Air pollution is a leading environmental cause of lung cancer, yet the underlying biological pathways remain poorly understood. Identifying circulating biomarkers that capture early molecular responses may clarify how air pollutants contribute to carcinogenesis and help identify individuals at elevated risk. We conduct a prospective nested case-control study within two Cancer Prevention Study cohorts, profiling more than 1100 metabolites in pre-diagnostic plasma samples from 1357 participants. Residential concentrations of six major air pollutants are estimated at the time of blood draw. Here we show that eight circulating metabolites are associated with both air pollution exposure and subsequent lung cancer risk. Four metabolites, including γ-glutamylglutamine, phenylacetylglutamate, N-(2-furoyl)glycine, and 4-vinylguaiacol glucuronide, significantly mediate associations for particulate matter and ozone (adjusted q-value < 0.2). These findings suggest that air pollution may promote lung cancer partly through metabolic pathways related to inflammatory and oxidative processes, providing key insights into potential mechanisms and targets for prevention.
Cytomegalovirus (CMV) infections often occur as opportunistic infections among immunocompromised hosts. We report a case of CMV colitis that resulted in colonic perforation in a patient undergoing chemotherapy for more than 2 years for metastatic colorectal cancer (mCRC). A 61-year-old man receiving long-term chemotherapy for mCRC presented with persistent diarrhea and anorexia. Colonoscopy revealed ulcerating colorectal lesions. Following admission, he exhibited signs of peritoneal irritation and bloody stools. Computed tomography demonstrated intraperitoneal free air, prompting an emergency operation. Considering the perforations in the descending colon, we performed Hartmann's operation. However, in addition to the histopathological results, bloody stools persisted postoperatively; thus, enteritis caused by CMV infection was suspected. Furthermore, CMV pp65 antigen-positive blood cells were detected, leading to the diagnosis of CMV colitis. Consequently, ganciclovir was administered, and persistent bloody stools resolved. CMV infection occurs asymptomatically during childhood and then remains latent in the body over time. Although CMV colitis is common in patients undergoing chemotherapy for hematologic malignancies, it is rare in mCRC cases. However, immunocompromised patients receiving long-term steroid therapy for chemotherapy are at a high risk of CMV reactivation. Therefore, CMV colitis should be considered one of the differential diagnoses based on persistent diarrhea and bloody stools, as well as ulcer formation observed on colonoscopy. Although CMV enteritis during colorectal cancer chemotherapy is rare, CMV colitis should be suspected if patients experience prolonged diarrhea or bloody stools during chemotherapy. Therefore, early diagnosis by detecting CMV antigen-positive blood cells is important.
Microvascular free flap reconstruction represents the standard approach for restoring bone and soft tissue defects following oral cancer resection. Systemic inflammatory response syndrome (SIRS) is known to influence surgical outcomes, however the determinants and risk factors contributing to its development remain incompletely understood. This retrospective study aimed to identify risk factors for SIRS and their association with postoperative complications in-patients undergoing oral cancer surgery with simultaneous microvascular reconstruction. A total of 123 consecutive patients (37 females and 86 males) who underwent oral cancer surgery with curative intent and primary defect reconstruction using microvascular free flaps at the university medical center of Rostock between January 2011 and December 2016 were included and analyzed. Data were retrospectively extracted from the institutional hospital information systems Copra, Medlinq and SAP. SIRS was observed in 51 cases (41.5%). Univariate analyses identified multiple significant predictors for the occurrence of SIRS (p < 0.05), including number of additional needed operations, anastomosis revisions, intraoperative blood loss, hemoglobin drop, postoperative blood transfusions, inflammatory markers, preoperative leukocyte count, postoperative ibuprofen and dexamethasone use, ICU stay and Clavien-Dindo score. In multivariate analysis, preoperative leukocyte count (adj. OR = 1.3, 95% CI: 1.16-1.79), postoperative transfusions (adj. OR = 1.003, 95% CI: 1.002-1.006), intraoperative blood loss (adj. OR = 1.002, 95% CI: 1.001-1.003), postoperative dexamethasone (adj. OR = 0.032, 95% CI: 0.002-0.62) and ibuprofen administration (adj. OR = 14.6, 95% CI: 1.3-163.70) remained independent predictors. Clinicians should be aware of risk factors associated with systemic inflammatory response after major oral cancer surgery. Preoperative leukocyte count and intraoperative blood loss should be given particular attention, as they emerged as critical independent predictors. The observed associations may suggest a protective association for dexamethasone and a risk-increasing association for ibuprofen administration. Both findings, however, should be regarded as exploratory signals rather than definitive clinical guidance. Given the limited number of exposed patients, potential causal relationships require further investigation.
Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Type 2 diabetes mellitus (T2DM), the most prevalent endocrine disorder, is commonly managed with Metformin, an antidiabetic medication that has demonstrated potential anticancer properties. This meta-analysis aimed to discover the association between Metformin use and the risk of lung cancer in patients with T2DM. A comprehensive search of online databases was conducted up to January 1, 2026, to identify relevant observational studies. After screening, appropriate data were extracted. Meta-analyses utilized the most fully adjusted hazard ratio (HR) with corresponding 95% confidence intervals (CI) as the effect measures. All statistical analyses were performed using R Statistical Software. The pooled analysis of 29 observational studies showed a significant reduction in lung cancer risk among Metformin users compared with nonusers (HR: 0.85, 95% CI: [0.77-0.94], p = 0.002). Subgroup analyses revealed significant associations in cohort studies (HR: 0.79, 95% CI: [0.70-0.89], p < 0.01) and in studies conducted in Asia (HR: 0.82, 95% CI: [0.68-0.99], p = 0.04). Extended Metformin use (> 3 years) was associated with a significant reduction in lung cancer risk (HR: 0.87, 95% CI: [0.79-0.95]; p < 0.01), whereas no significant effect was observed for shorter durations. This meta-analysis indicated a potential protective effect of Metformin use in individuals with T2DM against lung cancer, with a significant risk reduction observed, particularly among long-term users and in Asian populations. The significant associations identified in cohort studies and in extended-duration use underscore metformin's promise in lung cancer prevention.
Timely cancer diagnosis in children and adolescents is important to improving outcomes. We aimed to quantify time to diagnosis and assess variations by patient, demographic and system-level factors. We conducted a population-based study of individuals aged 0-19 years diagnosed with one of 12 cancers from 2010 to 2022 in Québec, Canada. The diagnostic interval was defined as the time from first cancer-related healthcare encounter to diagnosis. We calculated medians and interquartile ranges (IQRs) overall and by cancer type and used multivariable quantile regression to identify factors associated with time to diagnosis at the 25th, 50th and 75th percentiles. Among 2927 patients, diagnostic intervals differed by cancer type, age and rurality, but not by sex, material or social deprivation. Median intervals were longest for carcinomas (100 days; IQR 33-192) and shortest for leukaemias (8 days; IQR 3-44). Older children had longer intervals. Compared with children living in Montréal, living in regional areas and other large urban centres was associated with longer 50th and 75th percentiles of time to diagnosis for hepatic (30 days; 95% confidence interval [CI], 6-53) and central nervous system (CNS) tumours (91 days; 95% CI, 23-159). Diagnostic intervals were shorter in 2020-2022 across several cancer sites, with CNS tumours showing reductions across all quantiles and a higher proportion of emergency department visits as the first cancer-related healthcare encounter. Shorter diagnostic intervals in 2020-2022 suggest that pandemic-related changes in care pathways may have expedited diagnosis for some cancers.
