To study the progression of newly diagnosed breast cancer patients towards cardioembolic disorders (CDs) and ischaemic or structural heart disease (ISH) within a multistate framework that includes death as an absorbing state, in order to evaluate long-term cardiovascular burden and to examine whether the observed patterns may reflect short-term acute events or longer-term effects potentially associated with treatment. CD and ISH occurrences following breast cancer treatment may have different underlying biological mechanisms, potentially leading to different survival patterns across patient groups defined by breast cancer characteristics, and we sought to explore this.

Two continuous-time multistate Markov models described patients' transitions among three states: time of breast cancer diagnosis, first occurrence of CD or ISH, and death, depending on patients' molecular subtype, tumour stage, age and radiation treatment status.

Altogether 36 778 patients from the Norwegian Cancer Registry, linked with information on cardiovascular events from the Norwegian Patient Registry, diagnosed earliest in 2006, followed until their first cardiovascular event and/or death or throughout 2020.

HR-/HER2- patients had the highest HR for a first CD event compared with HR+/HER2- patients (HR 1.51, 95% CI 1.39 to 1.65), with no significant differences observed between the remaining groups. For first ISH event, HR-/HER2+, HR+/HER2+ and HR-/HER2- patients had HRs of 1.91 (95% CI 1.61 to 2.27), 1.64 (95% CI 1.43 to 1.88) and 1.56 (95% CI 1.44 to 1.69), respectively, compared with HR+/HER2- patients.

Long-term cardiovascular burden for patients with breast cancer may be more strongly influenced by chronic vascular and myocardial damage, likely driven by treatment-related cardiotoxicity and cumulative exposure compared with acute thromboembolic mechanisms. A multistate Markov modelling approach proved valuable for capturing the dynamics for patients to move between the states breast cancer diagnosis, CD or ISH event and death, and may guide more tailored follow-up and use of cardioprotective strategies.

Thymic neuroendocrine tumours (T-NETs) are rare, aggressive malignancies with distinct biology and poor outcomes. Current management is extrapolated from other neuroendocrine tumours (NETs), highlighting a critical need for a synthesised understanding of their unique molecular and immune landscape.

We conducted a comprehensive narrative review (2000-2026) of T-NETs, interrogating PubMed, Embase, Web of Science and Scopus. Focus was placed on clinicopathology, molecular alterations, tumour immune microenvironment and therapeutic outcomes.

T-NETs encompass a spectrum from well-differentiated carcinoids to high-grade carcinomas. Their molecular drivers are grade-specific, featuring TP53 (tumour protein p53)/RB1 (retinoblastoma 1) loss and chromosomal instability in high-grade tumours, alongside prevalent chromatin remodelling and PI3K (phosphatidylinositol 3-kinase)-mTOR (mechanistic target of rapamycin) dysregulation. The immune microenvironment is predominantly "inflamed", with heterogeneous PD-L1 (programmed death-ligand 1)/VISTA (V-domain Ig suppressor of T-cell activation) expression and T-cell infiltration that is often restrained by a myeloid-rich stroma. For clinical management, surgical resection is curative for localised disease. In advanced stages, therapy is extrapolated from other NETs and includes somatostatin analogues (for somatostatin receptor-positive tumours), everolimus, temozolomide-based regimens and, in selected cases, peptide receptor radionuclide therapy. Immunotherapy and novel combinations represent emerging investigational avenues.

T-NETs are biologically distinct thymic malignancies. Improved care will require thymus-specific molecular and immune profiling, standardised diagnostic criteria, and prospective collaborative studies to move beyond extrapolated treatment paradigms.

FLAURA2 demonstrated that adding chemotherapy to osimertinib improved overall survival compared with osimertinib monotherapy in metastatic epidermal growth factor receptor-mutated (EGFR-mut) non-small-cell lung cancer (NSCLC). Notably, only 60% of patients in the osimertinib monotherapy arm received second-line therapy after discontinuing first-line osimertinib. Aims We hypothesized that a higher proportion of patients on osimertinib monotherapy receive second-line therapy at academic medical centers in the United States (US).

