Low muscle mass (LMM) is a risk factor for adverse health outcomes, but its prognostic relevance in cancer remains insufficiently studied. We investigated the independent and combined effects of LMM and obesity on mortality in cancer patients. This cohort study included 635,867 cancer patients. LMM was defined as the lowest quartile on the appendicular skeletal muscle mass index (ASMI). Obesity was defined as body mass index ≥25 kg/m2 and abdominal obesity as waist circumference ≥90 cm (males) and ≥85 cm (females). Patients were classified into four groups based on muscle mass and obesity status. Cox proportional hazards models calculated adjusted hazard ratios (HRs) and 95
BACKGROUND:This prospective Phase 2 trial assessed a novel de-escalation strategy for upfront neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (NAC-TPF) to avoid postoperative radiotherapy (PORT) and chemoradiotherapy (POCRT) for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS:Patients with HPV-associated resectable OPSCC were enrolled. Invasive surgery or PORT/POCRT was an inclusion criterion if upfront surgery was performed. Treatment started with three cycles of NAC-TPF, followed by surgery. The primary endpoint was the centrally reviewed pathological complete response (pCR) rate after NAC-TPF. Levels of high-risk HPV RNA in tumor specimens and plasma circulating tumor (ct) HPV DNA, and quality of life (QOL) scores were assessed. RESULTS:Of 32 eligible patients, 30 patients underwent transoral surgery after NAC-TPF. R0 resection was confirmed in 31 patients. pCR and virological complete response rate at both the primary site and lymph nodes were 65.6% and 64.5%, respectively. No PORT/POCRT was performed in 91%. All QOL scores recovered to baseline values or improved within 1 year. Twenty-three patients showed undetectable ctHPV DNA levels after NAC-TPF. CONCLUSION:Although the primary endpoint was not met, NAC-TPF in HPV-associated resectable OPSCC achieved clinically meaningful pCR, enabling avoidance of PORT/POCRT in the majority of patients. (Clinical trial registration numbers: jRCT1041220029).
BACKGROUND:Optimal dosing of the programmed death-1 (PD-1) inhibitor pembrolizumab remains poorly defined. Dosing has been guided by achieving complete peripheral receptor occupancy, which may not reflect immune activation. We investigated relationships between dose, systemic and intratumoural pharmacokinetics, receptor occupancy, and immune activation in non-small cell lung cancer. METHODS:A physiological pharmacokinetic model describing plasma and intratumoural kinetics was extended with receptor occupancy and interleukin-2 (IL-2) induction parameters derived from ex vivo experiments. Simulations compared three approved regimens-2 mg/kg Q3W, 200 mg Q3W, and 400 mg Q6W. RESULTS:All regimens produced near-complete PD-1 receptor occupancy in both compartments. Despite this, IL-2 concentrations were predicted to change throughout the dosing interval, tracking pembrolizumab concentration rather than receptor occupancy. The 400 mg Q6W regimen yielded the highest IL-2 levels. Changes in intratumoural IL-2 concentration were less pronounced than in plasma. CONCLUSION:Receptor occupancy did not predict immune activation, suggesting it's an inadequate pharmacodynamic surrogate for pembrolizumab. These findings challenge current PD-1 inhibitor dose selection strategies and highlight the need for robust pharmacodynamic markers and clearer definition of the immune activation required for optimal efficacy.
BACKGROUND:The prognostic significance of PD-L1 expression in unresectable/recurrent gastric cancer treated by first-line chemotherapy without an immune checkpoint inhibitor (ICI) remains unclear. The phase III trial JCOG1013 demonstrated no overall survival (OS) or progression-free survival (PFS) benefit of docetaxel/cisplatin/S-1 over cisplatin/S-1. This ancillary analysis of JCOG 1013 evaluated the prognostic value of PD-L1 expression. METHODS:PD-L1 expression was assessed in pretreatment tumor specimens using the Dako 28-8 pharmDx assay. Combined positive score (CPS) and tumor proportion score (TPS) were calculated. PD-L1 positivity was defined as CPS ≥ 5 or TPS ≥ 1%. Univariable and multivariable analyses were performed for OS and PFS. RESULTS:Among 741 patients enrolled in JCOG1013, 540 patients were included. In univariable analyses, neither CPS ≥ 5 nor TPS ≥ 1% was significantly associated with OS or PFS. In multivariable analyses, CPS ≥ 5 was not significantly associated with OS (HR 0.86, 95% CI 0.71-1.04; p = 0.127) or PFS (HR 0.92, 95% CI 0.77-1.11; p = 0.392); however, TPS ≥ 1% was significantly associated with longer OS (HR 0.78, 95% CI 0.62-0.97; p = 0.028) and PFS (HR 0.76, 95% CI 0.62-0.94; p = 0.012). CONCLUSIONS:TPS ≥ 1% is an independent favorable prognostic factor for survival in patients with unresectable/recurrent gastric cancer receiving chemotherapy alone. CLINICAL TRIAL REGISTRATION:UMIN000007652.
