Benoit Lattuca

M.D Mathieu Kerneis

M.D Anis Saib

M.D Lee S Nguyen

M.D Laurent Payot

Olivier Barthelemy

M.D Claude Le Feuvre

PhD; Gérard Helft

Rémi Choussat

Professor Jean-Philippe Collet
email: jean-philippe.collet@psl.aphp.fr

M.D Olivier Barthélemy

PhD Remi Choussat

PhD Gilles Montalescot

MD, PhD Johanne Silvain

On-Versus Off-Hours Presentation and Mortality of ST-Segment Elevation Myocardial Infarction Patients Treated With Primary Percutaneous Coronary Intervention

Keywords: myocardial infarction, percutaneous coronary intervention, revascularization, admission time, mortality Angiotensin-Converting-Enzyme Inhibitors or Angiotensin-Receptor Blockers CAD: Coronary Artery Disease FMC: First Medical Contact LBBB: Left Bundle Branch Block LVEF: Left Ventricular Ejection Fraction MICU: Mobile Intensive Care Unit PCI: Percutaneous Coronary Intervention SO: Symptom Onset STEMI: ST-segment Elevation Myocardial Infarction

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Appropriate and timely reperfusion therapy has dramatically reduced mortality and morbidity of acute myocardial infarction (MI) [START_REF] Puymirat | Association of changes in clinical characteristics and management with improvement in survival among patients with ST-elevation myocardial infarction[END_REF][START_REF] Puymirat | Cardiogenic shock in intensive care units: evolution of prevalence, patient profile, management and outcomes, 1997-2012[END_REF]. However, the organization of a local or a national ST-segment elevation MI (STEMI) network maintaining a high standard of care is a major public health issue and a challenge for each health care system worldwide. Indeed, STEMI patients need to be treated as soon as possible after symptom onset to have a benefit from the primary percutaneous coronary intervention (PCI) [START_REF] Cannon | Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction[END_REF][START_REF] De Luca | Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts[END_REF][START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF]. Thus, treatment delays are used as quality measurements for emergency care network and for hospital performances. Short symptom-onset-to-treatment time is best guaranteed in hospitals with an established interventional cardiology program with a 24hours/7days PCI service [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF]. The use of a mobile intensive care unit (MICU) with on-board emergency physicians, providing rapid and direct transfer to a PCI center while delivering pre-hospital therapies is unique to the French health care system. However, the impact on clinical outcomes of admission time, on-versus off-hours (weekday nights, weekends, and holidays) is still matter of debate. Prior studies suggested a higher mortality of STEMI patients treated during off-versus on-hours [START_REF] Magid | Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction[END_REF][START_REF] Kostis | Weekend versus weekday admission and mortality from myocardial infarction[END_REF] as a consequence of a lower likelihood of receiving evidence based treatments or timely reperfusion therapies [START_REF] Magid | Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction[END_REF][START_REF] Ryan | Optimal timing of intervention in non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Registry[END_REF]. Other studies provided conflicting results with similar outcomes depending on admission time but included populations from different heath care systems [START_REF] Jneid | Impact of time of presentation on the care and outcomes of acute myocardial infarction[END_REF][START_REF] Bell | Mortality among patients admitted to hospitals on weekends as compared with weekdays[END_REF][START_REF] Casella | Off-hour primary percutaneous coronary angioplasty does not affect outcome of patients with ST-Segment elevation acute myocardial infarction treated within a regional network for reperfusion: The REAL (Registro Regionale Angioplastiche dell'Emilia-Romagna) registry[END_REF][START_REF] Maier | Time of admission, quality of PCI care, and outcome of patients with ST-elevation myocardial infarction[END_REF][START_REF] Sadeghi | Magnitude and impact of treatment delays on weeknights and weekends in patients undergoing primary angioplasty for acute myocardial infarction (the cadillac trial)[END_REF].

The aim of this study was to assess the association between admission time with patient's care, procedure characteristics and clinical outcomes at one year within a contemporary high-volume STEMI network of patients referred for primary PCI.

METHODS

Study design and patient population

Consecutive patients admitted for primary PCI at the catheterization laboratory (cath-lab) of the Pitié-Salpêtrière University Hospital, Paris (France) were included in the prospective e-Paris registry. STEMI was defined as the presence of chest pain or symptoms of myocardial ischemia, associated with new or presumed new electrocardiographic abnormalities in the STsegment (elevation at the J point of at least 0.2 mV in leads V1 V2 V3 and at least 0.1mV in at least two contiguous leads), or new left bundle branch block (LBBB), associated with elevation of cardiac enzymes at least three times above the upper limit of normal [START_REF] Steg | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF]. The final diagnosis of STEMI was confirmed by the presence of an acute coronary artery occlusion during the coronary angiography. Patients discharged without a final diagnosis of STEMI were excluded. Criteria for cardiogenic shock included: a systolic blood pressure of less than 90 mmHg or the use of catecholamine therapy to maintain a systolic pressure of at least 90 mmHg. The main objective was to compare the rate of in-hospital and one-year mortality according to on versus off-hours admission. The secondary objective was to compare time delays and therapeutic management between the two groups of patients. The registry was approved by the local ethical committee of the University Hospital Pitié-Salpêtrière of Paris.

Definitions of admission time and treatment delay

Admission time was considered as the arrival time in the cath-lab. Admission onhours was defined as admission from Monday through Friday 8 AM -6 PM and off-hours during night shifts (>6 PM to <8AM), weekends and holidays, respectively. Time delays from symptom onset (SO) to first physical medical contact (FMC) (patient-related time), from FMC to sheath insertion (physician-related time) and from SO to sheath insertion (total ischemic time) were carefully characterized. More detailed time delays including prehospital activation time (from FMC to activation call), transfer time (from activation call to cath-lab door), installation time (from cath-lab door to sheath insertion) and PCI time (from sheath insertion to angioplasty) were provided when available.

Organization of the STEMI Network

The University Hospital of Pitié-Salpêtrière and the corresponding two MICU teams cover the south-east area of the Paris STEMI network, which represents approximately one quarter of the Parisian population. It offers a 24hours/7days service for primary PCI, cardiac surgery and mobile extracorporeal life support. FMC can be made through MICU contact with on-board emergency physician, trained in 17-lead ECG interpretation, and deciding transfer to a PCI center and administrating pre-hospital treatment. Patients can also be triaged for direct primary PCI within the emergency department. The cath-lab can be activated either by the emergency department or the MICU team. Primary PCI is performed by the on-call senior interventional cardiologist according to contemporary interventional guidelines in STEMI presenters [START_REF] Steg | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF]. Only the culprit lesion was treated with secondary PCI in case of multivessel disease. All patients received at least aspirin and anticoagulation during transfer and a loading dose of an oral P2Y 12 inhibitors as soon as possible [START_REF] Steg | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF]. Type and dose of anticoagulant did not change during the study period with intravenous enoxaparin as a preferred choice according to local guidelines, while clopidogrel was gradually replaced by prasugrel and then ticagrelor as they became available and recommended as first line therapy following the European STEMI Guidelines. No patient received fibrinolytics. Clinical and biological data were collected during hospitalization and an echocardiographic evaluation of the left ventricular ejection fraction (LVEF) was performed at discharge, after coronary reperfusion, and therefore excluded the most severe patients who died within the first days after the STEMI. A systematic follow-up was performed at one-year to evaluate vital status of all the patients.

Statistical Analysis

Continuous variables were presented as mean ± standard deviation (SD) and were compared with the Student's t test. Categorical variables were expressed as rate or proportion and compared by the chi square test or the Fisher's exact test. According to the ACC/AHA Task Force on Performance Measures [START_REF] Krumholz | ACC/AHA clinical performance measures for adults with ST-elevation and non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures on ST-Elevation and Non-ST-Elevation Myocardial Infarction)[END_REF], time intervals were expressed as median with Inter-quartile range (IQR) [25th-75th percentile] and the non-parametric Wilcoxon rank-sum test was used for group comparisons (on-hours vs. off-hours admission) of time delay. A multivariate Cox regression analysis was conducted to identify independent factors associated with mortality and included the following variables: age (as a continuous variable), smoking status, family history of coronary artery disease, blood pressure at admission, heart rate at admission, admission time, presentation as early presenter (<2 hours between symptom onset and admission), cardiac arrest, cardiogenic shock, radial access, multivessel disease (defined as two-or three-vessel disease), successful revascularization and beta blockers treatment, angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker treatment). All variables significantly associated with mortality in univariate analysis (p-value<0.1) were included in the multivariate model. All tests were two-sided with a significance level fixed at 5%.

RESULTS

Baseline Characteristics

From January 2003 to September 2013, 2167 consecutive patients with a confirmed STEMI diagnosis and available treatment delays were included in this analysis. Among them, 1048 patients (48.3%) were admitted during on-hours and 1119 patients (51.7%) during off-hours (figure 1). Baseline characteristics were well-balanced between the two groups, including proportions of high-risk STEMI represented by out-of-hospital cardiac arrest patients (7.9% vs. 8.8%; p=0.55) and cardiogenic shock patients (12.3% vs. 14.7 %; p=0.16) (table 1).

