Living Donor Liver Re-Transplantation for Recurrent

cancers

Case Report Living Donor Liver Re-Transplantation for Recurrent Hepatoblastoma in the Liver Graft following Complete Eradication of Peritoneal Metastases under Indocyanine Green Fluorescence Imaging

Nobuhiro Takahashi 1 , Yohei Yamada 1,2,*, Ken Hoshino 1 , Miho Kawaida 3, Teizaburo Mori 1, Kiyotomo Abe 1, Takumi Fujimura 1, Kentaro Matsubara 4, Taizo Hibi 4,5 , Masahiro Shinoda 4, Hideaki Obara 4, Kyohei Isshiki 6,7, Haruko Shima 6, Hiroyuki Shimada 6, Kaori Kameyama 3, Yasushi Fuchimoto 1,8, Yuko Kitagawa 4 and Tatsuo Kuroda 1

1 Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan; [email protected] (N.T.); [email protected] (K.H.); [email protected] (T.M.); [email protected] (K.A.); [email protected] (T.F.); [email protected] (Y.F.); [email protected] (T.K.) 2 Department of Pediatric Surgery, National Center for Child Health and Development, Tokyo 157-0074, Japan 3 Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan; [email protected] (M.K.); [email protected] (K.K.) 4 Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan; [email protected] (K.M.); [email protected] (T.H.); [email protected] (M.S.); [email protected] (H.O.); [email protected] (Y.K.) 5 Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-0862, Japan 6 Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan; [email protected] (K.I.); [email protected] (H.S.); [email protected] (H.S.) 7 Children’s Cancer Center, National Center for Child Health and Development, Tokyo 157-0074, Japan 8 Department of Pediatric Surgery, International University of Health and Welfare, Chiba 286-0048, Japan * Correspondence: [email protected]

Received: 11 April 2019; Accepted: 25 May 2019; Published: 26 May 2019

Abstract: The curability of chemotherapy-resistant hepatoblastoma (HB) largely depends on the achievement of radical surgical resection. Navigation techniques utilizing indocyanine green (ICG) are a powerful tool for detecting small metastatic lesions. We herein report a patient who underwent a second living donor liver transplantation (LDLTx) for multiple recurrent HBs in the liver graft following metastasectomy for peritoneal dissemination with ICG navigation. The patient initially presented with ruptured HB at 6 years of age and underwent 3 liver resections followed by the first LDLTx with multiple sessions of chemotherapy at 11 years of age. His alpha-fetoprotein (AFP) level increased above the normal limit, and metastases were noted in the transplanted liver and peritoneum four years after the first LDLTx. The patient underwent metastasectomy of the peritoneally disseminated HBs with ICG navigation followed by the second LDLTx for multiple metastases in the transplanted liver. The patient has been recurrence-free with a normal AFP for 30 months since the second LDLTx. To our knowledge, this report is the first successful case of re-LDLTx for recurrent HBs. Re-LDLTx for recurrent HB can be performed in highly select patients, and ICG navigation is a powerful surgical tool for achieving tumor clearance.

Keywords: hepatoblastoma; indocyanine green; living donor liver transplantation; transplant oncology

Cancers 2019, 11, 730; doi:10.3390/cancers11050730 www.mdpi.com/journal/cancers Cancers 2019, 11, 730 2 of 8

1. Introduction The introduction of cisplatin-based chemotherapy has provided significant survival benefits for patients with metastatic hepatoblastoma (HB) [1]; however, chemotherapy-resistant tumors can only be cured by complete surgical resection. Surgical management of metastases is known to improve a patient’s prognosis regardless of their sensitivity for chemotherapy, with a goal of clearing away all metastatic lesions [2]. Indocyanine green (ICG) is a reagent widely used to evaluate the liver function before hepatectomy. Recently, several series of navigation surgery using ICG for detecting small metastatic HBs were reported [3–6]. This technique involves the selective uptake of ICG by hepatocytes and HB cells, which allows for the selective visualization of such lesions in near-infrared mode. We herein report the first application of ICG navigation surgery for peritoneal dissemination of HBs for a patient who suffered from chemotherapy-resistant recurrence of HBs four years after the first rescue living donor liver transplantation (LDLTx). Simultaneously, the patient was found to have multiple metastases in the transplanted liver, presumably derived from peritoneally disseminated tumors. We conducted sequential transplantation involving clearing of the dissemination by ICG navigation surgery followed by re-transplantation from a living donor. To our knowledge, this report describes the first case of successful re-transplantation for recurrent HBs in the transplanted liver. The potential application of ICG navigation surgery along with LTx and the indications for re-transplantation for recurrent HBs are discussed.

