Establishing the role of the human microbiome in patients with a presumed pancreatic or periampullary (pre)malignancy and pancreatic resection.

The human microbiome and its role in health and disease has recently received
rising attention. Studies show that the microbiome plays a role not only in the
cancer risk and carcinogenesis, but also in the susceptibility to therapy and
the course of the disease and treatment. [1, 2]
Growing evidence suggest that the effect of microbes also applies to
pancreatic and periampullary cancer, diseases with a very poor prognosis. There
is supportive evidence that the composition of the oral microbiota may play a
role in the etiology of pancreatic cancer [3] and can be used as a valuable
biomarker. [4, 5] Alternations in microbiome composition exist not only in
saliva, but also among several other body sites including gut and pancreatic
tissues in patients with pancreatic cancer compared to healthy populations. [6]
As for periampullary cancer, despite the smaller number of studies on the
subject, increasing evidence similarly points to a close link with the
microbiome. [7, 8] Similar to other types of cancer, the microbiome in patients
with pancreatic and periampullary cancer may also provide the opportunity to
enhance the effectiveness of chemotherapeutic agents and immunotherapies by
maintaining the right type of microbiota and by eliminating others with the use
of by dietary measures, administration of short-chain fatty acids, antibiotics,
pre- and/or probiotics or faeces transplantation. [9-11]
Tumor resection is currently the only potentially curative option for
pancreatic and periampullary cancer. Due to a rising incidence, extension of
resectability criteria and improved detection of (pre)malignancies, the number
of pancreatic resections is expected to increase. Pancreatic resection, in
particular pancreatoduodenectomy (PD), is a complex surgical procedure with a
high risk of complications (30% to 73%). [12, 13] Research shows that the gut
microbiome is central to postoperative complications after abdominal surgery,
in particular in colorectal cancer surgery. [14, 15] For pancreatic surgery
specific, microbial changes in the pre- or postoperative period were associated
with a higher risk for developing postoperative complications. [16-18] Besides
an increased risk of morbidity and mortality, postoperative complications can
also cause reduced quality of life and may lead to worse oncological outcomes.
[19, 20] Additionally, these changes could potentially be treated with already
available and relatively inexpensive strategies (e.g. probiotics, antibiotics
or feces transplantation), potentially improving the poor prognosis of these
patients.
Although these are important clues, previous studies were generally small,
produced contradictory results, lacked clear hypotheses and longitudinal
designs, and did not include all clinically important outcomes such as major
postoperative complications, as well as response to chemotherapy and survival.
Therefore, there remains a clear need for an adequately sized, longitudinal
study that investigate both the upper and lower gastrointestinal (GI) tract.

This study will provide insights into the role of gut microbes from the upper
(saliva) and/or lower GI (rectal/faecal) microbiota in the occurrence of
postoperative complications in patients with resectable pancreatic and
periampullary presumed (pre)malignancies. More specifically, the hypotheses
include, but are not limited to:

1. Patients at risk of severe complications after pancreatic surgery harbor
saliva and/or rectal/faecal microbiota profiles that are characterized by a
shift from mainly beneficial, non-inflammatory and non-invasive microbes (e.g.
Bacteroidetes and butyrate-producers) to a more dysbiotic profiles (e.g.
Gammaproteobacteria and Cocci).
2. Prior to the occurrence of the postoperative complication, there is a
domination/bloom of pathobiont(s) in the saliva and/or rectal/faecal
microbiomes.
3. The tumor microbiome is one of the sources of (infectious) complications
after pancreatic resection.
4. Translocation of GI bacteria can occur through various routes
(hematogenously, transductally or transperitoneal) to the site of the
postoperative complication.
5. Certain bacteria break down chemotherapy or enhance the effect. Therefore,
saliva and/or rectal/faecal microbiome compositions may determine the degree of
response to (neo-) adjuvant chemotherapy.
6. To what extent the saliva and/or rectal/faecal microbiomes recover
postoperatively affects the efficacy of adjuvant chemotherapy (and thus
survival).

The primary objective of this study is to classify patients that undergo
pancreatic resection into high and low risk groups for postoperative
complications (see study protocol 8.3 for definitions), based on longitudinal
saliva and/or rectal/faecal microbiome profiles.
Secondary objectives include, but are not limited to, finding associations
between saliva and/or rectal/faecal microbiome profiles and long term
oncological outcomes (i.e. site of recurrence, disease free survival, overall
survival), complications of neoadjuvant and/or adjuvant chemotherapy, response
to neoadjuvant chemotherapy as judged by computed tomography (CT) scan and
histological respons, complications associated with bile duct drainage and
postoperative endo- and exocrine insufficiency.

Prospective observational cohort study.
Monocenter study including 200 patients from the Regional Academic Cancer
Center Utrecht (RAKU).

There are no additional risks for patients participating in this study. At
most, patients may experience some discomfort (such as bruising after blood
sampling).

The burden on patients participating in the study is also minimal. Most
sampling times will be combined with an already scheduled hospital visit, with
the sampling itself taking a few minutes at most. A schedule for the collection
moments can be found in '8.3 Study procedures' of the study protocol.