Search

Background: Despite the increasing efficacy of chemotherapy, permanently unresectable colorectal liver metastases are associated with poor long-term survival. We aimed to assess whether liver transplantation plus chemotherapy could improve overall survival., Methods: TransMet was a multicentre, open-label, prospective, randomised controlled trial done in 20 tertiary centres in Europe. Patients aged 18-65 years, with Eastern Cooperative Oncology Group performance score 0-1, permanently unresectable colorectal liver metastases from resected BRAF-non-mutated colorectal cancer responsive to systemic chemotherapy (≥3 months, ≤3 lines), and no extrahepatic disease, were eligible for enrolment. Patients were randomised (1:1) to liver transplantation plus chemotherapy or chemotherapy alone, using block randomisation. The liver transplantation plus chemotherapy group underwent liver transplantation for 2 months or less after the last chemotherapy cycle. At randomisation, the liver transplantation plus chemotherapy group received a median of 21·0 chemotherapy cycles (IQR 18·0-29·0) versus 17·0 cycles (12·0-24·0) in the chemotherapy alone group, in up to three lines of chemotherapy. During first-line chemotherapy, 64 (68%) of 94 patients had received doublet chemotherapy and 30 (32%) of 94 patients had received triplet regimens; 76 (80%) of 94 patients had targeted therapy. Transplanted patients received tailored immunosuppression (methylprednisolone 10 mg/kg intravenously on day 0; tacrolimus 0·1 mg/kg via gastric tube on day 0, 6-10 ng/mL days 1-14; mycophenolate mofetil 10 mg/kg intravenously day 0 to <2 months and switch to everolimus 5-8 ng/mL), and postoperative chemotherapy, and the chemotherapy group had continued chemotherapy. The primary endpoint was 5-year overall survival analysed in the intention to treat and per-protocol population. Safety events were assessed in the as-treated population. The study is registered with ClinicalTrials.gov (NCT02597348), and accrual is complete., Findings: Between Feb 18, 2016, and July 5, 2021, 94 patients were randomly assigned and included in the intention-to-treat population, with 47 in the liver transplantation plus chemotherapy group and 47 in the chemotherapy alone group. 11 patients in the liver transplantation plus chemotherapy group and nine patients in the chemotherapy alone group did not receive the assigned treatment; 36 patients and 38 patients in each group, respectively, were included in the per-protocol analysis. Patients had a median age of 54·0 years (IQR 47·0-59·0), and 55 (59%) of 94 patients were male and 39 (41%) were female. Median follow-up was 59·3 months (IQR 42·4-60·2). In the intention-to-treat population, 5-year overall survival was 56·6% (95% CI 43·2-74·1) for liver transplantation plus chemotherapy and 12·6% (5·2-30·1) for chemotherapy alone (HR 0·37 [95% CI 0·21-0·65]; p=0·0003) and 73·3% (95% CI 59·6-90·0) and 9·3% (3·2-26·8), respectively, for the per-protocol population. Serious adverse events occurred in 32 (80%) of 40 patients who underwent liver transplantation (from either group), and 69 serious adverse events were observed in 45 (83%) of 54 patients treated with chemotherapy alone. Three patients in the liver transplantation plus chemotherapy group were retransplanted, one of whom died postoperatively of multi-organ failure., Interpretation: In selected patients with permanently unresectable colorectal liver metastases, liver transplantation plus chemotherapy with organ allocation priority significantly improved survival versus chemotherapy alone. These results support the validation of liver transplantation as a new standard option for patients with permanently unresectable liver-only metastases., Funding: French National Cancer Institute and Assistance Publique-Hôpitaux de Paris., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: To compare outcomes after laparoscopic versus open major liver resection (hemihepatectomy) mainly for primary or metastatic cancer. The primary outcome measure was time to functional recovery. Secondary outcomes included morbidity, quality of life (QoL), and for those with cancer, resection margin status and time to adjuvant systemic therapy., Patients and Methods: This was a multicenter, randomized controlled, patient-blinded, superiority trial on adult patients undergoing hemihepatectomy. Patients were recruited from 16 hospitals in Europe between November 2013 and December 2018., Results: Of the 352 randomly assigned patients, 332 patients (94.3%) underwent surgery (laparoscopic, n = 166 and open, n = 166) and comprised the analysis population. The median time to functional recovery was 4 days (IQR, 3-5; range, 1-30) for laparoscopic hemihepatectomy versus 5 days (IQR, 4-6; range, 1-33) for open hemihepatectomy (difference, -17.5% [96% CI, -25.6 to -8.4]; P < .001). There was no difference in major complications (laparoscopic 24/166 [14.5%] v open 28/166 [16.9%]; odds ratio [OR], 0.84; P = .58). Regarding QoL, both global health status (difference, 3.2 points; P < .001) and body image (difference, 0.9 points; P < .001) scored significantly higher in the laparoscopic group. For the 281 (84.6%) patients with cancer, R0 resection margin status was similar (laparoscopic 106 [77.9%] v open 122 patients [84.1%], OR, 0.60; P = .14) with a shorter time to adjuvant systemic therapy in the laparoscopic group (46.5 days v 62.8 days, hazard ratio, 2.20; P = .009)., Conclusion: Among patients undergoing hemihepatectomy, the laparoscopic approach resulted in a shorter time to functional recovery compared with open surgery. In addition, it was associated with a better QoL, and in patients with cancer, a shorter time to adjuvant systemic therapy with no adverse impact on cancer outcomes observed.

