One Step Nucleic Acid Amplification (OSNA) Versus Ultrastaging to Detect Sentinel Lymph Node Metastasis in Endometrial Cancer: a Randomized, Multicenter, Controlled Trial (SENT-OSNA Study)
Phase: NA
Conditions: Endometrial Cancer
Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

 
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One Step Nucleic Acid Amplification (OSNA) versus 
ultrastaging to detect sentinel lymph node metastasis in 
endometrial cancer: a randomized, multicenter, controlled trial 
(SENT-OSNA study). 
 
 
SPONSOR 
 
UOC Ginecologia Oncologica 
Policlinico Agostino Gemelli IRCCS 
Largo A. Gemelli 8, 00168 
Rome ITALY 
 
PRINCIPAL INVESTIGATOR 
 
Prof. Francesco Fanfani 
UOC Tumore dell9endometrio 
Policlinico Agostino Gemelli IRCCS 
Rome ITALY 
 
SUB-INVESTIGATORS 
 
Prof. Giovanni Scambia 
UOC Ginecologia Oncologica 
Policlinico Agostino Gemelli IRCCS 
Rome ITALY 
 
Dr. Nicolò Bizzarri 
UOC Ginecologia Oncologica 
Policlinico Agostino Gemelli IRCCS 
Rome ITALY 
 
 
PATHOLOGIST 
Prof. Gian Franco Zannoni 
Gynecopathology and Breast Pathology Unit 
Policlinico Agostino Gemelli IRCCS 
Rome ITALY 
 
 
STATISTICIAN 
Prof. Diana Giannarelli 
Facility of Epidemiology and Biostatistics 
Policlinico Agostino Gemelli IRCCS 
Rome ITALY 
 
 
 
 

 
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PURPOSE OF THE STUDY  
The objective of this study is to compare the ability to detect sentinel lymph node metastasis 
between OSNA (One Step Nucleic Acid Amplification) method and ultrastaging in the lymph nodes 
of women with apparent early-stage endometrial cancer. 
 
BACKGROUND 
Endometrial cancer is the most frequent gynecological cancer in developed countries [1]. The 
incidence of this malignancy has raised in the last years with an estimated increase of 1% every 
year [2]. It is known that lymph node metastasis represents a major prognostic factor, and it is an 
indication to adjuvant chemo-radiotherapy [3]. Sentinel node (SLN) mapping is now widely used in 
the staging process for apparent uterine-confined endometrial cancer. This is supported by large 
literature evidence [4,5] and consequently, incorporated into international guidelines [3,6]. 
Accuracy and sensitivity of SLN in endometrial cancer has been shown to be promising not only in 
low and intermediate risk cases, but more recently, also in high-risk patients [7,8]. It is well known 
that ultrastaging protocol of SLN allows the diagnosis of a higher number of low volume 
metastases [9]. Nevertheless, there is a large heterogeneity in literature regarding ultrastaging 
standardization with not universally accepted protocol [10]. 
More recently, the One Step Nucleic Acid Amplification (OSNA) method has been proposed to 
diagnose lymph node metastasis. OSNA is a rapid assay, able to detect the presence of 
cytokeratin 19-mRNA in SLN, consisting of a short homogenization followed by amplification of 
cytokeratin 19 mRNA directly from the lysate [11]. The choice of CK19 derived by its high 
prevalence in endometrial cancer tissue (98% of primary tumors in a study by Nagai et al [16]); 
therefore, the CK19 gene was selected as a suitable marker for OSNA assay to target lymph node 
metastasis. Different studies have described the use and the accuracy of OSNA for the detection 
of nodal metastases in endometrial cancer [12-15]. Nevertheless, the evidence supporting the use 
of OSNA in endometrial cancer is still poor, particularly when compared with other malignancies 
[17]. 

 
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Recently, a prospective, multicentric, interventional study including patients with apparent early-
stage endometrial cancer who underwent primary surgical staging with SLN mapping was 
published. SLNs were serially sectioned with 2-mm slices perpendicular to the longest axis of the 
node: the odd slices were submitted to ultrastaging, whereas the even slices to the OSNA analysis. 
Diagnostic performance was calculated taking ultrastaging as referral standard. The study 
concluded that OSNA method had high specificity and high accuracy in detecting SLN metastasis 
in apparent early-stage endometrial cancer. The advantage of the OSNA method could be 
represented by the possibility to analyze the entire lymph node thus eliminating sampling bias [18]. 
Nevertheless, a randomized study comparing the ability of OSNA versus ultrastaging to detect SLN 
metastases in endometrial cancer has not been performed yet and might represent the only way to 
definitively understand the role of OSNA in endometrial cancer. 
 
