Search Results (1,558)

The growing number of breast cancer survivors is expected to increase the absolute number of locoregional recurrences requiring management, necessitating improvements in treating recurrences or tumours that occur within the initial radiation field (IFR). However, there are no guidelines on reirradiation (RT2) for breast cancer IFRs. We aimed to investigate locoregional practice patterns and outcomes. We retrospectively identified patients who received adjuvant RT1 for resected breast cancer and subsequently received curative-intent RT2 for IFRs at two large tertiary centres. A chart review obtained treatment, patient, and tumour characteristics. Descriptive statistics were calculated to characterize practice patterns, toxicity, and survival outcomes. Thirty-five patients met inclusion criteria across 18 years, with mean follow-up time of 43 months. Median time from RT1 to progression was 70.1 months. Most IFRs were in the breast or chest wall alone (48.6%). Regional nodal irradiation (RNI) was given in 23% of RT1 and 48.6% of RT2. Complete field overlap occurred in 60% of patients. Ten patients (28.6%) had a second recurrence (i.e., after RT2). Five-year OS was 65.4%, the median OS was not reached, and the mean OS was 73.7 months (95% CI 59.8–87.7 months). Freedom from recurrence (after RT2) was 71%. Shorter time to initial recurrence was associated with second recurrence (p = 0.018), and second recurrence was found to be predictive of death (p < 0.001). Four (11.4%) patients developed fibrosis, 75% of which developed after RT1. Eight (22.9%) patients developed lymphedema, 75% of which developed after RT1, all of which were documented as stable after RT2. Managing breast cancer IFRs with RT2 appears to be a feasible approach with reasonably consistent practice patterns in appropriately selected patients. Toxicity appears to be driven by the initial treatment course, and survival outcomes are acceptable. Full article

Circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) have emerged as promising non-invasive biomarkers for the immunotherapy response in advanced non-small cell lung cancer (NSCLC). However, their clinical utility remains uncertain due to variability in findings across studies. We conducted a systematic review and meta-analysis of studies from 2014 to 2024, assessing the predictive value of ctDNA and CTCs in advanced NSCLC patients receiving immunotherapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Forty-four studies were included (28 ctDNA, 16 CTC cohorts). High baseline ctDNA was associated with worse OS (pooled HR = 1.38, 95% CIs: 1.17–1.63), while baseline CTC detection predicted worse PFS (pooled HR of 3.65 (95% CIs: 1.58–8.41) and OS (pooled HR = 2.30, 95% CIs: 1.54–3.44). An on-treatment ctDNA decrease or clearance was associated with improved PFS (pooled HR = 0.34, 95% CIs: 0.25–0.47) and OS (pooled HR = 0.33, 95% CIs: 0.24–0.44). Evidence for other ctDNA- and CTC-derived biomarkers (blood tumour mutational burden, genomic alterations, dynamic CTC changes, and CTC PD-L1 expression) was limited or inconsistent. The interpretation of these findings is limited by heterogeneity in assay platforms, biomarker definitions, the analytical threshold, and sampling timepoints across studies. While ctDNA and CTCs show significant potential as predictive biomarkers in advanced NSCLC, further validation is needed in larger prospective studies using standardized assays. At present, ctDNA and CTC monitoring can complement but cannot replace radiological assessments in guiding immunotherapy decisions for NSCLC patients. Full article