Introduction: The microarchitecture of liver metastases (LMs), or histopathological growth pattern (HGP), has been demonstrated to be a significant prognostic factor in patients undergoing resection of colorectal liver metastases (CRLMs). Currently, however, HGP can be only determined on the operative specimen. Therefore, the development of new tools to predict the HGP of CRLMs before surgery and to understand the mechanisms that drive these patterns is important for improving individualization of therapeutic management. In this study, we analyzed data from a retrospective series of patients who underwent surgery for CRLMs to compare primary tumor characteristics, including markers of local aggressiveness and migratory capacity, and HGP of liver metastases., Methods: Data from a retrospective series of 167 patients who underwent curative-intent resection of CRLMs and in whom pathological samples from both primary tumor and liver metastases were available were reviewed. At the primary tumor level, KRAS mutational status, grade of differentiation, and tumor budding were assessed. HGP was scored in each resected CRLM, according to consensus guidelines, and classified as desmoplastic (dHGP) or non-desmoplastic (non-dHGP). Associations between primary tumor characteristics and HGP of CRLMs were evaluated using a binary logistic regression model. Overall survival and disease-free survival were evaluated using Kaplan-Meier and multivariable Cox regression analyses., Results: CRLMs were classified as dHGP in 36% of the patients and as non-dHGP in 64%. Higher rates of moderately or poorly differentiated primary tumors were observed in the non-dHGP CRLM group (80%), as compared with the dHGP group (60%) (OR = 3.6; 95%CI: 1.6-7.05; p = 0.001). Higher rates of tumor budding were observed in the non-dHGP CRLM group, with a median tumor budding value of 4 as compared with 2.5 in the dHGP group (p = 0.042). In the entire series, 5-year overall and disease-free survival were 43% and 32.5%, respectively. The non-dHGP CRLM group had worse post-hepatectomy survival, with 5-year overall and disease-free survival of 32.2% and 24.6%, respectively, as compared with 60.8% and 45.9%, respectively, for the dHGP group (p = 0.02)., Conclusion: Colorectal tumors with moderate or poor differentiation and those with high tumor budding are more frequently associated with CRLMs with a non-dHGP. This suggests that primary tumor characteristics of local aggressiveness and migratory capacity could preferentially promote the development of CRLMs with an infiltrating pattern and that these parameters should be considered as part of new scores for predicting HGP before surgery. This finding may stimulate new lines of research for more individualized therapeutic decision in patients with CRLM candidate to surgery., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Histopathological growth patterns (HGPs) of liver metastases represent a potential biomarker for prognosis after resection. They have never been studied in neuroendocrine tumor liver metastases (NETLM). This study evaluated if distinct HGPs can be observed in resected NETLM and if they have prognostic value. Sixty-three patients who underwent resection of NETLM between 01-01-2001 and 31-12-2021 were retrospectively included. HGPs were scored on Haematoxylin&Eosin slides using light microscopy, distinguishing desmoplastic- (dHGP), pushing- (pHGP) and replacement HGP (rHGP). Average HGP scores were calculated per patient. Each patient was classified according to predominant HGP. Overall and Disease-Free Survival (OS and DFS) were evaluated through Kaplan-Meier analysis and Cox regression. Eighteen patients had predominant dHGP (29%), 33 had predominant pHGP (52%) and 11 had predominant rHGP (17%). One patient had mixed HGP (2%). Five-year OS was 76% (95%CI: 66-87%) for the overall cohort. Five-year OS was 92% (95%CI: 77-100%) for dHGP, was 73% (95%CI: 59-91%) for pHGP, 50% (95%CI: 25-100%) for rHGP. Five-year DFS was 39% (95%CI: 19-83%) for dHGP, 44% (95%CI: 27-71%) for rHGP and 50% (95%CI: 23-100%) for pHGP. There was no significant association between HGP and OS or DFS in multivariable analysis. Distinct HGPs could be identified in NETLM. In patients who underwent resection of NETLM, no association was found between HGPs and postoperative survival. Half of the patients with NETLM have a predominant pushing growth pattern, which is a rare growth pattern in liver metastases from breast and colorectal cancer., (© 2023. The Author(s).)

