We analysed reimbursement differences for prostate (PC), renal cell (RCC), and urothelial (UC) cancers drugs in Canada, France, England, Wales, Scotland, Spain, Italy, and Portugal, assessing substantial clinical benefit (SCB) and pivotal trials characteristics. This is a retrospective analysis of PC, RCC, and UC drug-indication pairs (2005-2024). Approvals were identified via FDA and EMA. Reimbursement recommendations were reviewed. Primary endpoint was reimbursement rate by SCB, tumour type, and country. Trial characteristics, overall survival (OS), and quality of life (QoL) were analysed. SCB was defined by ESMO-MCBS v1.1. Statistical significance set at p < .05. Fifty-five drug-indication pairs for PC (20), RCC (20), and UC (15) were analysed. Most trials were randomized, open-label, phase 3, and in the metastatic settings. Canada (PC: 85%, RCC: 75%, UC: 53%) and France (PC: 85%; RCC: 75%; UC: 33%) had highest reimbursement rates; while Portugal, lowest (PC: 65%; RCC: 50%; UC: 20%). Among SCB indications, PC reimbursement was highest in Canada, France, and Spain (91%), and lowest in England (64%). For RCC, was highest in Canada, France, and Italy (100%), and lowest in Portugal (57%). For UC, was highest in Canada (100%), and lowest in Wales and England (33%). OS was primary endpoint in 47% trials; QoL was assessed in 25%. OS benefit was observed in 53%; QoL in only 9%. This study reveals marked international variation in genitourinary cancer drug reimbursement, particularly in Europe and for UC-even for indications with SCB. Most trials lacked evidence of OS or QoL benefit.

Aneuploidy is prevalent across human cancers, yet its specific contributions to tumor evolution remain poorly understood. In this issue, Cross, Nowinski, Cresswell, Mossner, and colleagues present a longitudinal analysis of 755 samples from 167 patients with colorectal cancer, uncovering the temporal dynamics of karyotype evolution in this tumor type. See related article by Cross et al., p. 218.

ABSTRACT Introduction Endoglin has been extensively studied as an anti-angiogenic target, with preclinical work highlighting its critical role in tumor vasculature. TRC105 (carotuximab), a monoclonal antibody against endoglin, progressed through multiple clinical trials and was well tolerated, yet outcomes were disappointing, revealing a gap between preclinical findings and patient benefit. Recent insights into endoglin biology in the tumor microenvironment suggest that more precise, informed strategies are needed to fully realize its therapeutic potential. Areas covered This review summarizes key advances in endoglin biology, including its endothelial and non-endothelial roles and context-dependent effects across tumor and stromal compartments. We discuss preclinical therapeutic strategies and clinical trial experience with TRC105 and examine the translational challenges and future considerations needed to achieve potential clinical benefit. Expert opinion Preclinical studies have greatly advanced our understanding of endoglin biology, but the key challenge lies in identifying the biologic context where endoglin drives tumor progression. Future progress requires a deeper mechanistic resolution of endoglin’s roles across tumor type and disease stage, along with the development of biomarkers incorporating spatial expression patterns. Successful translation will depend on matching endoglin-targeted therapy to patients and tumor ecosystems most likely to benefit, shifting from broad anti-angiogenic application to precision stromal targeting.

Diffuse hemispheric glioma, H3 G34-mutant (DHG-H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high-resolution copy number profiling of a series of 60 DHG-H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187-gene mutation and fusion targeted neuro-oncology next-generation sequencing panel (n = 60) and Oncoscan chromosomal microarray (n = 26) by a single laboratory (2018-2022). A subset of cases had immunohistochemical results for OLIG2 (n = 42), p53 (n = 48), and ATRX (n = 46), and methylation array data (n = 8). Median age at testing was 21 years (range, 12-50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3-3A G34 mutations included G34R (n = 56; 94%), G34V (n = 3), and a non-canonical G34E (n = 1). Concurrent mutations most often involved TP53 (n = 55; 92%), ATRX (n = 50; 83%), and PDGFRA (n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy-neutral loss of heterozygosity (cnLOH) encompassing TP53. This copy number profile was reminiscent of that seen in Grade 4 IDH-mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high-resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG-H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH-a copy number abnormality that has been largely unrecognized-for this new 2021 World Health Organization central nervous system tumor type.

