BMC Cancer

Background: Platinum-based chemotherapy is known to cause severe and debilitating hearing loss, but unlike cisplatin, the true incidence of carboplatin-induced hearing loss remains unclear. We evaluated functional hearing outcomes in children receiving carboplatin to determine the incidence and severity of ototoxicity. Procedure: We identified a large cohort of children with cancer treated with carboplatin and graded their audiograms using the SIOP ototoxicity scale. Patients with inadequate audiological follow-up, prior hearing loss, or exposure to cisplatin were excluded. Fishers exact test, logistic regression, and ROC analyses were performed to investigate associations of demographic, treatment, and exposure-related risk factors with incidence of hearing loss. Results: 200 patients were included, all of whom had been treated with carboplatin. Only nine (4.5%) patients developed clinically significant hearing loss (SIOP grade [≥]2). Younger age at first exposure to carboplatin was the only significant predictor of hearing loss (OR = 0.7888, p=0.0241). Age [≤]28 months was significantly associated with hearing loss (OR 12.37, p=0.0042). No other risk factors or exposures were statistically significant. Conclusions: Clinically significant carboplatin-associated hearing loss was uncommon (incidence 4.5%). We show that young age is the single-most important risk factor for hearing loss; of nine children who developed hearing loss, eight were aged [≤]28 months. Children below this age have twelve-fold higher odds of developing hearing loss compared to those above this age (OR 12.37). These findings will allow physicians to provide more appropriate counselling to families regarding ototoxic risk and support intensified hearing surveillance in young children.

BackgroundIn RAS-mutant tumors, ERK phosphorylates the mitochondrial fission GTPase DRP1 to promote mitochondrial fission. DRP1 activity is tumor-promoting in pancreatic and other RAS-driven cancers, but its role in therapeutic resistance is unknown. MethodsWe developed a panel of patient-derived pancreatic cancer cell lines resistant to the MEK inhibitor trametinib. We used immunofluorescence imaging, in vitro growth assays and orthotopic xenografts to determine the role of DRP1 in trametinib resistance. ResultsWe find that trametinib-resistant cells exhibit increased expression and phosphorylation of DRP1 compared to sensitive counterparts. Quantitative analysis of mitochondrial structure reveals that mitochondria in resistant cells are morphologically distinct and relatively smaller than sensitive cells treated with trametinib. Genetic and pharmacological inhibition of both c-Myc and CDK6 are sufficient to block DRP1 phosphorylation in resistant cells, suggesting that activation of a c-Myc-CDK6 signaling axis drives reactivation of mitochondrial fission in the absence of MAPK signaling. Importantly, deletion of DRP1 leads to either growth inhibition or re-sensitization to trametinib in resistant lines. ConclusionThese findings suggest DRP1 contributes to drug resistance, and that inhibition of mitochondrial fission might be a promising therapeutic strategy to combat resistance to MAPK and RAS inhibitors.

Accurate risk stratification of pigmented skin lesions is critical for early melanoma detection and for reducing unnecessary excisions. Artificial intelligence (AI) is increasingly applied to dermoscopic image analysis, but its diagnostic performance relative to standard dermoscopy in real-world clinical settings remains uncertain. To address this gap, we conducted a systematic review and meta-analysis of prospective clinical studies directly comparing AI alone, dermoscopy, and AI-assisted clinicians for malignancy risk assessment of pigmented skin lesions. We systematically searched PubMed, Embase, Web of Science, and Cochrane Library from inception to January 2026. Ten studies with 17 diagnostic arms (10 dermoscopy arms, 6 AI-alone arms, and 1 AI-assisted clinician arm) were included. Pooled sensitivity and specificity were 0.773 (95% CI, 0.648-0.863) and 0.793 (95% CI, 0.673-0.877) for dermoscopy, and 0.757 (95% CI, 0.428-0.928) and 0.859 (95% CI, 0.619-0.958) for standalone AI. Summary ROC curves showed overlapping performance, indicating that autonomous AI is broadly comparable to dermoscopy but does not demonstrate a consistent advantage. Heterogeneity in AI performance was driven almost entirely by threshold effects rather than by differences in inherent model capacity. AI-assisted clinicians showed promising results (sensitivity 1.000, specificity 0.837) in a single study, but more evidence is needed. Our findings suggest that, at present, AI should be viewed as a complementary decision-support tool rather than a replacement for dermoscopic evaluation. The study provides valuable evidence for clinicians, guideline developers, and researchers working on AI integration into melanoma diagnostic pathways.

