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PubMed2026

Integrated morphologic, immunophenotypic, and molecular profiling of advanced upper tract urothelial carcinoma across tumor compartments supports biopsy-based testing.

Upper tract urothelial carcinoma (UTUC) is an aggressive malignancy with limited molecular characterization in advanced disease. FGFR3 alterations are well established in low-grade urothelial carcinoma, but their prevalence, stability, and biological significance in locally advanced and metastatic UTUC remain only partially defined. We performed an integrated morphologic, immunohistochemical, and molecular analysis of 24 locally advanced and/or metastatic UTUC from 20 patients. FGFR3 status was assessed by RT-PCR across multiple tumor compartments, including biopsies, primary tumors, lymph-node metastases, and distant metastatic sites. Immunohistochemistry included CK20, CK5, GATA3, p53, and mismatch repair proteins. Targeted next-generation sequencing (NGS) was used to characterize co-occurring genomic alterations and to assess concordance with p53 immunophenotype. FGFR3 alterations were identified in 50% of patients and in 54.2% of analyzed tumors. FGFR3 status showed high intra-patient stability, with concordance between primary tumors and distant metastases in 90% of cases, whereas concordance with lymph node metastases was lower (50%), suggesting site-specific clonal divergence. Despite advanced stage, 92.3% of FGFR3-altered tumors displayed papillary urothelial carcinoma morphology, and most showed a luminal immunophenotype (61.5% by CK20/CK5 and 69.2% by GATA3/CK5). Targeted NGS revealed additional pathogenic alterations in 75% of patients, most frequently involving RTK/RAS/MAPK signaling (70%), cell-cycle regulation (25%), and PI3K/AKT pathway components (10%). TP53 mutations co-occurred with FGFR3 alterations in 60% of FGFR3-mutated patients and showed 90.4% concordance with p53 immunohistochemistry. Finally, a few cases exhibited complex, multi-site FGFR3 mutational patterns, consistent with intratumoral clonal evolutions. In conclusion, FGFR3 alterations are frequent and remarkably stable in advanced UTUC, even in high-grade and metastatic disease. These findings support the reliability of FGFR3 testing on limited diagnostic material and reinforce its relevance for therapeutic stratification. UTUC emerges as a molecularly dynamic disease in which early oncogenic drivers such as FGFR3 continue to shape tumor biology and therapeutic vulnerability at advanced stages.

Humans↗

PubMed2026

Germline variants and impact on lung cancer outcomes following chemotherapy: A systematic review.

BACKGROUND: Lung cancer is the primary cause of cancer deaths in the UK and globally, and the main subtypes are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many treatment options are available, with platinum-based chemotherapy being a key component for many patients. However, variation in survival outcomes exists among individuals of European ancestry, which makes it important to identify germline genetic variants that help guide decision-making and optimise patient treatment and outcomes. METHOD: A systematic literature search was conducted in PubMed and Web of Science for lung cancer studies investigating the impact of germline genetic variants on systemic anti-cancer therapy (SACT) outcomes in populations of European ancestry. The review was conducted according to the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) and Synthesis without Meta-Analysis (SWiM) guidelines. RESULTS: A total of 20 studies were included in the review out of 4469 on NSCLC and SCLC, encompassing 3639 patients. The most thoroughly investigated area was NSCLC treated with platinum-based chemotherapy. Genetic variants associated with overall survival and/or progression-free survival included XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln. For non-platinum-treated NSCLC and SCLC, there was insufficient evidence to conduct a meaningful investigation. CONCLUSION: The XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln variants showed potential associations with survival outcomes among patients of European ancestry with NSCLC after platinum-based chemotherapy. To support clinical implementation, large real-world pharmacogenomics studies stratified by ancestry are needed to overcome statistical power and heterogeneity limitations.

Humans↗

PubMed2026

Gastric carcinoma classification in the WHO 6th edition (2026): Updated framework and emerging entities.

