Targets

For patients with relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior lines of therapy, T-cell-redirecting therapies—including the bispecific CD3xCD20 antibody (BsAbs) mosunetuzumab (mosu) and chimeric antigen receptor T-cell (CAR-T) therapies such as axicabtagene ciloleucel (axi-cel), lisocabtagen maraleucel (liso-cel), and tisagenlecleucel (tisa-cel)—are approved by the FDA and EMA. Treatment selection should consider patient-related factors, prior therapeutic exposure, and toxicity profiles. We describe the 20-year history of a patient with R/R FL. At the fourth relapse, both BsAbs and CAR-T cells were available; however, due to the cumulative toxic burden and the high risk of cytopenias, mosu was selected as the preferred option. During mosu, the patient developed pure red cell aplasia unrelated to infections. Despite achieving a partial response after eight cycles of mosu, this complication led to the decision to proceed with allogeneic stem cell transplantation (allo-HSCT). The course was ultimately complicated by severe early toxicity with massive hemoptysis, acute respiratory failure, and hemorrhagic alveolitis, resulting in a fatal outcome. This case illustrates the delicate balance required in selecting between BsAbs and CAR-T therapy in R/R FL. Contributing factors to the patient’s fragility included profound immune status, transfusion-dependent red cell aplasia, prior cumulative chemotherapy, and pulmonary toxicity associated with conditioning regimens. The case underscores the importance of individualized treatment strategies and suggests that earlier integration of novel T-cell-redirecting therapies may mitigate cumulative toxicity and infection risk. Individualized therapeutic planning is critical in heavily pretreated R/R FL. In select cases, bridging strategies using BsAbs can provide disease control and facilitate transplantation. Still, careful assessment of patient fitness, marrow reserve, and cumulative toxicity is essential to minimize the risk of fatal complications.

In Norway, organized cervical cancer screening was cytology-based until 2023, and women screened in 2013–2015 were largely unvaccinated. We conducted a retrospective, population-based cohort study to assess whether co-testing with a 3-type HPV mRNA assay improves detection of high-grade cervical lesions in women < 40 years. Among 11,395 women screened in Northern Norway and followed for 8–10 years, 2807 formed a co-testing cohort (ThinPrep cytology plus PreTect SEE; HPV16/18/45) and 8588 formed a cytology-only cohort. The endpoint was histologically confirmed CIN2+. Sensitivity for CIN2+ was 63.7% with cytology alone and 71.0% with co-testing (absolute +7.3 percentage points; p = 0.034). In the co-testing cohort, HPV mRNA was detected in 10.2% of women, of whom 46.0% developed CIN2+, while CIN2+ risk in HPV mRNA-negative women was 5.2%. Co-testing produced wide risk gradients: CIN2+ risk was 58.3% in double-positive women (HPV mRNA-positive and ASC-US+) and 3.3% in double-negative women (HPV mRNA-negative and normal cytology), with no cervical cancers observed in the latter group. In this cytology-based, largely unvaccinated setting, co-testing with a 3-type HPV mRNA assay improved detection performance and long-term risk stratification in women < 40 years, supporting its use as a quality-assurance and triage tool within organized screening programs.

Aberrant activation of fibroblast growth factor receptor 1 (FGFR1) drives tumor progression in multiple cancer types, yet existing FGFR1 inhibitors suffer from suboptimal target selectivity and dose-limiting toxicities. This study describes an integrated computational approach for the identification of novel FGFR1 inhibitors. We established a computational pipeline incorporating ligand-based pharmacophore modeling, multi-tiered virtual screening with hierarchical docking (HTVS/SP/XP), and MM-GBSA binding energy calculations to evaluate interactions within the FGFR1 kinase domain. From an initial library of 9019 anticancer compounds, three hit compounds exhibited superior FGFR1 binding affinity compared to the reference ligand 4UT801. Scaffold hopping was performed to generate 5355 structural derivatives, among which candidate compounds 20357a–20357c showed improved bioavailability and reduced toxicity as predicted by absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. Molecular dynamics (MD) simulations validated stable binding modes and favorable interaction energies for these candidates. Collectively, our study identifies structurally novel FGFR1 inhibitors with optimized pharmacodynamic and safety profiles, thereby advancing targeted anticancer drug discovery.