Caroline Durand

Zeidoun Al-Muheisen

Pauline Piraud-Fournet

Laurent Tholbecq

A public Bath-House, a caravanserai and a luxurious villa in Khirbat ADH-DHARĪḤ (ṬAFĪLAH, Jordan) : report on the 2013 excavation season

Introduction

A new excavation campaign was carried out in Dharīḥ between the 18 th and the 30 th of May 2013, on behalf of the French-Jordanian Archaeological Mission of Khirbat adh-Dharīḥ (dir. Profs. Zeidoun al-Muheisen -Yarmouk University, and François Villeneuve -University Paris Panthéon Sorbonne) 1 . Three operations were undertaken on different buildings, in order to complement the previous excavations (Fig. 1). Soundings and cleaning were undertaken by P. Piraud-Fournet in the northern house of village V1, which is the largest domestic building of the site, in order to determine its phasing and chronology. At the same time, work was carried out in Area A, about 150 m south of the sanctuary's southern entrance (second court), on both a Nabataean/ Roman mansio (L. Tholbecq) and the associated public baths (C. Durand).

House V1. New Discoveries: a Stable, a Bathtub and some Elements of Dating (P. Piraud-Fournet) Around twenty domestic buildings were found in Dharīḥ, on the hill overlooking the Nabataean-Roman sanctuary. House V1, excavated between 1984 and 1996 2 is the largest, and has the most interesting features (Fig. 2; al-Muheisen and Villeneuve 2000; [START_REF] Villeneuve | Le Sanctuaire Nabatéen et Romain de Dharih (Jordanie): Nouvelles Découvertes[END_REF]. In 2007, the plan of the house was updated and, together with a review of its architecture, new clues came to light [START_REF] Al-Muheisen | A large Nabataean-Roman period house at adh-Dharih[END_REF]. The finds from the excavations, which are currently being studied, suggest that the house was founded between the 1 st and 2 nd centuries AD, while the material from the destruction/abandonment layers is no later than the 4 th century (al-Muheisen and [START_REF] Al-Muheisen | Nouvelles Recherches à Khirbet ad-Dharih (Jordanie du Sud)[END_REF]. The 2013 season was short, with specific goals. First, it was necessary to highlight the troughs between rooms D and E, by cleaning and replacing several fallen blocks to their original position. We needed to understand the original layout in room L, which may be a bathtub, better. Finally, soundings were conducted in the northern and southern parts of the house, in order to date their construction precisely.

Description of House V1

House V1, on the northern slope of the hill, is a compact block covering a surface of at least 900 m 2 , and is comprised of three adjoining sections with two courtyards. The southern part of the house is organised around a trapezoidal courtyard (A, 118 m 2 ). The only known entrance is located on the east side of this courtyard. To the south, the platform provides access to two paved rooms, (B and C). To the west, it provides 1. We would like to warmly thank François Villeneuve and Zeidoun al-Muheisen, who allowed us to undertake this mission, for their help and support. The team consisted of six people: Pauline Piraud-Fournet (IFPO), architect and archaeologist, Laurent Tholbecq (ULB), archaeologist, Caroline Durand (IFPO), archaeologist and ceramicist, Moussa Ali Moussa Serbel, technician and restorer (Yarmouk University) and Gabriel Humbert, logistics. The Department of Antiquities was represented by Aimad al-Drous (DoA, Tafila). This campaign was funded by the University Paris Sorbonne and the CNRS, with logistical support from IFPO Amman. Many thanks are also due to Thibaud Fournet (CNRS-IFPO), for his help and suggestions about the private and public bath installations of Dharīḥ. 2. In 1984, François Villeneuve excavated Room G; the rest of the structure was excavated by Zeidoun al-Muheisen and his team between 1992 and 1996. access, via two doors, to a central room (D), which is surrounded on three sides by a wide U-shaped corridor €. The northern section is different in its orientation and its installations. It is aligned 13.5° further to the west, and one of the most interesting installations in this part is a large paved courtyard, or esplanade (S) in front of the northern face of the vestibule (J). This esplanade has a dominant position and a panoramic view over Wādī al-Laʻbān and the hills of Wādī al-Ḥasā, as well as over the sanctuary, about a hundred metres lower down.

The western part of the house complex consists of six rooms. Two adjoining rooms to the north (K and L); one long, paved, L-shaped corridor (M) and two other, contiguous rooms (N and O); and a small, square, paved room (P). Rooms (N and O) form one room, with the imprint of a robbed clay tile floor still visible. This room has a kind of alcove, which becomes wider in its façade, with a T-shaped plan. The interior faces of the western and southern walls are cut by five vertical channels, characteristic of rooms heated by hypocausts. The underground part was well preserved until 2012, with the low surrounding walls of brick and the remains of twenty pilae stacks of fired clay, which carried the suspensura of fired clay slabs, still in situ. However, it has recently been completely destroyed. Several more or less contemporary houses, such as a beautiful villa at Wadi Musa and the az-Zantur houses in Petra (EZ III and EZ IV), also have heated rooms of this type, some of which have been interpreted as private baths (Nehmé and Villeneuve 1999: 62-71;[START_REF] Kolb | Les Maisons Patriciennes d'az-Zantûr[END_REF]Kolb and Keller 2001: 319).

Field Operations in 2013 Cleaning and Restoration in Rooms (D) and (E) -A Room with Troughs

Rooms (D) and (E) present an unusual organization; a central room surrounded on three sides by narrow corridors, with the walls separating the central room and the corridor pierced by troughs (Fig. 3). This configuration is usually found in southern Syrian houses of the Roman and Byzantine eras (Clauss-Balty 2008: 62-70; Bodo and Clauss-Balty 2009). In the late 19 th -early 20 th centuries, Melchior de Vogué (Vogüé 1865) and Howard Butler [START_REF] Butler | Archaeological Expedition to Syria, II A: Southern Syria[END_REF]) interpreted these facilities as mangers for animals (horses or cows), with the feed stored in the central room while the animals were kept in the corridors. Since then, many such stables have been identified in domestic contexts in Syria (for example Clauss-Balty 2010); in the Negev, in Mampsis, Oboda and Sobata [START_REF] Negev | The Late Roman and Byzantine Periods[END_REF][START_REF] Negev | The Late Roman and Byzantine Periods[END_REF]; in the Jowlan (or Golan; Al-Halabi 2012), etc 3 . The cleaning of the bestpreserved wall in House V1, between (D) and (E), supports this hypothesis. One bevelled block (D1), inward sloping, was still in place 1.10 m above the ground-level (the correct height for animals). Three other stones with a similar shape had fallen to the floor, two on the northern side (D2 and D3) and one on the southern (E4). The wall has been consolidated with cement mortar, and many blocks have been reconstructed in their original placement (Figs. 45).

The first interpretation is that these were feeding troughs for domestic animals. Nevertheless, access to rooms (D) and (E) may have been difficult for animals, due to their position in the house, relatively far from the main entrance. Another, less convincing, hypothesis is that these troughs were storage vats for crops or for the precious commodities of the house. In a second construction phase, the troughs were blocked with small stones in mortar and earth, and a plain wall was built to separate the room from the corridors; a door was also built into this wall. The blocks of this door, found on the floor, have also been reconstructed. As a large monolithic trough is still standing in room (D), we suppose that, during this second phase, animals (probably smaller, goats or sheep?) were kept in this room. This type of installation 3. An international conference, held in Paris in May 2015, presented studies and hypotheses regarding ancient buildings or rooms with troughs found in North Africa and the Middle East. Concerning Dharih: see Piraud-Fournet, forthcoming. has rarely been identified in Jordan. However, other troughs are attested at Dharīḥ, in the mansio or caravanserai built along the access way to the sanctuary (see infra).

Rooms (C) and (D-E) (

Excavations in Room (C)-Foundation Trench of a Main Wall in the Southern Section

During the 2013 season, a 1 m by 2 m square was opened inside room (C), along the threshold of the door. The aim was to determine the date of construction of this room and the southern part of the house. The paved floor in this area lies directly on the bedrock, or sometimes on a slab formed by small stones (Fig. 6). A trench was cut into the bedrock and the foundation of the wall with the threshold was built into it. This foundation is made of rows of stones and stone shards bound by a strong lime mortar. The earth inside the trench did not reveal any pottery, but three small sherds of Nabataean pottery were discovered in the wall foundation, dated from the end of 1 st c. to the beginning of the 2 nd c. A.D.

Excavation in Room (L)-a Possible Bathtub

Room (L) is a small rectangular room, mainly accessible from hallway (M) through a door with a broken threshold (Fig. 7). Cleaning of this room has allowed us to complete its description. An interesting installation is located

Overview of the restored southern wall separating rooms (D)

and (E) ( © P. P.-F. 2013). on the western side of the room. A large stoneniche seems to have been added to an existing room, or was built independently at the same time. A sunken monolithic basin was found in this niche in 1993, accessible by some sort of door in the front wall. Embedded in this wall was a square stone which formed a receptacle with a spout, allowing liquid to flow into the basin. This basin, of slightly trapezoidal shape, measures 0.80 m in length, 0.63 m to 0.56 m in width, and 0.40 m in depth for the most part. Above the monolithic basin, the inner walls of the structure are constructed of thin, horizontally placed sandstone slabs, embedded in a layer of mortar. None of the previous assumptions regarding this niche appear to be convincing; fortunately, the 2013 season provided new information. The southern part of the basin is cut so as to form a seat flanked by two small inclined ramps (Fig. 8). An outflow hole was found in the bottom of the basin. In order to understand the direction of the outflow, we opened a sounding of 1.50 m by 3 m in front of the stone niche.

Excavation of the foundation trench of the front wall of room (C). Discovery of the soleplate (

The floor of the room no longer survives. We found only the thick layer of whitewash (thickness: 0.15 m) which supported it, which was based on another layer of earth and small stones. Both covered a layer of compact earth containing a lot of charcoal, animal bones and some pottery (all from the end of the 1 st to the beginning of 2 nd c. A.D.). Under these layers, as we expected, a large channel made of stoneblocks was discovered (Fig. 9). All the loci we dug inside this channel yielded, prima facie, Nabataean pottery (end of the 1 st to the beginning of 2 nd c. A.D.). We also sampled the ashy layer for future archaeobotanical studies. Since the liquid from the basin was removed by means of a wide channel, it is tempting to describe it as a bathtub. The bather entered the niche at the front, settled on the small seat and washed. It is possible that the drain was clogged and his body was partially submerged in the basin, or that the user washed himself with water flowing from the spout, which then flowed out through the drain. The two small inclined ramps beside the seat may have been designed to facilitate the water drainage. The channel is surprisingly large considering the small evacuation-hole of the basin (diameter 0.04-0.05 m). It was probably part of the main common sewer under the house, possibly coming from heated rooms (N) and (O), or from the west, running under the basin of the room (L). Unfortunately, the material under the basin has collapsed, and it is not possible at this time to determine the source of this sewer.