The sixth edition of the WHO Classification of Digestive System Tumours (2026) represents an important step in the continuing evolution of gastric carcinoma classification. While preserving morphology as the foundation of diagnosis, it incorporates advances in molecular pathology, genotype-phenotype correlations, tumour evolution, and predictive biomarker assessment. This review summarizes the development of the WHO classification from the third edition (2000) to the sixth edition (2026) and highlights its relationship with other major classification systems, including those of Laurén, Nakamura, and the Japanese Gastric Carcinoma Association (JGCA). Major histological categories remain largely unchanged; however, several important conceptual and diagnostic refinements have been introduced. These include recognition of crawling-type adenocarcinoma as a distinctive variant of tubular adenocarcinoma, subclassification of poorly cohesive carcinoma into signet-ring cell and non-signet-ring cell subtypes, introduction of the concept of pure signet-ring cell carcinoma, and increased emphasis on tumour evolution. The sixth edition also expands and refines the spectrum of uncommon gastric carcinoma subtypes, including gastric carcinoma with lymphoid stroma, AFP-producing carcinoma, micropapillary adenocarcinoma, gastric adenocarcinoma of fundic-gland type, and gastric sarcomatoid carcinoma. Crucially, molecular subgroups originally proposed by The Cancer Genome Atlas (TCGA) and actionable biomarkers-including HER2 (ERBB2), Claudin 18.2, mismatch repair deficiency/microsatellite instability (dMMR/MSI), and programmed death-ligand 1 (PD-L1)-have transitioned from research-based categories into essential tools for precision oncology. Rather than providing exhaustive diagnostic criteria, this review offers a conceptual framework and encourages consultation of the original WHO text for full details. These advances illustrate the transition of gastric carcinoma classification from a predominantly morphology-based system toward an integrated histomolecular framework that more closely links pathological diagnosis with tumour biology, prognostication, and therapeutic stratification.

Crawling-type adenocarcinoma↗

PubMed2026

Splenic hilum nodal involvement in resected left-sided pancreatic cancer: meta-analysis.

BACKGROUND: Splenectomy is standard of care during left pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) to obtain adequate lymphadenectomy. However, evidence supporting this approach is lacking. Splenic preservation would reduce short-term morbidity and is essential for emerging oncological adjunctive therapies, including immunotherapy and personalized cancer vaccines. This study reviewed the incidence of splenic hilum nodal involvement (SHNI) in left-sided PDAC. METHODS: A systematic review of the PubMed, Embase, and Cochrane databases was performed, identifying studies published from inception to July 2026. Outcomes of interest were the rate of SHNI (station 10), overall survival, and the rate of splenic artery nodal involvement (SANI; station 11). Meta-analyses were conducted using random-effects models. Subgroup analyses for SHNI were performed per tumour localization (pancreatic neck, body, tail). RESULTS: Among 2776 screened studies, 22 with 2260 patients undergoing left pancreatectomy for PDAC were included. The pooled prevalence of SHNI was 3.7% (95% confidence interval (c.i.) 2.2% to 6.2%); 1.1% for pancreatic body PDAC (95% c.i. 0.3% to 4.3%) and 9.7% for pancreatic tail PDAC (95% c.i. 3.5% to 24.0%). SHNI was not significantly associated with survival (pooled hazard ratio 2.05; 95% c.i. 0.89% to 4.72; P = 0.072). The pooled prevalence of SANI was 39.1% (95% c.i. 25.1% to 55.1%). CONCLUSION: In patients undergoing left pancreatectomy for PDAC, the presence of SHNI is rare, particularly in pancreatic body cancer (1.1%). These findings suggest that the relevance of routine splenectomy remains unclear, especially for pancreatic body PDAC. However, because the quality of current evidence is low, further investigation in prospective studies is required.

Humans↗

PubMed2026

Neoplasms in prune belly syndrome: A novel case of early-onset metastatic bladder carcinoma and systematic review of reported tumors.