2. Case Report The patient presented with hypovolemic shock due to the rupture of HB when he was 6 years old. The initial stage was Pretreatment Tumor Extent (PRETEXT) II (V0, P0, E0, F0, R1, C0, N0, M0) [7]. He underwent right hepatic artery embolization and chemotherapy consisting of cisplatin (80 mg/m2) and tetrahydropyranyl adriamycin (THP-ADR) (30 mg/m2) followed by right lobectomy based on the protocol described in Japanese Study Group for Pediatric Liver Tumor (JPLT)-1 [8]. The initial histological analysis revealed HB without features of hepatocellular carcinoma. Two adjuvant cycles of the same regimen were added postoperatively. However, as the HB recurred in the remnant of the liver a year later (at 7 years of age), the patient underwent partial resection followed by an additional 4 cycles of the same regimen. Unfortunately, the tumor recurred in the remaining lobe of the liver, so partial resection was performed again when he was 8 years old. Postoperatively, 4 cycles of the C5V regimen (cisplatin (90 mg/m2), 5-ﬂuorouracil (600 mg/m2) and vincristine (1.5 mg/m2)) were provided. At 9 years of age, magnetic resonance imaging (MRI) revealed the recurrence of HB in the liver, so the patient was referred to our center and underwent living donor liver transplantation (LDLTx) as a rescue treatment. Irinotecan (CPT-11) was selected as an adjuvant therapy after LDLTx. The details of his treatment course and AFP values are shown in Figure1. A histological analysis revealed wholly epithelial-type (fetal subtype) HB, intrahepatic metastasis(im)(+), s0, vp1, vv0, va0, b0 and sm( ). The postoperative − course was uneventful, and the patient was discharged after a month. Cancers 2019, 11, x 3 of 8 clearly identified in white-light mode (Figure 3A,C), the corresponding view in near-infrared mode Cancers(Figure2019 3B,D), 11, 730 showed well-demarcated nodules in the parietal peritoneum and mesocolon adjacent3 of 8 to the transplanted liver, all of which were successfully excised.

Cancers 2019, 11, x 3 of 8

clearly identified in white-light mode (Figure 3A,C), the corresponding view in near-infrared mode (Figure 3B,D) showed well-demarcated nodules in the parietal peritoneum and mesocolon adjacent to the transplanted liver, all of which were successfully excised.

FigureFigure 1. TheThe clinical clinical course course of of the the patient. patient. The The years years after after the the initial initial presentation presentation are areplotted plotted on the on thehorizontal horizontal axis, axis, and and the the values values of ofalpha-fetoprot alpha-fetoproteinein (AFP) (AFP) are are plotted plotted on on the the vertical axis.axis. BlueBlue arrowheadsarrowheads indicateindicate laparotomieslaparotomies otherother thanthan livingliving donordonor liverliver transplantationtransplantation (LDLTx).(LDLTx). BarsBars onon thethe bottombottom representrepresent thethe chemotherapeuticchemotherapeutic regimen.regimen. CITA: cisplatincisplatin 8080 mgmg/m/m22 andand tetrahydropyranyltetrahydropyranyl adriamycinadriamycin (THP-ADR)(THP-ADR) 3030 mgmg/m/m22,, C5V:C5V: cisplatincisplatin 9090 mgmg/m/m22,, 5-ﬂuorouracil5-fluorouracil 600600 mgmg/m/m22 and vincristine 1.51.5 mgmg/m/m22,, CPT-11:CPT-11: Irinotecan 2020 mgmg/m/m22.

