Frontiers in Oncology

Purpose/Objective There is paucity of data reporting outcomes of breast cancers with initial internal mammary nodal involvement and no visceral metastases, treated with curative hypofractionated radiotherapy . We report the outcomes from a tertiary centre alongside spatial patterns of recurrences in the above group Material/Methods For this retrospective cross-sectional study, consecutive patients contoured as per the ESTRO 2013 guidelines, treated between 2016-2022 were eligible if their diagnostic imaging demonstrated involvement of the internal mammary nodes. Radiotherapy (40 Gy/15#/3 weeks) was delivered to the residual breast / thoracic wall, SCF region corresponding to the ESTRO lymph node level 4 and internal mammary chain nodes. Residual IMN/ level 4 nodes received a boost of 10Gy/5#. Spatial mapping of sites of recurrence at the local site and three nodal sites (axilla, SCF and IMN) was performed using deformable image registration. Sites of recurrence at the local site and three nodal levels were contoured separately. Volumetric intersection of the recurrent gross tumour volume (GTV_recurrence) with treated clinical target volume (CTV) was calculated. Actuarial overall (OS), disease free survival (DFS) & cumulative incidence of local (LR), regional (RR) and loco-regional recurrence(LRR) were calculated using Kaplan Meier method. Univariate comparison of outcomes with or without residual disease was performed using the log rank test. Results The median age of the 61 eligible women was 49 years. 77% received neoadjuvant chemotherapy and the rest adjuvant chemotherapy. 82% patients had a mastectomy. Axillary lymph node dissection was done in 96.7%. Boosts to residual IMN and SCF nodes were delivered to 21(34.4%) and 2 (3.3%) respectively. Median follow up was 3.6 years. Out of the 61 patients, 42 patients were disease free with an estimated 3 year disease free survival of 75% (95% CI 64, 88%). Spatial mapping of locoregional recurrence was possible in all but 1 patient with local (only) recurrence who was lost to follow-up after mammogram only. Among the patients with loco regional recurrence 1 had recurrence in local site + SCF +axilla, 3 had recurrence in the SCF+axilla, 2 in the SCF+IMN and 1 in the axilla+SCF+IMN. Only one patient had isolated axillary recurrence or isolated SCF recurrence. There were no IMN only recurrences. Among the 8 patients with nodal recurrence, a total of 27 individual GTV_recurrence were identified in the axilla(n=11), SCF(n=11) and IMN (n=5). IMN recurrences showed complete or partial overlap with CTV. SCF recurrences were a mix with predominantly in-field recurrences while axillary recurrences occurred outside the treated volume.Four (6.6%) patients had Grade 2 lymphoedema as documented late side effect. Conclusion Aggressive treatment of IMN disease with adjuvant radiation is effective with good locoregional control. Systemic recurrences are common and may benefit from intensification strategies.

Background: Patients aged [&le;]50 years with early-stage HR+/HER2- breast cancer are considered to have an aggressive disease biology and are treated with chemotherapy. However, a subset may still experience favourable outcomes without chemotherapy. Commercially available prognostic tests help guide such treatment decisions, but most are developed and validated predominantly in Western populations, with an underrepresentation of Asian patients. In this study, we explore the prognostic value of CanAssist Breast (CAB), a proteomic prognostic test, in optimal treatment management of patients aged [&le;]50 years. Methods: This study includes a previously published retrospective cohort. The performance of CAB was evaluated using Kaplan-Meier analysis, with 5-year Distant recurrence-free interval (DRFI) from diagnosis as the endpoint; the study also used multivariate analysis to evaluate the independent prognostic value of CAB. Results: In the retrospective cohort, CAB identified 70% as low-risk (LR) and 30% as high-risk (HR) with DRFI of 93.1% (P<0.0001); further classification showed 64% LR and 36% HR in the Asian and 75% LR and 25% HR in the Caucasian subgroup. In patients with N0 disease, CAB identified 85% as LR and 15% as HR. In N+ patients, CAB identified 49% as LR. All CAB LR patients have an acceptable DRFI of >90% at 5 years from diagnosis. Conclusions: Based on the results presented, CAB adds prognostic value for patients [&le;]50 years and can be used as a treatment guidance tool for these patients.