PURPOSE: Prune Belly Syndrome (PBS) is a rare congenital malformation complex characterized by cryptorchidism, urinary tract abnormalities and deficiency of the abdominal wall musculature. Although advances in neonatal and reconstructive care have substantially improved survival, the long-term risk of malignancy in this population remains poorly defined. We report a novel case of early-onset metastatic bladder carcinoma in a patient with PBS and perform a systematic review of all tumors described in association with the syndrome. METHODS: A systematic literature review was performed according to PRISMA guidelines and registered in PROSPERO (CRD420251072086). Databases searched through April 2025 included PubMed, Embase, Web of Science, ClinicalTrials.gov, Cochrane, and SciELO. Reported tumor cases in PBS patients were identified and classified as either PBS-associated or not. We additionally describe a new case of invasive bladder carcinoma. RESULTS: Seventeen studies comprising 20 patients met inclusion criteria. Tumors directly related to the genitourinary tract accounted for half of the cases. Bladder carcinoma was the most frequent neoplasm (35%), followed by hepatoblastoma (25%). Bladder tumors occurred at markedly younger ages and often presented as advanced diseases. Our index case involved a 33-year-old man with PBS who developed metastatic muscle-invasive urothelial carcinoma and died shortly after diagnosis. DISCUSSION: Improved survival in PBS has led to recognition of new late complications, including malignancy. Tumorigenesis may be influenced by chronic urinary stasis, infection, catheterization, cryptorchidism, and underlying genitourinary developmental abnormalities. These findings should be interpreted as hypothesis-generating given the limited number of reported cases. CONCLUSION: Although uncommon, malignancies in PBS may occur earlier and behave more aggressively than in the general population. Given the current level of evidence, careful long-term follow-up with clinical awareness is warranted, rather than routine invasive screening for all patients.

Humans↗

PubMed2026

Prophylactic folinic acid prevents pemetrexed myelosuppression: A randomized trial toward safer treatment with chemotherapy in non-small cell lung cancer.

Background Pemetrexed is a cornerstone in advanced non-small cell lung cancer treatment. Although generally well tolerated, severe myelosuppression occurs in 26% of patients. Preventing chemotherapy-associated toxicity has become increasingly important with the introduction of osimertinib combined with pemetrexed-based chemotherapy. Due to substantial toxicity, this regimen is often not administered to frail patients. Folinic acid prophylaxis can mitigate pemetrexed-induced toxicity, however its preventive use has not been routinely studied. We aimed to investigate the efficacy of folinic acid prophylaxis to reduce myelosuppression. Methods Fifty patients treated with pemetrexed were randomized (1:1) to receive pemetrexed with or without oral folinic acid prophylaxis on days 2-4 after each chemotherapy cycle. The primary endpoint was absolute neutrophil count (ANC) after the first chemotherapy cycle. Secondary endpoints included ANC after the second cycle, grade neutropenia, treatment efficacy, renal function and incidence of dose modifications. Results Twenty-four patients received folinic acid and twenty-six served as controls. Higher ANC were observed in the folinic acid group after the first cycle (median 3.79; IQR 2.22-4.93 vs. 1.85; IQR 1.43-3.78; p.

Humans↗

PubMed2026

Genetic regulation of CPEB3-mediated alternative polyadenylation associated with survival of patients with hepatocellular carcinoma.

BACKGROUND: Alternative polyadenylation (APA) is a key post-transcriptional mechanism that regulates gene expression by modulating 3'UTR length, its dysregulation has been implicated in carcinogenesis. How genetic variants influence APA to affect hepatocellular carcinoma (HCC) prognosis remains unclear. METHODS: Prognosis-APA quantitative trait loci (apaQTL) were performed using genotype and APA profiling from TCGA data. A two-stage survival analysis in 848 Chinese and 369 TCGA LIHC patients and functional validation were used to identify prognostic apaQTL in HCC progression. RESULTS: A total of 2,025 and 817 significant APA events were identified in Chinese and TCGA cohort, respectively. Besides, 859 events were associated with poor prognosis in HCC and enriched in RNA splicing / metabolism pathways. We detected 32,034 significant apaQTLs, predominantly enriched in 3'UTRs and RBP-binding regions. CPEB3 was prioritized as a key APA regulator RBP; its low expression correlated with poor patient survival and promoted proliferation, migration, and invasion in HCC cells. Notably, a functional apaQTL variant rs2037547, located in GSK3B and mediated by CPEB3, demonstrated a poor survival of HCC patients in both cohort (pooled HR=1.29, p=0.016). Mechanistically, rs2037547 promoted aberrant APA at proximal poly(A) sites of GSK3B through CPEB3, leading to increased expression of short 3'UTR isoform. This regulatory alteration enhanced HCC cell proliferation, invasion, and migration, and contributed to HCC progression. CONCLUSION: These findings elucidated the distinct role of apaQTL-mediated APA dysregulation in HCC prognosis, providing insights for prognostic stratification and potential targets for personalized therapy in HCC.