Background Platinum refractory paediatric germ cell tumours (GCTs) carry a poor prognosis, with five year survival below 30% and no validated molecular stratification tool. The biological mechanisms underlying platinum resistance in this population remain poorly defined, limiting the development of targeted therapeutic strategies and early warning biomarkers. Methods We performed integrated plasma multi-omics profiling in 105 pediatric GCT patients (54 refractory and 51 treatment naive) using data-independent acquisition proteomics, untargeted metabolomics, and exploratory lipidomics. Candidate biomarkers were validated using ELISA and spatial multiplex immunofluorescence. Predictive models were constructed using logistic regression and evaluated by ROC analysis, calibration, and decision-curve analysis. Results Multiomics integration has revealed the coordinated dysregulation of sphingolipid metabolism, extracellular matrix remodeling, and immune checkpoint signaling in refractory diseases. Lipidomic analysis demonstrated a significant depletion of sphingolipid associated species, including lysophosphatidylserine, lysophosphatidylethanolamine, and phosphatidylserine. Proteomic profiling identified the upregulation of LAG3 and HTRA1, which was validated by ELISA. Multiplex immunofluorescence demonstrated the spatial enrichment of exhausted CD8 + LAG3 T cells adjacent to CK-PAN tumor cells in refractory tumors. A plasma biomarker panel integrating LAG3, HTRA1, and AFP showed improved discrimination of refractory disease (AUC = 0.821) compared with AFP alone. Conclusions Our study identified a sphingolipid HTRA1 LAG3 immune evasion axis as a defining molecular feature of refractory pediatric germ cell tumors and proposed a clinically applicable plasma biomarker panel for early risk stratification.

Background Emerging evidence suggests irreversible electroporation (IRE) with standard-of-care (SOC) chemo-therapy may improve survival in patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) when compared to SOC alone. This study evaluates the overall survival (OS) and progression-free survival (PFS) of Stage 3 PDAC patients treated with SOC plus IRE with the NanoKnife System versus SOC alone. Methods This prospective, multicenter study included two cohorts from the DIRECT registry: an IRE cohort from sites offering IRE as part of clinical care, and a comparator SOC cohort of prospectively enrolled and contemporaneous retrospective patients. Enrollment spanned 08/05/2019 to 02/05/2023, with follow-up through at least 24 months, death, or loss to follow-up. Included were 137 patients (99 IRE; 38 SOC), aged [&ge;]18 years with Stage 3 PDAC and no progression after three months of SOC therapy. Results Median (interquartile range) time from diagnosis to enrollment was 8 (6-10) months for IRE and 4 (3-6) for SOC (p<0.0001). Median OS and PSF from enrollment were 18 (95% confidence interval [CI]: 15-24) months and 9 (95% CI: 7-12) months for IRE, and 10 (95% CI: 8-14) months and 6 (5-8) months for SOC, respectively (p<0.0001 and p=0.009). Adverse events occurred in 80% (79/99) of IRE patients and 95% (36/38) of SOC patients; 29% (29/99) of the IRE cohort experiencing an IRE-related adverse event. Conclusions IRE was associated with improved OS versus SOC alone and may be an effective consolidative treatment for Stage 3 PDAC after three months of induction chemotherapy.

