The tumor microenvironment of VETC+ hepatocellular carcinoma is enriched of immunosuppressive TAMs spatially close to endothelial cells.

BACKGROUND AND AIM: VETC (vessel that encapsulate tumor cluster) is a peculiar vascular phenotype observed in hepatocellular carcinoma (HCC), associated with distant metastases and poor outcome. VETC has been linked to the Tie2/Ang2 axis and is characterized by lymphocytes poor (cold) tumor microenvironment (TME). In this setting the role of Tumor Associated Macrophages (TAMs) has never been explored. Aim of the study is to investigate the presence and features of TAMs in VETC+ HCC and the possible interplay between TAMs and endothelial cells (ECs). METHODS: The series under study included 42 HCC. Once separated according to the VETC phenotype (21 VETC+; 21 VETC-) we stained consecutive slides with immunohistochemistry for CD68, CD163 and Tie2. Slides were then scanned and QuPath used to quantify morphological features. RESULTS: VETC+ cases were significantly (p < 0.001) enriched with large, lipid rich CD163+ TAMs (M2 oriented) that were spatially close to ECs; HCC cells significantly (p: 0.002) overexpressed Tie2 with a polarization toward ECs. CONCLUSIONS: The pro-metastatic attitude of VETC is sustained by a strict morphological relationship between immunosuppressive M2-TAMs, ECs and Tie2-expressing HCC cells.

ICG-Enhanced Compression Anatomical Segment 7 Segmentectomy in Laparoscopic and Robotic Approach.

BACKGROUND: Minimally invasive anatomical resection (AR) for posterosuperior lesions is technically challenging.1,2 The Glissonean approach or puncture technique is generally selected.3,4 The tumor-feeding portal pedicle compression AR (C-AR) is an established procedure in open surgery.5 This technique has benefited from the association with indocyanine green (ICG) fluorescence, used to enhance the anatomical area to be resected.6 Recently, C-AR via the minimal access approach has been reported.7 Herein, we report the first cases of laparoscopic and robotic segment 7 (S7) segmentectomy using the ICG-enhanced compression technique. PATIENTS AND METHODS: Two cases of CHILD-class A hepatocellular carcinoma (HCC) in segment 7 with a liver stiffness less than 7 kPa treated by laparoscopic and robotic anatomical S7 segmentectomies were reported. Using the intraoperative ultrasound (IOUS), the tumor-bearing portal pedicle and the level targeted for compression were identified. The right hemiliver was adequately mobilized to allow handling of the organ during dissection. Using the grasper and the probe itself, the S7 Glissonean pedicle was transparenchymally compressed under real-time IOUS control. To further enhance the visibility of the discolored S7, ICG was administered intravenously, obtaining the compressed area to be resected as a non-stained one. Dissection was performed under intermittent Pringle maneuver up to exposing the right hepatic vein, dividing the Glissonean pedicle to segment 7 and then completing the resection. RESULTS: Pathologic findings demonstrated a 4.9 cm and 7.3 cm HCC with a R0-resection margin (> 1 cm in both). Postoperative complications were nil. The patients were discharged 6 days after surgery. CONCLUSIONS: This preliminary experience shows that the C-AR is a feasible and reliable technique in laparoscopic and robotic approach for posterosuperior lesions. Further studies are needed to investigate its applicability and standardization.

Anatomical liver resection using the ultrasound-guided compression technique in minimal access surgery.