RNA-binding proteins↗

PubMed2026

GSTT1 promotes stemness and FGFR inhibitor sensitivity in pancreatic cancer through regulation of CD133 (PROM1).

Pancreatic ductal adenocarcinoma (PDA) is among the deadliest malignancies, driven by metastatic progression and profound cellular heterogeneity. We previously identified glutathione S-transferase theta 1 (GSTT1) as a regulator of a slow-cycling, highly metastatic tumor cell population, suggesting that GSTT1High cells may possess stem-like properties. Here, we define the functional and molecular features of this subpopulation in metastatic PDA. Using a mCherry-tagged Gstt1 reporter system in metastatic murine PDAC cells, we enriched for Gstt1High cells and observed increased tumor sphere formation, accompanied by upregulation of stemness-associated genes including PROM1 (CD133) and activation of Wnt and FGF signaling pathways. In human PDA models, CD133HighGSTT1High cells exhibited enhanced tumor sphere initiation and expansion compared to other populations, defining a maximal stem-like state. Notably, sensitivity to FGFR inhibitors was observed only under tumor sphere conditions, highlighting a context-dependent therapeutic vulnerability. Mechanistically, FGFR3 expression correlated with GSTT1 and CD133 levels, and FGF signaling was required to sustain this state. GSTT1 knockdown reduced CD133 protein levels, impaired tumor sphere formation, and altered sensitivity to FGFR inhibition. These findings were largely recapitulated in patient-derived PDA organoids, where GSTT1 and PROM1 co-expression predicted increased tumor sphere formation and enhanced response to the multi-kinase inhibitor Nintedanib. Together, these results identify a GSTT1HighCD133High stem-like subpopulation in metastatic PDA and identify an FGFR-dependent signaling axis that sustains this state, representing a potential therapeutic vulnerability.

AC133 Antigen↗

PubMed2026

3D epigenomic remodelling mediated by Foxa1 drives gemcitabine resistance in pancreatic cancer.

Gemcitabine remains a cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), yet the emergence of resistance constitutes a major clinical challenge with poorly understood epigenomic mechanisms. Here, we identified the pioneer transcription factor Foxa1 as a master regulator of gemcitabine resistance through multi-omics analysis. Mechanistically, Foxa1 drives widespread super-enhancer (SE) reprogramming and 3D genome remodelling in resistant cells, which coordinately activates the expression of key resistance genes, notably Rrm1 and Cdadc1. This is accompanied by increased chromatin accessibility, elevated H3K27ac enrichment at SEs, and enhanced Foxa1 binding at regulatory elements. Moreover, post-translational stabilization of Foxa1 via USP7-mediated deubiquitination sustains this epigenomic program. Genetic ablation of Foxa1 or specific SE regions near Rrm1 resensitizes resistant cells to gemcitabine. Building upon this mechanism, we demonstrate that bromodomain and extraterminal (BET) inhibitors, which disrupt SE function, potently reverse resistance. Notably, the clinical-stage BET inhibitor AZD5153, in combination with gemcitabine, achieves robust tumor suppression and overcomes resistance in cell-derived xenograft (CDX) models by dismantling the Foxa1-mediated resistant transcriptome and reinvigorating drug sensitivity. Our findings establish Foxa1-orchestrated enhancer reprogramming as a fundamental mechanism of gemcitabine resistance and unveil a promising epigenetic therapy to restore treatment efficacy in PDAC.

