American Journal of Primatology 71:400–408 (2009) RESEARCH ARTICLE First Description of the Surgical Anatomy of the Cynomolgus Monkey Liver CORINNE VONS1, SYLVIE BEAUDOIN2,3, NADA HELMY1,4, IBRAHIM DAGHER1,4, ANNE WEBER4, 1,4 AND DOMINIQUE FRANCO 1 AP-HP, Department of Surgery, Antoine-Bécle`re Hospital, University Paris XI, Clamart, France 2 AP-HP, Department of Surgery, Saint-Vincent de Paul Hospital, Paris, France 3 Laboratoire d’anatomie et organogenèse, Universitè Paris V, Paris, France 4 Inserm U804, Bicêtre Hospital, Kremlin-Biceˆtre, Paris XI, France No detailed description of nonhuman primate liver anatomy has been reported and little is known about the similarity between such livers and human liver. The cynomolgus monkey (Macaca fascicularis) was used to establish a preclinical model of genetically modified hepatocytes auto transplantation. Here, we report information gleaned from careful observation and notes obtained from 59 female cynomolgus monkeys undergoing 44 anatomical hepatic resections, 12 main portal vein division dissections and selective branch ligations, and 46 portographies. Additionally, three anatomical liver dissections after total resection at autopsy were performed and served to confirm peroperative observations and for photography to provide illustrations. Our results indicate that the cynomolgus monkey liver has four lobes: the median (the largest), the right and left lateral, and the caudate lobes. In 60% (N 5 20) of individuals the portal bifurcates into right and left portal veins, in the remaining 40% (N 5 14) the portal vein trifurcates into right anterior, right posterior, and left portal veins. The anatomy and branching pattern of the hepatic artery and bile ducts closely follow those of the portal branches. Functionally, the cynomolgus monkey liver can be divided into eight independent segments. Thus, we report the first detailed description of the hepatic and portal surgical anatomy of the cynomolgus monkey. The cynomolgus monkey liver is more similar to the human liver than are livers of any small or large nonprimate mammals that have been described. Am. J. Primatol. 71:400–408, 2009. r 2009 Wiley-Liss, Inc. Key words: liver; anatomy; cynomolgus monkey INTRODUCTION Liver anatomy in dogs and pigs has been extensively described [Court et al., 2003; Kamimura et al., 1997; Peng et al., 2005; Van Minh, 1996; Veeragandham et al., 1993]. However, no detailed description of nonhuman primate liver anatomy has been reported and although the liver anatomy of nonhuman primates may be closely related to that of humans little is known about the similarities. Previous research on nonhuman primate liver anatomy has mostly documented external liver morphology [Houssin et al., 1988; Miller et al., 1978; Voss, 1970]. In 1995, we decided to establish a preclinical model in a nonhuman primate with the goal of treating children suffering from inherited metabolic liver disease [Andreoletti et al., 2001; Vons et al., 2001]. We chose to utilize a nonhuman primate for this purpose rather than other large mammals, for example pigs, with the hypothesis that it may be more similar to human. The cynomolgus monkey (Macaca fascicularis, also known in the literature as M. irus or the crab-eating monkey) was chosen because the animal laboratory of our institute has r 2009 Wiley-Liss, Inc. extensive experience in rearing this species. This monkey has the advantage of a small size, unlike the baboon utilized by Grossman [Grossman et al., 1992], facilitating manipulation. Moreover, relatively small numbers of hepatocytes (600 106) were isolated from the left hepatic lobe after resection (20% of total liver but only 40–60 g per animal). These hepatocytes required subsequent genetic modification in vitro before autotransplantation. However, because they are small, the cynomolgus monkey has the disadvantage of poor tolerance to prolonged anaesthesia and a particularly high risk of peroperative hypothermia. Therefore, we performed hepatic surgery in a facility already specialized in the Contract grant sponsors: AFM (Association Franc- aise contre les Myopathies); Inserm. Correspondence to: Corinne Vons, AP HP, Department of Surgery, Jean Verdier Hospital, Avenue du 14 Juillet, 93143 Bondy Cedex, France. E-mail: [email protected] Received 7 May 2008; revised 20 December 2008; revision accepted 26 December 2008 DOI 10.1002/ajp.20667 Published online 4 February 2009 in Wiley InterScience (www. interscience.wiley.com). Anatomy of the Cynomolgus Monkey Liver / 401 use of monkeys. Previously available information about the anatomy of the cynomolgus monkey liver was limited. Over the last 10 years, we have performed more than 100 surgical