Background: Neuroendocrine tumours (NETs) are heterogeneous neoplasms with several treatment options. Response rates, disease progression, and haematological toxicities can limit the use of some indicated treatments. Case Presentation: A 73-year-old woman with a well-differentiated grade 2 pancreatic NET (Ki-67 18%) underwent surgical resection and later developed hepatic recurrence. First-line treatment with sunitinib plus octreotide achieved temporary disease stabilisation. Upon progression, peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE was initiated, resulting in stable disease but complicated by grade 3 thrombocytopenia. Two years later, PRRT retreatment was performed due to disease progression, which led to grade 4 thrombocytopenia. Further treatments with capecitabine and everolimus were limited by progression and significant thrombocytopenia. Therapy was switched to streptozocin plus 5-fluorouracil, which resulted in recovery of platelet counts, absence of haematological toxicity, and a sustained radiologic response until March 2025, when she presented with hepatic progression. FOLFOX chemotherapy was initiated but discontinued after one cycle due to severe thrombocytopenia. Deterioration in general condition ultimately led to supportive care and death in March 2026. Conclusions: This case highlights the risk of cumulative haematological toxicity with PRRT, particularly in retreatment settings. Careful patient selection and close monitoring are essential. Streptozocin-based chemotherapy may be an effective and well-tolerated alternative for patients with treatment-limiting toxicity. Full article

Background: Extrachromosomal DNA (ecDNA) amplification represents a distinct mechanism of genomic instability in cancer, increasingly recognized for its role in aggressive disease progression. This review examines how ecDNA drives tumour evolution and assesses its potential as both a prognostic marker and therapeutic target. Methods: The authors integrate findings from multiple detection platforms—including FISH, whole-genome sequencing, and specialized reconstruction algorithms—and present data across diverse cancer types; no preregistration is noted, and no animal studies are included. Results: ecDNA consists of circular, acentric DNA elements carrying high-copy oncogene amplifications (such as EGFR, MYC, MDM2, and CDK4). Unlike chromosomal DNA, ecDNA segregates unevenly during cell division, generating intratumoral heterogeneity, accelerating adaptation to selective pressures, and promoting resistance to therapy. Pan-cancer surveys summarized here reveal ecDNA in a significant subset of tumours, with particularly high frequencies in liposarcoma, glioblastoma, and HER2-positive breast cancer, and consistent associations with worse clinical outcomes. Conclusions: The authors conclude that ecDNA amplification serves as a credible adverse prognostic indicator and holds promise for refining risk stratification and guiding treatment strategies. However, they stress that clinical adoption remains constrained by the absence of standardized, scalable, and reproducible detection. Full article

Central chondrosarcoma is the second most common primary malignant bone tumour, and grade progression markedly worsens prognosis. The contributions of lipid metabolic reprogramming and epigenetic co-dysregulation to grade progression remain poorly characterised. We integrated a bulk RNA-seq discovery cohort of 53 graded central chondrosarcomas (GSE299759) with a single-cell analysis of eight chondrosarcomas (GSE184118). Because the atypical cartilaginous tumour (ACT) and dedifferentiated groups each comprised only three samples, the Grade 3 versus Grade 2 contrast was pre-specified as the primary comparison. Curated panels of 44 lipid metabolism genes and 50 epigenetic regulators were assessed by differential expression and a correlation-based connectivity ranking, evaluated by permutation testing. In the primary Grade 3 versus Grade 2 comparison, SQLE, ACACA, and FASN were upregulated (FDR < 0.05), indicating a grade-associated increase in de novo lipogenesis. In the exploratory Grade 3 versus ACT comparison, additional lipid genes (HMGCR, LDLRAP1) and the epigenetic regulators EHMT2 and SIRT2 showed altered expression, although the small ACT group limits these estimates. A connectivity ranking highlighted FASN, KMT2C, TET2, SETD5, and KDM5B; permutation testing confirmed this co-expression structure was non-random (p < 0.0001). Single-cell analysis showed FASN, SETD5, and KDM5B are expressed predominantly in malignant cells, whereas KMT2C and TET2 are not, indicating cell-type heterogeneity. De novo lipogenesis upregulation is the most consistent lipid alteration in high-grade central chondrosarcoma, nominating SQLE, ACACA, and FASN as candidates for experimental investigation. Full article

