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Published in final edited form as: Eur J Surg Oncol. 2023 Aug 6;49(10):106997. doi: 10.1016/j.ejso.2023.106997

Impact of liver cirrhosis and portal hypertension on minimally invasive limited liver resection for primary liver malignancies in the posterosuperior segments: an international multicenter study

Chetana Lim a, Olivier Scatton a, Andrew GR Wu b, Wanguang Zhang c, Kiyoshi Hasegawa d, Federica Cipriani e, Jasper Sijberden f, Davit L Aghayan g, Tiing-Foong Siow h, Safi Dokmak i, Paulo Herman j, Marco V Marino k,l, Vincenzo Mazzaferro m, Adrian KH Chiow n, Iswanto Sucandy o, Arpad Ivanecz p, Sung-Hoon Choi q, Jae Hoon Lee r, Mikel Prieto s, Marco Vivarelli t, Felice Giuliante u, Andrea Ruzzenente v, Chee-Chien Yong w, Mengqiu Yin x, Constantino Fondevila y,z, Mikhail Efanov aa, Zenichi Morise ab, Fabrizio Di Benedetto ac, Raffaele Brustia ad, Raffaele Dalla Valle ae, Ugo Boggi af, David Geller ag, Andrea Belli ah, Riccardo Memeo ai, Salvatore Gruttadauria aj,ak, Alejandro Mejia al, James O Park am, Fernando Rotellar an,ao, Gi-Hong Choi ap, Ricardo Robles-Campos aq, Xiaoying Wang ar, Robert P Sutcliffe as, Johann Pratschke at, Eric CH Lai au, Charing CN Chong av, Mathieu D’Hondt aw, Kazuteru Monden ax, Santiago Lopez-Ben ay, T Peter Kingham az, Alessandro Ferrero ba, Giuseppe Maria Ettorre bb, Daniel Cherqui bc, Xiao Liang bd, Olivier Soubrane be, Go Wakabayashi bf, Roberto I Troisi bg, Tan-To Cheung bh, Atsushi Sugioka bi, Ho-Seong Han bj, Tran Cong duy Long bk, Rong Liu bl, Bjørn Edwin g, David Fuks be, Kuo-Hsin Chen h,bq, Mohammad Abu Hilal bm,bn, Luca Aldrighetti e, Brian KP Goh bo,bp,*; International robotic, laparoscopic liver resection study group investigators
PMCID: PMC10866151  NIHMSID: NIHMS1945894  PMID: 37591027

Abstract

Introduction:

To assess the impact of cirrhosis and portal hypertension (PHT) on technical difficulty and outcomes of minimally invasive liver resection (MILR) in the posterosuperior segments.

Methods:

This is a post-hoc analysis of patients with primary malignancy who underwent laparoscopic and robotic wedge resection and segmentectomy in the posterosuperior segments between 2004 and 2019 in 60 centers. Surrogates of difficulty (i.e, open conversion rate, operation time, blood loss, blood transfusion, and use of the Pringle maneuver) and outcomes were compared before and after propensity-score matching (PSM) and coarsened exact matching (CEM).

Results:

Of the 1954 patients studied, 1290 (66%) had cirrhosis. Among the cirrhotic patients, 310 (24%) had PHT. After PSM, patients with cirrhosis had higher intraoperative blood transfusion (14% vs. 9.3%; p = 0.027) and overall morbidity rates (20% vs. 14.5%; p = 0.023) than those without cirrhosis. After coarsened exact matching (CEM), patients with cirrhosis tended to have higher intraoperative blood transfusion rate (12.1% vs. 6.7%; p = 0.059) and have higher overall morbidity rate (22.8% vs. 12.5%; p = 0.007) than those without cirrhosis. After PSM, Pringle maneuver was more frequently applied in cirrhotic patients with PHT (62.2% vs. 52.4%; p = 0.045) than those without PHT.

Conclusion:

MILR in the posterosuperior segments in cirrhotic patients is associated with higher intraoperative blood transfusion and postoperative morbidity. This parameter should be utilized in the difficulty assessment of MILR.

Keywords: Laparoscopic liver, posterosuperior segments, Minimally invasive liver, Cirrhosis, Difficulty score

INTRODUCTION

Liver resection (LR) is one of the first-line curative treatments for patients with compensated cirrhosis and primary malignancy. In the setting of LR, cirrhosis has been associated with increased intraoperative bleeding, liver decompensation, morbidity, and mortality.

It has been suggested that minimally-invasive surgery may offer better tolerance in cirrhotic patients as the laparoscopic approach has been shown to decrease the complications after liver surgery 1–7. Since the seminal consensus meeting in 2008 8 and its subsequent updates 9, 10, the adoption of minimally invasive liver resection (MILR) has been increasing worldwide. MILR in the anterolateral segments, even in selected patients with cirrhosis, has been considered safe and effective. More recently, MILR in the posterosuperior segments, (the“difficult segments”) have been performed with comparable outcomes to the open approach 11–14. The extent of resection as well as the quality and quantity of remnant liver have been the main considerations when planning an open LR, while additional factors such as location and size of tumor, and proximity to vessels have been the main considerations when planning a MILR. However, the impact of cirrhosis on the difficulty and outcomes of MILR has still not been clearly defined.

To date, four major difficulty-scoring systems (DSS) are commonly utilized to grade the technical difficulty of MILR 15–19. Although the Iwate system 18 was the only system to consider the degree of cirrhosis; it considers only Child-Pugh B cirrhosis as a significant factor of difficulty and does not distinguish between patients with Child-Pugh A cirrhosis and those without cirrhosis. Recently, a nationwide multicenter survey showed that cirrhosis was an independent risk factor for impaired outcomes, including mortality, in patients undergoing MILR, even in expert centers 20. Moreover, center expertise was found as an independent protective factor against postoperative liver failure in cirrhotic patients and was also associated with successful completion of resections of the posterosuperior segments. However, there were several limitations worth highlighting in this study 20. Firstly, it included MILR for all pathologies including liver metastases and benign tumors which were more likely to be in the non-cirrhotic arm and a potential confounder. Secondly, it included all types and extent of liver resections in the analyses. It has been demonstrated previously that the impact of cirrhosis on the outcomes of MILR differs with the extent and difficulty of the liver resections 21.

Hence, in this study, we aimed to assess the impact of cirrhosis and portal hypertension on the technical difficulty and outcomes of MILR for primary liver malignancies in the posterosuperior segments.