procedures involving the liver of this species, including 44 hepatic resections, 12 selective portal branch ligations, 46 radiological examinations of portal veins, and three autopsies. We report here the data recorded during the course of these procedures. The aim of this article is to describe the surgical anatomy of the liver and portal triad and to document the vascular and segmental anatomy of the cynomolgus monkey liver. We discuss its similarity to and difference from the liver of other animals used for experimental purposes, and the human liver. METHODS The monkeys were maintained in the primate unit of the ‘‘Institut National de la Recherche Agronomique (INRA)’’ at Jouy-en-Josas, France. They were housed individually, in standard primate cages with free access to food and water. All were in good general health and all tested seronegative for the simian herpes virus. (The simian herpes B virus can be transmitted to humans through bite or scratch or spit. There is no treatment for the infection and nearly 80% of humans who contract the disease die as a result). No animal was sacrificed for the purposes of these experiments or only to describe its anatomy. All research reported in this article adhered to the American Society of Primatologist (ASP) Principles for the Ethical Treatment of Nonhuman Primates. All experiments were performed according to the guidelines of the French Ministry of Agriculture that regulates animal research in France. The protocol was approved by the Comité Régional d’Ethique en matière d’Expérimentation Animale (Creea ‘‘Ile-de-France-Sud’’). Altogether, between 1995 and 2000, data were recorded from 59 female cynomolgus monkeys, aged 774 years (range 3–15 years), and weighing 3.670.7 kg (range 3.1–5.5 kg). Animals were sedated with an intramuscular injection of 10 mg/kg ketamine and 10 mg/kg atropine to allow their transport from the facility to the operating room. Anesthesia was induced by inhalation of an increasing concentration of halothane (0.2%) and intravenous sufental (0.3 mg/kg) (Sufentas, Janssen-Cilag, SA, Issy-les-Moulineaux, France). The trachea was intubated and the lungs were manually ventilated with 100% O2 throughout the surgical period. The end-tidal CO2 was monitored continuously so that hypoventilation or hyperventilation could be avoided. Anesthesia was maintained with halothane (0.7–1.5%). Subcutaneous sufentanil (0.2 mg/kg) was administered at the end of surgery for postoperative analgesia. When the animals had sufficient spontaneous ventilation, the trachea was extubated. Forty-four animals underwent anatomical resections (34 of the left lateral lobe and 10 of the right lateral lobe) in a first phase. During these 44 resections, liver lobulation and the extra hepatic aspect of the portal vein and artery and their division were gleaned from careful observation and notes. Information about vascularization, i.e., portal vein, hepatic artery, and hepatic vein, of the two resected lobes (34 left and 10 right) was also recorded. Resected livers (34 left lateral lobes and 10 right lateral lobes resected) were weighed. Then, in a second phase, ligations of both the left portal vein and the right anterior portal vein were performed in 12 additional animals to induce liver parenchyma regeneration of the nonligated lobe (corresponding to the region supplied by the right posterior portal vein). Portal vein division dissections were performed at the hilum of the liver for selective ligation using an anterior approach; therefore, the origins of the left and right portal vein were documented. In 46 of these 56 animals, a catheter was inserted in the inferior mesenteric vein and connected to a subcutaneous chamber placed in the lower left quadrant of the abdominal wall. Permanent access to the portal vein was therefore possible via the port under light general anesthesia and the portal system could be opacified by injection of 3 ml of contrast medium (Hexabrixs 320 mg/ml, Guerbet, Zurich, Switzerland) into the inferior mesenteric vein. Thirty-four portographies following left lateral lobe resection allowed the analysis of the portal division, the portion that was resected being at the periphery of the liver. Twelve additional portographies following selective left portal vein and right anterior portal vein ligations assessed the appropriateness of the anatomical description of the origins of the ligated right anterior portal vein and left portal vein, and of the nonligated right posterior portal vein. Three additional animals, which died in the primate unit from causes unassociated with this work, were used for anatomical studies. They were mostly used for photography: indeed good quality pictures were