Background/Objectives: While MRI is effective for glioma diagnosis, it has limitations in grading, treatment planning, and prognostication. Since hypoxia is associated with higher-grade gliomas and poorer outcomes, PET imaging with hypoxia-specific tracers has been shown to improve glioma assessment. This systematic review and meta-analysis aimed to evaluate the performance of hypoxia PET imaging in glioma diagnosis and prognostication. Methods: Systematic searches were conducted across PubMed, Web of Science, and Scopus through 31 January 2025. Only studies assessing the diagnostic or prognostic value of PET with ¹⁸F-labelled nitroimidazole (¹⁸F-FMISO, ¹⁸F-FAZA, ¹⁸F-FRP170, or ¹⁸F-FETNIM) or ⁶²Cu-labelled ATSM hypoxia tracers in patients with gliomas were included. Hierarchical models were used to evaluate pooled performance on differentiating glioblastoma from lower-grade gliomas. Results: Thirty-eight articles (n = 1156 patients) were eligible for inclusion, and eleven articles (n = 296 patients) were suitable for meta-analytical calculations. The extent of hypoxia on PET imaging was generally correlated with isocitrate dehydrogenase (IDH) mutation status and histological angiogenesis. Hypoxia PET was effective at differentiating glioblastoma from lower-grade gliomas and at predicting overall and progression-free survival. In a pooled analysis, ¹⁸F-FMISO PET displayed high sensitivity (98%) and specificity (94%) for differentiating glioblastoma from lower-grade gliomas. Conclusions: Hypoxia PET has the potential to predict tumour biology, and it may be a reliable modality in combination with MRI to provide complementary information for glioma diagnosis, grading, treatment planning, and prognostication. It may be particularly useful for ruling out glioblastoma in patients with otherwise equivocal imaging; however, this would need to be validated prospectively with standardized image acquisition and interpretation criteria. Full article

Durvalumab consolidation after definitive chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC) but real-world data comparing PD-L1-defined subgroups are limited. This retrospective single-centre study analyzed overall survival (OS) and progression-free survival (PFS) in 142 patients with inoperable stage III NSCLC with definitive CRT between 2015 and 2022. All tumours were assessed for PD-L1 expression, including retrospective testing, where required. Patients were assigned into three cohorts: PD-L1-positive with (PD-L1+mD; n = 57) and without (PD-L1+oD; n = 44) durvalumab maintenance and PD-L1-negative without durvalumab (PD-L1−oD; n = 41). Mean follow-up was 44.0 months. Median OS was 27.3, 15.1 and 23.4 months for PD-L1+mD, PD-L1+oD, and PD-L1−oD, respectively. Median PFS was 18.4, 10.5 and 13.4 months for PD-L1+mD, PD-L1+oD, and PD-L1−oD, respectively. OS and PFS were significantly improved with durvalumab in PD-L1-positive patients (p = 0.043 and p = 0.027). PD-L1-negative patients showed no significant OS or PFS differences versus PD-L1+oD. Immunotherapy-related pneumonitis ≥grade 1 was documented in 15.7% patients. In real-world practice, durvalumab improves OS and PFS in PD-L1-positive unresectable stage III NSCLC and its omission appears particularly unfavourable. Full article

Carcinoid heart disease is a progressive right-sided valvulopathy caused by serotonin and other vasoactive mediators released by metastatic neuroendocrine tumours. As oncological therapies have extended survival, cardiac disease has become a leading determinant of mortality. Operative mortality has decreased to 5–6% in contemporary high-volume centres, and long-term survival appears increasingly determined by tumour biology rather than cardiac disease when surgery is appropriately timed. The principal determinant of operative outcome is preoperative right ventricular function; symptom-based referral alone is insufficient because many patients remain compensated until ventricular dysfunction is advanced. This review synthesises the evidence on surgical timing, operative strategy, prosthesis selection, perioperative endocrine management, and emerging transcatheter options. Tricuspid valve replacement is required in the majority of patients, with concomitant pulmonary valve replacement advocated where concurrent disease is present. Bioprosthetic valves are preferred. Continuous perioperative octreotide infusion has substantially reduced the incidence of carcinoid crisis. Structured multidisciplinary decision-making integrating echocardiographic surveillance, biomarker monitoring, and oncological status assessment is essential. Full article