Association between admission times and mortality

A one-year follow-up was completed for 95.3% of the patients. There was no association between on-and off-hours admission time and in-hospital (8.1% vs. 7.0%, respectively; p=0.49) or one-year all-cause mortality (11.0% vs. 11.1%, respectively; p=0.89) (central illustration). Likewise, one-year mortality among patients without cardiac arrest or cardiogenic shock (n=1780, 83.3%) did not differ according to admission time (4.5% vs. 5.3%, p=0.51, for on and off-hours, respectively) (figure 2). Patients with cardiac arrest or cardiogenic shock had a higher in-hospital and one-year mortality rates compared with the other patients of the population (41% vs 1.6% (p<0.001) and 43.6% vs 4.9% (p<0.001), respectively).

Variables associated with an increased risk of mortality were found to be related to the severity of both the underlying coronary artery disease and clinical presentation but without significant predictive value of admission time (table 2). Beta-blockers and Angiotensin-Converting-Enzyme Inhibitors or Angiotensin-Receptor Blockers (ACE-i/ARB) treatment at discharge were associated with improved in-hospital and one-year survival.

Comparison of the delays and treatments between on-hours with off-hours

The SO-FMC time was similar during on-and off-hours patients (120 [55-291] vs. 126 [61-282] minutes, p=0.25) (figure 3 andtable 3). The median FMC to sheath insertion time did not differ between the two groups (90 [67-135] minutes vs 93 [69-139] minutes, p=0.58). The delays to achieve coronary angiogram and reperfusion were not different between the 2 groups, especially the time of patient installation on the cath-lab table and the operator time needed to perform the PCI after the sheath insertion (supplemental table A).

The use of radial access was high and similar in both groups with respectively 85.6% and 87.5% (p= 0.27) during on-and off-hours procedures. Patients received the same medical therapy regarding anti-thrombotic drugs, statins, ACE-i/ARB, and beta blockers, regardless of the admission time.

DISCUSSION

In an urban organized high-volume STEMI network using mobile intensive care unit for transfer, STEMI patients admitted off-hours have the same clinical characteristics, treatment delays and medical management as the one admitted during on-hours. This equality of care translates into similar outcomes when STEMI patients undergo primary PCI during on-versus off-hours with similar in-hospital and one-year mortality.

Delivering a high quality 24hours/7days service remains a challenge, especially because human resources and expertise may differ during day and night leading to variations in time delays and staff performance such as sleep deprivation and fatigue [START_REF] Needleman | Nurse staffing and inpatient hospital mortality[END_REF][START_REF] Cavallazzi | Association between time of admission to the ICU and mortality: a systematic review and metaanalysis[END_REF]. Previous studies have reported that STEMI patients admitted during off-hours may have higher mortality [START_REF] Magid | Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction[END_REF][START_REF] Kostis | Weekend versus weekday admission and mortality from myocardial infarction[END_REF][START_REF] Ryan | Optimal timing of intervention in non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Registry[END_REF][START_REF] Mizuguchi | Onset-to-device time of patients who arrive at off-hours: Importance of prehospital management and public awareness for patients with ST-segment elevation myocardial infarction[END_REF][START_REF] Sorita | Off-hour presentation and outcomes in patients with acute myocardial infarction: systematic review and meta-analysis[END_REF][START_REF] Pathak | Disparities in use of same-day percutaneous coronary intervention for patients with ST-elevation myocardial infarction in Florida, 2001-2005[END_REF][START_REF] Lotfi | The impact of the distance from the interventional cardiologist's home to the hospital during off hours[END_REF] but reported data are inconsistent due to the disparities of populations, behaviors, networks, health care systems, reperfusion strategies and associated medical treatments [START_REF] Selvaraj | Off-Hours" Versus "On-Hours" Presentation in ST-Segment Elevation Myocardial Infarction: CHAMPION PHOENIX Findings[END_REF][START_REF] Enezate | Comparison of Outcomes of ST-Elevation Myocardial Infarction Treated by Percutaneous Coronary Intervention During Off-Hours Versus On-Hours[END_REF][START_REF] Reinstadler | Impact of Off-Hours Versus On-Hours Primary Percutaneous Coronary Intervention on Myocardial Damage and Clinical Outcomes in ST-Segment Elevation Myocardial Infarction[END_REF][START_REF] Noman | Mortality outcome of outof-hours primary percutaneous coronary intervention in the current era[END_REF]. The following potential factors have been reported in prior studies to explain the greater mortality observed among off-hours STEMI patients: 1/ the lower likelihood of receiving evidence based treatments [START_REF] Ryan | Optimal timing of intervention in non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Registry[END_REF][START_REF] Sorita | Off-hour presentation and outcomes in patients with acute myocardial infarction: systematic review and meta-analysis[END_REF][START_REF] Lotfi | The impact of the distance from the interventional cardiologist's home to the hospital during off hours[END_REF] or timely reperfusion therapies with less frequently coronary angiograms performed during off-hours (7, 20); 2/ longer presentation or reperfusion times (6) ; 3/ lower successful rate of primary PCI (26) ; 4/ an unbalanced proportion of the sickest patients such as cardiac arrest patients or cardiogenic shock patients [START_REF] Sorita | Off-hour presentation and outcomes in patients with acute myocardial infarction: systematic review and meta-analysis[END_REF][START_REF] Berger | Comparison of in-hospital mortality for acute myocardial infarction in Switzerland with admission during routine duty hours versus admission during out of hours (insight into the AMIS plus registry)[END_REF][START_REF] Glaser | Factors associated with poorer prognosis for patients undergoing primary percutaneous coronary intervention during off-hours: biology or systems failure?[END_REF] ; 5/ unsuitable skilled or sufficient coronary care staff [START_REF] Needleman | Nurse staffing and inpatient hospital mortality[END_REF][START_REF] Cavallazzi | Association between time of admission to the ICU and mortality: a systematic review and metaanalysis[END_REF] ; 6/ lower availability of cardiologists according to regional system (29, 30) ; 7/ and limited access to cath-lab facilities particularly for non-North American and non-European locations [START_REF] Sorita | Off-hour presentation and outcomes in patients with acute myocardial infarction: systematic review and meta-analysis[END_REF]. Therefore, no comparison should be performed as if there was only a unique model of STEMI network.

Our analysis demonstrates that a well-organized urban STEMI network allows to bridge the gap between on-hours and off-hours management and provide the same quality of care whatever time of admission. Beyond the widespread use of primary PCI approach with skilled and experienced medical and paramedical teams, such results has been achieved by implementing several structural changes such as a unique national emergency number (#15), a patients was similar across the on-hours and off-hours groups without impact of admission time on prognosis, due to a similar management even for the most severe patients.

Limitations

First, this is a single center registry which may not reflect the overall Paris STEMI network. Second, we choose sheath insertion time instead of door-to-balloon time because it was constantly mentioned in medical records from our registry as starting point of the coronary angiogram. However, the concept of "hospital door" is questionable in our STEMI network using MICU that bypasses the emergency room and the "balloon" time may be biased by long procedures, associated with delayed reperfusion, and does not always correspond to effective reperfusion, excluding patients with aborted MI, patient treated by thrombo-aspiration only or patients treated medically. Third, our data provide the experience of a high-volume center among an urban STEMI network using a medical ambulance system and dedicated to radial primary PCI. We acknowledge that our results cannot be extrapolated to all health care systems but rather illustrated the feasibility of an efficient STEMI network in a highly skill center with cardiovascular surgeon on site. Although all cardiology centers should strive for an optimal network organization with inter-disciplinary therapeutic protocol, team training and optimized patient's pathway, such a network depends also on distance to access of primary PCI platform, cardiac assistance and transplant capabilities and local practices and experience.

CONCLUSION

In a well-organized heath care system, the time of admission is not associated with the risk of mortality at one-year among unselected STEMI patients. Mortality of STEMI patients, which has been dramatically reduced over the years, is mainly driven by severity of clinical presentation on admission. However, reduction of the total ischemic time, should still remain an important objective facing both patient and physician related times.

PERSPECTIVES WHAT IS KNOWN?

Appropriate and timely reperfusion therapy has dramatically reduced morbidity and mortality of acute myocardial infarction. However, the impact of admission time on clinical outcomes is still matter of debate.

WHAT IS NEW?

This present analysis brings new evidence related to the specific features of the French health care system based on a trained mobile intensive care unit with on-board emergency physicians, providing rapid and direct transfer to a PCI centre while delivering pre-hospital therapies. Thus, a well-organized high-volume urban STEMI network leads to a similar quality of care irrespective of the admission time even among unselected consecutive patients and among the sickest patients with cardiogenic shock.