Triple-negative breast cancer (TNBC) remains highly lethal due to aggressive metastasis and profound immunosuppression by regulatory T cells (Tregs). Here, we present a biomimetic liquid metal (LM)-based photothermal immunotherapeutic nanoplatform exploiting gallium-based LMs to orchestrate cascade amplification of antitumor immunity. The engineered nanoplatform (B-LM-DMX-αCD25) integrates an LM photothermal core with dual immunomodulatory components-anti-CD25 antibody for Treg depletion and stimulator of interferon genes (STING) agonist 5,6-dimethylxanthenone-4-acetic acid (DMX) for innate immune activation-while blood-derived camouflaging enhances immune evasion and tumor accumulation. Quantitative RT-PCR of 13 immune-related genes confirmed STING engagement, robust CD8+ cytotoxic T-cell infiltration, and Treg depletion in treated tumors. This platform operates through three synchronized mechanisms: (1) selective intratumoral Treg depletion dismantling immunosuppression; (2) near-infrared-triggered LM-mediated photothermal therapy (58°C within 5 min) inducing immunogenic cell death and releasing tumor-associated antigens; and (3) STING pathway activation promoting dendritic cell maturation and tumor-specific cytotoxic T-cell responses, collectively transforming immunologically "cold" TNBC into immune-responsive tumors. In orthotopic 4T1 models, the nanoplatform achieves significant tumor regression with enhanced survival, while in metastatic models, it reduces pulmonary metastatic nodules and extends median survival beyond 70 days. This work establishes a paradigm-shifting biomimetic LM-based nanodelivery strategy addressing fundamental immunological barriers in TNBC through coordinated photothermal-immunotherapy, offering a clinically translatable approach for TNBC.
The WHO Global Initiative for Childhood Cancer (GICC) targets a global survival rate of 60% for childhood cancer, focusing initially on six common and curable cancers. This study assessed the risk of treatment abandonment (TxA) and the impact on survival of five of these cancers in sub-Saharan Africa in preparation for a cash transfer intervention. This multi-centre, prospective, observational cohort study included newly diagnosed children (<16 years) with Burkitt lymphoma (BL), acute lymphoblastic leukaemia (ALL), Wilms tumour (WT), retinoblastoma (RB) or Hodgkin disease (HD), enrolled between January 2022 and April 2024 from hospitals in Ethiopia (n = 2) and Uganda. Event-free survival (EFS) was estimated using Kaplan-Meier methods, and the cumulative incidence of TxA was estimated using competing risks methods. Of 370 patients enrolled (median age 6 years, 62% boys), ALL was the most common diagnosis (30%, 112/370). Median follow-up was 26 months (range 6-35 months). The overall risk of treatment abandonment was 43%, ranging from 20% in Mbarara, Uganda to 54% in Gondar, Ethiopia. It was highest in patients with WT (48%) and RB (49%). Overall, 2-year EFS was 28% (confidence interval [CI] 24%-34%) with TxA as an event and 59% (53%-66%) when TxA cases were censored. The overall risk of treatment abandonment is high, 43%, in this baseline 'Zero Abandonment' study in participating hospitals in Ethiopia and Uganda. Treatment abandonment significantly affects survival, currently 28%, and potentially to increase to 59% if treatment abandonment was completely prevented.
