Oral Microbiota Mouth Off in Cystic Pancreatic Tumors

Article reposted from Genetic Engineering & Biotechnology News March 15, 2019.

Scientists at the Karolinska Institutet report that the presence of oral bacteria in cystic pancreatic tumors is associated with the severity of the tumor. The team, whose study (“Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer”) appears in Gut, hopes the results can help to improve the diagnosis and treatment of pancreatic cancer.

“Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can progress to invasive pancreatic cancer. Associations between oncogenesis and oral microbiome alterations have been reported. This study aims to investigate a potential intracystic pancreatic microbiome in a pancreatic cystic neoplasm (PCN) surgery patient cohort.

“Paired cyst fluid and plasma were collected at pancreatic surgery from patients with suspected PCN (n=105). Quantitative and qualitative assessment of bacterial DNA by qPCR, PacBio sequencing (n=35), and interleukin (IL)-1β quantification was performed. The data were correlated to diagnosis, lesion severity, and clinical and laboratory profile, including proton-pump inhibitor (PPI) usage and history of invasive endoscopy procedures,” the investigators wrote.

“Intracystic bacterial 16S DNA copy number and IL-1β protein quantity were significantly higher in IPMN with high-grade dysplasia and IPMN with cancer compared with non-IPMN PCNs. Despite high interpersonal variation of intracystic microbiota composition, bacterial network and linear discriminant analysis effect size analyses demonstrated co-occurrence and enrichment of oral bacterial taxa including Fusobacterium nucleatum and Granulicatella adiacens in cyst fluid from IPMN with high-grade dysplasia. The elevated intracystic bacterial DNA is associated with, but not limited to, prior exposure to invasive endoscopic procedures, and is independent from the use of PPI and antibiotics.

“Collectively, these findings warrant further investigation into the role of oral bacteria in cystic precursors to pancreatic cancer and have added values on the etiopathology as well as the management of pancreatic cysts.”

Pancreatic cancer is one of the most lethal cancers in the west. The disease is often discovered late, which means that in most cases the prognosis is poor. But not all pancreatic tumors are cancerous. For instance, there are cystic pancreatic tumors (pancreatic cysts), many of which are benign. A few can, however, become cancerous.

It is currently difficult to differentiate between these tumors. To rule out cancer, many patients therefore undergo surgery, which puts a strain both on the patient and on the healthcare services. Now, however, researchers at Karolinska Institutet have found that the presence of bacteria inside the cystic tumors is linked to how severe the tumor is.

“We find most bacteria at the stage where the cysts are starting to show signs of cancer,” said corresponding author Margaret Sällberg Chen, DDS, PhD, docent and senior lecturer at the department of dental medicine, Karolinska Institutet. “What we hope is that this can be used as a biomarker for the early identification of the cancerous cysts that need to be surgically removed to cure cancer, this will in turn also reduce the amount of unnecessary surgery of benignant tumors. But first, studies will be needed to corroborate our findings.”

The researchers examined the presence of bacterial DNA in fluid from pancreatic cysts in 105 patients and compared the type and severity of the tumors. Doing this they found that the fluid from the cysts with high-grade dysplasia and cancer contained much more bacterial DNA than that from benign cysts.

To identify the bacteria, the researchers sequenced the DNA of 35 of the samples that had high amounts of bacterial DNA. They found large variations in the bacterial composition between different individuals, but also a greater presence of certain oral bacteria in fluid and tissue from cysts with high-grade dysplasia and cancer.

“We were surprised to find oral bacteria in the pancreas, but it wasn’t totally unexpected,” said Sällberg Chen. “The bacteria we identified has already been shown in an earlier, smaller study to be higher in the saliva of patients with pancreatic cancer.”

The results can help to reappraise the role of bacteria in the development of pancreatic cysts, she noted. If further studies show that the bacteria actually affect the pathological process it could lead to new therapeutic strategies using antibacterial agents.

The researchers also studied different factors that could conceivably affect the amount of bacterial DNA in the tumor fluid. They found that the presence of bacterial DNA was higher in patients who had undergone invasive pancreas endoscopy, a procedure that involves the insertion of a flexible tube into the mouth to examine and treat pancreatic conditions thus the possible transfer of oral bacteria into the pancreas.

“The results were not completely unequivocal, so the endoscopy can’t be the whole answer to why the bacteria is there,” Sällberg Chen continued. “But maybe we can reduce the risk of transferring oral bacteria to the pancreas by rinsing the mouth with an antibacterial agent and ensuring good oral hygiene prior to examination. That would be an interesting clinical study.”

The Importance of Resection Margin Status in Pancreatic Surgery

The following study was recently published in the British Journal of Surgery and below is a summary of the article.

Validation of at least 1 mm as cutoff for resection margins for pancreatic adenocarcinoma of the body and tail.

Hank, T., Hinz, U., Tarantino, I., et al.

One of the major goals of surgical resection of a pancreatic tumor is to clear the body of all local disease. A resection margin is the outer edge of the tissue that was removed. The margins of the resected specimen are reviewed by the pathologists and should ideally be free of disease. Traditionally, R0 represents no cancer at the margins, while R1 represents microscopic disease at the margin, and R2 is representative of gross disease at the margins (seen by naked eye). In recent times, the topic of an R0 resection with disease located within 1mm of the margin has gained interest in the surgical community.

Using an institutional database, the authors identified 455 patients and classified resection status as either R0, R1 less than 1 mm, and R1 direct.

Median survival (time from surgery to death)

  • R0: 62.4 months
  • R1< 1mm from margin: 24.6 months
  • R1 direct: 17.2 months

Postoperative chemotherapy group median survival

  • R0: 68.6 months
  • R1< 1mm from margin: 32.8 months
  • R1 direct: 21.4 months

An important aspect of the study was that the authors not only analyzed the survival rates of all patients but also studied trends of survival in patients who received postoperative chemotherapy. Since postoperative chemotherapy is known to be related with survival, the authors wanted to demonstrate that margin status was independently associated with improved survival.

The results of the study confirm the importance of resection margin as they independently predicted survival in these patients regardless of their postoperative chemotherapy status. In particular, the survival benefit of clean resection margins beyond 1mm are highlighted. The differences observed in all reported median survivals were statistically significant.

Note: published data suggests that the same findings hold true for Whipple procedures. In short, R0 resections are associated with improved survival of all pancreatic adenocarcinomas, regardless of pancreatic surgery type.

You can read the entire article here.

Summary by: Michael J. Wright, Department of Surgery, Johns Hopkins School of Medicine