Ideal Surgical Margin to Prevent Early Recurrence After Hepatic Resection for Hepatocellular Carcinoma.

BACKGROUNDS AND AIMS: Postoperative early recurrence after hepatic resection for hepatocellular carcinoma (HCC) poses a challenge to surgeons, and the effect of a surgical margin is still controversial. This study aimed to identify an ideal margin to prevent early recurrence. METHODS: A total of 226 consecutive patients who underwent primary curative hepatic resection for solitary and primary HCC were enrolled. The definition of early recurrence was determined using the minimum P value approach. Logistic regression analysis was used to identify the risk factors of early recurrence. The receiver-operating characteristic (ROC) curve was used to identify the optimal cut-off of the surgical margin and early recurrence. RESULTS: Recurrence within 8 months induced the poorest overall survival (P = 2×10-15). ROC analysis showed that the optimal cut-off value of the surgical margin was 7 mm. The risk factors of early recurrence (≤ 8-month recurrence) were preoperative alpha-fetoprotein levels ≥ 100 ng/ml (Odds ratio [OR] 4.92 [2.28-10.77], P < 0.0001) and a surgical margin < 7 mm (OR 3.09 [1.26-8.85], P = 0.01) by multivariable analysis. The probability of early recurrence ranged from 5.0% in the absence of any factors to 43.5% in the presence of both factors. Among patients with alpha-fetoprotein levels ≥ 100 ng/ml, non-capsule formation, or microvascular invasion, there was a significant difference in 5-year overall survival between surgical margins of < 7 mm and ≥ 7 mm. CONCLUSIONS: A > 7-mm margin is important to prevent early recurrence. Patients with HCC and alpha-fetoprotein levels > 100 ng/ml, non-capsule formation, or microvascular invasion may have a survival benefit from a ≥ 7-mm margin.

What did the European Liver Transplant Registry bring to liver transplantation?

Since its foundation in 1985, the European Liver Transplant Registry has evolved to become an important tool to monitor the liver transplantation activity in Europe. The vast amount of data collected on 169 473 liver transplantations performed in 153 238 recipients has also resulted in scientific publications. Without doubt, several of these have influenced the daily practice of liver transplantation. This paper gives an overview of the development, the functioning, and the scientific activity of the European Liver Transplant Registry during more than three decades. Indeed, it can be said that the registry helped to advance the practice of liver transplantation not only in Europe but also worldwide.

Impact of Surgical Treatment for Recurrence After 2-Stage Hepatectomy for Colorectal Liver Metastases, on Patient Outcome.

OBJECTIVE: To evaluate the impact of repeat surgery for recurrence on the long-term survival after 2-stage hepatectomy (TSH) for extensive colorectal liver metastases (CRLM). BACKGROUND: Although TSH is now deemed effective for selected patients with extensive bilobar CRLM, disease recurrence after TSH is very frequent because of the extensive tumor load. METHODS: Among a total cohort of 1235 patients who underwent hepatectomy for CRLM between 1992 and 2012, 139 with extensive bilobar CRLM were scheduled for TSH. Of these, 93 patients had completion of TSH and were enrolled in this study. RESULTS: The 5-year overall survival (OS) rate after TSH was 41.3%. Twenty-two patients (23.7%) had a concomitant extrahepatic disease (EHD), and curative resection of concomitant EHD was achieved in 13 patients. Among the 81 patients who achieved complete tumor removal for primary, CRLM, and concomitant EHD, 62 (76.5%) had recurrence. Repeat surgery was performed in 38 patients; 35 for recurrence after curative surgery and 3 for liver recurrence with unresected concomitant EHD or primary tumor. Of these 38 patients, 31 were salvaged. The patients who underwent repeat surgery had a significantly longer OS than those who did not (45.8% vs 26.3%; P = 0.0041). A multivariate analysis revealed that repeat surgery was an independent prognostic factor of the OS after TSH (hazard ratio 0.31, P = 0.0012). CONCLUSIONS: Repeat surgery for recurrence after TSH may be crucial for the long-term survival in patients with extensive bilobar CRLM. Intensive oncosurgical surveillance is essential to avoid missing the chance for repeat surgery after TSH.

Prognostic Value and Prediction of Extratumoral Microvascular Invasion for Hepatocellular Carcinoma.