difficult to obtain during surgery because of the very small size of the animals and the small abdominal incisions. However, after autopsies, the whole liver with the entire inferior vena cava (IVC) could be resected. Resected livers were fixed in formaldehyde solution (37%) for 1 month. Whole livers and their ventral, caudal, dorsal, and cranial surfaces were photographed first. Livers were then carefully dissected. The portal vein and the hepatic artery and their branches, the bile ducts, and the gall bladder were isolated. About fifty photographs were taken of the three whole livers totally resected, documenting each of their surfaces, with the livers being moved to provide different Am. J. Primatol. 402 / Vons et al. views; each step of dissection of the portal triad was also photographed. We did not dissect the median hepatic vein during surgery to determine whether it was joined by any left or right hepatic veins before entering the IVC and therefore cannot describe it. A professional draughtsman then drew the illustrations presented here from these detailed photographs. The records and descriptions performed during all these procedures were combined for analysis to describe: (1) the external aspect of the liver and its lobation; and (2) portal vein, portal division, and branches (44 measurements were performed during hepatic resections and 12 during selective vein ligations) and to a lesser extent hepatic arteries and bile ducts, and branches of right and left hepatic veins. Small arteries, bile ducts, and main hepatic veins were not dissected during surgery to avoid increased risk to the animals. Small arteries and bile ducts were too small after their main convergence or divergence to be clearly identified during autopsy. We paid particular attention to portal division and segmentation of the cynomolgus monkey liver because arteries and bile duct are known to follow them, and because major differences between humans and other mammals—especially pigs and dogs—concern portal division [Court et al., 2003; Left Lateral Lobe Right Lateral Lobe Kamimura et al., 1997; Peng et al., 2005; Van Minh, 1996; Veeragandham et al., 1993]. Our examination of portal vascularization in the cynomolgus monkey included an assessment of its segmental distribution. We were able to develop a nomenclature consistent with that of the human liver. RESULTS Lobes and Fissures In all 59 monkeys, the liver was divided into three main lobes separated by two deep interlobular fissures: the median lobe and the left and right lateral lobes. A fourth less well-delimited lobe, called the caudate lobe, was dorsal. The median lobe The ventral surface of the liver is almost exclusively the median lobe (Fig. 1a). This lobe is the largest of the three main lobes and it partially covers the others (Fig. 1a). On its anterior border, there is a groove visible on the ventral side of the liver corresponding to the insertion of the falciform ligament, the free border of which contains the round ligament, i.e., the obliterated umbilical vein (Fig. 1a). The falciform ligament attaches the median Gall bladder Round ligament Right Median Lobe Median Lobe Left Median Lobe Left Lateral Lobe Right Lateral Lobe Caudate Lobe Round ligament a The two protuberances of the caudate lobe b Caudate Lobe Right Lateral Lobe Caudate Lobe Left Lateral Lobe Left Lateral Lobe The two protuberances of the caudate lobe Median Lobe Inferior Vena Cava with the endings of the right, median and left hepatic veins c d Fig. 1. External aspect of the cynomolgus monkey liver with its four lobes. (a) Ventral surface of the cynomolgus monkey liver; (b) caudal surface of the cynomolgus monkey liver; (c) cranial surface of the cynomolgus monkey liver; (d) dorsal surface of the cynomolgus monkey liver. Am. J. Primatol. Anatomy of the Cynomolgus Monkey Liver / 403 lobe to the diaphragm and to the anterior wall of the abdomen. On the caudal surface of the liver, the median lobe is subdivided by a deep umbilical fissure, which extends almost up to the hilum, giving the appearance of two separated median lobes, which we called the left and right median lobes (Fig. 1b). The gall bladder also lies on the caudal surface of the liver, to the right of the deep fissure described above, and separates the right median lobe into two smaller parts, on its right and left sides (Fig. 1b). Left lateral lobe The left lateral lobe is clearly visible on the caudal surface of the liver (Fig. 1b). It can only be seen with difficulty on the ventral surface of the liver because it is almost entirely hidden by the median lobe (Fig. 1a). The left lateral lobe is thin but large, and trapezoidal in shape, with a small protuberance on its