Cell confluency is a major determinant of cell-cell communication, protein interactions, access to nutrients, and signalling dynamics, thereby significantly impacting biological outcomes. Lung cancer cells like A549 are widely used as screening models for scientific studies wherein their growth in vitro progress from non-confluent to confluent growth. In this study, we investigated the transcriptomic adaptations associated with the transition of A549 cells from baseline non-confluent to confluent growth. Comparative transcriptomic analysis between confluent and cells at baseline identified 815 upregulated and 671 downregulated transcripts. Pathway enrichment analysis of deregulated transcripts in confluent cells revealed enhanced cholesterol and sterol biosynthetic pathways, along with suppression of chromosomal segregation and mitotic pathways. At confluency, an increased expression of glucose transporters (SLC2, SLC60, and SL37 families) and glycolytic pathways, and a decrease in amino acid transporters (SLC1, SLC7, SLC38, and SLC36) and amino acid metabolic pathways is observed. A reduced one-carbon metabolic signature (SHMT2, DHFR, and MTHFD2) and enhanced fatty acid precursor synthesis (HMGCLL1, ALDH6A1, and AASS) were also observed at confluency. 1H NMR profiling of culture media revealed higher glucose and glutamine utilisation with lactate accumulation during culture maturation. Collectively, the data suggest transcriptome-level rewiring in A549 cells with preferential biosynthesis of lipids and sterols at confluency and underscore the importance of considering culture maturity in cancer biology, metabolism, and therapeutic studies.

Background and Objectives: Robotic-assisted natural orifice specimen extraction surgery (NOSES) is a minimally invasive approach for mid-rectal cancer, but it is technically complex and lacks a standardized operational framework. This study aimed to propose and preliminarily validate a structured modular robotic NOSES II surgical procedure for mid-rectal cancer. Methods: This was a retrospective observational study that consecutively enrolled 11 patients with mid-rectal cancer who underwent modular robotic NOSES-II surgery at our center between December 2024 and August 2025. All procedures were performed by the same surgical team strictly following the predefined six-module structured surgical protocol. Perioperative indicators, pathological outcomes, and patient-reported outcomes (PROs) at 4 to 8 months postoperatively were collected. Key techniques were analyzed via high-definition surgical videos. Results: All 11 procedures were completed successfully without conversion to open surgery. The mean operative time was 299.6 plus or minus 54.2 minutes, and the mean intraoperative blood loss was 94.1 plus or minus50.6 mL. The mean number of harvested lymph nodes was 17.4 plus or minus 8.4, with a 100% R0 resection rate. No severe complications (Clavien-Dindo grade [&ge;] III) occurred. The mean postoperative hospital stay was 8.2 plus or minus 1.5 days. Postoperative PROs indicated good defecatory function, urinary function, and overall quality of life. Conclusions: Preliminary findings demonstrate that the structured modular robotic NOSES-II procedure is safe and feasible for the treatment of mid-rectal cancer. This modular protocol provides a clear and reproducible technical framework for this complex procedure, and it is expected to achieve favorable functional preservation while ensuring oncological radicality.

Background: Prostate cancer enzalutamide treatment is approved at a standard dose of 160 mg daily. Concerns for real-world patients -- older and more fragile than those enrolled in clinical trials -- have prompted consideration of initiating treatment with lower doses, but the long-term efficacy of this approach remains unknown. We evaluate the long-term survival and longevity in patients treated with standard versus upfront low-dose enzalutamide. Methods: Retrospective analysis of 151 patients treated with enzalutamide (102 receiving 160 mg; 49 receiving [&le;]80 mg) between 2014--2021 at the Centre Hospitalier Universitaire de Martinique, with complete follow-up through end of life (98.7% completeness of follow-up). Primary outcomes were overall survival (OS), progression-free survival (PFS), and longevity (attained age). Results: Doses [&le;]80 mg were associated with longer median OS (36.3 vs. 20.7 months), improved restricted mean OS (difference of 0.7 years, p=0.05), and enhanced longevity (median 82.5 vs. 78.3 years, p=0.004). PSA response rate at 12 weeks was higher with lower-dose (71.4% vs. 48.8%, p=0.016). In multivariable models adjusted for prognostic factors, [&le;]40 mg compared with 160 mg was non-inferior regarding OS (HR=0.61, 95% CI 0.36--1.06), superior regarding PFS (HR=0.59, 95% CI 0.35--0.99), and superior regarding longevity (HR=0.48, 95% CI 0.28--0.84). Bone metastasis, poor performance status, PSA response, time to PSA nadir, and disease duration were independent predictors of outcomes. A post-hoc analysis revealed a strong association between dose and physician-prescribing profiles, ranging from "endorse-lowest-dose" to "never-deviate-from-full-dose". Conclusions: Lower doses of enzalutamide were non-inferior to full-dose. Dose-adapted strategies warrant further investigation.