Sleep disturbance is highly prevalent among cancer patients and closely associated with depressive symptoms. However, it remains unclear whether sleep problems present at cancer diagnosis primarily reflect depression or also indicate an underlying biological susceptibility. This study aimed to examine the relationships between sleep disturbance, depressive symptoms, and systemic inflammatory-nutritional burden in newly diagnosed, treatment-naïve cancer patients. In this cross-sectional study, sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) in patients at diagnosis before oncological treatment. Poor sleep quality (PSQ) was defined as PSQI ≥ 5, and sleep disturbance severity was evaluated using the total PSQI score. Depressive symptoms were measured with the Hospital Anxiety and Depression Scale-Depression subscale (HADS-D). Systemic inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase-to-albumin ratio (LAR), were calculated from routine laboratory data. Multivariable logistic regression and generalized linear models assessed factors associated with PSQ and sleep disturbance severity, respectively. Receiver operating characteristics (ROC) analyses evaluated the discriminatory performance of depressive symptoms and inflammatory indices. Stratified analyses were conducted according to depression status (HADS-D < 8 vs. ≥ 8). Sleep disturbance was highly prevalent at diagnosis. Depressive symptom burden was independently associated with both PSQ and higher PSQI scores. Importantly, systemic inflammatory indices remained independently associated with sleep disturbance after adjustment for depressive symptoms and clinical variables. NLR showed moderate discriminatory ability for PSQ, while LAR was independently associated with sleep disturbance severity. ROC analyses indicated that depressive symptoms and inflammatory burden jointly improved discrimination of PSQ. In stratified analyses, LAR remained significantly associated with PSQI scores regardless of depression status. Sleep disturbance at cancer diagnosis is independently associated with both depressive symptoms and systemic inflammatory-nutritional burden, suggesting that it may reflect not only psychological distress but also underlying biological processes. Routine sleep assessment alongside inflammatory markers may help identify vulnerable patients and support early supportive care planning.
The pathogenicity of Staphylococcus aureus is well-recognized, stemming from its potent toxins and invasive capabilities. However, disseminated infections caused by methicillin-sensitive S. aureus (MSSA) are prone to being overlooked clinically. This study aims to report a case of disseminated invasive infection caused by MSSA in an immunocompromised patient, highlighting the clinical challenges in diagnosis, treatment, and outcomes. In October 2022, the patient was found to have a pulmonary nodule (65 × 53 mm); in April 2023, a biopsy confirmed a diagnosis of lung cancer; on November 21, 2024, a PICC line was inserted to administer chemotherapy. After completing chemotherapy, the patient was discharged home, where he gradually developed diarrhea. On December 3, 2024 (12 days after chemotherapy), the patient began experiencing shortness of breath and coughing. The patient presented with septic shock, acute respiratory distress syndrome (ARDS), and acute renal failure. Imaging studies revealed bilateral pulmonary infiltrates; a chest X-ray showed a "white lung" sign, and a CT scan demonstrated multiple nodules and cysts consistent with hematogenous dissemination. Methicillin-sensitive Staphylococcus aureus (MSSA) was detected via tNGS, blood culture, and bone marrow culture. Despite a series of antimicrobial treatments, the infection spread to the bone marrow and spleen. Although the treatment regimen was ultimately adjusted to cefoxitin combined with clindamycin and the symptoms of the infection were brought under control, the persistence of the previous infection and a secondary Enterococcus faecalis infection, combined with the progression of lung cancer, ultimately led to multiple organ failure, and the patient died on day 28. MSSA can cause rapidly progressive disseminated infection in immunocompromised patients, even with susceptible strains. Early diagnosis using tNGS and targeted antibiotic therapy are critical. Strict catheter care and infection control measures are essential to prevent such life-threatening complications.