His AFP remained within normal range for 45 months after the first LDLTx and then began to rise without any precedent events when he was 14 years old. MRI showed nodules in the transplanted Figure 1. The clinical course of the patient. The years after the initial presentation are plotted on the liver, whichhorizontal prompted axis, and us the to performvalues of exploratory alpha-fetoprot laparotomy.ein (AFP) are The plotted pathological on the findingsvertical axis. of metastatic Blue lesionarrowheads in the liver indicate were HB, laparotomies which consistent other than with living the donor original liver histology transplantation at the (LDLTx). time of the Bars first on LDLTxthe (Figurebottom2A,B). represent Elastica the van chemotherapeutic Gieson (EVG) stainregimen. of theCITA: specimen cisplatin is80also mg/m shown,2 and tetrahydropyranyl indicating the HB surroundedadriamycin by elastic (THP-ADR) fiber of30 portalmg/m2, veins C5V: (Figurecisplatin2 90C). mg/m Intraoperatively,2, 5-fluorouracil we 600 found mg/m peritoneal2 and vincristine nodules other1.5 than mg/m metastatic2, CPT-11: lesions Irinotecan in the 20 livermg/m that2. turned out to be metastatic HBs (Figure2D,E).

Figure 2. (A,B,C) The pathological findings of the metastatic nodule in the liver, which were compatible with wholly epithelial-type (fetal subtype) hepatoblastoma (HB) with vascular invasion. (A,B; H.E. stain, A;100×, B;200×, C; Elastica van Gieson(EVG) stain, 200×). (D) The arrowhead represents the peritoneal nodule adjacent to the transplanted liver, which was noted in the first laparotomy after the first LDLTx procedure. (E) The pathological findings of the peritoneal nodule is shown in Figure (H.E. stain, 100×).

FigureFigure 2. 2.(A (,AB,,CB),C The) The pathological pathological findings findings of the of metastatic the metastatic nodule innodule the liver, in whichthe liver, were which compatible were withcompatible wholly with epithelial-type wholly epithelial-type (fetal subtype) (fetal hepatoblastoma subtype) hepatoblastoma (HB) with vascular (HB) with invasion. vascular (A invasion.,B; H.E. stain,(A,B;A H.E.; 100 stain,, B; 200 A;100×,, C; Elastica B;200×, van C; GiesonElastica (EVG) van Gieson(EVG) stain, 200 ). (Dstain,) The 200×). arrowhead (D) The represents arrowhead the × × × peritonealrepresents nodule the peritoneal adjacent tonodule the transplanted adjacent to liver, the whichtransplanted was noted liver, in which the first was laparotomy noted in after the thefirst firstlaparotomy LDLTx procedure. after the first (E) LDLTx The pathological procedure. findings (E) The of pathological the peritoneal findings nodule of is the shown peritoneal in Figure nodule (H.E. is

stain,shown 100 in ).Figure (H.E. stain, 100×). ×

Cancers 2019, 11, 730 4 of 8

We then planned to perform ICG navigation surgery to achieve complete eradication of the disseminated HBs several days later. The study was approved by the institutional ethical review board of Keio University School of Medicine (approval No. 20160226). ICG (0.5 mg/kg) was given 72 h prior to the operation to minimize the background uptake by the normal hepatocytes. A Photodynamic Eye system® (PDE®; Hamamatsu Photonics, Hamamatsu, Japan) was used to visualize the lesions taking up ICG in near-infrared mode. While the exact locations of the disseminated HBs were not clearly identiﬁed in white-light mode (Figure3A,C), the corresponding view in near-infrared mode (Figure3B,D) showed well-demarcated nodules in the parietal peritoneum and mesocolon adjacent to theCancers transplanted 2019, 11, x liver, all of which were successfully excised. 4 of 8

FigureFigure 3. 3.White-light White-light modemode (A(A,C,C)) andand correspondingcorresponding near-infrared near-infrared mode mode (B (B,D,D) )findings ﬁndings in inthe the peritonealperitoneal cavity cavity at at the the time time of of the the second second laparotomylaparotomy after the the first ﬁrst LDLTx LDLTx procedure procedure are are shown, shown, macroscopicmacroscopic image. image.

