incidence and mortality rates of tumors have resulted in significant social and economic burdens, posing a major global threat to human life and societal development. In recent years, molecular targeted therapy for tumors has become a research hotspot. C-MET, the receptor for hepatocyte growth factor (HGF), plays a crucial role in the HGF/C-MET signaling pathway, which is involved in various processes such as tumor cell growth, invasion, migration, angiogenesis, epithelial-mesenchymal transition, tumor microenvironment remodeling and therapeutic resistance. Several C-MET-targeting strategies have been developed, including small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs) against C-MET or HGF, antibody-drug conjugates (ADCs), nucleic acid aptamers, soluble receptors, natural compounds, and proteolysis targeting chimeras (PROTACs) targeting MET. These inhibitors have demonstrated encouraging anti-tumor effects in both preclinical and clinical studies, with several already available on the market. However, further research is still needed on the activation mechanisms of the HGF/C-MET signaling pathway and its interactions with other receptor tyrosine kinases, which will aid in identifying suitable patients for these treatments. This review provides a comprehensive overview of the structure, regulation, signaling pathways, and functions of C-MET, along with recent advances in C-MET inhibitors, offering valuable insights for cancer therapy.

Hypoxia, a hallmark of solid tumors, poses a significant challenge in cancer therapy due to its association with poor prognosis and resistance to conventional treatments. Oncolytic viruses represent a promising treatment strategy, as they selectively replicate within cancer cells and lyse them, potentially including those in hypoxic tumor regions. Here, we examined how hypoxic conditions influence the activity of enadenotucirev (EnAd), a clinically relevant group B oncolytic adenovirus previously detected in hypoxic areas of xenograft tumors. We demonstrated that hypoxia enhances virus production by boosting transcription and translation of immediate-early, early, and late adenoviral genes. The immediate-early gene E1A was upregulated within 2 h (17-fold) after virus entry under hypoxia, driven by a conserved hypoxia-response element (HRE) in its promoter. Mechanistic studies revealed that the hypoxia-inducible factor (HIF)-2α and HIF-1β heterodimers bind to this HRE, transactivating E1A. By inducing E1A expression, hypoxia also elevated viral genome synthesis, structural protein production, and therapeutic transgene expression, underscoring the potential of EnAd to target the hypoxic tumor microenvironment. This is the first report of a functional HRE in a human adenovirus, conserved across 59 adenovirus genotypes, and identifies hypoxia as a driver of enhanced oncolytic activity with implications for adenovirus-based therapies in solid tumors.

An increasing number of octogenarian patients are being diagnosed with lung cancer, but they are less likely to receive surgery because of fragility. As a result, the optimal management of lung cancer in octogenarians remains unclear. Here we report a case of an octogenarian patient with locally advanced non-small-cell lung cancer (NSCLC) who achieved long-term survival via surgery followed by adjuvant targeted therapy.

A 68-year-old man presented to our thoracic surgery department for evaluation of a left upper-lobe pulmonary nodule detected on chest CT scan. The oncologic history extended over 7 years. In December 2014, the patient was diagnosed with colorectal adenocarcinoma (ileocecal junction) by colonoscopy, and he underwent a laparoscopic right hemicolectomy and lymph node dissection. Postoperative pathological examination revealed a grade II-III adenocarcinoma of the ileocecal region (ulcerative type), infiltrating into the muscularis. Surgical margins were free of tumor. No metastasis was identified in the examined lymph nodes, including paracolic (19), paracolic (7), intermediate mesenteric (23), and central vascular (2) lymph nodes, corresponding to a pathologic stage of pT2N0M0. The patient recovered well and was placed on regular follow-up.

A 19-year-old woman presented with low back pain and dyspnea that had begun approximately 3 months earlier, with low back pain progressively worsening since onset. The patient has no significant medical history or recurrent respiratory conditions. She was residing in a rural village located in Ağrı Province in the Eastern Anatolia Region, Turkey, inhabited by approximately 30 families. Sheep and cattle breeding were the main agricultural activities in this village. She had spent her entire life in the same area without any domestic or international travel.