BACKGROUND: Segmental or subsegmental anatomical resection (AR) of hepatocellular carcinoma (HCC) in minimal access liver surgery (MALS) has been technically proposed. The Glissonean approach or dye injection technique are generally adopted. The tumor-feeding portal pedicle compression technique (C-AR) is an established approach in open surgery, but its feasibility in the MALS environment has never been described. METHODS: Eligible patients were prospectively enrolled to undergo laparoscopic or robotic ultrasound-guided C-AR based on HCC location and preoperative identification of a single tumor-feeding portal pedicle. Initial C-AR experience was gained with laparoscopic cases in the beginning of 2020. Following our progressive experience in laparoscopic C-AR, patients requiring AR for HCC were consecutively selected for robotic C-AR. RESULTS: A total of 10 patients underwent minimal access C-AR. All patients had Child-Pugh A HCC. The surgical procedures included 6 laparoscopic and 4 robotic C-AR. Median tumor size was 3.1 cm (range 2-7 cm). All procedures had R0 margin. Postoperative complications were nil. CONCLUSION: C-AR technique is a feasible and promising technique for patients eligible for laparoscopic and robotic AR for HCC. Further data are necessary to validate its applicability to more complex minimal access AR.

Upfront Surgery versus Neoadjuvant Perioperative Chemotherapy for Resectable Colorectal Liver Metastases: A Machine-Learning Decision Tree to Identify the Best Potential Candidates under a Parenchyma-Sparing Policy.

Addressing patients to neoadjuvant systemic chemotherapy followed by surgery rather than surgical resection upfront is controversial in the case of resectable colorectal -liver metastases (CLM). The aim of this study was to develop a machine-learning model to identify the best potential candidates for upfront surgery (UPS) versus neoadjuvant perioperative chemotherapy followed by surgery (NEOS). Patients at first liver resection for CLM were consecutively enrolled and collected into two groups, regardless of whether they had UPS or NEOS. An inverse -probability weighting (IPW) was performed to weight baseline differences; survival analyses; and risk predictions were estimated. A mortality risk model was built by Random-Forest (RF) to assess the best -potential treatment (BPT) for each patient. The characteristics of BPT-upfront and BPT-neoadjuvant candidates were automatically identified after developing a classification -and -regression tree (CART). A total of 448 patients were enrolled between 2008 and 2020: 95 UPS and 353 NEOS. After IPW, two balanced pseudo-populations were obtained: UPS = 432 and NEOS = 440. Neoadjuvant therapy did not significantly affect the risk of mortality (HR 1.44, 95% CI: 0.95-2.17, p = 0.07). A mortality prediction model was fitted by RF. The BPT was NEOS for 364 patients and UPS for 84. At CART, planning R1vasc surgery was the main factor determining the best candidates for NEOS and UPS, followed by primitive tumor localization, number of metastases, sex, and pre-operative CEA. Based on these results, a decision three was developed. The proposed treatment algorithm allows for better allocation according to the patient's tailored risk of mortality.

Hepatectomy versus Chemotherapy for Resectable Colorectal Liver Metastases in Progression after Perioperative Chemotherapy: Expanding the Boundaries of the Curative Intent.

Disease progression (PD) at neoadjuvant chemotherapy for patients with colorectal liver metastases (CLMs) is considered a contraindication to hepatic resection. Our aim was to estimate the overall survival (OS) in patients undergoing surgery compared with those treated exclusively with chemotherapy in cases of PD. Patients from a single centre with PD were analyzed and subdivided into two groups: hepatectomy (HEP) versus chemotherapy (CHT). An Inverse Probability Weighting (IPW) was run to balance the baseline differences between the two groups. A Cox regression was carried out on identifying factors predicting mortality. From 2010 to 2020, 105 patients in PD to at least one line of chemotherapy were analyzed. Of these, 27 (25.7%) underwent hepatic resection. After a median follow-up of 30 (IQR 14-46) months, 61.9% were dead. The OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 95 and 46.8% for HEP (p < 0.001). After IPW, two balanced pseudopopulations were obtained: HEP = 85 and CHT = 103. The OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 97.8 and 49.3% for HEP (HR 0.256, 95%CI: 0.08-0.78, p = 0.033). After IPW, in the multivariate model, surgery resulted in the only protective variable (HR 0.198, 95%CI: 0.08-0.48, p = 0.0016). Our results show that hepatic resection could offer a chance of a longer OS than the prosecution of chemotherapy only in originally resectable patients.