AllAll specimens specimens that that were were visualized visualized by PDE by® PDEwere® histologicallywere histologically positive positive for HB tissues.for HB Thereafter,tissues. meticulousThereafter, examination meticulous examination of the entire of abdominal the entire abdominal cavity by PDEcavity® wasby PDE performed,® was performed, whichrevealed which norevealed other metastatic no other lesionsmetastatic besides lesions the besides aforementioned the aforementioned area in the area right in upperthe right quadrant. upper quadrant. However, theHowever, transplanted the transplanted liver graft was liver infiltrated graft was withinfiltrat diedffuse with metastatic diffuse metastatic HBs. After HBs. a two-monthAfter a two-month interval, anotherinterval, laparotomy another laparotomy utilizing ICG utilizing navigation ICG navigation (0.5 mg/ kg(0.5 of mg/kg ICG wasof ICG administered was administered three three days days before before laparotomy) was performed to explore whether or not there were any residual disseminated laparotomy) was performed to explore whether or not there were any residual disseminated HBs. HBs. Although numerous uptakes of ICG in the transplanted liver were noted, we confirmed the Although numerous uptakes of ICG in the transplanted liver were noted, we confirmed the complete complete absence of any extrahepatic lesions in the abdomen. absence of any extrahepatic lesions in the abdomen. In a multidisciplinary conference, we discussed whether or not, provided the all detectable In a multidisciplinary conference, we discussed whether or not, provided the all detectable extrahepatic metastases were brought under control, re-transplantation is rational from an extrahepaticoncological metastases perspective were and broughtis the only under curative control, option. re-transplantation In Japan, since the is rationalnumber fromof deceased an oncological donor perspectivetransplantations and is isthe limited only (50–60 curative liver option. transplantat Inions Japan, from since deceased the numberdonors per of year), deceased a second donor transplantationsLDLTx was considered. is limited The (50–60 patient liver and transplantations the family were well from informed deceased of donorsthe risk of per recurrence year), a secondeven LDLTxafter wasa second considered. LDLTx but The remained patient and willing the familyto proc wereeed. The well institutional informed of review the risk board of recurrence approved the even aftersecond a second LDLTx. LDLTx but remained willing to proceed. The institutional review board approved the second LDLTx.Prior to the second LDLTx, CPT-11 (20 mg/m2) was administered to delay the growth of the tumorPrior cells. to the The second AFP LDLTx,value decreased CPT-11 (20 from mg /439m2) ng was/ml administered to 297 ng/ml to after delay 2 thecycles growth of CPT-11. of the tumorThe cells.second The AFPLDLTx value was decreased performed from when 439 the ng patient/ml to 297was ng 14/ mlyears after old, 2 cycleswhich ofwas CPT-11. 62 months The after second the LDLTx first wasLDLTx. performed Again, when 0.5 themg/kg patient of ICG was was 14 yearsadministered old, which intravenously was 62 months three after days the prior first to LDLTx. the second Again, 0.5LDLTx. mg/kg ofFortunately, ICG was administered no extrahepatic intravenously tumor was obse threerved days at the prior time to of the the second second LDLTx. LDLTx, Fortunately, although no extrahepaticmultiple instances tumor of was the observeduptake of atICG the in time the explanted of the second liver LDLTx, were visualized although by multiple PDE® (Figure instances 4A,B). of the Of note, the hepatectomy of the donor was delayed until it was confirmed that no new extahepatic metastases were seen by PDE®. The ICG-positive lesions in the liver were compatible with HBs pathologically. Postoperatively, an additional two cycles of CPT-11 were provided. The patient has been recurrence-free for 30 months since the second LDLTx, with the value of AFP being within the normal limit (Figure 1).

