800 mg avelumab, given every 2 weeks, in combination with axitinib, is an approved first-line treatment option for patients with metastatic renal cell carcinoma (mRCC). Less frequent administration of avelumab would be preferable to patients and service providers but has not been previously explored. We retrospectively analysed the clinical outcomes of patients from two academic centres who received 4-weekly avelumab plus axitinib between Oct 2019 and Oct 2023. Patients in cohort 1 (C1) were treated with 4-weekly avelumab from the start of therapy. Patients in cohort 2 (C2) initially received standard 2-weekly avelumab and were later switched to 4-weekly infusions. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated. We identified 94 patients in total, 46 patients in C1 and 48 patients in C2. The majority (56%) of patients in both cohorts had IMDC favourable-risk disease. The ORR in C1 was 53% and the median PFS was 22.1 months. In C2, the median time to switch was 4.9 months (range 1.8-35.6) and median time on 4-weekly avelumab was 16.7 months (range 0.9-39.1). Toxicity was consistent with prior reports. Limitations include retrospective design. These preliminary data support prospective evaluation of modified avelumab scheduling in patients with mRCC. Reducing treatment burden stands to improve patient quality of life and lower associated costs.
Limited studies exist on the gross appearance of osteochondral allografts (OCAs) at the time of second-look arthroscopy to determine whether the graft and adjacent cartilage have signs of degeneration contributing to failure. To describe the gross appearance of OCAs and the adjacent cartilage at the time of a second-look knee operation to help propose an accurate definition of structural and clinical OCA failure and to standardize and classify the intraoperative findings associated with structural graft failure. Case series; Level of evidence, 4. A retrospective review was conducted on all patients who underwent knee OCA transplantation and a subsequent procedure with graft visualization. At second look, grafts were classified using intraoperative imaging and operative reports as nonfailing or failing, with structural failure defined as grade 3 or 4 OCA degeneration (Outerbridge classification system) or moderate-to-severe (>2 mm) peripheral chondral delamination. The status of cartilage adjacent to the graft, including degeneration and delamination, was recorded. Patient characteristics, surgical factors, and graft and cartilage characteristics were evaluated for associations with functional outcomes and subsequent reconstruction (revision OCA, unicompartmental knee arthroplasty, or total knee arthroplasty). Functional outcomes were assessed using the International Knee Documentation Committee, the Osteoarthritis Outcome Score for Joint Replacement, and the Veterans RAND 12-Item Health Survey from index transplantation to the second-look procedure. Of 1152 OCAs performed, 129 grafts (11.2%) from 127 patients underwent a subsequent procedure for symptomatic patellofemoral pathology that included a second-look evaluation at a mean of 2.20 ± 2.06 years. A total of 42 grafts (32.6%) were classified as demonstrating structural graft failure at a mean of 3.17 ± 2.17 years. Structural failure was attributed to graft degeneration (81%) and chondral delamination (21%). Significant cartilage damage adjacent to the OCA border was present in 13 nonfailing grafts (14.9%) and 17 failing grafts (40.5%). Concomitant procedures at index surgery were predictive of structural success (P = .0044), whereas patients with more previous procedures were more likely to experience structural failure (P = .0319). At a mean of 3.14 years from the index OCA, revision reconstruction was performed in 42.9% of patients with structural failure, compared with 9.2% without structural failure. Structural failure classification at second look was strongly correlated with clinical failure (P < .00001). Clinical failure after OCA transplantation appears to be multifactorial. Characterization of macroscopic graft morphology may help surgeons better define clinical and structural failure of OCA transplantation. Future study is required to evaluate the influence of adjacent cartilage and the factors associated with this finding.