The imaging-based assessment of response to treatment is essential for treatment planning and outcome prediction in oncology. Standardized classification systems enable reproducible follow-up assessments and improve comparability in the clinical practice and research. Depending on the tumor type and treatment approach different evaluation criteria and imaging modalities are applied. Metabolic information plays acentral role in the assessment of hematological diseases and is gaining relevance in the assessment of solid tumors, which have previously been evaluated primarily based on their size. Additionally, the mechanism of action of the respective treatment should be considered, such as an expected size reduction after chemotherapy, altered contrast agent uptake after locoregional therapy or atypical response patterns, such as pseudoprogression after immunomodulatory therapy, which make repeated follow-up imaging mandatory. This article provides astructured overview of clinically relevant imaging-based response criteria and their specific applications.

Abstract Spinal metastases are a common complication of systemic malignancies, significantly affecting patients' quality of life and survival. This observational and retrospective study aims to evaluate the epidemiological characteristics of patients undergoing surgery for spinal metastases at A.C. Camargo Cancer Center, as well as their functional status up to 60 days postsurgery. Medical records of patients treated between March 2022 and August 2024 were analyzed, including variables such as age, sex, tumor type, pre- and postsurgical functional status, metastasis location, and the type of intervention performed. The outcomes analyzed include postsurgical functional status, hospital discharge rates, hospitalization periods, and mortality rates. The analysis was conducted using the Stata 13 (StataCorp LLC.) software with appropriate statistical tests. The results provide an updated overview of the clinical profile and functional outcomes of operated patients, helping optimize the management of spinal metastases.

Pheochromocytomas and paragangliomas (PPGL) are rare endocrine tumors with high heritability. Carriers of pathogenic variants (PVs) in susceptibility genes face a lifelong risk of recurrence or metastatic disease. Quality of life (QoL) in patients with PPGL, a history of PPGL and PV carriers, remains insufficiently studied. We assessed patient-reported QoL in patients with PPGL before and after surgery and in carriers of susceptibility PVs for the development of PPGLs within the prospective ProsPheo study. QoL was evaluated using standardized questionnaires (SF-12, PHQ-D, and GAD-7). A total of 202 participants were analyzed. SF-12 physical component summary scores (PCS) differed significantly across subgroups (P = .006), with the lowest PCS scores in patients with metastatic PPGL (40.3) and unresected head and neck paragangliomas (HNPGL) (40.0), compared with PV carriers after curative PPGL resection (50.2). Within metastatic disease, hormonally active tumors showed lower PCS scores than inactive tumors (36.9 vs 46.2; P = .03). Perceived physical health in carriers of a PV without history of a PPGL was significantly lower compared to the age-matched general population. Mental health was not significantly impaired across all subgroups. Clinically relevant anxiety was reported in 15.2% of PV carriers and 21.7% of patients with unresected HNPGLs, compared with about 5.9% in the general population. Patient-reported physical health was reduced in patients with metastatic PPGLs, unresected HNPGLs, and PV carriers without prior PPGL, whereas patients after curative PPGL resection reported QoL comparable to the general population, regardless of PV status, suggesting that annual follow-up has minimal impact on QoL.