STUDY OBJECTIVES 
Primary: 
To compare the ability to detect sentinel lymph node metastasis between OSNA and ultrastaging. 
 
Secondary: 
- 
Outcomes of SLN metastasis according to molecular classification 
- 
3 and 5-year disease-free survival in OSNA versus ultrastaging negative patients 
- 
3 and 5-year overall survival in OSNA versus ultrastaging negative patients 
- 
Total Tumor Load (=sum of CK19 copies from each SLNs) and correlation with prognosis and 
other clinico-pathologic characteristics (LVI, T, molecular classification etc.) 
- 
GTL (= The maximal CK19 mRNA copy number among valued sentinel nodes) 
- 
Dimension of SLN metastases and other histological parameters (multifocality of tumoral 
deposits, extranodal spread, neoplastic emboli in extranodal tissue) at ultrastaging and 
correlation with prognosis 
 
 

 
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ENDPOINTS 
Primary: 
Incidence of SLN metastasis in OSNA versus ultrastaging groups 
 
Secondary: 
- 
Outcomes of SLN metastasis according to molecular classification 
- 
3 and 5-year disease-free survival in OSNA versus ultrastaging negative patients 
- 
3 and 5-year overall survival in OSNA versus ultrastaging negative patients 
- 
Incidence of endosalpingiosis in ultrastaging arm 
- 
Total Tumor Load (=sum of CK19 copies from each SLNs) and correlation with prognosis and 
other clinico-pathologic characteristics (LVI, T, molecular classification etc.) 
- 
GTL (= The maximal CK19 mRNA copy number among valued sentinel nodes) 
- 
Dimension of SLN metastases and other histological parameters (multifocality of tumoral 
deposits, extranodal spread, neoplastic emboli in extranodal tissue) at ultrastaging and 
correlation with prognosis 
 
STUDY DESIGN 
Prospective, multicenter, non-inferiority, randomized study. It concerns an interventional study 
and post-market analysis. 
 
TARGET POPULATION 
Endometrial cancer patients undergoing SLN biopsy 
 
INCLUSION CRITERIA 
- 
Histologically confirmed endometrial cancer 
- 
Apparent (pre-operative) FIGO stage I-II 
- 
Radical surgery 
- 
Attempt of SLN mapping 

 
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- 
obtaining informed consent/consent to the processing of personal data 
EXCLUSION CRITERIA 
- 
Uterine sarcoma (including endometrial stromal sarcoma) 
- 
Fertility sparing surgery 
- 
Dedifferentiated histology 
- 
Undifferentiated histology 
- 
Neoadjuvant therapy 
- 
Previous surgery to pelvic lymph nodes 
- 
Lymph nodes with short axis >15 mm at pre-operative imaging [19] 
- 
inability to provide informed consent/consent to the processing of personal data 
STUDY DURATION 
4 years of accrual (and 3-years follow-up for a total of 7 years) 
 
STUDY PROCEDURES 
All patients undergo pre-operative workup including hysteroscopic biopsy, transvaginal ultrasound 
scan, abdominal magnetic resonance imaging scan and/or computed tomography scan (to be 
performed within 60 days from the surgery for endometrial cancer). Surgical staging consists of 
total hysterectomy, bilateral salpingo-oophorectomy and SLN mapping algorithm [20].  
If SLN is detected and retrieved, patient can be spared the same side systematic pelvic 
lymphadenectomy. A side-specific lymphadenectomy in case of failed SLN mapping is 
recommended. If empty lymph node packet (no evidence of lymph node tissue documented in the 
specimen) at final histology is found, patient will be reoperated with lymphadenectomy only if 
uterine factors/retrieved SLN (in one side) are not sufficient to define the potential need for 
adjuvant treatment. 
Patients will be randomized pre-operatively (after signing the consent form) to SLN analysis by 
OSNA versus ultrastaging (Figure 1). SLN undergoing OSNA analysis will not be analyzed during 
the surgery (no action taken intra-operatively according to OSNA results). 