Purpose The Karolinska Liver Metastases (KaroLiver) cohort was established to investigate associations between clinical characteristics and histopathological features in patients treated with curative intent for colorectal cancer liver metastases (CRLM). The cohort combines whole-slide digital histopathology images with detailed oncological, surgical, radiological and survival data, enabling comprehensive analyses of treatment trajectories, clinical outcomes and metastatic tumour biology. Participants KaroLiver is a retrospective observational cohort comprising all consecutive patients who received curative-intent, liver-directed treatment for CRLM at Karolinska University Hospital in Stockholm, Sweden. The hospital is the primary regional referral centre for HPB surgery, serving the population of approximately 2.5 million people in the Stockholm-Gotland healthcare region. Patient enrolment is continuously updated in accordance with amended ethical approvals and evolving scientific questions. The cohort currently comprises 811 patients who underwent 1204 liver interventions between February 2012 and January 2022. Detailed clinical, oncological, surgical, pathological, molecular, recurrence and survival data are collected. Findings to date Median overall survival (OS) in the current cohort is 51.0 months (95% CI 46.2-57.1 months), and median recurrence-free survival (RFS) is 10.4 months (95% CI 9.2-11.9 months). The five-year OS rate is 44.9% (95% CI 41.2-48.8%). Studies using the cohort have so far identified a liver injury-derived stromal capsule in a subset of metastases, associated with improved survival. The cohort has also enabled the identification of histopathological markers of tumour biology, sex-based differences in treatment and survival, and associations between post-hepatectomy liver failure and oncological outcomes. Future plans Current research priorities include advanced histology-based prognostic scoring, sex differences in recurrence and retreatment, tumour biology and outcomes in early-onset versus average-onset CRLM, as well as CT- and MRI-based radiomics, all integrated within KaroLiver's histopathological framework. Data sharing is supported, given that regulatory requirements are met. Retrospective accrual and outcome updates will continue for current and future studies, subject to the required approvals.

Background: Uveal melanoma (UM) and cutaneous melanoma (CM) both originate from the same cell line. This proposes the possibility of a shared mechanism between entities, requiring explicit investigation. Methods: Data from GWAS Catalog and DisGeNET were used to identify shared variation-disease associations (VDAs) between UM and CM. The results were validated using the Ensembl database. In the next step, the STRING database was used to identify the protein-protein interaction. Results: Subsequently, 109 unique VDAs were identified for UM and 880 for CM. However, only 2 VDAs were found to be shared among UM and CM in different ethnic groups. These shared VDAs were rs12203592 of the IRF4 gene, rs12913832 of the HECT and RLD domain-containing E3 ubiquitin protein ligase 2 (HERC2) gene. Notably, PPI network assessment through STRING showcased that OCA2 and IRF4 directly interacted with HERC2. Conclusion: While HERC2 acts as a poor prognostic factor in uveal melanoma, IRF4 status is a key prognostic indicator in both UM and CM. Identifying IRF4 allele contributions enables a better understanding of melanoma pathogenesis and fosters the development of disease-specific approaches.

Long-term data describing cancer patterns in Iraq remain generally limited. This retrospective observational study was conducted to evaluate the distribution and longitudinal patterns of malignant solid tumors diagnosed over a period of 12 years (2014-2025) at a major tertiary oncology center in the Kurdistan Region of Iraq. Demographic characteristics, cancer types, and temporal trend changes in cancer distribution were analyzed. Comparisons were made between the first (2014-2019) and second (2020-2025) halves of the study period. Descriptive statistics, Chi-square tests, and linear regression analyses were used to evaluate the temporal trends. After excluding records with incomplete data, 11,704 patients were included. Breast cancer was the most frequently diagnosed malignancy, accounting for over one-quarter of all cases, followed by lung, colorectal, prostate, and bladder cancers, in descending order. Women represented the majority of patients, and the mean age at diagnosis increased significantly over time. In general, the relative distribution of colorectal, genitourinary, pancreatic, uterine, and thyroid cancers increased during the study period, whereas breast and lung cancers showed a modest but significant proportional decline despite remaining the most common malignancies. A marked reduction in case numbers was observed in 2020, followed by progressive recovery in subsequent years. To conclude, cancer patterns in the Kurdistan Region of Iraq changed substantially during the 12-year study period, with increasing proportions of colorectal and several other malignancies alongside an older age at diagnosis. These findings likely reflect a combination of demographic changes, evolving lifestyle-related risk factors, and improvements in cancer detection and referral. The results provide contemporary evidence to support regional cancer control strategies, screening programs, resource allocation, and future epidemiological research.