This is a retrospective cohort study of 115 patients with metastatic EGFR-mut NSCLC treated with first-line osimertinib monotherapy at an academic medical center in the United States from February 2018 to July 2024. Analyses included Kaplan-Meier survival estimation, log-rank test, multivariate Cox regression, Wilcoxon rank-sum test, and Fisher's exact test. Most patients were female (74%) and had a history of never-smoking (69%); 50% were Asian, and 93% of patients had adenocarcinoma histology. The median time to treatment failure (TTF) for all patients on first-line osimertinib was 25.3 months (95% CI: 18.6-37.5). The median TTF was 15.7 months (CI: 13.1-22.0) for patients with TP53-mut disease and 42.2 months (CI: 36.9-NR) for patients with TP53 wild-type tumors (log-rank test, p < 0.001). Of the 115 total patients, 66 (57.4%) discontinued first-line osimertinib. Of these 66 patients, 26 (39.4%) either died or pursued hospice. Forty (60.6%) of the 66 patients experienced progression of disease and subsequently received second-line therapy.

Only 61% of patients with metastatic EGFR-mut NSCLC received second-line therapy after osimertinib at our institution, similar to the second-line therapy rates in the control arm of FLAURA2.

Anitocabtagene autoleucel (anito-cel), a B-cell maturation antigen (BCMA)-directed autologous chimeric antigen receptor (CAR) T-cell therapy with a synthetic d-domain binder (ddBCMA), may have efficacy in patients with relapsed or refractory multiple myeloma.

In a phase 1 study, we evaluated the safety and efficacy of anito-cel (dose level 1, 100×10⁶ CAR+ T cells; dose level 2, 300×10⁶ CAR+ T cells) in patients with relapsed or refractory multiple myeloma who had received three or more lines of therapy previously or had triple-class refractory disease. Primary end points were adverse events during the treatment period and establishment of the recommended phase 2 dose. In complementary in vitro studies, we compared the anito-cel ddBCMA binder with a dual variable heavy-chain domain of a heavy chain-only antibody (dual-VHH) binder corresponding to the published sequence for ciltacabtagene autoleucel.

Of 40 patients enrolled, 38 received anito-cel. All 38 patients had an adverse event during the treatment period, and 37 patients (97%) had an adverse event of grade 3 or higher. Among patients who received the recommended phase 2 dose (100×10⁶ CAR+ T cells), 94% had cytokine release syndrome of grade 1 or 2, with no events of grade 3 or higher. A total of 16% of the patients had immune effector cell-associated neurotoxicity syndrome (ICANS) of grade 1 or 2, and 1 patient (3%) had a grade 3 event. No non-ICANS or delayed neurotoxic effects occurred. At a median follow-up of 38.1 months, all 38 patients (100%) had had a response, with 79% having a complete response. The 24-month progression-free survival was 57%; the median progression-free survival was 30.2 months. The 36-month overall survival was 65%. The ddBCMA binder had a faster off-rate than the dual-VHH binder; although cytotoxicity was similar with the two therapies, ddBCMA CAR T cells led to less cytokine release and did not result in activation without antigen or in off-target cytotoxic effects.

Anito-cel therapy led to a high incidence of response among patients with heavily pretreated relapsed or refractory multiple myeloma. Cytokine release syndrome and ICANS of grade 3 or higher were rare. (Funded by Arcellx and Kite, a Gilead company; ClinicalTrials.gov number, NCT04155749.).

Wilms tumor is the most common renal malignancy in children. Survival rates now exceed 90% with multimodal therapy. This study aims to retrospectively analyze 104 pediatric Wilms tumor patients diagnosed over a 47-year period at our institution, examining demographic characteristics, tumor staging, treatment modalities, complications, recurrence rates, and survival outcomes.

This retrospective single-center study included 104 pediatric patients diagnosed with Wilms tumor between January 1, 1978, and January 31, 2025. Patients were stratified into early (1978-2005) and late (2006-2025) periods. Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional hazards regression.

The 5-year overall survival (OS) and event-free survival rates were 61.1% and 57.3% in the early era, 86.8% and 81.5% in the late era, and 73.6% and 65.8% in the overall cohort. OS was significantly lower in patients with anaplasia (p=0.035), advanced-stage disease (p=0.004), and in those treated in the early era (p=0.009). In multivariable analysis, treatment era and metastatic disease at diagnosis were independently associated with poorer survival, whereas anaplasia did not retain statistical significance after adjustment.

Survival outcomes improved substantially over time. Metastatic disease at diagnosis and treatment era were the strongest independent predictors of survival, while advanced stage and anaplasia were associated with outcome in univariable analyses.