Radiomics has been widely explored as a non-invasive biomarker in head and neck squamous cell carcinoma (HNSCC), yet its clinical role remains unclear. Tissue-based biomarkers differ in their susceptibility to spatial sampling. Biomarkers such as PD-L1 expression, immune-cell infiltration, necrosis, and immune exclusion may exhibit substantial spatial heterogeneity, whereas HPV/p16 status and some genomic alterations are generally more stable across the tumor. Nevertheless, localized sampling may incompletely capture heterogeneity in selected clinical contexts. This mismatch becomes clinically relevant when treatment decisions, particularly for chemoradiotherapy, immunotherapy, or de-escalation, are based on potentially non-representative biopsy findings. In this narrative review, we argue that the role of radiomics is not to outperform established biomarkers, but to contextualize them by capturing spatial heterogeneity related to hypoxia, necrosis, stromal architecture, and immune exclusion. We synthesize current evidence linking radiomic features to these biological processes and map them to specific clinical decision points, including larynx preservation, immunotherapy stratification, and recurrence assessment. Rather than serving as a standalone predictor, radiomics may provide complementary spatial information that helps identify situations in which biopsy-derived biomarkers should be interpreted with caution. Although current evidence is largely retrospective, radiomics offers a pragmatic framework for integrating spatial information into biomarker-guided clinical workflows.
BACKGROUND:Elevated serum triglycerides (TG) are associated with poor prognosis in non-small cell lung cancer (NSCLC), but the mechanisms underlying this association remain unclear. Elucidating the role of TG in NSCLC metastasis may reveal novel therapeutic targets. METHODS:A retrospective analysis was performed in 77 NSCLC patients stratified by serum TG levels. Survival was assessed using Kaplan-Meier analysis, and metastasis rates were compared using chi-square tests. Hypertriglyceridemia was modelled in mice. Extracellular matrix (ECM)-constrained invasion assays were conducted in NSCLC cell lines. Lipid β-oxidation and RhoA signalling were interrogated using pharmacological inhibition and genetic silencing of CPT1A and RhoA. RESULTS:Patients with hypertriglyceridemia (TG > 2.3 mmol/L) had significantly shorter overall survival (log-rank p = 0.009) and higher rates of lymph node metastasis (84.4% vs. 37.9%) and distant metastasis (31.3% vs. 3.4%) than normotriglyceridemic patients (TG < 1.7 mmol/L). Mechanistically, TG enhanced lipid β-oxidation, activating RhoA-driven cytoskeletal remodelling that enabled tumour cells to overcome ECM confinement and acquire metastatic competence. Pharmacological inhibition or genetic silencing of CPT1A or RhoA significantly suppressed TG-induced invasion and metastasis. CONCLUSIONS:Elevated serum TG promotes NSCLC metastasis through a lipid β-oxidation-RhoA-cytoskeletal axis. Targeting lipid catabolism and cytoskeletal dynamics may represent a therapeutic strategy for hypertriglyceridemia-associated NSCLC.
Examine rural–urban disparities in prostate-specific antigen (PSA) testing and participation in shared decision-making (SDM) following the 2018 USPSTF guidelines. We analyzed data from the 2019, 2021, and 2023 cycles of the National Health Interview Survey including men ≥55 years, excluding those with a history of prostate cancer or missing data. We tested three outcomes: (1) ever received a PSA test; (2) past 12-month PSA testing; and (3) participation in SDM (assessed in 2019 only). The main exposure was rural–urban classification of respondents’ residence. There were 15,393 eligible respondents. After adjusting for sampling weights and the complex sampling design, 18
Pathology is central to many biologically driven cancer clinical trials. Biomarker-led and translational studies depend on robust tissue pathways, cellular and molecular assays, pathology-derived endpoints, and clinically meaningful interpretation of discovery science. Where trials depend on tumour material, biomarker-defined eligibility or mechanism-focused endpoints, pathology expertise should be embedded early, before protocols, budgets, and assays are fixed. Early pathology input strengthens feasibility, specimen governance, assay selection, quality assurance, and the long-term value of collected samples. In the UK, the Clinical Trials Pathology Advisory Group, now within the new Pathological Society of Great Britain and Ireland Clinical Trials Pathology subcommittee, provides a practical route for pre-submission specialist review. This Perspective argues that pathology is core infrastructure for biologically rich trials, linking discovery science to clinical translation.
