{"doi":"10.1093/oncolo/oyaf162","title":"A phase 0, window of opportunity study of parasympathetic stimulation with bethanechol in localized pancreatic adenocarcinoma prior to surgery","abstract":"BACKGROUND: The parasympathetic branch of the autonomic nervous system has shown tumor-suppressive effects in preclinical models of pancreatic adenocarcinoma (PDAC) by inhibiting cancer stem cells and suppressing inflammatory cytokine production. Based on these findings, we hypothesized that bethanechol, an FDA-approved parasympathomimetic agent targeting muscarinic receptors, could enhance treatment efficacy in PDAC. METHODS: We conducted a phase 0/window of opportunity study evaluating short-term parasympathetic activation with fixed dose bethanechol (100 mg twice daily) in subjects with resectable or borderline resectable PDAC prior to surgery. The primary endpoint was a change in cell proliferation by Ki-67 expression compared to stage-matched controls. Secondary endpoints included tissue expression of stem cell markers (CD44), infiltrating immune cells (CD8a, Granzyme B, and CD68), and changes in circulating inflammatory cytokine concentrations. RESULTS: Seventeen patients were enrolled with 13 eligible for analysis of endpoints. Median age was 74 (59-86), 6 female (46%), all ECOG 0-1, and median duration of treatment was 8 days (7-13). R0 resections were achieved in 9 patients (69%). There was no difference in Ki67 and CD44 tissue biomarkers between bethanechol-treated and control samples. Decreased numbers of Granzyme B-expressing cells were seen in bethanechol-treated tissues. Bethanechol treatment was associated with the suppression of circulating IL-18. The most common treatment-related adverse events (TRAE) were hot flashes (30.7%), urinary frequency (15.4%), increased salivation (15.4%), hyperhidrosis (7.7%), and nausea (7.7%). There were no Grade 3 or higher adverse effects. No surgical complications were attributed to bethanechol treatment. CONCLUSION: Bethanechol 100 mg twice daily is well tolerated in patients with PDAC in this small phase 0/window of opportunity study (NCT03572283). Bethanechol treatment was associated with decreased Granzyme B positive cells and decreased circulating IL-18 consistent with an anti-inflammatory role for parasympathetic muscarinic signaling in PDAC.","journal":"The Oncologist","year":2025,"id":525881,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1401419,"name":"Valeria Mezzano-Robinson","orcid":null,"position":1,"is_corresponding":false},{"id":1304800,"name":"Qiongyu Shi","orcid":null,"position":2,"is_corresponding":false},{"id":1401420,"name":"Nadine Kuriakose","orcid":null,"position":3,"is_corresponding":false},{"id":347520,"name":"Beth Schrope","orcid":"0000-0003-0313-8120","position":4,"is_corresponding":false},{"id":246238,"name":"Michael D. Kluger","orcid":"0000-0003-4311-078X","position":5,"is_corresponding":false},{"id":642062,"name":"Kazuki N. Sugahara","orcid":"0000-0002-4946-192X","position":6,"is_corresponding":false},{"id":70183,"name":"John A. Chabot","orcid":null,"position":7,"is_corresponding":false},{"id":322445,"name":"Gulam A. Manji","orcid":"0000-0001-9817-2414","position":8,"is_corresponding":false},{"id":347518,"name":"Paul E. Oberstein","orcid":"0000-0001-5918-6004","position":9,"is_corresponding":false},{"id":260144,"name":"Helen Remotti","orcid":"0000-0003-1555-9299","position":10,"is_corresponding":false},{"id":68288,"name":"Timothy C. Wang","orcid":"0000-0001-5730-3019","position":11,"is_corresponding":false},{"id":3641,"name":"Susan E. Bates","orcid":"0000-0001-6708-0330","position":12,"is_corresponding":false},{"id":260145,"name":"Ruth A. White","orcid":"0000-0002-4274-4468","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-19T02:50:25.860105Z","pmid":"40448309","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}