Epstein-Barr virus (EBV) DNA in blood is associated with many diseases, though most often it is not linked to any disease. EBV DNA can be measured in whole blood, PBMCs, serum, or plasma. Using the most sensitive assays, viral DNA can be detected in PBMCs in nearly all individuals who have been infected. Among organ transplant recipients, higher EBV DNA copy numbers in PBMCs may reflect the degree of immunosuppression and could help guide pharmacologic management. In patients with EBV-PTLD, treatment with rituximab or other anti-B cell therapies typically eliminates measurable EBV DNA in PBMCs, even when the disease continues to progress-making further PBMC measurements of limited value. In other settings, such as HIV associated lymphoma, nasopharyngeal carcinoma (NPC), or Hodgkin lymphoma (HL), EBV DNA levels in PBMCs do not appear useful for diagnosis or monitoring. Measurement of viral DNA in cell-free (CF) DNA is fundamentally different from measurement in PBMC or whole blood, as EBV DNA is generally undetectable in CF DNA in most seropositive individuals without EBV associated disease. In NPC and HL, evidence suggests that CF EBV DNA typically originates from tumor cells and is not packaged in virions. Persistence of CF DNA correlates closely with residual tumor presence. In NPC and NK/T cell lymphoma (NK/TCL), CF DNA assays are now commonly used for tumor monitoring. This is not yet standard in EBV-positive HL but represents a promising area for further research. EBV DNA is also assayed in whole blood in many clinical settings. This approach can detect high copy numbers in both cellular and CF compartments with minimal processing, but it obscures compartment-specific differences. Studies of EBV DNA fragmentomics and methylation in plasma offer new insights into tumor presence and potentially tumor type.

Background: Gastric cancer remains one of the most common types of cancer and a major cause of cancerrelated deaths. It ranks as the fifth most frequently diagnosed cancer and the fourth leading cause of mortality worldwide. The Tumor Microenvironment (TME) consists of tumor cells, extracellular matrix, immune cells, cytokines, and other components. Among these, immune cells- particularly T lymphocytes- plays a crucial role as regulatory factors in TME. In particular, T lymphocytes, especially CD8+ Cytotoxic T Cells (CTLs) are recognized as key anti-tumor immune cells. The aim of the study was to evaluate the expression of CD8+ tumor infiltrating lymphocytes in gastric adenocarcinoma and their association with histological grade and pathological stage. Materials and methods: This cross-sectional observational study was conducted in the Department of Pathology, Sir Salimullah Medical College, Dhaka from March 2022 to February 2024. A total of 50 gastrectomy samples with a histologically confirmed diagnosis of gastric adenocarcinoma were included in this study. The expression of CD8+ in TILs were evaluated in formalin-fixed and paraffin embedded specimens by immunohistochemistry. The CD8+ TILs were categorized as positive and negative expressions. Histopathological results were analyzed and statistical analysis was done using Statistical Package for Social Science (version 26.0). Results: In this study showed that among 50 cases, 68% (n=34) were male and 32% (n=16) were female. The major tumor type, poorly differentiated type of adenocarcinoma reported was 38%. CD8+ intra tumoral and stromal TIL expression was positive in 33 (66%) and 35 (61%) cases respectively. A significant association was found between intra tumoral CD8+ TILs and histological tumor grade (p value=0.037) pathological stage (pvalue = 0.005) but no significant association was seen with nodal status (p value =0.759). Similarly, a significant association was observed between the stromal CD8+ TILs with histologic grades (p value= 0.012) and pathological stage (p value = 0.035) but not with nodal status (p value = 0.434). Conclusion: As part of tumor microenvironment CD8+ TIL influence the progression and differentiation of gastric adenocarcinoma. These expression levels can be utilized as indicators of biological behavior and prognosis as well as in therapeutic purpose of gastric adenocarcinoma. JCMCTA 2025 ; 36 (2) : 46-52

The HYAL1 paradox in cancer: From complex tumor biology to novel therapeutic strategies.

Same mutation, different fates: The Yin-Yang of BRAF-driven therapeutic responses in melanoma and colorectal cancer.

Single-cell sequencing analysis reveals CHURC1 as a non-canonical oncoprotein governing goblet cell-driven colorectal tumorigenesis.