In the Hellenistic world, small individual tubs, most usually "hip-baths", are well documented in private homes and in public baths, in Egypt [START_REF] Fournet | Heating Systems of Greek Baths. New evidence from Egypt[END_REF] and Palestine [START_REF] Hoss | Baths and Bathing. The Culture of Bathing and the Baths and Thermae in Palestine from the Hasmoneans to the Moslem Conquest[END_REF]. It seems that from the end of the 1 st c. A.D., hip-baths from the Greek tradition tend to disappear in favor of immersion baths from the Roman tradition. In Jordan, recent works undertaken in Petra, on the top of Umm al-Biyara, uncovered a thermal building with small individual tubs (Schmid and Bienkowski 2011) 4 . These are not equipped with seats, but their walls are made of long slabs, set on their edges and joined with mortar. This building, dated by the excavators to the 1 st c. A.D., may be a good parallel for the House V1 bathtub. Another interesting parallel comes from southern Syria, where many dwellings have been explored. Ancient houses from the villages of Amra and Hit (Bodo and Clauss-Balty 2009: 241-242), dated by architectural studies to around the 3 rd c. A.D., have a niche in some rooms (approximately 1 m 2 and 1.80 m height). Some have a small basin inside the niche, while on the door jamb, outside the niche, is a protruding stone with a receptacle and a small conduit passing through the wall. Thanks to this installation, interpreted as a small sink, one can supply water from outside to the small basin inside the niche. This discovery allows us to imagine that, in House V1, a servant discreetly provided water to a person sitting in the bathhouse. If it is indeed a bath, Room (L) could be a bathroom, but we need to confirm this through further exploration.

Conclusion

Elucidating the trough system and discovering a probable small, sophisticated bathtub contribute to our knowledge of ancient habitation in Jordan. The southern side of this house seems to be a domestic area, with three residential rooms with paved floors and plastered walls, a stable and a large service courtyard with elements specific to domestic activities (kitchen items). On the northern side, we can perhaps recognize a luxurious area with a heated chamber, a possible bathroom, a room which may have stored betyls, a terrace overlooking the main sanctuary and a hypothetical large reception room. These two parts have undergone a transformation, and the first is probably older than the second, although the material collected during excavation does not yield conclusive evidence. The organization of the house and the findings of this season further support the suggestion that it could have belonged to a wealthy owner, perhaps the family who built the sanctuary, administered its possessions or took care of the religious services.

Area A

In 2001 and 2004, soundings were opened in a relatively flat area (alt. ca. 710 m) situated between the wadi (alt. 685 m) and the village (735 m), at about 150 meters south-west of the sanctuary [START_REF] Villeneuve | Le Sanctuaire Nabatéen et Romain de Dharih (Jordanie): Nouvelles Découvertes[END_REF], 1504-1506). They revealed the presence of an ancient caravanserai and its associated bathcomplex on both sides of a c. 4 m wide unpaved way (Fig. 10). elevation of the rather poorly built walls reaches c. 1.50 m. Due to the position of the excavation squares, and despite the opening of a probe on the supposed north-eastern angle of the building (A10), the plan of the complex and the limits of the inner open-air court remain hypothetical. The complex is interpreted as a mansio, which housed visitors to the sanctuary, as nothing in its construction method or the finds seem to point towards a military function or occupation of the building.

A Roman

The building opens on its western side through a c. 1.90 m wide gate. So far, this seems to be its only existing access, as no other opening has been identified in the northern (probe A6) and southern walls (probe A4) of the complex (although its eastern limit remains unexplored). This gate connected the path from the neighboring bath-complex (see infra) to a 3.80 m by 8.2 m porch (room A5), which opened on its eastern side by a second gate, accessing an open-air inner court. This western porch was originally divided into two square rooms of equal size by a very poorly built E-W wall, which supported two N-S arches on both sides of the wall. Surprisingly, this internal dividing wall and the eastern wall of the porch sit directly on Iron Age and/or Bronze Age structures (Fig. 11). The floor of the porch is crossed by a roughly built water channel, running from the east (inner court) to the street; its function (sewer?) remains unclear. The connection between this water channel and the baths is not established. On the west, in front of the main gate, the surface of the road has been paved with heavy flagstones (a c. 2 m by 1.5 m paved surface). The porch is apparently flanked on the north by two unexcavated rooms. The northwestern exterior corner of the caravanserai has been unearthed (probe A1). South of the entrance porch is a 3.7 m by 2 m room open to the inner court (room A9 north).

South of the central inner court, two large parallel rooms were partly excavated in 2004 (rooms A8+A4 on the south, of at least 12 m by 2.5 m; rooms A9 South+A11 on the north, of at least 12 m by c. 3 m). This last room, accessed by the northern room through a 2.05 m wide gate with a grooved threshold stone in situ, was originally closed by a double door. Due to the existence of V-shaped feeders in the parting wall c. 1 m from the floor, they are interpreted as stables, probably used to shelter animals (horses, mules or donkeys; Fig. 12). If one considers that this door is centered on the inner court, one can possibly imagine a c. 19 m wide room.

This feature is not unparalleled in Jordan. For instance, an early Roman mansio excavated in Khirbat as-Samra and connected to the Via Nova Traiana exhibits similar patterns, with long rooms reaching c. 17.5 m and almost 22 m (Humbert 1993: 92-93, Fig. 40-41). The presence of feeders, together with the absence of exterior buttresses, platforms, ventilation systems or specific storage vessels, exclude here an interpretation of these rooms as granaries or horrea (see e. The possible existence of an eastern row of rooms is suggested by symmetry with the western row (c. 5 m wide). In this case, the main entrance gate to the stables would have been centered on the main N-S axis of the building. A 2 m by 2 m probe in the eastern sector of the southern room (A4), opened in 2004, proved that the rough pavement made of boulders was built on a 2/3 cm thick yellowish mortar connected to the foundation of the southern wall. It appears to demonstrate that this pavement was built together with the southern wall of the caravanserai. Due to its mediocre quality, and unlike the other pavements of the complex from both the rooms and the inner court, this rough pavement was not repaired during the Byzantine period.

During the 2013 season, a 7.5 m by 2 m square was opened north of room A11 (open space A12). The aim was to have a better understanding of the inner court partly identified by the probe opened in 2004 east of the main porch. Surprisingly enough, no tumble or destruction of the upper elevation of the walls was discovered in the eastern half of the probe. This leads us to the conclusion that some of the building material was looted in this area, unlike the western side of the court, where the tumble of building material was found. The excavation 12. View of the beveled feeders in the "stables?" ( © L. T. 2013).

uncovered the base of a pavement, which was probably looted during the Byzantine period. We reached a similar conclusion in 2004 from the opening of the probe east of A5, where dumped ceramic material from the late 1 st c. A.D. was found to be connected to this base (see infra). There is so far no evidence of any inner portico. The excavation of the building is indeed rather frustrating, as part of the construction material was looted both after, and seemingly before, the destruction of the building. In the exposed rooms, the destruction debris/tumble covered what is interpreted as the base elevation of the pavements, of which no single element has so far been found in situ.

The date of the building can be established from several converging chronological clues delivered by independent loci. The earliest data connected to the building's use dates from the end of the 1 st or the beginning of the 2 nd century AD (Fig. 13). When identified, occupation levels can be dated to the 2 nd and 3 rd centuries. Ceramic finds associated with the destruction levels are dated to the late 3 rd or early 4 th c. AD. Several shops were built along the road. Room A3 (3.70 m by 3.70 m) abuts the northwestern angle from the caravanserai, and Room A8 was opened during a secondary stage in the south-western angle of the building, reducing the original length of Room 11.

Looking for general comparisons, in addition to the mansio of Kh. as-Samra, one could point to several settlements identified through surveys and excavations as Nabataeo-Roman caravanserais built along the Petra-Gaza road; e.g. in Mo'a, Sha'ar Ramon/Qaṣr al Mahale and Oboda [START_REF] Cohen | Hellenistic, Roman and Byzantine Sites in the Negev Hills[END_REF](Cohen : 1135(Cohen -1145;;Erickson-Gini 2010: 17-24). As far as one can tell, Qaṣrr at-Tayyiba, in the Wādī Arabah, seems typologically and chronologically close to our building (Smith et al. 1997: 62-63;Smith 2010: 36-37).

A Public Bath-Complex (C. Durand)
As well as the caravanserai/mansio, the public bath-complex was discovered in 2001, and excavation continued in 2004 and 2013. A first restoration, with identification of the rooms and bathing circuit, was proposed in 2008 [START_REF] Durand | Les Lampes Nabatéennes et Romaines de Khirbat Adh-Dharih (Jordanie). I er -IV ème siècles ap[END_REF]. However, the southern part of the building was not completely excavated, and restoration was still hypothetical. The main objective of the 2013 campaign was to complement this excavation in order to obtain the general plan of the bath complex (Fig. 14). Our goal was also to better understand its organization, particularly the water and heating systems.

The 2001 and 2004 campaigns have established that this building belongs to the axial row type (Krencker 1929: Abb. 234-240 (Type 1); Nielsen 1990 (vol. II): 51, Fig. 1; see also [START_REF] Rebuffat | Vocabulaire Thermal[END_REF]. The rooms adjoined each other, and the bather had to come back the same way in order to leave the building. The entrance of the building (Room A, apodyterium) is located in the north. It is a small rectangular room (4 m by 3 m), with a paved floor. Only two rows of rectangular slabs against the eastern wall were found in situ. The rest of the pavement has been removed, probably during the Byzantine period, when a small Christian community settled in Dharīḥ and built a village in the first court of the ancient Nabataean temple. This entrance leads to a second, larger and square room (Room B, 5 m by 5 m). Its pavement has been removed, together with that of Room A. It was the cold room of the bath complex (frigidarium). In the center of this room, we found a square cavity, formed by four large blocks embedded in the ground under the paving. Its function is still undetermined; it could correspond to the location of a central supporting pillar, possibly of wood. The western part of the building is extremely damaged and leveled, due to the slope of the hill. Therefore, the rooms located in this part could not be formally identified. The small room located in the north-west corner of the building (room C) was interpreted as a latrine, because of its situation close to the entrance and to the cold room. A deep sounding in the northeastern corner of this room demonstrated that the walls, as in the caravanserai, were partially founded on former rectangular structures, probably dating from the Bronze Age.

Room B opened to the south, leading to a small room (1 m by 3 m) which was interpreted as the tepidarium (warm room, Room D). This room was a connecting zone between the cold part of the building, and the heated rooms. The following room (Room E, 2 m by 4 m) was heated with a hypocaust system, fueled via a (Schmid 1996: 206-207, Figs. 700-701 heating channel in rectangular bricks located in the western wall of the room (praefurnium 1). Warm air was diffused vertically and horizontally through the rows of tubuli placed against the walls of the room. It was evacuated from the roof by several embedded chimneys, as evidenced by the vertical grooves regularly placed in the walls. This kind of device is known in Syria between the 2 nd and the 4 th c. AD, for example in the Roman baths of Bosra (Fournet 2007: 253). According to the traditional plan of Roman baths, this room must have been a cleaning/sweating room (destrictariumlaconicum). Although the rest of the building remained unexcavated at the end of the 2004 season, the presence of a second heated room to the south was already suspected, as there were four channels running under the southern wall of Room E.

