Pilot Study: Can Ultrasound Guided Biopsy be Used as an Alternative to Hysteroscopy in the Detection of Endometrial Cancer?
Phase: NA
Conditions: Endometrial Cancer, Endometrial Neoplasms, Endometrial Hyperplasia, Endometrial Polyp
Sponsor: Imperial College London

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Application of advanced diagnostic tools in endometrial cancer 
 
 
 
 
Version 13 
 
 
 
MAIN SPONSOR: Imperial College London/Imperial College Healthcare NHS Trust (delete as 
applicable) 
FUNDERS:  
STUDY COORDINATION CENTRE: Hammersmith Hospital 
NRES reference: 210195 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Management Group 
 

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Chief Investigator: Miss Sadaf Ghaem-Maghami (gynaecological oncology consultant) 
 
Co-investigators: Mr Joseph Yazbek (gynaecological oncology consultant) 
Prof Zoltan Takats (Analytical Chemist and creator of iKnife) 
Prof Andrea Rockall (radiology consultant and visiting professor) 
Dr Nishat Bharwani (radiology consultant) 
Miss Diana Marcus (clinical research fellow) 
 
 
Clinical Queries 
 
Clinical queries should be directed to Dr Diana Marcus Clinical Research Fellow, who will 
direct the query to the appropriate person 
 
 
Sponsor 
 
Imperial College London is the main research Sponsor for this study.  For further information 
regarding the sponsorship conditions, please contact the Head of Regulatory Compliance at: 
 
 
 
Joint Research Compliance Office 
Imperial College London & Imperial College Healthcare NHS Trust 
2nd Floor Medical School Building 
St Mary’s Hospital 
Praed Street 
London 
W2 1NY 
Tel: 020759 41862 
 
 
Funder 
 
This protocol describes the aforementioned study and provides information about procedures for 
entering participants.  Every care was taken in its drafting, but corrections or amendments may be 
necessary. These will be circulated to investigators in the study.  Problems relating to this study 
should be referred, in the first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the NHS Research Governance Framework for 
Health and Social Care (2nd edition). It will be conducted in compliance with the protocol, the Data 
Protection Act and other regulatory requirements as appropriate.  
 
 
 

Appendix 2 JRO/SOP/012 
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Table of Contents 
1. INTRODUCTION 
6 
1.1 
BACKGROUND 
6 
2.  STUDY OBJECTIVES 
7 
3.  STUDY DESIGN 
8 
3.1 
STUDY OUTCOME MEASURES 
8 
3.1 
MAIN STUDY 
8 
4. 
PARTICIPANT ENTRY 
10 
4.1 
PRE-REGISTRATION EVALUATIONS 
10 
4.2 
INCLUSION CRITERIA 
10 
ALL WOMEN PRESENTING TO RAPID ACCESS GYNAECOLOGY CLINIC WITH POSTMENOPAUSAL 
BLEEDING OR INTERMENSTRUAL BLEEDING 
10 
4.3 
EXCLUSION CRITERIA 
10 
4.4 
WITHDRAWAL CRITERIA 
10 
5. 
ADVERSE EVENTS 
10 
5.1 
DEFINITIONS 
10 
5.3 
REPORTING PROCEDURES 
11 
6. 
ASSESSMENT AND FOLLOW-UP 
11 
7. 
STATISTICS AND DATA ANALYSIS 
11 
8. 
REGULATORY ISSUES 
12 
8.1 
ETHICS APPROVAL 
12 
8.2 
CONSENT 
12 
8.3 
CONFIDENTIALITY 
12 
8.4 
INDEMNITY 
12 
8.5 
SPONSOR 
12 
8.6 
FUNDING 
12 
8.7 
AUDITS 
12 
9. 
STUDY MANAGEMENT 
13 
10. 
PUBLICATION POLICY 
13 
10. 
REFERENCES 
13 
EXAMPLE APPENDICES 
13 
APPENDIX 1. 
SUMMARY OF INVESTIGATIONS & TREATMENT OF PATIENT (BLUE 
ROUTINE, RED TRIAL) 
15 
ASSESSMENTS 
15 
 
 
 

Appendix 2 JRO/SOP/012 
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GLOSSARY OF ABBREVIATIONS 
PMB 
Post menopausal Bleeding 
IMB 
Intermenstrual Bleeding 
REIMS 
Rapid Evaporative Ionisation Mass spectrometry 
DESI 
Desorption Electrospray Ionization 
DWI 
Diffusion weighted image 
 