WHAT IS NEXT?

Despite a well-organized STEMI network, reduction of the total ischemic time, should still remain an important objective to improve clinical outcomes, facing both patient and physician dependent times.

Central Illustration: Impact of admission time on one-year survival rate

The curves represent time-to-survival curves up to one-year follow-up. The red curve represents the patients admitted on-hours, and the black one, those admitted off-hours.

Figure 1 :Figure 2 :

 12 Figure 1: Study flow chart

Figure 3 :

 3 Figure 3: Treatment delays according to time admission.

Table 1 -

 1 Baseline characteristics of the population. Variables are expressed in number (%) or mean±SD. ACEi/ARB indicates Angiotensin-Converting-Enzyme inhibitor/Angiotensin Receptor Blocker; CAD: Coronary Artery Disease; LVEF: Left Ventricular Ejection Fraction; PCI: Percutaneous Coronary Intervention and TIMI: Thrombolysis In Myocardial Infarction. *Data for this variable were available for 1699 patients. # Multivessel disease was defined by two-or three-vessel disease †Patients were mostly treated by clopidogrel given that prasugrel is available in our center since 2010 and ticagrelor since 2012.

		TOTAL	ON-Hours	OFF-Hours
	VARIABLES	n = 2167	n = 1048	n = 1119	p-value
			(48.3%)	(51.7%)
	Age (years)	62.7 ± 14	63.0 ± 14	62.5 ± 14	0.44
	Male sex	1652 (76.3%)	778 (78.1%)	874 (74.3%)	0.04
	Body Mass Index > 30 (kg/m²)	215 (15.3%)	112 (15.2%)	103 (15.3%)	1.00
	Diabetes	401 (18.5%)	188 (18.2%)	213 (18.8%)	0.77
	Dyslipidemia	924 (42.6%)	460 (43.9%)	464 (41.4%)	0.27
	Active smoking	916 (42.3%)	425 (40.6%)	491 (49.9%)	0.14
	High Blood Pressure	984 (51.3%)	497 (47.4%)	487 (43.5%)	0.08
	Family history of CAD	439 (20.3%)	218 (20.8%)	221 (19.9%)	0.64
	Killip ≥ 2	293 (13.5%)	141 (13.4%)	152 (13.6%)	0.95
	Cardiogenic shock	294 (13.6%)	129 (12.3%)	165 (14.7%)	0.16
	Cardiac arrest	181 (8.4%)	83 (7.9%)	96 (8.8%)	0.55
	Infarct localization*				0.24
	-Anterior	901 (53.1%)	436 (51.1%)	465 (55.0%)
	-Lateral	167 (9.8%)	95 (11.1%)	72 (8.5%)
	-Inferior/Posterior	631 (37.1%)	323 (37.8%)	308 (36.5%)
	Radial access	1876 (86.6%)	897 (85.6%)	979 (87.5%)	0.27
	Multivessel disease #	965 (44.5%)	467 (44.6%)	498 (44.4%)	0.13
	Pre-PCI TIMI 0-1 flow	1474 (68.0%)	710 (67.7%)	814 (72.7%)	0.52
	Post-PCI TIMI 3 flow	1935 (89.3%)	941 (89.8%)	992 (88.6%)	0.81
	Creatinine at admission (µmol/L)	71 ± 50	71 ± 48	72 ± 52	0.83
	Troponin peak (µg/mL)	48 [18-110]	47 [15-113]	48 [20-109]	0.88

Table 3 -

 3 Treatment delays and discharge medications.

			ON-Hours	OFF-Hours
		TOTAL
	Characteristics		n = 1048	n = 1119	p-value
		n = 2167
			(48.3%)	(51.7%)
	Early Presenters<2 hours	486 (22.4%)	254 (24.2%)	232 (20.6%)	0.13
	Median patient-related time (min)
		121 [60-286] 120 [55-291]	126 [61-282]	0.25
	Symptom Onset -First Medical Contact
	Median physician-related time (min)
		90 [68-138]	90 [67-135]	93 [69-139]	0.58
	First Medical Contact -Sheath insertion
	Median total ischemic time (min)	201 [130-
			200 [125-390] 210 [135-387]	0.28
	Symptom Onset -Sheath insertion	387]
	ACE-i/ARBs	1718 (79.3%) 838 (80.0%)	880 (79.0%)	0.64
	Statins	1860 (85.8%) 903 (86.2%)	957 (85.5%)	0.66
	Beta-blockers	1687 (77.8%) 809 (77.2%)	878 (78.4%)	0.51
	Diuretics	418 (19.3%)	195 (18.6%)	223 (20%)	0.47
	Variables are expressed in number (%) or median and interquartile ranges.
	ACE-I indicates Angiotensin-Converting-Enzyme Inhibitors and ARBs, Angiotensin-
	Receptor Blockers.

The present study was funded by Allies in Cardiovascular Trials Initiatives and Organized Networks ACTION Group www.action-coeur.org Disclosures: B. Lattuca has received research grants from Biotronik, Daiichi-Sankyo, Fédération Française de Cardiologie and Institute of CardioMetabolism and Nutrition; consultant fees from Daiichi-Sankyo and Eli Lilly; and lecture fees from AstraZeneca and Novartis. M. Kerneis has received research grants from Sanofi, Fédération Française de Cardiologie, Société Française de Cardiologie, ESC, AstraZeneca, Daiichi-Sankyo, Lilly, Bayer. L.S. Nguyen has received research grants from Fédération Française de Cardiologie, Société Française de Cardiologie and consultant fees from CorWave. G. Helft has received research grants from Abbott, Boston Scientific, Medtronic, Sanofi, Fédération Française de Cardiologie and consultant fees from Bayer, BMS, Boehringer-Ingelheim, Servier. JP Collet has received research grants from AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eli-Lilly, Fédération Française de Cardiologie, Lead-Up, Medtronic, MSD, Sanofi, WebMD.

emergency department and MICU physicians without confirmation of STEMI diagnosis by the cardiology team, a 24hours/7days PCI service with on-site seniors cardiologist, a shock team with mobile extracorporeal life support facility for the sickest patients, and a similar access to evidence-based treatments whatever admission time. However, the average median time from first medical contact to coronary reperfusion was longer than the optimal recommended 90 minutes [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF]. This is a meaningful concern given that each 30-minute delay in door to reperfusion time is associated with a 20-30% relative increase in in-hospital mortality [START_REF] Mcnamara | Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction[END_REF][START_REF] Rathore | Association of door-to-balloon time and mortality in patients admitted to hospital with ST elevation myocardial infarction: national cohort study[END_REF]. We previously identified long transfer between referring emergency departments and our PCI center as a major cause that can be handled. Indeed, one third of our STEMI population present spontaneously to emergency departments for seeking medical attention instead of directly activating the STEMI network by calling the national MICU emergency line #15 [START_REF] Silvain | Impact of transfer time on mortality in acute coronary syndrome with ST-segment elevation treated by angioplasty[END_REF]. Our analysis demonstrates that we may improve mainly by reducing the patient-related time. Physician-related time is subject to logistical constraints that are difficult to overwhelm. It should be rather seen as quality indicators of the overall system and should be kept as short as possible.

In this analysis, we observed a much higher rate of one-year mortality compared with recent randomized trials performed within modern STEMI networks (i.e.: 4.3% in the control group of the EUROMAX trial) [START_REF] Fabris | One-year Mortality for Bivalirudin vs Heparins Plus Optional Glycoprotein IIb/IIIA Inhibitor Treatment Started in the Ambulance for ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of the EUROMAX Randomized Clinical Trial[END_REF]. The high rate of cardiogenic shocks and cardiac arrests in this unselected population that was referred to our center with an on-site dedicated shock team with ventricular assist devices and heart transplantation facilities is the most-likely explanation [START_REF] Combes | Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome[END_REF]. Nevertheless, this rate was similar to the latest Swedish nation-wide registries enrolling unselected STEMI patients, reporting a 14.1% one-year mortality rate [START_REF] Szummer | Improved outcomes in patients with STelevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995-2014[END_REF].

More importantly, we report that, despite a high proportion of severe STEMI patients as compared to previous studies in this setting [START_REF] Magid | Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction[END_REF][START_REF] Mizuguchi | Onset-to-device time of patients who arrive at off-hours: Importance of prehospital management and public awareness for patients with ST-segment elevation myocardial infarction[END_REF][START_REF] Lotfi | The impact of the distance from the interventional cardiologist's home to the hospital during off hours[END_REF], the proportion of the most severe


Hamid Gualous

G Alcicek

Youssef Diab

A Hammar

Pascal Venet

K Adams

M Akiyama

C Marumo

Lithium Ion capacitor characterization and modelling

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

I. INTRODUCTION

Lithium Ion capacitor is a new storage device which combines high power density and high energy density compared to conventional supercapacitor of the market. It has four time higher energy density than conventional supercapacitor. The structure of the LIC is composed by two electrodes. The positive one is formed by activated carbon as in double layer capacitor. The negative electrode uses lithium ion doped carbon. This new electrode technology boosts the capacity of the negative electrode and increases the electrical potential difference. The electrolyte is based on the Li Ion.