Introduction: The histological growth pattern (HGP) of colorectal liver metastases (CRLMs) reflects tumor biology and local infiltrating behavior. In patients undergoing surgery for CRLMs, we investigated whether HGP and surgical margin status interact when influencing prognosis., Methods: Clinicopathological data, margin status, and HGP were reviewed in patients who underwent resection of CRLMs. R1 margin was defined when cancer cells were present at any point along the margin. HGPs were scored according to international guidelines, identifying patients with desmoplastic (DHGP) or non-desmoplastic (non-DHGP) CRLMs., Results: Among 299 patients, 16% had R1 resection and 81% had non-DHGP CRLMs. Non-DHGP was the only predictive factor for R1 resection (18.7% versus 7.4% in DHGP, p = 0.04). Poorer 5-year overall survival was observed in both R1 and non-DHGP groups in univariate analysis (27.6% in R1 versus 45.6% in R0, p = 0.026, and 37.2% in non-DHGP versus 59.2% in DHGP, p = 0.013), whereas non-DHGP but not R1 remained associated with worse prognosis in multivariate analysis. In patients with non-DHGP, R1 margin has no prognostic impact., Conclusions: In patients undergoing resection of CRLMs, the prognostic value of poor tumor biology, such as in patients with non-DHGP, exceeds that of surgical radicality., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Study Purpose: The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases., Methods: The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection., Results: Not applicable., Conclusion: DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR., Trial Registration: Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019)., (© 2022. The Author(s).)

Background: Distinct Histopathological Growth Patterns can be identified in liver metastases from melanoma, breast and colorectal cancers. For each of these distinct liver metastasis types the HGP has proven a biomarker for survival after partial hepatectomy, with the desmoplastic type marking favourable prognosis. Whether HGPs can be considered a pan-cancer phenomenon remains unknown. This study therefore evaluates the presence of HGPs and their prognostic value across non-colorectal non-neuroendocrine liver metastases., Methods: A retrospective multicentre cohort study was performed in patients who underwent curative intent resection of non-colorectal non-neuroendocrine liver metastasis. HGPs were assessed on Haematoxylin and Eosin slides according to consensus guidelines and classified as desmoplastic or non-desmoplastic. Overall- and recurrence-free survival were evaluated using Kaplan-Meier and multivariable Cox regression analysis., Results: In total, 132 patients with liver metastasis from 25 different tumour types were eligible for analysis, of which 26 (20%) had a desmoplastic HGP. Five-year OS and RFS (95%CI) were 53% (36-78%) versus 40% (30-53%), and 33% (19-61%) versus 15% (9-27%) for patients with desmoplastic compared to non-desmoplastic metastases, respectively (p = 0.031 & p = 0.004). On multivariable analysis (adjusted HR [95%CI]) a desmoplastic HGP was prognostic for both OS (0.46 [0.25-0.86]) and RFS (0.38 [0.21-0.69])., Conclusions: This study demonstrates that HGPs apply to liver metastases across a wide variety of primary tumour origins. They hold a prognostic value in these cases, suggesting that HGPs could represent a pan-cancer biomarker for survival after surgical resection of liver metastases., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background and Objectives: The histological growth pattern (HGP) represents a strong prognostic factor in patients undergoing surgery for colorectal liver metastases (CRLM). We evaluated whether the combination of HGP with clinico-metabolic parameters could improve its prognostic value., Methods: In a series of 108 patients undergoing resection of CRLM, the HGP of CRLM was scored according to international guidelines. Baseline clinico-metabolic clinical status was evaluated using a metabolic-Clinical Risk Score (mCRS), combining traditional Memorial Sloan Kettering-CRS parameters with the tumor-to-liver glucose uptake ratio as measured with 18 Fluorodeoxyglucose/positron emission tomography., Results: In patients with desmoplastic HGP (DHGP) CRLM (20% of all patients), 5- and 10-years overall survival (OS) and disease free survival (DFS) were 66% and 43% and 37% and 24.5%, as compared with 35% and 21% and 11% and 11% in the non-DHGP group (p = 0.07 and 0.054). Among DHGP patients, those with a low-risk mCRS had improved postoperative outcomes, 5- and 10-years OS and DFS reaching 83.3% and 62.5% and 50% and 33%, as compared with 18% and 0% and 0% and 0% in high-risk mCRS patients (p = 0.007 and 0.003). In contrast, mCRS did not influence postoperative survivals in non-DHGP patients., Conclusions: Combining the clinico-metabolic characteristics with the HGP may improve prognostication in patients undergoing surgery for CRLM., (© 2021 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Post hepatectomy liver failure (PHLF) after ALPPS has been related to the discrepancy between liver volume and function. Pre-operative hepatobiliary scintigraphy (HBS) can predict post-operative liver function and guide when it is safe to proceed with major hepatectomy. Aim of this study was to evaluate the role of HBS in