 
 
KEYWORDS 
 
Innovations 
Endometrial 
Cancer 
3D 
Ultrasound 
Radiomics 
 
 
STUDY SUMMARY 
 
TITLE Effectiveness of advanced diagnostic tools in women with endometrial cancer: A 
prospective cohort study 
DESIGN Prospective 
AIMS (1) Determine the performance characteristics of ultrasound-guided biopsy 
(using fine forceps e.g. Bettochi forceps) in the detection of endometrial 
malignancy and hyperplasia. 
(2) Assess the diagnostic accuracy of 3D USS, compared to MRI and final 
histology with respect to myometrial invasion of endometrial cancer. 
(3) Determine whether pelvic imaging (USS pelvis, MRI pelvis and MR 
spectroscopy) using radiomics can predict grade and type of tumour and 
prognosis. 
(4) Determine if REIMS can diagnose cancer and normal tissue from womb 
biopsy samples and lymph glands 
  
OUTCOME MEASURES Primary outcome measures:  
(1) Histological diagnosis of ultrasound guided biopsy compared to routine care 
(hysteroscopy guided biopsy). Diagnostic ability (sensitivity, specificity, NPV, 
PPV) will be compared to gold standard. 
(2) Accuracy of diagnosing myometrial invasion in 3D USS compared to MRI 
(3) Comparison of radiomics model against standard histological diagnosis in the 
determination of grade and type of tumour.  
 
Secondary outcome measures:  
(1) Patient satisfaction (visual analogue score) of USS guided biopsy 
(2) Comparison of accuracy of diagnosis of grade and type of tumour using MR 
spectroscopy compared to gold standard histopathology 
(3) Diagnosis of endometrial cancer and hyperplasia (pre-cancer) in endometrial 
biopsy samples, and diagnose lymph node metastasis (spread of cancer to 

Appendix 2 JRO/SOP/012 
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lymph glands), using REIMS, compared with standard histology. Comparison of 
mass spectroscopy findings of lymph nodes with the primary tumour (the womb 
cancer) 
 
POPULATION 500 women referred to rapid access clinic with postmenopausal bleeding or 
intermenstrual bleeding. An additional 100 women will be recruited who were 
referred to Imperial college following a diagnosis of cancer in other hospitals.  
ELIGIBILITY All women presenting to rapid access gynaecology clinic with postmenopausal 
bleeding or intermenstrual bleeding 
EXCLUSION 
 
   DURATION  
Anyone lacking capacity. <18years old. Pregnant. Any contra-indication carry 
out a biopsy 
8 years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
 
Endometrial cancer is a tumour originating in the endometrium (womb lining); it is the most 
common gynaecological cancer in the UK. In 2012, there were almost 100,000 new cases 
diagnosed in Europe. The lifetime risk of developing endometrial cancer is 1.7%-2.6%. 
Endometrial cancer classically presents with postmenopausal bleeding (bleeding after the 
menopause), or intermenstrual bleeding (bleeding imbetween periods).  
Although routine management for these women does vary, in general a screening test is 
performed, typically a pelvic (internal) ultrasound to assess the endometrium (womb lining). 
A thin and regular endometrial line is associated with a very low risk of endometrial cancer. 
The pre-test probability of endometrial cancer in women presenting with postmenopausal 
bleeding is approximately 10%, but this increases with age and other risk factors [Gredmark]. 
In cases where the endometrial thickness is above the threshold for investigation an 
endometrial biopsy (sampling cells from the womb lining) is indicated. The biopsy can be 
taken blindly or under scan or hysteroscopic guidance. Hysteroscopy, the insertion of a small 
camera into the womb to visualise the womb lining allows direct visualization of the cavity.  
 
