Innovations in pancreatology

In paper I, we explored the presence and potential significance of intracystic pancreatic microbiomes in patients with suspected pancreatic cystic neoplasms (PCNs), who underwent pancreatic surgery. Paired samples of plasma and cyst fluid were gathered from 105 patients, and bacterial DNA was analyzed using quantitative polymerase chain reaction (qPCR) and PacBio sequencing. Levels of Interleukin (IL)-1β were also quantified. Results indicate significantly higher levels of intracystic bacterial DNA, IL-1β and lipopolysaccharide (LPS) in intraductal papillary mucinous neoplasms (IPMNs) with high-grade dysplasia (HGD) and IPMNs with invasive cancer compared to non-IPMN PCNs. While intracystic microbiota composition varied greatly among individuals, analyses revealed the co-existence and enrichment of bacterial taxa of the oral cavity, containing Granulicatella adiacens and Fusobacterium nucleatum, in IPMN with HGD. Increased levels of bacterial DNA within the cysts were correlated with prior exposure to endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) with biopsy, but independent of proton-pump inhibitor (PPI) and antibiotic usage. These findings emphasize the possible significance of oral microbiome in the development of precursors of pancreatic cancer and provide insights into their etiopathology and management. Further investigation is warranted.

In paper II, our investigation focused on cultivating pancreatic microbiome from PCNs with suspicion of invasive cancer, aiming to shed light on its potential importance in the initiation and progression of pancreatic cancer. Pancreatic cyst fluid samples acquired during surgery revealed culture positivity predominantly in the IPMN group of lesions. Within the bacteria isolates, Gammaproteobacteria and Bacilli were identified as dominant, using MALDI-TOF MS profiling analysis. Ex vivo co-culture models with pancreatic cell lines showed consistent pathogenic properties in cultivated bacteria, mainly Enterococcus faecalis, Klebsiella pneumoniae, and Granulicatella adiacens, including intracellular survival capability, induction of cell death, and genotoxic effects resembling double-stranded DNA breaks. These findings provide novel perspectives into the pancreatic microbiota’s potential involvement in the association between PCNs and cancer.

Paper III is a retrospective observational cohort study assessing the outcomes of total pancreatectomy with islet autotransplantation (TP-IAT). This study included patients operated between 2004 and 2020 at Karolinska University Hospital. We focused on the safety, morbidity, mortality, and function of the islet graft. A total of 24 patients were operated with TP-IAT, with the islet autotransplantation (IAT) site being either the liver or skeletal muscle of the forearm. The 90-day mortality was zero, and the major postoperative morbidities were primarily related to the total pancreatectomy procedure. Postoperative fasting C-peptide levels were detectable, with higher levels observed in patients in the liver-IAT subgroup. While insulin independence was not attained, patients in the liver-IAT subgroup required significantly lower insulin doses at the last follow-up compared muscle-IAT subgroup. TP-IAT appears safe with tolerable risks, but achieving insulin independence should not be anticipated, as the reported five-year insulin independence is 20%. The liver may be a superior site for islet autotransplantation compared to skeletal muscle.

Paper IV is a multicenter retrospective cohort study comparing the outcomes of surgery with or without neoadjuvant therapy (NAT) in patients with pancreatic cancer (PC) suspected of portal venous involvement. Data from 361 patients who underwent NAT and 690 patients who underwent upfront surgery (US) from nine centers between 2007 and 2017 were analyzed. Patients who received NAT had fewer venous resections and less venous infiltration, perineural invasion, angioinvasion, lymph node involvement, and R1 resections compared to those who underwent US. In patients undergoing venous resection, there were no significant differences in major postoperative complications and reoperations between the US and NAT groups. However, patients who received NAT without venous resection experienced fewer major complications, reoperations, and lower 90-day mortality compared to those who underwent US. Furthermore, NAT was associated with better overall survival. These findings suggest that NAT may improve patient selection for surgery and lead to fewer complications and better survival outcomes in PC patients with venous involvement.

List of scientific papers

I. Rogier Aäron Gaiser, Asif Halimi, Hassan Alkharaan, Liyan Lu, Haleh Davanian, Katie Healy, Luisa W Hugerth, Zeeshan Ateeb, Roberto Valente, Carlos Fernández Moro, Marco Del Chiaro, Margaret Sällberg Chen. Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer. Gut. 2019 Dec;68(12):2186- 2194. doi: 10.1136/gutjnl-2018-317458. Epub 2019 Mar 14.
https://doi.org/10.1136/gutjnl-2018-317458

II. Asif Halimi, Giorgio Gabarrini, Michał Jacek Sobkowiak, Zeeshan Ateeb, Haleh Davanian, Rogier Aäron Gaiser, Urban Arnelo, Roberto Valente, Alicia Y W Wong, Carlos Fernández Moro, Marco Del Chiaro, Volkan Özenci, Margaret Sällberg Chen. Isolation of pancreatic microbiota from cystic precursors of pancreatic cancer with intracellular growth and DNA damaging properties. Gut Microbes. 2021 Jan- Dec;13(1):1983101. doi: 10.1080/19490976.2021.1983101.
https://doi.org/10.1080/19490976.2021.1983101

III. Klara Fröberg, Asif Halimi, Miroslav Vujasinovic, José Caballero-Corbalan, Urban Arnelo, Ernesto Sparrelid, Olle Korsgren, Johannes-Matthias Löhr, Torbjörn Lundgren, Poya Ghorbani. Outcome after total pancreatectomy with islet autotransplantation: A European single-center study. Scand J Surg. 2023 Dec 25:14574969231220176. doi: 10.1177/14574969231220176.
https://doi.org/10.1177/14574969231220176

IV. Asif Halimi, Eline S. Zwart, Bengi S. Yilmaz, Benediktas Kurlinkus, Reea Ahola, Marco Del Chiaro, Ernesto Sparrelid, Elena Rangelova, Laura Maggino, Giuseppe Malleo, Gabriella Lionetto, Roberto Salvia, Keith J. Roberts, Francesco Giovinazzo, Massimo Falconi, Stefano Crippa, Giulio Belfiori, Geert Kazemier, Patrick Maisonneuve, Johanna Laukkarinen, Güralp O. Ceyhan. Neoadjuvant therapy is superior to upfront surgery for pancreatic cancer with venous involvement. [Manuscript]