During the 2013 season, this room (F) was partially excavated. According to the plan of the building, it was interpreted as the caldarium, which is usually characterized by the presence of a hot pool. The room is slightly larger than Room E (c. 3 m by 4 m), becoming narrower in its western part (ca. 2 m wide). A thick destruction layer was excavated, containing numerous fragments of ceramic pipes (tubuli), together with different sized bricks and mortar pieces, which have confirmed the hypothesis of a second heated room. Due to the short duration of the campaign, the hypocaust was not excavated this year. On the northern, southern and eastern walls of the room, one can notice several rectangular projections, regularly disposed. These are characteristic of the heated rooms in Roman baths, which flanked the "tubuli panels" placed against the walls. In addition, at least two semi-circular grooves (chimneys) have been uncovered in the south-eastern corner of the room. In the western part of the room, the thickening of the northern and southern walls probably indicates the limits of a large pool (ca. 2 m by 1 m) built against the western wall. A heating channel is visible in the center of this wall (praefurnium 2; Fig. 15), although it has not been excavated yet; two stacks of bricks appear on each side of the opening. This praefurnium appears to be embedded in a rectangular structure (c. 2 m by 0.7 m), built against the western wall in Room H. It could be the supporting base of a heated cistern, directly linked to the pool, just on the other side of the wall.

Room H was excavated in its southern part. It is a long, rectangular corridor type, located to the west of rooms F, G and probably E. This corridor facilitated entry of the fuel for the furnaces which heated rooms E and F (praefurnia 1 and 2), as evidenced by the thick layer of ashes (c. 30 cm) located just under its surface. This ashy layer was partly removed in front of the rectangular structure, by means of a sounding c. 1.50 m wide. This revealed a floor level which can probably be interpreted as the circulation floor (Fig. 16) 6 . Due to the slope of the hill, the north-south wall closing Room H to the west has almost totally disappeared. Consequently, the location of the access door to the corridor from outside the building cannot be determined. However, a door which opened to Room G, located to the south of Room F, and which was partly excavated on its eastern side in 2004, was discovered (Fig. 17). Unlike rooms E and F, it is a simple room without a heating system. A stack of rectangular bricks in the middle of its northern wall suggested the presence of another heating channel opening to Room F (praefurnium 3). This praefurnium was partly excavated in 2013, after removal of the deep destruction layer (Fig. 18).

The water system for this bath-complex is still poorly understood; further investigation in the western part of the building, under the foundation level, would probably provide more information. Similarly, other than construction material (tubuli and bricks), the pottery found in the bath is very scarce and does not establish a definite date. Nevertheless, it does suggest a utilization period between the 2 nd and the 4 th c. AD. A complete Roman lamp, found near the praefurnium 2, is dated to the 2 nd to 3 rd c. AD (Fig. 19; same type : Durand 2011: 72, n. 32-37;'Amr 2004: 242, Fig. 5).

Based on its organization, this bath-complex seems to be inspired by the Campanian architectural model, which was diffused throughout the whole Roman Empire during the 1 st c. AD. The closest parallel in the Near East can be found at Sleim (Southern Syria), where the baths are dated to the 1 st c. AD or the beginning of the 2 nd c. AD (Fournet 2010).

Another close example, both in its plan and its date, is the Roman bath recently excavated in Xèron Pelagos, in the Egyptian Eastern Desert [START_REF] Redon | L'armée et Les Bains en Egypte Hellénistique et Romaine[END_REF].

Conclusions for Area A

The discovery of a mansio and its associated bath-complex in Dharīḥ is of special interest. The identical phasing of these buildings suggests they both belong to a single phase which was initiated at the turn of the 2 nd century AD. Their construction seems therefore contemporary to the rebuilding of the main sanctuary. The association between a caravan-station and a bath is common in the Roman world. Examples in the Nabataean area include Sha'ar Ramon (Erickson-Gini 2010: 22), En Hatzeva (Cohen 1994: 205) and Mampsis [START_REF] Negev | The Late Roman and Byzantine Periods[END_REF] in the Negev; Humeima [START_REF] Oleson | Humeima Hydraulic Survey[END_REF][START_REF] Reeves | of the Hisma Desert[END_REF], Bir Madhkur (Smith 2010: 39) and Gharandal [START_REF] Darby | Roman Fort Amidst the Dunes: The 'Ayn Gharandal Archaeological Project[END_REF][START_REF] Keller | Archaeology in Jordan, 2010 and 2011 Seasons[END_REF] in Jordan. Nevertheless, as far as we know, similar accommodation infrastructures have never been found in the Roman Near East within a religious complex; we can therefore assume that this complex was eventually used by pilgrims who frequented the regional sanctuary of Dharīḥ. Moreover, an eventual link between the construction of this complex and the Roman military presence in the region after the annexation of the Nabataean kingdom is not confirmed, since the caravanserai does not seem fortified (for the link between the bath and the army in Roman Egypt, see Redon 2010).

  © P. P.-F. 2013). 4. Left, on the wall, the trough blocks (D1), (D2) and (D3). On the right, the trough block (E4) (© P. P.-F. 2013).

  Locus 1101) supporting the pavement ( © P. P.-F. 2013). 7. Plan of room (L) ( © P. P.-F. 2013).

  8. Sunken monolithic basin inside the niche ( © P. P.-F. 2013). 9. The bathtub in the niche and the channel during excavations ( © P. P.-F. 2013).

  Mansio (L. Tholbecq) A c. 30 m by 20 m building, organized around a courtyard (c. 19 m by 12 m) and surrounded by independent rooms was discovered at Khirbat ad-Dharīḥ during the 2001 season, on the southern access-way to the temple area. It was partly excavated in 2001, 2004 and 2013. The general layout of the building has been defined through several probes, the main work focusing on the south-western rooms of the building (Villeneuve and al-Muheisen 2008: 1504-1506) 5 . The maximum preserved 4. The discoveries of the "International Umm al-Biyara Project" were presented by Piotr Bienkowski at the ICHAJ conference in Berlin in May 2013. See also online reports 2010 (http://www. auac.ch/iubp/season2010/iubp_2010_text03c.html) and 2012 (http://www.auac.ch/iubp/season2012/iubp_2012_text03b. html), Figs. 9 and 11. 5. The excavations were directed jointly by François Villeneuve and Zeidoun al-Muheisen. Square supervisors were Laurent Tholbecq (Squares DH01-A1, DH01-A3, DH01-A4, DH01-A5North, DH01-A6; DH04-A5South, DH04-A10; DH13-A12); Béatrice and François Villeneuve (DH04-A7), Nural-Dîn al-Saad and Mohammad al-Mearaj (DH04-A4, DH04-A8, DH04-A9, DH04-A11).

  g. at Lejjûn, Crawford 2006: 235-240, Fig. 9.; Fig. 3.3).

  11. Iron Age and/or Bronze Age structures located under the mansio ( © L. T. 2013).

  6. Some ash samples were collected in order to analyze the botanical remains. The study will be conducted by Charlène Bouchaud (Muséum d'Histoire Naturelle, Paris).

  15. View of praefunium 2 ( © C. D. 2013).

  17

  . The door between rooms H and G ( © C. D. 2013). 16. View of the floor level under the ashy layer, Room H ( © C. D. 2013).

Plan of House V1. Grey sections indicate areas investigated during the 2013 season ( © P. P.-F. 2013).

Plan of Area A. The mansio and the bath-complex. Grey sections indicate areas investigated during the 2013 season ( © J. Humbert 2004).

Plan and restoration of the Nabataean-Roman baths of Dharih ( © C. D. 2013).


Au Professeur

Vincent Costalat

Nicolas Menjot

Cyril Dargazanli

Imad Derraz

Arthur Coget

Pierre-Henri Lefevre

Gregory Gascou

Federico Cagnazzo

Carlos Riquelme

A Mehdi Mahmoudi

Mathilde Carrière

Eve Denis

A Marine Dumon

Laurie-Anne Godchaux

Diviez Julien

Philippe Lam

Carole Chevalier

A L'équipe D'

Arnaud De Villeneuve

Kovacsik Helene

Bommart Sebastien

Zarqane Hamid

Vanoverschelde Juliette

Valérie Monnin-Bares

Benoit

A Réjane Martin

Renaud Sales

Fabien De Oliveira

Caroline Mandoul

Juliette Coutureau

Emma Pages-Bouic

Mohamad Azhar Meerun

Carole Allimant

Benjamin Rivière

Astrid Herrero

Fabrizio Panaro

Eric Assenat

Christophe Cassinotto

Denis Mariano-Goulart

Boris Guiu
email: b-guiu@chu-montpellier.fr.

Prof Boris Guiu

Large, multifocal or portal vein-invading hepatocellular carcinoma (HCC) downstaged by Y90 using personalized dosimetry: safety, pathological results and outcomes after surgery

Keywords: Interventional radiology, Hepatology, Surgery, Nuclear medicine Selective internal radiation therapy, hepatocellular carcinoma (HCC), liver cancer, resection, transplantation Clinical trial number: NCT05045573 Selective internal radiation therapy, hepatocellular carcinoma (HCC), liver cancer, resection, transplantation

pour toutes les connaissances indispensables qu'ils m'ont transmises en neuroradiologie diagnostique et interventionnelle A Nicolas Lebouq pour toutes les précieuses connaissances qu'il m'a transmis en neuroradiologie pédiatrique notamment par son investissement et expertise au staff de pédiatrie

A Docteur Carole Allimant, de m'avoir accompagné pendant toute la phase de recueil de données et d'écriture de la thèse. Merci pour tes idées brillantes qui non seulement ont donné jour à ce travail mais qui bénéficieront à de nombreux patients.

A l'équide de Saint Eloi,

A Marie-Ange Pierredon-Foulongne, Valentina Scembri, Ali Belgour, Christophe Cassinotto, Lauranne, Julie Lonjon, Margaux Hermida, Bachir Benoudifa et Laure Escal. Vous m'avez initié à la radiologie diagnostique et interventionnelle lors de mon passage chez vous en premier semestre. Votre rigueur, votre maitrise de la radiologie oncologique et votre investissement dans le service est, pour moi, un exemple à suivre.

A Ancelin, Philippe, Héloïse, Nicolas et Anthony, mes premier co-internes. Merci pour votre entraide et votre bonne humeur pendant tout le stage.

A l'équipe de Beau Soleil,

A Muriel Viala-Trentini, Julie Bolivar, Julie Colleau, Benjamin Langman, Florian Danière et Silvia Gaudin pour l'initiation à l'imagerie pelvienne, l'ostéoarticulaire, la neuroradiologie. Large, multifocal or portal vein-invading hepatocellular carcinoma (HCC) downstaged by Y90 using personalized dosimetry: safety, pathological results and outcomes after surgery.

RÉSUMÉ

Contexte

La radio-embolisation (RE) a récemment été reconnue comme un traitement d'accompagnement à la chirurgie pour les carcinomes hépatocellulaires (CHC) précoces avec des taux élevés de nécrose histologique complète (NHC). Chez les patients avec un thrombus tumoral de la veine porte (TTVP), des tumeurs multifocales ou de grandes tailles, la RE a principalement un rôle palliatif et la chirurgie reste discutable.