In theory an ultrasound-guided biopsy using a very fine forceps (such as Bettocchi) could be 
used instead of hysteroscopy- guided biopsies of the endometrium. In the literature, only case 
reports exist; showing its use in the context of investigations for postmenopausal bleeding in 
women with cervical stenosis [Hammoud]. The technique of ultrasound-guided biopsy is 
ubiquitous when used elsewhere in the body. It is frequently used to provide histological 
diagnosis of pelvic masses, (presumed ovarian origin), both abdominally (scanning of the 
tummy) and transvaginally (internally). Potentially ultrasound guided biopsies could be used 
as a cheaper, faster and less painful alternative to a hysteroscopy directed biopsies. This 
technique has not been evaluated before in endometrial cancer.  
Once the endometrial biopsy is performed, it is sent to the histologist for further examination. 
Histological analysis may take several days and patients are either brought back to clinic for 
discussion of the results or are given a telephone appointment. The patient often will not 
know the result of the test for up to 2 weeks; thus causing a lot of unnecessary anxiety and 
distress. Novel diagnostic tests, such as rapid evaporative ionization mass spectrometry 
(REIMS) may enable real time point of care diagnosis for the first time.  
REIMS technique uses standard electrosurgical methods to convert tissue constituents into 
gas-phase ionic species amenable to mass spectroscopy [Balog, Schafer]. The coupling of 
electrosurgical dissection with REIMS technology has been coined the iKnife or ‘intelligent 
surgical device’; and it enables near-real-time characterisation of human tissues in vivo. It 
uses a combination of principal component analysis (PCA) and linear discriminant analysis 
(LDA) to translate spectral data into more relevant clinical information. Studies have shown 
that all human tissues have distinctive phospholipid characteristics; and it is these that are 
interrogated by mass spectroscopy (MS) to provide a tissue signature [Balog]. The surgical 
aerosol produced by tissue ablation harbours a plethora of information that is not currently 
used, but could be used to help intra-operative decision-making and diagnoses. Ex-vivo 
studies have demonstrated clear identification of major tissue types; lung, colon and liver 
[Balog]. Furthermore, it has been used in vivo to identify intestinal cancer, polyps and the 
origin of metastatic lesions [Balog]. Unpublished data by Takats and Ghaem-Maghami’s 

Appendix 2 JRO/SOP/012 
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group have shown that REIMS technology can distinguish between normal, benign, 
borderline and malignant ovarian masses with nearly 100% diagnostic accuracy [Phelps]. Part 
of this research project is to evaluate this new technology in endometrial cancer; in particular 
to assess if REIMS can diagnose cancer and pre-cancer from biopsies taken in clinic to allow 
a true one stop diagnosis. 
 
In desorptive electrospray ionisation (DESI) samples of histological slides are taken and 
imaged pixel-by-pixel; producing mass spectra for each pixel (Takats). It can therefore 
provide topographically localized biochemical information to supplement standard 
histopathological classification systems. 
 
Once a diagnosis of cancer is confirmed on biopsy, women get staged to assess the level of 
spread. Current gold standard is an MRI. A large proportion of women, however, are unable 
to undergo or complete an MRI scan due to their morbid obesity or claustrophobia. To this 
end, many have assessed the role of ultrasound in staging endometrial cancer as a cheaper 
and easier alternative to an MRI. In the last 20 years there has been a rise in the use of 3D 
ultrasound as it has become commercially available. There is, however a paucity of data on 
the role of 3D ultrasound in the assessment of myometrial invasion. This research project will 
assess whether 3D ultrasound is a safe, effective alternative to MRI to assess the depth of 
spread of womb cancer.  
Lastly, the use of radiomics, which is the analysis of vast amounts of quantitative information 
from imaging, is an emerging technology, used to provide predictive models. The idea being 
that images of MRIs and Ultrasound from women with known endometrial cancer can be 
used to develop models which can accurately predict type of tumour and prognosis. This has 
been applied in a number of cancers such as prostate and lung but not for endometrial cancer.  
 
1.2 
RATIONALE FOR CURRENT STUDY 
 
This study will assess the application of new technologies such as ultrasound-guided 
biopsies, 3D ultrasound and Rapid evaporative ionization mass spectrometry (REIMS) in 
women with suspected endometrial cancer. These technologies may offer more effective 
and/or cheaper alternative methods to assess women with suspected cancer. If successful, 
these technologies can be used in the rapid access gynaecology clinic to provide point of care 
diagnosis of endometrial cancer from an endometrial biopsy (using REIMS) and accurate 
assessment of lymph node involvement to help intra-operative decision-making. 
 