Laparoscopic Ultrasound-Guided R1 Vascular Liver Resection for Colorectal Liver Metastases at Caval Confluence.

BACKGROUND: Patients with tumors involving the hepatic vein (HV) at the caval confluence (CC) usually receive major hepatectomies or HV grafting. For colorectal liver metastases (CLM), tumor-vessel detachment (R1vasc) has proven to be oncologically adequate.1-3 However, parenchyma-sparing R1vasc surgery has usually been confined to the open approach. The technical tricks for accomplishing this kind of surgery in laparoscopy are disclosed. METHODS: A patient with a CLM in contact with the middle HV (MHV) and left HV (LHV) at the CC underwent liver resection. No signs of vascular invasion were observed at preoperative imaging. On the basis of the low rate of tumor-vessel regression after chemotherapy,4 technical feasibility, and low tumor burden, patient was considered for upfront surgery. Surgery consisted in: (1) left liver mobilization with full exposure of the CC; (2) identification of the common trunk's root and its encirclement by tape; (3) the use of ultrasound to rule out HV invasion and to define a resection area favoring a transection plane smoothly approaching the point of vascular contact; and (4) careful vascular detachment by blunt dissection in a caudocranial fashion to separate the lesion from HVs. RESULTS: A limited resection of segments, four superior and two with MHV-LHV detachment, was performed. Operation time was 285 min, with 52 min of cumulative Pringle time and 20 ml of blood loss. Postoperative course was uneventful. The in-hospital stay was 6 days. CONCLUSION: Similarly to open surgery, laparoscopic R1vasc surgery for CLM at CC is feasible and represents an alternative to major hepatectomy. HV control by tape is recommended to manage any bleeding that may occur during tumor-vessel detachment.

Transversal hepatectomies: Classification and intention-to-treat validation of new parenchyma-sparing procedures for deep-located hepatic tumors.

BACKGROUND: Deep-located liver tumors involving hepatic veins at the caval confluence or main Glissonean pedicles generally require a major hepatectomy. An intraoperative ultrasound guidance policy opened a possibility to opt for parenchyma-sparing procedures as alternatives to major hepatectomy, called transversal hepatectomies. We ought to standardize the procedure and analyze the surgical outcome, oncological suitability, and salvageability. METHODS: This is a retrospective cohort study. All consecutive patients undergoing hepatectomies for liver tumors between January 2005 and August 2020 were reviewed. Transversal hepatectomies were classified as follows: upper transversal hepatectomy: resection of the posterosuperior segments along with at least 1 hepatic vein and preservation of the anteroinferior ones; roller coaster hepatectomy: transversal hepatectomy with tumor vessel detachment from at least 2 hepatic veins; and lower transversal hepatectomy: amputation of the distal portion of at least 1 hepatic vein with tumor vessel detachment from first/second-order Glissonean pedicles. Morbidity, mortality, local recurrences, and salvageability in cases of relapse were considered. RESULTS: A total of 61 transversal hepatectomies were performed: 40 (66%) upper transversal hepatectomies, 19 (31%) roller coaster hepatectomies, and 2 (3%) lower transversal hepatectomies. The median preserved liver volume was 67% (range 41-86). Mortality was 0, and major morbidity was 6%. Local recurrence occurred in 7 (11%) patients. Ten out of 34 (29%) patients with liver-only recurrence received redo surgery. CONCLUSION: Transversal hepatectomies offer a new parenchyma-sparing perspective for the management of complex tumor presentation, which would otherwise demand major tissue removal or even unresectability. Safety, adequate local control, and salvageability are further pillars of this approach herein systematized.

Meta-analysis on prognostic value of KRAS mutation in resected mass-forming cholangiocarcinoma.