Méthodes

Dans cette étude rétrospective, nous avons évalué la tolérance, la réponse radiologique, la réponse histologique et la survie des patients atteints de CHC avec des TTVP, des tumeurs multifocales ou de grande taille, opérés après RE avec une dosimétrie personnalisée. [START_REF] Marrero | Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases[END_REF]. Yet, randomized-controlled trials (RCT) (7-9) established a longer time to progression (TTP) and an improved safety and quality of life after TARE vs. TACE.

Résultats

In case of PVTT, TARE is not recommended because of negative phase III RCTs in BCLC C stage. Several explanations have been put forward to account for such negative results, among which: a poor selection of patients, a learning curve achieved through these trials and the absence of modern dosimetry, in contradiction with basic principles of radiation therapy [START_REF] Llovet | Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma[END_REF][START_REF] Salem | Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience[END_REF]. The DOSISPHERE-01 multicenter RCT has recently refocused attention on TARE by demonstrating the superiority of personalized dosimetry over standard dosimetry used in prior negative phase III trials. At interim analysis, the primary endpoint (objective response) was met (71% vs. 36%, P=0.0074) despite the inclusion of poor-prognosis tumors (mean size >10 cm, PVTT in 2/3 cases). Median overall survival (OS) was also more than doubled with personalized dosimetry (26.5 vs. 10.7 months, P=0.0096) and it far exceeded the OS following systemic treatments, albeit recommended. Based on pre-treatment single photon emission computed tomography (SPECT)-CT, personalized dosimetry aimed at delivering high tumor-absorbed dose while keeping >30% hepatic reserve (i.e., untreated liver) for safety purposes.

Surgical treatment of BCLC B or C generally remains controversial [START_REF] Allaire | New frontiers in liver resection for hepatocellular carcinoma[END_REF]. Moreover, resection of large, multifocal or PVTT HCC frequently implies a major hepatectomy, thereby raising the additional issue of insufficient future liver remnant (FLR). All this may explain why TARE is mainly considered as a palliative treatment with no hope of cure in these tumors. Consequently, little is known in this poor prognosis population about the pathological response and patient's outcome after surgery following Yttrium-90 (Y90) downstaging. In DOSISPHERE-01, eleven patients with unresectable HCC (n=8/11 with PVTT) were downstaged by Y90 and eventually underwent surgery (91% R0). The accumulated experience of radiation segmentectomy and lobectomy in early tumors revealed that Y90 allows tumor control, contralateral hypertrophy and an embedded test of time to prevent surgery in patients with aggressive tumor biology [START_REF] Salem | Yttrium-90 Radioembolization for the Treatment of Solitary, Unresectable HCC: The LEGACY Study[END_REF][START_REF] Lewandowski | Y radiation lobectomy: Outcomes following surgical resection in patients with hepatic tumors and small future liver remnant volumes[END_REF]. Taken collectively, these data suggest a potential role of Y90 as a downstaging strategy, even in HCC patients with PVTT, multifocal or large tumors.

The aim of this study was to evaluate safety, radiological and pathological response and outcomes in HCC patients with PVTT, multifocal or large tumors, who underwent surgical treatment after Y90 TARE using personalized dosimetry. We present the following article in accordance with the STROBE reporting checklist (available at https:// hbsn.amegroups.com/article/view/10.21037/hbsn-22-184/rc)

Methods

Patient selection

Consecutive patients who underwent TARE between December 2015 and October 2021 were included. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This retrospective study was approved by our institutional review board (IRB-UH Montpellier; accreditation number: 198711 and the IRB ID is 202100933) and written informed consent was obtained from all patients. Inclusion criteria were: HCC diagnosed by histopathology or by the imaging criteria of the European Association for the Study of the Liver (EASL); patients treated by TARE using Y90-loaded glass microspheres for a large (i.e., >8 cm) and/or multifocal (all >2 cm to ensure reliable assessment of both imaging response and tumorabsorbed dose) tumor, and/or presenting PVTT; patient who underwent surgical resection or liver transplantation (LT). Exclusion criteria were: patients undergoing additional treatment (either systemic or liver-directed therapy) in the treated zone to capture the pure effects of TARE at pathology; extra-hepatic disease.

In our tertiary center, TARE is indicated in BCLC A patients with non-resectable ≥5 cm HCC, in BCLC B patients or in BCLC C patients with PVTT. In addition, the following criteria had to be fulfilled: preserved liver function (Child-Pugh < B7), unilobar disease with sufficient hepatic reserve (>30%), ECOG 0-1, normal bilirubin level (<2 mg/dL), absence of severe renal impairment [glomerular filtration rate (GFR) <30 mL/min/1.73 m 2 ] and absence of extrahepatic spread. Our policy granted the exception to bilobar disease when it was predominant in one lobe and thermal ablation could efficiently cure the contralateral disease. TARE either served as a bridge/downstaging therapy to surgery or as a palliative treatment in inoperable patients.

TARE was validated by a multidisciplinary tumor board dedicated to liver tumors, including interventional radiologists, hepatologists, oncologists and liver surgeons. Over the study period, our policy was to systematically consider surgery after a test-of-time period ≥3 months, provided enough FLR [standardized FLR (sFLR) ≥40%] and tumor control were achieved. LT was considered only when the tumor was downstaged without any other tumor occurrence for at least 6 months and after external experts appointed by the biomedicine agency in France had given their agreement.

Pretreatment and radioembolization technique

All patients underwent angiography and 99m-Technetium macroaggregated albumin (MAA) SPECT-CT before TARE with Y90 glass microspheres to ensure complete tumor (and PVTT, when present) targeting, while preserving as much nontumoral parenchyma as possible. The lung shunt fraction was determined, extrahepatic MAA distribution was checked and the activity required was calculated using the Medical Internal Radiation Dosimetry (MIRD) method to deliver at least 205 Gy to the tumor and >250-300 Gy if possible, while maintaining <150 Gy to whole liver, in accordance with the personalized dosimetry concept [START_REF] Garin | Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial[END_REF]. A Y90positron emission tomography (PET)/CT was systematically performed within 24 hours following TARE.

The pre-and post-treatment absorbed doses were determined from pre-TARE SPECT/CT and post-TARE Y90-PET/CT. In case of tumor multifocality, the absorbed dose delivered to each nodule was estimated for a per-tumor analysis, whereas the lowest tumor-absorbed dose among tumor nodules was recorded for a per-patient analysis.

Baseline imaging and follow-up

Baseline imaging was performed less than one month before TARE and clinical, biological and imaging [CT or magnetic resonance imaging (MRI)] follow-up was conducted every 3 months thereafter. Adverse events related to TARE were classified according to the CTCAE 5.0 grading. Imaging review was carried out by two readers to assess imaging response upon modified response criteria in solid tumors (mRECIST), with discrepancies adjudicated by consensus. As in the LEGACY study [START_REF] Salem | Yttrium-90 Radioembolization for the Treatment of Solitary, Unresectable HCC: The LEGACY Study[END_REF], we dichotomized localized mRECIST, defined as the tumor response within the treated zone, and mRECIST, which assessed localized tumor response but also distant tumor progression.

PVTT and hepatic vein tumor thrombus (HVT) were classified as described elsewhere [START_REF] Cerrito | Treatment of hepatocellular carcinoma in patients with portal vein tumor thrombosis: Beyond the known frontiers[END_REF]. Since PVTT/HVT are considered non-measurable upon mRECIST, we considered: (I) complete response (CR) both when tumor response (upon mRECIST) outside PVTT/HVT was complete and when PVTT displayed unenhancement on follow-up images, without any increase in its diameter and without any proximal extension; (II) progressive disease either when progression was noted (upon mRECIST) outside PVTT/HVT, or when increased diameter or extension of a contrast-enhanced PVTT was encountered; (III) partial response (PR) or stable disease (SD), as defined by mRECIST for tumor assessment outside PVTT/HVT, together with the absence of both diameter increase and proximal extension of the PVTT. The same principles were applied to localized mRECIST.

In this study, imaging response on the last follow-up preceding surgery and the best response between TARE and surgery were recorded.

Surgery

sFLR volumetric evaluations were determined using CT/ MRI scans, as described elsewhere [START_REF] Ribero | Standardized liver volumetry for portal vein embolization[END_REF]. Surgery was performed by experienced (10 to 20 years) liver surgeons working at our tertiary transplant center. Time from TARE to resection or transplantation, 90-day mortality, morbidity according to Dindo-Clavien classification [START_REF] Dindo | Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey[END_REF] and post hepatic liver failure (PHLF) according to International Study Group of Liver Surgery (ISGLS) criteria [START_REF] Fukushima | Assessment of ISGLS definition of posthepatectomy liver failure and its effect on outcome in patients with hepatocellular carcinoma[END_REF] were reported.

Pathology analysis

The explant was evaluated from archived slides by one experienced (>10 years in liver pathology) pathologist for evidence of gross and histological necrosis. After formalin fixation, the resected liver was examined using 4-6 mm slice thickness. For the per-tumor analysis, the percentage of necrosis was reported for each nodule and classified into three groups as previously described [START_REF] Gabr | Correlation of Y90absorbed radiation dose to pathological necrosis in hepatocellular carcinoma: confirmatory multicenter analysis in 45 explants[END_REF][START_REF] Toskich | Pathologic Response of Hepatocellular Carcinoma Treated with Yttrium-90 Glass Microsphere Radiation Segmentectomy Prior to Liver Transplantation: A Validation Study[END_REF][START_REF] Vouche | Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy[END_REF][START_REF] Riaz | Radiologicpathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres[END_REF]: complete pathological necrosis (CPN), extensive (50-99%) and partial (<50%) tumor necrosis. For the per-patient analysis, the poorest pathological response was considered in case of tumor multifocality. The resection margin, the degree of tumor differentiation (poor, moderate or well differentiated) and the presence of microscopic vascular emboli were also evaluated.

Statistical analysis

Continuous variables were described using means ± standard deviation or median and range. Median [and 95% confidence interval (CI)] follow-up was calculated using the reverse Kaplan-Meier method. Progression-free survival (PFS) was defined as the time from TARE to the first recurrence, death or last follow-up. OS was defined as the interval between TARE and death (any cause) or last follow-up. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. A robust variance estimator was used systematically. All the analyses were performed with the Stata software, version 16.1 (Stata corporation, College Station, TX, USA). A P value <0.05 was considered significant.

Results

Population (Figure 1)

Over the study period, 116 patients underwent TARE with Y90 glass microspheres. Ninety-two had HCC, among whom 25 (27%) were surgically-treated (22 resections and 3 LT). The main reasons for unresectability included progressive disease after TARE, severe portal hypertension precluding resection, severe renal, respiratory or cardiac impairment, advanced age and patient's refusal. Two surgically-treated patients did not meet the inclusion criteria because they had neither PVTT, nor large or multifocal HCC. Four patients were excluded because they had received additional treatments prior to surgery. One patient was diagnosed with hepatocholangiocarcinoma on the final pathology report and was therefore excluded.