medio-caudal area, which partially covers the left side of the portal triad and a part of the gall bladder (Fig. 1b). It weighs 40–60 g (n 5 34). When the deep fissure between the median and the left lateral lobes is opened and its small internal protuberance resected, the left lateral lobe can be seen to be connected to the rest of the liver by only a very thin portion of parenchyma, which contains its vessels: its hepatic vein is at the superior part of the band of hepatic parenchyma between the lobe and the rest of the liver, just inferior to its portal vein and at some distance below its artery. The bile duct coming from left lateral lobe was too small to be clearly identified (Fig. 2a). The left lateral lobe is attached to the diaphragm by a thin ligament, the left triangular ligament. Right lateral lobe The right lateral lobe is clearly visible on the caudal surface of the liver (Fig. 1b). It is thin and pyramidal. It weighs 50–60 g (n 5 10). It is attached to the diaphragm by a thin ligament, the right Left Median Lobe Right Median Lobe Confluence of hepatic ducts Cystic duct Caudate lobe The fourth lobe of the liver, called the caudate lobe, can be seen only on the dorsal (Fig. 1d) and cranial (Fig. 1c) surfaces of the liver and, to a lesser extent, on its caudal surface (Fig. 1b). The caudate lobe, with its rectangular shape, occupies all the dorsal side of the liver and completely encircles the IVC (Fig. 1b and c). On the caudal surface, the inferior portion of the caudate lobe can be seen dorsal to the portal pedicle and ventral to IVC, where it forms two lateral horizontal protuberances, visible on either side of the portal pedicle (Fig. 1b). It has a large connection with the right lateral lobe. However, it is not connected to the left lateral lobe. Vessels and Bile Ducts In all 59 monkeys, the portal triad and extra hepatic portal divisions could be observed during 44 hepatic resections, 12 portal vein division dissections and ligations, 34 portographies and, to a lesser extent, on photographs taken during three autopsies (the basis of the illustrations). Portal vein and divisions The extra-hepatic portion of the portal vein was 10–15 mm long and 2–3 mm in diameter (56 measurements) and was devoid of branches. The portal Left Lateral Lobe hepatic vein, portal vein, artery Gallbladder Right Lateral Lobe triangular ligament. When the median and right lateral lobes are spread along the right fissure, which is not as deep as the left fissure, the right lateral lobe can be seen to be connected to the rest of the liver only by a thin portion of parenchyma, which contains its hepatic vein in the superior part, and inferior the portal and arterial branches and bile duct (Fig. 2b). The bridge of parenchyma connecting the right lateral lobe to the rest of the liver is thicker than that connecting the left lateral lobe and a portion lies behind the IVC (Fig. 1d). Hepatic artery and division Right Median Lobe Gallbladder Right Lateral Lobe hepatic vein Anterior right portal vein Left Lateral Lobe Left portal vein Portal vein a Left Median Lobe Posterior right portal vein Small trunk of right portal vein b Fig. 2. Caudal surface of the cynomolgus monkey liver with exposure of portal triad, the left and right lateral lobes, and their portal pedicles. (a) Exposure of the elements of the portal triad (caudal surface, the left deep fissure has been opened and the internal small protuberance of the left lateral liver resected); (b) exposure of the portal vein and its branches. Exposure of the right lateral lobe (caudal surface, the right deep fissure has been opened). Am. J. Primatol. 404 / Vons et al. vein divides at the hepatic hilum into right and left veins supplying the right and left parts of the liver. However, the anatomy of division of the portal vein differs between individual female animals. In 20 portographies (60%), the right portal vein had a very short trunk (2–3 mm) before it divided into anterior and posterior branches of 1–2 mm in diameter (Fig. 3a). This is the case in the illustration shown in Figure 2b: after dissection of the liver of one of three autopsied animals, opening the deep left fissure between the left and median lobes and retracting upwards both the hepatic artery and the bile duct, revealed, in this monkey, a portal bifurcation and the right portal vein with a short common trunk. In 14 portographies (40%), however, there was a trifurcation of the portal vein (Fig. 3b): the trunk of the right branch was absent with immediate division into anterior and posterior branches. Both these patterns, bifurcation (60%) and trifurcation (40%), were also observed during 12 portal vein division dissections before selective