The BCL-2 inhibitor venetoclax has transformed outcomes for older or frail patients with acute myeloid leukemia (AML), and its resistance mechanisms are becoming better defined, including compensatory and lineage-associated switches toward MCL-1 or BCL-xL dependence, oncogenic signaling activation, blast phenotype, and differentiation stage. Additional putative mechanisms-such as emerging BAX mutations, mitochondrial structure remodeling, integrated stress response, and metabolic adaptations, including enhanced amino acid uptake and fatty acid oxidation to sustain oxidative phosphorylation-require further validation.

The hypoxic tumor microenvironment (TME) of hepatocellular carcinoma (HCC) featured overexpressed hypochlorite (ClO-), which represented both a biochemical hallmark and a potential therapeutic trigger. Herein, POR-CA, a near-infrared (NIR) activatable prodrug constructed by conjugating cinnamic acid to a 4-(4-aminophenyl) porphyrin fluorophore, was reported. Exposure to ClO- produced a concentration-dependent decrease in near-infrared fluorescence, enabling fluorescence-quenching sensing under the tested conditions. Spectroscopic characterization confirmed rapid and sensitive ClO- responsiveness with favorable pH stability. Notably, the porphyrin backbone acted as an intrinsic photosensitizer to generate reactive oxygen species (ROS) under 660 nm laser irradiation for photodynamic therapy (PDT). HRMS provided evidence consistent with ClO--induced cleavage and formation of a TAPP-related fragment. POR-CA exhibited differential dark cytotoxicity in HepG-2 and LO-2 cells and light-dependent phototoxicity under the tested conditions. These results supported POR-CA as an in vitro proof-of-concept platform integrating ClO--responsive fluorescence-quenching sensing with light-dependent phototoxicity, while the contribution of the released cinnamic-acid-derived component remained to be established. Nonetheless, this molecular design perspective served as a valuable reference for subsequent translational optimization.

Malignant pleural effusions (MPEs) are almost always exudative, with only an estimated 3-4% meeting biochemical criteria for a transudate. Light's criteria remain the standard method for classifying pleural effusions, and transudative effusions typically do not undergo cytologic evaluation. This may delay the diagnosis of malignancy in rare cases where malignant cells are present in a biochemically transudative effusion. We present a 41-year-old homeless man with no established primary care who presented with progressive muscle cramping and was found to have severe electrolyte abnormalities, leukocytosis, and a right-sided pleural effusion with new bilateral pulmonary nodules on computed tomography. Pleural fluid analysis met clear transudative criteria by Light's criteria (protein ratio 0.24, LDH ratio 0.44). However, cytology revealed clusters of atypical cells consistent with pulmonary adenocarcinoma, confirmed by thyroid transcription factor-1 (TTF-1) positivity. The patient had no identifiable cause of transudative effusion, including heart failure, cirrhosis, nephrotic syndrome, or significant hypoalbuminemia. This case illustrates a rare presentation of malignant pleural effusion masquerading as a transudate in the absence of confounding systemic conditions. The mechanism likely involves early pleural metastatic involvement before the development of significant vascular permeability changes or lymphatic obstruction. This report underscores the importance of maintaining clinical suspicion for malignancy despite transudative biochemistry, particularly when features such as unilateral effusion, atypical imaging findings, or absence of an alternative systemic cause are present.