BACKGROUND: Despite survival improvements for other cancers, the prognosis of resected mass-forming cholangiocellular carcinoma (MFCCC) remains dismal. As a possible background of that, biologic factors could play some role. KRAS mutation has been investigated in the present systematic review and meta-analysis. METHODS: MEDLINE, Embase and Cochrane Library databases were searched for studies reporting overall survival (OS) following liver resection for MFCCC with known KRAS status. Secondary outcomes included completeness of resection (R1 vs R0), pathological lymph node (LN) rate, tumor burden (multiple vs single), perineural invasion (PI) rate. RESULTS: Eight studies comprising 604 patients resected for MFCCC were eligible for analysis. Of these, 23% of patients were mKRAS. The mKRAS MFCCC showed lower 1-year OS [odd ratio (OR) 3.45, 95% confidence interval (CIs) 1.85-6.42; p < 0.001], 3-years OS (OR 4.82, 95% CI 2.63-8.84; p < 0.001), and 5-years OS (OR 10.60, 95% CI 3.12-36.03; p < 0.001) compared to wtKRAS. Pooled-R1 resection rate was 18% for mKRAS and 23% for those with wtKRAS (OR 1.71, 95%CIs 0.70-4.19; p = 0.239). The pooled-pathological LNs rate was 23% in mKRAS vs 17% (OR 2.36, 95%CIs 0.75-7.48; p = 0.144). The pooled-multifocality rate was 55% in mKRAS vs 19% (OR 5.38, 95%CIs 1.76-16.48; p = 0.003), while the pooled-PI was 77% vs 31% (OR 6.59, 95%CIs 2.13-20.37; p = 0.001). CONCLUSION: The KRAS mutation is relatively frequent in MFCCC. The mKRAS is strongly associated with a shortened survival and higher tumoral aggressiveness. Testing for KRAS mutations could be a valuable adjunct in opening a scenario to new treatments and improving prognosis of patients with MFCCC.

Very Early Recurrence After Liver Resection for Colorectal Metastases: Incidence, Risk Factors, and Prognostic Impact.

BACKGROUND: Liver resection for colorectal metastases is affected by a non-negligible recurrence rate. The earlier the recurrence, the worse the prognosis. We analyzed an unexplored topic, i.e., the incidence, predictive factors, and prognostic impact of very early recurrence (≤ 3 months after hepatectomy). METHODS: All consecutive liver resections for colorectal metastases performed between 2004 and 2017 were retrospectively reviewed. Inclusion criteria were available recurrence status at 3 months after resection and follow-up ≥ 12 months. RESULTS: Overall, 484 patients were analyzed; 56 (11.6%) had very early recurrence. Independent predictors were number of metastases (very early recurrence in 3.7% of patients with solitary metastasis, 8.1% of those with 2-9 metastases; 20.0% of those with 10-14 metastases; 44.4% of those with ≥ 15 metastases, p < 0.001) and extrahepatic disease (very early recurrence in 23.2% of patients with vs. 10.1% of those without extrahepatic disease, p = 0.017). Very early recurrence rate in patients with ≥ 15 metastases and simultaneous extrahepatic disease was 71.4%. Patients with very early recurrence had poor survival (5-year survival 17.3% vs. 44.5% of non-very early recurrence patients, p < 0.001), worse than patients with 3-to-6 months recurrence (p = 0.070), and no different from unresected patients (p = 0.114). Fifteen patients with very early recurrence (26.8%) underwent repeated treatment with adequate survival (at 3 years 42.2%), but seven had a further recurrence within 3 months. CONCLUSIONS: Very early recurrence occurs in about 12% of patients undergoing aggressive surgery for colorectal metastases. The risk is increased in patients with numerous metastases or extrahepatic disease. Very early recurrence is associated with very poor prognosis, similar to that of unresected patients, and a low chance of effective repeated treatment.

Stent-free duct-to-duct biliary reconstruction after hepatectomy for liver tumors involving biliary confluence at the hepatic hilum: a monocentric experience.