ligation of branches of the right portal vein (seven bifurcations and five trifurcations of portal vein). After the right portal vein divides, just upstream from its point of entry into the liver, the posterior branch curves posterior-laterally, lying in a horizontal plane, and separates into ascending and descending branches, heading toward the right lateral lobe (Figs. 2b and 3). The anterior branch curves forward, lies in a vertical plane, and divides to supply the part of the median lobe located on the right side of the gall bladder (ramus ascendens) [Couinaud, 1957] (Figs. 2b and 3). Observation and measurements performed during 34 anatomical resections of the left hepatic lobe revealed that the extra-hepatic portion of the left portal vein was much longer than that of the right portal vein and its course could be subdivided into two parts: a transversal part 5–7.5 mm long and a 4–5 mm-long section that curves anteriorly and to the left as an arch toward the base of the umbilical fissure. Just before turning and entering the umbilical fissure, there was a 1–2 mm-diameter branch from the left portal vein to the left lateral lobe (34 measurements). The part of the left portal vein that curves anteriorly and to the left of the base of the umbilical fissure was extrahepatic; close to the umbilical ligament, it divides into two branches, to the right and left. All the left branches are outside the hepatic parenchyma and are covered by peritoneum. Hepatic arteries Hepatic arteries could be observed in their extra-hepatic portion in all 44 resections performed in female cynomolgus monkeys; however, observations during the 12 additional anterior portal vein division dissections and the three postmortem total Fig. 3. Opacification of portal vein and branches and illustrations. Note that the small portal branch to the left lateral lobe has been ligated and is not opacified. (a) Bifurcation of the portal vein (60% of cases); (b) trifurcation of the portal vein (40% of cases). Am. J. Primatol. Anatomy of the Cynomolgus Monkey Liver / 405 liver dissections were more comprehensive. The common hepatic artery lies within the hepatic pedicle anterior to and to the left of the portal trunk. The division of the hepatic artery is at the same level as that of the portal vein and of bile duct confluence (Fig. 2a). At the portal division, the common hepatic artery divides into two branches (Fig. 2a). The hepatic artery and its branches follow portal branches all along their length. The IVC emerges from the liver for 5–7 mm before passing through the diaphragm and entering the heart (44 measurements during section of the coronal ligament before resection of the left or the right hepatic lobes). The infra hepatic IVC was studied in livers retrieved during the three autopsies. It enters the liver between the portal pedicle and the caudate lobe and rapidly it becomes entirely embedded in the hepatic parenchyma. Gall bladder and bile ducts The gall bladder, cystic duct, and main bile ducts could be observed in their extra-hepatic portion in all female cynomolgus monkeys during the 44 hepatic resections. Right and left bile ducts were more confidently observed during the 12 anterior portal vein division dissections and the three postmortem total liver dissections. The gallbladder is long and fusiform and lies within a fossa on the inferior surface of the large median lobe. It is deeply embedded in the liver (Fig. 1b), and the fundus can only sometimes be seen protruding on the anterior side of the liver. The cystic duct is long, joining the common bile duct close to the first portion of the duodenum. The common bile duct lies anterior to and to the right side of the main portal vein. It is the lateral structure furthest to the right within the peritoneal sheath of the portal triad, 2–3 mm to the right of the common hepatic artery. The confluence of the right and left bile ducts is adjacent to the hilum of the liver (Fig. 2a). Right and left bile ducts lie anterior to the right and left portal veins. Posterior and anterior branches of the right bile duct lie on the anterior side of the posterior and anterior branches of the right portal vein. The anterior and posterior right bile ducts always join the main bile duct in close proximity to each other. Smaller bile ducts could not be clearly identified. Functional Anatomy Hepatic veins There are three main hepatic veins (right, left, and median). Resections of the left lateral hepatic lobe (34 cases) and of the right lateral hepatic lobe (10 cases as well as), the three autopsies demonstrated that the left hepatic vein is formed by two branches that drain the left lateral and left median lobes, respectively. The