Pediatric gliomas constitute the most prevalent central nervous system tumors in children, and aberrations in BRAF signaling contribute to their pathogenesis by disrupting the MAPK pathway. Targeted inhibition of this pathway using agents such as vemurafenib may hold therapeutic promise.

PNOC002 was a multicenter trial conducted through the Pediatric Neuro-Oncology Consortium in patients younger than 25 years with recurrent or progressive BRAF^V600E-mutant brain tumors. This combined phase 0/1 study aimed to establish the recommended phase II dose (RP2D) and assess preliminary efficacy, including tumor growth trajectories and rebound (defined as ≥25% increase in lesion size within 6 months, usually within 3 months, of stopping therapy).

Thirty-patients (range, 3-23 years) were treated at the RP2D of 550 mg/m² twice a day: 22 low-grade glioma (LGG) and 8 high-grade glioma (HGG). PFS at 6 months (PFS6) for the entire cohort was 80% (95% CI, 67 to 96). In patients with LGG, PFS6 was higher at 86% (95% CI, 73 to 100), compared with 63% (95% CI, 37 to 100) in patients with HGG. The best responses were stable disease (13 patients) and partial responses (13 patients). Four patients experienced PD, with three patients in the HGG cohort. Responsiveness varied by lesion type, with cystic lesions showing a larger and longer-lasting decrease in tumor size than solid lesions. Of 13 patients with LGG who discontinued treatment and had follow-up imaging, 3 (23%) experienced rebound within 78-97 days. The most common grade 3 adverse event was maculopapular rash (57%).

Vemurafenib showed efficacy in children with recurrent or progressive BRAF^V600E-mutant brain tumors with acceptable toxicity. However, the rebound rate of 23% warrants further investigation.

Preoperative chemoradiotherapy (CRT) can reshape the composition of the tumor immune microenvironment (TIME) in locally advanced rectal cancer (LARC), augmenting T-cell density and activation. As TIME may provide predictive insights, we analyzed the association of immune cell distribution and remodeling after CRT with pathologic response and clinical outcomes in patients with LARC derived from the STAR-01 (fluorouracil-based CRT plus/minus oxaliplatin) trial.

Tumor-infiltrating lymphocytes (TILs) were assessed by standard stains and immunostains (CD3, CD20, CD4, CD8, FOXP3, PD-1, and CD68). Immune cell populations in pretreatment biopsies and post-treatment surgical specimens were compared and associated with complete pathological response (ypT0N0) and overall (OS) and event-free (EFS) survival.

We retrieved 413 samples from 303 patients from the original cohort, including 110 paired pretreatment biopsies and post-treatment surgical tumor specimens. In pretreatment biopsies, CD20⁺ cell counts were associated with improved EFS (P = .051), independent of other prognostic factors. After therapy, intermediate-high TILs, CD3⁺ cells, low CD4⁺/CD8⁺ ratio, and CD68⁺ macrophage counts significantly increased, whereas FOXP3⁺ and CD20⁺ cells decreased. ypT0N0 was associated with low CD4⁺/CD8⁺ ratio (P < .001), reduced CD68⁺ (P = .001), and absence of eosinophils (P < .001) in post-treatment surgical specimens. In post-treatment specimens, low CD4⁺/CD8⁺ ratio and CD20⁺ cell counts were significantly associated with both improved EFS (CD4⁺/CD8⁺: P = .016; CD20⁺ cells: P = .002) and OS (CD4⁺/CD8⁺: P = .005; CD20⁺ cells: P = .014). This prognostic role was confirmed in a multivariable analysis for CD20⁺ cells.

In LARC, CRT reshapes the type and amount of immune cell contents, and the effects on certain immune populations are associated with tumor regression and clinical outcome.

To develop and validate a magnetic resonance fingerprinting (MRF)-based habitat imaging framework for noninvasively decoding intratumoral heterogeneity (ITH) and preoperatively predicting isocitrate dehydrogenase (IDH) mutation status in diffuse gliomas.

In this prospective study (January 2024-September 2025), 141 adults with diffuse gliomas (56 IDH-mutant, 85 IDH-wildtype) were enrolled. Tumors were segmented into three habitats via K-means clustering of coregistered MRF-derived T2 and free water maps. A habitat-based radiomic model for IDH status was developed in a training cohort (n = 98) and validated in an independent test cohort (n = 43). Its performance was compared against a conventional whole-tumor model using area under the curve (AUC) and net reclassification improvement (NRI). Pathophysiological validation was performed by correlating habitats with the Ki-67 proliferation index, dynamic contrast-enhanced magnetic resonance imaging (K^trans), and apparent diffusion coefficient (ADC). The prognostic value for progression-free survival (PFS) was also assessed.