GGH intronic variant rs3780130 is associated with methotrexate levels in children with brain tumors.

Integrative machine learning reveals hidden and emerging co-regulatory gene networks for multi-phase glioblastoma outcome prediction.

Enhancing nanomedicine efficacy in KPC pancreatic tumors through ketotifen-mediated tumor microenvironment remodeling.

Combining GLIM phenotypic criteria improves survival prediction in cancer-associated malnutrition.

Glioblastoma (GB) is the most aggressive type of brain tumor in adults, and the chemical agent temozolomide (TMZ) is widely used for its treatment. However, TMZ resistance can lead to therapeutic failure. The aim of this study was to investigate the effect of the bioflavonoid fisetin on GB cell growth and on overcoming TMZ resistance in TMZ-sensitive, inherited-resistant, and acquired-resistant GB cells the effect of fisetin on TMZ efficacy evaluin primary GB cells. GB cell lines (T98G; intrinsic TMZ-resistant, A172; TMZ-sensitive, A172-R; acquired TMZ-resistant) and primary GB cells derived from patient samples were treated with effective doses of TMZ (ranging from 900 to 1000 μM), fisetin (ranging from 13.78 to 16.40 μM), or a combination of both. TMZ resistance was acquired in A172 cells through stepwise increases in TMZ concentration. Real-time cell proliferation was measured using the xCELLigence system. The migratory capacity of the cells was evaluated using a wound-healing assay. The RNA expression of the epithelial-to-mesenchymal transition (EMT)-inducing transcription factor E-box-binding homeobox 1 (ZEB1) was assessed by quantitative polymerase chain reaction. Cell assays were analyzed by analysis of variance, and ZEB1 expression was analyzed by t-test. Fisetin substantially enhanced the effect of TMZ in all the cell lines included in the present study, as evidenced by significant decreases in cell proliferation and wound-healing, and in ZEB1 expression (p<0.0001). In addition, TMZ+fisetin reduced ZEB1 expression in primary GB tumors but not in butterfly GB cells. Fisetin alone was effective against GB; importantly, the TMZ+fisetin combination demonstrated greater efficacy than TMZ alone by enhancing sensitivity to TMZ through downregulation of ZEB1 in various resistant models, including patient-derived samples. Since ZEB1 is associated with EMT and drug resistance, fisetin may be a promising anticancer candidate to improve chemotherapeutic efficacy in resistant GB and to shed light on personalized treatments, pending further preclinical research.

Drug resistance, characterized by high heterogeneity and complex mechanisms, poses a significant challenge in cancer treatment. Stratifying resistant tumors into biologically and clinically meaningful subgroups can improve prognostic evaluation and help guide treatment decisions. However, the DNA methylation-based subtypes of resistant tumors have not yet been comprehensively characterized. DNA methylation profiles from resistant tumors were retrieved from public database including TCGA and GEO. For each tumor type resistant to a specific treatment drug, consensus clustering based on the most variable methylated probes was conducted to identify the DNA methylation subtypes of resistant tumors. For low-grade glioma (LGG) resistant to Temozolomide, consensus clustering of highly variable CpGs identified two subtypes: cancer resistance CpG island methylator phenotype-positive (CR_CIMP+) and -negative (CR_CIMP-). The CR_CIMP- subtype associates with poorer prognosis, reduced drug response, and more advanced histology, exhibiting higher tumor mutation burden and greater activity in drug resistance-related pathways, such as PI3K/AKT/mTOR signaling. CR_CIMP subtypes with distinct clinical or molecular features were also identified in pancreatic adenocarcinoma and bladder urothelial carcinoma resistant to Gemcitabine, as well as in non-small cell lung cancer resistant to anti-PD1/PD-L1 immunotherapy. Based on predicted drug responses, the study screens candidate drugs for each CR_CIMP subtype. Finally, a random forest model is proposed to predict CR_CIMP subtypes in LGG patients resistant to Temozolomide. This study uncovers DNA methylation subtypes within resistant tumors, enabling more precise stratification to inform prognosis and therapy selection.