BackgroundObesity significantly increases the risk of prognosis and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). While research on the interactions between obesity and the tumor microenvironment (TME) is mostly confined to a few interactions at a time, leaving a gap in the comprehensive understanding of obesity-driven PDAC. We set out to develop a cell-type-resolved model of obesity-driven PDAC using bulk transcriptomic data to investigate TME changes. MethodsWe conducted an integrated transcriptomic analysis of PDAC patients from the CPTAC-3 cohort (n=140) stratified by BMI. A custom immune and stromal functional gene signature database covering 65 cell types was constructed, followed by LLM-assisted review, overlap control, and validation. BayesPrism deconvolution using matched single-cell references was used to derive expression profiles for each cell type. Stabl, a machine-learning algorithm, was used to identify BMI-associated signatures. Bayesian hierarchical modeling, using both continuous and categorical BMI change, was applied to estimate effect sizes and assess the statistical credibility of the signature changes using the 95% Highest Density Interval (HDI) excluding zero. Virtual multiplex immunofluorescence was generated from whole-slide H&E images using gigaTIME to assess the spatial manifestation of BMI-associated TME changes in tissue ResultsBulk pathway analysis showed that ECM homeostasis and primary immunodeficiency pathways deteriorated with increasing BMI. However, Bayesian modeling revealed cell-type-specific, non-linear dynamics. Stromal populations in overweight (OW) individuals were altered, with changes in ECM synthesis and inflammatory signaling that stabilized rather than intensified during obesity. Immune compartments also showed diverse trajectories: CD4+ T cells remained functional in OW but collapsed in obesity; CD8+ T cells progressed linearly from activation to chronic exhaustion. NK cells exhibited non-monotonic behavior, and monocyte and B cell lineages became impaired prior to clinical obesity. Cell-cell interaction analysis showed a shift from a T cell and dendritic cell-centric adaptive interactome in normal weight patients to a neutrophil-dominated inflammatory network in OW. Spatial analysis showed stromal-trapped CD8+ T cells were compressed closer to the tumor boundary with rising BMI. ConclusionsOverweight status represents a critical tipping point in tumor microenvironmental reprogramming, challenging linear models of obesity-associated immune modulation and suggesting that early metabolic interventions may prevent PDAC functional deterioration. Model is available at https://obese-pdac-model.streamlit.app/ O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/721695v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@b1c8cdorg.highwire.dtl.DTLVardef@1f61b7forg.highwire.dtl.DTLVardef@876c60org.highwire.dtl.DTLVardef@dc32b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) affects many people receiving taxane treatment for breast cancer. Symptom trajectories vary, with some recovering, and others experiencing persistent, or delayed worsening (coasting) symptoms. The prevalence and predictors of these trajectories remain unclear. This study identified the prevalence and biopsychosocial predictors of CIPN persistence, improvement, and coasting within three months post-treatment. Methods: This secondary analysis included participants treated with taxanes for stage I-III breast cancer who completed the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-4 (FACT/GOG-NTX-4) at baseline, post-chemotherapy, and three months later. A minimally important difference (MID) from baseline on the FACT/GOG-NTX-4 defined persistence, improvement, coasting, and no MID-CIPN (below the MID threshold at each assessment) trajectories. Baseline assessments included self-reported pain/well-being, sensory, balance, and lower limb physical functioning measures, and sociodemographic and treatment data were collected. Results: Among 102 participants (51.57{+/-}11.24 years), persistence occurred in 34.3%, improvement in 25.5%, coasting in 6.9%, and no MID-CIPN in 33.3%. Compared to no MID-CIPN, older age (OR=1.120; 95%CI: 1.026-1.222), higher expected pain (OR=1.630; 95%CI: 1.082-2.456), and cold hyperalgesia at the foot (OR=1.130; 95%CI: 1.018-1.254) predicted persistence. Lower fatigue predicted improvement (OR=0.904; 95%CI: 0.845-0.968). No predictors were identified for coasting. Conclusion: CIPN trajectories are heterogeneous. Age and pre-treatment pain expectations, cold hyperalgesia, and fatigue differentiate patients with persistent CIPN and those likely to improve from those with no CIPN. Implications for Cancer Survivors: Early identification of individuals at risk for persistent neurotoxicity may support risk stratification and guide targeted supportive care strategies.

BackgroundFor pancreatic cancer, practical blood-based tests for early detection and postoperative surveillance remain elusive. We sought to develop a qPCR-measurable serum microRNA (miRNA) panel that robustly discriminates pancreatic cancer from non-cancer controls and other malignancies. MethodsWe profiled 255 serum miRNAs in batch 1 (n=72) and selected 27 candidates. Candidates were refined in batch 2 (n=552) and cross-batch evaluation was performed with batch 3 (n=391) to derive a miRNA model. Independent validation used batch 4 (n=616). Clinical relevance was assessed in an independent clinical cohort of resection patients with samples obtained preoperatively and at 1 and 12 months postoperatively. ResultsThe miRNA model trained on batches 2 and 3 achieved an area under the curve (AUC) of 0.91 and 0.83 for pancreatic cancer versus non-cancer controls and non-cancer plus other cancers, respectively, when independently validated in batch 4. Stage-wise AUCs in batch 4 were 0.91 (I), 0.94 (II), 0.86 (III) and 0.90 (IV). In the clinical batch, the score decreased postoperatively (preoperative vs month 1; p<0.01) and was higher in recurrence than non-recurrence (p<0.001). ConclusionsThe developed compact miRNA qPCR assay discriminated pancreatic cancer across independent assay batches and showed clinical relevance for postoperative surveillance. Clinical Trial RegistrationNot applicable.

BackgroundHomozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene is a frequent genetic alteration in cancer. MTAP, which creates adenine from 5-methylthioadenosine (MTA), is constitutively expressed in all tissues throughout the body. Previously, we described a novel strategy to specifically target MTAP-deleted cancer cells by combining the antipurine prodrug 2-fluoroadenine (2FA) with MTA. In vitro, this combination efficiently killed MTAP- cancer cells, but in vivo the combination was much less effective in vivo. Here, we explored the role of xanthine oxidase (XO) in this process. Materials and MethodsVarious combinations of 2FA, MTA, and the xanthine oxidase inhibitor febuxostat (FX) were tested in various cancer cell lines grown in vitro and in mice. LC-MS/MS was used to examine the levels and ratio of intracellular 2-FA-containing nucleotides compared to adenine-containing nucleotides. Results and conclusionsThe treatment of cells with 2FA+MTA in vitro resulted in much higher 2FANP/ANP ratios than the same treatment in vivo. The addition of XO to culture media in vitro effectively abolished the killing by 2FA, and this effect was fully reversed by the addition of febuxostat (FX), a xanthine oxidase inhibitor. In vivo, the addition of FX to 2FA results in increased cell killing and toxicity and a 1000% increase in the amount of 2FA converted to 2-FA-monophosphate (2FAMP). Xenograft studies using MTAP- HT1080 and MiaPaCa-2 cell lines have shown that a 2FA/MTA/FX cocktail can cause tumor regression in vivo. These studies suggest that the combination of 2FA/MTA/FX should be explored as a treatment for MTAP- cancer.

Background and ObjectivesIntravesical gemcitabine/docetaxel (Gem/Doce) is an effective therapy for Bacillus Calmette- Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), achieving 50% complete responses at 2 years. However, the genomic determinants underlying response and resistance to Gem/Doce remain poorly defined. Our objective was to define the mutational landscape of BCG-unresponsive NMIBC and nominate genomic features associated with response or resistance Gem/Doce. MethodsPatients with BCG-unresponsive NMIBC treated with Gem/Doce were classified as responders (recurrence-free survival [RFS] >12 months) or non-responders (RFS <12 months). Whole-exome sequencing was performed on tumors prior to Gem/Doce treatment (n=23). Single nucleotide variants were identified and annotated using a Cancer Genome Analysis pipeline. Copy number alterations were inferred with ABSOLUTE, and clonal architecture was reconstructed using PhylogicNDT. Key Findings and LimitationsResponders demonstrated significantly prolonged time to high-grade recurrence (3.5 vs 42 months, p<0.001) and cystectomy compared with non-responders (9.5 months vs not reached; p<0.001). Non-responders exhibited higher tumor mutational burden (13.66 vs 8.71; p=0.02) and more frequent whole-genome doubling (2/2 non-responders vs 0/1 responders; p=0.33). Phylogenetic analyses revealed clonal BAP1 and subclonal BRCA2 mutations in responders, whereas non-responders harbored clonal FGFR3 mutations. Limitations include small sample size and retrospective design. Conclusions and Clinical ImplicationsDistinct genomic features underlie differential response to Gem/Doce in BCG-unresponsive NMIBC. In responders, alterations in DNA repair pathways (e.g., BRCA2) may sensitize tumors to chemotherapy, while non-responders with FGFR3 mutations may benefit from alternative targeted strategies. These findings warrant validation in larger cohorts and support the development of biomarker-driven clinical trials. Patient summaryIn this report we analyzed bladder tumors and found that some tumors respond well to treatment because they have defects in repairing DNA, making them more vulnerable to chemotherapy. In contrast, tumors that do not respond to chemotherapy harbor different genetic changes that help them survive and grow. These findings may help physicians choose more effective and personalized treatments in the future.