predicting PHLF after ALPPS, defining a safe cut-off., Methods: A multicenter retrospective study was approved by the ALPPS Registry. All patients selected for ALPPS between 2012 and 2018, were evaluated. Every patient underwent HBS during ALPPS evaluation. PHLF was reported according to ISGLS definition, considering grade B or C as clinically significant., Results: 98 patients were included. Thirteen patients experienced PHLF grade B or C (14%) following ALPPS-2. The HBS and the daily gain in volume (KGR FLR ) of the future liver remnant (FLR) were significantly lower in PHLF B and C (p = .004 and .041 respectively). ROC curves indicated safe cut-offs of 4.1%/day (AUC = 0.68) for KGR FLR , and of 2.7 %/min/m 2 (AUC = 0.75) for HBS FLR . Multivariate analysis confirmed these cut-offs as variables predicting PHLF after ALPPS-2., Conclusion: Patients presenting a KGR FLR ≤4.1%/day and a HBS FLR ≤2.7%/min/m 2 are at high risk of PHLF and their second stage should be re-discussed., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Recent studies indicate that a group of patients with cirrhosis receiving a liver transplantation for hepatocellular cancer (HCC) beyond the Milan Criteria (MC) can achieve a similar outcome compared to patients within these criteria. This study aims to investigate the value of the Asan critera (AC), up-to-7 criteria (UT7), French alpha-foetoprotein (AFP) model and Metroticket 2.0 (MT2.0) model compared to the MC., Methods: 526 patients transplanted for non-metastatic HCC were analyzed. Patient groups within and beyond MC and extended criteria were determined according to radiological assessment and AFP value at listing., Results: Overall survival (OS) and recurrence (RR) rates were similar between patients within MC and all extended criteria. Five-year OS within MC was 71.3% compared to 70.9% for AC, 71.4% for UT7, 69.7% for AFP-model and 71.0% for MT2.0 criteria. Five-year RR within MC was 12.3% compared to 13.5% for AC, 13.0% for UT7, 14.3% for AFP-model and 13.2% for MT2.0 criteria. Patients beyond MC but within the extended criteria had tendency towards higher recurrence., Conclusions: All validated extended criteria (AC, UT7, AFP-model and MT2.0) could be proposed as alternatives to the MC with similar outcome. Prospective data are awaited to assess recurrence beyond MC., Competing Interests: Declaration of competing interest No conflict of interest reported in relation to the presented work., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The benefit of surgery in patients with non-colorectal non-neuroendocrine liver metastases (NCRNNELM) remains controversial. At the population level, several statistical prognostic factors and scores have been proposed but inconsistently verified. At the patient level, no selection criteria have been demonstrated to guide individual therapeutic decision making. We aimed to evaluate potential individual selection criteria to predict the benefit of surgery in patients undergoing treatment for NCRNNELM., Methods: Data for 114 patients undergoing surgery for NCRNNELM were reviewed. In this population, we identified an early relapse group (ER), defined as patients with unresectable recurrence < 1 year postoperatively who did not benefit from surgery (N = 28), and a long-term survival group (LTS), defined as patients who were recurrence-free ≥ 5 years postoperatively and benefited from surgery (N = 20). Clinicopathologic parameters, the Association Française de Chirurgie (AFC) score, and a modified 4-point Clinical Risk Score (mCRS) (excluding CEA level) were analyzed and compared between LTS and ER groups., Results: The majority of patients were female and a majority had an ASA score ≤ 2 at the time of liver surgery. The median age was 55 years. Almost half of the patients (46%) presented with a single-liver metastasis. Intermediate- and low-risk AFC scores represented 40% and 60% of the population, respectively. Five- and 10-year overall survival (OS) and disease-free survival (DFS) rates were 56% and 27%, and 30% and 12%, respectively. Negative prognostic factors were the size of liver metastases > 50 mm and delay between primary and NCRNNELM <24 months for OS and DFS, respectively. AFC score was not prognostic while high-risk mCRS (scores 3-4) was predictive for the poorer OS. The clinicopathologic parameters were similar in the ER and LTS groups, except the presence of N+ primary tumor, and the size of liver metastases was significantly higher in the ER group., Conclusion: In patients with resectable NCRNNELM, no predictive factors or scores were found to accurately preoperatively differentiate individual cases in whom surgery would be futile from those in whom surgery could be associated with a significant oncological benefit.

Background: Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT., Methods: Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4 + and CD8 + T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups., Results: Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4 + and CD8 + T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3 + cells was observed in the peri-tumoral area in patients receiving < 100 Gy, whereas a higher ratio of intra-tumoral CD4 + cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival., Conclusions: SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.