Pleomorphic carcinoma (PC) of the lung is a rare, aggressive non-small cell lung cancer. Neutrophil extracellular traps (NETs) are linked to tumour progression, but their relevance in pulmonary PC is unknown. We evaluated the prognostic impact of intratumoral NETs and CD66b+ neutrophil infiltration in PC versus adenocarcinoma. Among 1148 patients who underwent pulmonary resection for primary lung cancer, 813 patients with adenocarcinoma and 17 with PC were analysed. Clinicopathological factors and survival were compared and propensity score matching was applied. NETs and neutrophils were quantified by CD66b immunohistochemistry and citrullinated histone H3/myeloperoxidase immunofluorescence. PC was associated with heavier smoking, more vascular invasion, and more advanced stage than adenocarcinoma (all p < 0.001). The patient characteristics were comparable after matching. Overall and recurrence-free survival were both worse in the PC group (both p < 0.001) and remained poorer after matching. Cox analysis identified NET-positive area (% per high-power field) as an independent predictor of worse overall survival (hazard ratio 1.14, 95% confidence interval 1.01-1.30; p = 0.033). Pulmonary PC shows intense neutrophil infiltration and abundant intratumoral NETs, both associated with poor survival. Quantitative assessment of NETs may serve as a biomarker and therapeutic target in PC.
The randomised METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with nivolumab for metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer. In a post hoc analysis, we investigated whether tumour mutations or patients' systemic inflammation might provide insights into responsiveness to the METIMMOX regimen. Patients received either oxaliplatin-based chemotherapy (control group) or alternating two cycles each of chemotherapy and nivolumab (experimental group), with progression-free survival (PFS) as the primary endpoint. Tumour biopsies were sequenced with the TruSight Oncology 500 assay. The median tumour mutational burden (TMB; in mutations/megabase) was 8 (range, 1-13). The experimental-arm patients with TMB ≥9 or BRAF-V600E mutation (n = 17) achieved median PFS of 19.8 months (95% confidence interval, 11.3-28.3), longer (p = 0.0090) than experimental-arm patients with TMB < 9 not BRAF-V600E (n = 19) and control-arm patients with either TMB and BRAF status combination (n = 31). With TMB ≥9 or BRAF-V600E and normal, non-inflammatory level of C-reactive protein when starting nivolumab (n = 11), median PFS was 35.0 months (95% confidence interval, 6.8-63.0; p < 0.0001). TMB, somatic BRAF status and systemic inflammation should be prospectively investigated as practical biomarkers for predicting potential responsiveness to immune checkpoint inhibitors in metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer.
Meningiomas represent a common type of brain tumours and arise from the arachnoid cap cells which line the dural coverings of the brain. These predominantly benign tumours cause strong morbidity due to their intracranial location. Due to a lack of established pharmacological treatment approaches, surgery and radiotherapy remain the standard in clinical management of these tumours. Here, we created a primary meningioma cell culture model and tested molecular compounds targeting key tumour-driving signalling pathways using cell viability assays and isobologram analysis. We found significant drug vulnerabilities within the meningioma-driving cell signalling network. Effective drugs included metformin, inhibitors of STAT3 and focal adhesion kinase (FAK), and the anti-inflammatory phytochemical sulforaphane, known as NRF2 pathway inducer and NFκB pathway inhibitor. Interestingly, FAK inhibitor Y15 and sulforaphane showed synergistic activity across cells of distinct meningioma patients, indicating this combination as a potential therapy approach. Overall, we present a molecular targeting strategy for meningiomas that could pave the way for less invasive clinical management of these tumours and, as a result, help reduce patient mortality and morbidity. Metformin and sulforaphane both have FDA and EU pharmaceutical approval and thus could be repurposed promptly to establish a new meningioma therapy regimen.
