BACKGROUND:Primary pulmonary salivary gland-type tumors (PSGTs) are rare but clinically significant tumors that originate from the submucosal glands of the tracheobronchial tree. Cytologic samples taken during bronchoscopy are a key component of preoperative evaluation. However, cytologic diagnosis remains challenging because of the submucosal growth and morphologic overlap of PSGTs. In addition, current knowledge of the cytohistologic correlation of PSGTs is fragmented. The objective of this study was to assess the effectiveness of cytologic diagnoses of PSGTs. METHODS:A comprehensive, systematic literature search of the PubMed database was conducted to identify studies with cytologic and histologic diagnoses of PSGTs. Comprehensive data on diagnostic and clinical factors, when available, were collected for all individual patients. The data were tabulated in Microsoft Excel and analyzed using OpenMeta (Analyst) software. RESULTS:In total, 49 studies comprising 106 patients were identified. Final cytohistologic concordance was demonstrated in 48.1% of cases. Fine-needle aspiration showed the highest sensitivity (75.0%), followed by bronchial/tracheal washing (38.1%), and bronchial brushing (34.2%). Adenoid cystic carcinoma was the most common histologic subtype, accounting for 67 cases, followed by mucoepidermoid carcinoma, which accounted for 27 cases. CONCLUSIONS:The cytologic diagnosis of rare PSGTs remains challenging. Overall, cytohistologic concordance was 48.1%. However, fine-needle aspiration demonstrated greater diagnostic accuracy than exfoliative cytology and may facilitate a more accurate preoperative assessment.
BACKGROUND:This study aimed to evaluate Bladder EpiCheck (BE) performance in detecting urothelial carcinoma (UC) and HG (high-grade) events in patients with indeterminate cytology and negative cystoscopy. METHODS:This prospective study included 63 patients who presented with indeterminate urinary cytology and negative cystoscopy between October 2022 and April 2024. A repeated urine sample was obtained and analyzed via both urinary cytology and BE test. Patients were followed for 1 year. The diagnostic performance of each test was assessed. Logistic regression models were developed to estimate the risk of UC and HG events on the basis of repeated cytology and BE results. RESULTS:Thirty-two patients (51%) experienced a UC event, of which 25 (78%) were HG events. Sensitivity (SN) for detecting UC events was significantly higher (80% vs. 17%; p < .001) for BE compared to repeated urinary cytology, whereas repeated cytology demonstrated higher specificity (SP) (59% vs. 96%; p = .02). Similar SN differences were observed for HG disease (80% vs. 25%; p < .001). However, when suspicious for high-grade urothelial carcinoma was considered a positive cytology result, no statistically significant differences were observed between BE and repeated cytology in either SN or SP. A prognostic model combining repeated cytology and BE outperformed models using baseline cytology combined with either test alone in predicting UC and HG events. CONCLUSIONS:In patients with indeterminate urinary cytology and negative cystoscopy, BE provided complementary diagnostic information for the detection of UC events and HG disease. The combination of BE and repeated urinary cytology provided the most accurate risk assessment.
BACKGROUND:Precision oncology requires diagnostic sampling that delivers molecularly actionable material quickly and safely. In non-small cell lung cancer (NSCLC), core-needle biopsy (CNB) remains common. Yet fine-needle aspiration (FNA) has re-emerged with rapid on-site evaluation (ROSE), optimized cell blocks, and next-generation sequencing. The objective of this study was to compare the economic costs of FNA versus CNB with respect to an FNA-first with predefined CNB escalation strategy for NSCLC clinical pathways. METHOD:The authors synthesized evidence on diagnostic adequacy, complication rates, and molecular performance of cytology versus core tissue. A microcosting framework decomposed total diagnostic episode costs into sampling, processing, complications, and remedial procedures. This framework was applied to Sweden's Standardized Cancer Care Pathway for NSCLC using decision-tree modeling and sensitivity analyses. RESULTS:Modern cytology workflows with ROSE achieve a nondiagnostic sampling rate ≤6% and support programmed death-ligand 1 and broad next-generation sequencing with high mutation concordance to surgical specimens. Compared with CNB, FNA incurs fewer major complications and facilitates repeat sampling. In the Swedish illustration, an FNA-first pathway with ROSE reduced expected per-patient diagnostic cost by approximately 33% (7748 vs. 11,637 Swedish krona). The results were robust to ±50% variation in complication rates and ±5%-10% variation in adequacy. CONCLUSIONS:Reframing adequacy around molecular fitness and time to actionability supports FNA where ROSE exists, with codified, same-episode CNB escalation. This approach advances safety, capacity, and timeliness without compromising molecular yield. The authors provide a transferable cost-consequence model and implementation checklist for health systems. Local recalibration is required for absolute cost values, and multisite calibration is encouraged to establish generalizability across the different settings.