Background: Breast cancer liver metastases (BCLM) is considered a systemic disease with poorly defined selection criteria for surgery and little evidence for the appropriate timing of surgery., Methods: Postoperative outcomes of patients operated for BCLM were retrospectively reviewed and compared based on the timing of surgery, with the early surgery (ES) group treated ≤12 months after BCLM diagnosis, and late surgery (LS) group operated >12 months after diagnosis., Results: Seventy-two patients with BCLM underwent liver surgery, including 37 and 35 in the ES and LS groups, respectively. Demographic and preoperative characteristics were similar between the groups, except that multifocal liver disease was more frequent in the LS group (p = 0.008). The LS group had a morbidity rate of 38%, compared to 11% in the ES group (p = 0.015). No postoperative deaths occurred. In the whole cohort, median progression-free (PFS) and overall survival (OS) were 19 and 50 months, respectively, and 1-, 3- and 5-year PFS and OS were 63%, 41%, 24% and 93%, 66%, 43%, respectively, with no significant difference observed between the ES and LS groups. Multivariate analysis revealed that breast cancer progesterone receptor negativity (HR = 3.34, p = 0.03) and a size of LM > 40 mm (HR = 3.11, p = 0.01) were significant negative prognostic factors for PFS. Only a size of LM > 40 mm (HR = 2.79, p = 0.008) was significantly associated with shorter OS., Conclusion: A prolonged preoperative observational period does not improve long-term outcomes after liver surgery in patients with resectable BCLM, suggesting that early management can safely be proposed to those patients, with good oncological outcomes., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The prevalence of chemotherapy associated liver injuries (CALI), especially SOS (sinusoidal obstruction syndrome) and NRH (nodular regenerative hyperplasia) might be reduced since the introduction of routine use of biological agents with chemotherapy in colorectal liver metastases (CRLM)., Methods: One hundred patients with CRLM having undergone at least one liver segment resection were prospectively included, and chemotherapy data recorded. Specimens were reviewed by a single pathologist and CALI were described. Prevalence of CALI was compared to our previous experience published in 2013. NRH diagnosis was performed on reticulin special stain, by contrast to our previous study. Postoperative outcome was analysed., Results: Bevacizumab was more frequently administrated in patients of the present study: 53/100 (53%) compared to 20/151 (13%), p < 0.0001. Overall, in the present series, SOS was only observed in 28/100 (28%) patients compared to 116/151 (77%) in 2013 (p < 0.001). When looking specifically to patients receiving Bevacizumab with Folfox, we observed a reduced SOS prevalence compared to Folfox alone (p = 0.008). A higher prevalence of NRH was found in the present study, related to increased detection accuracy, but in patients receiving Bevacizumab in association with Folfox, this prevalence was also reduced compared to Folfox alone (p = 0.03). Both SOS and NRH were associated with severe complications (p = 0.008 and p = 0.005, respectively) and postoperative liver insufficiency (p < 0.001 and p < 0.01, respectively)., Conclusions: The routine use of Bevacizumab in association with Folfox significantly reduced CALI prevalence, in turn linked to severe postoperative complications., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background/purpose: Preoperative selective internal radiation therapy (SIRT) may improve the results of partial hepatectomy (PH) or radiofrequency destruction (RF) for hepatocellular carcinoma (HCC) in patients with cirrhosis. The aim of this study was to evaluate the feasibility and safety of this combined approach., Methods: Patients with cirrhosis and HCC selected for PH or RF were prospectively included and systematically proposed for preoperative SIRT. Feasibility and safety of SIRT and post-SIRT PH or RF were assessed., Results: Thirty patients were included. SIRT was contraindicated in seven, due to lack of access to tumour artery or to hepato-pulmonary shunts. SIRT was performed in 23 patients without significant complications. Post-SIRT, surgery was refuted in seven patients, due to tumour progression or the patient's deteriorating condition. After surgery, major complications were observed in 2/16 patients (12.5%) and one patient died 52 days post-surgery. A major tumour pathological response was seen in most patients who underwent surgery after SIRT., Conclusions: On intention-to-treat basis, the overall feasibility of combining preoperative SIRT and surgery was limited. Preoperative SIRT did not increase expected operative morbidity, but post-SIRT, a third of patients were refuted for surgery. Accurate selection criteria and potential long-term oncological benefit of this approach remains to be determined. ClinicalTrials.gov NCT01686880., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Although the number of colorectal liver metastases (CLM) is decreasingly considered as a contraindication to surgery, patients with 10 CLM or more are often denied liver surgery. This study aimed to evaluate the outcome after liver surgery and to identify prognostic factors of survival in such patients., Methods: The study population consisted of a multicentre cohort of patients with CLM (N=12 406) operated on, with intention to resect, from January 2005-June 2013 and whose data were prospectively collected in the LiverMetSurvey registry., Results: Overall, the group ⩾10 CLM (N=529, 4.3%) experienced a 5-year overall survival (OS) of 30%. A macroscopically complete (R0/R1) resection (72.8% of patients) was associated with a 3- and 5-year OS of 61% and 39% vs 29% and 5% for R2/no resection patients (P<0.0001). At multivariate analysis, R0/R1 resection emerged as the strongest favourable factor of OS (HR 0.35 (0.26-0.48)). Other independent favourable factors were as follows: maximal tumour size <40 mm (HR 0.67 (0.49-0.92)); age <60 years (HR 0.66 (0.50-0.88)); preoperative MRI (HR 0.65 (0.47-0.89)); and adjuvant chemotherapy (HR 0.73 (0.55-0.98)). The model showed that 5-year OS rates of 30% was possible provided R0/R1 resection associated with at least an additional favourable factor., Conclusions: Liver resection might provide long-term survival in patients with ⩾10 CLM staged with preoperative MRI, provided R0/R1 resection followed by adjuvant therapy. A validation of these results in another cohort is needed.