 
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Figure 1. Study protocol scheme. 
 
 
Surgical approach consists of laparoscopic or robot-assisted according to body mass index. 
Patients with intra-operative evidence of enlarged lymph nodes and/or with extrauterine disease 
will not be included in the final analysis but will be considered in the intention to treat. 
Adjuvant therapy will be administered according to final histology risk factors. 
SLN found to be metastatic at OSNA and ultrastaging will receive adjuvant chemo-radiotherapy in 
case of micro- and macro-metastases. ITCs will be considered as negative lymph nodes and will 
not undergo adjuvant therapy (unless for uterine factors). 
Molecular profile will be also performed on hysterectomy specimens. 
 
POSSIBLE RISKS & BENEFITS 
This study will explore the sensitivity and specificity of OSNA in identifying metastases in the lymph 
nodes. The test will compare the existing standard (ultrastaging) with the OSNA. 
The OSNA device is CE-marked and has been proven to be inherently safe and reliable in other 
cancers including endometrial. All testing is ex-vivo and hence the patient safety will not be 
Apparent FIGO 
stage I-II 
endometrial
cancer
undergoing SLN 
mapping
SLN(s) analyzed with OSNA
SLN(s) analyzed with ultrastaging
RANDOMIZE 
(patients) 
1:1
PRIMARY ENDPOINT: 
Incidence of SLN metastasis

 
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affected. The lymph nodes used in this study are dissected following the routine surgical procedure 
and will be analysed by ultra-staging or OSNA.  
It is possible that this study will show that the clinical performance of OSNA is non-inferior to ultra-
staging.  
The results of the study will be widely disseminated as it is likely to influence future patient care.  
Benefits to the institution: Moreover, the user will be informed before the study about the correct 
use of the devices and reagents. This is accomplished via user trainings that provide specific 
information on how to use the device, reagents and other ancillary material. These informational 
trainings are also supplemented by the instructions for use provided with the kits, which include 
warnings and precautions for the user, as well as known limitations of the device. OSNA could be 
in the position to provide analysis results of the whole lymph node faster and more accurately and 
standardised than the reference test thereby saving time to process and expedite results for 
patients as well as resulting in significant cost saving to the health authorities. 
DESCRIPTION DEVICE 
Identification 
RD-210 and LYNOAMP CK19E, hereinafter referred to as OSNA. 
Manufacturer 
Sysmex Corporation, 1 Chome-5-1 WakinohamakaigandMri, ChkM-ku, KMbe-shi, HyMgo-ken 651-
0073, Japan  
Intended purpose 
OSNA for detection and quantification of CK19 mRNA in surgically removed lymph node(s) lysate 
of breast, colorectal, gastric cancer patients using the automated Gene Amplification Detector RD-
210. Use in diagnosis of lymph node metastasis and aid to diagnose the size of metastasis and 
metastases burden in the lymph node(s). To be used by health care professionals and properly 
trained personnel. 
 
Analyte or marker  
The marker is cytokeratin 19 mRNA (CK19), which is present in positive lymph nodes of 

 
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endometrial cancer patients. 
 
Specimen type 
OSNA is performed using lymph nodes.  
 
Technical and functional features 
A certain amount of primer solution, enzyme solution and sample is pipetted by the pipetting unit of 
the RD-210 into the respective detection cell in the reaction block of the instrument. The reaction 
solution is mixed and the reaction block subsequently heats up to a defined reaction temperature 
(64 °C). A first reverse transcription reaction is followed by the amplification reaction of target 
genes (CK19 mRNA), if any, in the sample.  
 
 
The detection principle is based on turbidity measurement. Magnesium pyrophosphate, which is a 
by-product of the amplification reaction, is a complex that causes turbidity and leads to a change in 
the transmitted light. Transmission of light is measured in the detection cell at a wavelength of 465 
nm. 
 
The reaction is monitored in real time. The measuring point, which is defined as rise time, is the 
point where the reaction curve reaches a turbidity of 0.1. 

