Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC. METHODS: Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality. RESULTS: In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1-) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation. CONCLUSION: Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors. TRIAL REGISTRATION NUMBER: NCT02562898.

Incidence and Recovery of Vocal Fold Immobility Following Pediatric Cardiac Operations.

BACKGROUND: Loss of laryngeal function after congenital cardiac surgery causes morbidity and prolongs hospitalization. Early diagnosis of vocal fold immobility (VFI) and referral to pediatric otolaryngology (pOTO) aids in laryngeal rehabilitation. Understanding the incidence and recovery rates of VFI enables counseling for families of infants undergoing high-risk surgery. METHODS: A retrospective chart review from November 2014 to July 2019 of infants postcardiac surgery where the aortic arch or surrounding structures were manipulated and were screened via flexible fiberoptic laryngoscopy (FFL) at a single institution was performed. Patients were divided into five surgical categories: Norwood procedure, aortic arch augmentation via median sternotomy, arterial switch operation, coarctation repair via lateral thoracotomy, and cardiac surgeries including ligation of a patent ductus arteriosus (PDA). Patients undergoing isolated PDA ligation were excluded. RESULTS: One hundred ninety-nine qualifying operations occurred during this period; 28 patients did not undergo FFL before discharge and were excluded from the analysis. Immediately following cardiac surgery, 34% (58 of 171 patients) had VFI. Follow-up was completed by 38 of 58 patients with VFI. Complete recovery was demonstrated in 63% (24 of 38) of patients by 6 months and in 86% (33 of 38) within 18 months. The highest risk occurred with the Norwood procedure and arch augmentation via median sternotomy. CONCLUSIONS: Infants undergoing surgery involving the aortic arch and surrounding structures have high rates of VFI. Follow-up by pOTO is recommended to optimize laryngeal rehabilitation. Most patients have spontaneous recovery within 18 months of cardiac surgery.