Background: The waiting interval after chemoradiotherapy (CRT) is an interesting therapeutic window to treat patients with synchronous liver metastases (SLM) from rectal cancer., Methods: A retrospective analysis was performed of 18 consecutive patients (M/F 10/8, age (range) 60 (51-75) years) from five institutions who underwent liver resection of SLM during the waiting interval after CRT for rectal adenocarcinoma., Results: All patients underwent interval liver surgery for a median (range) of 4 (2-14) liver metastases. Metastases involved a median (range) of 4 (1-7) liver segments. Median (range) time between end of CRT and liver surgery was 22 (6-45) days. Laparoscopic liver surgery was performed in 12 (67%) patients. No severe complications (Clavien-Dindo ≥ 3b) occurred after liver surgery. Median (range) length of hospital stay after liver surgery was 5 (1-10) days. All patients subsequently underwent rectal resection at a median (range) of 10 (8-13) weeks after end of CRT. Median (IQR) time-to-progression after liver surgery was 4.2 (2.8-9.2) months., Conclusions: The waiting interval after neoadjuvant CRT is a valuable option to treat SLM from rectal cancer. More data are necessary to confirm its oncological efficacy.

In oncosurgical approach to colorectal liver metastases, surgery remains considered as the only potentially curative option, while chemotherapy alone represents a strictly palliative treatment. However, missing metastases, defined as metastases disappearing after chemotherapy, represent a unique model to evaluate the curative potential of chemotherapy and to challenge current therapeutic algorithms. We reviewed recent series on missing colorectal liver metastases to evaluate incidence of this phenomenon, predictive factors and rates of cure defined by complete pathologic response in resected missing metastases and sustained clinical response when they were left unresected. According to the progresses in the efficacy of chemotherapeutic regimen, the incidence of missing liver metastases regularly increases these last years. Main predictive factors are small tumor size, low marker level, duration of chemotherapy, and use of intra-arterial chemotherapy. Initial series showed low rates of complete pathologic response in resected missing metastases and high recurrence rates when unresected. However, recent reports describe complete pathologic responses and sustained clinical responses reaching 50%, suggesting that chemotherapy could be curative in some cases. Accordingly, in case of missing colorectal liver metastases, the classical recommendation to resect initial tumor sites might have become partially obsolete. Furthermore, the curative effect of chemotherapy in selected cases could lead to a change of paradigm in patients with unresectable liver-only metastases, using intensive first-line chemotherapy to intentionally induce missing metastases, followed by adjuvant surgery on remnant chemoresistant tumors and close surveillance of initial sites that have been left unresected.

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) was recently developed to induce rapid hypertrophy and reduce post-hepatectomy liver failure in patients with insufficient remnant liver volume (RLV). However, mortality rates >12% have been reported. This study aimed to analyze the perioperative course of ALPPS and to identify factors associated with morbi-mortality., Methods: Between April 2011 and September 2013, 62 patients operated in 9 Franco-Belgian hepatobiliary centres underwent ALPPS for colorectal metastases (N = 50) or primary tumors, following chemotherapy (N = 50) and/or portal vein embolization (PVE; N = 9)., Results: Most patients had right (N = 31) or right extended hepatectomy (N = 25) (median RLV/body weight ratio of 0.54% [0.21-0.77%]). RLV increased by 48.6% [-15.3 to 192%] 7.8 ± 4.5 days after stage1, but the hypertrophy decelerated beyond 7 days. Stage2 was cancelled in 3 patients (4.8%) for insufficient hypertrophy, portal vein thrombosis or death and delayed to ≥9 days in 32 (54.2%). Overall, 25 patients (40.3%) had major complication(s) and 8 (12.9%) died. Fourteen patients (22.6%) had post-stage1 complication of whom 5 (35.7%) died after stage2. Factors associated with major morbi-mortality were obesity, post-stage1 biliary fistula or ascites, and infected and/or bilious peritoneal fluid at stage2. The latter was the only predictor of Clavien ≥3 by multivariate analysis (OR: 4.9; 95% CI: 1.227-19.97; p = 0.025). PVE did not impact the morbi-mortality rates but prevented major cytolysis that was associated with poor outcome., Conclusions: The inter-stages course was crucial in determining ALPPS outcome. The factors of high morbi-mortality rates associated with ALPPS are linked to the technique complexity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Gadoxetic acid (Gd-EOB-DTPA) is a 'hepatocyte-specific' contrast agent for magnetic resonance (MR) in both the vascular and the hepatobiliary