Hepatocyte Nuclear Factor 3-alpha↗

PubMed2026

Patient-reported outcomes with tarlatamab in extensive-stage small cell lung cancer after platinum-based chemotherapy: results from the phase 3 DeLLphi-304 trial.

BACKGROUND: Extensive-stage small cell lung cancer (ES-SCLC) is associated with a high symptom burden and impaired health-related quality of life (HRQoL). This prespecified analysis from the phase 3 DeLLphi-304 trial evaluated patient-reported outcomes (PROs) for tarlatamab versus standard-of-care (SoC) chemotherapy following first-line platinum-based therapy. METHODS: DeLLphi-304 is a multicenter, open-label, randomized phase 3 study in adults with ES-SCLC. PROs were assessed using validated instruments, including the EORTC QLQ-C30, EORTC QLQ-LC13, FACT-G GP5, BPI-SF, and the EQ-5D-5L visual analogue scale. Change from baseline, response rates, and time to deterioration in these PROs were analyzed. RESULTS: PRO data from all 509 patients enrolled were evaluated. Compliance with QLQ-C30 and QLQ-LC13 assessments remained above 69% through 19 weeks. A higher proportion of patients receiving tarlatamab achieved symptom or functional improvement at 19 weeks compared with SoC in chest pain (19% vs 10%), cough (35% vs 26%), dyspnea (22% vs 7%), physical functioning (13% vs 8%), and global health status (23% vs 15%), respectively. Tarlatamab also delayed deterioration in symptoms, physical functioning, and pain at worst relative to SoC. FACT-G GP5 results indicated that patients receiving tarlatamab were less bothered by treatment side effects over time. CONCLUSIONS: In addition to its previously reported antitumor activity, tarlatamab demonstrated clinically meaningful improvements in symptoms and HRQoL compared with SoC. These findings support a favorable benefit-risk profile of tarlatamab in patients previously treated for ES-SCLC.

Humans↗

PubMed2026

Feasibility of routine clinical liquid-based cytology for lung cancer compact panel testing.

BACKGROUND: The Lung Cancer Compact Panel (cPANEL) is a recently approved highly sensitive multiplex gene panel in Japan that supports both DNA- and RNA-based next-generation sequencing. Although cytological specimens are acceptable for cPANEL, unfixed cell pellets or dedicated preservation tubes are typically recommended. However, evidence remains limited regarding whether residual liquid-based cytology (LBC) cell suspensions prepared for routine cytological diagnosis can be used directly for cPANEL testing without dedicated molecular preservation or additional preanalytical processing. In this study, we evaluated the feasibility of applying LBC specimens that are widely used in contemporary clinical practice to cPANEL. METHODS: We analyzed DNA and RNA quality in 69 clinical LBC specimens. Among these, 51 specimens containing non-small cell lung cancer cells with previously determined driver alteration status were subjected to cPANEL testing to evaluate assay concordance with clinical companion diagnostic results. RESULTS: DNA integrity was generally well preserved (DNA Integrity Number [DIN]: 6.2 ± 1.5). In contrast, RNA integrity showed greater variability (DV200: 16.4 ± 12.1%). ThinPrep-fixed specimens demonstrated lower DIN and DV200 values compared with CytoRich Red-fixed specimens. Although all samples successfully passed the DNA-based cPANEL assay, six cases (11.8%) failed the RNA-based assay, with RNA yield being a major contributing factor. Among the 46 evaluable specimens, concordance was 95.7% and sensitivity was 92.3%, or 88.9% including RNA module failures as cPANEL-negative. CONCLUSIONS: With appropriate fixative selection and adequate cellularity, cPANEL using clinical LBC specimens may serve as a practical diagnostic platform. We demonstrated that routine LBC specimens can be directly applied to cPANEL without special preanalytical processing.

Humans↗

PubMed2026

Clinical pharmacokinetics of afatinib: A systematic review.