BACKGROUND:Cancer and stroke are major causes of morbidity and mortality, with an increasing shared burden. This study aimed to provide population-based estimates of ischemic stroke (IS) risk after cancer diagnosis across multiple cancer sites and demographic subgroups. METHODS:A retrospective cohort study was conducted linking the Israel National Cancer and Stroke Registries. Residents ≥40 years old diagnosed with first invasive cancer during 2014-2021 were followed for first-ever IS within 1 year. IS risk was assessed using standardized incidence ratios (SIRs) and analyzed by cancer site, time since diagnosis, cancer stage, and demographic subgroups. One-year cumulative incidence was estimated with death as a competing event. RESULTS:Among 182,221 patients, the SIR for IS within 1 year after cancer diagnosis was 1.8 (95% confidence interval [CI], 1.7-1.9). Risk peaked during the first 3 months (SIR, 2.5; 95% CI, 2.2-2.7). The highest SIRs were observed for pancreatic (SIR, 5.9; 95% CI, 4.8-7.3) and lung (SIR, 3.9; 95% CI, 3.4-4.4) cancers. SIRs decreased with age from 3.6 (95% CI, 2.8-4.6) among adults 40-54 years old to 1.4 (95% CI, 1.3-1.6) among those ≥75 years old. SIRs increased with stage, from 1.2 (95% CI, 1.0-1.4) in localized disease to 2.8 (95% CI, 2.5-3.2) in metastatic disease. One-year cumulative incidence of IS was 0.62%, ranging from 0.30% in breast cancer to 1.62% in pancreatic cancer. CONCLUSIONS:The early period after cancer diagnosis represents a critical window of increased IS risk. Incorporating targeted cerebrovascular risk assessment into oncologic care may facilitate earlier identification of high-risk subgroups and support tailored prevention strategies.
This news section offers Cancer readers timely information on events, public policy analysis, and topical issues. In this issue, the FDA approves a test that enables the identification of patients who are positive for ctDNA and can benefit from adjuvant atezolizumab after cystectomy. In addition, the HERMES trial supports a shortened stereotactic body radiation therapy schedule without added toxicity for patients with prostate cancer, and the FDA grants accelerated approval to BCL‐2 inhibitor sonrotoclax for mantle cell lymphoma.
Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.
BACKGROUND:The role of peri-operative radiation therapy in thymic epithelial tumors remains controversial, and randomized data are lacking. The authors evaluated recurrence patterns, pathologic predictors of recurrence, and long-term survival among patients who underwent surgery and received peri-operative radiation at a high-volume tertiary center. METHODS:The authors conducted a retrospective cohort study of patients who had thymic malignancies treated surgically between 2004 and 2021. Clinical, pathologic, and treatment data were collected. Outcomes were assessed using Kaplan-Meier and Cox regression methods, and propensity score overlap weighting was applied to adjust for baseline differences between the radiation and no-radiation groups. RESULTS:In total, 360 patients were included, of whom 175 (48.6%) received peri-operative radiation. Among irradiated patients, 62 (35.4%) developed recurrence, most commonly in the pleura (76%); in-field recurrences were rare (5%). Tumor invasiveness was the strongest predictor of recurrence, particularly vascular invasion (odds ratio, 6.0; 95% confidence interval, 2.3-15.7). Histologic subtype was not associated with recurrence. Survival did not differ between groups on unadjusted comparison (hazard ratio, 1.02; 95% confidence interval, 0.63-1.67; p = .93). After overlap weighting, radiation was associated with overall survival (hazard ratio, 0.49; 95% CI, 0.26-0.90; p = .02). CONCLUSIONS:In patients with surgically treated thymic malignancies, tumor invasiveness, especially vascular invasion, was the strongest predictor of recurrence and should guide risk stratification. Failure was predominantly pleural, with rare in-field recurrence, indicating good local control but a need for better strategies against pleural relapse. Survival benefit from peri-operative radiation remains uncertain and should be tested prospectively.