BackgroundThe MDM2-p53 signaling pathway plays a central role in tumor suppression, and genetic variants that disrupt this pathway may influence breast cancer (BC) susceptibility. However, data from South Asian populations, particularly Bangladesh, remain limited. MethodsA case-control study was conducted in Bangladeshi women, including BC patients and healthy controls (HCs). Genotyping of MDM2 polymorphisms was performed using PCR-based methods. Circulating MDM2 and p53 protein levels were measured using enzyme-linked immunosorbent assays (ELISA). Associations between genotype, protein levels, BC status, and clinicopathological features were evaluated using appropriate statistical models. ResultsA strong and genotype-specific association was observed for MDM2 rs2279744. Women carrying the heterozygous TG genotype had a markedly increased risk of BC across additive, dominant, and over-dominant models, whereas the GG genotype showed a protective effect under the recessive model. In contrast, rs937282 did not show a significant association with BC risk. Circulating MDM2 levels were significantly elevated in patients compared with controls and varied by rs2279744 genotype, while circulating p53 levels showed an opposite trend. A strong inverse correlation was observed between serum MDM2 and p53 levels, supporting dysregulation of the MDM2-p53 feedback loop. Elevated MDM2 levels were also noted in HER2-positive and triple-positive BC subtypes. ConclusionTogether, these findings indicate that the MDM2 rs2279744 polymorphism contributes to BC susceptibility in a genotype-specific manner, likely through disruption of the MDM2-p53 regulatory balance. However, the absence of functional validation limits direct causal inference.

BackgroundThe ketogenic diet is being explored as an adjuvant intervention in breast cancer because it lowers circulating glucose and elevates ketone bodies such as {beta}-hydroxybutyrate (BHB), but how individual ER+ breast cancer subtypes adapt to these conditions remains poorly characterized. We examined metabolic responses to BHB supplementation under glucose restriction in two ER+ breast cancer cell lines, asking whether metabolic adaptation patterns differ between models. MethodsMCF-7 and T47D cells were cultured under high glucose, glucose-restricted (5% of standard), or glucose-restricted with 10 mM BHB conditions and profiled by comprehensive two-dimensional gas chromatography-mass spectrometry (GCxGC-MS). Pairwise Welchs t-tests with Benjamini-Hochberg false discovery rate (FDR) correction were applied to identify treatment-responsive metabolites. Targeted assays quantified intracellular glycine, SHMT1 protein, and total branched-chain amino acid (BCAA) concentrations across a BHB dose range (2.5-15 mM). Patient tumor transcriptomic data from TCGA (n=1,084) and paired tumor-normal samples from GSE58135 (n=20) were analyzed for genes involved in one-carbon, ketone body, and BCAA metabolism. ResultsMCF-7 and T47D cells exhibited markedly divergent metabolic responses to BHB. In MCF-7 cells, BHB supplementation produced a broad pattern-level metabolic shift: 75% of detected metabolites trended upward when BHB was added to glucose-restricted cultures (C vs. B comparison), with 1,4-butanediol reaching nominal significance (FC=2.35, p=0.016) and a 4.1-fold trend increase in lactic acid (p=0.11), although no individual metabolite survived FDR correction. T47D cells showed essentially no metabolic response to BHB at the global level. Targeted assays detected an elevation in glycine at 5 mM BHB in both cell lines that did not follow a monotonic dose response and was not accompanied by changes in SHMT1 protein expression. Total BCAA levels were elevated by BHB in T47D cells but remained unchanged in MCF-7 cells. In paired patient samples, OXCT1 (log2FC = -1.41), SHMT1 (log2FC = -1.31), and ACAT1 (log2FC = -1.07) were significantly downregulated in ER+ tumors relative to matched normal tissue (adjusted p < 0.001 for all three). ConclusionsER+ breast cancer cell lines show heterogeneous metabolic responses to BHB supplementation under glucose restriction. The broad pattern of metabolite elevation in MCF-7 but not T47D cells suggests that capacity to utilize ketone bodies as metabolic substrate varies between ER+ models. The downregulation of OXCT1, ACAT1, and SHMT1 in ER+ tumors compared to normal tissue identifies these enzymes as candidate biomarkers that may help stratify which patients are likely to benefit from ketogenic interventions. Findings related to individual metabolites should be regarded as exploratory and require validation in larger, adequately powered cohorts.