The present study compared the efficacy and safety of non-intubated video-assisted thoracoscopic surgery (NIVATS) with intubated video-assisted thoracoscopic surgery (IVATS) for lobectomy in the treatment of lung cancer through a systematic review and meta-analysis. A total of six electronic databases were searched for studies comparing NIVATS and IVATS published up to October 2024. After rigorous screening and quality assessment, perioperative outcomes and postoperative complications were systematically analyzed from 18 studies, comprising three randomized controlled trials, six propensity score-matched studies and nine retrospective studies. A total of 2,313 patients with lung cancer underwent thoracoscopic lobectomy, of whom 1,082 underwent NIVATS and 1,231 underwent IVATS. The results revealed that NIVATS significantly reduced operative time [mean difference (MD)=11.02; 95% confidence interval (CI), -18.78 to -3.27], lymph nodes harvested (MD=-0.67; 95% CI, -1.24 to -0.11), anesthesia waking time (MD=-22.88; 95% CI, -33.13 to -12.64), feeding time (MD=-4.53; 95% CI, -5.74 to -3.32), chest tube indwelling time (MD=-0.68; 95% CI, -1.16 to -0.21) and hospital stay (MD=-1.16; 95% CI, -1.57 to -0.74) compared with the IVATS group. Total complications [odds ratio (OR)=0.53; 95% CI, 0.31 to 0.90], particularly sore throat (OR=0.18; 95% CI, 0.10 to 0.33) and pneumonia (OR=0.54; 95% CI=0.30 to 0.98) were significantly lower in the NIVATS group than in the IVATS group. Re-intubation occurred in 4.33% of NIVATS patients, while conversion to thoracotomy rates were similarly low in the NIVATS (0.69%) and IVATS (0.60%) groups. Importantly, NIVATS was associated with significantly improved overall survival [hazard ratio (HR)=0.63; 95% CI, 0.40 to 0.98] and recurrence-free survival (HR=0.62; 95% CI, 0.46 to 0.85). No significant differences were observed for anesthesia time, blood loss, hoarseness, air leakage or arrhythmia. Under the enhanced recovery after surgery framework, NIVATS appears to be a safe and technically feasible alternative to IVATS, with the potential to improve patient outcomes based on the available evidence. Its clinical adoption is supported by the evidence in the present study, offering a basis for informed decision-making.
Sunitinib is a multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor effects. Angiogenesis inhibitor-induced hypertension results from both short-term changes in vasoactive substances and by long-term microvascular rarefaction. This study investigated the relationship between late-onset hypertension and prognosis of cancer patients treated with sunitinib. We retrospectively analyzed time to hypertension and time to disease progression in patients treated with sunitinib. Of 92 patients, 62 were eligible for analysis. Clinical outcomes were compared among patients who remained normotensive, those who developed hypertension within 3 months, and those who developed hypertension after 3 months following the initiation of sunitinib treatment. At baseline, blood pressure was below 140/90 mmHg in all groups. Sunitinib was administered for renal cell carcinoma (74.2%), pancreatic neuroendocrine tumor (14.5%), and gastrointestinal stromal tumor (11.3%). Hypertension developed in 27 (43.5%) patients after sunitinib treatment. The severity of hypertension did not differ between the early onset (within 3 months) and late-onset (after 3 months) groups. Progression-free survival for all cancer types and for renal cell carcinoma was significantly longer in the late-onset hypertension group than in the normotensive or early onset hypertension groups. Late-onset hypertension was associated with prolonged progression-free survival in sunitinib-treated patients. Long-term structural changes in the vasculature may underlie the association between late-onset hypertension and a better prognosis.
Despite widespread insurance coverage and USPSTF recommendations, less than 20% of eligible individuals undergo annual lung cancer screening nationally. This low uptake suggests that innovative screening modalities and referral pathways are needed. We hypothesize that utilizing community pharmacies for screening and connecting patients to either traditional imaging or novel, blood-based modalities will improve uptake among eligible patients. We describe a multiphase study. First, during the initial phase, to assess the feasibility of community pharmacist-led lung cancer screening (LCS) and, subsequently, a randomized stepped-wedge trial expansion phase comparing pharmacist LCS intervention to usual care in ten community pharmacies. We plan to enroll 250 participants in the initial phase and 1000 participants in the expansion phase (500 participants in the usual care arm and 500 participants in the intervention arm). The primary endpoint is the proportion of LCS-eligible participants who receive a screening recommendation from a pharmacist and who both accept the recommendation and complete the screening. This study will test the feasibility and efficacy of pharmacy-based LCS programs. By investigating an alternative LCS referral location and modality, our novel intervention seeks to supplement traditional primary care-based interventions to increase overall LCS rates. We hypothesize that this strategy can increase LCS rates 20% from baseline.