Digital health is expanding the range of delivery options available for cancer prevention and may support the development of integrated in-person, digital, and hybrid models. This commentary proposes a framework for cancer prevention delivery across modalities. It argues that the expansion of virtual platforms for cancer-related psychosocial and behavioral interventions may be redefining prevention pathways rather than merely adding digital options. It highlights the possible redistribution of some interventions, such as human papillomavirus vaccination and hepatitis B vaccination, toward in-person services, while cancer-related psychosocial interventions such as cancer prevention-related education can increasingly be delivered through digital platforms, which may improve access and continuity for some populations, although benefits depend on digital access, program design, and implementation context. It also raises concerns about fragmentation, equity, and implementation.
The incidence of hepatocellular carcinoma (HCC) has increased in the United States. Historically, HCC rates are higher among males than females and among racial and ethnic minorities compared with non-Hispanic White (NHW) individuals. However, HCC incidence patterns have changed over time. We examined how sex and race/ethnicity-specific incidence rate ratios (IRR) for HCC have evolved. Age-adjusted HCC incidence rates were calculated using the Surveillance Epidemiology and End Results (SEER) 12 Program. Trends in sex- and race/ethnicity-specific IRRs were evaluated overall and by age group (< 50 vs. ≥50 years). IRRs were calculated as the ratio of age-adjusted rates for each comparison group to the reference group (male-to-female; racial/ethnic group-to-NHW), allowing assessment of relative disparities independent of absolute incidence. From 1992 to 2022, 68,023 HCC cases were identified. Incidence increased through the early 2010s before stabilizing and declining after 2015. HCC incidence remained higher among males than females; however, the male-to-female IRR declined from 3.29 to 3.11, with the most pronounced decline among adults aged <50 years. The non-Hispanic Asian/Pacific Islander (NHAPI)-to-NHW IRR declined from 5.86 to 1.87, while non-Hispanic Black (NHB)-to-NHW and Hispanic-to-NHW IRRs declined more modestly. Age-stratified analyses showed more pronounced declines in some relative disparities among younger adults, although several estimates were not statistically significant. Sex- and race/ethnicity-specific relative disparities in HCC incidence narrowed over three decades. These findings indicate attenuation of relative disparities, while substantial differences in absolute HCC incidence persisted across demographic groups.
Delays from diagnosis to first treatment are a persistent challenge in Mexico. Retrospective observational cohort at the National Cancer Institute (INCAN), Mexico City (November 2017–December 2021). Women with first-time breast cancer and complete dates for diagnosis and treatment start were included. Primary outcome was diagnosis-to-treatment interval (DTI) in days; timeliness was defined as initiation ≤ 30 days. Bivariate tests and multivariable logistic regression were used (two-sided α = .05). We included 425 women. Median DTI was 18 days (IQR 14–24) among timely cases and 42 days (IQR 35–55) among delayed cases. By care period, median DTI was 28 days pre-pandemic and 23.5 days during the pandemic; the proportion initiating ≤ 30 days was similar (58.7 vs 61.9
BACKGROUND:The PD-L1 combined positive score (CPS) is a biomarker predicting responses in gastric cancer (GC) immunotherapy. OBJECTIVES:We aimed to develop a deep learning-based model to predict responses to nivolumab in GC using PD-L1 28-8 immunohistochemistry. METHODS:A cell-detection network was trained on 1927 patches from 88 whole-slide images to generate a computational positive cell ratio (cPCR). The predictive performance of cPCR was evaluated in an independent cohort of 147 patients treated with nivolumab plus chemotherapy. RESULTS:The overall objective response rate (ORR) was 49.66%. ORR was 56.12% in patients with PD-L1 CPS ≥ 5 and 36.73% in those with CPS < 5. Using cPCR, ORR was 56.03% for cPCR ≥5 and 25.81% for cPCR <5. The AUCs of CPS (0.586) and cPCR (0.601) did not differ significantly, but net reclassification analysis showed superior predictive performance for cPCR (p = 0.0269). Incorporating cPCR with tumour-stroma ratio through stepwise variable selection enabled construction of a risk-score model that improved prediction of immunotherapy benefit. CONCLUSIONS:In conclusion, we developed a cPCR-based model and risk-score system that more accurately forecasts nivolumab response in GC, offering a promising tool for optimising immunotherapy selection.