hepatic vein draining the left lateral lobe had a 3–4 mm-long extra-hepatic segment (Fig. 2a; 34 resections). The right hepatic vein is also formed by two branches that drain the right lateral and right median lobes, respectively. The hepatic vein draining the right lateral lobe had a very short extra-hepatic segment (Fig. 2b). Inferior vena cava Details concerning the supra hepatic IVC could be obtained from careful observation and notes made during 44 hepatic resections and three autopsies. The description of the functional anatomy of the human liver, by Couinaud, divided the liver into hepatic segments on the basis of portal pedicle distribution and hepatic vein location [Couinaud, 1957]. This type of distribution is also found in animals with a lobed liver and therefore the same classification can be applied [Couinaud, 1957; Kogure et al., 1999]. The cynomolgus monkey liver can be divided into eight independent segments, each with its own vascular inflow, outflow, and biliary drainage (Fig. 4a). The caudate lobe is segment I and is posterior (not shown). The left lateral lobe is segment II and is a left posterior segment (Fig. 4a). The median lobe is divided by the main portal scissura (which runs posterior from the middle of the gall bladder fossa to the right side of the IVC) into a left anterior sector, containing segment III laterally (left median lobe) and segment IV medially (left side of the right median lobe) (Fig. 4a), and a right anterior sector, containing segments V and VIII (right side of the right median lobe) on its inferior and superior faces, respectively (Fig. 4a). The right lateral lobe corresponds to a right posterior sector, containing segments VI and VII on its inferior and superior faces, respectively (Fig. 4a). In the cynomolgus monkey there are thus four posterior segments (I, II, VII, and VI) and four anterior segments (III, IV, V, VIII). Comparisons of the lobation and portal distribution of the cynomolgus monkey liver with the livers of other animals is shown in Figure 4 in which the right lateral and left lateral lobes are shown with darker shading in all species (Fig. 4b: rat; Fig. 4c: pig; and Fig. 4d: human). DISCUSSION As far as we are aware, this article presents the first description of the surgical anatomy of the cynomolgus monkey liver and, indeed, of any nonhuman primate liver. These findings were obtained during research for other aims, and no animal was sacrificed or hurt for this study. We show that the cynomolgus monkey liver is lobated, like the liver of the other large mammals most frequently used for research purposes, namely pigs and dogs. But more importantly, this study documents how the cynomolgus monkey liver differs from that in other Am. J. Primatol. 406 / Vons et al. a. Cynomolgus monkey liver b. Rat liver Anterior right portal vein Anterior right portal vein Posterior right portal vein Posterior right portal vein c. Pig liver Anterior right portal vein Posterior right portal vein d. Human liver Anterior right portal vein Posterior right portal vein Fig. 4. Comparison of lobulation and portal distribution in (a) cynomolgus monkey liver; (b) rat liver; (c) pig liver; (d) human liver. The right lateral and left lateral lobes are shown with darker shading in all species to demonstrate their divergence. nonprimate mammals: among all large mammals whose livers have been described, the cynomolgus monkey liver is the most similar to that in humans. Several articles have described the anatomy of the pig’s liver [Camprodon et al., 1977; Kamimura et al., 1997; Peng et al., 2005; Van Minh, 1996] and a few the anatomy of the dog’s liver [Sleight & Thomford, 1970; Veeragandham et al., 1993]. There are only three reports of surgical liver resection in nonhuman primates, one using an anatomic resection technique [Houssin et al., 1988] and the others a nonanatomic finger fracture technique [Talcott & Dysko, 1991] or an automatic stapling device [Nolan & Conti, 1980]. For our research purposes, we mostly performed resections of a small anatomic area, the left lateral lobe, this being straightforward, as in pigs and dogs. To a lesser extent, the right lateral lobe was easily and safely resected because of the band of parenchyma situated between this lobe and the rest of the liver and also because the right lateral lobe is larger than the left lateral lobe. During these resections we could carefully observe liver lobation Am. J. Primatol. and triad structures of this specimen. Additionally, during portal vein division dissections and branch ligations, and portographies, we were able to describe portal division in a large number of individual animals. The main anatomical difference reported to date between