Figure 1 shows the elementary structure of EDLC and Li-ion capacitor structure. It can be seen that the negative LIC electrode is formed by Li doped Carbone. The equivalent capacitance is formed by the positive electrode capacitance Cdl in series with the negative one Cli. The equivalent capacitor can be expressed as following:

Cli 1 Cdl 1 C 1 eq + = (1)
where Cli >> Cdl ⇒ dl eq C C ≈

(2) H. Gualous (1) , G. Alcicek (1) , Y. Diab (3) , A. Hammar (2) , P. Venet (3) , K. Adams (4) , M. Akiyama (4) , C. Marumo (5) (1) FCLAB- The equivalent capacitance value is determined from the Li-ion capacitor discharge and charge at constant current between Vmax = 3.8V and Vmin = 2.2V (figure 4). The equivalent capacitance value is calculated using the following expression: For DC ESR measurement is based on the discharge at constant current (cf. discharge voltage figure 5). The time between the end of charge and the start discharge is fixed at 30 mn this duration can be reduced because of the very low Li-ion capacitor self discharge compared with double layer capacitor. The ESR is calculated by using the following expression:

I 3 U ESR ∆ = (4)
∆U3 is the drop voltage obtained from the intersection of the auxiliary line extended from the straight part and the time base at time of discharge start, I is the constant current of Li-ion capacitor discharge.

B. AC characterization

The Li-ion capacitor AC characterization was realized using an Electrochemical Impedance Spectroscopy (EIS). To characterize the studied device, the sweep in frequency must be done for various voltage levels. EIS allows the study of the influence of frequency on the Li Ion capacitor. Figure 6 It assumed as a first approximation that Li-ion capacitor is modelled by a resistance in series with capacitance. Using the EIS results we deduced the C evolutions as a function of DC voltage. Figure 7 represents the experimental results. It can be seen that Liion capacitor equivalent capacitance decreases with voltage when V<3V and the capacitance increases. We have described in this paper t Li-ion capacitor, its characterization and modelling. This new energy storage device presents a high energy density compared to conventional supercapacitor and a high power density compared to battery. It can be used for energy and power applications, in particular for electric heavy vehicles.

We have presented Li capacitor and its electrical parameters according to electrical model. It shows high capacitance density with relatively high resistance, it is due to the nature of electrolyte employed. This resistance limits efficiency of the component for high current values (>200A). Capacitance shows two linear behaviours, under and above 3V, it may be due to the lithium doping effect. Electrical model and characterization methods applied to supercapacitors kept valid in the case of Li-capacitor. In our future papers, we try to study thermal behaviour and ageing of Li-ion capacitors.

Fig. 1 :

 1 Fig. 1: Elementary structure of EDLC and Li-ion capacitor (JM Energy [1])The Li Ion capacitor studied in this paper ( figure2) is fabricated by JM Energy. Their parameters are: nominal capacitance: 2000F; volume 124ml; weight: 208g,

Fig. 2 :

 2 Fig. 2: Lithium Ion capacitor II. LI ION CAPACITOR CHARACTERIZATION A. DC characterization Li-ion capacitor is charged and discharged under constant current constraints for several current values.Figure 3 represents the Li-ion capacitor voltage evolution as a function of time. The current of charge and discharge is fixed at 100A at ambient temperature; the device voltage varies between its nominal voltage 3.8V and 2.2V. Charge discharge result shows that voltage curves can be fitted with linear curve. The DC ESR and C measuring methods are based on the Li-ion capacitor discharge at constant current. At the first approximation, Li-ion capacitor can be characterized by an equivalent series resistance and by an equivalent capacitance. The leakage current and the Li-ion capacitor inductive behavior can be neglected. The method used to determine ESR and C is presented in figure 4 and 5.

Figure 3 Fig. 3 :

 33 Fig. 3: Li-ion capacitor voltage evolution during charge and discharge, the current is regulated at 100A

  the current of discharge, ∆t = t1 and ∆V=V2 -V1. Where V1 = Vmin + 40%*(Vmax -Vmin) and V2 = Vmin + 80%*(Vmax -Vmin).

Fig. 4 :

 4 Fig. 4: Li-ion capacitor discharge at constant current In the equation (3), I is the current, ∆t can be the duration of charge or discharge and ∆V is the Li-ion capacitor voltage variation. Using this expression we have determined the equivalent capacitance of charge and discharge and for 50A, 100A, 150A and 200A. TableIgives the Li Ion capacitor of charge (Ceqch) and discharge (Ceqdis).

Fig. 5 :

 5 Fig. 5: Charge and discharge of Li Capacitor at constant current

Fig. 6 :

 6 Fig. 6: Li Ion capacitor imaginary part as a function of real part for 2.2V, 2.6V, 3V; 3.4V and 3.8V

Fig. 7 :

 7 Fig. 7: C variations with Li-ion capacitor voltage The dc voltage dependency of ESR is depicted in figure 8. No as the classical double layer capacitor, an increase in voltage leads to decrease the ESR. This means in high voltage, we can obtain best discharging power.

Fig. 8 :

 8 Fig. 8 : ESR v. frequency for different voltages Figure 9 shows the variation of capacitance versus the frequency for different voltage from this figure, it(s clear that the Li-ion capacitor equivalent capacitance C is not linear with voltage.

Fig. 9 :

 9 Fig. 9: Capacitance v. frequency for different voltages

Figure 11 :

 11 Fig. 10: Multipenatrability model

TABLE I

 I

	.	EQUIVALENT CAPACITANCE OF CHARGE AND
	DISCHARGE FOR SEVERAL CURRENT VALUES
	Current	Ceqch	Ceqdis(F)	Ceqdis/Ceqch
	(A)	(F)
	50	2118	2100	99%
	100	2083	2004	96%
	150	2024	1955	96%
	These results shows that Li-ion capacitor coulombic
	efficiency (Ceqdis/Ceqch) is very high (>96%) compared
	with battery.

TABLE II

 II

	.	ESR OF 2000F LI-ION CAPACITOR
	Current (A)	ESR (mΩ)
	50	1.84
	100	1.70
	150	1.78
	ESR variations with current for these three values can
	be neglected.


L Bilger

P Kauffmann

C Brunhuber

P Bilbault

Pierrick Le Borgne
email: pierrick_med@yahoo.fr

Une lésion du sinus frontal A frontal sinus lesion

Keywords: Diplopie, mucocèle Diplopia, mucocele

scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

L'histoire

Une femme, âgée de 72 ans, consultait aux urgences pour une diplopie permanente évoluant depuis 8 jours. Ses antécédents étaient marqués par une cardiopathie ischémique, un accident vasculaire cérébral ischémique et une insuffisance rénale chronique. L'interrogatoire retrouvait une rhinorrhée purulente bilatérale évoluant depuis 10 jours associée à une douleur rétro-orbitaire gauche. L'examen clinique initial retrouvait une diplopie binoculaire verticale avec une diminution de la mobilité du globe oculaire gauche vers le haut et la gauche ainsi qu'un ptosis homolatéral. L'accommodation, l'acuité et le champ visuel étaient normaux, de même que le reste de l'examen neurologique. L'absence de mydriase ou d'anisocorie faisait finalement évoquer une atteinte extrinsèque du nerf oculomoteur. La biologie aux urgences était sans anomalie. Un scanner crânio-facial sans injection était pratiqué (fig. 1).

Le diagnostic

Une mucocèle frontale à extension orbitaire.

Les commentaires

Fig. 1 .

 1 Fig. 1. Scanner crânio-facial sans injection, reconstruction frontale oblique (A), reconstruction


Caterina Monini
email: monini@ipnl.in2p3.fr

Gersende Alphonse

Claire Rodriguez-Lafrasse

Etienne Testa

Michael Beuve

Étienne Testa

Michaël Beuve

Comparison of biophysical models with experimental data for three cell lines in response to irradiation with monoenergetic ions

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Due to its increased efficiency in inducing biological damage, particle therapy offers advantages over the standard radiotherapy modalities for the treatment of radioresistant, unresectable tumors close to organs at risk [START_REF] Durante | Charged-particle therapy in cancer: clinical uses and future perspectives[END_REF][START_REF] Karger | RBE and related modeling in carbon-ion therapy[END_REF]. Several experimental studies have shown evidence that the relative biological effectiveness (RBE) of ions with respect to photons depends on multiple parameters related to the incident beam, the irradiation conditions and the intrinsic properties of the biological system [START_REF] Karger | RBE and related modeling in carbon-ion therapy[END_REF]. Therefore, to optimize the 3-dimensional distribution of the dose to be received by the patient during a session, the predictions of RBE are integrated into the treatment planning system (TPS). While the first approach used in clinics was based on RBE values derived empirically from the in-vitro response of a well-known tumor cell line to neutron beams [START_REF] Hirao | Heavy ion synchrotron for medical use -HIMAC project at NIRS, Japan[END_REF], the progressive diffusion of active beam delivery favored the implementation of biophysical models in the TPS. This triggered the development and the improvement of many frameworks, the most acknowledged ones being the Local Effect Model (LEM) and the Microdosimetric Kinetic Model (MKM).