Sex differences in cancer incidence and survival have been documented, but underlying mechanisms remain unclear. We examined sex differences in incidence and survival for non-sex-specific cancers and the role of socioeconomic factors and comorbidity. All individuals living in Denmark from 2004-2020 were included. Incidence rate ratios (IRRs) and excess mortality ratios (EMRs) for 35 cancers were estimated using Poisson regression adjusted for age and year. Modification of associations between sex and death by cohabitation, education and comorbidity was assessed. A total of 7,339,667 individuals were followed for 99,832,998 person-years, during which 355,339 were registered with a primary malignancy (197,375 males, 157,964 females). Males had a 52% higher risk of cancer and upon cancer diagnosis 10% higher mortality than females. IRRs were elevated (with confidence intervals excluding the null) for 24 cancers and EMRs for 16 cancers in males. One in six cancers and one in five cancer deaths in males could have been avoided if male rates matched female rates. Disparities were greatest among males living alone, particularly for alcohol- and smoking-related cancers. Sex differences in cancer must be addressed and translated into interventions that promote equality between sexes, specifically focusing on socioeconomically vulnerable males.
Risk-based screening includes varying screening protocols for women based on their risk of breast cancer. The WISDOM trial incorporates universal genetic testing for nine susceptibility genes into risk assessment. Carriers of high-penetrance mutations are offered an annual MRI. One-third of the women with a mutation would not have qualified for genetic testing based on traditional criteria.
Stage III non-small cell lung cancer (NSCLC) comprises a broadly heterogeneous disease with historically poor survival, and treatment decisions must account for both pathophysiology and resectability. Despite conclusions from older trials that questioned the role of surgery, modern evidence supports surgical resection as an indispensable component of treatment when performed by experienced thoracic surgeons. Advances in neoadjuvant systemic therapy, particularly chemo-immunotherapy, have significantly improved outcomes and reinforced the added value of surgery in appropriately selected Stage III NSCLC patients. In PACIFIC, consolidation durvalumab after concurrent chemoradiation improved progression-free (16.9 vs 5.6 months) and overall survival (47.5 vs 29.1 months). Also, perioperative pembrolizumab reduced progression or death by 42% (*P* < 0.0001) and improved pCR and major pathologic response. Additional trials (NEOTORCH, NADIM 2) showed large reductions in events and higher pCR rates with checkpoint inhibitors plus chemotherapy. Collectively, these data underscore that Stage III NSCLC requires both systemic therapy and durable local control, and neoadjuvant chemo-immunotherapy followed by surgery can significantly improve oncologic outcomes without increasing perioperative mortality in carefully selected patients.
Neutrophils are the most abundant granulocytes in the tumor microenvironment and exert both pro- and anti-cancer effects. Activated neutrophils can release neutrophil extracellular traps (NETs) that have been proposed to promote tumor progression and metastasis. We aimed to clarify the significance of NETs and granulocytes in colorectal cancer. Our study population consisted of three independent colorectal cancer cohorts (N = 1927). We identified NETs showing positivity for citrullinated histone H3 (Cit-H3) and granulocytes expressing CD66b (CEACAM8) with multiplex immunohistochemistry and used digital image analysis and machine learning tools to calculate their densities in tumor samples. Associations between NET and granulocyte densities with clinicopathologic characteristics, tumor-infiltrating immune cells, prognosis, and systemic inflammation markers were examined. The densities of Cit-H3+ NETs positively correlated with macrophage densities and mesenteric serum levels of CX3CL1 and ANGPT2, but were not associated with survival. Higher CD66b+ granulocyte density was associated with longer colorectal cancer-specific survival independent of conventional prognostic parameters. In the largest cohort (N = 1090), multivariable HR for high vs. low CD66b+ granulocyte density was 0.53 (95%CI 0.38-0.73, PTrend < 0.001). Our findings indicate that while neutrophil infiltration is associated with favorable colorectal cancer outcomes, the presence of intratumoral Cit-H3+ NETs does not predict survival.