 
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The concentration of the sample is calculated from the obtained rise time and a calibration curve 
(three different calibrators with three different concentrations of CK19 mRNA) which has been set 
up prior to sample analysis. 
 
Specimen collection and storage 
Excised lymph nodes shall be immediately refrigerated (2 to 8 °C) or stored on ice (0 to 4 °C) 
without drying to avoid RNA degradation. Use sterile biopsy sample containers, tightly fastened to 
avoid tissue dehydration. Recommended transport time between surgery and laboratory is within 
15 minutes. If OSNA cannot be performed within eight hours after resection, human lymph nodes 
shall be stored at -80 °C.  
The weight of lymph nodes for homogenisation shall be within a range of 25 to 600 mg. 
For lymph nodes exceeding 600 mg, dissection of the node to sub-samples is mandatory. 
Create as few sub samples as necessary (25 to 600 mg) in order for all of the tissue to be 
analysed.  
 
Samples 
The samples that will be included are SLNs from women with endometrial cancer. The SLNs will 
be analysed by using ultra-staging and the OSNA method. For this purpose, indocyanine green will 

 
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be applied as tracer.  
 
Proficiency panel 
Only trained personnel who have passed the proficiency test for the usage of the RD-210, 
LYNOAMP CK19 and all required equipment will be allowed to use OSNA in this study.  
 
Measures to minimise bias  
Care must be taken to avoid introducing a spectrum bias. This can be achieved by a strict 
consecutive recruitment of cases.  
In addition, the laboratory personnel performing the OSNA method must be blinded against the 
results of the reference standard and vice versa.  
 
Test procedure  
SLNs deriving from SLNB will be dissected carefully from the surrounding adipose tissue and 
submitted to ultra-staging or shock frozen in liquid nitrogen and stored at 3 80ÚC for further OSNA 
analysis. 
 
SLN undergoing ultra-staging: 
The SLN will be fixed in 10% buffered formalin, embedded in paraffin and submitted to permanent 
sections as follows. From each paraffin block (slice), levels at 150 ¿m interval will be sliced. At 
each level, three adjacent sections will be cut and the first section of each level will be stained with 
H&E. If no tumour can be detected, then the second section will be stained with IHC using the anti-
cytokeratin AE1:AE3 in order to detect a low volume metastatic disease by using a light 
microscope. The third is kept as a spare section and can be used to repeat staining if necessary. If 
upon IHC no micro- or macrometastasis are detected, then the node will be judged as negative. 
Conversely, if IHC detects a metastasis greater than 0.2 mm, then it will be judged as positive 
(macrometastasis: > 2.0 mm; micrometastasis: > 0.2 mm but f 2.0 mm).  The presence of ITCs 
(clusters of tumour cells no greater than 0.2 mm) should be documented in the results table, but 

 
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the node will be considered negative. The dimension of SLN metastases will be documented in 
mm. 
  
SLN undergoing the OSNA analysis: 
The SLN will be immediately refrigerated (2 to 8 °C) or stored on ice (0 to 4 °C) without drying to 
avoid RNA degradation. Use sterile biopsy sample containers that are tightly fastened to avoid 
tissue dehydration. Recommended transport time between surgery and laboratory is within 15 
minutes, however if the nodes are stored in the refrigerator or on ice without drying, the time can 
be prolonged to up to eight hours until final storage at 3 80ÚC for further OSNA analysis. 
Throughout the evaluation, samples should be tested with OSNA according to the 8Test Procedure9 
described in the instructions for use supplied with the reagents and shown in Figure 2.  
 
Figure 2: Scheme describing the OSNA workflow 
Briefly, frozen samples are homogenised in 4 ml of lysing buffer for 90 s at 25,000 rpm using 
stainless steel blades or for 60 s at 10,000 rpm using LYNOPREP Blade Set and centrifuged for 
one minute at 10,000 x g. Subsequently, Cytokeratin 19 mRNA is amplified by Reverse 
Transcription Loop-mediated Isothermal Amplification (RT-LAMP) in the RD-210. Automated 
amplification with a ready-to-use reagent kit is performed directly from the sample lysate, with no 
RNA purification necessary, according to the manufacturer9s instructions. Lymph nodes are 

 
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defined as 8negative9 or 8positive9 according to established cut-off values21. Therefore, negative 
nodes are classified for Cytokeratin 19 mRNA ccP/¿l as less than 250. Lymph nodes with possible 
ITCs are classified for Cytokeratin 19 mRNA ccP/¿l as 160 3 249. Lymph nodes positive for 
micrometastases (+) show mRNA Cytokeratin 19 levels of 250-4,999 ccP/¿l and those nodes with 
macrometastases (++) show 5,000 mRNA ccP/µl or more. In Figure 3, an example of a result table 
is shown. 
 