Roux-en-Y hepaticojejunostomy (HJ) is the standard of care for biliary reconstruction. Its weaknesses are the loss of the sphincter functionality, which could lead to repeated cholangitis, and the reduced endoscopic accessibility to the biliary tree. In the context of liver transplantation it has been shown that duct-to-duct biliary anastomosis may be suitable as an alternative to HJ, significantly reducing the risk of cholangitis. Here we present our experience on stent-free duct-to-duct reconstruction, performed in six patients receiving hepatectomy with resection of the biliary confluence. Operative mortality was nil. Anastomotic leak occurred in four patients and resolved spontaneously in all cases. One patient developed anastomotic stricture 17 months after surgery and only one patient developed tumor recurrence at the anastomotic site; in both cases the endoscopic stenting succeeded in restoring the ducts patency. With a median follow-up of 24 months (range 19-28 months), no cholangitis or other biliary-related complications were observed. Our experience, although limited, shows satisfactory oncological and functional outcomes, confirming all previously published results.

Prediction of remnant liver volume using 3D simulation software in patients undergoing R1vasc parenchyma-sparing hepatectomy for multiple bilobar colorectal liver metastases: reliability, clinical impact, and learning curve.

BACKGROUND: Assessment of the future liver remnant (FLR) is routinely performed before major hepatectomy. In R1-vascular one-stage hepatectomy (R1vasc-OSH), given the multiplanar dissection paths, the FLR is not easily predictable. Preoperative 3D-virtual casts may help. We evaluated the predictability of the FLR using the 3D-virtual cast in the R1vasc-OSH for multiple bilobar colorectal liver metastases (CLM). METHODS: Thirty consecutive patients with multiple bilobar CLMs scheduled for R1vasc-OSH were included. Predicted and real-FLRs were compared. Propensity score-matched analysis was used to determine the impact of 3D-virtual cast on postoperative complications. RESULTS: Median number of CLM and resection areas were 12 (4-33) and 3 (1-8). Median predicted-FLR was 899 ml (558-1157) and 60% (42-85), while for the real-FLR 915 ml (566-1777) and 63% (43-87). Median discrepancy between predicted and real-FLR was -0.6% (p = 0.504), indicating a slight tendency to underestimate the FLR. The difference was more evident in more than 12 CLMs (p = 0.013). A discrepancy was not evident according to the number of resection areas (p = 0.316). No mortality occurred. Patients in virtual-group had lower major complications compared to nonvirtual-group (0% vs 18%, p-value 0.014). CONCLUSION: FLR estimation based on 3D-analysis is feasible, provides a safe surgery and represents a promising method in planning R1vasc-OSH for patients with multiple bilobar CLMs.

Renal resistive index as a predictor of postoperative complications in liver resection surgery. Observational study.

Mortality after liver surgery reduced during the last three decades to less than 2%, but post-operative morbidity occurs in 20-50% of cases. Patients are often considered eligible for post-operative intensive-care unit (ICU) admission. Predicting which patients that are at higher risk could lead to a more precise perioperative management. We investigated whether renal resistive index (RRI), alone or along with other items, can predict post-operative complication after hepatic resection. All consecutive patients undergoing hepatectomy for primary or metastatic neoplasm at our Institution between February 2015 and March 2017 were enrolled. They received RRI measurement before entering in operative room and after awakening from general anesthesia. 183 Patients were enrolled. High surgical invasiveness, surgery time > 360 min, pre-operative RRI and postoperative serum lactate clearance < - 6%, showed to be associated with postoperative complications. Pre-operative RRI, complex liver resection, long-lasting surgery and poor lactate clearance (cLac) close to awakening from general anesthesia, all together may permit to classify the risk of post-operative adverse outcome after hepatic resection surgery.

Ultrasound-guided anatomical liver resection using a compression technique combined with indocyanine green fluorescence imaging.