The LEM I [START_REF] Scholz | Computation of cell survival in heavy ion beams for therapy. The model and its approximation[END_REF][START_REF] Kramer | Treatment planning for heavy-ion radiotherapy: physical beam model and dose optimization[END_REF], II [START_REF] Elsässer | Cluster effects within the local effect model[END_REF], III [START_REF] Elsässer | Accuracy of the local effect model for the prediction of biologic effects of carbon ion beams in vitro and in vivo[END_REF] ascribes the biological effectiveness of ions to the specific energy deposition pattern at "local" scale, which is estimated in terms of a radial dose (D(r)). Although enabling fast and efficient calculations, the use of the expected quantity D(r) to describe processes occurring at the nanoscale leads to some incongruities; for example, the shoulder in cell survival curves results from an artifact due to the superimposition of the radial doses associated to several impacting ions [START_REF] Beuve | Formalization and theoretical analysis of the LEM[END_REF]. The issue was solved in the LEM IV [START_REF] Elsasser | Quantification of the relative biological effectiveness for ion beam radiotherapy: direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning[END_REF], a substantially different version of the local effect model in which the cell nucleus is divided into critical regions corresponding to DNA giant loops. In these domains the microscopic spatial distribution of DNA double strand breaks is computed on the basis of the radial dose.

The MKM [START_REF] Hawkins | A microdosimetric-kinetic model of cell death from exposure to ionizing radiation of any let, with experimental and clinical applications[END_REF] combines a microdosimetric description of the energy deposition (accounting for the statistical fluctuations) with a kinetic representation of the repair and injury processes. The probability of cell survival, however, is not computed considering an average process over the irradiation configurations, but simply in terms of a Poisson distribution of the mean number of lethal lesions. The distribution is corrected defining a geometry for the cell nucleus in order to avoid the overestimation of the ions efficacy in the tumor [START_REF] Hawkins | A microdosimetric-kinetic model for the effect of non-Poisson distribution of lethal lesions on the variation of RBE with LET[END_REF].

More recently, NanOx [START_REF] Cunha | NanOx: A new theoretical framework for predicting radiation effectiveness in the context of particle therapy[END_REF][START_REF] Monini | NanOx predictions of cell survival probabilities for three cell lines[END_REF][START_REF] Monini | Study on the influence of NanOx parameters[END_REF] was developed by the authors to address the challenge of implementing the stochasticity of the energy depositions at nanometric and microscopic scales when predicting radiation-induced effects. This is fulfilled in the modeling of the number of radiation impacts associated to a given dose, of the dose-deposition pattern along the track and of the inter-track processes. The cell inactivation is ascribed to two classes of biological events occurring at different spatial and temporal scales, in a manner similar to that proposed by Katz et al. [START_REF] Katz | Inactivation of cells by heavy ion bombardment[END_REF]. Local lethal events are attributed to one track and are described in terms of nanodosimetry, while global events resulting from the contribution of several tracks are represented by the accumulation of oxidative stress and sublethal damages.

We decided to benchmark the predictions issued from these models against experimental data to verify if the implementation of a fully stochastic theory at nano and micro-scale had an impact on the precision of the predictions. In this paper we considered as biological endpoint the slope of cell survival curves since this is the one reported most extensively in the literature, both for measurements and theoretical calculations.

MATERIALS AND METHODS

Experimental data

Our study focused on the response of three cell lines to monoenergetic beams of several ion types (from hydrogen to neon) and energies (from 0.8 to 266 MeV/n).We chose normal lung fibroblast (V79) and ovary (CHO-K1) cells from a Chinese hamster due to the large amount of data available in the literature, and human tumor cells from salivary glands (HSG) since head and neck cancers match the therapeutic indications for particle therapy.

The experimental α values were gathered from the database made available by the PIDE project [START_REF] Friedrich | Systematic analysis of RBE and related quantities using a database of cell survival experiments with ion beam irradiation[END_REF]. Although for most of the measurements the error bars are not reported, the great data dispersion allows one to infer the important biological variability and the effects of the use of different biological and irradiation protocols. In spite of this dispersion, however, it is noticeable that α values rise for LET values up to 150-200 keV/ m (depending on the ion type), and drop for higher LET values. The initial trend is associated to the action of swift ions, which scarcely ionize the traversed biological tissues by depositing only small amounts of energy; progressively slower ions, on the contrary, produce a considerable ionization density in the medium leading to the increase of the biological effectiveness. The decrease of the α curves is due to the "overkill" effect, which may be explained in terms of two phenomena: firstly, for constant irradiation doses the fluence of incident particles is inversely proportional to the LET, and secondly, the tracks of high LET ions are narrow; the probability of hitting the cellular sensitive targets and inducing biological damages is, thus, fairly low.

Models predictions

The α values predicted by the LEM I, II, III, IV and the MKM for all the considered radiation types and cell lines were extracted from [START_REF] Elsasser | Quantification of the relative biological effectiveness for ion beam radiotherapy: direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning[END_REF][START_REF] Russo | Development of a radiobiological database for carbon ion treatment planning systems[END_REF] and for each of these models, the calculations were reported only for the irradiation cases for which published results could be found. The values of α predicted by NanOx, on the contrary, were computed by the authors especially for this work. Precisely, theoretical cell survival curves were first calculated as explained in [START_REF] Cunha | NanOx: A new theoretical framework for predicting radiation effectiveness in the context of particle therapy[END_REF][START_REF] Monini | Study on the influence of NanOx parameters[END_REF],

and then a linear fit at low doses allowed extraction of the slope α.

As Table 1 shows, all the models were evaluated considering a unique set of parameters per cell line, i.e. avoiding tuning and optimizations which would depend on the irradiation ion type. As explained in [START_REF] Elsasser | Quantification of the relative biological effectiveness for ion beam radiotherapy: direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning[END_REF][START_REF] Monini | NanOx predictions of cell survival probabilities for three cell lines[END_REF][START_REF] Russo | Development of a radiobiological database for carbon ion treatment planning systems[END_REF], the choice of the parameters was made in order to optimize the conformity between the predicted α values and the experimental ones available from the literature.

Benchmark estimator

In order to quantify the agreement between the predictions issued from each model and the data, we computed the χ 2 as:

= ∑ (1)
In Eq. 2, M represents the total number of experimental points pertaining to the PIDE dataset [START_REF] Friedrich | Systematic analysis of RBE and related quantities using a database of cell survival experiments with ion beam irradiation[END_REF] for a given cell line and ion type, and (respectively ) denotes the i th experimental (resp. predicted) α value.

RESULTS

Figure 1 shows the slope α as a function of LET for HSG, V79 and CHO-K1 cells in response to hydrogen, helium, carbon, oxygen and neon ions. While the LEM I was inadequate to reproduce the experimental trend for almost all of the considered cell lines and radiation types, some amelioration was visible for the LEM II and III, mostly in the high LET

range. An important disagreement between theoretical and observed α values, however, was apparent in the low LET range: the curves predicted by the LEM II (except for CHO-K1 cells in response to carbon ions) and by the LEM III in the case of irradiation by light ions, were overestimated, whilst the curves predicted by the LEM III for heavy ions irradiation, on the contrary, were underestimated. On the other hand, the experimental increase of α for LET values up to 150-200 keV/ m and the subsequent decrease observed for higher LET were overall well reproduced by the MKM, the LEM IV and the NanOx model. Figure 2 and Table 2 present the χ 2 estimator for each model, cell line and ion type. The intercomparison highlighted that NanOx's predictions were the most precise over the seven configurations, yielding the minimum χ 2 in three cases: for HSG cells in response to He ions, for V79 cells in response to C ions and for CHO-K1 cells in response to C ions. Our model was followed by the LEM IV and the MKM, which achieved the smallest χ 2 in two cases each.

DISCUSSION

The optimization of treatment plans in particle therapy strongly relies on the link between the energy deposition pattern and the expected biological response. Since such a link is currently provided by the biophysical model specifically implemented, it is of utmost importance to review and compare the main existing frameworks.