Background: Head and neck cancer (HNC) patients experience clinically significant anxiety and depression in 65-85% of cases during active treatment. Current supportive care lacks personalized, real-time non-pharmacological interventions. Skitii is a novel HRV-adaptive music therapy system that uses continuous RMSSD (root mean square of successive differences) monitoring via a Polar H10 chest sensor to select music in real-time, targeting parasympathetic recovery (RMSSD >=30ms). Methods: This is a prospective, open-label, randomized controlled trial (1:1 allocation) at Yenepoya Medical College Hospital, Mangalore, India. Adults aged 18-75 years with confirmed head and neck cancer (any subsite, Stage I-IV) undergoing radiotherapy and/or chemotherapy with baseline distress (HADS >=8 or NCCN Distress Thermometer >=4) will be enrolled. Participants are randomized to Skitii adaptive music therapy (20-minute sessions, 3 times daily, 3 weeks) or static music therapy control. Skitii uses a two-phase algorithm: Phase 1 (0-2.5 minutes) uses heart rate as a stress proxy for immediate music selection; Phase 2 (2.5-20 minutes) uses RMSSD to adapt music every 2.5 minutes when physiological state changes by >=20%. Primary endpoints are HADS-Anxiety score and resting RMSSD at Week 3. Sample size is 70 (35 per arm), powered at 80% to detect a 2.5-point HADS difference (SD=3.8, alpha=0.05, 15% dropout). Analysis is ANCOVA, intent-to-treat. Discussion: This is the first randomized controlled trial evaluating RMSSD-based adaptive music therapy in cancer patients. The active control design isolates the effect of the adaptive algorithm from music exposure alone. If positive, results will support a scalable, cost-effective supportive care intervention with objective physiological monitoring, and provide the clinical evidence base for CDSCO Class B medical device approval for Skitii in India, with future CE Mark and FDA applications planned. Trial Registration: Clinical Trials Registry - India CTRI CTRI/2025/11/116732

Abstract: Background: More than half of metastatic melanomas arise from patients initially diagnosed with early-stage melanoma. Objective biomarkers are needed to better identify high-risk patients. Objective: To evaluate the prognostic value of multiple histopathological characteristics in predicting distant metastasis risk, in early-stage melanoma. Methods: Using data from discovery set (n=442) and a population-based validation cohort (n=306, sampled from 5,815 patients) of the Dutch Early-Stage Melanoma (D-ESMEL) study, we investigated 14 histopathological characteristics of melanoma and their tumor micro-environment (TME) in an unprecedented integration, by expert pathologist scoring and automated quantitative measurements derived from a validated automated segmentation. Results: Increased immune infiltrates (40% in cases vs. 50% in controls) were associated with lower risk of metastasis. Automated immune cell density was predictive in both the discovery set and the validation cohort, outperforming the manual pathological tumor infiltrating lymphocytes. The remaining histopathological features, including mitotic activity, did not retain independent value after controlling for current staging variables. Limitations: TME evaluation in standard Hematoxylin-Eosin slides. Conclusion: TME reaction is an important determinant of melanoma progression. The automated quantification of immune cell density appears to be a biomarker for distant metastasis risk. Further investigation into specific immune cell subtypes is required to facilitate clinical integration.

Abstract Introduction: MET tyrosine kinase (TKI) therapy has improved outcomes in patients with non-small cell lung cancer (NSCLC) harboring MET alterations. However, primary and acquired resistance ultimately limits durability of response. This study evaluated the safety and efficacy of the MET inhibitor capmatinib with the MEK inhibitor trametinib in patients with metastatic MET-driven NSCLC who had progressed on prior treatment with at least one MET inhibitor. Methods: A multicenter phase I study evaluated capmatinib in combination with trametinib in patients with advanced stage NSCLC harboring activating MET alterations and prior exposure to at least one MET TKI. A 3+3 dose-escalation design was employed to assess safety and tolerability of the combination. Results: Three patients (n = 3) were enrolled in the study and completed a median of 3 cycles of therapy. Dose-limiting toxicities, including rash, edema, and nausea, necessitated dose reductions in the first two patients and initiation of the third patient at a lower dose level. Ultimately, all patients discontinued therapy due to treatment-related adverse events. The study was terminated early due to poor accrual and TRAEs. No radiographic objective responses were observed. Conclusions: In this phase I trial, capmatinib plus trametinib was associated with significant treatment-related adverse events and treatment was discontinued in all participants. Based on these findings, further investigation of this combination of MET and MEK inhibitors is not recommended.