BACKGROUND: Anatomical resection (AR) is a recommended surgical treatment for hepatocellular carcinoma (HCC). However, the conventional procedure (dye injection) for AR is difficult to reproduce. As an alternative, the tumour-feeding portal pedicle compression technique (finger-compression technique) has been proposed as an easy and reversible procedure. Here, we propose a new method combining indocyanine green (ICG) imaging with the finger-compression technique. METHODS: Eligible patients were prospectively enrolled to undergo ICG compression (ICG-C) anatomical hepatectomy for HCC. RESULTS: Fifteen patients underwent AR using the ICG-C technique. Overall, the surgical procedures included six segmentectomies, seven subsegmentectomies, and two right posterior sectionectomies. The median tumour size was 5.8 cm (range 2-7 cm). All procedures had an R0 margin. There were no major complications among patients, and minor morbidity occurred in three patients. CONCLUSIONS: ICG-C is a safe, feasible and effective technique for patients eligible for AR.

Assessment of the American College of Surgeons surgical risk calculator of outcomes after hepatectomy for liver tumors: Results from a cohort of 950 patients.

BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) calculator has been endorsed to counsel patients regarding complications. The aim of this study was to assess its ability to predict outcomes after hepatectomy. METHODS: Outcomes generated by the ACS-NSQIP were recorded in a consecutive cohort of patients. By using established classifications of complications, post-hepatectomy insufficiency and bile leak, the calculator was tested by the comparison of expected versus observed rates of events. The performance of the calculator was tested by using c-statistic and Brier score. RESULTS: 950 patients who underwent hepatectomy between January 2014 and June 2019 were included. Predicted rates were significantly lower than actual rates: the mean ACS-NSQIP morbidity was 17.97% ± 8.4 vs. actual 37.01% ± 0.56 (P < 0.001); the mean ACS-NSQIP mortality was 0.91% ± 1.48 vs. actual 1.76% ± 0.11 (P < 0.001). Predicted length of stay (LOS) was significantly shorter: mean ACS-NSQIP was 5.81 ± 1.66 days vs. actual 10.91 ± 4.6 days (P < 0.001). Post-hepatectomy liver insufficiency and bile leak were recorded in 6.8% and 11.9% of patients, respectively. These events were not expressed by the calculator. C-statistic and Brier scores showed low performance of the calculator. CONCLUSION: The calculator underestimates the risks of complications, mortality and LOS after hepatectomy. Refinements of the ACS-NSQIP model that account for organ-specific risks should be considered.

Indocyanine Green Compression Technique for Anatomical S8 Dorsal Subsegmentectomy for Hepatocellular Carcinoma.

BACKGROUND: Anatomical resection (AR) is a recommended surgical treatment for hepatocellular carcinoma (HCC), although the conventional procedure (dye injection) for AR is difficult to reproduce.1,2 The tumor-feeding portal pedicle compression technique has been proposed as an easy, reversible, repeatable, and oncologically suitable procedure,3-5 and its only drawback is the sometimes faint discoloration of the compressed area. For enhancing its visibility, indocyanine green (ICG) fluorescence imaging has been introduced. This technique is herein disclosed while performing an anatomical S8 dorsal subsegmentectomy. METHODS: A 66-year-old male was admitted for a 3.7 cm HCC in segment 8 dorsal (S8d) grown in non-alcoholic steatohepatitis. The preoperative liver function was graded as Child-Pugh class A. After adequate liver mobilization, the subsegmental Glissonian pedicle to S8d was identified by intraoperative ultrasound (IOUS) and compressed transparenchymally between the probe and the surgeon's fingertip positioned at the opposed side of the liver. Once IOUS-guided vessel compression had begun, ICG was administered intravenously. The compressed vessel created a non-stained area, which was marked using electrocautery. RESULTS: An anatomical S8d subsegmentectomy using the ICG compression technique was performed. There was no congested area and the right hepatic vein was exposed at the hepatocaval confluence because the resection was conducted in a subsegmental fashion. There was no morbidity and no blood transfusions were necessary. The patient was discharged on day 6 after surgery. CONCLUSIONS: This video shows, for the first time, the finger compression technique successfully implemented by ICG imaging for performing an AR for HCC.