Mrio Spggiri , Kir A Tull , Griel Aguiluz , Pierpolo Di Cocco , Lol Cstro Gil ,Enrico Benedetti , IvoG Tzvetnov , PierCristoforo Giulinotti

a Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA

b Division of General, Minimally Invasive, and Robotic Surgery, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA

Surgical resection remains the only definitive treatment for colorectal liver metastasis (CRLM).However, only a minority of cases are deemed resectable at the time of diagnosis.Systemic chemotherapy along with hepatic artery infusion (HAI) is an effective and safe regional chemotherapy modality for the downstaging of patients with isolated unresectable CRLM [1].This modality improves patient response rate up to 80% and secondary resection rate up to 47% in isolated unresectable CRLM [2].The limited usage of this therapy could be due to the morbidity and mortality associated with open surgery in a population with a reduced chance of long-term survival.The application of minimally invasive techniques circumvents the complications related to laparotomy and decreases the recovery time needed to initiate chemotherapy [3].Although the robotic-assisted HAI pump placement has been previously described [ 1 , 4 ], to our best knowledge, we report the first case using indocyanine green (ICG) forinvivoperfusion test.

A 60-year-old Hispanic male with history of insulin-dependent diabetes, hypertension, and hyperlipidemia presented with dizziness and fatigue.Radiological imaging showed a cecal mass and bilobar liver metastasis, proven adenocarcinoma by biopsy.A laparoscopic right hemicolectomy for resection of the primary cecal tumor was performed.Due to liver disease and large lesion encasing the three hepatic veins, it was deemed unresectable by a multidisciplinary team, and the patient was referred for combined systemic and HAI chemotherapy three months after laparoscopy( Fig.1 ).CT of the chest, abdomen, and pelvis and PET/CT were performed to rule out extrahepatic disease.

For the robotic-assisted HAI pump device placement, the patient was placed supine on a split leg table.A diagnostic laparoscopy ruled out peritoneal metastases or carcinomatosis.Trocar placement is depicted in Fig.2 A, B.ThedaVinci?SiTM robot(Intuitive Surgical Inc., Sunnyvale, CA, USA) cart was placed over the patient’s right shoulder.The procedure started with a cholecystectomy.Next, the common hepatic artery (CHA), the bifurcations of the right gastric artery (RGA), the gastroduodenal artery (GDA),and the proper hepatic artery (PHA) were skeletonized ( Fig.2 C and Video S1).The RGA was ligated with 4-0 Prolene and transected.About 3 cm of the GDA were isolated, and the pancreaticoduodenal arteries were ligated.The pump was placed in a fascial pocket in the abdomen’s left lower quadrant and secured with 3-0 silk.The catheter was introduced into the abdomen.The CHA and PHA were clamped, and a 3-mm transverse arteriotomy was performed on the GDA.The catheter was inserted and fixated.Three mg of ICG were injected through the HAI pump to visualize isolated hepatic perfusion (analysis for biliary studies ranges between 3-5 mg).The endoscope’s vision mode was switched from normal illumination to the integrated fluorescence imaging mode, and immediately after injection, the liver was uniformly fluorescent, and the CRLM was identified, with no evidence of extrahepatic perfusion( Fig.3 A and B).The patient remained stable throughout the procedure, with minimal blood loss, and was transferred to the ICU.

A postoperative nuclear medicine study confirmed isolated hepatic uptake of tracer with bilobar disease ( Fig.3 C and D).The patient was discharged on postoperative day (POD) 1.Pathology confirmed no perihepatic lymph node involvement.Chemotherapy was initiated on POD 13.Neoadjuvant systemic chemotherapy regimen consisted of mFOLFOX (oxaliplatin IV 85 mg/m2, leucovorin IV 400 mg/m2, 5-fluorouracil continuous IV 20 0 0 mg/m2over 46 h) on day 1 and 15.HAI infusion of floxuridine (FUDR)was given [0.12 mg/kg/d × pump-volume × weight (kg)/pump flowrate]along with dexamethasone (1 mg/mL ×pump-volume/pump flowrate) on day 1 of every cycle.The pump was emptied and filled with heparin (10 0 0 IU/mL ×pump-volume) on day 15.Dose adjustments of FUDR were made based on the aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels.Chemotherapy was administered in 28-day cycles for six cycles.HAI pump chemotherapy was alternated every 14 days.After 6 months, follow-up CT scan showed partial response ( Fig.1 C and D),main lesion sparing the right hepatic vein, and the rest decreased in size.A curative left hepatectomy with three wedges resection and one radiofrequency ablation of the right lobe was performed.Two and a half years follow-up after the initial diagnosis, the patient had been doing well, without recurrence.