METHODS

Study design

This was a retrospective analysis of 5466 patients from 60 centers who underwent pure laparoscopic and robotic minor liver resections of the posterosuperior segments between 2004 and 2020. Of these, 2515 MI-LLR were performed for hepatocellular carcinoma (HCC), hepatocholangiocarcinoma or intrahepatic cholangiocarcinoma. All institutions obtained their respective approvals according to their local center’s requirements. This study was approved by the Singapore General Hospital Institution Review Board and the need for patient consent was waived. The deidentified data were collected in the individual centers. These were collated and analyzed centrally at the Singapore General Hospital.

Only patients who underwent totally pure laparoscopic or robotic liver resections were included. Hand-assisted or laparoscopic-assisted cases were excluded. Patients who underwent concomitant major operations such as bilio-enteric anastomoses, colectomies, stoma reversal, gastrectomies, splenectomies and vascular resections were excluded. Patients who underwent concomitant minor operations such as hernia repair, local ablation and hilar lymph node dissection were included. Finally, 1954 cases of laparoscopic and robotic LLR of the posterosuperior segments were included in the final analysis.

Definitions

Posterosuperior segments included segments 1/4a/7/8 22. Only minor resections were included and these were classified as segmentectomies or wedge/partial resections. Traditional major resections classified as resection of three or more contiguous segments were excluded. Additionally, right anterior and right posterior sectionectomies were also considered as major resections in this study and excluded 23. Diameter of the largest lesion was used in the cases of multiple tumors. Cirrhosis was defined as F4 fibrosis on pathological examination. Clinically significant portal hypertension was defined based on radiological and clinical criteria such as the presence of ascites, esophageal varices or splenomegaly with a platelet count of less than 100,000/μL as portal venous pressure/hepatic venous pressure gradient was not routinely measured in most centers. In this study only patients with portal hypertension and cirrhosis were analyzed. Data on the hepatic venous gradient was not available. Difficulty of resections were graded according to the Iwate scoring system 18. Postoperative complications were classified according to the Clavien-Dindo classification and recorded for up to 30 days or during the same hospitalization 24. The use of the Pringle maneuver, intraoperative blood loss and blood transfusion, conversion rate, and duration of operation were considered surrogates of surgical difficulty.

Statistical analyses

Propensity score matching (PSM) and Coarsened Exact Matching (CEM) were used to estimate the effect of varying degrees of liver cirrhosis on MI-LLR. For PSM, the propensity score is estimated with a mixed effect logistic regression. The fixed effect factors used in calculating the propensity score are the baseline variables stated in Tables 1, 3 and 5 respectively. A random-effects parameter is also included in the model to account for between center variations. For PSM of comparison of Child-Pugh A cirrhotic versus non-cirrhotic liver in Tables 1, patients of one stratum are matched 1:1, using nearest neighbor matching without replacement or discard, utilizing logit link, to patients of the other strata. To improve matching, a small caliper is used to achieve good balance of < 0.1 across all variables after matching. During matching, any patient with missing data in any of the variables used for matching will be discarded. Similar methodology is employed for PSM comparison in Tables 3 and 5. Due to the small number of patients in Child’s B cirrhosis, for Table 3, an additional 1:2 PSM analysis was done. In this 1:2 PSM analysis, some Child’s A patients were discarded due to high difference in propensity score from the Child’s B patients after matching.

Table 1.

Comparison between baseline characteristics of MILR in Child-Pugh A cirrhosis vs. non-cirrhosis

Entire unmatched cohort 1:1 PSM (nearest neighbour matching) 1:1 CEM
All (N = 1817) Child A Cirrhosis (N = 1153) Non-cirrhosis (N = 664) P-value Child A Cirrhosis (N = 516) Non-cirrhosis (N = 516) P-value (paired) Child A Cirrhosis (N = 224) Non-cirrhosis (N = 224) P-value (paired)
Mean age (SD), yrs 64.00 [55.00, 71.00] 63.00 [55.64, 71.00] 64.00 [54.00, 72.00] 0.920 63.60 [56.00, 70.00] 63.56 [54.00, 71.00] 0.747 64.00 [57.00, 69.25] 64.00 [56.75, 70.00] 0.538
Male sex, n (%) 1353 (74.5) 854 (74.1) 499 (75.2) 0.650 382 (74.0) 389 (75.4) 0.671 182 (81.2) 182 (81.2) NA
Robotic, n (%) 243 (13.4) 120 (10.4) 123 (18.5) 134 (26.0) 127 (24.6) 1.000 42 (18.8) 42 (18.8)
Laparoscopic, n (%) 1574 (86.6) 1033 (89.6) 541 (81.5) <0.001 433 (83.9) 434 (84.1) 210 (93.8) 210 (93.8) NA
Previous abdominal surgery, n (%) 336 (19.0) 204 (18.4) 132 (19.9) 0.449 96 (18.6) 101 (19.6) 0.750 24 (10.7) 24 (10.7) NA
Year of surgery, n (%)
2004–2009 30 (1.7) 15 (1.3) 15 (2.3) 0.069 7 (1.4) 9 (1.7) 0.558 23 (10.3) 23 (10.3) NA
2010–2015 378 (20.8) 255 (22.1) 123 (18.5) 92 (17.8) 103 (20.0) 201 (89.7) 201 (89.7)
2016–2021 1409 (77.5) 883 (76.6) 526 (79.2) 417 (80.8) 404 (78.3)
ASA score, n (%)
 1/2 1282 (70.6) 787 (68.3) 495 (74.5) 0.005 387 (75.0) 381 (73.8) 181 (80.8) 181 (80.8) NA
 3/4 535 (29.4) 366 (31.7) 169 (25.5) 129 (25.0) 135 (26.2) 0.718 43 (19.2) 43 (19.2)
Tumor type, n (%)
 HCC 1666 (91.7) 1096 (95.1) 570 (85.8) <0.001 487 (94.4) 490 (95.0) 0.742 217 (96.9) 217 (96.9) NA
 ICC/cholangiohepatoma 151 (8.3) 57 (4.9) 94 (14.2) 29 (5.6) 26 (5.0) 7 (3.1) 7 (3.1)
Median tumor size, mm [IQR] 28.00 [20.00, 40.00] 30.00 [20.00, 40.00] 30.00 [21.50, 40.00] 0.596 30.00 [20.00, 40.00] 29.50 [20.00, 40.00] 0.667 25.00 [20.00, 34.00] 25.00 [20.00, 35.00] 0.391
Multiple tumors, n (%) 142 (7.8) 100 (8.7) 42 (6.3) 0.090 29 (5.6) 33 (6.4) 0.703 2 (0.9) 2 (0.9) NA
Wedge/partial, n (%) 1068 (58.8) 710 (61.6) 358 (53.9) 0.002 273 (52.9) 288 (55.8) 0.377 137 (61.2) 137 (61.2) NA
Segmentectomy, n (%) 749 (41.2) 443 (38.4) 306 (46.1) 243 (47.1) 228 (44.2) 87 (38.8) 87 (38.8)
Concomitant minor surgery excluding cholecystectomy, n (%) 94 (5.2) 46 (4.0) 48 (7.2) 0.004 21 (4.1) 15 (2.9) 0.405 0 (0.0) 0 (0.0) NA
Hilar lymph node dissection, n (%) 42 (2.3) 10 (0.9) 32 (4.8) <0.001 8 (1.6) 3 (0.6) 0.228 0 (0.0) 0 (0.0) NA
Median Iwate difficulty score, [IQR](range) 6.00 [5.00, 9.00] (3, 11) 7.00 [5.00, 9.00] (3, 11) 7.00 [5.00, 9.00] (4, 11) 0.551 7.00 [5.00, 9.00] (3, 11) 6.00 [5.00, 9.00] (4, 11) 0.423 6.00 [5.00, 9.00] (4, 10) 6.00 [5.00, 9.00] (4, 10) NA
Iwate difficulty, n (%) <0.001 NA NA
 Low 2 (0.1) 1 (0.1) 1 (0.2) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0)
 Intermediate 997 (54.9) 686 (59.5) 311 (46.8) 251 (48.6) 270 (52.3) 134 (59.8) 134 (59.8)
 High 695 (38.2) 416 (36.1) 279 (42.0) 222 (43.0) 204 (39.5) 77 (34.4) 77 (34.4)
 Expert 123 (6.8) 50 (4.3) 73 (11.0) 42 (8.1) 41 (7.9) 13 (5.8) 13 (5.8)
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Footnotes:

MILR indicates minimally invasive liver resection; PSM, propensity score matching; CEM, coarsened exact matching; SD, standard deviation; NA, not available; ASA, American Society of Anesthesiologists; HCC hepatocellular carcinoma; ICC intrahepatic cholangiocarcinoma; IQR, interquartile range.

Table 3.

Comparison between baseline characteristics of MILR in Child-Pugh A vs. Child-Pugh B cirrhosis

Entire unmatched cohort 1:1 PSM (nearest neighbour) 1:2 PSM (nearest neighbour, calipers used)
All (N = 1290) Childs A (N = 1153) Childs B (N = 137) P-value Childs A (N = 65) Childs B (N = 65) P-value Childs A (N = 121) Childs B (N = 68) P-value
Mean age (SD), yrs 63.00 [55.00, 71.00] 63.00 [55.64, 71.00] 60.00 [48.00, 68.00] 0.533 62.00 [54.00, 70.00] 64.30 [55.00, 72.00] 0.485 64.00 [56.00, 71.00] 64.65 [55.75, 72.20] 0.737
Male sex, n (%) 964 (74.7) 854 (74.1) 110 (80.3) 0.139 50 (76.9) 52 (80.0) 0.814 95 (78.5) 54 (79.4) 1.000
Robotic, n (%) 138 (10.7) 120 (10.4) 18 (13.1) 15 (23.1) 13 (20.0) 26 (21.5) 14 (20.6)
Laparoscopic, n (%) 1152 (89.3) 1033 (89.6) 119 (86.9) 0.406 58 (89.2) 55 (84.6) 0.606 106 (87.6) 58 (85.3) 0.821
Previous abdominal surgery, n (%) 211 (16.9) 204 (18.4) 7 (5.1) <0.001 3 (4.6) 5 (7.7) 0.683 9 (7.4) 5 (7.4) 1.000
Year of surgery, n (%)
2004–2009 19 (1.5) 15 (1.3) 4 (2.9) 2 (3.1) 2 (3.1) 3 (2.5) 2 (2.9)
2010–2015 304 (23.6) 255 (22.1) 49 (35.8) 15 (23.1) 18 (27.7) 31 (25.6) 19 (27.9)
2016–2021 967 (75.0) 883 (76.6) 84 (61.3) <0.001 48 (73.8) 45 (69.2) 0.880 87 (71.9) 47 (69.1) 0.908
ASA score, n (%)
 1/2 886 (68.7) 787 (68.3) 99 (72.3) 38 (58.5) 42 (64.6) 75 (62.0) 43 (63.2)
 3/4 404 (31.3) 366 (31.7) 38 (27.7) 0.391 27 (41.5) 23 (35.4) 0.571 46 (38.0) 25 (36.8) 0.989
Tumor type, n (%)
 HCC 1231 (95.4) 1096 (95.1) 135 (98.5) 63 (96.9) 64 (98.5) 119 (98.3) 66 (97.1)
 ICC/cholangiohepatoma 59 (4.6) 57 (4.9) 2 (1.5) 0.080 2 (3.1) 1 (1.5) 1.000 2 (1.7) 2 (2.9) 0.620
Median tumor size, mm (IQR) 25.00 [19.00, 40.00] 25.00 [18.00, 35.25] 25.00 [20.00, 37.00] 0.989 30.00 [18.00, 40.00] 25.00 [20.00, 37.00] 0.811 28.00 [18.00, 40.00] 25.00 [19.75, 39.00] 0.828
Multiple tumors, n (%) 124 (9.6) 100 (8.7) 24 (17.5) 0.002 7 (10.8) 9 (13.8) 0.789 20 (16.5) 9 (13.2) 0.695
Wedge/partial liver resection, n (%) 791 (61.3) 710 (61.6) 81 (59.1) 39 (60.0) 42 (64.6) 75 (62.0) 44 (64.7)
Segmentectomy, n (%) 499 (38.7) 443 (38.4) 56 (40.9) 0.642 26 (40.0) 23 (35.4) 0.710 46 (38.0) 24 (35.3) 0.830
Concomitant minor surgery excluding cholecystectomy, n (%) 49 (3.8) 46 (4.0) 3 (2.2) 0.475 6 (9.2) 3 (4.6) 0.505 6 (5.0) 3 (4.4) 1.000
Hilar lymph node dissection, n (%) 11 (0.9) 10 (0.9) 1 (0.7) 1.000 2 (3.1) 1 (1.5) 1.000 2 (1.7) 1 (1.5) 1.000
Median Iwate difficulty score excluding Childs score, [IQR] (range) 6.00 [5.00, 8.00] (3, 11) 6.00 [5.00, 8.00] (4, 11) 5.00 [5.00, 8.00] (3, 10) 0.892 6.00 [5.00, 9.00] 5.00 [5.00, 8.00] 0.394 6.00 [5.00, 9.00] 5.00 [5.00, 8.00] 0.991
Iwate difficulty exclude Childs score, n (%)
 Low 1 (0.1) 1 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)
 Intermediate 725 (56.2) 686 (59.5) 39 (28.5) 31 (47.7) 35 (53.8) 62 (51.2) 35 (51.5)
 High 469 (36.4) 416 (36.1) 53 (38.7) 22 (33.8) 18 (27.7) 35 (28.9) 20 (29.4)
 Expert 95 (7.4) 50 (4.3) 45 (32.8) <0.001 12 (18.5) 12 (18.5) 0.210 24 (19.8) 13 (19.1) 1.000
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Footnotes:

MILR indicates minimally invasive liver resection; PSM, propensity score matching; SD, standard deviation; ASA, American Society of Anesthesiologists; HCC hepatocellular carcinoma; ICC intrahepatic cholangiocarcinoma; IQR, interquartile range.

Table 5.

Comparison between baseline characteristics of MILR in cirrhotic patients with and without portal hypertension

Entire unmatched cohort 1:1 PSM (nearest neighbour matching) 1:1 CEM
All (N = 1283) Cirrhosis PHT (N = 310) Cirrhosis NPHT (N = 973) P-value Cirrhosis PHT (N = 227) Cirrhosis NPHT (N = 227) P-value Cirrhosis PHT (N = 116) Cirrhosis NPHT (N = 116) P-value (paired)
Mean age (SD), yrs 63.00 [55.00, 71.00] 64.15 [56.25, 71.00] 63.00 [54.00, 71.00] 0.836 63.00 [55.50, 71.00] 63.00 [55.00, 70.60] 0.658 63.62 [56.00, 69.62] 63.00 [55.00, 70.00] 0.432
Male sex, n (%) 960 (74.8) 218 (70.3) 742 (76.3) 0.043 168 (74.0) 174 (76.7) 0.566 93 (80.2) 93 (80.2) NA
Robotic, n (%) 138 (10.8) 35 (11.3) 103 (10.6) 59 (26.0) 53 (23.3) 23 (19.8) 23 (19.8)
Laparoscopic, n (%) 1145 (89.2) 275 (88.7) 870 (89.4) 0.808 199 (87.7) 201 (88.5) 0.885 113 (97.4) 113 (97.4) NA
Previous abdominal surgery, n (%) 210 (16.9) 63 (20.3) 147 (15.8) 0.079 46 (20.3) 54 (23.8) 0.403 13 (11.2) 13 (11.2) NA
Childs A, n (%) 1144 (89.3) 253 (81.6) 891 (91.8) 193 (85.0) 190 (83.7) 111 (95.7) 111 (95.7)
Childs B, n (%) 137 (10.7) 57 (18.4) 80 (8.2) <0.001 34 (15.0) 37 (16.3) 0.755 5 (4.3) 5 (4.3) NA
Year of surgery, n (%)
2004–2009 19 (1.5) 5 (1.6) 14 (1.4) 3 (1.3) 3 (1.3)
2010–2015 304 (23.7) 68 (21.9) 236 (24.3) 44 (19.4) 46 (20.3) 13 (11.2) 13 (11.2)
2016–2021 960 (74.8) 237 (76.5) 723 (74.3) 0.668 180 (79.3) 178 (78.4) 0.750 103 (88.8) 103 (88.8) NA
ASA score, n (%)
 1/2 884 (68.9) 187 (60.3) 697 (71.6) 152 (67.0) 143 (63.0) 79 (68.1) 79 (68.1)
 3/4 399 (31.1) 123 (39.7) 276 (28.4) <0.001 75 (33.0) 84 (37.0) 0.391 37 (31.9) 37 (31.9) NA
Tumor type, n (%)
 HCC 1222 (95.2) 300 (96.8) 922 (94.8) 221 (97.4) 220 (96.9) 116 (100.0) 116 (100.0)
 ICC/cholangiohepatoma 61 (4.8) 10 (3.2) 51 (5.2) 0.194 6 (2.6) 7 (3.1) 1.000 0 (0.0) 0 (0.0) NA
Median tumor size, mm (IQR) 25.00 [19.00, 40.00] 26.00 [20.00, 40.00] 25.00 [18.00, 40.00] 0.664 26.00 [20.00, 40.00] 26.00 [20.00, 35.00] 0.940 25.00 [20.00, 32.00] 25.00 [20.00, 31.25] 0.802
Multiple tumors, n (%) 124 (9.7) 28 (9.0) 96 (9.9) 0.747 17 (7.5) 18 (7.9) 1.000 0 (0.0) 0 (0.0) NA
Wedge/partial liver resection, n (%) 790 (61.6) 194 (62.6) 596 (61.3) 140 (61.7) 138 (60.8) 82 (70.7) 82 (70.7)
Segmentectomy, n (%) 493 (38.4) 116 (37.4) 377 (38.7) 0.725 87 (38.3) 89 (39.2) 0.918 34 (29.3) 34 (29.3) NA
Concomitant minor surgery excluding cholecystectomy, n (%) 49 (3.8) 10 (3.2) 39 (4.0) 0.649 9 (4.0) 9 (4.0) 1.000 0 (0.0) 0 (0.0) NA
Hilar lymph node dissection, n (%) 11 (0.9) 2 (0.6) 9 (0.9) 1.000 2 (0.9) 1 (0.4) 1.000 0 (0.0) 0 (0.0) NA
Median Iwate difficulty score, [IQR] (range) 6.00 [5.00, 8.00] (4, 11) 6.00 [5.00, 9.00] (4, 11) 6.00 [5.00, 8.00] (4, 11) 0.904 6.00 [5.00, 9.00] (4, 11) 6.00 [5.00, 9.00] (4, 11) 0.990 6.00 [5.00, 8.00] (4, 10) 6.00 [5.00, 8.00] (4, 10) NA
Iwate difficulty, n (%)
 Low 1 (0.1) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
 Intermediate 724 (56.4) 166 (53.5) 558 (57.3) 121 (53.3) 121 (53.3) 79 (68.1) 79 (68.1)
 High 466 (36.3) 116 (37.4) 350 (36.0) 87 (38.3) 85 (37.4) 36 (31.0) 36 (31.0)
 Expert 92 (7.2) 28 (9.0) 64 (6.6) 0.385 19 (8.4) 21 (9.3) 0.161 1 (0.9) 1 (0.9) NA
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Footnotes:

MILR indicates minimally invasive liver resection; PSM, propensity score matching; CEM, coarsened exact matching; SD, standard deviation; PHY, portal hypertension; NPHT no portal hypertension NA, not available; ASA, American Society of Anesthesiologists; HCC hepatocellular carcinoma; ICC intrahepatic cholangiocarcinoma; IQR, interquartile range

For CEM, continuous variables were coarsened using an automatic binning algorithm based on Sturge’s rule into bins. Patients were 1:1 matched using with nearest neighbor matching without replacement within each stratum, any unmatched units in the stratum will be dropped. This methodology is applied to all 3 CEM models. After matching, balance is checked via standardized mean difference across the covariates, with a threshold of 0.1 being indicative of tight match.

Love plot of each match’s covariate balance is plotted and presented below (Supplementary data S1-S6).

For continuous variables, weighted mean difference is presented, and two sample weighted t-test were used to calculate the standard error and p-values. For categorical variables, generalized linear and ordered logistic regression models were used to calculate the odds ratios, confidence intervals, and p-values. For unpaired comparisons of frequencies of categorical variables, Chi-squared and Fisher’s exact tests were used. For the unpaired comparisons of median values and interquartile ranges, Mann-Whitney U test is used, and for the comparisons of mean values and standard deviations, one-way test is used. When appropriate, paired tests are used - McNemar’s test is used for categorical variables and Wilcoxon Signed-Rank test is used for continuous. The statistical analyses were performed with RStudio version 1.4.1717, R version 4.1.0.

RESULTS

The study population included 1954 patients. Among these, 1290 (66%) patients had cirrhosis and 664 (34%) did not have cirrhosis. Among the 1290 patients with cirrhosis, 310 (24%) had PHT and 137 (11%) were Child-Pugh B.

Comparison between patients with Child-Pugh A cirrhosis and those without cirrhosis

The demographic, clinicopathological and perioperative data of pre- and post-matching groups are shown in Tables 1 and 2. Common major (grade ≥ 3) postoperative surgical complications included infected collections (n=19), bile leak (n =24), postoperative bleeding (n=3) and liver decompensation (n=4).

Table 2.

Comparison between perioperative outcomes of MILR in Child-Pugh A cirrhosis vs. non-cirrhosis

Entire unmatched cohort 1:1 PSM (nearest neighbour) 1:1 CEM
All (N = 1817) Child A Cirrhosis (N = 1153) Non-cirrhosis (N = 664) P-value Child A Cirrhosis (N = 516) Non-cirrhosis (N = 516) P-value (paired) Child A Cirrhosis (N = 224) Non-cirrhosis (N = 224) P-value (paired)
Open conversion, n (%) 105 (5.8) 68 (5.9) 37 (5.6) 0.856 37 (7.2) 30 (5.8) 0.450 13 (5.8) 7 (3.1) 0.239
Median operating time [IQR], min 224.00 [164.00, 305.00] 233.50 [167.25, 330.00] 230.00 [168.50, 317.00] 0.469 233.50 [167.25, 330.00] 225.00 [166.50, 310.00] 0.499 208.00 [160.00, 300.00] 220.00 [155.00, 300.00] 0.292
Median blood loss [IQR], ml 193.50 [50.00, 350.00] 200.00 [50.00, 400.00] 190.00 [60.00, 400.00] 0.646 200.00 [50.00, 400.00] 192.50 [60.00, 400.00] 0.445 150.00 [50.00, 300.00] 150.00 [50.00, 350.00] 0.908
Blood loss > 500 mls, n (%) 258 (14.7) 159 (14.3) 99 (15.4) 0.587 87 (17.5) 82 (16.4) 1.000 29 (13.4) 32 (14.5) 0.766
Intraoperative blood transfusion, n (%) 196 (10.8) 129 (11.2) 67 (10.1) 0.513 72 (14.0) 48 (9.3) 0.027 27 (12.1) 15 (6.7) 0.059
Pringle maneuver applied, n (%) 1020 (56.9) 647 (56.9) 373 (57.0) 0.981 307 (60.6) 281 (55.3) 0.101 138 (62.4) 126 (56.8) 0.257
Mean postoperative stay, d [IQR] 6.00 [4.00, 9.00] 6.00 [4.93, 9.00] 6.00 [4.00, 8.00] 0.061 6.00 [4.93, 9.00] 6.00 [4.00, 8.00] 0.125 6.00 [4.00, 9.00] 6.00 [5.00, 8.54] 0.999
Postoperative morbidity, n (%) 333 (18.3) 227 (19.7) 106 (16.0) 0.055 103 (20.0) 75 (14.5) 0.023 51 (22.8) 28 (12.5) 0.007
Major morbidity (Clavien-Dindo grade> 2), n (%) 94 (5.2) 59 (5.1) 35 (5.3) 0.977 39 (7.6) 29 (5.6) 0.268 16 (7.1) 13 (5.8) 0.689
Reoperation, n (%) 11 (0.6) 7 (0.6) 4 (0.6) 1.000 5 (1.0) 2 (0.4) 0.371 2 (0.9) 1 (0.4) 1.000
30-day readmission, n (%) 53 (2.9) 31 (2.7) 22 (3.3) 0.539 20 (3.9) 18 (3.5) 0.868 9 (4.0) 5 (2.2) 0.423
30-day mortality, n (%) 2 (0.1) 1 (0.1) 1 (0.2) 1.000 1 (0.2) 1 (0.2) 1.000 0 (0.0) 0 (0.0) NA
In-hospital mortality, n (%) 5 (0.3) 2 (0.2) 3 (0.5) 0.362 2 (0.4) 1 (0.2) 1.000 0 (0.0) 1 (0.4) 1.000
90-day mortality, n (%) 4 (0.2) 2 (0.2) 2 (0.3) 0.626 2 (0.4) 2 (0.4) 1.000 0 (0.0) 1 (0.4) 1.000
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Footnotes:

MILR indicates minimally invasive liver resection; PSM, propensity score matching; CEM, coarsened exact matching; IQR, interquartile range; d, days

Before matching, patients with cirrhosis more frequently had ASA score ≥ 3 and HCC, and less frequently underwent robotic LR, segmentectomy and hilar lymph node dissection (Table 1). Patients with cirrhosis tended to undergo less complex hepatectomies (Table 1). Patients with cirrhosis tended to have higher overall morbidity (p = 0.055; Table 2).