 
 
 
 
 
 
 
 
Figure 3: Scheme showing an example of the OSNA outcome 
The OSNA lysates will be stored by the study sites for further molecular analysis. 
 
 
DATA MANAGEMENT 
Data and results recording 
All submitted data will be anonymised and no patient identifiable information will be collated during 
the course of the study except locally to answer any queries that may arise. The results of OSNA 
assay and ultra-staging will be reported on electronic study report form (eSRF). Upon completion 
of the both assays, the Principal Investigator and/or Study Coordinator reviews the recorded data 
for completeness, accuracy and legibility.  
The eSRF together with the clinical performance study report will be made available to Sysmex 
upon finalisation of the testing.   

 
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To protect the subject9s or patient9s privacy, no personal data shall appear anywhere on the eSRF. 
 
Data and results management plan 
All data will be filed in eSRF by each study site. Data will be stored for at least five years. All 
laboratory results are strictly confidential.   
Principal Investigator and Study Coordinator will check the eSRF, and corrections or clarifications 
of data entered in each eSRF will be resolved by sending a query to the responsible investigator. 
The errors are corrected in the original database by the Principal Investigator. Then, the cleaned 
database (= final database) is signed and locked (= included as pdf file in Annex of the CPSR) by 
the Principal Investigator.  
All data will be summarised in a final report in the English language by the Principal Investigator, 
including a material and methods section, results tables, discussion and conclusion per item. The 
final report will be authorised and signed by the Principal Investigator. 
The data should be clearly legible and marked with the name of the laboratory and initialled by the 
responsible investigator. 
TRANSLATIONAL SUB-STUDIES: 
- 
Molecular profile including POLE on tumor tissue 
- 
Molecular profile including POLE on lymph node metastases 
- 
Circulating tumor-free DNA taken at following timepoints: pre-operatively, 1-month PO, 12 
months PO 
Aim:  
o Correlation between free CT DNA and OSNA versus ultrastaging SLN metastasis 
 
- 
Complete blood count and CRP taken at following timepoints: pre-operatively, 1-month PO, 
12 months PO 
- 
Microbiome correlation with SLN metastasis 
 
STATISTICAL CONSIDERATIONS 
SAMPLE SIZE CALCULATION: 

 
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This is a non-inferiority randomized trial with the incidence of patients with metastatic SLN as 
primary endpoint. Based on recent literature, incidence of patients with metastatic SLN detected by 
ultrastaging has an average value of 11% [21-23]. Assuming a -4% as the maximum allowable 
difference in detection rate to declare non-inferiority, a power of 80% and a significance level of 
2.5% (one-side) a sample size of 1922 (961 per arm) is needed. Two interim analyses are 
planned, one after the first 640 and the second after 1280 patients. At the first interim analysis null 
hypothesis (inferiority of OSNA with respect to ultrastaging) will be rejected at a significance level 
<0.00010 otherwise the study will go on and at the second analysis the null hypothesis will be 
rejected at a significance level of 0.0059. The final analysis will use 0.0189 as significance 
threshold.  The O9Brien Fleming alpha spending function was used to define these values. 
 
STATISTICAL ANALYSIS: 
The primary endpoint is defined as the proportion of patients with positive SLN over the total of 
randomized patients. This proportion will be reported together with the 95% confidence interval to 
better identify the range of inferential values.  
Incidence of isolated tumor cells, micro- and macro-metastasis will be calculated. 
Number of copies of CK19 mRNA to define volume of metastases will be adapted from previous 
reports [12]. 
To describe the sample, quantitative variables will be summarized using median and interquartile 
range while categorical items will be  reported as absolute counts and percentages. Patients will 
be described according the arm they were randomized to. A first analysis will be performed on an 
Intent-To-Treat basis, considering all randomized patients. A secondary analysis will be performed 
on the Per-Protocol population.   
 
