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Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer-CAF interaction.

Background: Cancer-associated fibroblasts (CAFs) are key players in the tumor microenvironment (TME) due to their abundance in most solid tumors and active crosstalk with cancer cells, and promote the initiation of tumor formation, tumor growth, angiogenesis, metastasis, and therapeutic resistance. In this study, we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). Experimental Design: We established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells using in vitro co-culture models, conditioned medium, and in vivo xenograft mouse models. Next, RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we then verified the biological activity of the identified molecule on NSCLC cells in vitro and in vivo mouse model. Results: Cancer cells showed enhanced cell proliferation, migration, and drug resistance by co-culture with CAFs or CAF-derived conditioned medium. RNA sequencing analysis revealed that CAFs showed higher expressions of POSTN, a matricellular protein, than NFs. Single-cell RNA sequencing data of NSCLC from public database confirmed that POSTN-positive fibroblasts were highly enriched in lung tumor tissues but rarely observed in normal lung tissues, suggesting CAF-specific POSTN expression in lung cancer. Recombinant POSTN increased cell proliferation via NSCLC cells’ ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for Osimertinib treatment. Conclusion: Our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN in TME could be a potential therapeutic strategy for NSCLC. Citation Format: Mao Yoshikawa, Fumiaki Takatsu, Ken Suzawa, Tomohiro Habu, Ohki Masayoshi, Kazuma Iwata, Naoki Matsuda, Yin Min Thu, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka. Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5845.

In survivors of head and neck cancer (HNC), second primary lung cancer (SPLC) often develop as a result of a common risk factor, that is, smoking. A multicenter experience was reviewed to evaluate how the history of a diagnosis of HNC affects the outcomes of patients undergoing pulmonary resection for SPLC.A multicenter retrospective analysis of patients hospitalized between January 2012 and December 2018 was performed. From a cohort of 4521 patients undergoing therapeutic pulmonary resection for primary non-small cell lung cancer, 100 patients with a previous history of HNC (HNC group) were identified. These patients were compared with a control group consisting of 200 patients without an HNC history from the same cohort pair-matched with operating facility, age, sex, and pathologic stage of lung cancer.At the time of surgery for SPLC, the HNC group showed malnutrition with a lower prognostic nutritional index compared with the control group (P.001). The HNC group was determined to have postoperative complications more frequently (P = .02). The 5-year overall survival rates in the HNC and control groups were 59.0% and 83.2%, respectively (P.001). Statistically, HNC history, lower prognostic nutritional index, squamous cell lung cancer, and TNM stage were identified to be independently associated with poor survival.Patients with SPLC after primary HNC often present with malnutrition and are predisposed to postoperative complications and poor survival after pulmonary resection.

Infective endocarditis (IE) demonstrates a broad array of clinical presentations and complications. However, IE with prominent abdominal findings is uncommon. We encountered a case of IE caused by Staphylococcus aureus that presented a large mesenteric abscess and was initially diagnosed as an intra-abdominal infection. There are few reports of IE with mesenteric abscess formation. Even if an intra-abdominal abscess is the main symptom, the possibility that it is part of a systemic infection should be considered if the causative organism is atypical or if symptoms are present in multiple organs. Physicians should always be aware of the possibility that IE may mimic other diseases, including intra-abdominal infections.

Little is known on the clinical effects of chloride on critically ill patients. We conducted this retrospective, observational study in 488 critically ill patients to investigate the incidence of chloride abnormalities, effects of hypochloremia in acid-base disorders, and association between chloride and clinical outcome. The study involved retrieval of arterial blood gas analyses, biochemical and demographical data from electrical records as well as quantitative acid-base analyses. For statistical analysis, the patients were stratified into three groups according to their chloride level (normal range: 98–106 mEq/L). The distribution of chloride levels was hyperchloremia 16.6%, normochloremia 74.6%, and hypochloremia 8.8%. The hypochloremic group was significantly alkalemic ( 𝑃 < 0 . 0 0 0 1 ) and has significantly higher apparent strong ion difference (SIDa) ( 𝑃 < 0 . 0 0 0 1 ) compared to the two other groups. The hypochloremic group had significantly longer stays in the ICU and hospital ( 𝑃 < 0 . 0 0 0 1 ) with higher mortality ( 𝑃 < 0 . 0 0 0 1 ). However, multiple regression analysis showed that chloride was not an independent factor of poorer outcome. In conclusion, the acid-base characteristics of the hypochloremic patients were alkalemia coexisting with higher SIDa. And although it was not an independent prognostic factor, hypochloremia was related to poorer outcome in critically ill settings.