The 2023/2024 influenza vaccine included an updated H1N1 component designed to better match a new clade of H1N1 that had multiple mutations in antigenic epitopes of hemagglutinin. Despite this update, the vaccine trended towards being less effective against the vaccine-matched H1N1 clade than the parental H1N1 clade lacking the new antigenic mutations. Here we measure neutralization titers of serum antibodies from individuals who had received either a recombinant protein or an egg-derived vaccine against a set of viruses with hemagglutinins from 58 H1N1 strains representative of the diversity during the 2023/2024 season. We find that egg-derived vaccine recipients, but not recombinant protein vaccine recipients, had a relatively lower boost in neutralizing titers to the new clade that the updated vaccine was designed to target. We suggest that the difference in the extent that the egg-derived versus recombinant protein vaccines boosted neutralizing titers to the new H1N1 clade is because the seed strain for the egg-derived vaccine strain had acquired a reversion of a key antigenic mutation (K142R) present in that clade. Our results show how egg-derived versus recombinant protein vaccines can elicit different relative titer boosts against different subsets of viral strains, a phenomenon that could impact vaccine effectiveness.
The environmental impact of cancer care is an emerging concern, yet therapeutic strategies that may incidentally reduce greenhouse gas (GHG) emissions remain poorly described. The 2025 ESMO Congress, where nearly 3000 abstracts were presented, offered an opportunity to identify clinically validated approaches that could lower the carbon footprint of oncology. All abstracts from the 2025 ESMO Congress were reviewed. Studies suggesting meaningful downstream reductions in drug use, visit frequency, treatment duration, or overall care intensity were selected. For each, GHG emissions were estimated using the ECOVAMED drug carbon-footprint database and standard emission factors. Ten abstracts were identified. They spanned primary prevention, therapeutic de-escalation, reduced dose or duration of systemic therapy, biomarker-guided treatment selection, and non-pharmacological interventions. Several strategies demonstrated non-inferior or improved clinical outcomes while substantially lowering treatment-related emissions. Notably, none of the selected studies had explicitly assessed environmental impact. Multiple strategies presented at ESMO 2025 appear capable of improving patient outcomes while reducing the environmental burden of cancer care. Systematically integrating environmental endpoints into clinical research would help identify such win-win approaches and advance a more sustainable oncology practice.
Measuring population immunity is crucial for epidemic preparedness, but methods to translate individual immunity into population-level immunity metrics remain underdeveloped. We aimed to develop and evaluate population immunity estimators using influenza as a model pathogen. In this multicountry, retrospective observational study, we analysed 41 835 serum samples from six studies in China, Hong Kong, Viet Nam, and the USA across 27 influenza epidemics in 2009-24. We constructed four population-immunity estimators from individual antibody titres: geometric mean titre, proportion of non-naive individuals, proportion of population immune, and relative reduction in reproductive number calculated using a next-generation matrix framework. We evaluated the ability of these estimators to predict which subtype (H1N1 vs H3N2) would dominate, to predict whether epidemics would be larger or smaller than the previous season, and to correlate with subsequent cumulative incidence in a longitudinal Hong Kong cohort spanning eight influenza seasons with within-epidemic serum collection. Subtype-specific relative changes in these estimators from previous seasons correctly predicted 57-86% of H1N1-dominant seasons and 100% of H3N2-dominant seasons, with an area under the receiver operating characteristic curve (AUROC) of 79-93%. The estimators correctly predicted larger epidemics in 67-83% of cases and smaller epidemics in 90-100% of cases, with an AUROC of 83-92%. Performance varied by estimator and influenza subtype, with wide uncertainty intervals for some estimates indicating modest precision. In the longitudinal Hong Kong cohort, all four estimators negatively correlated with subsequent 30-day cumulative incidence for H1N1 (Pearson correlations -0·23 to -0·46), whereas H3N2 correlations were mostly non-significant. We developed and validated four complementary population immunity estimators derived from individual antibody titres that showed predictive utility for influenza subtype dominance and epidemic size direction across diverse settings. These estimators could inform seasonal influenza preparedness, surveillance prioritisation, and health-care resource planning. Hong Kong Health Bureau and Research Grants Council.