Recently, Stewart et al. [START_REF] Stewart | A comparison of mechanism-inspired models for particle relative biological effectiveness (RBE)[END_REF] pointed out the differences among the LEM IV, the MKM and the Repair-Misrepair-Fixation (RMF) model in the input parameters, the relevant biological targets and the computational strategies. The main principles and the seemingly contradictory aspects of the models were discussed, but the article did not report an extensive benchmark of the different predictions against radiobiological measurements. Stewart et al. concluded that "future comparisons of model predictions with experimental data are needed to fully discriminate among competing mechanisms and models of particles RBE". We hence decided to test the accuracy of well-known cell survival models considering a common biological endpoint, the α(LET) curves of HSG, V79 and CHO-K1 cells in response to monoenergetic irradiations, and as well as to examine the predictive power of NanOx. In order to quantify the agreement of the predictions with the experimental measurements found in the literature, a χ 2 calculation was performed for each cell line and irradiation type: NanOx yielded the lowest χ 2 for more configurations than the other models. This result should be considered in light of two facts: first, in some cases the difference in the χ 2 was small; and second, according to the published references several calculations were missing for the seven irradiation configurations that we considered. In particular, since the LEM IV predictions were available for only 3 cases, this model achieved the highest percentage of lowest χ 2 values. More generally, our study highlighted that the predictions issued by the LEM IV, the MKM and the NanOx model were appropriate considering the important dispersion of the experimental data, while the LEM I, II and III did not satisfactorily reproduce the observed biological effect of ions.

Even though the irradiation of in-vitro cells considered in our study are by far not representative of particle therapy treatments, a question may arise on the relevance of the current implementation of biophysical models in the clinical TPS.

The LEM I represents the standard in the European particle therapy facilities since it minimizes the risk of overestimating the doses prescribed to patients, and complies with the need of radiotherapists to rely on stable protocols. However, its description of the radiobiological response of V79, CHO-K1 and HSG cells was the least accurate among the models considered in our study. A modified version of the MKM (mMKM [START_REF] Inaniwa | Treatment planning for a scanned carbon beam with a modified microdosimetric kinetic model[END_REF]22,23]) developed by Kase et al. is instead integrated in the Japanese clinical TPS. It predicts the decrease of RBE caused by the overkill effect owing to a revised saturation correction, and is based on amorphous track structure models (i.e. on the controversial radial dose), allowing fast calculations. We believe that in the context of clinical research it would be relevant to evaluate the predictive qualities of other biophysical models and of the several modified and improved versions of the existing frameworks. This could be achieved, for example, by performing calculations with each model in clinical conditions and trying to correlate them to clinical data; it would be fruitful to bridge over the advances in research and the clinical routine of particle therapy.

In conclusion, we showed in this paper that NanOx predictions for three cell lines irradiated by monoenergetic ions were more often more accurate than the ones issued from 5 other biophysical models; however, in some cases the difference with respect to the LEM IV and the MKM was small, and some theoretical calculations were missing. More reliable conclusions may be derived if an experimental dataset characterized by lower biological variability was available, and if all the biophysical models were tested more systematically for a wide range of irradiation configurations. estimator for all the models and irradiation configurations presented in Fig. 2 1

HSG cells V79 cells CHO-K1 cells

Figure 1 :

 1 Figure 1: Evolution of the slope α with LET for HSG, V79 and CHO-K1 cells irradiated by hydrogen, helium, carbon, oxygen and neon ions. The experimental values gathered from the PIDE database[START_REF] Friedrich | Systematic analysis of RBE and related quantities using a database of cell survival experiments with ion beam irradiation[END_REF] are compared with the predictions provided by the four versions of the LEM (when available), the MKM and NanOx. The data relative to the LEM and the MKM are extracted from[START_REF] Elsasser | Quantification of the relative biological effectiveness for ion beam radiotherapy: direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning[END_REF][START_REF] Russo | Development of a radiobiological database for carbon ion treatment planning systems[END_REF]. All the models are evaluated considering a single set of parameters for each cell line, which have been chosen as they optimize the agreement with the experimental points.

Figure 2 :

 2 Figure 2: χ 2 associated to each radiobiological model on the basis of the experimental and predicted points of Figure 1. The symbols represent the values computed separately for HSG, V79 and CHO-K1 cells irradiated by hydrogen, helium, carbon and neon ions. The solid lines, instead, are for visual guidance purposes only.

Table 1 :

 1 =0.313 Gy -1 α x =0.316 Gy -1 α 0 =0.313 Gy -1 z 0 =15654 Gyβ x =0.062 Gy -2 β x =0.062 Gy -2 β=0.062 Gy -2 =0.184 Gy -1 α x =0.129 Gy -1 α 0 =0.184 Gy -1 z 0 =22789 Gy β x =0.020 Gy -2 β x =0.049 Gy -2 β=0.020 Gy -2 σ=8117 Gy D t =70/15/60 Gy D t =3 Gy R d =0.1 µm h=225841 R N =4.2 µm R N =5 µm R n =4.2 µm β G =0.041 Gy -2R SV =4.9 µm Values of the LEM (I-IV), MKM and NanOx parameters with which the predicted α(LET ) curves of Figure1have been obtained. The set of parameters of each model was determined to optimize the agreement with the experimental data, as reported in[START_REF] Elsasser | Quantification of the relative biological effectiveness for ion beam radiotherapy: direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning[END_REF][START_REF] Monini | Study on the influence of NanOx parameters[END_REF][START_REF] Russo | Development of a radiobiological database for carbon ion treatment planning systems[END_REF].

	1

Table 2 :

 2 Values of the χ 2

ACKNOWLEDGMENTS

This work was supported by ITMO Cancer (Project Nos. PC201312 and PC201606) and was performed in the framework of the LABEX PRIMES (ANR-11-LABX-0063) within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency. We thank Jayde Livingstone for her careful reading.

DECLARATION

The authors declare no conflicts of interest.


MD Louis De Mestier
email: louis.demestier@aphp.fr

MD c , Margot Armani

MD, PhD Jérôme Cros

MD a , Olivia Hentic

MD Vinciane Rebours

MD e , Guillaume Cadiot

MD, PhD Alain Sauvanet

MD, PhD Anne Couvelard

MD, PhD Rachida Lebtahi

MD, PhD Philippe Ruszniewski

Lesion-by-lesion correlation between uptake at FDG PET and the Ki67 proliferation index in resected pancreatic neuroendocrine tumors

Keywords: neuroendocrine tumors, pancreas, Ki67, FDG-PET, grade

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Pancreatic neuroendocrine neoplasms are classified depending on the pathological assessment of differentiation and tumor pathological grade (G), which is determined by the Ki67 proliferation index [START_REF] Klöppel | Neoplasms of the neuroendocrine pancreas[END_REF]. The 2017 WHO classification distinguishes well-differentiated G1, G2 and G3 pancreatic neuroendocrine tumors (PanNET) from poorly-differentiated G3 pancreatic neuroendocrine carcinomas [START_REF] Klöppel | Neoplasms of the neuroendocrine pancreas[END_REF]. This classification is of paramount importance for prognostic evaluation and therapeutic management. Nevertheless, the evaluation of Ki67 is subject to heterogeneity due to sampling bias, inter-and intra-tumor heterogeneity [START_REF] Couvelard | Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors[END_REF][START_REF] Yang | Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification[END_REF][START_REF] Singh | Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease[END_REF].

Tumor uptake on 18fluorodeoxyglucose (FDG) positron-emitting tomography (PET) may be relevant for the prognostic evaluation of PanNET. Higher tumor uptake, evaluated by the tumor maximal standardized uptake value (SUVmax) or the tumor-to-liver SUVmax ratio (SUVmax T/L), seems correlated to increased Ki67 and worse prognosis [START_REF] Binderup | 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors[END_REF][START_REF] Abgral | Performance of (18)fluorodeoxyglucose-positron emission tomography and somatostatin receptor scintigraphy for high Ki67 (≥10%) well-differentiated endocrine carcinoma staging[END_REF][START_REF] Bahri | High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation[END_REF][START_REF] Ezziddin | Prognostic stratification of metastatic gastroenteropancreatic neuroendocrine neoplasms by 18F-FDG PET: feasibility of a metabolic grading system[END_REF][START_REF] Bucau | 18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation[END_REF]. Accordingly, the diagnostic sensitivity of FDG-PET is higher for PanNET with Ki67 ≥ 10% [START_REF] Abgral | Performance of (18)fluorodeoxyglucose-positron emission tomography and somatostatin receptor scintigraphy for high Ki67 (≥10%) well-differentiated endocrine carcinoma staging[END_REF][START_REF] Tomimaru | Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors[END_REF]. The intensity of FDG-PET uptake was reported to be a better prognostic tool than Ki67 [START_REF] Ezziddin | Prognostic stratification of metastatic gastroenteropancreatic neuroendocrine neoplasms by 18F-FDG PET: feasibility of a metabolic grading system[END_REF][START_REF] Tomimaru | Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors[END_REF].

Especially, Ezziddin et al. [START_REF] Ezziddin | Prognostic stratification of metastatic gastroenteropancreatic neuroendocrine neoplasms by 18F-FDG PET: feasibility of a metabolic grading system[END_REF] reported that a metabolic grading system ([mG], mG1, SUVmax T/L <1; mG2, SUVmax T/L 1-2.3; mG3, SUVmax T/L > 2.3) was more discriminant for prognosis than the pathological grade.