To provide insight into the efficacy and safety of oncolytic viruses (OVs) in advanced malignancies. We reviewed 188 clinical trials, including 5410 patients. This review mainly summarized the clinical landscape of OVs, including the immune response, clinical response, and treatment-related adverse events (TRAEs). We found that the most common tumor type targeted was melanoma (1586/541029.3%) and most patients were treated with OVs monotherapy (2893/541053.5%) via intratumoral (2917/541054.4%) or intravenous (1686/541061.2) delivery. Sixty-eight (68/18836.2%) and 74 (74/18836.4%) studies evaluated the tumor microenvironment and systemic immune response, respectively. Importantly, an increase in tumor-specific cytotoxic T lymphocytes was reported in 15 (8.0%) trials. There were 103 (54.8%) and 13 (6.9) studies reporting humoral and cellular virus-specific immune responses, respectively. 129 (129/18868.6%) studies evaluated clinical efficacy in 3536 patients, with objective response and disease control of 870 (24.6%) and 2615 (59.1%), respectively. Subgroup analysis revealed an objective response in 522 (34.5%) and disease control in 953 (62.9%) of the 1514 patients in the herpes simplex virus (HSV) subgroup. The percentages of patients with objective response and disease control for different administration routes, including intratumoral (29.3%; 63.1%) and intravenous (18.1%; 52.8%) injections, and for different treatments including combination (31.8%; 65.1%) and monotherapy (17.3%; 55.1%), were summarized. Immunotherapy may be a promising combination therapy, with objective response and disease control occurring in high proportions of patients (35.9%; 59.9%). Moreover, OVs demonstrated a manageable safety profile, with most TRAEs being Grades 1-2. This study provides a general overview of the status of OVs clinical trials, but further research is needed to determine the optimal treatment regimen and combination strategy.

Immune checkpoint inhibitors (ICIs) achieve sufficient receptor occupancy at much lower than standard approved doses. We hypothesized that ultra-low-dose nivolumab would retain clinical efficacy. In this phase III randomized superiority trial, patients with advanced solid tumors (Eastern Cooperative Oncology Group 0-1) and progression on ≥1 prior line of systemic therapy were randomly assigned 1:1 to ultra-low-dose nivolumab (20 mg intravenously once every 2 weeks) or standard chemotherapy (docetaxel or paclitaxel, as per tumor type). Treatment continued until progression or intolerable toxicity. The primary end point was overall survival (OS). From June 2020 to February 2024, we enrolled 500 patients: 250 per arm; 52% had head and neck and 36% lung cancers. The median number of prior lines of therapy was 1 (range, 1-8); 29% had received ≥2 prior lines. Median OS was significantly longer with ultra-low-dose nivolumab: 5.88 months (95% CI, 4.99 to 7.13) versus 4.70 months (95% CI, 3.91 to 5.65; hazard ratio [HR], 0.80 [95% CI, 0.66 to 0.97]; P = .022). One-year OS was 27.3% versus 16.9%. Median progression-free survival was similar: 2.04 months (95% CI, 2.00 to 2.10) with ultra-low-dose nivolumab and 2.09 months (95% CI, 2.04 to 2.17) with chemotherapy (HR, 1.03 [95% CI, 0.86 to 1.23]; P = .77). Grade ≥3 treatment-related adverse events were less frequent with ultra-low-dose nivolumab (42.5% v 60.8%; P < .001). Quality of life (QoL) was significantly better with ultra-low-dose nivolumab. Ultra-low-dose nivolumab significantly improves OS versus chemotherapy in pretreated solid tumors, with fewer severe toxicities and better QoL. These findings support re-evaluation of ICI dosing strategies and may enhance global access.