Metabolic Phenotyping and Systems Biology in Surgery
A systems perspective can improve surgical decision making both before and after surgery in
real time. Specifically, we hypothesize that it may provide diagnostic and prognostic
information of importance that is more accurate than current biochemical approaches. This is
because it accounts for important environmental influences on surgical outcome such as
pharmacotherapy and the gut microbiota.
The secondary hypothesis is that this approach can provide real time molecular feedback to
the operator during surgery about tissue type and pathology.
This work will therefore need to study patients having surgery under a range of different
conditions and states, and by varying types of surgical intervention. It is known that
patients with cancer for example have quite different metabolic requirements to those
without. This has significant implications for the development of personalized management
strategies for patients with cancer undergoing surgery. It is essential that this study
definitively proves that the technology is able to make a description between patients with
significantly different disease states and also that it can differentiate this from the type
and magnitude of the surgical procedure being performed and the timing of the surgery.
Therefore, this work will involve a heterogeneous patient cohort.
This study will be subject to research governance structures provided internally within the
department of Biosurgery and Surgical technology in conjunction with the section of
Biomolecular medicine for the safe use of samples and machinery. It will also possess a
clinical steering committee to assess the progress, clinical outcomes, safety and timely
completion of the work.
Two separate clinical groups will be recruited for this trial. The first will be those
patients undergoing elective procedures, the second will be those undergoing emergency
procedures. Each of these groups will contain subcategories of clinical conditions, upon
which the study will focus.
Elective surgery (n=200):
A. Patients with cancer. This will include patients with malignancy of the gastrointestinal
and colorectal tract (including those excised by microsurgery) cancer of the breast or solid
tumors of the kidney.
B. Patients with benign diseases of the bowel requiring surgery e.g. inflammatory bowel
disease C. Benign surgical conditions, usually operated on in a day surgery setting. These
will specifically be of the biliary tree (gall stones) and the anterior abdominal wall (e.g.
Patients will be recruited if seen under the 'two week' wait rule with suspected cancer for
the general surgery, upper GI surgery, Breast and Urology surgery teams at St. Mary's
hospital in the outpatient setting.
Patients attending for elective inpatient surgery under the general, upper GI or breast
surgery teams at St. Mary's hospital, London will be recruited at the pre admission clinic.
Acute surgery (n=200)
Patients presenting to Accident and emergency under the care of the general surgery on call
team will be recruited into this study group. This study group will have the following
A. Acute abdominal pain, as per the previous ethical clearance B. Patients with acute sepsis
thought to be of surgical origin. C. Patients suffering major trauma with an Injury severity
score of >15, multiple injuries, who require surgery or who have >1 organ system that is
failed or who are admitted to the intensive care department.
All patients under the age of 18 years All patients who are pregnant Patients receiving
Advanced Life Support by cardiopulmonary resuscitation on their arrival in hospital.
Patients with advanced cancer only suitable for palliative care at presentation to the
Patients presenting for the first time with other known malignancies for which they are
receiving treatment e.g. Prostate cancer Patients already recruited into other clinical
This study will be broken down into two separate phases:
Preclinical work for biofluid analysis in elective and acute surgical admissions has already
been performed in both animal and human studies in Magic Angle Spinning (MAS)-1H NMR (also
known as solid state NMR as the tissue does not require preparation), MS, and Matrix
Assisted Laser Desorption Ionization (MALDI)-MS. Samples from previous studies gained under
ethical clearance will be analyzed using these techniques for methodological optimization.
This will entail metabonomic and metagenomic profiling of colorectal cancer samples (Ethics
Ref: 07/H0712/112 and 06/Q0403/16) and from samples taken from patients with acute
pancreatitis and the acute abdomen (Ethics Ref: 05/Q0403/201).
Non essential (i.e. Benign or pathologically normal tissue) excised and due for incineration
taken from consenting patients during routine surgery will be collected for analysis by:
Mass spectrometry of smoke plumes collected from a range of electrocautery devices. This
will allow optimization of MS protocols and it will define the chemical parameters for
normal tissue and for various tissue types.
b. Malignant tissue excised from breast, colon and upper GI cancers will be tested for its
capacity to detect normal and malignant disease by the use of the intelligent knife ex vivo.
This will be performed under the guidance of histopathologists, and it will not interfere
with pathological staging or treatment of cancers.