Breast cancer is one of the most prevalent cancers worldwide and a leading cause of cancer-related mortality. However, early detection of the disease can significantly reduce the mortality rate of cancer patients. The current detection methods of breast cancer are expensive, time consuming, invasive and require professional assistance. To overcome these challenges, a minimally invasive low-cost paper-based point-of-care (POC) electrochemical sensing platform has been developed for early-stage detection of breast cancer. The proposed sensor is fabricated using a screen-printing technique, incorporating two-dimensional Ti3C2 (MXene) nanosheets onto the working electrode. These nanosheets provide enhanced electrochemical performance, enabling an exceptionally low limit of detection (LOD) ∼ 4 cells mL-1) attributed to their high conductivity and large surface area. The electrode surface is further functionalized with specific aptamers, facilitating selective target recognition. The proof-of-concept study was validated using multiple cell lines, including A549 (lung cancer cells), NIH3T3 (fibroblast), and HEK293 (kidney cells), and MDA-MB-231(breast cancer cell line), to evaluate the specificity of the developed aptasensor. The sensing mechanism relies on the selective binding of aptamers to Mammaglobin A proteins expressed on circulating tumor cells (CTCs). This interaction induces conformational changes in the aptamer, resulting in measurable alterations in the electrochemical properties at the electrode interface. The conjugation of the biomarker with the aptamer upon aptamer-protein interaction, results in a change in current, which is sensed by cyclic voltammogram (CV). The resulting signal is used to plot a calibration curve for quantitative analysis. Further, these sensing experiments are validated using in vitro experiments with human blood serum as a proof of concept. Overall, the developed paper-based electrochemical POC device offers significant advantages, including affordability, ease of use, rapid response, and quantitative detection capability.
High levels of immune suppression are a common intrinsic mechanism of resistance in metastatic breast cancer that calls for developing immunotherapeutic combinations to broaden treatment responses. Histone deacetylase (HDAC) inhibitors can sensitize tumors to dual checkpoint inhibition in patients. Here, we investigated the tumor microenvironment (TME) of breast metastases by combining experimental and clinical data with theory to elucidate the mechanism of response to treatment with the HDAC inhibitor entinostat combined with anti-PD-1 and anti-CTLA-4. Knowledge-guided subclustering of single-cell RNA-sequencing (scRNA-seq) data and cell circuit analyses from murine breast-to-lung metastases identified 39 cell states and salient interactions, of which myeloid, T cell, and B cell subpopulations were most affected. Analyses of patient biopsies and blood via spatial proteomics and flow cytometry corroborated the preclinical findings, showing increased T cell and B cell activation, mature tertiary lymphoid structures, and increased CD8+ T cell-macrophage distances in responders to entinostat + nivolumab + ipilimumab. Combination treatment increased immunoglobulin production in patients and mice, and murine studies demonstrated increased tumor-targeting IgG and implicated B cells as necessary for treatment response. Inhibition of the ICAM1 and IFNγ pathways in myeloid cells partially recapitulated treatment effects on CD8+ T cells observed via scRNA-seq. Mathematical modeling of tumor-immune dynamics implicated simultaneous modulation of multiple TME interactions as required for response to the combination treatment. Overall, this study identifies lymphoid and myeloid cell contributions to response to treatment with HDAC inhibitors and immune checkpoint blockade, providing a framework for discovering interactions driving responses in complex TMEs.