Immunotherapy resistance remains a major barrier to achieving sustained patient improvement in non-small cell lung cancer (NSCLCs). Here, through integrating CODEX, metabolomics, CyTOF, ATAC-seq, and single-cell spatial transcriptomics from NSCLC tumors, we uncover an unrecognized role of ALDH9A1 in promoting resistance to anti-PD-1 therapy. In immunocompetent, but not immunocompromised mouse models, loss of ALDH9A1 markedly restrains tumor growth. This effect is accompanied by increased maturation of tertiary lymphoid structures and reduced accumulation of protumorigenic MDSCs within tumor immune microenvironment. Mechanistically, ALDH9A1-driven carnitine production elevates acetyl-CoA levels, remodels chromatin accessibility, and activates Il1b superenhancers in tumor cells, thereby promoting MDSC polarization and CD8+ T cell exhaustion. In vivo, genetic or pharmacological inhibition of ALDH9A1, or antibody-mediated IL-1β neutralization, suppresses tumor progression and restores sensitivity to anti-PD-1 therapy. IL-1β further activates NF-κB and upregulates ALDH9A1, establishing a feedback ALDH9A1-IL-1β loop. Importantly, the ALDH9A1/IL-1β axis is frequently hyperactivated in NSCLC patients and correlates with inferior responses to anti-PD-1 immunotherapy. Together, this study reveals a previously unappreciated NSCLC-specific immunoregulatory pathway and identifies ALDH9A1 as a promising therapeutic target for improving immunotherapy efficacy.

We aimed to investigate the influencing factors for recurrence of International Federation of Gynaecology and Obstetrics (FIGO) type II submucosal myoma with a diameter of 4-5 cm following hysteroscopic myomectomy, and to establish an individualised prediction model for the risk of postoperative 3-year recurrence.

Measurable residual disease (MRD) follow-up is recommended for treatment response evaluation in acute myeloid leukemia (AML) clinical trials according to ELN 2025 guidelines. The aim of this study was to implement a standardized follow-up of patients using a harmonized MRD flow approach across 30 French hematology laboratories participating in AML clinical trials. To obtain comparable results, the network established recommendations from wet-lab procedures to clinical reports. We designed a 3-tube panel with mandatory 8-color common markers per tube, according to ELN recommendations, to identify leukemia-associated immunophenotype/different-from-normal (LAIP/DfN) patterns in bulk cells and leukemic stem cell (LSC)-enriched populations in the CD34+CD38- fraction. A backbone of CD34/CD38/CD45/CD117 was used, completed by lineage markers for the first tube, LSC-associated markers for the second tube, and monocytic and differentiation markers for the third tube. This panel can be used in 8-, 10-, and 12-color formats and implemented on multiple conventional flow cytometer platforms. We propose flow cytometer settings adapted to each platform. Harmonization of sensitivity between the four platforms was performed using 8-peak rainbow beads. Immunostaining was performed after bulk lysis. To detect bias between platforms, the staining index was tested using fresh healthy bone marrow samples in parallel on the four platforms. Regular bone marrow quality-control samples were shared among laboratories for wet external quality assessment (EQA) to verify all steps of the protocol. Finally, standardization of the data analysis strategy obtained in the centers was evaluated using dry EQA by sharing MRD FCS data files. The feasibility of this multicenter approach requires harmonization of instrument sensitivity and sample preparation, as well as training and systematic education of analytical operators.

This study evaluated efficacy and safety of concurrent chemoradiotherapy (CCRT) versus CCRT plus adjuvant chemotherapy (CCRT+ACT) in 2018 Federation International of Gynecology and Obstetrics (FIGO) Stage III locally advanced cervical cancer (LACC) patients. This study provides clinical evidence to optimize treatment strategies for stage III LACC.

Over 4 million Americans annually miss healthcare appointments - including for cancer screening and treatment - due to transportation insecurity. We performed a scoping review to understand how transportation affects cancer screening and stage at diagnosis, and to make recommendations for measuring transportation-related factors in this context.