human and described animal livers includes the division of the main portal vein [Couinaud, 1957]. This difference also distinguishes the cynomolgus monkey liver from the livers of other large mammals including those of the pig and the dog. Therefore, the cynomolgus monkey liver appears to be most similar to the human liver. There are, nevertheless, differences. In particular, the caudate lobe encircles the IVC in all cynomolgus monkey livers, whereas this is observed in only 5% of humans [Hawkins et al., 2005]. Couinaud [Couinaud, 1957; Couinaud & Rene, 1981] divided the human liver into eight segments. Dissections of lobes of small and large mammals demonstrated the same internal segmentation regardless of their external appearance [Couinaud, 1957]. Anatomy of the Cynomolgus Monkey Liver / 407 Our study confirms that this segmental anatomy can also be applied to the lobated liver of the cynomolgus monkey. One consequence of the division of the liver into self-contained units is that each segment can be resected without damaging the remaining segments. The cynomolgus monkey liver differs from pig and rat livers as concerns lobation, and more importantly portal division (Fig. 4a): the lateral lobe in the cynomolgus monkey is more posterior than those in other mammals, whether large or small. In addition, the portal vein division in the cynomolgus monkey differs markedly from that in other small and large mammals. The emergence of the sectoral portal branch supplying the right anterior sector (segments V and VIII) is different. In the rat and the pig, this branch emerges from the portal vein, distant from the emergence of the sectoral branch (Ramus cysticus) supplying the right posterior sector (segments VI and VII) [Camprodon et al., 1977; Couinaud, 1957; Court et al., 2003; Kamimura et al., 1997; Peng et al., 2005; Robert, 1997] (Fig. 4b and c). The right anterior portal vein therefore drains into the left portal vein. In cynomolgus monkey and human, the branch supplying the right anterior sector (segments V and VIII) is either one of the two branches of the right portal vein (ramus ascendens) or one of the branches of trifurcation of the portal vein (Fig. 4a and d). In the cynomolgus monkey, this trifurcation is found in 40% of cases. In human, such trifurcation is only found in 10–15% of individuals [Deshpande et al., 2002]. The cynomolgus monkey liver, like those of other monkeys, is presumably closer phylogenetically to the human liver than are those of other animals, in view of the evolutionary divergence between small mammals (including rodents), large mammals (pigs and dogs), and primates (humans and monkeys). On the basis of the theory that the development of the liver during gestation is similar to its evolution from small to large mammals (‘‘ontogeny recapitulates phylogeny’’), the similarities between mammalian livers, including that of humans, could be used to elucidate the anatomical variations in the human liver, such as the portal branches [Deshpande et al., 2002] and left hepatic vein [Reichert et al., 2000]. Considering the portal branches, Deshpande noted a variant of the anatomy of portal division, a trifurcation, in 15% of humans [Deshpande et al., 2002], as in 40% of cynomolgus monkeys: the right anterior portal vein supplying the right anterior segments V and VIII divides from the left portal vein a short distance from its origin [Deshpande et al., 2002]. This is similar to the dog [Sleight & Thomford, 1970] and pig [Camprodon et al., 1977; Couinaud, 1957; Court et al., 2003; Kamimura et al., 1997; Peng et al., 2005; Robert, 1997]. Considering the left hepatic vein, Reichert described three patterns of left hepatic venous drainage in humans [Reichert et al., 2000]: the most common variant, observed in 73% of cases, is the union of segments II and III veins to form a principal left hepatic vein at the umbilical fissure; the second most commonly observed pattern is separate large veins (14%), similar to that found in the cynomolgus monkey liver in our study. The cynomolgus monkey liver has the same right and left separation as in humans. Because of the presence of a right and left portal veins, a large anatomical resection (right and left hepatectomy) can be performed using the virtual main portal fissure [Houssin et al., 1988]. This type of large resection cannot be achieved easily in pigs or dogs, for example, in which a right hepatectomy would be more difficult and lead to damage of the vascularization of the left and median lobes and subsequently to the death of the animal [Couinaud, 1957]. Accurate description of cynomolgus monkey liver, its lobation and the location, and distribution of its vessels, provide