BACKGROUND: Afatinib is commonly used in the treatment of non-small cell lung cancer (NSCLC). This systematic review summarizes clinical pharmacokinetics (PK) evidence focusing on the effect of disease state and drug interactions on afatinib exposure. METHODS: Google Scholar, Science Direct, PubMed, and the Cochrane library were searched for human studies reporting the clinical PK of afatinib. The search yielded 24 articles that met the predefined inclusion criteria. RESULTS: Afatinib exposure increased slightly more than dose proportionally, with higher doses producing greater AUC0-24 and Cmax values. The apparent oral clearance reported after administration of the oral solution was lower than that observed following tablet administration. The Cmax of afatinib increases by 38.5% after coadministration with ritonavir and exposure decreases 34.3% with rifampicin. The Cmax decreases 31.45% when given with pemetrexed. Both the AUC0-24 and Cmax increase in NSCLC and tumor state. The AUC0-24 of afatinib is 2.61 folds higher following multiple oral doses among patients with solid tumors. Afatinib exposure is 22.1 % higher in renal impaired patients than in healthy controls. In grade 2 diarrhea, the AUC0-24 of afatinib is 83.93% higher as than in grade 0-1 diarrhea in solid tumor patients. CONCLUSION: This systematic review provides an updated synthesis of clinical PK evidence on afatinib. Afatinib exposure is influenced by dose, repeated administration, renal impairment, diarrhea associated toxicity, and P-glycoprotein mediated drug interactions. These findings may support individualized dosing, toxicity-guided dose adjustment, and future development of PK models for afatinib.

Humans↗

PubMed2026

Validation of the lung immune prognostic index in extensive-stage small cell lung cancer: Post hoc analysis of the caspian and IMpower133 phase 3 trials.

BACKGROUND: The Lung Immune Prognostic Index (LIPI) is an inflammation-based biomarker associated with outcomes to immunotherapy across several tumor types. Its prognostic value in extensive-stage small-cell lung cancer (ES-SCLC), however, remains insufficiently validated. We aimed to validate the prognostic impact of LIPI in ES-SCLC using data from two phase III trials. METHODS: Patients enrolled in the CASPIAN (NCT03043872) and IMpower133 (NCT02763579) trials were included. LIPI groups were defined as good (dNLR<3 and LDH<ULN), intermediate (dNLR≥3 or LDH≥ULN) and poor (dNLR≥3 and LDH≥ULN). Overall survival (OS) and progression-free survival (PFS) were assessed across LIPI categories and treatment arms. RESULTS: LIPI was available for 1140 patients (Good: 34%, Intermediate: 49%, Poor: 17%), including 708 treated with chemotherapy-immunotherapy and 432 with chemotherapy alone. Poor LIPI was associated with unfavorable characteristics, including lower albumin levels and higher rate of liver metastases. Median OS was 14.6 months (95%CI: 12.4-15.9) for LIPI Good, 10.9 (10.1-11.5) for Intermediate, and 8.4 (7.1-9.3) for Poor (p < 0.0001). In multivariate models adjusted on gender, age, ECOG, treatment arm and metastatic sites, LIPI remained an independent prognostic factor for OS (HR Poor vs. Good: 1.76, 95%CI: 1.45-2.15, p < 0.001) and PFS (HR: 1.59, 95%CI: 1.33-1.90, p < 0.001). Although patients with poor LIPI derived limited benefit from immunotherapy, no significant treatment-LIPI interaction was observed. CONCLUSION: This large post hoc analysis confirms LIPI as a robust and clinically applicable prognostic biomarker in ES-SCLC. Patients with poor LIPI have substantially worse outcomes and limited benefit from immunotherapy, highlighting the need for novel therapeutic strategies in this subgroup.

Humans↗

PubMed2026

Assessing time to symptomatic progression, a patient-relevant efficacy endpoint, in the MARIPOSA study in non-small cell lung cancer.