Overall, 18 patients were included in our series. Baseline

TARE and related events

Most patients (13/18) received lobar TARE [right (n=10), left (n=3)], and the remaining patients underwent sectorial and segmental TARE for two and three of them, respectively. Baseline total tumor volume was 82 mL (range, 15-1,769 mL) and baseline perfused-liver volume was 677 mL (range, 265-2,331 mL). A discrepancy between pre-treatment SPECT-CT estimated dosimetry and posttreatment PET-CT results was noticed in two patients: one had a preferential flow in the non-tumor-bearing segment due to vasospasm, which resulted in a poor tumor dose on the post-treatment PET-CT. The other patient had less Post operative wound requiring reintervention under GA 1 [START_REF] Marrero | Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases[END_REF] Post operative wound dehiscence 1 [START_REF] Marrero | Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases[END_REF] Biloma requiring intervention under GA 2 [START_REF] Allaire | New frontiers in liver resection for hepatocellular carcinoma[END_REF] 4b (hemorrhagic shock) 1 [START_REF] Marrero | Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases[END_REF] Blood loss (mL) 700 [300-2,000] 90-day mortality 0 PHLF Absent

[78]

Grade A 0

Grade B (clinical ascites) 2 [START_REF] Salem | Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience[END_REF] Grade C 0 Not applicable (liver transplantation) 2 [START_REF] Salem | Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience[END_REF] Hospital stays (days) 12 ICU stays (days) 6 The data are expressed as n [%] or median [range]. GA, general anaesthesia; PHLF, post hepatectomy liver failure; ICU, intensive care unit.

radiation delivered to the proximal portion of the portal vein thrombosis without any technical explanation. TARErelated adverse events were all mild and transient (Table S1).

No radioembolization-induced liver disease (REILD) or pneumonitis was observed. Baseline and pre-operative data on biochemical liver function tests are collected in Table S2.

Tumor response

Localised mRECIST

Seven (39%) patients achieved CR prior to surgery, whereas 10 (56%) achieved PR and 1 (6%) had SD. Response rates were identical when considering the last follow-up preceding surgery and the best response between TARE and surgery. The median time to achieve best response was 3 months (range, 2-11 months).

mRECIST CR prior to surgery was noted in 7/18 (39%) patients, PR in 8/18 (44%), SD in 1/18 (6%) patients and progressive disease in 2/18 (11%) patients. Progressive disease occurred in the untreated zone and was accessible to a curative treatment. Both patients received intraoperative thermal ablation during surgery. Considering the best response between TARE and surgery, CR was noted in 7/18 (39%) patients, PR in 10/18 (56%) patients and SD in 1/18 (6%) patient.

Median baseline alpha fetoprotein (AFP) was 16.2 ng/mL (range, 2.2-3,071 ng/mL) and AFP 3 months after TARE was 12.9 ng/mL (range, 1.7-85 ng/mL) [P= not significant (NS)]. Data specific to patients with PVTT are summarized in Table S3.

Surgery

Eleven patients underwent major hepatectomy (Brisbane classification), 2 received LT and 5 patients had less extended resections. In patients who underwent major hepatectomy, volumetric evaluations showed a median sFLR of 48% (range, 36-70%) at baseline and 67% (range, 48-107%) the week preceding surgery, which determined a median FLR hypertrophy of 36% (range, 4-81%).

The median time from TARE to surgery was 6.2 months (range, 2-14.6 months). The most common treatment was right hemi-hepatectomy (11/18). The other patients underwent left lobectomy (n=3), segmentectomy (n=1), bisegmentectomy with additional wedge resection (n=1) and LT (n=2). Parenchymal dissections were performed using CUSA Dissectron ® (Integra Life Sciences Corp., Tokyo, Japan) in all cases of resection. Of note, the transplanted patients both presented PVTT at baseline. Median surgery time was 406 minutes (range, 232-672 minutes). Perioperative data are collected in Table 2. Overall, 33% (n=6) ≥ grade III Dindo-Clavien complications were recorded. Two grade B PHLF occurred with full recovery after diuretic therapy. No 90-day mortality was observed.

Pathological results

All patients had R0 resection. In per-tumor analysis (n=22), CPN, extensive necrosis and partial necrosis were achieved respectively in 8 (36%), 10 (45%) and 4 (18%) tumors. In per-patient analysis, CPN, extensive necrosis and partial © HepatoBiliary Surgery and Nutrition. All rights reserved.

HepatoBiliary Surg Nutr 2022 | https://dx.doi.org/10.21037/hbsn-22-184 necrosis occurred respectively in 28%, 50% and 22% of patients. Microscopic vascular emboli were reported in 6/18 (33%) patients. Evaluation of cellular differentiation was possible in 12/18 patients (5 had no residual viable tumor cells and one presented extensive necrosis devoid of viable cells for tumor grading). Tumors were well-, moderately-, and poorly-differentiated in 1, 5, and 6, respectively. Median tumor size was 37 mm (range, 20-93 mm) in tumors showing CPN, 65 mm (range, 34-111 mm) in those with extensive necrosis and 56 mm (range, 29-150 mm) in case of partial necrosis (P=0.24). Baseline AFP levels were highest in patients with CPN with a median of 38 ng/mL (range, 3.5-3,071 ng/mL) (P=0.7). Median AFP levels in patients with extensive and partial necrosis were 15 ng/mL (range, 2.2-1,032 ng/mL) and 16 ng/mL (range, 3.4-16.7 ng/mL) respectively (P=0.7). All patients presenting CPN had PVTT at baseline. In PVTT patients, 36% (5/14) exhibited CPN and none presented microscopic vascular emboli on the explant. Of note, 79% (11/14) exhibited CPN of the PVTT.

Dosimetric considerations

The whole liver-absorbed dose was 99 Gy (range, 30-150 Gy). Post-treatment perfused-liver dose was 202 Gy (range, 123-650 Gy). In per-tumor analysis, the median pre-and post-treatment tumor-absorbed doses were 386 Gy (range, 169-967 Gy) and 331 Gy (range, 31-1,131 Gy) respectively. Tumor-absorbed doses were greater in patients presenting CPN (Table 3). Post-treatment tumorabsorbed dose significantly differed in tumors that exhibited complete (446 Gy), extensive (320 Gy) and partial (187 Gy) pathological necrosis (P=0.045) (Figure 2).

Radiologic-pathologic correlation (Table 4)

All patients (5/5) with CPN had CR according to best mRECIST response. Conversely, 71% (5/7) of patients with CR according to best mRECIST response achieved CPN. The remaining patients (2/7) with CR had extensive tumor necrosis at pathology.

Time to surgery and pathological necrosis

Median time from TARE to surgery was 8.3 months (range, 5.8-14.6 months) in patients with CPN, 4.3 months (range, 3.7-13.6 months) in patients with extensive necrosis and 4.9 months (range, 2.1-10.5 months) in patients with partial necrosis. Delay from TARE to surgery was longer in CPN patients (P=0.05).

Patient's outcome (Figure 3)

During a median follow-up of 29.6 months (95% CI: 15.4-32.9 months), 4/18 patients died and 7/18 (39%) patients recurred, which determined a median PFS of 49.3 months (95% CI: 14 months-NR) and a median OS of 61.8 months (95% CI: 31.4 months-NR) (Table 5). PFS at 1 and 2 years were 82.6% (95% CI: 55.3-94.1%) and 58.9% (95% CI: 29.3-79.6%), respectively. OS at 1 and 2 years were 93.8% (95% CI: 63.2-99.1%) and 85.9% (95% CI: 54-96.3%), respectively. HCC-related mortality was 1/18. Relapse location and the outcomes of recurring patients are summarized in Table 6. Causes of death in non-relapsing patients were: sudden cardiac arrest (1 patient, 7 months after LT) without any tumor relapse, severe cryptococcal meningitis (1 patient, 7 months after surgery) and septic choc (1 patient, 16.8 months after surgery). Of note, one patient had a nodular implant in the right ventricle, whose metastatic nature was confirmed on biopsy. Interestingly the patient had an initial right HVT. The two other patients with HVT did not develop lung metastasis after a 27-and 28-month follow-up, although one relapsed within the liver. The non-recurring HVT patient also presented PVTT at baseline but achieved CPN.

All 3 patients with incomplete pathological response on the PVTT recurred. Among 7 patients with microscopic vascular emboli, 57% (4/7) recurred.

Among 7 recurring patients, 86% (6/7) remained eligible either to a new curative treatment or to a systemic therapy, whereas one had supportive care due to old age. Two patients underwent additional surgery upon first relapse (LT and segmentectomy, respectively). Three patients received

Discussion

The present study shows that successful downstaging of poorprognosis HCCs can potentially be achieved by Y90 TARE with personalized dosimetry, which yields a high rate of imaging and pathological response. The potential of TARE to successfully bridge/downstage to LT or resection has been widely demonstrated in early HCC, especially through radiation lobectomy [START_REF] Gabr | Outcomes of Surgical Resection after Radioembolization for Hepatocellular Carcinoma[END_REF] and segmentectomy [START_REF] Salem | Yttrium-90 Radioembolization for the Treatment of Solitary, Unresectable HCC: The LEGACY Study[END_REF]. In this context, pathological data have revealed high rates of CPN for small, solitary and treatment-naïve tumors [START_REF] Gabr | Correlation of Y90absorbed radiation dose to pathological necrosis in hepatocellular carcinoma: confirmatory multicenter analysis in 45 explants[END_REF][START_REF] Toskich | Pathologic Response of Hepatocellular Carcinoma Treated with Yttrium-90 Glass Microsphere Radiation Segmentectomy Prior to Liver Transplantation: A Validation Study[END_REF][START_REF] Vouche | Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy[END_REF][START_REF] Riaz | Radiologicpathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres[END_REF]. Our cohort has brought up new data in HCC with PVTT, multifocal disease and large tumors. At baseline, the HCCs in our series were all unresectable and not only outside conventional criteria for LT including the AFP model and Milan criteria, but also outside the extended University of California San Francisco (UCSF) criteria. They were however successfully downstaged using only one single Y90 treatment. According to AASLD/BCLC [START_REF] Reig | BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update[END_REF][START_REF] Heimbach | AASLD guidelines for the treatment of hepatocellular carcinoma[END_REF], PVTT patients should undergo systemic therapy, whereas patients with multifocal or large HCCs should be considered for TACE (and optionally for TARE); either for palliative care or as a downstaging strategy to LT. We observed a median OS and PFS of respectively 61.8 months and 49.3 months in our cohort, including 78% of patients with PVTT. These survival outcomes far exceed expectations in this poor prognosis population: the results of systemic therapies in this context are considerably worse, as illustrated by the median OS and TTP of respectively 8.1 months and 4.1 months after sorafenib (SHARP trial) [START_REF] Bruix | Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial[END_REF], and by the 14.2-month median OS and the 6.7-month PFS after atezolizumab-bevacizumab (IMBRAVE150 trial) [START_REF] Cheng | Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma[END_REF]. Upfront surgical resection of PVTT HCC usually results in poor outcome [START_REF] Torzilli | A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group[END_REF] and was shown to perform no better than sorafenib [START_REF] Costentin | Sorafenib vs surgical resection for hepatocellular carcinoma with macrovascular invasion: A propensity score analysis[END_REF]. Even in expert centers and with progressive refinements in dosimetry, TARE used as a palliative treatment provides a median OS ranging from 16.6 to 32 months in Child-Pugh A patients with branch PVTT [START_REF] Garin | Boosted selective internal radiation therapy with 90Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept[END_REF][START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF][START_REF] Spreafico | Development of a prognostic score to predict response to Yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion[END_REF][START_REF] Salem | Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-© HepatoBiliary Surgery and Nutrition. All rights reserved[END_REF]. Therefore, our results suggest an improved outcome of TARE downstaging to surgery over systemic therapy or upfront surgery or TARE alone.