BackgroundRecent evidence suggests that cancer can exhibit splicing alterations that give rise to tumour-specific isoforms. One example is NUMB, which produces four isoforms (p72, p71, p66, and p65) through alternative splicing of exons 3 and 9. Traditionally considered a tumour suppressor, it also has been considered an oncogene. We propose that this duality is due to isoform-specific expression. ResultsUsing public databases, we identified a tumour-associated switch in NUMB isoform expression: p72/p71 are upregulated in tumours, whereas p66/p65 are more expressed in non-tumour tissues. These isoforms correlate differently with cellular processes. NUMBL, a NUMB homolog, behaves similarly to p65. We identified two transcriptional clusters: one characterized by high expression of p72/p71, and another by p66/p65/NUMBL. Each group was associated differently with the Notch, WNT/{beta}-catenin, Hedgehog, and Hippo signalling pathways, suggesting isoform-specific regulatory roles. Analysis of breast cancer cell lines (CCLE) led to a NUMB score based on isoform expression, which classified cell lines into biologically distinct groups. The p72/p71-enriched group showed distinct signatures, pathway activity, and drug sensitivity. Applying this score to TCGA-BRCA samples revealed a significant link between high NUMB-score and poor survival, confirmed by Kaplan-Meier analysis. ConclusionsNUMB emerges as a potential oncogenic contributor and biomarker in splicing-based personalised medicine, highlighting isoform-specific expression as a clinically relevant determinant of tumour behaviour, pathway activity, and therapeutic response.

Background: Self-reported confidence in health information seeking does not reliably predict accurate health knowledge, yet the population-level distribution of this discordance and its demographic predictors have received limited direct study. This study aimed to identify and characterize a Confident-Incorrect phenotype among U.S. adults: individuals with high perceived health information competence who simultaneously hold inaccurate or fatalistic beliefs about cancer. Methods: Cross-sectional analysis of HINTS 7 (N = 7,278). A Confidence Index (3-item digital literacy composite (Cronbach's = 0.674) and an Evidence-Consistent Knowledge Score (factual cancer knowledge minus a cancer fatalism composite; fatalism subscale = 0.563) were computed and combined into a discordance framework. Median-split classification produced four phenotypes. Gaussian Mixture Model clustering with four components provided moderate independent validation (inter-method agreement = 65.2%). Survey-weighted multinomial logistic regression (n = 5,771; McFadden pseudo-R2 = 0.129) examined phenotype predictors. Results: An estimated 20.3% of U.S. adults were classified as Confident-Incorrect. They reported confidence levels similar to Well-Informed adults (z = 0.72 vs. 0.82) but scored 2.8-fold lower on objective cancer knowledge (0.74 vs. 2.06 out of 4) and exhibited the highest cancer fatalism of any phenotype (3.17 vs. 1.65 out of 4). Only 14.3% correctly identified alcohol as a cancer risk factor (vs. 58.8% of Well-Informed adults). Cancer screening rates did not differ meaningfully across phenotypes. Lower education (OR = 0.754), Hispanic ethnicity (OR = 1.788), non-Hispanic Black race (OR = 1.893), higher social media use (OR = 1.097), and lower trust in scientists (OR = 0.749) independently predicted Confident-Incorrect membership. Conclusions: An estimated one in five U.S. adults is overconfident in health information competence while holding substantially inaccurate beliefs about cancer prevention. Cancer screening rates did not follow the expected gradient across phenotypes, a null finding that cautions against inferring immediate behavioral impact from observed belief gaps. Interventions targeting specific factual errors and cancer fatalism are more likely to reach this group than general health literacy programs.

