Major Postoperative Complications Limit Adjuvant Therapy Administration in Patients Undergoing Pancreatoduodenectomy for Distal Cholangiocarcinoma or Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Guidelines for perioperative systemic therapy administration in patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma (PDAC) and distal cholangiocarcinoma (dCCA) are evolving. Decisions regarding adjuvant therapy are influenced by postoperative morbidity, which is common after pancreatoduodenectomy. We evaluated whether postoperative complications are associated with receipt of adjuvant therapy after pancreatoduodenectomy. METHODS: A retrospective analysis of patients undergoing pancreatoduodenectomy for PDAC or dCCA from 2015 to 2020 was conducted. Demographic, clinicopathologic, and postoperative variables were analyzed. RESULTS: Overall, 186 patients were included-145 with PDAC and 41 with dCCA. Postoperative complication rates were similar for both pathologies (61% and 66% for PDAC and dCCA, respectively). Major postoperative complications (MPCs), defined as Clavien-Dindo >3, occurred in 15% and 24% of PDAC and dCCA patients, respectively. Patients with MPCs received lower rates of adjuvant therapy administration, irrespective of primary tumor (PDAC: 21 vs. 72%, p = 0.008; dCCA: 20 vs. 58%, p = 0.065). Recurrence-free survival (RFS) was worse for patients with PDAC who experienced an MPC [8 months (interquartile range [IQR] 1-15) vs. 23 months (IQR 19-27), p < 0.001] or who did not receive any perioperative systemic therapy [11 months (IQR 7-15) vs. 23 months (IQR 18-29), p = 0.038]. In patients with dCCA, 1-year RFS was worse for patients who did not receive adjuvant therapy (55 vs. 77%, p = 0.038). CONCLUSION: Patients who underwent pancreatoduodenectomy for either PDAC or dCCA and who experienced an MPC had lower rates of adjuvant therapy and worse RFS, suggesting that clinicians adopt a standard neoadjuvant systemic therapy strategy in patients with PDAC. Our results propose a paradigm shift towards preoperative systemic therapy in patients with dCCA.

A spatially dynamic cohort of regulatory genes in the endomesodermal gene network of the sea urchin embryo.

A gene regulatory network subcircuit comprising the otx, wnt8, and blimp1 genes accounts for a moving torus of gene expression that sweeps concentrically across the vegetal domain of the sea urchin embryo. Here we confirm by mutation the inputs into the blimp1cis-regulatory module predicted by network analysis. Its essential design feature is that it includes both activation and autorepression sites. The wnt8 gene is functionally linked into the subcircuit in that cells receiving this ligand generate a beta-catenin/Tcf input required for blimp1 expression, while the wnt8 gene in turn requires a Blimp1 input. Their torus-like spatial expression patterns and gene regulatory analysis indicate that the genes even-skipped and hox11/13b are also entrained by this subcircuit. We verify the cis-regulatory inputs of even-skipped predicted by network analysis. These include activation by beta-catenin/Tcf and Blimp1, repression within the torus by Hox11/13b, and repression outside the torus by Tcf in the absence of Wnt8 signal input. Thus even-skipped and hox11/13b, along with blimp1 and wnt8, are members of a cohort of torus genes with similar regulatory inputs and similar, though slightly out-of-phase, expression patterns, which reflect differences in cis-regulatory design.