EVALUATION PHASES 
Study site initiation 
An initiation meeting shall be conducted (in person or remotely) and documented by the Study 
Coordinator at the beginning of the clinical performance study.  

 
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Names, initials, signatures and functions shall be documented on the training log. 
Prerequisites for initiation:  
A. Signed clinical performance study plan; copies shall be provided to all parties involved  
B. Instructions for use of the IVD product provided 
C. Required number of IVD devices are available at the investigation site 
D. Any financial arrangements between the study sites and Sysmex are documented in 
separate agreements 
E. Any required application(s) to begin the clinical performance study in a given country have 
been submitted to the appropriate regulatory authority(ies) for review, acceptance or 
permission 
F. Ethics Committee9s approval/favourable opinion has been obtained and documented where 
required 
G. Evidence of GCP training of all study personnel 
 
Training 
Only trained and experienced persons can perform the assays for this evaluation. 
Training of all involved parties shall be documented in the training log and should include training 
of the CPSP and instructions for use.    
The 8Test Procedure9 described in the instructions for use supplied with the reagents should be 
used throughout the evaluation. A proficiency panel should be tested by all persons involved in 
conducting the clinical performance study tests, test results shall be attached to the training log.  
The CPSP should be clearly understood by all members of the study team.  
The training log is sent to the Study Coordinator before starting the study.    
 
Conduct of the study 
Testing of the samples must be done by a trained person whose name and function shall be put on 
the eSRF.    
Any issues observed during the testing phase shall be reported to the Study Coordinator and 

 
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discussed.  
Monitoring activities will be performed to verify compliance with the CPSP, issue reporting, 
adequate study site resources, storage and accountability of the IVD devices, and to ensure that 
records are accurate, complete, up-to-date, and stored and maintained appropriately.  
 
Quality assurance 
For quality assurance purposes, submission of all specimens (preferably in digital form) and full 
pathology report (preferably in digital form, original language and English translation), will be 
required at least from two patients per centre (randomly selected by the Study Coordinator or 
Principal Investigator) and reviewed centrally at Policlinico Agostino Gemelli IRCCS. Additional 
cases will be reviewed in case a major discrepancy is found from the protocol. The centre may be 
closed and the patients from the respective centre withdrawn for the final analysis if critical 
discrepancies or repeated major discrepancies are identified. 
 
Centers will be selected according to: 
- 
Availability of OSNA device 
- 
Adherence to ESGO quality indicators for endometrial cancer items (Appendix 1) [24]: QI6, 
QI8, QI9, QI19, QI20 
 
End of the study 
The following documentation shall be available at end of the study:  
- 
Completed and signed eSRFs 
- 
Clinical performance study report, signed by the investigator(s).  
 
Clinical performance study plan amendments and deviations 
Any deviation from the clinical performance study plan will be reported to the Principal Investigator 
and Study Coordinator and documented in the clinical performance study report. 
Amendments to the clinical performance study plan shall be agreed between the Sysmex, Study 

 
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Coordinator and the Principal Investigator. The amendment will not be implemented before the 
approval is obtained from all involved parties. 
 
Statements of compliance and ethical principles  
The study shall be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, with GCP and any regional or national regulations. 
The study shall not begin until the Ethics Committee9s approval, favourable opinion or waiver is 
obtained. 
The investigator will perform the clinical performance study in accordance with the applicable laws 
and regulations, including the applicable privacy laws and recognised ethical principles laid down 
in the Declaration of Helsinki. The study will be carried out in restricted laboratories in accordance 
with the applicable laws and in conformity with the European recognised quality standards. 
 
Adverse device effects and device deficiencies 
All devices applied in this study are already CE marked according to 98/79/EC except for the use 
in endometrial cancer. Only trained personnel shall use the device. 
Any adverse device effect or observed device deficiency as defined below that is encountered 
during the clinical performance study will be recorded and reported to the Study Coordinator and 
documented in the clinical performance study report. 
" 
Adverse device effect: adverse event related to the use of an IVD medical device under 
evaluation. This includes any adverse event resulting from insufficient or inadequate 
instruction for use, installation operation, or any malfunction of the IVD medical device 
under evaluation. Additionally, any event resulting from the use error or from intentional 
misuse of the device under evaluation. 
¥ 
Any serious adverse device effect or device deficiency that could have led to a serious 
adverse device effect, as defined below, shall be reported without unjustified delay to the 
Study Coordinator; this information shall be promptly followed by a detailed written report. 
" 
Serious adverse device effect: adverse device effect that has resulted in any of the 

 
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consequences characteristic of a serious adverse event that has led to death, to serious 
deterioration in health or to foetal distress, foetal death, or a congenital abnormality or birth 
defect. 
 