 
2.  STUDY OBJECTIVES 
 
Objectives:  
(1) Determine the performance characteristics of ultrasound-guided biopsy (using fine 
forceps e.g. Bettochi forceps) in the detection of endometrial malignancy and hyperplasia. 
(2) Assess the diagnostic accuracy of 3D USS, compared to MRI and final histology with 
respect to myometrial invasion of endometrial cancer. 
(3) Determine whether pelvic imaging (USS pelvis, MRI pelvis and MR spectroscopy) using 
radiomics can predict grade and type of tumour and prognosis. 
(4) Determine if REIMS can diagnose cancer and normal tissue from womb biopsy samples 
and lymph glands 

Appendix 2 JRO/SOP/012 
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3.  STUDY DESIGN 
 
Prospective cohort study  
Setting: Imperial College NHS Trust Hospitals, London 
Participants:  500 women referred to rapid access clinic with postmenopausal bleeding or 
intermenstrual bleeding. An additional 100 women will be recruited who were referred to 
Imperial college following a diagnosis of cancer in other hospitals.  
Duration: 3 years 
 
3.1 
STUDY OUTCOME MEASURES 
 
Primary outcome measures:  
(1) Histological diagnosis of ultrasound guided biopsy compared to routine care 
(hysteroscopy guided biopsy). Diagnostic ability (sensitivity, specificity, NPV, PPV) will be 
compared to gold standard. 
(2) Accuracy of diagnosing myometrial invasion in 3D USS compared to MRI 
(3) Comparison of radiomics model against standard histological diagnosis in the 
determination of grade and type of tumour.  
 
Secondary outcome measures:  
(1) Patient satisfaction (visual analogue score) of USS guided biopsy 
(2) Comparison of accuracy of diagnosis of grade and type of tumour using MR 
spectroscopy compared to gold standard histopathology 
(3) Diagnosis of endometrial cancer and hyperplasia (pre-cancer) in endometrial biopsy 
samples, and diagnose lymph node metastasis (spread of cancer to lymph glands) using 
REIMS, compared with standard histology. Comparison of mass spectroscopy findings of 
lymph nodes with the primary tumour (the womb cancer) 
 
3.1 
MAIN STUDY  
 
PART 1: PRE-DIAGNOSIS OF CANCER  
All women presenting to the rapid access clinic with postmenopausal bleeding (PMB) and 
intermenstrual bleeding (IMB) will be approached for consent for inclusion into this study 
(group A). When women normally attend this clinic the doctor will discuss what will happen - 
this includes an internal (pelvic scan) and an examination. If the womb lining is thickened on 
the scan the patient will need a tissue biopsy (this is not that common, most women only 
need a scan), this will be taken at the same time as the examination in clinic. The device 
used to take the tissue biopsy is called a pipelle. Only if the patient still needs a biopsy but 
the patient can't tolerate the examination, or the sample is insufficient or focal (in a small 
area of the womb as opposed to generalised) then the patient will need to have a 
hysteroscopy. Hysteroscopy is a procedure in which a hysteroscope; a small camera, is 
inserted into the womb under local or general anaesthetic. If a patient needs hysteroscopy 
this will occur at a different appointment.  
In this study, all women in group A will be approached for enrolment into the study. Patients 
will be identified in the gynaecology clinic in Imperial NHS trust (where patients with post 
menopausal bleeding and suspected cancer get referred). Patients will be identified by the 
clinical consultants (who are also research supervisors) and clinical research fellow. Patient 
medical notes will not be used prior to clinic to identify patients, instead the patients will be 
selected as they attend clinic. At the point of consent, patients will be de-identified given a 
trial number and anonymised.  