Safety of TARE and surgery

Regarding safety, only mild and transient adverse events were reported in our series after TARE, in keeping with the literature [START_REF] Vouche | Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy[END_REF][START_REF] Garin | Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial[END_REF]. As previously reported [START_REF] Gabr | Outcomes of Surgical Resection after Radioembolization for Hepatocellular Carcinoma[END_REF], surgeons could easily differentiate the TARE-treated liver from the untreated liver due to increased inflammation and induration, but they noticed frequent adhesions to adjacent structures which may have complicated surgical resection. Nevertheless, surgery after TARE was safe in our cohort with no 90-day mortality, no grade C PHLF and a 33% rate of ≥ III Dindo-Clavien complications. Perioperative outcomes remained within the range reported for surgical resection without prior TARE [START_REF] Gelli | Liver Resection for Early Hepatocellular Carcinoma: Preoperative Predictors of Non Transplantable Recurrence and Implications for Treatment Allocation[END_REF].

Pathological response

Despite high tumor burden and poor prognosis of our HCC series, CPN occurred after Y90 alone in a significant number of tumors (36%). Of note, all CPN occurred in PVTT HCC, suggesting that PVTT can be completely cured by TARE using personalized dosimetry. Higher rates (47-68%) were reported in pathological series after radiation segmentectomy, but only early HCCs were involved [START_REF] Gabr | Correlation of Y90absorbed radiation dose to pathological necrosis in hepatocellular carcinoma: confirmatory multicenter analysis in 45 explants[END_REF][START_REF] Toskich | Pathologic Response of Hepatocellular Carcinoma Treated with Yttrium-90 Glass Microsphere Radiation Segmentectomy Prior to Liver Transplantation: A Validation Study[END_REF][START_REF] Vouche | Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy[END_REF]. Not only did our cohort present frequent PVTT, but the median tumor size was also twice as large (5.3 vs. 2.3-2.6 cm) as that of the previous series. In a series including 5/38 patients with PVTT [START_REF] Riaz | Radiologicpathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres[END_REF], CPN was reported in 33% of >5 cm tumors, in line with our findings. The larger the tumor, the lower the chance of CPN, due to dose deposition heterogeneity and/or difficulty to reach an efficient dose threshold while keeping safe whole-liver absorbed dose. Not surprisingly, tumors achieving CPN received a significantly greater radiation dose than the others (446 Gy for CPN, 320 Gy and 187 Gy for extensive and partial necrosis respectively, P=0.045) on post-TARE Y90-PET/CT, reflecting the actual dose delivered to the tumor. Similar findings have been reported in T1-T2 solitary [START_REF] Gabr | Correlation of Y90absorbed radiation dose to pathological necrosis in hepatocellular carcinoma: confirmatory multicenter analysis in 45 explants[END_REF][START_REF] Vouche | Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy[END_REF] or T2-T3 (4) HCC.

Achieving CPN after pretransplant locoregional therapies heralds lower recurrence and better survival in LT recipients compared to those exhibiting partial necrosis [START_REF] Dinorcia | Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium[END_REF][START_REF] Ravaioli | Partial necrosis on hepatocellular carcinoma nodules facilitates tumor recurrence after liver transplantation[END_REF]. Gabr et al. [START_REF] Gabr | Outcomes of Surgical Resection after Radioembolization for Hepatocellular Carcinoma[END_REF] identified pathological necrosis as a significant prognosticator of recurrence in 31 HCC patients (only one with PVTT) undergoing surgical resection after TARE. In our series of HCC with PVTT, large, or multifocal tumors, no patient with CPN recurred during follow-up, whereas median PFS was 22.5 months in those who did not achieve CPN (P<0.001). Therefore, our findings also support pathological necrosis as a predictor of recurrence in this specific population.

Imaging response

In our series, the best objective response rate (ORR) was obtained at 3 months. While upon localized mRECIST, ORR was high, i.e., 94% (39% CR, 52% PR), it amounted to 83% upon mRECIST (39% CR, 44% PR), thereby confirming the great potential of TARE as a downstaging strategy. A significant correlation between imaging and pathological response has been shown after radiation segmentectomy [START_REF] Bruix | Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial[END_REF][START_REF] Dinorcia | Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium[END_REF][START_REF] Ravaioli | Partial necrosis on hepatocellular carcinoma nodules facilitates tumor recurrence after liver transplantation[END_REF]. Predicting CPN would be highly desirable to avoid unnecessary surgical resection; it is however beyond the scope of our study. Interestingly, all patients presenting CPN after surgery had prior CR on imaging. Conversely, among patients with CR, 71% (5/7) had CPN. Patients with CR on imaging had longer PFS than the others (p<0.001), with only one CR patient recurring at 4 years, whereas 55% of PR/SD patients relapsed at a median time of one year. Taken collectively, these data support referring to surgery the patients exhibiting CR on imaging at 3 months.

Resection or LT after Y90 downstaging

In a very recent study assessing TARE in PVTT patients (n=17) as a downstaging strategy to LT [START_REF] Serenari | Deceased Donor Liver Transplantation After Radioembolization for Hepatocellular Carcinoma and Portal Vein Tumoral Thrombosis: A Pilot Study[END_REF], the intentionto-treat analysis showed that only 29% (5/17) actually received LT roughly 2 years after TARE. This long delay is accounted for by the ≥6-month duration of sustained radiological response which is required before patients gain HCC exception points. Among them, 3 had tumor recurrence within 1 year of LT. In this study, a median PFS of 12.1 months after TARE was reported in the whole cohort, 34.6 months in transplanted and 10.3 months in non-transplanted patients. Our results outperform these findings with a 49.1% median PFS and OS rates comparable to those of this study's transplanted patients, which suggests that resection should be favored whenever possible, keeping LT for non-resectable patients (n=2 in our series) or as salvage therapy, especially in the current context of graft shortage. Additionally, Serenari et al. [START_REF] Serenari | Deceased Donor Liver Transplantation After Radioembolization for Hepatocellular Carcinoma and Portal Vein Tumoral Thrombosis: A Pilot Study[END_REF] raised the ethical issue of the use of deceased donors for HCC patients with macrovascular invasion, given the high recurrence rate [60% in deceased donor liver transplantation (DDLT)] in their cohort. This addresses the important question of appropriate patient selection for surgery. Downstaging/ bridging using Y90 TARE basically carries an embedded test of time over several months, particularly useful to select less aggressive tumors [START_REF] Titano | Transarterial Chemoembolization and Radioembolization across Barcelona Clinic Liver Cancer Stages[END_REF]. In contrast with systemic therapies, the simulation phase based on 99m-Technetium MAA SPECT-CT as part of TARE, provides both an accurate patient selection and a really personalized approach. Interestingly, Y90 also causes contralateral hypertrophy of the untreated FLR during the waiting period, allowing patients to reach safe volumetric thresholds to perform resection [START_REF] Lewandowski | Y radiation lobectomy: Outcomes following surgical resection in patients with hepatic tumors and small future liver remnant volumes[END_REF][START_REF] Palard | Dosimetric parameters predicting contralateral liver hypertrophy after unilobar radioembolization of hepatocellular carcinoma[END_REF]. The median time from radioembolization to surgery was 6.2 months in our cohort, in line with data found in the literature [START_REF] Toskich | Pathologic Response of Hepatocellular Carcinoma Treated with Yttrium-90 Glass Microsphere Radiation Segmentectomy Prior to Liver Transplantation: A Validation Study[END_REF][START_REF] Riaz | Radiologicpathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres[END_REF]. The optimal time from Y90 treatment to resection remains debated [START_REF] Palard | Dosimetric parameters predicting contralateral liver hypertrophy after unilobar radioembolization of hepatocellular carcinoma[END_REF][START_REF] Madoff | Improving the Safety of Major Resection for Hepatobiliary Malignancy: Portal Vein Embolization and Recent Innovations in Liver Regeneration Strategies[END_REF], reflecting the complex balance between a higher chance to select patients with limited tumor aggressiveness and higher risks to lose a chance for cure. The existence of a temporal effect between TARE and tumor necrosis has been suggested, a longer time allowing for an optimal cytotoxic effect [START_REF] Toskich | Pathologic Response of Hepatocellular Carcinoma Treated with Yttrium-90 Glass Microsphere Radiation Segmentectomy Prior to Liver Transplantation: A Validation Study[END_REF][START_REF] Riaz | Radiologicpathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres[END_REF]. This is also supported by our findings of a longer delay between Y90 and resection in patients presenting CPN vs. the others. Nevertheless, the best tumor response on imaging was noted at 3 months.

Timing for resection after Y90

The nontreated liver volume steadily increased over the 6 months following Y90 TARE, in line with previous reports [START_REF] Lewandowski | Y radiation lobectomy: Outcomes following surgical resection in patients with hepatic tumors and small future liver remnant volumes[END_REF][START_REF] Palard | Dosimetric parameters predicting contralateral liver hypertrophy after unilobar radioembolization of hepatocellular carcinoma[END_REF]. All patients reached safe sFLR volume threshold. Nevertheless, we observed two cases of grade A-B PHLF. This might be explained by discrepancies between liver volume and function, as shown in a recent study on functional changes evaluated on 99m-Tc mebrofenin scintigraphy after Y90 with personalized dosimetry [START_REF] Allimant | Hepatobiliary Scintigraphy and Glass 90Y Radioembolization with Personalized Dosimetry: Dynamic Changes in Treated and Nontreated Liver[END_REF]. Functional data highlighted a significant decrease of FLR function until 2-3 months after Y90. Such volume/ function discrepancy had already been reported in other liver regeneration strategies, such as after portal vein embolization (PVE) [START_REF] De Graaf | Increase in future remnant liver function after preoperative portal vein embolization[END_REF] or after associating liver partition and portal vein ligation (ALPPS) [START_REF] Olthof | Large, multifocal or portal vein-invading hepatocellular carcinoma (HCC) downstaged by Y90 using personalized dosimetry: safety, pathological results and outcomes after surgery[END_REF]. As after ALPPS, during the first 3 months following Y90, the FLR (i.e., nontreated liver) volume overestimated its function, which could lead to unsafe liver resection caused by insufficient FLR function. Thus, waiting at least 3 months after Y90 would be advisable both to restore baseline whole liver function and to benefit from contralateral functional liver regeneration [START_REF] Allimant | Hepatobiliary Scintigraphy and Glass 90Y Radioembolization with Personalized Dosimetry: Dynamic Changes in Treated and Nontreated Liver[END_REF]. The optimal test-of-time period should therefore range between 3 to 6 months.