To develop and validate a pretreatment computed tomography (CT)-derived model for predicting major pathological response (MPR) to neoadjuvant immunochemotherapy in resectable non-small-cell lung cancer (NSCLC). This multicenter retrospective study included 287 patients with stage IB-III NSCLC treated with neoadjuvant immunotherapy plus chemotherapy followed by surgery. Patients from Center A formed the training cohort (n = 224), and patients from Center B formed the external validation cohort (n = 63). Two-dimensional (2D) and three-dimensional (3D) intratumoral heterogeneity scores (ITHscores) were derived from venous-phase pretreatment CT using local radiomics, K-means clustering and connected-component topology. Candidate predictors included clinicopathological variables, ITHscores and blood-derived inflammatory indicators. Eight machine-learning algorithms were compared, and the final model was selected using cross-validation and feature ablation. Shapley additive explanations (SHAP) analysis was used to interpret feature contributions. Non-MPR tumors showed significantly higher 2D and 3D ITHscores than MPR tumors in both cohorts (all P < 0.001). CatBoost was selected as the optimal algorithm. SHAP analysis identified 2D ITHscore and 3D ITHscore as the two most influential predictors, with mean absolute SHAP values of 0.403 and 0.326, respectively. The final parsimonious model retained 2D ITHscore, 3D ITHscore and systemic immune-inflammation index. It achieved AUCs of 0.824 in the training cohort and 0.792 in the external validation cohort, outperforming the clinical and ITH-only models. Calibration and decision curve analyses showed acceptable agreement and potential clinical utility. CT-derived topological intratumoral heterogeneity, combined with systemic inflammation, may provide a non-invasive pretreatment biomarker for predicting MPR in resectable NSCLC.
We measured dasatinib concentrations in paired plasma and cerebrospinal fluid (CSF) samples from children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Blood samples were collected from children at 0 h (pre-dasatinib) and 2 h post-dasatinib, along with CSF. After validating a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for dasatinib in both matrices, we quantified drug concentrations in plasma and CSF and expressed blood-brain barrier penetration as the plasma-to-CSF concentration ratio. Twenty children with Ph+ ALL, who received oral dasatinib (60-80 mg/m2·day), were included in this study. The median age was 10.8 (5-16) years, with 13 males (65%) and 7 females (35%). In plasma, the mean dasatinib concentrations were 1.3 ± 0.7 ng/mL at 0 h and 101.6 ± 42.1 ng/mL at 2 h. In CSF, the mean dasatinib concentration was 0.5 ± 0.2 ng/mL at 2 h. The median paired plasma/CSF concentration ratio was 225:1 (98:1-406:1). In conclusion, despite therapeutic systemic levels, dasatinib penetrates poorly into CSF in children with Ph+ALL.
Across many solid tumor types, cancer-associated fibroblasts (CAFs) are abundant and heterogeneous, with distinct subpopulations exerting immunomodulatory functions. Here we identify a novel population of immunomodulatory CAFs (imCAFs) in primary lung adenocarcinoma and pulmonary metastases, characterized by cell adhesion molecule L1-like (CHL1) expression and enriched in immune regulation and chemokine signaling programs. Through single-cell and spatial transcriptomics, we demonstrate that imCAFs are spatially colocalized with CXCR3+ regulatory T (Treg) cells, a hyper-suppressive subset accumulating at the tumor border. imCAFs produce CXCL9, driving CXCR3+ Treg cell recruitment and promoting an immunosuppressive microenvironment. CXCR3+ Treg cells display enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3- counterparts. Genetic ablation of Cxcr3 in Treg cells or Cxcl9 in stromal cells reduces Treg cell accumulation, enhances CD8+ T cell activation and decreases tumor burden. Analogous CHL1+ imCAF-like fibroblasts in human non-small cell lung cancer colocalize with Treg cells, and elevated CHL1 expression is associated with reduced cytotoxicity and decreased progression-free survival, highlighting the imCAF-CXCL9-CXCR3+ Treg axis as a promising therapeutic target.