a valuable background for future liver surgery in this nonhuman primate and strengthens its potential as a model for development of surgical techniques applicable to humans. ACKNOWLEDGMENTS We thank Lien Nguyen and Elisabeth Heseltine for help with the English language. We also thank the editor and reviewers of the Journal of Primatology, for their very helpful comments. The authors are grateful for financial support from AFM (Association Franc- aise contre les Myopathies) and from Inserm. All research reported in this study adhered to the American Society of Primatologist (ASP) Principles for the Ethical Treatment of Nonhuman Primates. All experiments were performed according to the guidelines of the French Ministry of Agriculture that regulates animal research in France. The protocol was approved by the Comité Régional d’Ethique en matière d’Expérimentation Animale (Creea Ile-de-France-Sud). REFERENCES Andreoletti M, Loux N, Vons C, Nguyen TH, Lorand I, Mahieu D, Simon L, Di Rico V, Vingert B, Chapman J, Briand P, Schwall R, Hamza J, Capron F, Bargy F, Franco D, Weber A. 2001. Engraftment of autologous retrovirally transduced hepatocytes after intraportal transplantation into nonhuman primates: implication for ex vivo gene therapy. Hum Gene Ther 12:169–179. Camprodon R, Solsona J, Guerrero JA, Mendoza CG, Segura J, Fabregat JM. 1977. Intrahepatic vascular division in the pig: basis for partial hepatectomies. Arch Surg 112:38–40. Couinaud C. 1957. Le foie. etudes anatomiques et chirurgicales. Masson: Paris. Couinaud C, Rene L. 1981. Report of the work of the Academy of Surgery during 1980. Chirurgie 107:8–12. Court FG, Wemyss-Holden SA, Morrison CP, Teague BD, Laws PE, Kew J, Dennison AR, Maddern GJ. 2003. Segmental nature of the porcine liver and its potential as a model for experimental partial hepatectomy. Br J Surg 90:440–444. Am. J. Primatol. 408 / Vons et al. Deshpande RR, Heaton ND, Rela M. 2002. Surgical anatomy of segmental liver transplantation. Br J Surg 89:1078–1080. Grossman M, Raper SE, Wilson JM. 1992. Transplantation of genetically modified autologous hepatocytes into nonhuman primates: feasibility and short-term toxicity. Hum Gene Ther. 3:501–510. Hawkins WG, DeMatteo RP, Cohen MS, Jarnagin WR, Fong Y, D’Angelica M, Gonen M, Blumgart LH. 2005. Caudate hepatectomy for cancer: a single institution experience with 150 patients. J Am Coll Surg 200:345–352. Houssin D, Vigouroux C, Filipponi F, Rossat-Mignod JC, Dousset B, Hamaguchi M, Bokobza B, Icard P, Mathey C, Pras-Jude N. 1988. One liver for two: an experimental study in primates. Transpl Int 1:201–204. Kamimura R, Ishizaki N, Suzuki S, Tanaka K, Taira A. 1997. Division of donor liver for successful split-liver transplantation in pigs. Exp Anim 46:315–317. Kogure K, Ishizaki M, Nemoto M, Kuwano H, Makuuchi M. 1999. A comparative study of the anatomy of rat and human livers. J Hepatobiliary Pancreat Surg 6:171–175. Miller JL, Gee SJ, Krieger RI, Ruebner BH. 1978. Closed needle liver biopsy for assessment of monooxygenase activity in rhesus monkeys (Macaca mulatta). J Med Primatol 7:1–7. Nolan TE, Conti PA. 1980. Liver wedge biopsy in chimpanzees (Pan troglodytes) using an automatic stapling device. Lab Anim Sci 30:578–580. Peng CH, Shi LB, Zhang HW, Peng SY, Zhou GW, Li HW. 2005. Establishment of a new pig model for auxiliary partial Am. J. Primatol. orthotopic liver transplantation. World J Gastroenterol 11:917–921. Reichert PR, Renz JF, D’Albuquerque LA, Rosenthal P, Lim RC, Roberts JP, Ascher NL, Emond JC. 2000. Surgical anatomy of the left lateral segment as applied to living– donor and split-liver transplantation: a clinicopathologic study. Ann Surg 232:658–664. Robert B. 1997. Anatomie comparée des mammifères domestiques. Vol. I. Paris: Splanchnologie. Sleight DR, Thomford NR. 1970. Gross anatomy of the blood supply and biliary drainage of the canine liver. Anat Rec 166:153–160. Talcott MR, Dysko RC. 1991. Partial lobectomy via a ligature fracture technique: a method for multiple hepatic biopsies in nonhuman primates. Lab Anim Sci 41:476–480. Vanminh T. 1996. Anatomic basis of pig liver partition for experimental transplantation and perspective in xenotransplantation. Transplant Proc 28:61–62. Veeragandham RS, Brown SB, Emond JC. 1993. Improved technique of 70% hepatectomy in dogs. Eur Surg Res 25:396–398. Vons C, Loux N, Simon L, Mahieu-Caputo D, Dagher I, Andreoletti M, Borgnon J, Dirico V, Bargy F, Capron F, Weber A, Franco D. 2001. Transplantation of hepatocytes in nonhuman primates: a preclinical model for the treatment of hepatic metabolic diseases. Transplantation 72:811–818. Voss WR. 1970. Primate liver and spleen biopsy procedures. Lab Anim Care 20:995–997.