Background: Recurrence rates following curative resection for hepatocellular carcinoma (HCC) remain persistently high, benefit from adjuvant immunotherapy varies substantially across patients, and the field currently lacks a standardized framework to characterize the postoperative host immune contexture. Purpose: To propose and validate a Multi-stage Precision Stratification (MPS) framework and evaluate its value in prognostic stratification and prediction of immunotherapy response. Methods: The Immune Health Index (IHI = S + R - E) integrating immune surveillance (S), immune exhaustion (E), and immune reserve (R) was constructed to define four immune phenotypes. Prognostic value was assessed in four public HCC cohorts (n=931) with single-cell transcriptomic validation (GSE140228, 61,690 cells); a blood-count-based clinical version cIHI_v8 was constructed in the Qinghai QPHCC cohort (n=490 survival analysis). Results: IHI was an independent protective prognostic factor in TCGA-LIHC (multivariate HR=0.795, P=0.034); four-cohort random-effects meta-analysis yielded HR=0.818 (95% CI: 0.696-0.961), I-squared=31.4%. QPHCC cIHI_v8 multivariate HR=0.452, HR=0.715 after ALBI adjustment; Bayesian evidence synthesis yielded BF_10=1280 for cIHI_v8 (>100 constitutes Decisive evidence), whereas the 4-cohort meta BF_10=2.19 (Anecdotal). Following NLP-based reverse stage derivation (n=490, achieving full AJCC/BCLC stage coverage from 0%), IHI remained significant after AJCC adjustment (HR=0.8642, P=0.000079), IHI provided positive incremental C-index across all stage-adjusted models; stratified analysis showed the strongest effect in early-stage (AJCC I-II: HR=0.8109, P<0.0001) and MVI-negative patients (HR=0.8538, P=0.0020). Bootstrap 1000x resampling: median HR=0.8646 (95% CI: 0.7985-0.9443), all iterations yielded HR<1. Conclusions: The MPS framework provides a mechanism-driven biological stratification tool for adjuvant immunotherapy in post-resection HCC, moving from "fixed-protocol extrapolation" to "immune contexture navigation."

BackgroundAnesthetic agents administered during surgery are one of the key perioperative factors affecting immune modulation in cancer patients. This comparative study elucidated the mechanisms by which the volatile anesthetic, isoflurane and the intravenous anesthetic, propofol impacted apoptosis signaling in CD4+ helper T (Th) cells. MethodsFlow cytometry was used to analyze apoptosis, mitochondrial function and reactive oxygen species (ROS) generation, while Western blotting, ELISA and RT-qPCR were employed to study protein/gene expression in sorted CD4{square} Th cells from perioperative breast cancer female patients (anesthetized with isoflurane or propofol, n=15 per group) and Jurkat T cells. ResultsPatient-derived CD4{square} Th cells and Jurkat T cells exhibited that isoflurane at clinically relevant concentrations triggered apoptosis through mitochondrial depolarization, ROS generation, DNA damage, and activation of caspase-3/7. Specific use of caspase-3/7 inhibitor, Z-DEVD-FMK and antioxidant N-acetyl cysteine rescued isoflurane-induced apoptosis. Further, isoflurane relative to propofol, activated p38 mitogen-activated protein kinase (MAPK), and use of p38 inhibitor, SB203580 suppressed isoflurane-induced apoptosis. Collectively, these findings validated the involvement of the ROS-p38-caspase-3/7 axis in isoflurane-associated apoptosis signaling. On the other hand, propofol conserved mitochondrial integrity, reduced oxidative stress, and maintained higher proliferative capacity. Interestingly, isoflurane-associated apoptosis was transient, with postoperative recovery in patients and similar rescue from apoptosis was evident in Jurkat T cells within 24-48 h of drug removal. ConclusionsBy integrating analyses of patient-derived CD4+ Th cells with mechanistic validations in Jurkat T cells, this study identified the ROS-p38-caspase-3/7 signaling axis and the reversible nature of isoflurane-induced apoptosis.