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Prior to any imaging or examination women will be told what the research involves and if 
they are happy to proceed. They can consent to all or part of the study. The extra elements 
of the study include: a 3D ultrasound (not just standard 2D), a second pipelle biopsy sample 
(only if patients actually would have needed a pipelle anyway) and ultrasound guided biopsy 
(again only if patients actually would have needed a hysteroscopy guided biopsy). Each will 
now be discussed in more detail.  
All women (group A) will receive a pelvic (internal) ultrasound as per routine care. In addition 
to the normal 2D ultrasound, women will receive a 3D ultrasound and images will be saved. 
This adds an additional 1-2 minutes scan time. Depending on the clinician it is sometimes 
performed as part of routine care.  
If the endometrium (womb lining) is thickened >4mm on ultrasound they will require an 
endometrial biopsy. Usually this will be a pipelle. If the patient is agreeable a second 
endometrial sample will be taken specifically for research. The histology of first sample will 
be analysed by conventional pathology and the second sample will be analysed by the new 
technology REIMS/DESI. REIMS is Rapid Evaporative Ionization Mass Spectrometry and 
DESI is Desorption Electrospray Ionization. Both are new technologies that use mass 
spectrometry to analyse chemical composition, and in this case tissue composition. REIMS 
has been dubbed the 'iKnife' or 'intelligent knife' colloquially as when coupled with surgical 
diathermy the gas pattern produced is unique to the tissue and helps surgeons know where 
to cut. The diagnostic ability of this new technology will be compared against the gold 
standard, which is histological examination.  
In cases where the pipelle biopsy cannot be performed in clinic due to poor tolerance, 
insufficient material or focal lesions a hysteroscopy guided biopsy will be required (local or 
GA). In this case, the patients will be offered an ultrasound (USS) guided biopsy in the first 
instance, this will be performed at the same time in clinic. The biopsy will be taken under 
scan guidance using a very fine forceps such as Bettochi forceps. These forceps are used 
routinely during hysteroscopy so whilst the instruments are common the application is novel. 
The biopsy results of this will be sent for standard histology. If the results are inadequate 
patients will be sent for standard hysteroscopy and biopsy. Patients will also be asked to 
assess tolerability of the procedure using a visual analogue score.  
The tissue generated from the study will be stored in a tissue bank subcollection in a locked 
and secure freezer in the Institute of Reproductive and developmental biology building on 
the Hammersmith Hospital site. The sample labels will be coded in order to maintain 
confidentiality and only authorized members of the research team will have access to the 
samples. At the end of the research period the tissue samples will be kept for up to 10 years. 
They would remain securely stored and may be used in subsequent research. It is hoped 
that the tissue could be used to validate any biomarkers that arise from the study using a 
combination of immunohistochemical, epigenetics, protein and gene expression analysis. 
Any data generated from tissue analysis will be stored on Imperial College computers and 
will be accessed only by members of the research team directly involve in the project.  
PART 2: AFTER DIAGNOSIS OF CANCER  
In those women with confirmed cancer on histology (subgroup B) - an MRI is performed to 
assess stage of cancer (current routine standard of care). This will include T1, T2, DWI and 
contrast enhanced sequences. Patients referred to Hammersmith Hospital from other trusts 
who are diagnosed with endometrial cancer will be approached for consent and enrolment 
into latter part of study. These patients will have had an MRI but may not have had all the 
sequences needed and may therefore require a further MRI scan with additional sequences. 
MR spectroscopy will be performed on a subset of patients with confirmed cancer (20 
patients).  

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Definitive management of endometrial cancer includes a hysterectomy and the surgical 
specimen will be examined for depth of myometrial invasion. In the meantime, the saved 3D 
images from the rapid access clinic will be analysed and rendered to predict the stage of the 
endometrial cancer. The results of 3D ultrasound, and MRI will be compared against the 
stage found on the gold standard test (on histological examination).  
In women with confirmed endometrial cancer who later go on to require lymphadenectomy 
as part of standard care (e.g. advanced stage, type 2 tumours or high grade) following MDT 
discussion will have their lymph nodes examined ex-vivo using REIMS/iKnife/DESI in 
addition to the gold standard histopathological examination. The diagnostic capabilities of 
this new technology to identify cancerous lymph nodes will be compared to standard 
histopathological diagnosis. If this technology is accurate at diagnosing involved lymph 
nodes it could be used in vivo to enhance intra- operative decision-making. In addition to 
build the data for endometrial tissue, women receiving surgery will also be consented for an 
additional endometrial biopsy (under GA or as an ex-vivo sample).  
FOLLOW UP:  
Following surgery patients will continue with routine standard of care and follow up. Patients 
will be followed up for 5 years to provide 5-year survival data. Images from ultrasound, MRI 
pelvis and MR spectroscopy will be analysed to see if they can predict the 5-year survival.  
 
4. 
PARTICIPANT ENTRY  
 
4.1 
PRE-REGISTRATION EVALUATIONS  
No need for any specific screening tests prior to participant entry into the study.  
 
4.2 
INCLUSION CRITERIA 
All women presenting to rapid access gynaecology clinic with postmenopausal bleeding or 
intermenstrual bleeding 
 
4.3 
EXCLUSION CRITERIA 
Anyone lacking capacity. <18years old. Pregnant. Any contra-indication carry out a biopsy 
 
4.4 
WITHDRAWAL CRITERIA 
Withdrawal procedure occurs if patients choose to exit the study or if they loose capacity. 
After withdrawal from the study the anonymised tissue already obtained with consent will 
remain stored for the duration of the study. In addition, the clinical details up till the point of 
withdrawal of the patient from the study will remain on file. 
 
