Brief Summary

Pancreatic cancer (PC) is a solid malignancy with a dismal prognosis. It has a 5-year survival rate of approximately 8%. This is due to the usually late diagnosis, to chemoresistance, and to intrinsic biological aggressiveness. Risk factors for PC are smoking, alcohol, chronic pancreatitis, obesity, and diabetes. Recently, research has been dedicated to the identification of a causal connection between certain pathogenic microorganisms, especially of the oral flora, and PC. This would ultimately allow to identify new biomarkers to adopt for early diagnosis, or to create new strategies for prevention. Oral microbiota, periodontal disease and neoplastic risk When referring to "oral microbiota" (OM), about 700 hundreds bacterial species are mentioned, colonizing the oral cavity. A change in the normal flora of the oral cavity is commonly indicated with the term "dysbiosis". The causal connection between oral microbiota, periodontal disease and neoplastic risk is possibly triple. First, it has been found that oral flora substantially differentiates between cancer patients and controls. In particular, the most predominant phyla in cancer patients are Firmicutes and Actinobacteria, whereas Proteobacteria, Fusobacteria, and Bacteroides are more common in healthy controls. This highlights the possibility of a direct causal connection between dysbiosis and neoplastic risk. Second, oral dysbiosis represents the main risk factor of PD that per sé is a risk factor of many cancers. Third, the conditions leading to oral dysbiosis (alcohol, smoking, obesity, diabetes, chronic drugs intake, dietary habits, etc.) are the most well known risk factors either for cancer and oral dysbiosis. The common denominator is always represented by chronic inflammation and migration of microorganisms to distant sites, ultimately promoting neoplastic progression. This tangled net of causal connections sheds light on the potential important role of the oral cavity and PD as independent risk factors for many cancers, and as modifiable elements to reduce the neoplastic risk and to perform prevention(15). Oral microbiota, periodontal disease and pancreatic cancer In 2012, the pioneering study by Farrell et al. showed that bacteria of the OM can discriminate PC patients from healthy subjects. Since then, few other studies have shown that changes of the OM are independent risk factors for PC and that the OM of PC patients differs than controls. The involved bacterial species are many and their role seems to be contrasting on the basis of the study considered. Farrell et al. found that the combined adoption of Neisseria elongata and Streptococcus mitis distinguished PC patients from healthy controls (both showed low levels in PC patients, AUC of combined sensitivity 0.9), and that higher levels of Granulicatella adiacens and Streptococcus Mitis distinguished PC patients from chronic pancreatitis ones. Torres et al. found a higher ratio of Leptotrichia to Porphyromonas in PC patients. Fan et al. reported that Porphyromonas gingivalis, Prevotella intermedia, Alloprevotella and Aggregatibacter actinomycetemcomitans are associated with a higher risk of PC, whereas Fusobacteria and Leptotrichia were associated with a decreased risk. Another study evaluating the diversity of OM in three groups of individuals (PC patients, patients suffering from Intraductal papillary mucinous neoplasms \[a pancreatic preneoplastic condition\], and healthy controls), excluding current smokers and users of antibiotics, found no differences in the OM, although patients with PC had a higher proportion of Firmicutes compared with Intraductal Papillary Mucinous Neoplasms (IPMNs) and controls. Lastly, a recent study by Gaiser et al. showed that the cystic fluid of patients submitted to surgery for IPMNs contained bacterial species that are commonly found in the oral cavity, including, among the others, Granulicatella adiacens, Fusobacterium nucleatum. These two, in particular, were higher in the cohort of individuals with IPMNs with high-grade dysplasia, indicating a pivotal role in tumorigenesis(19). As regards PD, the first studies demonstrating an association between PD and PC date back to the mid of 2000's, and they were confirmed afterward, even adjusting confounders such as diabetes, pancreatitis, hyperlipemia, smoking or alcohol-related conditions. PD is strictly connected to oral hygiene, that seems to be associated to an increased risk of PC. It is now clear that PD can concur to development of PC in several ways, promoting chronic inflammation, spreading continuously to distant organs (including pancreas) pro-tumorigenic bacteria, or promoting a chronic alteration of the immune function that make the individual more prone to develop a cancer.

Trial Health

At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date

Enrollment

120

participants targeted

Target at P50-P75 for all trials

Timeline

Completed

Started Jul 2021

Typical duration for all trials

Geographic Reach

1 country

2 active sites

Status

unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

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Study Timeline

Key milestones and dates

2.4 years study duration

First Submitted

Initial submission to the registry

May 26, 2021

Completed

2 months until next milestone

Study Start

First participant enrolled

July 26, 2021

Completed

11 days until next milestone

First Posted

Study publicly available on registry

August 6, 2021

Completed

1.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

June 30, 2023

Completed

6 months until next milestone

Study Completion

Last participant's last visit for all outcomes

December 31, 2023

Completed

Last Updated

August 6, 2021

Status Verified

January 1, 2021

Enrollment Period

1.9 years

First QC Date

May 26, 2021

Last Update Submit

August 5, 2021

Conditions

Oral Microbiome Pancreatic Cancer IPMN Parodontopathy

Outcome Measures

Primary Outcomes (3)

Qualitative analysis of the dental plaque microbiome in patients with pancreatic cancer vs. healthy controls and IPMN patients
Whole-Genome Sequencing analysis
Baseline (At enrollment)
Correlation analysis between periodontal status and dental plaque microbiome
According to the periodontal status (appropriate scores will be used), patients will be divided into distinct groups. The proportional means of abundance of selected genera and species, and bacterial load (real-time data) between these groups will be analyzed using the Mann-Whitney U-test. Correlations between mean distributions of the genera and species and the parodontal status scores values will be analysed using the Spearman Correlation Coefficient.
Baseline (At enrollment)
Quantitative analysis of the dental plaque microbiome in patients with pancreatic cancer vs. healthy controls and IPMN patients
Whole-Genome Sequencing analysis
Baseline (At enrollment)

Secondary Outcomes (1)

Qualitative analysis of OM and periodontal status between the various stages of PC
Baseline (At enrollment)

Study Arms (5)

Pancreatic cancer patients - Explorative phase

Pancreatic cancer patients evaluated at the Pancreatic Surgery Unit of the Pancreas Institute of the University of Verona will be enrolled. Fifteen PC patients per stage will be selected (15 Stage I/II, Stage III, Stage IV). Patients may have been scheduled for surgery or for biopsy for future systemic treatments. An oral microbiota (dental plaque) sample will be collected and a periodontal and dental assessment will be performed, before any therapeutic procedure, together with orthopantomography