Background: Bladder cancer has entered an era in which immune checkpoint blockade (ICB) and antibody-drug conjugate (ADC)-based combinations are reshaping clinical management. However, transcriptomic scores that connect prognosis, tumor microenvironment state, and treatment response are incompletely defined. Methods: Open-access TCGA-BLCA RNA-seq, clinical, mutation, copy-number, and RPPA data were downloaded from the Genomic Data Commons (GDC). Tumor-normal differential expressions, survival screening, LASSO-Cox modeling, train-test validation, GEO validation, pathway enrichment, immune signature scoring, mutation/CNV/RPPA support, drug sensitivity prediction, single-cell/spatial localization, and ICB validation were performed using reproducible Python and R scripts. A reduced model was derived using only genes shared by TCGA, GSE13507, and GSE31684. The fixed formula was then applied without refitting to IMvigor210 and GSE176307. Results: A five-gene model composed of EMP1, AHNAK, TNFRSF14, CLEC2D, and GSDMB retained TCGA internal prognostic value (train C-index 0.693, test C-index 0.605, all-sample C-index 0.667; TCGA test log-rank p = 0.015), although GEO survival validation in GSE13507 and GSE31684 was modest. High-risk tumors were enriched for epithelial-mesenchymal transition (EMT), TNF-alpha/NF-kB signaling, inflammatory response, hypoxia, complement, CAF, macrophage, checkpoint, and cytotoxic programs. Single-cell and spatial analyses localized the score to basal tumor, endothelial, fibroblast, and perivascular compartments. In IMvigor210, risk scores were higher in ICB non-responders than responders (Wilcoxon p = 0.044; AUC for non-response = 0.580), high-risk tumors had a lower responder rate (17.6% vs. 28.0%), and high risk predicted poorer OS (log-rank p = 0.016; multivariate continuous risk HR = 3.15, p = 0.044). GSE176307 showed directionally consistent but non-significant response results (AUC = 0.576). Conclusions: The five-gene score is best interpreted not as a standalone universal prognostic classifier, but as a compact stromal-EMT and immune-suppression phenotype associated with inferior ICB response. These findings support a framework linking prognosis, microenvironment biology, immunotherapy resistance, and therapeutic hypotheses in bladder cancer.

Background The number of novel cancer therapies approved for use in England by the National Institute for Health and Care Excellence is increasing. Monitoring the adoption of new therapies is important to assess equity of access and evaluate real-world prescribing practices. OpenPrescribing Hospitals has recently been launched to facilitate analysis of open secondary care medicines data in England. Using this platform, we set out to describe the use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including the frequency of dose reductions, within National Health Service (NHS) hospitals in England between January 2019 and December 2024. Methods The monthly proportion of each CDK4/6 inhibitor relative to total CDK4/6 inhibitor use was calculated at hospital level. Regional variation was assessed across Cancer Alliances by comparing the proportions of each CDK4/6 inhibitor used within each alliance in 2021 and 2024. Use of lower strength palbociclib and abemaciclib was used as a proxy for dose reductions. Findings There was more than a 3-fold increase in the use of CDK4/6 inhibitors between 2019 and 2024. In 2019, 78.6%, 11.9% and 9.5% of CDK4/6 inhibitors used were palbociclib, abemaciclib and ribociclib, compared with 40.2%, 41.2% and 18.6% in 2024. There was variation in the relative percentage change in use of each agent by Cancer Alliance. Use of lower strengths was common for both palbociclib (60%) and abemaciclib (63%). Interpretation Changes in usage appeared responsive to publication of key evidence and regulatory milestones. There was a higher apparent frequency of dose reductions than reported in clinical trials. OpenPrescribing Hospitals is an accessible, publicly available tool for understanding uptake and use of medicines in NHS hospitals in England.

Background and Purpose: Rare thoracic tumors face persistent exclusion from clinical trials. To address this, we characterized the representation, geographical distribution, mechanisms of action, and clinical outcomes of Phase I trials in thymic epithelial tumors (TETs) and mesothelioma. Materials and Methods: Phase I solid-tumor trials from Jan 1995 to Jan 2026 were identified on ClinicalTrials.gov and processed using Python to extract trial status. A Python pipeline identified TET and mesothelioma trials and divided them into resulted and non-resulted trials. Resulted trials underwent manual review, and publication status was verified through PubMed, Google Scholar, and LARVOL CLIN. Results: Of 6,610 Phase I trials screened, 3.1% (n=203) included rare thoracic tumors. Among these, 11.3% (n=23) reported results, 34.8% (8/23) advanced beyond Phase I, and 21.7% (n=5) were published in high-impact journals (IF > 10). Targeted therapies dominated classifications (65.2%), followed by immunotherapies (34.8%) and antibody-drug conjugates (ADCs; 8.7%). Reported efficacy outcomes showed wide ranges: objective response rate (ORR, 0-44%), progression-free survival (PFS, 1.3-8.3 months), and overall survival (OS, 3.0-19.3 months). Fatigue was the most frequent toxicity, observed in 58% of targeted therapy trials and 100% of immunotherapy and ADC cohorts. No novel agents achieved subsequent disease-specific FDA approval. Geographically, among 96 trial locations, 49.0% were concentrated in Europe and 21.9% in the United States. Conclusions: Current Phase I trials exhibit a striking scarcity of research for mesothelioma and TETs, concentrated predominantly in high-income regions. Bridging this gap requires prioritizing rare thoracic tumors and building clinical infrastructure in underrepresented countries to enhance trial access and diversity. Keywords: Thymic epithelial tumors, Mesothelioma, Phase I clinical trials, ClinicalTrials.gov, Rare thoracic malignancies.