Nivolumab is effective in treating patients with esophageal squamous cell carcinoma (ESCC). The efficacy of nivolumab in combination with neoadjuvant chemoradiotherapy (CRT) remains unclear. In this phase II trial with Simon's 2-stage design, neoadjuvant nivolumab, paclitaxel, and cisplatin were administered with radiotherapy followed by esophagectomy to patients with locally advanced ESCC. The primary endpoint was pathological complete response (pCR). The secondary endpoints were feasibility, safety, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). A total of 17 patients were enrolled in stage I. Fourteen patients received esophagectomy, with pCR achieved in 4, below the criterion for continuing to stage II. All grade and ≥grade 3 treatment emergent adverse events (TEAEs) occurred in 15 and 4 patients, respectively. Immune-related TEAEs occurred in 7; none were ≥ grade 3. The median durations of RFS, PFS, and OS were 8, 12, and 25 months, respectively. Patients with high expression of PD-L1 had higher pCR rate (100% vs 18%, P = 0.019). Nivolumab in combination with neoadjuvant CRT is safe for patients with locally advanced ESCC, and may be beneficial in those with high PD-L1 expression. NCT05130684.
Pancreatic ductal adenocarcinoma (PDAC) presents as a cancer with an especially poor prognosis, largely due to the challenges surrounding its early diagnosis. Liquid biopsy has emerged as a promising, noninvasive method for screening across a variety of cancers. This approach is limited, however, by the extensive heterogeneity of biological samples, a challenge that teams are looking to address using artificial intelligence (AI) and machine learning (ML) strategies. By harnessing the ability of ML algorithms to extract the most salient features from complex datasets, researchers can identify biomarkers with high predictive value for PDAC. This review explores the current landscape of AI-powered liquid biopsy for early PDAC diagnosis, focusing on specific techniques and their respective degrees of success. Following PRISMA-ScR guidelines, 85 studies were extracted from PubMed and Scopus with a final 18 studies included. The majority of papers utilized blood (n = 15) as the source of liquid biopsy, with the remainder analyzing urine, bile, or cyst fluid. Random forests (n = 9) and support vector machines (n = 7) were the most frequently implemented ML models, while two papers focused on deep learning methods. Limitations include the lack of standardized reporting for model performance metrics and small cohort sizes with non-granular labels.
In the COMET study of women with DCIS, surgery done at the time of diagnosis did not reduce the subsequent incidence of invasive cancer at two years, compared to a ‘watchful-waiting’ approach. This leads us to re-think the conventional view of the natural progression of breast cancer.
Aurora kinase B (AURKB) is overexpressed in lung cancer and is associated with poor prognosis. AZD2811 is an AURKB inhibitor that demonstrated tolerability during a Phase I dose-escalation study in patients with advanced solid tumours, including small-cell lung cancer (SCLC). Here we report the dose-expansion results. Eligible patients received nanoparticle-formulated AZD2811 500 mg IV (Day 1; 21-day cycles) with granulocyte colony-stimulating factor (Day 8). Dose-expansion endpoints included: preliminary antitumour activity, safety/tolerability, pharmacokinetics, and biomarker-based disease monitoring. One of 21 enrolled patients achieved a partial response for an objective response rate of 4.8%; stable disease ≥6 weeks was observed in 10 patients (47.6%). The most common AZD2811-related AEs were decreased neutrophil and white blood cell count, anaemia, and decreased platelet count; grade ≥3 AZD2811-related AEs occurred in 15/21 patients. Baseline ctDNA levels were prognostic, and on-treatment ctDNA changes mirrored clinical response and identified progression early, suggesting it could be an effective surrogate for tumour tissue. Molecular profiling of paired tumour biopsies demonstrated AZD2811 pharmacodynamic activity and identified genes/pathways potentially linked to response. A personalised surveillance strategy may provide a novel avenue to monitor SCLC, supporting further investigation and potential broader clinical application. NCT02579226.