However, these studies compared SUVmax (tumor pixel of highest uptake) determined on whole-body FDG-PET, with the Ki67 of the most easily accessible lesion that was generally sampled a long time ago and was not necessarily the lesion with highest uptake, leading to potential discrepancies. To better assess this relationship, we performed a lesion-by-lesion correlation between the preoperative SUVmax T/L ratio (and mG) and the Ki67 index (and the pathological grade) analyzed on surgically resected specimens of PanNET.

Methods

Patients

A retrospective analysis of consecutive patients operated on (primary tumor and/or metastases) for a pathologically proven sporadic or hereditary well-differentiated PanNET, between October 2010 and February 2018, was conducted at a tertiary center with expertise in neuroendocrine tumors. Patients were included if they had performed an FDG-PET within the 6 months prior to surgery. Surgery was always decided in NETdedicated multidisciplinary board. Patients were excluded if they had poorly-differentiated neuroendocrine carcinoma, or if they had received neoadjuvant antitumor treatment. Epidemiological, clinical and tumor data were extracted from patient records. Tumor stage was classified according to the 2017 UICC classification. Data collection was performed following patient agreement according to the declaration of Helsinki and Institutional Review Board approval (CEERB Paris Nord, IRB n° 00006477-15-073).

Target lesions

One or more target lesions measuring at least 1 cm were carefully selected in each patient. These target lesions had to be individualized and recognizable on preoperative hybrid PET/CT, on the surgical report and on the pathological report.

The Ki67 proliferation index of each resected target lesion was measured by immunohistochemistry on the "hotspot" areas, using a Ventana™ automate (Tucson AZ, USA) and a MIB1 antibody (Dako™, 1/100). We determined the histological differentiation and the pathological grade according to the 2017 WHO classification (G1, Ki67 < 3%; G2, 3% ≤ Ki67 ≤ 20%; G3, Ki67 > 20%) [START_REF] Klöppel | Neoplasms of the neuroendocrine pancreas[END_REF].

Hybrid PET/CT scanner acquisition was performed without intravenous contrast medium, 60 min after injection of 2.5 MBq/Kg of FDG. The attenuation-corrected PET data underwent standardized ordered-subset expectation maximization iterative reconstruction with 3 iterations and 21 subsets. The SUV was determined as a measure of FDG uptake using the region-of-interest technique. The maximum pixel (SUVmax) and a 1-mL sphere at the region of highest uptake (SUVpeak) were measured for each target lesion and normal liver parenchyma in each patient. To reduce potential partial-volume effects, the reference region of interest in the liver was kept consistently at 2 cm in diameter. We calculated the tumor-to-liver SUVmax ratio (SUVmax T/L), as well as the SUVpeak T / SUVmax L ratio (SUVpeak T/L).

Tumor uptake at preoperative somatostatin-receptor scintigraphy was centrally reviewed for each target lesion.

Planar and single-photon emission computed tomography images were performed at 24 hours after the injection of 200-220 MBq of 111 In-pentetreotide. Uptake was quantified following the Krenning scale (1, less than the liver uptake; 2, equal to the liver uptake; 3, more than the liver uptake but less than the spleen uptake; 4, more than the spleen/kidney uptake) [START_REF] Kwekkeboom | Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors[END_REF]. Krenning 3-4 uptake was considered strong.

Statistical analyses

Qualitative variables were described as frequencies (percentages) and compared using the Chi-2 or Fisher exact test. Continuous variables were described as medians (range) and compared using the Kruskal-Wallis test.

Ki67 inter-tumor heterogeneity was measured in patients with multiple target lesions and was considered significant in case of change in pathological grade. The correlations between Ki67 and the FDG-PET variables were explored using Pearson's test. To evaluate the discriminating value of the metabolic grading system proposed by Ezziddin et al. [START_REF] Ezziddin | Prognostic stratification of metastatic gastroenteropancreatic neuroendocrine neoplasms by 18F-FDG PET: feasibility of a metabolic grading system[END_REF] (mG1, SUVmax T/L <1; mG2, SUVmax T/L 1-2.3; mG3, SUVmax T/L > 2.3), AUC curves were performed to determine the values of SUVmax T/L and SUVpeak T/L that were best associated with G1 (vs G2-G3) and G3 (vs. G1-G2). The correlation between the metabolic grading system (using SUVmax T/L or SUVpeak T/L) with the pathological grade was explored using the Chi-2 test. The correlation between the pathological grade or mG with Krenning scale was also explored in patients who had performed preoperative somatostatin-receptor isotopic examination.

All tests were bilateral. Any p-value < 0,05 was considered significant. All the analyses were performed using the SPSS© (version 20, IBM™) and Prism (version 6, Graphpad™) softwares.

Results

Patients

Twenty-one patients (male gender 62%) with a median age of 49.9 years, were operated on for PanNET and/or associated metastases (Table 1). Four patients had a functioning syndrome (one VIPoma, one glucagonoma, one gastrinoma and one parathormone-related syndrome). One patient had genetic predisposition (von Hippel-Lindau syndrome). No patient had received antitumor treatment with neoadjuvant purpose. Two patients had received previous somatostatin analogs (the patient with VIPoma and the one with glucagonoma). Metastases were present in 43% of patients at the time of surgery. A pancreatic surgery was performed in 19 patients and a liver surgery in 9 patients, 7 patients having a combination of both. Surgery was performed with curative intent in all patients but three: two patients underwent the surgical resection of primary tumor in a metastatic setting, and one patient with VIPoma underwent pancreatic and liver debulking resection with antisecretory intent.

Target lesions

FDG-PET was performed within a delay of 2.4 months (0.03-6) before the surgical resection of the target lesions. No patient had uncontrolled diabetes mellitus at the time of FDG-PET. Thirty-six target lesions (median size, 20 mm) were identified in 21 patients, 12 of them having only one target lesion (Table 1). At pathological examination of the resected target lesions, 44%, 36% and 19% of them were classified as G1, G2 and G3 PanNET, respectively.

Among the patients with multiple target lesions, 4/9 (44%) had significant intra-tumor Ki67 heterogeneity with the coexistence of lesions with different pathological grade (two with G1 and G2, one with G2 and G3 and one with G1 and G3). Conversely, only 2/9 patients (22%) had significant heterogeneity at FDG-PET (one with mG1 and mG2 and one with mG2 and mG3). Somatostatin-receptor uptake was not correlated to pathological grade, as 58%, 18% and 100% of PanNET G1, G2 or G3 had Krenning 3-4 uptake. Similarly, somatostatin-receptor uptake was not correlated to mG, as 58%, 36% and 80% of PanNET mG1, mG2 or mG3 had Krenning 3-4 uptake.

Correlation between Ki67 and SUV

At the lesion level, Ki67 was correlated with SUVmax T/L (r=0.55, p<0.001) and SUVpeak T/L (r=0.56, p<0.001). The best mG1/mG2 and mG2/mG3 thresholds of both SUVmax T/L and SUVpeak T/L were 1 and

2.3, respectively (Table 2).

Median SUVmax T/L increased with the pathological grade: 0.76 (range 0.42-2.20, interquartile range 0.62-1.48), 1.41 (range 0.78-2.87, interquartile range 1.08-2.33) and 2.67 (range 0.94-3.76, interquartile range 1.09-3.67) for lesions G1, G2 and G3, respectively (p=0.005, Fig. 1A,1B). Similarly, median Ki67 values increased with the metabolic grade: 1 (range 1-60, interquartile range 1-5), 4 (range 1-40, interquartile range 1-14) and 25 (range 4-60, interquartile range 12-30) for lesions mG1, mG2 and mG3, respectively (p=0.005, fig. 1C,1D).

Examples are presented in the figure 2.

Preoperative mG was associated with the pathological grade assessed on the resected specimen (p=0.015, fig. 1B and1D). Only one lesion mG1 was finally G3 (Ki67=60%). Only one G3 lesion was mG1 and no G1 lesion was mG3 on preoperative FDG-PET. The results observed with SUVpeak T/L were very close and statistically significant as well (data not shown).

Discussion

Our study confirms the correlation between Ki67 and tumor uptake at FDG-PET [START_REF] Ezziddin | Prognostic stratification of metastatic gastroenteropancreatic neuroendocrine neoplasms by 18F-FDG PET: feasibility of a metabolic grading system[END_REF]. Preoperative mG was significantly associated with the pathological grade assessed on the resected specimen. Especially, all lesions but one with low FDG uptake (mG1) were G1 or G2, and all lesions with strong FDG uptake (mG3) were G3 or G2 with Ki67 > 10% (excepted one G2 lesion).