Background: Chronic inflammation is the most common histological feature in Benign Prostatic Hyperplasia (BPH), and T cells are a key component of immune infiltrate. Advanced BPH is commonly associated with the formation of nodules, but it remains unclear whether a link exists among T cell infiltration, nodular development, and BPH progression. Using a Toxoplasma gondii (T. gondii) model and human specimens, we characterize the subtypes of T cells present during prostatic hyperplasia and their association with nodular development of the prostate. Methods: Male CBA/j mice were intraperitoneally infected with T. gondii parasites, and flow cytometry was performed on the prostate to quantify the number of CD4+ and CD8+ T cells. Histology was used to score microglandular hyperplasia (MGH), and immunofluorescence was used to quantify and examine the locality of CD4+ and CD8+ T cells and compared that to human BPH tissue. Results: We found that infecting male mice with T. gondii resulted in an increase of both CD4+ and CD8+ T cells in the prostate acutely and that CD8+ cells remained sustained at chronically. We also established the presence of glandular nodule formation at this timepoint through hematoxylin and eosin (H&E) staining. Immunofluorescence revealed that CD8+ cells were found proximal to forming glandular nodules relative to non-nodular glands. We also found more CD8+ cells localized to non-nodular glands in nodular BPH tissue versus non-nodular BPH tissue. Finally, we discovered a higher prevalence of CD8+ cells in T. gondii IgG+ patients than in IgG- patients. All T. gondii IgG+ patients exhibited nodular BPH, whereas all but one IgG- patient exhibited non-nodular BPH. Conclusions: This study is the first to investigate the presence and location of CD4+ and CD8+ T cells within nodular and non-nodular BPH glands. We found an association of the presence of CD8+ T cells with nodular progression. This association held true in human prostate tissue. Translationally, CD8+ T cells may enhance nodular BPH progression, and T. gondii infection may promote this CD8+ T cell-mediated response.

Background Tumor hypoxia and abnormal vasculature are closely associated with aggressiveness in solid tumors. Therefore, noninvasive assessment of these features in primary breast cancer is needed. Photoacoustic (PA) imaging is an emerging modality that enables real-time visualization of vascular architecture and hemoglobin oxygenation. Methods Breast PA imaging was performed in patients with primary breast cancer using a bed-type PA imaging system equipped with a hemispherical sensor and a flat specimen holder enabling mild breast compression. Three independent evaluators assessed predefined characteristics of tumor-associated vasculature: centripetal/disrupted vessels and intratumoral vessel-like signals. Oxygenation (S-factor) of tumor-associated vessels was estimated using dual-wavelength laser irradiation at 756 and 797 nm. Results PA imaging was performed in 9 tumors from 8 patients. Eight tumors were evaluable, after the exclusion of 1 tumor with segmental bloody discharge. Centripetal/disrupted vessels were identified in 7 tumors (87.5%). Intratumoral vessel-like signals were observed in all tumors (100%), with higher signal density than in surrounding tissue in 5 lesions (62.5%). Increased intratumoral signal density was associated with a higher Ki67-labeling index (two-sided P = .01). Mean intratumoral S-factor level (76.9% {+/-} 9.1%) was significantly lower than that of peritumoral vessels at 5 mm (86.4% {+/-} 5.9%) and 20 mm (88.5% {+/-} 4.9%) from the tumor margin (two-sided P < .01). Conclusion PA imaging with a flat specimen holder enables noninvasive visualization of tumor-associated vasculature with reduced oxygenation in primary breast cancer. This approach may provide a novel imaging platform for the early detection and functional assessment of breast cancer.