Chronic infection with the hepatitis C virus (HCV) is the most significant risk factor for the development of hepatocellular carcinoma (HCC). It has been shown that the progression of HCV-related liver disease is mediated by both viral and host-specific factors. The HCV replication cycle is a host-dependent process that relies on intracellular signalling pathways within target cells. Thus, intracellular signal transduction plays a pivotal role in the modification of interactions between the host and HCV. These pathways are key regulators of liver diseases, including cirrhosis and HCC. In addition, HCV induces epigenetic modifications in the host genome that inhibit the expression of various tumour-suppressor genes. Some of these changes persist even after successful antiviral treatment and represent a continued risk for HCC development. Despite significant progress in the management of chronic HCV infection, this challenge remains unresolved. In this narrative review, we summarise the mechanisms of HCV-induced disease progression, focusing on the host immune response, the regulatory roles of viral and cellular proteins, and viral survival strategies during chronic infection. We also discuss HCV-induced epigenetic alterations that contribute to hepatocarcinogenesis both during infection and after viral clearance. These insights are important for identifying novel, reliable molecular biomarkers for patient surveillance and for designing new therapeutic approaches. Full article

Isolated Locoregionally Recurrent Pancreatic Adenocarcinoma (ILRPA) accounts for 25–30% of recurrences after radical resection, yet the role of salvage radiation (RT) in this setting remains controversial due to limited data. We aimed to evaluate the impact of salvage RT on survival outcomes compared with non-salvage RT in patients with ILRPA. We retrospectively analyzed data of patients with ILRPA post-radical resection treated at our centre between 2012 and 2021. Patients were categorized into two cohorts based on whether salvage RT was administered post-recurrence. Patients who received a minimum of 30 Gy in 10 fractions (BED₁₀ ≥ 39 Gy) were included for analysis. The clinical characteristics, treatments, and outcomes were analyzed. The chi-square or Fisher’s exact test for categorical variables and Student’s t-test or Wilcoxon rank sum test for continuous variables were utilized for comparisons. The Kaplan–Meier method and log-rank test were performed to compare overall survival (OS) and progression-free survival (PFS) between the two groups. OS and PFS were calculated from the time of locoregional recurrence until event or loss of follow-up. Thirty-two patients were identified, with sixteen patients in each group. The patients and tumour characteristics were balanced between the two cohorts, except for chemotherapy, where the salvage RT group tended to receive palliative chemotherapy more than the non-salvage group (p = 0.007). The median radiotherapy dose received for the salvage RT cohort was 50.4 Gy (BED₁₀ = 59.5 Gy). Chemotherapy was restarted in 75% either before, after, or during radiation, and only in 31.25% of patients in the non-salvage group (p = 0.013). Patients who received salvage RT had statistically significantly better median OS and PFS than those who did not (25.2 vs. 8.4 months, p = 0.0006, HR 0.25, 95% CI (0.11–0.59)), (15.6 vs. 7.2 months, p = 0.0006, HR 0.26, 95% CI (0.11–0.58), respectively). Ten patients (62.5%) developed distant metastases (DM) at least 3 months post-recurrence in the salvage RT cohort compared to five patients (31.25%) in the non-salvage RT cohort (p = 0.08). In the salvage RT group, 10/16 patients (62.5%) maintained locoregional disease control post-RT. Salvage RT was associated with better OS and PFS in patients with ILRPA, highlighting its potential as an essential treatment modality. While salvage RT appears beneficial, confounding factors like chemotherapy disparities between groups necessitate further investigation in prospective cohorts. Full article