INTRODUCTION: In the phase 3 randomized MARIPOSA study, amivantamab and lazertinib combination therapy demonstrated improved progression-free survival (PFS) and overall survival (OS) versus osimertinib in participants with previously untreated, epidermal growth factor receptor-mutated advanced non-small cell lung cancer. Time to symptomatic progression (TTSP) was introduced to assess clinical worsening and complement endpoints that investigate radiographic disease progression and patient-reported outcomes. TTSP provides an easily interpretable measure of disease-specific symptom worsening to further support patient experience. METHODS: In MARIPOSA, TTSP was quantitatively assessed as a secondary efficacy endpoint and defined as the time from randomization until participants experience disease-specific symptom worsening requiring a clinical intervention or treatment change, or death. To evaluate the impact of amivantamab and lazertinib on TTSP considering its established OS benefit against osimertinib, an exploratory analysis censoring death events was performed. RESULTS: At the final protocol-specified OS analysis (median follow up: 37.8 months), median TTSP was 43.6 months with amivantamab and lazertinib versus 29.3 months with osimertinib (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.57-0.83; p < 0.0001). Amivantamab and lazertinib reduced deaths following a TTSP event compared to osimertinib. A strong correlation between TTSP and PFS or OS was observed. CONCLUSIONS: Amivantamab and lazertinib significantly delayed TTSP versus osimertinib. TTSP offers a clinician-validated measurement of disease-specific symptom worsening, capturing symptoms perceived by patients that prompt clinical action. TTSP is highly correlated with PFS and OS, providing complementary insights alongside traditional endpoints. TTSP enhances understanding of treatment benefit and supports informed clinical decision-making by integrating patient experience.

Humans↗

PubMed2026

A novel peptide encoded by circTLL1 drives osimertinib resistance in lung cancer by modulating the NT5C2/Ras/PI3K axis.

BACKGROUND: Acquired resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, remains a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). Although circular RNAs (circRNAs) have been increasingly implicated in drug resistance, most studies have focused on their canonical role as microRNA sponges, while their capacity to encode functional micropeptides remains largely unexplored. This study aimed to identify novel circRNAs involved in osimertinib resistance and to characterize their regulatory functions at the protein level. METHODS: Osimertinib-resistant (OR) NSCLC cell lines were established and validated. High-throughput RNA sequencing was performed to compare the circRNA expression profiles between parental and OR cells. The function of the candidate circRNA was assessed through a series of in vitro and in vivo experiments, including cell viability assays, apoptosis analysis, and xenograft mouse models. Mechanistic investigations involved mass spectrometry, co-immunoprecipitation and western blotting to explore its protein-coding potential and downstream signaling pathways. RESULTS: We identified a novel circRNA, termed circTLL1, that was stably and significantly upregulated in OR-NSCLC cells. Functionally, overexpression of circTLL1 promoted osimertinib resistance, whereas its knockdown restored drug sensitivity both in vitro and in vivo. Mechanistically, we discovered that circTLL1 harbors an open reading frame (ORF) that is translated into a novel 90-amino-acid protein, which we designated circTLL1-90aa. Further investigation revealed that circTLL1-90aa directly interacts with and promotes the degradation of 5'-nucleotidase, cytosolic II (NT5C2), thereby uncoupling nucleotide metabolism from its normal regulatory constraints. The consequent downregulation of NT5C2 leads to elevated GTP levels and leading to the sustained activation of the downstream Ras/PI3K/AKT signaling pathway. CONCLUSION: Our findings unveil a previously unrecognized circRNA/micropeptide/metabolism cascade underlying osimertinib resistance. The identification of the circTLL1-90aa/NT5C2/Ras/PI3K axis not only expands the functional repertoire of the non-coding genome but also provides new insights into the complexity of drug resistance. Given its selective upregulation in resistant cells, circTLL1-90aa holds promise both as a predictive biomarker for treatment stratification and as an actionable therapeutic target, offering a novel strategy to overcome osimertinib resistance in NSCLC patients.

Pyrimidines↗

PubMed2026

Daily low-dose carboplatin or weekly carboplatin plus nab-paclitaxel for concurrent chemoradiotherapy in older patients with locally advanced non-small cell lung cancer (JCOG1914): A randomized phase 3 trial.

