Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer.

BACKGROUND & AIMS: As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach. METHODS: We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level. RESULTS: We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition. CONCLUSIONS: Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC.

Perioperative Drug Treatment in Pancreatic Surgery-A Systematic Review and Meta-Analysis.

INTRODUCTION: Pancreatic resections for malignant or benign diseases are associated with major morbidity and changes in physiology. To reduce perioperative complications and enhance recovery, many types of perioperative medical management have been introduced. The aim of this study was to provide an evidence-based overview on the best perioperative drug treatment. METHODS: The electronic bibliographic databases Medline, Embase, CENTRAL, and Web of Science were systematically searched for randomized controlled trials (RCT) evaluating perioperative drug treatments in pancreatic surgery. The investigated drugs were somatostatin analogues, steroids, pancreatic enzyme replacement therapy (PERT), prokinetic therapy, antidiabetic drugs, and proton pump inhibitors (PPI). Targeted outcomes in each drug category were meta-analyzed. RESULTS: A total of 49 RCT were included. The analysis of somatostatin analogues showed a significantly lower incidence of postoperative pancreatic fistula (POPF) in the somatostatin group compared to the control group (OR 0.58, 95% CI: 0.45 to 0.74). The comparison of glucocorticoids versus placebo showed significantly less POPF in the glucocorticoid group (OR 0.22, 95% CI: 0.07 to 0.77). There was no significant difference in DGE when erythromycin was compared to placebo (OR 0.33, 95% CI: 0.08 to 1.30). The other investigated drug regimens could only be analyzed qualitatively. CONCLUSION: This systematic review provides a comprehensive overview on perioperative drug treatment in pancreatic surgery. Some often-prescribed perioperative drug treatments lack high quality evidence and further research is needed.

Enucleation for low-grade branch duct intraductal papillary mucinous neoplasms: Long-term follow-up.

BACKGROUND: Pancreatic enucleation allows resection of branch-duct intraductal papillary mucinous neoplasms with full parenchyma preservation. The aim of this study was to assess intraductal papillary mucinous neoplasms recurrence and functional outcomes during long-term follow-up after enucleation. METHODS: Patient characteristics, as well as radiologic and clinicopathologic follow-up data of patients who underwent enucleation for branch-duct intraductal papillary mucinous neoplasms between 2004 and 2014, were analyzed. Quality of life was assessed using the EORTC QLQ-C30 and QLQ-PAN26 questionnaires. RESULTS: Seventy-four patients underwent enucleation for low-grade branch-duct intraductal papillary mucinous neoplasms in 71 and high-grade branch-duct intraductal papillary mucinous neoplasms in 3 patients. Long-term follow-up data were available for 66 patients (89%; median follow-up: 87 months). Radiologic imaging (n = 56) showed intraductal papillary mucinous neoplasm recurrence in 10 patients (18%) including local recurrence at the site of enucleation in 3 patients (5%) and new onset intraductal papillary mucinous neoplasms manifestation in 7 patients (13%) at a distant site in the pancreatic remnant. Four patients (6%) underwent reoperation. Two of these patients had intraductal papillary mucinous neoplasm-associated carcinoma, one of them at the enucleation site. During the follow-up period, no intraductal papillary mucinous neoplasm-related deaths occurred and no new onsets of insulin-dependent diabetes mellitus were observed. QLQ-C30 revealed a global health status of 66.0% and overall functioning and symptom scores of 81.0% and 22.8%, respectively. Additionally, QLQ-PAN26 showed an overall symptom score of 26.5%. CONCLUSION: Enucleation is an organ-preserving surgical treatment option for low-grade branch-duct intraductal papillary mucinous neoplasms with low local recurrence risk and excellent functional long-term outcome. However, postoperative life-long follow-up must be performed as for any type of partial pancreatectomy for intraductal papillary mucinous neoplasms due to the risk of recurrence and potential malignancy.

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.