Cancers 2019, 11, 730 5 of 8 uptake of ICG in the explanted liver were visualized by PDE® (Figure4A,B). Of note, the hepatectomy of the donor was delayed until it was conﬁrmed that no new extahepatic metastases were seen by PDE®. The ICG-positive lesions in the liver were compatible with HBs pathologically. Postoperatively, an additional two cycles of CPT-11 were provided. The patient has been recurrence-free for 30 months sinceCancers the 2019 second, 11, x LDLTx, with the value of AFP being within the normal limit (Figure1). 5 of 8

FigureFigure 4.4. (A) The sliced explanted liver in white-light modemode andand ((BB)) near-infrarednear-infrared mode.mode. TheThe hothot spotsspots inin near-infrarednear-infrared modemode werewere compatible compatible with with hepatoblastomas hepatoblastomas in in histology, histology, macroscopic macroscopic image image

3.3. Discussion AA surgicalsurgical approachapproach hashas shownshown markedmarked eefficacyfficacy forfor thethe treatmenttreatment ofof recurrentrecurrent HBs,HBs, whichwhich areare consideredconsidered highlyhighly chemo-resistant chemo-resistant [9]. [9]. A growing A growin numberg number of successful of successful metastasectomies metastasectomies for recurrent for pulmonaryrecurrent pulmonary metastases metastases of HBs and of aHBs subsequent and a subs tumor-freeequent tumor-free survival havesurvival been have reported been reported [10–12]; however,[10–12]; however, little is known little about is know the survivaln about benefit the survival in the eradication benefit in of peritonealthe eradication dissemination of peritoneal or the roledissemination of re-transplantation or the role forof re-transplantation recurrence in a transplanted for recurrence liver in graft. a transplanted liver graft. WhenWhen consideringconsidering the the indication indication of re-transplantation of re-transplantation for this for patient, this patient, three factors three were factors discussed were thoroughlydiscussed thoroughly in the multidisciplinary in the multidisciplinary team meeting. team First, meeting. the fact First, that the this fact patient that this initially patient presented initially withpresented ruptured with HBs ruptured at six years HBs at of six age years led to of the age hypothesis led to the thathypothesis the disseminated that the disseminated HBs did not developHBs did afternot develop the first LDLTxafter the but first existed LDLTx from but the existed beginning. fromThey the beginning. had not been They eradicated had not through been eradicated multiple operationsthrough multiple and chemotherapy operations and and chemotherapy subsequently and became subsequently chemo-resistant. became Thischemo-resistant. speculation wasThis compatiblespeculation withwas thecompatible operative with finding the operative that the dissemination finding that the was di localizedssemination in the was upper-right localized ofin thethe abdominalupper-right cavity, of the as abdominal confirmed throughcavity, as two confirme exploratoryd through laparotomies two exploratory and the second laparotomies LDLTx procedure. and the Assecond HB cases LDLTx that procedure. develop accompanying As HB cases that tumor develop rupture accompanying tend to recur tumor more rupture frequently tend and to recur result more in a poorerfrequently prognosis and result than in those a poorer without prognosis tumor than rupture those [7 ],without the patient tumor should rupture have [7], been the patient treated should with a morehave intensivebeen treated regimen with accordinga more intensive to the current regimen risk a stratificationccording to the [13 ].current Alternatively, risk stratification intraperitoneal [13]. chemotherapy,Alternatively, whichintraperitoneal has a role chemotherapy, in the treatment which of peritoneal has a metastasisrole in the of hepatocellulartreatment of carcinoma,peritoneal mightmetastasis be indicated of hepatocellular in cases in whichcarcinoma, intravenous might chemotherapy be indicated is inein ffcasesective in [14 ].which If ICG intravenous navigation waschemotherapy available at is the ineffective time of the[14]. first If ICG resection, navigation it might was have available helped at surgeonsthe time of identify the first the resection, presence, it locationmight have and helped extent ofsurgeons peritoneal identify disease, the and presence, the lesion location with theand uptakeextent of ICGperitoneal should disease, have been and sent the tolesion pathology. with the uptake of ICG should have been sent to pathology. Second,Second, thethe absence absence of lungof lung metastases metastases and theand timing the timing of recurrence of recurrence after the after first LDLTx the first procedure LDLTx wereprocedure interesting. were Theinteresting. tumor recurred The tumor after recurred an interval after of four an interval years following of four theyears first following LDLTx procedure the first andLDLTx rapidly procedure spread and as multiple rapidly hepatic spread metastases.as multiple Tohepatic our knowledge, metastases. the To longest our knowledge, interval between the longest LTx andinterval therecurrence between LTx of HB and was the 2.8 recurrence years, as reported of HB was in a 2.8 Japanese years, nationalas reported survey in [a15 Japanese]. These findingsnational indicatesurvey [15]. that theThese recurrent findings tumors indicate grew that very the slowly recurr andent tumors were localized grew very in the slowly abdominal and were cavity, localized which favorsin the abdominal our proposal cavity, for re-transplantation. which favors our Ifproposal the tumor for recurs re-transplantation. in the graft or If lungs the tumor soon afterrecurs the in first the LTx,graft whichor lungs indicates soon after that the the first tumor LTx, is which growing indica quicklytes that and the thus tumor is now is growing spreading quickly throughout and thus the is entirenow spreading body, then throughout such a patient the entire would body, not bethen indicated such a patient for additional would not surgery. be indicated Although for itadditional remains asurgery. matter ofAlthough debate howit remains long an a matter interval of is debate necessary how before long an a patientinterval may is necessary be considered before indicated a patient may be considered indicated for re-transplantation for recurrent HBs, we believe that at least a two- year period of normal AFP levels after the first LTx should be required. Regarding the time between the clearing of metastatic disease with ICG guided surgery and the second transplantation, we set a period of two months arbitrarily between the first and second exploratory laparotomy procedures. Then, the second LDLTx was scheduled one month later. Although re-transplantation must be performed before multiple liver metastases spread further, we considered it prudent to confirm the absence of newly developed peritoneal disease for several months before moving forward. In addition, although we did not check for the presence of circulating tumor cells in this specific patient,