Myeloid malignancies encompass a heterogeneous group of haematological disorders, primarily including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MDS is characterised by defective myeloid cell maturation, while MPNs involve the pathological overproduction of myeloid lineage cells. In the absence of timely diagnosis and effective clinical intervention, both entities carry a substantial risk of progression to acute myeloid leukaemia (AML). Although allogeneic haematopoietic stem cell transplantation remains the only potentially curative therapy, its application is frequently constrained by patient-related factors such as advanced age and comorbid conditions. While currently, hypomethylating agent therapy (azacitidine and decitabine) is mainly used in high-risk MDS patients, and ruxolitinib is primarily used in symptomatic primary myelofibrosis (PMF-MPN), their clinical efficacy remains suboptimal. More recently, focus has turned toward the role of the tumour microenvironment (TME) in disease pathogenesis and whether therapeutically targeting the TME, either alone or in combination with conventional therapy, could present a new treatment option. Emerging evidence underscores the significant influence of TME components, particularly macrophages and T cells, in modulating immune responses and shaping the leukaemic niche to either facilitate or hinder malignant progression. In response, a new generation of immune checkpoint inhibitors are being developed to target the TME, including PD-1/CTLA-4 blockers, macrophage-directed agents including CD47 inhibitors, and T cell-targeting checkpoint inhibitors such as TIM-1 and LAG-3. This review will describe the functional role of key TME constituents in the progression of myeloid malignancies and explore the current landscape and future potential of advanced cellular and molecular immunotherapies in the treatment of these disorders. Full article

Single-cell RNA sequencing (scRNAseq) captures unique profiles of individual cells and uncovers cell-to-cell communication (CCC) through ligand–receptor (LR) interactions. Moreover, it reveals signalling mechanisms underlying cellular heterogeneity and complexity in downstream responses in healthy and disease states. In this work, we developed a composite computational pipeline to track CCC patterns in the tumour microenvironment (TME) during Multiple Myeloma (MM) progression as a case study. Three publicly available scRNAseq datasets were analysed using basic single-cell analytics and stage-specific CCC networks were reconstructed with CellChat, in a microenvironment-specific approach. Basic network analytics (CytoHubba) were performed to identify key cell nodes based on network topology metrics; differential network rewiring (DyNet) was performed to calculate rewired nodes. Follow-up analyses were conducted with NicheNet to investigate downstream responses and target genes influenced by CCC. Our network analyses highlighted dendritic cells (DCs), plasmacytoid DCs (pDCs), hematopoietic stem cells (HSCs), red pulp macrophages (RPMs), natural killer (NK) cells, and T and B cells as important cell nodes. Moreover, in neutrophils, the HLA-DRA–JUN–FOS was shown to play a key role in the progression of monoclonal gammopathies of uncertain significance (MGUS) to active MM by supporting cancer hallmarks and MM pathophysiology. To conclude, our work suggests an explanatory–computational pipeline that incorporates well-known frameworks in a hypothesis-driven scope, which leads to results relevant to the pathophysiology of MM. Full article

Background/Objectives: Accurate automatic segmentation of multimodal magnetic resonance imaging (MRI) is essential for neurosurgical planning and image-guided procedures. However, existing three-dimensional segmentation models often struggle with low lesion-to-tissue contrast, ambiguous tumor boundaries, small enhancing tumor regions, and performance degradation caused by missing imaging modalities. This study aimed to develop a robust segmentation framework that improves cross-modal representation learning, boundary recovery, and segmentation performance under incomplete-input conditions. Methods: We propose PF-CMNet, a Progressive Frequency-Aware Cross-Modal Network with Missing-Modality Distillation for three-dimensional brain tumor segmentation. The network introduces a Cross-Modal Selective Frequency Attention module in the early encoder stage to model modality-specific frequency responses and spatially adaptive cross-modal correlations. A Progressive Cross-Scale Detail Fusion decoder is further employed to aggregate multilevel semantic features and refine high-resolution boundary details. To enhance robustness under missing-modality conditions, a teacher–student distillation strategy transfers full-modality predictions and shallow feature knowledge to a student network trained with random modality dropout. Results: On the MSD Task01_BrainTumour dataset, PF-CMNet achieved an average Dice score of 84.3%, with Dice scores of 79.6%, 82.8%, and 90.4% for enhancing tumor, tumor core, and whole tumor, respectively. On the BraTS2021 dataset, the model achieved an average Dice score of 88.2% and the lowest average 95th percentile Hausdorff distance among the compared methods. In predefined complete-modality absence stress tests, where unavailable MRI sequences were zero-masked to model the absence of input modalities rather than partial image degradation, the distilled model maintained average Dice scores of 78.64%, 82.58%, 58.39%, 82.03%, and 79.29% when FLAIR, T1, T1ce, T2, and T1 + T2 were unavailable, respectively. Conclusions: PF-CMNet provides a unified framework for multimodal brain tumor segmentation, improving full-modality segmentation accuracy, boundary consistency, and robustness to incomplete MRI inputs while maintaining a favorable accuracy–efficiency trade-off. Full article