This study is subject to strengths and limitations. The strengths lie first in our reporting on an HCC population with poor prognosis and no hope of cure © HepatoBiliary Surgery and Nutrition. All rights reserved.

HepatoBiliary Surg Nutr 2022 | https://dx.doi.org/10.21037/hbsn-22-184 according to current AASLD and BCLC guidelines. Second, we used pathology results as gold standard by selecting patients treated by Y90 using glass microspheres without concomitant treatment-whether systemic or locoregional-making it possible to capture the pure effects of TARE using personalized dosimetry. Limitations include the retrospective design, the absence of control arm and the small sample size. However, this is the largest study published to date in surgically-treated patients with PVTT, large or multifocal HCC after Y90, with a comprehensive analysis including dosimetric, safety, imaging, pathological and outcome data. Finally, an intention-to-treat analysis was not provided, since only the patients who underwent Y90 TARE and, subsequently, surgery was evaluated.

In conclusion, Y90 TARE using personalized dosimetry can provide high rates of imaging and pathological response in patients with PVTT, large or multifocal HCC. Subsequent surgery is safe and leads to outcomes that far exceed expectations in a population with an otherwise poor prognosis and no chance for cure. This study supports further trials to evaluate the potential benefit in this selected population of Y90 TARE downstaging followed by surgery over currently recommended systemic therapies.

RÉSUMÉ Contexte

La radio-embolisation (RE) a récemment été reconnue comme un traitement d'accompagnement à la chirurgie pour les carcinomes hépatocellulaires (CHC) précoces avec des taux élevés de nécrose histologique complète (NHC). Chez les patients avec un thrombus tumoral de la veine porte (TTVP), des tumeurs multifocales ou de grandes tailles, la RE a principalement un rôle palliatif et la chirurgie reste discutable.

Méthodes

Dans cette étude rétrospective, nous avons évalué la tolérance, la réponse radiologique, la réponse histologique et la survie des patients atteints de CHC avec des TTVP, des tumeurs multifocales ou de grande taille, opérés après RE avec une dosimétrie personnalisée.

Résultats

Entre décembre 2015 et octobre 2021, dix-huit patients (14/18 avec TTVP) ont été opérés après RE. Aucune mortalité à 90 jours n'a été rapportée. Le taux de réponse objective radiologique était de 95 %. Une NHC et une nécrose histologique étendue (50-99%) ont été observées respectivement dans 36% et 45% des tumeurs. La dose absorbée par la tumeur après RE différait significativement selon l'étendue de la nécrose histologique (P=0,045). Les médianes de survie globale et sans progression étaient respectivement de 61,8 mois [IC 95 % : 31,4 mois-non atteint (NA)] et 49,3 mois (IC 95 % : 14 mois-NA).

Conclusions

Des taux élevés de réponses radiologiques et histologiques ont été observés après RE chez les patients atteints de TTVP, de CHC de grande taille ou multifocaux. La chirurgie ultérieure est sûre avec des résultats dépassant de loin les attentes dans une population au pronostic autrement défavorable.

Spécialité

Radiologie interventionnelle ; Hépatologie ; Chirurgie ; Médecine nucléaire

Mots clés

Radiothérapie interne sélective ; carcinome hépatocellulaire (CHC) ; cancer du foie ; résection ; transplantation.

10 11 REMERCIEMENTS

 1011 Aux membres de mon JuryAu Pr Boris Guiu, de m'offrir l'opportunité de travailler avec votre équipe. Faire de la recherche à vos côtés est une immense honneur. Merci pour vos encouragements, votre écoute et votre disponibilité . Votre détermination à faire avancer la science pour améliorer la santé des patients est un exemple à suivre. Au Pr Eric Assenat, d'avoir accepté d'être membre de mon jury et d'apporter votre expertise oncologique. Au Docteur Fabrizio Panaro, d'avoir accepté d'être membre de mon jury et d'apporter votre expertise en chirurgie digestive.

A

  Quentin Filias pour l'entraide et la bonne humeur pendant tout le stage A l'équide de Gui de Chauliac, A Delebecq Jessica, Benjamin Monsonis, Nadia Ouzzin, Arthur Hamel-Senecal, William Wantz, Ugo Chamard-Champliaud pour les innombrables connaissances que vous m'avez apportez et je vous remercie pour votre disponibilité, votre écoute et votre accompagnement pendant tout le semestre. A Adamfa Coulibaly et à Morgane Lanouzière pour les bon moments pendant le stage, à la SIFEM et pour vos précieux conseils, votre bonne humeur et votre complicité A Maxime Pastor, Paul Segui, Thorgal Brun, Judith Legrand et à Tom Paunet pour l'entraide et la bonne humeur pendant tout le stage. Aux autres coninternes que j'ai croisé pendant mes stages A mes camarades de promotion, Louis Carmier, Jules Galerne, Chakir Hocine, Agathe Debeauvais pour l'entraide et la bonne humeur Aux manipulateurs, aux infirmières et autres paramédicaux sans qui exercer le travail de radiologue serait impossible. A ma famille Papa, Maman et Asif, sans qui je ne serai pas en France aujourd'hui pour leur écoute et leurs encouragements incommensurables Nuz pour son soutien et ses conseils A Rémi, qui m'encourage à être la meilleure version de moi-même et pour son soutien infaillible A la famille Richard (Géra, Sylvain, Lu, les tontons, Monique, Olive et Olivia) A Shal et Koum A Amandine, Méja, Atish, Kyan, Romain, Meena

Figure 2

 2 Figure 2 Association between pathological necrosis and posttreatment tumor-absorbed dose. CPN, complete pathological necrosis; CT, computed tomography; PET, positron emission tomography.

Figure 3

 3 Figure 3 Overall (A) and progression-free (B) survivals in the whole cohort. Progression-free survival according to complete radiologic response status (C) and complete pathological necrosis status (D). CR, complete response; CPN, complete pathological necrosis; mRECIST, modified response criteria in solid tumors; TARE, transarterial radioembolization.

Figure 4

 4 Figure 4 Example of a patient of our series showing baseline images of the tumor (star) and PVTT (arrow) (A) with complete targeting on the pre-treatment SPECT-CT (B) and post-treatment PET-CT (678 Gy) (C), complete radiologic response on the tumor (hollow star) and PVTT (hollow arrow) prior to surgery (D) and liver explant (E). A, anterior; P, posterior; CT, computed tomography; PVTT, portal vein tumor thrombus; SPECT, single photon emission computed tomography.

multifocal or portal vein-invading HCCs downstaged by Y90 using personalized dosimetry: safety, pathological results and outcomes after surgery INTRODUCTION

  Tout ceci peut expliquer pourquoi la RE est principalement considéré comme un traitement palliatif sans espoir de guérison dans ces tumeurs. Par conséquent, dans cette population de mauvais pronostic, on a peu de données sur la réponse

	histologique et le devenir des patients après une chirurgie suivant un downstaging à l'Yttrium-Introduction Y90 transarterial radioembolization (TARE) was recently endorsed in Barcelona clinic liver cancer (BCLC) recommendations (1), based on the results of the LEGACY study, which reported outcomes following TARE of ≤8 cm solitary hepatocellular carcinoma (HCC) comparable to Large, La radioembolisation (RE) a récemment été ajouté dans les recommandations du BCLC (1), 90 (Y90). those following curative-intent therapies (2). TARE was
	also supported by the high rate of complete pathological suite aux résultats de l'étude LEGACY. Cette étude rapporte des résultats comparables après Dans l'étude DOSISPHERE-01, onze patients atteints de CHC non résécable (n=8/11 avec response in this population (3-5). On the contrary, the place
	RE à ceux obtenus après des traitements à visée curative des carcinome hépatocellulaires of TARE in BCLC B/C HCCs and, more specifically, in TTVP) ont subi un downstaging après RE et ont finalement été opérés (91% R0). L'expérience large (>8 cm), multifocal HCCs or in HCCs with portal (CHC) uniques de ≤8cm (2). La RE était également soutenue par le taux élevé de réponse accumulée de la segmentectomie et de la lobectomie radique des CHC précoces a révélé que vein tumor thrombus (PVTT) is highly debated and
	histologique complète dans cette population (3-5). En revanche, la place de la RE dans les CHC BCLC B/C et, plus spécifiquement, dans les CHC de grande taille (>8cm), multifocaux pathological data in this context are lacking. la RE permet le contrôle tumoral, l'hypertrophie controlatérale et un test de temps intégré pour At intermediate stage and in the absence of level one éviter la chirurgie chez les patients avec une biologie tumorale agressive (2, 13). Prises evidence for OS improvement with TARE [vs. transarterial
	collectivement, ces données suggèrent un rôle potentiel de la RE comme stratégie de chemoembolization (TACE)], TACE is still the therapeutic
	option favored by BCLC and American Association for the downstaging, même chez les patients atteints de CHC avec TTVP, multifocaux ou de grande Study of Liver Diseases (AASLD) on account of its wider
	taille. availability
	L'objectif de cette étude était d'évaluer la sécurité, la réponse radiologique et histologique et
	le devenir des patients atteints de CHC avec des TTVP, des tumeurs multifocales ou de
	grande taille, qui ont été opérés après la RE utilisant une dosimétrie personnalisée.
	Spécialité
	Radiologie interventionnelle ; Hépatologie ; Chirurgie ; Médecine nucléaire
	Mots clés
	Radiothérapie interne sélective ; carcinome hépatocellulaire (CHC) ; cancer du foie ; résection
	; transplantation.

Entre décembre 2015 et octobre 2021, dix-huit patients (14/18 avec TTVP) ont été opérés après RE. Aucune mortalité à 90 jours n'a été rapportée. Le taux de réponse objective radiologique était de 95 %. Une NHC et une nécrose histologique étendue (50-99%) ont été observées respectivement dans 36% et 45% des tumeurs. La dose absorbée par la tumeur après RE différait significativement selon l'étendue de la nécrose histologique (P=0,045). Les médianes de survie globale et sans progression étaient respectivement de 61,8 mois [IC 95 % : 31,4 mois-non atteint (NA)] et 49,3 mois (IC 95 % : 14 mois-NA).

Conclusions

Des taux élevés de réponses radiologiques et histologiques ont été observés après RE chez les patients atteints de TTVP, de CHC de grande taille ou multifocaux. La chirurgie ultérieure est sûre avec des résultats dépassant de loin les attentes dans une population au pronostic autrement défavorable. ou avec thrombus tumoral de la veine porte (TTVP) est très débattue et les données pathologiques dans ce contexte manquent.