PurposeHigh dietary fibre intake has been linked to lower cancer risk, yet its role in prostate cancer treatment responses and radiotherapy tolerance remains unclear. We evaluated the effects of dietary fibres (inulin, pectin, {beta}-glucan) on prostate tumour growth, gut microbiota and intestinal response to ionising radiation (IR) in murine models. MethodsMale FVB and C57BL/6J mice were injected with murine Myc-CaP (FVB), RM-1 or DVL3 (C57BL/6J) prostate tumour cells and fed a low-fibre (0.2% cellulose) or high-fibre diet (10% inulin, pectin or {beta}-glucan). Some mice had tumour irradiation (6 Gy). Tumour volume, caecal weight and faecal microbiota relative abundance (by 16S rRNA gene sequencing) were analysed. Caecal contents fermentation acids were quantified by gas chromatography. The effects of dietary fibre on intestinal acute normal tissue toxicity post-irradiation (10-14 Gy) were assessed by intestinal crypt assay. ResultsInulin delayed average tumour growth in all models. Inulin and {beta}-glucan prolonged post-IR tumour control versus 0.2% cellulose (all p <0.05), in some but not all mice. Inulin, pectin and {beta}-glucan increased faecal acetate concentrations post-IR and mice demonstrated responder (R) vs non-responder (NR) phenotypes to diet/IR, associated with Bifidobacterium (inulin-R), Lactobacillus and Parasutterella (pectin-R) and Muribaculacaeae and Muribaculum ({beta}-glucan-R). High fibre-fed mice had enhanced intestinal crypt regeneration following 12 Gy compared to 0.2% cellulose-fed mice. ConclusionsHigh fibre diets slowed prostate tumour growth both alone and following 6 Gy IR, while protecting small intestines from radiation-induced injury. Effects may have been mediated via increased microbiota-driven metabolite production and enhanced epithelial regeneration, but more mechanistic work is required to explore causality. The differences in individual responses to various fibres should be investigated further, as this may have relevance to adopting dietary fibre supplementation strategies in human radiotherapy patients, and may reflect the recognised importance of an individuals baseline microbiota on dietary effects.

Background: Invasive fungal infection (IFI) is well recognised in children with acute leukaemia and allogeneic haematopoietic stem-cell transplantation but is poorly characterised in children with brain tumours. Children receiving intensive therapy for embryonal brain tumours (EBTs) have multiple potential risk exposures including corticosteroids, central venous access, neurosurgical devices, mucosal injury and myelosuppressive chemotherapy with, in selected protocols, autologous stem-cell rescue. Methods: We performed a single-centre retrospective cohort study of children aged 0-18 years treated for EBTs between 2015-2025. IFIs were classified as proven, probable, possible, or modified possible using EORTC/MSGERC and TERIFIC criteria. Clinical characteristics, treatment exposures, timing, microbiology and outcomes were described. IFI prevalence was calculated using exact binomial confidence intervals. Exploratory Cox proportional hazards analyses assessed associations with clinical and treatment factors. Results: Seventy-seven patients were included. Fourteen patients experienced 15 IFI episodes, giving a patient-level IFI prevalence of 18.2% (95% CI, 10.3-28.6%). Proven or probable IFI occurred in seven patients (9.1%; 95% CI, 3.7-17.8%). Nine episodes had microbiological evidence. Non-mould pathogens predominated, accounting for six of nine identified pathogens. Treatment on ACNS0334/ACNS0333 was associated with a lower hazard of proven/probable IFI compared with SJMB12 (HR 0.062; 95% CI, 0.002-0.78; p=0.031). Two patients had chemotherapy delays exceeding one month, one had persistent infection at 12 months; no deaths were directly attributed to IFI. Three patients received antifungal prophylaxis. Conclusion: Rates of IFI following intensive embryonal brain tumour therapy were comparable to those in other high-risk oncology populations. Local consideration of antifungal prophylaxis is warranted.