Metastatic heterogeneity has traditionally been explained by tumor-intrinsic evolution. A recent study by Peng-Winkler et al. challenges this paradigm by demonstrating that hepatic steatosis instructs colorectal cancer liver metastasis through fatty acid-dependent myelocytomatosis oncogene protein (MYC) activation. These findings identify host metabolism as an independent determinant of metastatic fate and suggest that precision oncology should extend beyond tumor genomics.
RNA-binding motif protein 15 (RBM15) is a key regulator of hematopoiesis and leukemogenesis, linking RNA metabolism, epitranscriptomic regulation, and lineage specification. Identified through the RBM15::MKL1 fusion in acute megakaryoblastic leukemia (AMKL), RBM15 functions within the N6-methyladenosine (m6A) writer complex, where its RNA-recognition motifs and Spen paralog and ortholog C-terminal domain enable site-specific methylation and protein recruitment. In hematopoietic stem and progenitor cells, RBM15 supports stem cell quiescence, self-renewal, and balanced lineage output, with additional roles in B cell, myeloid, and megakaryocytic differentiation. Mechanistically, RBM15 links m6A deposition to chromatin regulation, RNA export, and splicing. This review summarizes RBM15 structure, function, and regulation and highlights its emerging roles in leukemia, including AMKL and myelodysplastic syndromes, while outlining key questions for future studies.
G-protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a crucial immunotherapy target in relapsed/refractory multiple myeloma. Although the T-cell-engaging bispecific antibody talquetamab is currently the only approved anti-GPRC5D therapy, numerous promising agents are undergoing clinical evaluation. While anti-GPRC5D chimeric antigen receptor T cells show potential, this review focuses specifically on T-cell-engaging bispecific and trispecific antibodies. We highlight how GPRC5D differs clinically from B-cell maturation antigen, explore mechanisms of resistance, discuss novel therapeutic strategies including combination regimens and talquetamab as bridging therapy to chimeric antigen receptor T cells, and review key investigational T-cell engagers currently in development.
Hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer is the most common biologic subtype and carries a persistent risk of recurrence, particularly in patients with high-risk, early-stage disease. Cyclin-dependent kinase 4 and 6 inhibitors, initially established as a standard component of first-line therapy in the metastatic setting based on improvements in progression-free and overall survival, have since been evaluated in the adjuvant setting. While adjuvant palbociclib did not improve invasive disease-free survival, the monarchE and NATALEE trials demonstrated that abemaciclib and ribociclib, respectively, reduce recurrence risk in patients with high-risk, early-stage disease, with emerging overall survival data further supporting their use. However, the absolute magnitude of benefit varies substantially with baseline risk, and treatment-related toxicity and adherence challenges must be considered, as approximately 20% to 25% of patients discontinue therapy before completion. The integration of these agents into clinical practice also intersects with ongoing efforts to deescalate axillary surgery, as treatment eligibility has been largely defined by anatomic staging, particularly nodal status. Available data suggest that the incremental impact of axillary surgery on identifying candidates for cyclin-dependent kinase 4 and 6 inhibition is modest, especially among the favorable-risk populations now eligible for surgical deescalation. As the field evolves, advances in molecular risk stratification, genomic profiling, and dynamic biomarkers are poised to shift treatment selection from anatomic staging toward biologically driven approaches. Multidisciplinary decision-making that integrates tumor biology, anticipated absolute benefit, toxicity, patient preferences, and surgical considerations will be essential to ensure individualized care.
Tumors represent a heterogeneous set of neoplastic diseases, each composed of an intricate network of cancer cells residing in multiple alternative phenotypic states. Transitions between these phenotypic states, often termed 'phenotypic plasticity', enable them to execute specific steps in tumor progression and to develop therapeutic resistance. The phenotypic plasticity of tumor cells is mediated, in part, by cellular processes that orchestrate normal embryonic development and are hijacked by tumors. In this review, we discuss the contributions of these developmental programs to cancer cell phenotypic plasticity. We focus on epithelial-mesenchymal transition and ciliogenesis programs and discuss new insights into the mechanistic roles of these cellular processes in cancer progression and response to treatment.
Targeting transcription factor fusion-positive cancers has proven challenging for decades. In SARC037, Grohar et al. show that histology-specific dosing of trabectedin and low-dose irinotecan is active in advanced Ewing sarcoma and downregulates EWSR1::FLI1 activity.
Clinically impactful data from medical oncology, radiation oncology, and surgical oncology from this year are highlighted.