Fig.1.CT findings before hepatic artery infusion pump implantation, ( A) bilobar lesions, ( B) main lesion encasing the three hepatic veins; response after 6 months of treatment with regression of the main lesion nowinvolving the left middle hepatic veins ( C, D).

Although most patients with CRLM do not initially present as candidates for surgical resection, the combination of HAI directed regional chemotherapy and systemic chemotherapy has proven effective in downstaging stage IV cancer patients and bridging them to surgical resection [5].Downstaging with combination therapy could provide a more efficient way to select patients with tumor biology responsive to multimodal chemotherapy and surgical resection [2].Since liver metastases receive blood supply almost exclusively from the hepatic artery, direct chemotherapy through the hepatic artery allows an enhanced selective treatment delivery while limiting systemic side effects [6].Studies have reported downstaging from an initially inoperable to a potentially resectable state [ 7 , 8 ]and similar 5-year survival to patients with initially resectable lesions [ 8 , 9 ].Furthermore, the techniques to resect extensive bilobar metastases have improved over the last two decades allowing more comprehensive resection criteria [10].

An HAI catheter placement with conventional laparoscopy is a tedious procedure requiring challenging vasculature dissection,accessible only to fewhighly skilled laparoscopic surgeons [11].Robotic HAI pump placement is safe and associated with lower conversion rates and shorter length of stay in selected patients compared with laparoscopic placement [12].The integrated nearinfrared fluorescence imaging in the robotic platform allows ICG to be used for isolated hepatic perfusion test.In addition to preoperative imaging, this method increases the accuracy of identifying malignant masses [13]and achieving R0 resections [14].

This perfusion test is traditionally conducted with methylene blue; however, ICG has superior optical properties and requires lower doses for accurate detection.ICG’s prompt uptake and effi-cient clearance by the liver allows sustained visual identification of extrahepatic infusion [15].Future advancements of ICG and conjugated fluorophores to monoclonal antibodies are under investigation for “fluorescence-guided”surgery, real-timeinvivomicroscopy for resection margins evaluation, and accurate identification of metastatic lymph nodes [1].

In conclusion, the placement of an HAI pump using the robotic platform provides a minimally invasive option and minimal scaring to bridge patients to hepatic resection if down staging is successful.

Fig.2.Port setting for hepatic artery infusion pump placement.A and B : Robotic port 1 was placed on the right upper quadrant, the camera port to the right of the umbilicus, and robotic ports 2 and 3 on the left upper quadrant.The assistant port was placed to the left of the umbilicus.Celiac trunk dissection.C: The vasculature was skeletonized by first identifying the common hepatic artery (CHA) and tracking it down to the bifurcations of the right gastric artery, proper hepatic artery (PHA) and gastroduodenal artery (GDA).The right gastric artery had been transected.

Fig.3.Indocyanine green (ICG) in vivo perfusion test and nuclear medicine test for extrahepatic pump flow.Intraoperatively the hepatic artery infusion (HAI) pump was instilled with ICG.Firefly TM Fluorescence Imaging optics were initiated to detect extrahepatic flow.A: Prior to ICG infusion into the HAI pump; B: 10 min after ICG infusion into the pump with isolated hepatic uptake.On postoperative day 1 a nuclear medicine technetium 99 scan showed isolated hepatic uptake of tracer with HAI pump infusion( C), with further localization of bilobar CRLM disease ( D).CRLM: colorectal liver metastasis.

Acknowledgments

None.

CRediT authorship contribution statement

Mario Spaggiari:Conceptualization, Methodology, Visualization,Writing - original draft, Writing - review & editing.Kiara A Tulla:Writing - review & editing.Gabriela Aguiluz:Visualization, Writing - review & editing.Pierpaolo Di Cocco:Writing - review& editing.Lola Castro Gil:Writing - review & editing.Enrico Benedetti:Conceptualization, Supervision.Ivo G Tzvetanov:Conceptualization, Supervision.Pier Cristoforo Giulianotti:Conceptualization, Methodology, Supervision.

Funding

None.

Ethical approval

This study was approved by Internal Review Board (2011-1104).Informed consent for publication was obtained from the patient.

Competing interest

Pier Cristoforo Giulianotti has a consultant agreement with Covidien/Medtronic and Ethicon Endosurgery, and he also has an institutional agreement (University of Illinois at Chicago) for training with Intuitive.All other authors have no conflict of interest.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.hbpd.2021.09.009.