After matching, both groups were well balanced for all variables (Table 2, Supplementary Figures 1 and 2). After PSM, patients with cirrhosis had a higher intraoperative blood transfusion rate (14% vs. 9.3%; p = 0.027) and overall morbidity rate (20% vs. 14.5%; p = 0.023) than those without cirrhosis. After CEM, patients with cirrhosis tended to have higher intraoperative blood transfusion rate (12.1% vs. 6.7%; p = 0.059) and have higher overall morbidity rate (22.8% vs. 12.5%; p = 0.007; Table 2) than those without cirrhosis. There was no significant difference in other perioperative outcomes including median blood loss, need for Pringle maneuver, open conversion rate, median operating time, postoperative stay, readmission rate and postoperative mortality between both groups after matching (Table 2).

Comparison between Child-Pugh A and B cirrhotic patients

Tables 3 and 4 showed the demographic, clinicopathological and perioperative data of pre- and post-matching groups. Before PSM matching, patients with Child-Pugh B cirrhosis had less frequently history of abdominal surgery, surgery in the late era (≥ 2016), and had more frequently multiple tumors than those with Child-Pugh A (Table 3). Patients with Child-Pugh score B cirrhosis underwent more complex hepatectomies (Table 3). Patients with Child-Pugh B cirrhosis tended to have higher intraoperative blood transfusion (22.6% vs. 11.2%; p<0.001).

Table 4.

Comparison between perioperative outcomes of MILR in Child-Pugh A vs. B cirrhosis

Entire unmatched cohort 1:1 PSM (nearest neighbour) 1:2 PSM (nearest neighbour, calipers used)
All (N = 1290) Childs A (N = 1153) Childs B (N = 65) P-value Childs A (N = 65) Childs B (N = 65) P-value Childs A (N = 121) Childs B (N = 68) P-value
Open conversion, n (%) 72 (5.6) 68 (5.9) 4 (2.9) 0.172 4 (6.2) 1 (1.5) 0.371 5 (4.1) 1 (1.5) 0.422
Median operating time [IQR], min 222.00 [164.00, 300.00] 220.00 [163.00, 300.00] 205.00 [150.00, 255.00] 0.269 220.00 [170.00, 285.00] 205.00 [150.00, 255.00] 0.141 225.00 [175.00, 305.00] 210.00 [150.00, 276.00] 0.191
Median blood loss [IQR], ml 200.00 [50.00, 380.00] 197.00 [50.00, 350.00] 200.00 [65.00, 350.00] 0.745 200.00 [50.00, 300.00] 200.00 [65.00, 350.00] 0.596 196.50 [50.00, 390.50] 200.00 [92.50, 400.00] 0.525
Blood loss > 500 mls, n (%) 184 (14.8) 159 (14.3) 25 (18.8) 0.210 8 (12.3) 9 (13.8) 1.000 20 (16.9) 11 (16.7) 1.000
Intraoperative blood transfusion, n (%) 160 (12.4) 129 (11.2) 31 (22.6) <0.001 7 (10.8) 11 (16.9) 0.386 19 (15.7) 12 (17.6) 0.887
Pringle maneuver applied, n (%) 717 (56.4) 647 (56.9) 70 (52.6) 0.403 35 (58.3) 32 (51.6) 0.458 66 (57.4) 34 (52.3) 0.615
Mean postoperative stay, d [IQR] 6.00 [4.49, 10.00] 6.00 [4.00, 9.00] 7.00 [5.00, 12.00] 0.645 7.00 [5.00, 10.00] 7.00 [5.00, 12.00] 0.593 7.00 [5.00, 12.00] 7.50 [5.00, 12.00] 0.655
Postoperative morbidity, n (%) 262 (20.3) 227 (19.7) 35 (25.5) 0.135 18 (27.7) 12 (18.5) 0.286 30 (24.8) 14 (20.6) 0.633
Major morbidity (Clavien-Dindo grade> 2), n (%) 72 (5.6) 59 (5.1) 13 (9.5) 0.056 5 (7.7) 4 (6.2) 1.000 8 (6.6) 5 (7.4) 1.000
Reoperation, n (%) 8 (0.6) 7 (0.6) 1 (0.7) 0.594 0 (0.0) 1 (1.5) 1.000 0 (0.0) 1 (1.5) 0.360
30-day readmission, n (%) 37 (2.9) 31 (2.7) 6 (4.4) 0.396 3 (4.6) 4 (6.2) 1.000 4 (3.3) 5 (7.4) 0.287
30-day mortality, n (%) 2 (0.2) 1 (0.1) 1 (0.7) 0.201 1 (1.5) 0 (0.0) 1.000 1 (0.8) 1 (1.5) 1.000
In-hospital mortality, n (%) 4 (0.3) 2 (0.2) 2 (1.5) 0.058 1 (1.5) 1 (1.5) 1.000 1 (0.8) 2 (2.9) 0.294
90-day mortality, n (%) 4 (0.3) 2 (0.2) 2 (1.5) 0.058 1 (1.5) 1 (1.5) 1.000 1 (0.8) 2 (2.9) 0.294
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Footnotes:

MILR indicates minimally invasive liver resection; PSM, propensity score matching; IQR, interquartile range; d, days.

In the post-matching analysis, patients with Child-Pugh A cirrhosis and patients with Child-Pugh B cirrhosis both have similar baseline and preoperative characteristics. In the 1:1 PSM and 1:2 analysis, all key perioperative outcomes such as operation time, postoperative morbidity, blood transfusion rate, reoperation rate, postoperative length of stay and postoperative mortality were similar between the 2 groups.

Comparison between patients with and without portal hypertension

The demographic, clinicopathological and perioperative data of pre- and post-matching groups are shown in Tables 5 and 6. Before matching, comparison between the two groups showed higher prevalence of Child-Pugh B, ASA score ≥ 3 in the PHT group, whereas male sex was lower in the non-PHT group (Table 5). Before and after matching, Iwate “High” and “Expert” level resections were comparable between both groups. Before matching, Pringle maneuver was more frequently applied in the PHT group (64.2% vs. 54%; p = 0.002). The other perioperative outcomes were similar between both groups (Table 6).

Table 6.