phases., Aim: To evaluate the contribution of the hepatobiliary phase of Gd-EOB-DTPA MR in the diagnosis of small hepatocellular carcinoma (HCC) in cirrhotic patients under surveillance., Methods: Between 2008 and 2011, 48 consecutive small (10-30 mm) liver nodules were detected in 33 patients, who prospectively underwent contrast-enhanced ultrasound (CEUS), Gd-EOB-DTPA-enhanced MR and helical-computed tomography (CT) in a blind study. The diagnosis of HCC was established according to AASLD 2005 criteria., Results: Of the 48 nodules, 38 (79%) were diagnosed as HCC, 24 (63%) of them based on AASLD non-invasive criteria, 11 diagnosed at histology and 3 during follow-up. The typical vascular pattern (arterial hypervascularisation and venous/late washout) was detected in 30 (79%) HCC nodules by MR, in 22 (58%) by CT and in 17 (45%) by CEUS. Hypointensity during the MR hepatobiliary phase was observed in all HCC nodules and in 3 nonmalignant nodules (sensitivity 100%, specificity 70%, positive predictive value 93%, negative predictive value 100%, positive likelihood ratio 3.33, negative likelihood ratio 0). Eight (21%) of the 38 HCC nodules, 7 of which lacked the typical vascular features at any of the imaging modalities, showed washout in the portal/venous phase and hypointensity in the hepatobiliary phase at MRI, while this pattern was not detected in any nonmalignant lesion., Conclusions: Gadoxetic acid magnetic resonance may enhance the sensitivity of the non-invasive diagnosis of small hepatocellular carcinoma nodules in cirrhotic patients under surveillance. Double hypointensity in the portal/venous and hepatobiliary phases could be considered a new magnetic resonance pattern, highly suggestive of hypovascular hepatocellular carcinoma., (© 2012 Blackwell Publishing Ltd.)

Purpose: Tumor progression while receiving neoadjuvant chemotherapy (PD) has been associated with poor outcome and is commonly considered a contraindication to liver resection (LR). This study aims to clarify in a large multicenter setting whether PD is always a contraindication to LR., Methods: Data from the LiverMetSurvey international registry were analyzed. Patients undergoing LR for colorectal metastases without extrahepatic disease after neoadjuvant chemotherapy between 1990 and 2009 were reviewed., Results: Among 2143 patients, PD occurred in 176 (8.2 %). Risk of progression was increased after 5-FU or irinotecan (22.7 % vs. 6.8 % after other regimens, p < 0.0001; 14.9 % vs. 7.2 %, p < 0.0001), while it was reduced after oxaliplatin (5.6 % vs. 12.0 %, p < 0.0001) and still diminished among patients receiving targeted therapies (2.6 %). PD was an independent prognostic factor of survival at multivariate analysis (35 % vs. 49 %, p = 0.0006). In the PD group, 3 independent prognostic factors were identified: carcinoembryonic antigen (CEA) ≥ 200 ng/mL (p = 0.003), >3 metastases (p = 0.028), and tumor diameter ≥ 5 0 mm (p = 0.002). A survival predictive model showed that patients without any risk factors had 5-year survival rates of 53.3 %; good survival results were still observed if metastases were >3 or ≥ 50 mm (29.9 and 19.1 %, respectively). On the contrary, survival was less than 10 % at 3 years in the presence of >1 prognostic factor or CEA of ≥ 200 ng/mL., Conclusions: PD is a negative prognostic factor, but it is not an absolute contraindication to LR. Patients with PD could be scheduled for LR except for those with >3 metastases and ≥ 50 mm, or CEA ≥ 200 ng/mL in whom further chemotherapy is recommended.

The treatment of hepatocellular carcinoma (HCC) in cirrhotic patients is challenging: the incidence is increasing, the cirrhosis dramatically limits the tolerance to treatment possibilities, there are many therapeutic modalities but resources are limited, namely in the context of organ shortage for transplantation. Liver transplantation (LT) is the optimal treatment as it combines the largest tumor resection possible and the correction of the underlying liver disease. Due to organ shortage however, LT is reserved for early-stages HCC. Surgical resection and radiofrequency destruction represent potentially curative options in highly selected patients. Arterial embolizations, chemo- or radio-embolizations, allow local tumor control but are not curative. These techniques could be performed before surgical resection or LT, to downstage the tumor and/or to control tumor progression while waiting for a graft. Finally, sorafenib is the only systemic treatment which has shown a survival benefit in advanced HCC. The benefit of combination of sorafenib and surgical treatments remains undetermined. The challenge in the management of HCC in cirrhotic patients is to integrate both individual (age, comorbidities, cirrhosis stage, tumor stage, specific contraindications to LT, etc.) and collective variables (expected waiting time before LT) to determine the best therapeutic option for each patient. In this process, multidisciplinarity is a key for success.