Cancers 2019, 11, 730 6 of 8 for re-transplantation for recurrent HBs, we believe that at least a two-year period of normal AFP levels after the first LTx should be required. Regarding the time between the clearing of metastatic disease with ICG guided surgery and the second transplantation, we set a period of two months arbitrarily between the first and second exploratory laparotomy procedures. Then, the second LDLTx was scheduled one month later. Although re-transplantation must be performed before multiple liver metastases spread further, we considered it prudent to confirm the absence of newly developed Cancers 2019, 11, x 6 of 8 peritoneal disease for several months before moving forward. In addition, although we did not check forthe the presence presence of ofcirculating circulating tumor tumor cells cells seems in to this be specific associated patient, with a the poor presence prognosis of circulatingin patients with tumor cellshepatocellular seems to be carcinoma associated [16]. with With a poorrecent prognosis technical advances, in patients th withe absence hepatocellular of circulating carcinoma tumor cells [16 ]. Within HB recent patients technical may become advances, an objective the absence tests of to circulating justify liver tumor transplantation. cells in HB patients may become an objectiveThird tests and to justifymost importantly, liver transplantation. the technical feasibility of eradicating the HBs was discussed. In thisThird regard, and ICG most navigation importantly, surgery the played technical an essential feasibility role. of ICG, eradicating which is thewidely HBs used was to discussed. assess the In thisliver regard, function, ICG is navigation selectively surgerytaken up played by HBs an as essential well as normal role. ICG, hepatocytes which is but widely excreted used in to a delayed assess the liverfashion function, from isHB selectively tissue. Due taken to this up delayed by HBs excretio as welln, as the normal specific hepatocytes visualization but of excreted both primary in a delayed and fashionmetastatic from HBs HB tissue.in the surgical Due to thisfield delayed is possible. excretion, However, the specific several visualizationlimitations associated of both primary with this and metastatictechniqueHBs should in thebe mentioned. surgical field The isfalse-positive possible. However, rate with ICG several navigation limitations surgery associated is reported with to be this technique10–20% (number should be of mentioned. lesions that The were false-positive not pathologically rate with diagnosed ICG navigation as HBs surgery among is ICG-positive reported to be 10–20%lesions). (number Furthermore, of lesions in thatsurveys were of not hepatocellular pathologically carcinoma, diagnosed the as sensitivity HBs among and ICG-positive specificity lesions).were Furthermore,reported to vary in surveys depending of hepatocellular on the histology, carcinoma, liver function the and sensitivity timing of and surgery specificity after ICG were injection reported to[17–20]. vary depending In addition, on the the fluore histology,scence liver produced function by and ICG timing can only of surgerybe detected after when ICG injectionthe lesions [17 are–20 ]. Inlocated addition, 5–10 the mm fluorescence from the surface. produced Further by ICGstudies can w onlyill be beneeded detected in order when to theaddress lesions these are issues. located 5–10Despite mm fromthese thelimitations, surface. since Further ICG studiesnavigation will enab be neededles the detection in order of to nodules address <0.1 these mm issues. in diameter Despite theseand limitations,facilitates the since clear ICG demarcation navigation of enables tumors the[3,5 detection], we believe of nodules that this< 0.1technology mm in diameter is the best