Development of translational software for analytical interpretation of complex biochemical
metadata by non scientific staff will be developed using these data. This work will use
current intensive care clinical databases.
The aim is for the technology to be readily applicable to patients having surgery within the
NHS. Therefore, patients will be recruited from two surgical pathways:
Acute Care: Patient recruitment
Patients will be recruited whilst in Accident and Emergency. Only patients admitted via this
route will be eligible for study inclusion. Patients will be provided with an information
sheet and the patient will be left for 30 minutes to consider the study. Consent will be
taken in private, by an adequately qualified and trained individual. When consented,
patients will be asked to complete a questionnaire to provide medical and surgical history,
and metabolic information that could influence results.
It will not be possible to gain consent in some cases as patients may be unconscious or
unable to consent due to injury. In these cases samples will be taken, and when the patient
gains consciousness and capacity formal consent will be taken. If at this stage, the patient
states they do not want to be included in the study their samples will be withdrawn. In the
event of a patient's death, the samples will be included in the study. This is because the
capacity of these tests to predict mortality is a primary end point.
Elective Care: Patient recruitment
Patients will be recruited in the outpatient setting where ever possible to ensure that they
have adequate time to take on board the clinical information and to consent. We will sample
patients on their admission to hospital for treatment after the decision for surgery has
Samples will be collected at set time points during the patient journey in both cases.
Samples will be obtained at the same time as standard clinical investigations to minimize
discomfort for the patient, and they will not be taken in excess of standard sample times
prevent unnecessary investigation for the patient. Sample collection will be coordinated
with the clinical biochemistry team at St. Mary's hospital where ever possible to prevent
unnecessary and time consuming sampling.
Plasma and urine collection:
1. At their arrival in Accident and Emergency. Every 24 hours for the duration of their
admission or until surgery, discharge or treatment defined as surgical, radiological or
invasive therapeutic intervention.
If the patient remains in hospital for prolonged rehabilitation or non surgical therapy,
samples will be taken weekly until discharge.
First bowel motion after arrival in A+E. Preoperative and pre bowel preparation sample
before surgery. This will be given either in clinic or on the ward.
Tissue sample collection
In the event that patients are sent for routine endoscopic or biopsy, samples of tissue will
be taken for metabonomic analysis.
Analysis of smoke plumes by MS will be performed for each case. This will not interfere with
the standard operation and the operating surgeon will not be asked to make a decision based
on the data from the experiment. In cases of cancer resections, tissue samples will be
collected in keeping within the principals of oncological surgery. In the cases of breast
surgery, sentinel lymph nodes will also be harvested and analyzed by NMR. During colorectal
surgery, tissue from the mesorectum will be taken for analysis from standard collection
points and in upper GI cancer resections, similar principals will apply for sampling. In
acute or emergency situations, tissue will also be taken from areas of tissue thought to be
at risk of ischemia (e.g. anastomotic sites were bowel is to be joined).
Stool and small bowel effluent will be harvested at the time of surgery so that the effect
of surgery on the gut microbial ecosystem can also be accounted for.
c. Post operative.
Urine and plasma will be sampled daily post operatively in keeping with current clinical
practice for the first week. Where ever possible, no extra samples will be collected beyond
those sampled by the clinical staff.
Stool samples will also be collected. The first bowel motion will be collected after
surgery, and then each motion until the first week is completed, and then weekly after this.
The first motion from stoma / ileostomy: If stoma sited, daily samples will be taken for the
Weekly samples will then be collected until discharge.
In the event that a patient returns to theatre, the sample collection sequence will re
All clinical data will be recorded for the duration of the patient stay. This will refer to
pre operative information and assessment where possible, physiological data, radiological
findings, clinical biochemistry, surgical and clinical outcome and length of stay. This will
be anonymous and coded.
On discharge, patients will be bought back to clinic at 8 weeks for clinical assessment as
per the routine analysis. Samples of urine, blood and stool will be taken at this time.
Oncological patients will be followed up for five years as per the oncology protocol at St.
Mary's Hospital Paddington.
Observational Model: Case Control, Time Perspective: Prospective
Daily sampling of patients during the post operative period to determine early biomarkers for the development of sepsis
Ara W Darzi, PC, KBE
Imperial College London
United Kingdom: National Research Ethics Committee