Suspension or premature termination of the Clinical Performance Study 
The Principal Investigator can decide to immediately suspend or prematurely terminate the clinical 
performance study in case of: 
- 
occurrence of serious adverse device effects/device deficiencies 
- 
suspicion of unexpected risk to the users or other persons involved in the study 
- 
monitoring identifies serious deviations from the CPSP 
The Study Coordinator will justify the decision for suspension or premature termination of the CPS 
in writing to the Principal Investigator. All routine end of study activities shall be conducted. 
After risk assessment, it can be concluded to resume the suspended CPS. The Study Coordinator 
will inform the Principal Investigator with the decision including the rationale and the relevant 
supporting data. 
 
Clinical Performance Study Report and publication of the results 
The clinical performance study report will be written by the Principal Investigator and shall contain 
documented information on the clinical performance study plan, results and conclusions of the 
clinical performance study, including negative findings.  
The results and conclusions shall be transparent, free of bias and clinically relevant. The report 
shall contain sufficient information to enable it to be understood by an independent party without 
reference to other documents. The report shall also include, if appropriate, any clinical 
performance study plan amendments or deviations and data exclusions with the appropriate 
rationale. 
Upon completion of the multi-centric study project, the study sites and the Principal Investigator 
shall cooperate in publishing the results in a scientific journal relevant to the therapeutic area within 
maximum 12 months of the completion of the study project and subject to the provisions set forth 

 
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under this section.  
" 
The order of authorship will be based on the number of patients recruited by the study site. 
" 
The first and last authors will be authors from the sponsor institution, independent of the 
size of the recruited cohort at this site. 
" 
Only study sites which have contributed to the study with g2% of the total patients will be 
listed as co-authors; the remaining study sites will be listed in the acknowledgment section 
of the paper. Every further 5% of randomized patients, will grant an extra co-author from 
that institution. 
For this section, Principal Investigator shall provide Sysmex with a draft of any manuscript, 
presentation material or other written or printed document regarding the results and findings of the 
multi-centric study project at least thirty (30) days prior to its submission. Within twenty (20) days 
thereafter, Sysmex may request the exclusion of its proprietary information (including, but not 
limited to its confidential information).  
Data and findings gained at the individual study sites shall be presented in national and 
international congresses and published in scientific journals relevant to the therapeutic area of the 
study, subject to the provisions set forth under this section. For the avoidance of doubt, with the 
prior written consent of Sysmex and Principal Investigator, study sites shall have the right to 
publish or present their results and findings exclusively and firstly as a study site is an academic 
entity, provided that such publication is conducted within 24 months of the completion of the study 
project. For this section, study site and the study project responsible shall provide Sysmex and the 
Principal Investigator with a draft of any manuscript, presentation material or other written or 
printed document regarding the results and findings at least thirty (30) days prior to its submission. 
Within twenty (20) days thereafter, Sysmex may request the exclusion of its proprietary information 
(including, but not limited to its confidential information). 
 
 
 
 

 
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2. 
Lortet-Tieulent J, Ferlay J, Bray F, Jemal A. International Patterns and Trends in Endometrial Cancer Incidence, 
1978-2013. J Natl Cancer Inst. 2018;110(4):354-361. Doi:10.1093/jnci/djx214 
3. 
Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with 
endometrial carcinoma. Int J Gynecol Cancer. 2021;31(1):12-39. Doi:10.1136/ijgc-2020-002230 
4. 
Bogani G, Murgia F, Ditto A, Raspagliesi F. Sentinel node mapping vs. lymphadenectomy in endometrial cancer: 
A systematic review and meta-analysis. Gynecol Oncol. 2019;153(3):676-683. Doi:10.1016/j.ygyno.2019.03.254  
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