BACKGROUND AND PURPOSE: ROAM/EORTC-1308 is an international (Europe and Australasia) phase III randomised controlled trial (RCT) comparing radiotherapy (60Gy/30#) to observation after surgery for atypical meningioma. The treatment plans of all the patients randomised to radiotherapy were reviewed and approved prior to treatment delivery, either by the UK RTTQA group (European sites) or the Australian TROG (Australia and New Zealand). Pretrial credentialling included outlining and planning a benchmark case (DR). MATERIALS AND METHODS: Variations from the guidelines were noted in quality assurance (QA) reports both for DR and for the on-trial Individual Case Reviews (ICRs) and classed as major or minor. After recruitment had finished, a random 10% of the ICRs were independently reviewed for audit purposes. We used the QA reports to analyse the variations in the DR and in the ICRs RESULTS: 56 sites (20 UK, 25 EORTC, 11 TROG) undertook the DR of which 13 (23%) had major variations. During the trial 64 patients at 28 sites received radiotherapy, the median being 2 patients per site. Overall, 25 (39%) patient cases needed resubmitting: 22 (36%) sets of outlines (2 cases twice) and 12 (14%) treatment plans (1 plan twice). CONCLUSIONS: For complex radiotherapy of rare tumours, a DR is insufficient and prospective ICRs of all patients is required. The consistent high-quality radiotherapy in ROAM/EORTC1308 ensures the primary outcome (progression free survival) will be a robust assessment and any difference between treatment arms cannot be attributed to variation in radiotherapy treatment.

Objective: Tumor protein D52 (TPD52) is aberrantly expressed in various malignancies; however, its systematic expression profile, prognostic significance, tumor microenvironment associations, and functional mechanisms in breast cancer remain poorly defined. Methods: GEO and TCGA breast cancer expression datasets were integrated to identify differentially expressed genes (DEGs). We evaluated the diagnostic performance of TPD52 via protein-protein interaction (PPI) network analysis, GO/KEGG enrichment analysis and eleven machine learning algorithms. Immunohistochemistry verified TPD52 protein expression in clinical specimens, and Kaplan-Meier analysis assessed its prognostic significance. Analysis of single-cell transcriptomic data (GSE176078) revealed the cell-type-specific distribution of TPD52 and its intercellular communication network in the breast cancer microenvironment. Weighted gene co-expression network analysis (WGCNA) explored relationships between TPD52 and tumor microbiome, hypoxia signatures as well as microsatellite instability. Moreover, TPD52 was knocked down by siRNA in MCF7 cells, and its impacts on cell migration, invasion, proliferation and the MAPK/ERK signaling pathway were examined through wound healing, Transwell, CCK-8 and Western blot assays. Results: TPD52 was significantly overexpressed in breast cancer tissues at both the mRNA and protein levels. A random forest-based diagnostic model demonstrated high accuracy across multiple datasets. Kaplan-Meier analysis revealed that elevated TPD52 expression was associated with longer overall survival in specific subgroups, including the basal-like subtype, invasive lobular carcinoma, and N0/N1 stages. Single-cell analysis showed that TPD52 was predominantly expressed in tumor epithelial cells, which occupied a central position within the intercellular communication network. WGCNA further identified a positive correlation between TPD52 and a hypoxia-associated microbial module, as well as a negative correlation with a microsatellite instability module. In vitro functional assays confirmed that TPD52 knockdown significantly suppressed the migration, invasion, and proliferation of MCF7 cells, and led to reduced p-ERK1/2 protein levels. Conclusion: TPD52 promotes the malignant phenotypes of breast cancer cells through activation of the MAPK/ERK signaling pathway, yet its prognostic significance is subtype- and microenvironment-dependent. These findings establish TPD52 as both a diagnostically valuable biomarker and a mechanistically defined potential therapeutic target.

Traditional animal models are often inbred and genetically uniform. This makes them powerful for controlled experiments, but it limits how well they represent the patient-to-patient variation seen in real-world disease. Comparative oncology seeks to address this gap by studying naturally occurring cancers in outbred companion animals, especially dogs. Canine medicine offers two important advantages: first, prospective trials can often be completed faster than in humans and second, dogs are already part of the translational pipeline through pharmacokinetic and toxicology studies. Here, we assessed the transcriptional fidelity of human and canine invasive urothelial carcinoma in primary tumors and patient-derived organoids. We then used single-cell and spatial data to resolve the underlying cellular organization. Despite strong species and platform differences, human and canine tumors preserved the same major luminal-basal structure and a similar tumor microenvironment. The two species reached this shared biology through different recurrent mutations. These included FGFR3 alterations in humans and BRAF alterations in dogs, which converged on overlapping pathways and a luminal phenotype. Human and canine organoids also underwent a similar shift in culture. Both became more proliferative and metabolic while losing inflammatory programs. Thus, organoids preserved important tumor biology while introducing predictable platform effects. Single-cell and spatial analyses showed that the luminal-basal axis reflects a gradient of cell states organized around the tumor-stroma boundary, rather than two discrete tumor types. This helps explain why bulk RNA-sequencing subtypes are reproducible but coarse. Together, these findings define where canine and human bladder cancer agree, where they differ, and how dogs can support parallel therapeutic and diagnostic development.