BACKGROUND: Daily low-dose carboplatin with concurrent thoracic radiotherapy is the standard treatment for older patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) in Japan. METHODS: This open-label phase 3 trial was conducted at 38 institutions in Japan. Patients aged ≥ 75 years with LA-NSCLC were randomly assigned (1:1) to receive daily carboplatin (30 mg/m2) or weekly carboplatin (area under the curve, 2 mg·min/mL) plus nab-paclitaxel (30 mg/m2) with thoracic radiotherapy. Durvalumab maintenance therapy was recommended after treatment completion. The primary endpoint was overall survival, which was used to assess the non-inferiority of weekly carboplatin plus nab-paclitaxel compared to daily low-dose carboplatin. RESULTS: From December 2020 to March 2024, 124 patients were enrolled (carboplatin arm, 61 and carboplatin plus nab-paclitaxel arm, 63). In the planned interim analysis, the Bayesian predictive probability indicating the non-inferiority of carboplatin plus nab-paclitaxel compared with carboplatin in the final analysis was 8.0%, leading to early study termination for futility. The median overall survival was not estimable in the carboplatin arm; the estimated value in the carboplatin plus nab-paclitaxel arm was 26.1 months (hazard ratio, 1.56; 95% confidence interval, 0.79-3.11; p = 0.200). Two treatment-related and seven non-cancer-related deaths occurred in the carboplatin plus nab-paclitaxel arm. Patients in the carboplatin arm had better quality of life than those in the carboplatin plus nab-paclitaxel arm at 6 weeks (odds ratio, 0.39; 95% confidence interval, 0.18-0.81; p = 0.012). CONCLUSIONS: Daily low-dose carboplatin with concurrent thoracic radiotherapy remains the standard treatment for older patients with unresectable LA-NSCLC in Japan.

Humans↗

PubMed2026

A systematic review and network meta-analysis of single nucleotide polymorphisms associated with oral submucous fibrosis risk.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic and insidious oral disease characterized by hyalinization of the subepithelial connective tissue and progressive fibrosis of the oral submucosa. It is a precancerous condition of oral squamous cell carcinoma. Studies have demonstrated that single nucleotide polymorphisms (SNPs) are closely associated with susceptibility to OSF. This study aims to comprehensively evaluate the association between SNPs and OSF risk and to rank the strength of the association between different genetic models and OSF susceptibility. METHODS: Literature related to OSF was comprehensively searched from PubMed, Web of Science, Embase, Cochrane Library, CNKI, and Wangfang databases up to July 2025. Full-text case-control studies with patients diagnosed with OSF were included. Quality assessment was performed to evaluate the risk of bias. RevMan 5.4, GeMTC 0.14.3, and STATA 17.0 were used for the pairwise and Bayesian network meta-analysis. RESULTS: A total of 24 studies with 2545 cases and 3772 controls, covering 13 SNPs in 11 genes, were included in our meta-analysis. We found that CYP1A1 rs4646903:T>C, CYP1A1 rs1048943:A>G, GSTT1 null genotype, GSTM1 null genotype, and XRCC3 rs861539:C>T were associated with an increased risk of OSF, while MMP2 rs243865:C>T and MMP3 rs3025058: 5A>6A were associated with a decreased risk of OSF. Further Bayesian network meta-analysis indicated the top 5 genetic models with the highest association with OSF risk in network group 1 were the dominant model, homozygous model, allelic model, and recessive model of CYP1A1 rs1048943:A>G (ranked 1-4), and the heterozygous/dominant model of CYP1A1 rs4646903:T>C (both ranked 5). While the allelic models of XRCC3 rs861539:C>T and MMP3 rs3025058: 5A>6A ranked first for predicting OSF in group 2 and group 3, respectively. CONCLUSION: Some specific SNPs are significantly related to the risk of OSF. Among them, the dominant model of CYP1A1 rs1048943:A>G may be the most strongly associated genetic model with OSF risk. Future large-sample, well-designed studies with detailed genotype data are needed to validate the roles of these SNPs in OSF risk.

Humans↗

PubMed2026

Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.

IMPORTANCE: Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need. OBJECTIVE: To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled. INTERVENTIONS: Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life. RESULTS: Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04695925.

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