Previous studies suggested gross correlation between FDG uptake and tumor grade [START_REF] Binderup | 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors[END_REF][START_REF] Abgral | Performance of (18)fluorodeoxyglucose-positron emission tomography and somatostatin receptor scintigraphy for high Ki67 (≥10%) well-differentiated endocrine carcinoma staging[END_REF][START_REF] Bahri | High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation[END_REF][START_REF] Ezziddin | Prognostic stratification of metastatic gastroenteropancreatic neuroendocrine neoplasms by 18F-FDG PET: feasibility of a metabolic grading system[END_REF][START_REF] Bucau | 18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation[END_REF][START_REF] Tomimaru | Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors[END_REF]. However, in these studies SUVmax was compared to the Ki67 of the most easily accessible lesion, which was generally sampled a long time ago and was not necessarily the lesion of highest uptake, leading to potential discrepancies. The methodology proposed herein was likely more rigorous: 1) surgical specimens were used as gold standard for Ki67 analysis; 2) FDG uptake of each target lesion was compared to the Ki67 value of the same lesion, rather than that of a random lesion, aiming to reduce inter-tumor heterogeneity; 3) FDG-PET and sample/resection of the same lesion was performed within a close time range in order to reduce temporal heterogeneity; and 4) we did not include patients who had neoadjuvant therapy, which could have strongly influence both FDG uptake and pathological results.

The evaluation of the G in advanced PanNET relies on biopsies of the most accessible tumor localization at diagnosis, usually biopsy of a liver metastasis. This might be inappropriate in regard of the Ki67 heterogeneity highlighted in this study. Reasons are multiple: 1) sampling techniques (biopsy or surgery) may not provide equivalent specimen volume [START_REF] Singh | Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease[END_REF]; 2) inter-tumor heterogeneity, Ki67 being different between tumor localizations in about 30% of patients (generally higher in metastases) [START_REF] Singh | Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease[END_REF][START_REF] Dhall | Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors[END_REF][START_REF] Zen | Elevated Ki-67 labeling index in "synchronous liver metastases" of well differentiated enteropancreatic neuroendocrine tumor[END_REF][START_REF] Miller | Role of Ki-67 proliferation index in the assessment of patients with neuroendocrine neoplasias regarding the stage of disease[END_REF], and between metastases in 30% of cases [START_REF] Couvelard | Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors[END_REF][START_REF] Singh | Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease[END_REF]; 3) it is recommended to report the highest Ki67 which may only represent a small portion of the tumor in PanNET with important intratumor heterogeneity (35-50% of cases) [START_REF] Couvelard | Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors[END_REF][START_REF] Yang | Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification[END_REF]; 4) temporal heterogeneity, because tumor biology is likely influenced by natural and chemo-induced clonal selection, resulting in differences in Ki67 in about 35% of metachronous metastases [START_REF] Couvelard | Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors[END_REF][START_REF] Singh | Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease[END_REF]. In the present study, 44% of patients had significant Ki67 heterogeneity between multiple target lesions resected simultaneously. FDG-PET is less influenced by tumor heterogeneity. Indeed, Ki-67 is determined microscopically on hot spots of a very small part of the tumor (usually <0.1mm²), which is very different from the macroscopic imaging evaluation that provides a whole-body assessment, although a small percentage of tumor cells of higher grade may not be taken into account by FDG-PET. Moreover, Ki67 is usually determined in one single lesion but can be different in other localizations, which could be adequately taken into account by FDG-PET. In our study, significant inter-tumor heterogeneity at FDG-PET existed in 22% of patients, but without consequences for practice as FDG-PET is a whole-body examination and does not suffer from sampling bias.

We believe that the main contribution of FDG-PET could be to identify lesions with higher pathological grade than the lesion(s) biopsied for initial diagnosis (due to spatial and/or temporal intratumor heterogeneity). The lesion with the highest FDG uptake could be expected to be that with the highest Ki67 value and pathological grade, thus an important tumor localization to be taken into account for the management of the patient. Hence, FDG-PET could help guiding biopsies either during the initial work-up of PanNET or during evolution.

Otherwise, our results suggest that FDG-PET may not be useful for the management of patients with small-localized PanNET, since the distinction between G1 (candidate for surveillance) and G2 (candidate for surgery) is not accurate (except for mG3 lesions, which were all G2 or G3 in our series). Importantly, FDG-PET aims at supplementing pathological data by reducing the consequences of tumor heterogeneity on PanNET management.

Nevertheless and obviously, it cannot replace pathological evaluation of the proliferation index since the correlation between SUVmax T/L (or SUV peak T/L) and Ki67 was good but imperfect. Additionally, one must keep in mind that high FDG uptake can be secondary to VHL pathway inactivation (sporadic or constitutive) in some low-grade NET [START_REF] Bucau | 18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation[END_REF]. This may explain why some of the G1 pNET can have high FDG uptake but indolent behavior.

The main limitations of our study are those inherent to the retrospective study, and its relatively limited population due to stringent inclusion criteria (PanNET operated on with close preoperative FDG-PET and isotopic/pathology data available). Somatostatin-receptor tumor uptake could not be quantified as it was mainly measured on scintigraphy. Nevertheless, its correlation with the Ki67 index was not the purpose of this study.

Our study did not aim to report the postoperative outcomes, mainly because the patients' characteristics at baseline were too different. Indeed, our inclusion criteria mainly relied on the coexistence of PanNET, surgery and preoperative FDG-PET, in order to study the correlation between Ki67 and SUV, which does not rely on the indication for surgery (which could be very different between patients) or type of surgical procedure. Future studies should compare the prognostic impact of FDG-PET and Ki67 taking into account tumor heterogeneity, in a homogeneous cohort of patients.

In conclusion, this is the first study to demonstrate that Ki67 is correlated with SUVmax T/L (and SUVpeak T/L) on FDG-PET at the lesion scale. Tumor uptake on FDG-PET could predict the pathological grade of PanNET lesions and is less influenced by tumor heterogeneity. Hence, FDG-PET supplements the pathological evaluation of tumor biological aggressiveness and could be relevant at guiding biopsies.

Figure 1 .

 1 Figure 1. Correlation between pathological grade (G1, Ki67 < 3%; G2, Ki67 between 3% and 20%; G3, Ki67 > 20%) and metabolic grade (mG1, SUVmax T/L ≤ 1; mG2, SUVmax T/L between 1 and 2.3; mG3, SUVmax T/L > 2.3), in 36 lesions from 21 patients with pancreatic neuroendocrine tumors. Top, distribution of SUVmax T/L values (median and interquartile 25-75) (A) or metabolic grade (B) depending on pathologic grade. Bottom, distribution or Ki67 values (median and interquartile 25-75) (C) or pathologic grade (D) depending on metabolic grade.

Figure 2 .

 2 Figure 2. Examples of correlation between Ki67 proliferation index assessed on the resected specimens of pancreatic neuroendocrine tumors, and the tumor-to-liver maximal standardized uptake value (SUVmax T/L) measured on the preoperative 18 fluorodeoxyglucose positron-emitting tomography (FDG PET). Case 1 (A-C), PanNET of the pancreatic uncus (arrow) measuring 17 mm (A, transaxial contrast-enhanced CT) with low preoperative FDG uptake (SUVmax T/L 0.64; mG1) (B, transaxial PET/CT). At pathology, Ki67 was 1% (G1) (C, MIB1 immunostaining 20X). Case 2 (D-F), PanNET-associated metachronous 11-mm liver metastasis (arrow) localized in the segment VI (D, FDG-PET) with intermediate preoperative FDG uptake (SUVmax T/L 1.85; mG2) (E, transaxial PET/CT). At pathology, Ki67 was 8% (G2) (F, MIB1 immunostaining 20X).Case 3 (G-I), PanNET of the pancreatic head (arrow) measuring 30 mm and associated with synchronous metastases (G, FDG-PET) with high uptake on preoperative FDG uptake (SUVmax T/L 2.65; mG3) (H, transaxial PET/CT). At pathology, Ki67 was 30% (G3) (I, MIB1 immunostaining 20X).

Table 1 . Characteristics of 21 patients operated on for a pancreatic neuroendocrine tumor and/or associated metastases, in which 36 target lesions were identified Patients n=21Table 2 . Thresholds of SUVmax T/L and SUVpeak T/L used to define the metabolic grading system

 12

		Threshold for	Sensitivity	Specificity	Area under the
		distinguishing	(%)	(%)	ROC curve
	SUV max T/L = 1	G1 from G2/G3	80.1	56.2	0.80
	SUV max T/L = 2.3	G3 from G1/G2	57.1	89.7	0.78
	SUV peak T/L = 1	G1 from G2/G3	70	68.7	0.82
	SUV peak T/L = 2.3	G3 from G1/G2	57.1	89.7	0.78
	SUV, standardized uptake value; T/L, tumor/liver

Acknowledgments

The authors have no conflict of interest in relation with this article.

The authors did not receive any financial support for this work.

Age (years), median (range) 49.9 (27.9-61.