Background: The use of immune checkpoint inhibitors (ICIs) in the treatment of cancer has rapidly expanded over the last decade. However, there are several knowledge gaps in understanding how tumor cells evade the immune system. There is paucity of data in HPV negative oral cancer, particularly of the gingivobuccal region. Understanding the mechanism of immune system evasion in this cancer is vital for improving patient outcomes. Methods: We characterized the baseline immune milieu of oral cancer using immunohistochemistry (IHC) on whole tumor sections from 124 cases. Tumors were classified as hot or cold and further stratified into high-risk and low-risk groups. High-risk patients included those with lymph node metastasis at diagnosis/recurrence or distant metastasis within 2 years of treatment completion. Patients without these features were categorized as low risk. Validation by RNA-Seq and Joint Enrichment Analysis of Oncogenic and Immunologic Pathways was carried out in a subset of 46 cases. Results: Hot high-risk tumors (by IHC) were distinguished by elevated PD-L1 expression and reduced NK-cell, PD1, and CTLA-4 expression. There was no difference in the expression levels of CD3+, CD8+, granzyme, or perforin compared to hot low-risk tumors, findings that align with the definition of hot tumors. RNA-Seq revealed a gene signature associated with exhausted T-cells in hot high-risk tumors. Gene and pathway analyses identified differential upregulation of isoform-specific TOX, TCF, CXCR, RUNX, IRF, BRD and BCL6 genes, implicating immune cell exhaustion and tumor aggressiveness. Significantly downregulated genes included PDCD1, HAVCR2, ZAP70, and STAT, indicative of a disabled immune microenvironment. These findings support that a state of immune exhaustion in HHR tumors is driven by progenitor exhausted T-cells and terminally exhausted T-cells; independent of PD1-TIM3. Conclusion: These findings suggest that combining TOX/TCF/BCL6 inhibitors with immune checkpoint inhibitors in the adjuvant setting might benefit patients with hot high-risk tumors. Given the results, testing for a targeted exhaustion-related gene panel at diagnosis is recommended for oral cancers to stratify tumors as high-risk or low-risk. Larger validation studies and clinical trials are now warranted.

Background: African Americans (AA) experience disproportionate burden of colorectal cancer (CRC). Dysregulation of the Wingless-related integration site (WNT) pathways contributes to tumor progression, yet their prognostic roles in FOLFOX-treated CRC among AA patients remain understudied. Methods: We analyzed 2,562 CRC cases stratified by ancestry, age at onset, and FOLFOX treatment using Fisher's exact, chi-square, and Kaplan-Meier analyses from AACR Project GENIE and cBioPortal databases. To enhance data integration and interpretation, we applied AI-HOPE and AI-HOPE-WNT, conversational artificial intelligence (AI) platforms designed to integrate clinical, genomic, and treatment data through natural language-driven queries. Results: Overall survival analyses showed that early-onset CRC (EOCRC) AA patients treated with FOLFOX who had WNT pathway alterations experienced significantly better survival (p = 0.035). WNT pathway alterations were less frequent in late-onset AA patients treated with FOLFOX compared to those not treated (80% vs. 92%; p = 0.05). Conclusions: Chemotherapy exposure may influence pathway-specific mutation frequencies across ancestry and disease stage. AI-enabled integrative analyses highlight the potential of conversational AI platforms to accelerate biomarker discovery and reveal ancestry- and treatment-specific vulnerabilities in CRC.

Ultra-processed food (UPF) may contribute to increased energy intake and weight gain, but evidence synthesis from randomised controlled trials (RCT) is lacking. A pre-registered systematic review and meta-analysis of RCTs was conducted comparing UPF with less processed food (LPF) on energy intake and/or body weight in humans. Secondary analyses (meta-regression and sub-group) examined effects of UPF on appetite sensations, eating rate, palatability and considered the role of nutrient profile in explaining results. Ten eligible studies were included. UPF trial arms tended to have higher energy intake (standardised mean differences [SMDs]=0.18-0.44), but statistical significance varied between analytic models. Weight gain (SMD=0.65) and eating rate (SMD=0.96) were significantly greater in UPF trial arms. No significant differences in palatability, appetite sensations or energy intake later in the day were observed. Diets (UPF vs. LPF) used in trials were not matched for nutrient profile. Effects on energy intake varied if UPFs were higher (SMD=0.71) or similar (SMD=0.02) in energy density. Current RCTs are suggestive that UPFs may increase energy intake and body weight; however, results may be explained by energy density of foods used. Further research is needed to understand whether the level of processing impacts health outcomes independent to nutrient profile.