The MRF-habitat model outperformed the whole-tumor model for IDH genotyping (test AUC, 0.819 v 0.758; NRI, 0.833, P = .003). It identified a prognostically significant subregion (Subregion1) where T2 uniformity was an independent predictor of PFS (hazard ratio: 0.008; P = .033). Subregion2, a hypoxic-angiogenic niche, correlated with Ki-67 and exhibited higher K^trans and lower ADC in IDH-wildtype tumors (both P < .05). Patients stratified as high-risk by the model had significantly shorter median PFS (5.8 months v not reached, P = .043).

The MRF-based habitat framework noninvasively decodes ITH, improves preoperative IDH genotyping, and identifies pathophysiologically distinct subregions with prognostic relevance.

This study was designed to evaluate the impact of preoperative renal function on survival after laparoscopic radical cystectomy (RC) with/without concomitant nephroureterectomy (RCNU) for urothelial carcinoma (UC).

This retrospective cohort study matched 36 patients undergoing RCNU for synchronous bladder and upper tract urothelial carcinoma 1:2 to 72 RC-alone controls. Perioperative outcomes, overall survival (OS), recurrence-free survival (RFS), and renal function (eGFR) were analyzed. Cox regression identified independent prognostic factors for OS.

Baseline characteristics were well-balanced. The RCNU group had a significantly lower median preoperative eGFR (47.9 vs. 77.5 mL/min/1.73 m², P = 0.003). Multivariable analysis identified preoperative eGFR <60 mL/min/1.73 m² (hazard ratio [HR] = 1.933, 95% confidence interval [CI] 1.067-3.503, P = 0.030) and lymph node metastasis (HR = 4.022, 95% CI 2.182-7.413, P < 0.001) as independent predictors of worse OS. Although RCNU was associated with worse OS in univariable analysis, it was not an independent prognostic factor after adjustment (P = 0.077). No significant difference in RFS was observed (P = 0.315). Sensitivity analysis after re-matching for baseline renal function confirmed that RCNU was no longer associated with OS (HR = 1.82, 95% CI 0.91-3.64, P = 0.092), whereas preoperative eGFR <60 remained a significant predictor (HR = 2.27, 95% CI 1.13-4.54, P = 0.021).

Preoperative renal impairment (eGFR < 60 mL/min/1.73 m²) is a primary independent determinant of poor survival in patients undergoing radical surgery for UC, surpassing the prognostic contribution of the surgical procedure itself. Lymph node metastasis represents another crucial independent prognostic factor. These findings highlight the imperative for comprehensive preoperative renal function assessment and renal preservation-oriented strategies in the management of UC.

Glioblastoma multiforme remains one of the most aggressive and lethal central nervous system malignancies, primarily due to the restrictive nature of the blood-brain barrier which severely limits the efficacy of systemically administered chemotherapeutics. To address this critical challenge, this study aims to overcome the limitations of conventional glioblastoma treatment by developing solid lipid nanoparticles (SLNs) co-loaded with temozolomide and carmustine for targeted intranasal administration. The developed SLNs were synthesized and comprehensively evaluated for biodistribution and pharmacokinetics in mice following nose-to-brain delivery. Drug concentrations in the brain and peripheral tissues were quantified using a robust and validated HPLC method. Therapeutic efficacy was further investigated in an in vivo glioblastoma model established by intracerebral U87MG cell implantation. Tumor progression was monitored via precise volume measurements and survival analysis, while the safety profile was assessed through comprehensive acute and subacute toxicity studies. Pharmacokinetic analysis confirmed effective brain tissue distribution and sustained drug levels. Furthermore, the dual-loaded SLN treatment demonstrated a significant reduction in tumor volume and remarkably extended survival rates compared to the control and conventional treatment groups. Ex vivo pathological evaluations and systemic toxicity studies indicated no mortality or gross organic damage at the tested doses, suggesting an acceptable systemic safety profile under the evaluated conditions. However, further rigorous evaluations regarding local nasal mucosal toxicity and long-term renal accumulation are required to fully establish the safety limits of this carrier system. Overall, intranasally administered SLNs provide a promising nanoparticle-based strategy that offers a viable, low-toxicity alternative to improve clinical outcomes in aggressive brain tumors.