 
5. 
ADVERSE EVENTS 
 
5.1 
DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that: 
• 
Results in death 
• 
Is life-threatening – refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe 
 

Appendix 2 JRO/SOP/012 
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• 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death 
or hospitalisation but may jeopardise the subject or may require intervention to prevent one 
of the other outcomes listed in the definition above, should also be considered serious. 
 
5.3 
REPORTING PROCEDURES 
All adverse events should be reported.  Depending on the nature of the event the reporting 
procedures below should be followed.  Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.   
 
5.3.1 Non serious AEs 
All such events, whether expected or not, should be recorded.   
 
5.3.2 Serious AEs 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  
However, relapse and death due to endometrial cancer and hospitalisations for elective 
treatment of a pre-existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the JCRO at Imperial where in the opinion of the Chief 
Investigator, the event was: 
• 
‘related’, ie resulted from the administration of any of the research procedures; 
and 
• 
‘unexpected’, ie an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.  
The Chief Investigator must also notify the Sponsor of all SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 
Contact details for reporting SAEs 
Attention Miss D Marcus 
 
6. 
ASSESSMENT AND FOLLOW-UP  
 
Following surgery patients will continue with routine standard of care and follow up. Patients 
will be followed up for 5 years to provide 5-year survival data. Images from ultrasound, MRI 
pelvis and MR spectroscopy will be analysed to see if they can predict the 5-year survival.  
End of trial will be defined as when the last patient for recruitment received her operative 
surgery (and final histology was obtained) and has been followed up for 5 years.  
 
7. 
STATISTICS AND DATA ANALYSIS 
 

Appendix 2 JRO/SOP/012 
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Statistical analysis: Sample size was calculated on the basis of recently published work and 
anticipated ease of recruitment. It is estimated that approximately 10% of women attending 
rapid access clinic will have endometrial cancer. In previous studies assessing new 
endometrial sampling devices a population of 50 women was used. In this population it is 
expected that 80 women will require a hysteroscopy and could be offered an ultrasound 
guided biopsy.  
 
Data and all appropriate documentation will be stored for a minimum of 10 years after the 
completion of the study, including the follow-up period.   
 
 
8. 
REGULATORY ISSUES 
 
8.1 
ETHICS APPROVAL 
The Chief Investigator has obtained approval from the Research Ethics Committee.  The 
study must be submitted for Site Specific Assessment (SSA) at each participating NHS 
Trust.  The Chief Investigator will require a copy of the Trust R&D approval letter before 
accepting participants into the study.  The study will be conducted in accordance with the 
recommendations for physicians involved in research on human subjects adopted by the 
18th World Medical Assembly, Helsinki 1964 and later revisions. 
 
8.2 
CONSENT  
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information leaflet offered and time allowed for consideration.  Signed 
participant consent should be obtained.  The right of the participant to refuse to participate 
without giving reasons must be respected.  After the participant has entered the study the 
clinician remains free to give alternative treatment to that specified in the protocol at any 
stage if he/she feels it is in the participant’s best interest, but the reasons for doing so should 
be recorded.  In these cases the participants remain within the study for the purposes of 
follow-up and data analysis.  All participants are free to withdraw at any time from the 
protocol treatment without giving reasons and without prejudicing further treatment. 
 
8.3 
CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study 
and is registered under the Data Protection Act. 
 
8.4 
INDEMNITY 
Imperial College London holds negligent harm and non-negligent harm insurance policies 
which apply to this study/ Imperial College Healthcare NHS Trust holds standard NHS 
Hospital Indemnity and insurance cover with NHS Litigation Authority for NHS Trusts in 
England, which apply to this study (delete as applicable) 
 
8.5 
SPONSOR 
Imperial College London/Imperial College Healthcare NHS Trust (delete as applicable) will 
act as the main Sponsor for this study.  Delegated responsibilities will be assigned to the 
NHS trusts taking part in this study.   
 