Malignancy-associated hypercoagulability may cause arterial thrombotic events and acute limb ischemia. When combined with diabetic vasculopathy, rapid progression to gangrene and severe infection may occur. We report a patient with type 2 diabetes who developed acute limb ischemia and progressive diabetic foot gangrene. Despite prior endovascular therapy, severe infection with necrotizing soft tissue infection and osteomyelitis developed. A staged limb-salvage approach involving aggressive debridement, removal of infected bone, pedicled flap reconstruction, antimicrobial therapy, anticoagulation, metabolic optimization, and offloading resulted in successful wound closure and functional recovery. Subsequent investigation revealed pancreatic acinar cell carcinoma, and the patient later received systemic therapy and radiofrequency ablation for liver metastasis. This case highlights the complex interaction between advanced peripheral arterial disease, severe diabetic foot infection, and pancreatic acinar cell carcinoma (ACC)-associated hypercoagulability. Successful limb salvage was achieved through an integrated multidisciplinary strategy combining vascular intervention, aggressive surgical source control, staged reconstruction, antimicrobial therapy, anticoagulation, metabolic optimization, and oncologic management. Although causality between ACC-associated hypercoagulability and acute limb ischemia cannot be definitively established, this case demonstrates that durable wound healing and functional limb preservation can still be achieved in highly complex patients when treatment is coordinated within a staged, multidisciplinary framework.

IntroductionStimulated Raman histology (SRH) is a recent microscopic technique allowing real-time, label free, high-resolution microscopic images of unprocessed, unsectioned tissue. Tissue samples are imaged in the operating room using a mobile SRH microscope, visualizing histology within minutes.MethodsAim of this prospective first in human feasibility study was to evaluate the use of SRH to identify bladder cancer (BCa) and to test whether a histopathological grading between low- and high-grade tumors can be determined. Therefore, patients with suspicion of BCa, who underwent transurethral resection of bladder tumor were included. Suspicious papillary tissue was resected and subsequently scanned with an SRH microscope (NIO, Invenio Imaging Inc.). After a 10-sample training set, pathologists were tested on a 30-sample test set. Images which were initially classified wrong were re-evaluated within a consensus conference.ResultsThe scanning time was less than 180 seconds for all tissues samples. Individual pathologists' overall combined accuracy (CA) for interpretation of low and high grade SRH images was 76.5 % [95% confidence interval (CI): 65.8-85.3]. After the consensus conference pathologists' overall CA for interpretation of low and high grade SRH images was 96.3 % [95% CI: 89.6-99.2], respectively. The sensitivity for the identification of high-grade tumors was between 66.0 % and 66.7 % before the consensus conference, increasing to 100 % after pathologic consensus. The specificity of the three pathologists was between 83.3 % and 100 %. After the consensus conference, the specificity was on average 91.7 %.ConclusionAfter further investigations, including the testing against benign tissue, SRH might be a reliable point of care-technique to produce high-resolution images of unprocessed bladder tumors, allowing histopathological identification of BCa. Low- and high-grade tumors can be accurately discriminated.

Although sequencing costs have steadily decreased with advances in technology, they remain high for large scale studies. The design of traditional individual-disease sequencing studies is either case only or cases with relatively few controls, resulting in potential loss of statistical power for discovery of disease associated genes. Here we show that for a given number of sequenced cases, a large control sample size is critical to maximize power for rare variant burden analysis. Furthermore, we have developed an end-to-end workflow based tool (CoCoRV-nf) to facilitate the use of external biobank sequence resources as controls. The modules include consistent variant QC, variant annotation, ancestry population prediction, and gene based burden analysis using summary genotype information, and combined analysis from multiple independent results. The tool supports exomes and genomes from gnomAD and All of Us as controls with preprocessed datasets. We apply the tool in two rare neurological diseases: amyotrophic lateral sclerosis and neuroblastoma. For each disease, two case cohorts are paired with gnomAD and All of Us data, respectively, followed by a combined analysis. Not only did we recapture known genes, but also, we identified new candidate genes for both diseases. By leveraging multiple large external biobank sequence data, we demonstrate the feasibility of using our tool to maximize statistical power to identify new disease predisposition genes.