Comparison between perioperative outcomes of MILR in cirrhotic patients with and without portal hypertension

Entire unmatched cohort 1:1 PSM (nearest neighbour matching) 1:1 CEM
All (N = 1283) Cirrhosis PHT (N = 310) Cirrhosis NPHT (N = 973) P-value Cirrhosis PHT (N = 227) Cirrhosis NPHT (N = 227) P-value Cirrhosis PHT (N = 116) Cirrhosis NPHT (N = 116) P-value (paired)
Open conversion, n (%) 72 (5.6) 22 (7.1) 50 (5.1) 0.245 13 (5.7) 5 (2.2) 0.099 5 (4.3) 5 (4.3) 1.000
Median operating time [IQR], min 222.00 [165.00, 300.00] 206.00 [150.00, 280.00] 224.50 [165.75, 300.00] 0.165 206.00 [150.00, 280.00] 220.00 [162.00, 300.00] 0.222 202.00 [150.00, 271.25] 205.50 [160.00, 267.75] 0.757
Median blood loss [IQR], ml 200.00 [50.00, 380.00] 150.00 [50.00, 400.00] 200.00 [50.00, 350.00] 0.928 150.00 [50.00, 400.00] 170.00 [50.00, 330.00] 0.670 150.00 [77.50, 400.00] 200.00 [75.00, 333.00] 0.829
Blood loss > 500 mls, n (%) 183 (14.8) 53 (17.7) 130 (13.8) 0.120 35 (15.6) 30 (13.7) 0.583 17 (15.3) 16 (13.9) 0.838
Intraoperative blood transfusion, n (%) 158 (12.3) 37 (11.9) 121 (12.4) 0.889 29 (12.8) 33 (14.5) 0.658 10 (8.6) 11 (9.5) 1.000
Pringle maneuver applied, n (%) 714 (56.5) 197 (64.2) 517 (54.0) 0.002 140 (62.2) 118 (52.4) 0.045 76 (66.1) 64 (56.1) 0.200
Mean postoperative stay, d [IQR] 6.00 [4.68, 10.00] 6.00 [4.02, 11.00] 6.00 [4.20, 10.00] 0.166 6.00 [4.02, 11.00] 6.00 [4.00, 9.00] 0.235 6.00 [5.00, 8.00] 6.00 [4.00, 8.25] 0.573
Postoperative morbidity, n (%) 260 (20.3) 68 (21.9) 192 (19.8) 0.453 45 (19.8) 46 (20.3) 1.000 20 (17.2) 18 (15.5) 0.831
Major morbidity (Clavien-Dindo grade> 2), n (%) 72 (5.6) 21 (6.8) 51 (5.2) 0.381 14 (6.2) 15 (6.6) 1.000 3 (2.6) 3 (2.6) 1.000
Reoperation, n (%) 8 (0.6) 2 (0.6) 6 (0.6) 1.000 2 (0.9) 0 (0.0) 0.480 0 (0.0) 0 (0.0) NA
30-day readmission, n (%) 37 (2.9) 9 (2.9) 28 (2.9) 1.000 7 (3.1) 6 (2.6) 1.000 2 (1.7) 4 (3.4) 0.683
30-day mortality, n (%) 2 (0.2) 0 (0.0) 2 (0.2) 1.000 0 (0.0) 1 (0.4) 1.000 0 (0.0) 0 (0.0) NA
In-hospital mortality, n (%) 6 (0.5) 1 (0.3) 5 (0.5) 1.000 0 (0.0) 2 (0.9) 0.480 0 (0.0) 0 (0.0) NA
90-day mortality, n (%) 4 (0.3) 1 (0.3) 3 (0.3) 1.000 0 (0.0) 2 (0.9) 0.480 0 (0.0) 0 (0.0) NA
Open in a new tab

Footnotes:

MILR indicates minimally invasive liver resection; PSM, propensity score matching; CEM, coarsened exact matching; SD, standard deviation; NA, not available; ASA, American Society of Anesthesiologists; HCC hepatocellular carcinoma; ICC intrahepatic cholangiocarcinoma; IQR, interquartile range

After matching, both groups were well balanced for all variables (Table 5, Supplementary Figures 3 and 4). After PSM, Pringle maneuver was more frequently applied in the PHT group (62.2% vs. 52.4%; p = 0.045) than in the non-PHT group. After CEM, Pringle maneuver tended to be more frequently applied in the PHT group, but this was not significant (66.1% vs. 56.1%; p = 0.2). After matching, the other perioperative outcomes were similar between both groups (Table 6).

DISCUSSION

LR in the posterosuperior segments represents one of the most challenging situations in MILR, especially in patients with liver cirrhosis. The main findings of this study were as follows: 1) both robotic and laparoscopic segmentectomies and wedge resections were associated with acceptable outcomes in selected patients with cirrhosis and even in the presence of PHT, 2) the presence of cirrhosis was associated with significantly higher intraoperative blood transfusion and postoperative morbidity rates compared to non cirrhotics, and 3) Pringle maneuver was more frequently used in the presence of PHT. However, the mortality rate did not differ significantly even with the presence of cirrhosis in this series, which was contrary with a recent French nationwide series gathering data from more than 3000 patients, which reported a significant increased mortality rate in the cirrhotic population 20. A likely explanation for this difference in results was that the present study only focused on minor liver resections and did not include major hepatectomies.

MI-LLR in the posterosuperior segments in cirrhotic patients is technically challenging for the following reasons: 1) these segments are located in the upper right part of the abdominal cavity under the ribs, which makes them difficult to access, 2) the cirrhotic parenchymal texture is hard and dysmorphic, which makes the liver difficult to mobilize and to transect, and 3) cirrhosis is usually associated with a low platelet count and clinically significant PHT, which renders these procedures more susceptible to bleed. The current DSS of MILR are mainly based on the procedure-related (extent of resection 17, 18) and tumor-related variables (difficult location, size and proximity to major vessels 18). The Iwate system is the only classification of surgical difficulty of MILR which considered cirrhosis as a difficulty variable. However, it only considered Child-Pugh B cirrhosis as a factor influencing difficulty 18. In other words, the current DSS for MILR do not consider cirrhosis as a factor per se influencing the technical difficulty of MILR 19.