8.6 
FUNDING 
We have applied for funding from the wellbeing of women charity.  
 
8.7 
AUDITS  
The study may be subject to inspection and audit by Imperial College London under their 
remit as sponsor and other regulatory bodies to ensure adherence to GCP and the NHS 
Research Governance Framework for Health and Social Care (2nd edition).  
 

Appendix 2 JRO/SOP/012 
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9. 
STUDY MANAGEMENT 
 
The day-to-day management of the study will be co-ordinated through Dr Diana Marcus, 
clinical research fellow. 
 
 
10. 
PUBLICATION POLICY 
 
The data obtained from this study will be anonymised and analysed. The anonymised data 
will be published in peer-reviewed journals and presented in relevant conferences and at 
patient/public engagement events.  
 
 
10. 
REFERENCES 
Balog J, Kumar S, Alexander J, et al. In Vivo Endoscopic Tissue Identification by Rapid Evaporative 
Ionization Mass Spectrometry (REIMS). Angewandte Chemie (International ed in English) 2015; 
54(38): 11059-62.  
Gredmark T, Kvint S, Havel G, Mattsson LA. Histopathological findings in women with 
postmenopausal bleeding. Br J Obstet Gynaecol. 1995 Feb;102(2):133-6. 
Hammoud AO, Deppe G, Elkhechen SS, Johnson S. Ultrasonography-guided transvaginal 
endometrial biopsy: a useful technique in patients with cervical stenosis. Obstet Gynecol. 2006 
Feb;107(2 Pt 2):518-20 
Phelps D, Balog J, Gildea L, El-Bahrawy  M, Speller A, McKenzie J, Brown R, Ghaem-Maghami S, 
Takats Z.  Gynaecological Tissue Identification with the Surgical iKnife using Rapid Evaporative 
Ionisation Mass Spectrometry (REIMS); a prospective proof of concept study. (manuscript under 
review) 
Schäfer KC, Dénes J, Albrecht K, Szaniszló T, Balog J, Skoumal R, Katona M, Tóth M, Balogh L, 
Takáts Z. In vivo, in situ tissue analysis using rapid evaporative ionization mass spectrometry. Angew 
Chem Int Ed Engl. 2009;48(44):8240-2.  
Takats Z, Wiseman JM, Cooks RG. Ambient mass spectrometry using desorption electrospray 
ionization (DESI): instrumentation, mechanisms and applications in forensics, chemistry, and biology. 
Journal of mass spectrometry : JMS 2005; 40(10): 1261-75.   
 
EXAMPLE APPENDICES 
Appendices should be additional information to the protocol and can consist of: 
 
• 
Common Terminology Criteria for Adverse Events (NCI CTC) 
• 
RECIST criteria 
• 
WHO / ECOG Performance status  
• 
PIS, Consent form, GP letter (although may be more practical to have them 
separate) 
• 
Expected side effects 
• 
Schedule of events table 
 
 
 
 
 
 
 
 
 
 

Appendix 2 JRO/SOP/012 
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Appendix 2 JRO/SOP/012 
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Appendix 1. Summary of investigations & treatment of patient (blue routine, red trial) 
 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GROUP A: Women presenting  
with Postmenopausal 
bleeding/ intermenstrual 
bleeding attend Rapid access 
clinic 
Receive Pelvic Ultrasound 
(store images) ROUTINE, if ET 
>4mm needs histology 
Pipelle biopsy 
ROUTINE 
 
iKnife on samples to 
identify if cancer  (on 
2nd sample 
pipelle/Bx) 
Consent 2nd 
pipelle 
Ultrasound 
guided biopsy  
Surgery (usually Laparoscopic 
Hysterectomy + Bilateral 
Salpingo-oopherectomy) 
High risk remove lymph 
nodes 
Low risk (no need 
remove lymph nodes) 
Follow up – counselling 
(Correlate outcome with 
Radiomics/Mass spec) 
Routine staging (CT scan and 
MRI). May need extra MRI 
sequence 
MR spectroscopy 
(subgroup 20 
women)  
Histology 
Hysteroscopy and 
Biopsy 
TRIAL 
DIAGNOSIS 
STAGING 
SURGERY 
3D Ultrasound 
save images 
3D Ultrasound 
render images 
Hysteroscopy 
and biopsy 
Can’t tolerate/insufficient /focal 
GROUP B: Confirmed 
diagnosis of endometrial 
cancer 
If insufficient tissue