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Progressive leptomeningeal metastases (LM) are associated with intractable neurological symptoms and a poor prognosis, and effective treatment options are limited. Intrathecal (IT) pemetrexed has been shown to confer clinical benefit in lung adenocarcinoma, yet our understanding of the efficacy and safety of the treatment is limited. We report a patient with a long-standing history of leptomeningeal disease due to ALK-positive adenocarcinoma of the lung, previously controlled by increased doses of lorlatinib (125 mg/day). Rapid LM progression prompted the start of IT pemetrexed, after which the patient experienced immediate clinical improvement. The case provides additional support that IT pemetrexed can offer symptomatic relief and may be considered as a treatment option in advanced LM. Furthermore, the case illustrates that an increased dose of lorlatinib may efficiently control LM in patients with ALK-rearranged NSCLC, following progression on standard lorlatinib dosage., Competing Interests: Declarations. Conflict of interest: HW: Clinical Trial Support to Institution from AstraZeneca/Medimmune, Bayer, BMS, Genentech/Roche, Helsinn, Merck, SeaGen, Xcovery. Advisory Board Participant: IOBiotech, Mirati, OncoC4. Unpaid Consultant Work: BMS, Genentech/Roche, Merck, AstraZeneca. The other authors declare no conflicts of interest., (© 2024. The Author(s).)

High-order interactions associated with non-small cell lung cancer (NSCLC) survival may elucidate underlying molecular mechanisms and identify potential therapeutic targets. Our previous work has identified a three-way interaction among pack-year of smoking (the number of packs of cigarettes smoked per day multiplied by the number of years the person has smoked) and two DNA methylation probes (cg05293407 TRIM27 and cg00060500 KIAA0226 ). However, whether a four-way interaction exists remains unclear. Therefore, we adopted a two-phase design to identify the four-way gene-smoking interactions by a hill-climbing strategy on the basis of the previously detected three-way interaction. One CpG probe, cg16658473 SHISA9 , was identified with FDR-q ≤ 0.05 in the discovery phase and P ≤ 0.05 in the validation phase. Meanwhile, the four-way interaction improved the discrimination ability for the prognostic prediction model, as indicated by the area under the receiver operating characteristic curve (AUC) for both 3- and 5-year survival. In summary, we identified a four-way interaction associated with NSCLC survival among pack-year of smoking, cg05293407 TRIM27 , cg00060500 KIAA0226 and g16658473 SHISA9 , providing novel insights into the complex mechanisms underlying NSCLC progression., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Histopathological diagnosis of pulmonary tumors is essential for treatment decisions. The distinction between primary lung adenocarcinoma and pulmonary metastasis from the gastrointestinal (GI) tract may be difficult. Therefore, we compared the diagnostic value of several immunohistochemical markers in pulmonary tumors. Tissue microarrays from 629 resected primary lung cancers and 422 resected pulmonary epithelial metastases from various sites (whereof 275 colorectal cancer) were investigated for the immunohistochemical expression of CDH17, GPA33, MUC2, MUC6, SATB2, and SMAD4, for comparison with CDX2, CK20, CK7, and TTF-1. The most sensitive markers for GI origin were GPA33 (positive in 98%, 60%, and 100% of pulmonary metastases from colorectal cancer, pancreatic cancer, and other GI adenocarcinomas, respectively), CDX2 (99/40/100%), and CDH17 (99/0/100%). In comparison, SATB2 and CK20 showed higher specificity, with expression in 5% and 10% of mucinous primary lung adenocarcinomas and both in 0% of TTF-1-negative non-mucinous primary lung adenocarcinomas (25-50% and 5-16%, respectively, for GPA33/CDX2/CDH17). MUC2 was negative in all primary lung cancers, but positive only in less than half of pulmonary metastases from mucinous adenocarcinomas from other organs. Combining six GI markers did not perfectly separate primary lung cancers from pulmonary metastases including subgroups such as mucinous adenocarcinomas or CK7-positive GI tract metastases. This comprehensive comparison suggests that CDH17, GPA33, and SATB2 may be used as equivalent alternatives to CDX2 and CK20. However, no single or combination of markers can categorically distinguish primary lung cancers from metastatic GI tract cancer., (© 2023. The Author(s).)