and facilitatesavailable the to present clear demarcation to detect HBs. of tumorsOur patient [3,5], is we liv believeing proof that of the this emerging technology paradigm is the best of transplant available to oncology, the fusion of transplantation medicine and oncology to open new horizons in cancer present to detect HBs. Our patient is living proof of the emerging paradigm of transplant oncology, the treatment [21]. fusion of transplantation medicine and oncology to open new horizons in cancer treatment [21]. Based on the findings and the discussions mentioned above, our hypothesized mechanism of Based on the findings and the discussions mentioned above, our hypothesized mechanism of the recurrence that developed in this patient is presented in Figure 5. We propose the concept of the recurrence that developed in this patient is presented in Figure5. We propose the concept of “sequential transplantation”, which is the complete elimination of peritoneal dissemination using “sequential transplantation”, which is the complete elimination of peritoneal dissemination using ICG ICG navigation followed by the replacement of the affected liver. The fact that ICG navigation navigationallowed us followed to remove by thethe replacementnodules that ofwere the ot affherwiseected liver. invisible The factto the that naked ICG navigationeye despite allowedbeing uspathologically to remove the proven nodules disseminated that were otherwise HBs and that invisible the patient to the has naked been eye tumor-free despite being for 2.5 pathologically years since proventhe second disseminated LDLTx provides HBs and proof that of the this patient principle. has beenAs it tumor-freemight be too for early 2.5years to conclude since the that second the LDLTxpatient provides is cured, proof regular of thissurveillance principle. is Asmand it mightatory and be too switching early to the conclude immunosuppression that the patient regimen is cured, regularfrom tacrolimus surveillance to iseverolimus mandatory is andnow switching being considered the immunosuppression in the anticipation regimen of a potential from tacrolimus antitumor to everolimuseffect. is now being considered in the anticipation of a potential antitumor effect.

FigureFigure 5. 5.A schematicA schematic illustration illustration ofthe of hypothesizedthe hypothesized mechanism mechanism of recurrence of recurrence in this in patient. this patient. Multiple metastasesMultiple metastases in the liver in the graft liver are graft assumed are assumed to be derivedto be derived from from disseminated disseminated nodules nodules through through the portalthe portal vein. vein.

4. Conclusions In conclusion, re-LDLTx for multiple intra-graft HB metastases can be indicated for selected patients. ICG navigation provides the best surgical tool currently available for achieving complete eradication of HBs. Yet, as this case is the first attempted re-transplantation for recurrent HB, a prudent approach should be taken when considering the concept of sequential transplantation given the precious donor source.

Cancers 2019, 11, 730 7 of 8

4. Conclusions In conclusion, re-LDLTx for multiple intra-graft HB metastases can be indicated for selected patients. ICG navigation provides the best surgical tool currently available for achieving complete eradication of HBs. Yet, as this case is the ﬁrst attempted re-transplantation for recurrent HB, a prudent approach should be taken when considering the concept of sequential transplantation given the precious donor source.

Informed Consent: Written consent for publication was obtained from both parents of the patient. Funding: This research received no external funding. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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