Purpose: To investigate whether the malignancy of atypical nodules in cirrhosis can be identified at gadoxetic-acid-disodium(Gd-EOB-DTPA)-MRI by their hypointensity in the hepatobiliary(HB)-phase alone or combined with any other MR imaging features., Materials and Methods: One hundred eleven atypical nodules detected in 77 consecutive Gd-EOB-DTPA-MRIs were divided, based on arterial-phase behavior, into: Class I, isovascular (n = 82), and Class II, hypervascular without portal/delayed washout (n = 29). The two classes were further grouped based on HB-phase intensity (A/B/C hypo/iso/hyperintensity). Portal/venous/equilibrium-phase behavior and T2w features were also collected. Histology was the gold standard. Per-nodule sensitivity, specificity, negative and positive predictive values (NPV/PPV), and diagnostic accuracy were calculated for HB-phase hypointensity alone, and combined with vascular patterns and T2w hyperintensity., Results: Histology detected 60 benign and 51 malignant/premalignant nodules [10 overt hepatocellular carcinomas (HCCs) and 41 high-grade dysplastic nodules (HGDN)/early HCC]. Class IA contained 31 (94%) malignancies, IB one (3%), and IC only benign lesions. Class IIA had 100% malignancies, IIB three (37.5%) and IIC only two (28.5%). HB-phase hypointensity alone (Classes I-IIA) had 88% sensitivity, 91% NPV, and 93% diagnostic accuracy, superior (P < 0.05, P < 0.006, and P < 0.05, respectively) to any other MR imaging feature alone or combined., Conclusion: In atypical cirrhotic nodules, HB-phase hypointensity by itself is the strongest marker of malignancy., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: To prospectively assess the additional value of the hepatobiliary (HB) phase of Gd-EOB-DTPA-MRI in identifying and characterising small (≤ 2 cm) hepatocellular carcinomas (HCCs) undetermined in dynamic phases alone because of their atypical features, according to the AASLD criteria., Methods: 127 cirrhotic patients were evaluated with Gd-EOB-DTPA-MRI in two sets: unenhanced and dynamic phases; unenhanced, dynamic and HB phases. Sixty-two out of 215 nodules (29%) were atypical in 42 patients (33%)., Results: 62 atypical nodules were reported at histology: high-grade dysplastic nodules (HGDN)/early HCC (n = 20), low-grade DN (LGDN) (n = 21), regenerative nodules (n = 17) and nodular regenerative hyperplasia (n = 4). The sensitivity, specificity, accuracy, positive and negative predictive value (PPV, NPV) were increased by the addition of the HB phase: 88.4-99.4%, 88-95%, 88-98.5%, 97-99%, and 65-97.5%, respectively. Twenty atypical nodules were malignant (32%), 19 of which were characterised only during the HB phase., Conclusions: The HB phase is 11% more sensitive in the classification of HGDN/early HCC than dynamic MRI, with an added value of 32.5% in the NPV. The high incidence (33%) of atypical nodules and their frequent malignancy (32%) suggest the widespread employment of Gd-EOB-DTPA-MRI in the follow-up of small nodules (≤ 2 cm) in cirrhosis.

Background: The RFA procedures rely on a precise positioning of the radiofrequency electrode and the complete destruction of the tumour. This article presents new optimization techniques to improve such surgical procedures., Methods: A method to optimize the coverage of the tumour by successive RFA destructions and an in vitro procedure with simulated tumours have been developed., Results: The guidance system and optimization coverage have been tested on 3D simulation and by the surgeon in vitro on a heifer liver. In this context, the RFA electrode is optically tracked and guided., Conclusions: The optimization method provides needle placements that ensure a complete theoretical ablation of the tumour, and the guidance system helps the surgeon to reach each position of destruction., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Surgery is the best treatment modality for colorectal liver metastases. When initially unresectable, hepatic resection of metastases after downstaging by chemotherapy can provide a hope of long-term survival similar to that of primarily resected patients. Definitions of resectability have evolved with the emerging principle that if metastases can be completely resected regardless of their size and number,resection should be performed as the sole mean of achieving long-term survival. Specific surgical techniques can be combined to improve resectability. If the tumor is considered unresectable, recent developments make possible to render some tumors surgically resectable. Depending on the tumor size, number and location, neoadjuvant treatments, mainly chemotherapy, can be used, followed by resection. Resection may be contraindicated if the residual volume of liver is inadequate to avoid liver failure. This may be changed either by PVE or two-stage hepatectomy, both of which use the natural regenerative capacity of the liver. Local destructive therapies such as cryosurgery and radio-frequency can also be used in conjunction with resection for patients in whom all metastases are not surgically resectable. The present use of these ablative techniques is improving the percentages of unresectable patients considered for surgery. All of the above-described methods can be combined to achieve a surgical strategy that is as curative as possible, increasing the number of patients primarily unresectable, with a long-term survival hope similar to that of primarily resectable patients. To achieve this objective, a close collaboration between oncologists, radiologists, and surgeons is mandatory, with routine re-evaluation of patients for an adequate timing of each treatment.