Background/Objectives: The tumour immune microenvironment (TIME) critically influences colorectal cancer (CRC) progression and therapeutic response, yet mechanisms shaping immune phenotypes remain unclear. Mucin-type O-glycosylation regulates tumour–immune interactions at the cell surface. Methods: We analysed O-glycosylation activity in 988 colorectal cancer (CRC) tumours derived from three independent cohorts: The Cancer Genome Atlas (TCGA-CRC, n = 534), the Clinical Proteomic Tumour Analysis Consortium (CPTAC2-CRC, n = 106), and the Sidra–Leiden University Medical Center (Sidra-LUMC, n = 348). O-glycosylation activity was quantified using a transcriptomic gene signature and single-sample gene set enrichment analysis (ssGSEA). Tumours were stratified into high and low O-glycosylation groups based on the median score, and associations with immune phenotypes, genomic alterations, and tumour functional states were assessed. Results: High O-glycosylation tumours exhibited an immune-desert phenotype with reduced immune-inflamed (p = 3.65 × 10⁻¹⁰) and immune-excluded (p = 0.0070) signatures alongside increased immune-desert scores (p = 0.0049) and reduced Siglec signalling (p = 8.14 × 10⁻⁵). O-glycosylation was associated with genomic stability, including lower TP53 mutation frequency (p = 0.0056), reduced aneuploidy (p = 0.0116), and decreased fraction of genome altered (p = 0.0309). High O-glycosylation tumours also showed upregulation of multidrug resistance programmes and reduced epithelial–mesenchymal transition (p = 0.0141) and proliferation (p = 0.0294). Conclusions: O-glycosylation defines a CRC subtype characterised by immune exclusion, genomic stability, and multidrug resistance, highlighting its potential as a biomarker and therapeutic target. Full article

Advanced gastric and gastroesophageal junction (gastric/GOJ) adenocarcinomas have poor outcomes, and the benefit of immune checkpoint inhibitors (CPIs) remains limited. Bavituximab is a phosphatidylserine-targeting monoclonal antibody that modulates the immune and vascular tumour microenvironment. This Phase 2, open-label, multinational study evaluated bavituximab plus pembrolizumab in previously treated advanced gastric/GOJ. Patients were stratified into CPI-naïve (n = 61) and CPI-relapse (n = 19) cohorts. Bavituximab (3 mg/kg weekly) was combined with pembrolizumab (200 mg every 3 weeks) until disease progression or unacceptable toxicity. Primary endpoints included the safety and objective response rate (ORR) per RECIST 1.1. Secondary endpoints included the disease control rate (DCR), progression-free survival, overall survival, and exploratory biomarker analyses using the Xerna TME Panel and the neutrophil-to-lymphocyte ratio (NLR). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were fatigue (32.5%), constipation (31.3%), and decreased appetite (31.3%). The ORR was 13.1% in CPI-naïve and 5.3% in CPI-relapse patients; the median duration of response was 12.5 months in the CPI-naïve cohort. The DCR was 39.3% and 52.6% respectively. Higher ORRs were observed in patients with immune-high (B+) subtypes (21.9%), NLR < 4 (17.9%) and B+/NLR < 4 (33%). Bavituximab plus pembrolizumab was well tolerated but showed modest activity, with greater benefit in biomarker-defined subgroups, supporting the biomarker-driven development of tumour microenvironment-targeting combinations in advanced gastric/GOJ adenocarcinomas. NCT04099641. Full article