Adoptive cell therapies (ACT) and immune cell engagers (ICE) redirect or potentiate immune effector function against immune-tolerated antigens expressed on malignant cells, representing a distinct class of engineered immunotherapies beyond immune checkpoint blockade. These strategies have been particularly successful in hematologic malignancies; however, translation to solid tumours has been constrained by antigen heterogeneity, limited immune cell trafficking and persistence, an immunosuppressive tumour microenvironment, and on-target off-tumour toxicity. Despite these barriers, accumulating data and clinical experience with these therapies in solid tumours demonstrate feasibility, scalability, safety, and meaningful clinical activity. In light of recent regulatory approvals of ACT and ICE in solid tumours, we aim to provide a comprehensive clinician-oriented overview of these evolving therapeutic platforms. Herein, we review principles of antigen selection, mechanisms underlying investigational ACT and ICE, current barriers to clinical translation in solid tumours, strategies to overcome these limitations, and future prospects for immune-redirecting drug development in solid tumours.
Patients with clinical characteristics of increased cancer susceptibility without an identified genetic lesion are regularly seen in clinics. Association studies and matched normal/tumour sequencing have advanced the discovery of Cancer Susceptibility Genes (CSGs), with limitations when used independently. We reasoned that combining these strategies alongside mutational signatures and clinical data could improve CSGs identification. Using breast and ovarian cancer exome data from The Cancer Genome Atlas (TCGA-BRCA and TCGA-OV), we developed a genomic framework that evaluates exome-wide associations of Germline Pathogenic Variants (GPVs) harbouring second hits with Homologous Recombination Repair Deficiency (HRD) mutational signatures (HRDSig) to identify novel HRD-related CSGs. This is complemented by clinico-genomic analysis evaluating clinical and biological plausibility. Our framework confirmed significant associations with HRDSig of BRCA1/2 GPVs with second hits in both TCGA cohorts, validating its performance. THBS4 also reached significance but only co-occurred with other HRD-related events in TCGA-BRCA. Borderline significance was also observed for KIF13B and TESPA1, also only in TCGA-BRCA. The clinico-genomics approach further identified KIF13B and TESPA1, as well as RAD51B and other Fanconi Anaemia pathway-related genes, including FANCD2, warranting further validation. Our approach provides a framework for the identification of candidate HRD-related CSGs through combined statistical and clinico-genomics analyses. It is adaptable to other mutational signatures/cancer types and will be most effective when applied to larger and well-annotated datasets.
The high mutational burden in microsatellite unstable colorectal cancers (MSI CRCs) results in high immunogenicity, yet response rates to immunotherapy vary, suggesting underlying heterogeneity of the tumour immune landscape. Here, our aims were (1) to characterise the immune cell infiltrate and immune evasion in MSI CRCs, (2) to correlate these with clinical and genomic features, and (3) to compare these between Lynch syndrome (LS) and sporadic MSI CRCs. Immunohistochemistry was utilised to detect T cell and myeloid cell subsets. Whole-genome and RNA sequencing were utilised to analyse somatic variants, tumour clonality, neoantigen burden, antigen presentation, immune checkpoint expression, and consensus molecular subtypes. Our results revealed higher immune cell scores in LS tumours, depicting higher T cell infiltration, compared to sporadic tumours. Conversely, sporadic tumours displayed increased infiltration of protumorigenic M2-like macrophages and increased expression of immune checkpoints PDCD1LG2 and CD40LG. Across our MSI CRC cohort, high neoantigen burden was associated with low tumour clonality. Our findings reveal differences between sporadic MSI and LS tumours in T cell and myeloid immune cell landscapes, and in immune evasion. These differences may contribute to the variable immunotherapy responses among MSI CRC patients and are targetable by emerging therapeutic approaches.
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