However, in real-life practice, most surgeons consider that cirrhosis has an impact on technical difficulty of MILR 25. Several studies have reported the impact of cirrhosis on the outcomes of MILR 20, 21, 26, 27. However, several biases have precluded any robust conclusions. These reports were obtained from mono- 21, 27 or multicentric 20, 26 series in which DSS (if any) were heterogeneously used (Institut Mutualiste Montsouris (IMM) system in the study by Hobeika et al. 20, or both IMM and Iwate systems in the study by Goh et al. 21, none in the other studies 20, 26, 27). Major limitations of many these previous studies were the small sample size and the absence of matching 27. Furthermore, in these previous studies, a major confounding factor was the inclusion of patients with other pathologies including benign lesions and colorectal liver metastases in the non-cirrhotic cohort 20,21. These studies also included patients who underwent various extents of liver resections including both major and minor hepatectomies 27. Intuitively, it is likely that the degree of impact of cirrhosis on outcomes would depend on the extent and complexity of the MILR.

To our knowledge, this is the first multicentric study to assess specifically the impact of cirrhosis on the outcomes of minimally invasive minor LR in the posterosuperior segments in patients with primary malignancy. MI-LLR in the posterosuperior segments in patients with cirrhosis was associated with higher transfusion rate and postoperative morbidity rate. These results deserve several comments. As expected, MI-LLR in patients with cirrhosis is associated with worse outcomes compared to those without cirrhosis, which is in accordance with previous series 20, 21. Second, our study confirms that the differences in outcomes between MI-LLR in cirrhosis vs. non cirrhosis was more pronounced in patients undergoing more difficult resections 20, 21.More interestingly, the study by Hobeika et al. has stratified the analyses according to the extent of posterosuperior liver resection (i.e, wedge resection of the posterosuperior segments (grade I of the IMM system) vs. segmentectomy of the posterosuperior segments (grade III of the IMM system). This however was not the case in the present series as both segmentectomy and wedge resection of the posterosuperior segments were not analyzed separately. Third, the higher rate of intraoperative blood transfusion also contributed to the higher rate of postoperative morbidity 28.

The second aspect to consider during MILR for cirrhosis is the presence of PHT. The EASL guidelines 29 proposed a risk algorithm for postoperative liver decompensation following LR including three variables in the following order: presence of PHT, extent of resection and MELD score. In the present study, we found that MI-LLR in the posterosuperior segments in selected cirrhotic patients with PHT was associated with safe outcomes (hospital stay = 6 days, morbidity rate = 21.9%, major morbidity rate = 6.8%, 30-day readmission = 2.9%, 90-day mortality = 0.3%); and more interestingly, PHT did not increase the risk of complications after MILR. This is in accordance with a recent study showing that the laparoscopic approach was the sole independent predictor of achieving a textbook outcome in a series of 79 high-risk patients with PHT (all with hepatic venous gradient ≥ 10 mmHg) who underwent resection of HCC 30.

The third aspect concerns the outcomes of MI-LLR in patients with Child-Pugh B cirrhosis. This requires the following comments. First, only 11% (7% of the series) of cirrhotic patients were Child-Pugh B. Second, MI-LLR in the posterosuperior segments in well-selected patients with Child-Pugh B cirrhosis was feasible with reasonably good outcomes (hospital stay = 7 days, morbidity rate = 19.7%, major morbidity rate = 9.5%, 30-day readmission = 2.7%, 90-day mortality = 0.2%). All together, these results demonstrated that Child-Pugh B cirrhosis patients with tumors located in the posterosuperior segments should not be excluded from potentially curative limited resection.

Finally, we acknowledge several limitations with this study. Firstly, its retrospective nature over a long time period could result in information bias. Secondly, although two matching modalities including PSM and CEM were used in this study to improve the robustness of the analyses, residual bias cannot be entirely mitigated in the absence of randomization. Thirdly, a pooled analysis of data from multiple Western and Eastern centers introduces some inherent selection bias resulting from differing practices (Eastern centers tend to propose surgery while Western centers tend to refer Child-Pugh B cirrhosis patients for liver transplantation), and also difference in surgeon and center experience.

In conclusion, MI-LLR for tumors located in the posterosuperior segments in patients with cirrhosis was associated with higher intraoperative blood transfusion and postoperative morbidity, but overall acceptable outcomes compared to non-cirrhotics. This parameter should be utilized in the difficulty assessment of MILR.

Supplementary Material

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Study funding

Dr T. P. Kingham was partially supported by the US National Cancer Institute MSKCC Core Grant number P30 CA008748 for this study.

Dr M. Yin was partially funded by the Research Project of Zhejiang Provincial Public Welfare Fund project in the Field of Social development (LGF20H160028)

Dr Brian Goh was partially supported by the Intuitive Foundation Grant for this study. Any research findings, conclusions, or recommendations expressed in this work are those of the authors and not of the Intuitive Foundation

Declarations

We confirm all the authors are accountable for all aspects of the work

i) Dr Goh BK has received travel grants and honorarium from Johnson and Johnson, Olympus and Transmedic the local distributor for the Da Vinci Robot.

ii) Dr Marino MV is a consultant for CAVA robotics LLC.

iii) Johann Pratschke reports a research grant from Intuitive Surgical Deutschland GmbH and personal fees or non-fiNAcial support from Johnson & Johnson, Medtronic, AFS Medical, Astellas, CHG Meridian, Chiesi, Falk Foundation, La Fource Group, Merck, Neovii, NOGGO, pharma-consult Peterson, and Promedicis.

iv) Moritz Schmelzle reports personal fees or other support outside of the submitted work from Merck, Bayer, ERBE, Amgen, Johnson & Johnson, Takeda, Olympus, Medtronic, Intuitive.

v) Asmund Fretland reports receiving speaker fees from Bayer.

vi) Fernando Rotellar reports speaker fees and support outside the submitted work from Integra, Medtronic, Olympus, Corza, Sirtex and Johnson & Johnson.

vii) Troisi RI reports speaker fees and support outside the submitted work from Integra, Stryker, Medtronic, Medistim, MSD.

Footnotes

Data access

Data will be available from the corresponding author on reasonable request. It is not available publicly due to ethical and privacy concerns.

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Associated Data

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Supplementary Materials

1
NIHMS1945894-supplement-1.tiff (10.3MB, tiff)
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NIHMS1945894-supplement-2.tiff (10.3MB, tiff)
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NIHMS1945894-supplement-3.tiff (10.3MB, tiff)
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NIHMS1945894-supplement-4.tiff (10.3MB, tiff)
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NIHMS1945894-supplement-5.tiff (10.3MB, tiff)
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NIHMS1945894-supplement-6.tiff (10.3MB, tiff)

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