We report the results of a prospective trial aimed at describing the feasibility and accuracy of prostate-specific membrane antigen (PSMA) radio-guided surgery (RGS) during robot-assisted radical prostatectomy (RARP) with extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa). This was a phase 2 study (NCT04832958) that enrolled 82 patients with localized PCa and a lymph node invasion (LNI) risk >5%. All patients underwent preoperative PSMA positron emission tomography (PET). [99mTc]Tc-PSMA-I&S was administered intravenously the day before surgery, followed by single-photon emission computed tomography/computed tomography. Side effects, perioperative outcomes, and the performance characteristics of PSMA-RGS for LNI detection were measured. A total of 62 patients completed all study procedures and were included in the final analyses. Median blood loss and length of stay were 50 ml and 4 d, respectively. No adverse events after tracer administration or intraoperative complications were recorded. Four patients experienced a Clavien-Dindo grade 3 complication within 30 d. Overall, PSMA-RGS identified two additional patients with high-risk PCa and pathologically node-positive (pN1) disease compared with preoperative PSMA PET, exhibiting a lower positive predictive value (PPV) and a similar negative predictive value (NPV) in the per-patient analysis (PPV: 50% vs 70%; NPV: 83% vs 83%). The PPV and NPV at per-region analysis in patients with molecular imaging node-positive (miN1) disease were higher for PSMA-RGS than for PSMA PET (PPV: 55% vs 42%; NPV: 85% vs 81%). In conclusion, PSMA-RGS identifies additional patients with pN1 disease missed by preoperative PSMA-PET among men with high-risk PCa, and extends the ePLND template in patients with miN1 disease, in whom PSMA PET underestimates the nodal burden. However, its NPV is suboptimal for avoiding ePLND in patients with PCa who have a LNI risk >5% and negative PSMA-RGS findings during RARP.
NEDD9 (Neural precursor cell expressed developmentally downregulated 9) is a scaffolding protein that plays a central role in coordinating multiple oncogenic signaling pathways involved in tumor progression. It regulates diverse cellular processes, including cell migration, epithelial-mesenchymal transition, stemness, and therapeutic resistance, primarily through its function as a signaling integrator. Despite increasing evidence supporting the importance of NEDD9 in cancer, several key challenges remain, including a lack of systems-level understanding of its regulatory networks, incomplete characterization of its role in tumor immune microenvironment modulation, and difficulties in developing effective therapeutic strategies targeting this scaffold protein. In this review, we provide a comprehensive and integrative analysis of NEDD9 by systematically linking its structural features, multilayered regulatory mechanisms, diverse biological functions, and clinical relevance within a unified conceptual framework. We further emphasize its role as a dynamic signaling hub in cancer progression. Finally, we highlight key research priorities, including the need for multi-omics integration, improved understanding of context-dependent functions, and the development of innovative strategies targeting NEDD9-associated signaling and interaction networks, which may facilitate its translation into clinical applications.
Background/Objectives: The central role of G-protein coupled receptors (GPCRs) in tumor biology is becoming acknowledged. Yet their involvement in cancer stem cells (CSCs) niche is unknown. Molecular mechanisms of CSCs allow self-formation capacity, resistance to chemotherapy and immune therapy. Western blots, Co-immunoprecipitation (co-IP) analysis, RT-PCR, Lef/Tcf luciferase activity and Alpha Fold3 HANDDOCK v2.4 protein-protein docking interactions. It is demonstrated that protease-activated receptor 4 (PAR4) induces β-catenin levels, co-associates with LRP6 coreceptor and promotes DVL nuclear translocation. PAR4 induced β-catenin transcriptional activity is shown by TOPflash luciferase assay and enhanced downstream target genes levels. Significantly, PAR4 co-binds leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) as determined by co-IP and protein-protein docking analyses. We show also that another GPCR namely, GPR25 specifically expressed in the gastrointestinal tract cells, elicits β-catenin stabilization and co associates with LGR5. As was previously shown for PAR2 also PAR4 and GPR25 elicit β-catenin stabilization and they co-link with LGR5. We propose that GPCRs that potently induce β-catenin stabilization are potentially involved in the regulation of CSCs niche. Our data may provide future directions for potential partners in the cancer stem cell niche.