BACKGROUND:G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and are emerging as targets for the effective treatment of cancer. The role of orphan GPCR GPR52 in cancer has not been characterized. Low mRNA expression of GPR52 in breast tumours correlates with reduced overall survival, leading to the hypothesis that loss of GPR52 supports breast cancer progression. METHODS:CRISPR-Cas9 was used to knock out GPR52 in the human triple-negative breast cancer cell lines MDA-MB-468 and MDA-MB-231. 2D and 3D in vitro studies, electron microscopy, and a zebrafish xenograft model were used to assess the morphology and behaviour of GPR52 KO cells. RESULTS:Loss of GPR52 was associated with elevated levels of cAMP, increased cell-cell interaction in 2D cultures, more spindle-like morphology on collagen, altered 3D spheroid morphology, and increased propensity to organize and invade collectively. Zebrafish injected with GPR52 KO cells developed a greater total cancer area than control. RNA sequencing and proteomic analyses of GPR52-null cells revealed an increased cAMP signalling signature. Re-expression of GPR52 and inhibition of cAMP production rescued some GPR52 KO phenotypes. CONCLUSIONS:GPR52 loss is a potential mechanism by which breast cancer progression may occur and supports the investigation of GPR52 agonism as a therapeutic option for breast cancer. STATEMENT OF SIGNIFICANCE:Loss of the orphan GPCR GPR52 in human breast cell lines leads to increased cell clustering, hybrid/partial EMT, and increased tumour burden in zebrafish, further expanding our understanding of mechanisms driving cancer progression and opening the door to novel therapeutic approaches.
Despite the potential for primary care to optimize comorbidity management among breast cancer survivors, engagement with primary care providers (PCPs) remains low. This study comprehensively examined PCP-led care after breast cancer treatment to identify survivors who may benefit from targeted interventions to improve primary care engagement. We identified 1,582 posttreatment breast cancer survivors from the U.S. Behavioral Risk Factor Surveillance System survey. Weighted multivariable-adjusted logistic regression models were used to examine associations of sociodemographic, lifestyle, clinical, and survivorship-related factors with PCP-led care after cancer treatment. Overall, 72
Lung cancer screening using low-dose computed tomography (LDCT) is recommended for high-risk individuals, yet uptake remains low. We evaluated screening eligibility and completion among adults with lung cancer. In the 2024 National Health Interview Survey, adults aged ≥ 50 years with a lung cancer diagnosis within the past 10 years were included. Eligibility at diagnosis was determined using 2021 United States Preventive Services Task Force criteria based on self-reported smoking history. LDCT completion before diagnosis was assessed. Weighted multivariable logistic regression identified factors associated with outcomes. 115 participants were included (weighted n = 638,702). Eligibility could not be determined for 3.5
Prostate cancer remains a significant public health challenge globally, with marked regional disparities in Brazil linked to demographic, socioeconomic, and healthcare access factors. This study analyzed trends in disability-adjusted life years (DALYs), incidence, mortality, and prevalence of prostate cancer across Brazilian macroregions (1990–2021) using data from the Global Burden of Disease (GBD) database. Joinpoint regression was employed to identify temporal trends and average annual percentage changes (AAPCs), stratified by age and region. Data were extracted from GBD 2021, encompassing national and regional estimates. Statistical analyses included age-standardized rates, AAPC calculations, and pairwise comparisons to assess parallelism in trends. Results revealed substantial regional disparities: Southern and Southeastern regions exhibited the highest DALYs, incidence, and prevalence, patterns that are consistent with better diagnostic infrastructure and aging populations. In contrast, Northern regions showed lower rates but the steepest AAPC increases (e.g., incidence: + 2.59