Au stade intermédiaire et en l'absence de preuves de niveau 1 d'une amélioration de la survie globale après RE (par rapport à la chimio embolisation [CE]), la CE reste l'option thérapeutique privilégiée par le BCLC et l'AASLD en raison de sa plus grande disponibilité

[START_REF] Marrero | Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases[END_REF]

. Toutefois, des essais contrôlés randomisés (ECR) (7-9) ont établi un temps de progression plus longue et une amélioration de la sécurité et de la qualité de vie après la RE par rapport à la CE.

En cas de TTVP, la RE n'est pas recommandé en raison des résultats négatifs des ECR de phase III des CHC au stade C du BCLC. Plusieurs explications ont été avancées pour justifier ces résultats négatifs, parmi lesquelles : une mauvaise sélection des patients, une courbe d'apprentissage obtenue grâce à ces essais et l'absence de dosimétrie moderne, en contradiction avec les principes de base de la radiothérapie

[START_REF] Llovet | Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma[END_REF][START_REF] Salem | Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience[END_REF]

. L'ECR multicentrique DOSISPHERE-01 a récemment recentré l'attention sur la RE en démontrant la supériorité de la dosimétrie personnalisée sur la dosimétrie standard utilisée précédemment dans les essais de phase III négatifs. Le critère de jugement principal (réponse objective) était atteint (71% vs. 36%, p=0,0074) lors de l'analyse intermédiaire malgré l'inclusion de tumeurs de mauvais pronostic (taille moyenne >10cm, PVTT dans 2/3 des cas). La médiane de survie globale était plus que doublée avec la dosimétrie personnalisée (26,5 vs. 10,7 mois, p=0,0096) et elle dépassait de loin la médiane de survie globale des CHC sous traitements systémiques, pourtant recommandés. Selon les données du SPECT-CT pré thérapeutique, la dosimétrie personnalisée visait à délivrer une dose absorbée par la tumeur plus élevée tout en conservant une réserve hépatique de >30 % (c'est-à-dire le foie non traité) pour des raisons de sécurité.

Le traitement chirurgical des CHC BCLC B ou C demeure généralement controversé

[START_REF] Allaire | New frontiers in liver resection for hepatocellular carcinoma[END_REF]

. De plus, la résection d'un CHC de grande taille, multifocal ou avec TTVP implique fréquemment une hépatectomie majeure, soulevant ainsi le problème supplémentaire de l'insuffisance hépatique post hépatectomie.

Table 1

 1 Baseline characteristics of patients at TARE treatment (n=18)

	Variables	Values
	Age (years)	68 [49-85]
	Sex
	Male	16 [89]
	Female	2 [11]
	Underlying liver disease
	HVC/HVB	4 [22]
	OH	7 [39]
	NASH	6 [33]
	No liver disease	1 [6]
	AFP (ng/mL)	16 [2-3,071]
	Child-Pugh score
	A5	16 [89]
	A6	2 [11]
	MELD score	7 [6-16]
	ECOG
	0	9 [50]
	1	9 [50]
	BCLC stage
	A	1 [6]
	B	3 [17]
	C	14 [78]
	Treatment before TARE
	TACE †	1 [25]
	TA + TACE ‡	1 [25]
	Systemic treatment	1 [25]
	Segmentectomy	1 [25]
	Index tumor size (mm)	53 [20-150]
	Tumor distribution
	Unilobar	17 [94]
	Bilobar	1 [6]
	PVTT type (15)
	VP4	1 [7]
	VP3	5 [36]
	VP2	7 [50]
	VP1	1 [7]

Table 1 (

 1 continued)

Table 1 (

 1 continued)

	Variables	Values
	HVTT type (15)
	VV1	2 [67]
	VV2	1 [33]
	PVTT or HVTT	15[83]
	The data are expressed as n [%] or median [range]. † , TACE
	was performed 4 years before TARE and TARE was performed
	outside the initial TACE anatomical territory; ‡ , TACE was
	performed 2 years before TARE and TARE was performed
	outside the initial TACE anatomical territory. TARE, transarterial
	radioembolization; HVC, hepatitis C; HVB, hepatitis B; OH,
	alcoholic cirrhosis; NASH, non-alcoholic steatohepatitis; AFP,
	alpha fetoprotein; MELD, model for end-stage liver disease;
	ECOG, eastern cooperative oncology group; BCLC, Barcelona
	clinic liver cancer; TACE, transarterial chemoembolization; TA,
	thermal ablation; PVTT, portal vein tumoral thrombus; HVTT,
	hepatic vein tumor thrombus.

patient, tumor and treatment characteristics are summarized in Table

1

. Fourteen (78%) had PVTT, 2 (11%), multifocal disease and 5 (28%) large lesions. One multifocal patient had 2 tumors (with a sum of diameters of 82 mm) and the other, 3 tumors (with a sum of diameters of 110 mm). Overall, 83% (15/18) of the population had macrovascular invasion (PVTT or HVT). Three patients with PVTT also had large (>8 cm) tumors. No patient with multifocality had PVTT or large lesions. Three patients (17%) had HVT, which was associated with PVTT in 2/3 patients. A total of 22 tumors were available for per-tumor analysis. One patient had bilobar disease but received percutaneous thermal ablation in the contralateral lobe concurrently to TARE.

Table 2

 2 Perioperative data

	Surgical data	Values
	Clavien-Dindo classification
	3b
	Hemorrhagic complications requiring	1 [6]
	reintervention under GA

Table 3

 3 Dosimetric and pathologic response association

Table 4

 4 Response according to localized mRECIST and pathological necrosis

	Variables		Complete response	Partial response		Stable disease
	CPN (n=5)			5 [100]			0				0
	Extensive (n=9)			2 [22]			7 [78]				0
	Partial (n=4)			0			3 [75]				1 [25]
			Overall survival				Progression-free survival
	0	12	24	36	48	60	0	12	24	36	48
	Number at risk		Months from TRAE		Number at risk			Months from TRAE
		Progression-free survival				Progression-free survival
				P<0.001					P<0.001
	0	12	24	36		48	0	12	24	36	48
	Number at risk		Months from TRAE		Number at risk		Months from TRAE
		No CR (mRECIST)	CR (mRECIST)			No CPN	CPN

The data are expressed as n [%]. CPN, complete pathological necrosis; mRECIST, modified response evaluation criteria in solid tumors.

Table 5

 5 Patient characteristics and outcomes

	Patient	PVTT (15) HVT (15)	Baseline AFP (ng/mL)	Index tumor size (mm)	Best mRECIST response †	PN	MVE	Post-treatment tumor-absorbed dose (Gy)	TTS (months)	TTR (months)
	1	VP2	-	15.6	89	CR	Extensive	1	225	13.6	49.3
	2	VP4	-	44.2	111	PR	Extensive	0	169	8	21.5
	3	VP2	-	3,071	93	CR	CPN	0	304	5.8	-
	4	VP3	-	1,032	50	PR	Extensive	1	186	4.2	-
	5	VP2	-	3.4	32	SD	Partial	0	31	2.1	-
	6	VP3	-	7.5	47	PR	Extensive	0	322	4.1	10.3
	7	VP2	-	38.4	41	CR	CPN	0	394	7.8	-
	8	VP1	VV2	72.2	42	CR	CPN	0	388	8.3	-
	9	VP2	-	15.4	37	PR	Extensive	1	396	3.7	14
	10	VP2	VV1	2.2	77	PR	Extensive	1	318	7.2	22.5
	11	-	VV1	61	37	PR	CPN	0	515	6.2	7.4
					29	-	Partial	-	148	-	-

  CR, complete response; PR, partial response; SD, stable disease; MVE, microvascular embolism; TTS, time to surgery; TTR, time to recurrence; PN, pathological necrosis; CPN, complete pathological necrosis; VP1, tumor thrombus distal to the second-order branches of portal vein; VP2, invasion of the second-order branches of portal vein; VP3, thrombus in the first-order branches; VP4, tumor thrombus in main portal trunk or portal branch contralateral to primarily involved lobe (or both); VV1, tumor thrombus in a branch of the hepatic vein; VV2, tumor thrombus in the main trunk of the hepatic veins; VV3, thrombus reaching the right atrium.

			-	12.5	150	PR	Partial	1	225	3.5	10.1
	15	VP3	-	13.1	26	CR	CPN	0	293	9.7	-
					37	-	CPN	-	506	-	-
	16	-	-	60	91	CR	Extensive	0	311	4.3	-
	17	VP3	-	13.7	55	PR	Extensive	0	678	6.2	-
	18	VP2	-	69.8	74	PR	Extensive	0	655	3.9	-

† , best mRECIST response = best localized mRECIST response = localized mRECIST response prior to surgery. PVTT, portal vein tumoral thrombosis; HVT, hepatic vein thrombosis; AFP, alpha fetoprotein; mRECIST, modified response evaluation criteria in solid tumors;

Table 6

 6 Relapse location and outcome of recurring patients

	Patients	Relapse location	Treatment	Outcome
	1	Liver followed by pulmonary and	Segmentectomy, systemic treatment † , followed by	HCC-related mortality due to
		lymph nodes metastases	supportive care	rapidly progressive disease
	2	Simultaneous liver and bone	Bevacizumab and atezolizumab; radiation therapy	Complete radiologic response
		metastases	in the localized bone metastasis
	3	Cardiac metastasis	Systemic treatment ‡	Awaiting treatment evaluation
	4	Liver	TACI followed by PTA	Awaiting for LT
	5	Liver	Sorafenib followed by bevacizumab and	Stable disease
			atezolizumab
	6	Liver	LT	Mortality related to a sudden
				cardiac arrest
	7	Liver	Supportive care	-

†

, Nexavar followed by Lenmiva; ‡ , pembrolizumab due to a synchronous lingual tumor. HCC, hepatocellular carcinoma; TACI, transarterial chemo-infusion; PTA, percutaneous thermal ablation; LT, liver transplantation.

© HepatoBiliary Surgery and Nutrition. All rights reserved.HepatoBiliary Surg Nutr 2022 | https://dx.doi.org/10.21037/hbsn-22-184

© HepatoBiliary Surgery and Nutrition. All rights reserved. https://dx.doi.org/10.21037/hbsn-22-184

Acknowledgments

The authors thank Sandrine Guinodeau for revising the English.

B Guiu, C Allimant, MA Meerun; (II) Administrative support: B Guiu; (III

Funding: None. Footnote Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://hbsn. amegroups.com/article/view/10.21037/hbsn-22-184/rc Data Sharing Statement: Available at https://hbsn. amegroups.com/article/view/10.21037/hbsn-22-184/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn. amegroups.com/article/view/10.21037/hbsn-22-184/ coif). FP and BG serve as unpaid editorial board members of Hepatobiliary Surgery and Nutrition. CA and BG report receiving consulting fees from Boston scientific as consultants, and receiving payment from Boston scientific for presentations. The other authors have no conflict of interest to declare.

Ethical Statement:

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by our institutional review board (IRB -UH Montpellie; accreditation number: 198711 and the IRB ID is 202100933) and written informed consent was obtained from all patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the noncommercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/. ➢ Je donnerai mes soins gratuits à l'indigent et n'exigerai jamais un salaire au-dessus de mon travail.

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