BACKGROUND:Neoadjuvant chemoimmunotherapy (NACI) has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment. However, some patients still do not respond significantly, partly attributed to insufficient anti-tumor specific T-cells. Thus, identifying the underlying causes of impaired antitumor immunity has become an urgent priority to improve efficacy. METHODS:To investigate the link between anti-tumor specific T cells and NACI efficacy in treating HNSCC, we employed multicolor immunohistochemistry (mIHC) and single-cell RNA sequencing (scRNA-seq). To gain deeper insights into the regulatory mechanisms of these T cell populations, we performed cell-cell interaction analysis and spatial analysis. Furthermore, co-culture experiments were carried out to explore the interactions between the cells. RESULTS:Our scRNA-seq results indicated that the population of CD39+CD103+ (double-positive, DP) CD8+ T cells was dramatically increased in the responders of NACI-treated HNSCC patients, while mIHC analysis confirmed the correlation between DP CD8+ T cells density and NACI response. Functional assays demonstrated that DP CD8+ T cells constitute a distinct T cell subset exhibiting enhanced cytotoxic activity. The cell-cell interaction analysis revealed that DP CD8+ T cells were regulated by the CD90+CD138+ cancer-associated fibroblasts (CAFs) subset, which has been characterized as desmoplastic CAFs (dCAFs). In vitro mechanistic experiments suggested that CD90+CD138+ CAF-derived LAMA-4 may reduce the antitumor capacity of DP CD8+ T cells. CONCLUSIONS:Our study highlights the critical role of DP CD8+ T cells in enhancing NACI efficacy. Meanwhile, further research is warranted to explore the effects of targeting CD90+CD138+ CAFs,a thus regulating the function of DP CD8+ T cells.
BACKGROUND:Liver cancer remains a major global challenge, with limited benefit from immune checkpoint inhibitors due to strong immune evasion. Emerging evidence indicates that chromatin modifiers shape tumor immunogenicity, but their roles in liver cancer immunity are not fully understood. METHODS:We investigated the role of the histone demethylase KDM2A in liver cancer using genetic silencing in vitro and in vivo. We evaluated mitochondrial function, redox balance, genomic stability, and performed transcriptomic and epigenomic analyses to assess immune pathway changes and H3K36me2 distribution. Immune infiltration was analyzed in human liver tumors and syngeneic mouse models. RESULTS:KDM2A silencing caused mitochondrial dysfunction, redox imbalance, and DNA damage, leading to activation of innate and adaptive immune pathways. It also reshaped H3K36me2 deposition at loci regulating chemokine signaling, metabolism, and T-cell recruitment. In human liver tumors, high KDM2A expression correlated with poor differentiation, macrophage enrichment, and exclusion of CD8⁺ T cells, consistent with an immune-excluded phenotype. In syngeneic models, KDM2A loss increased intratumoral CD8⁺ T-cell infiltration. CONCLUSIONS:KDM2A acts as a key epigenetic regulator of mitochondrial function, genomic stability, and the tumor immune microenvironment in liver cancer. Targeting KDM2A may enhance tumor immunogenicity and improve responses to immunotherapy, representing a promising therapeutic strategy.
B7 homologue 3 (B7-H3) is a promising therapeutic target in oncology. While its expression on tumour cells is well established, its distribution and role within the tumour microenvironment (TME) remain less clearly defined. This review systematically evaluates B7-H3 protein expression across human TME compartments and explores reported associations with tumour progression and clinical outcomes. A comprehensive literature search was conducted up to June 2025, identifying studies that assessed and quantified B7-H3 expression in the TME of solid human tumours. Thirty-one studies met the inclusion criteria. B7-H3 expression was frequently reported in tumour-associated vasculature, where higher levels have been reported to associate with aggressive histopathological features and reduced survival. Stromal expression, predominantly in cancer-associated fibroblasts, was identified in over half of the tumour types studied and was associated with immune evasion and stromal remodelling gene signatures, although findings varied across studies. Within the immune compartment, B7-H3 was most abundantly expressed in myeloid-derived suppressor cells, macrophages, and dendritic cells, and has been reported to associate to immunosuppressive phenotypes, advanced disease stage and poorer clinical outcomes. These findings identify tumour vasculature and myeloid-derived cells as B7-H3-positive compartments within the TME, although their clinical and therapeutic relevance requires further validation. PROSPERO registration number: CRD420251129792