BACKGROUND: There are few reports on microvascular invasion (MVI) located intra- or extratumorally and prognosis of hepatocellular carcinoma (HCC). OBJECTIVE: The aim of this study was to evaluate patient outcome according to the location of MVI, and to build a nomogram predicting extratumoral MVI. METHODS: We included 681 consecutive patients who underwent hepatic resection (HR) or liver transplantation (LT) for HCC from January 1994 to June 2012, and evaluated patient outcome according to the degree of vascular invasion (VI). A nomogram for predicting extratumoral MVI was created using 637 patients, excluding 44 patients with macrovascular invasion, and was validated using an internal (n = 273) and external patient cohort (n = 256). RESULTS: The 681 patients were classified into four groups based on pathological examination (148 no VI, 33 intratumoral MVI, 84 extratumoral MVI, and 29 macrovascular invasion in patients who underwent HR; 238 no VI, 50 intratumoral MVI, 84 extratumoral MVI, and 15 macrovascular invasion in patients who underwent LT). Multivariate analysis revealed that extratumoral MVI was an independent risk factor for overall survival in patients who underwent HR (hazard ratio 2.62, p < 0.0001) or LT (hazard ratio 1.99, p = 0.0005). Multivariate logistic regression analysis identified six independent risk factors for extratumoral MVI: α-fetoprotein, tumor size, non-boundary type, alkaline phosphatase, neutrophil-to-lymphocyte ratio, and aspartate aminotransferase. The nomogram for predicting extratumoral MVI using these factors showed good concordance indices of 0.774 and 0.744 in the internal and external validation cohorts, respectively. CONCLUSIONS: The prognostic value of MVI differs according to its invasiveness. The nomogram allows reliable prediction of extratumoral MVI in patients undergoing HR or LT.

Potential of a cure in patients with colorectal liver metastases and concomitant extrahepatic disease.

BACKGROUND AND OBJECTIVES: We aimed to define the cure rate in patients with colorectal liver metastases (CRLM) and concomitant extrahepatic disease (EHD) on the 5-year disease-free survival (DFS) after surgery, and identify the factors for predicting a cure. METHODS: Patients who underwent hepatectomy for CRLM with concomitant EHD were identified. Those followed for >5 years after surgery were enrolled. A cure was defined as DFS of >5 years after the last curative surgery. RESULTS: A cure was achieved in 24/175 (13%) patients (intention-to-treat [ITT] cohort), and 22/109 (19%) patients who underwent complete resection for both hepatic and extrahepatic metastases (EHD resection cohort). A multivariate analysis identified primary T1-2 (relative risk [RR] 47.4, P = 0.0001), metachronous metastasis (RR 4.9, P = 0.026), carbohydrate antigen 19-9 (CA19-9) ≤37 U/mL (RR 8.37, P = 0.015), number of liver and EHD tumors (RR 11.2, P = 0.0058), and non-incidental EHD diagnosis (RR 8.41, P = 0.018) as independent factors that predicted a cure in the ITT cohort; and primary T1-2 (RR 22.2, P = 0.013), primary N0 (RR 4.42, P = 0.031), metachronous metastasis (RR 6.48, P = 0.013), and CA19-9 ≤37 U/mL (RR 27.4, P = 0.012) in the EHD resection cohort. CONCLUSIONS: Even when concomitant EHD is present, a potential of cure could be achieved with aggressive oncosurgical approach.

Salvage Versus Primary Liver Transplantation for Early Hepatocellular Carcinoma: Do Both Strategies Yield Similar Outcomes?

BACKGROUND DATA: In compensated cirrhotics with early hepatocellular carcinoma (HCC-cirr), upfront liver resection (LR) and salvage liver transplantation (SLT) in case of recurrence may have outcomes comparable to primary LT (PLT). OBJECTIVE: An intention-to-treat (ITT) analysis comparing PLT and SLT strategies. METHODS: Of 130 HCC-cirr patients who underwent upfront LR (group LR), 90 (69%) recurred, 31 could undergo SLT (group SLT). During the same period, 366 patients were listed for LT (group LLT); 26 dropped-out (7.1%), 340 finally underwent PLT (group PLT). We compared survival between groups LR and LLT, LR and PLT, and PLT and SLT. RESULTS: Feasibility of SLT strategy was 34% (31/90). In an ITT analysis, group LLT had better 5-yr/10-yr overall survival (OS) compared with group LR (68%/58% vs. 58%/35%; P = 0.008). Similarly, 5-yr/10-yr OS and disease-free survival (DFS) were better in group PLT versus group LR (OS 73%/63% vs. 58%/35%, P = 0.0007; DFS 69%/61% vs. 27%/21%, P < 0.0001). Upfront resection and microvascular tumor invasion were poor prognostic factors for both OS and DFS, presence of satellite tumor nodules additionally predicted worse DFS. Group SLT had similar postoperative and long-term outcomes compared with group PLT (starting from time of LT) (OS 54%/54% vs. 73%/63%, P = 0.35; DFS 48%/48% vs. 69%/61%, P = 0.18, respectively). CONCLUSIONS: In initially transplantable HCC-cirr patients, ITT survival was better in group PLT compared with group LR. SLT was feasible in only a third of patients who recurred after LR. Post SLT, short and long-term outcomes were comparable with PLT. Better patient selection for the "resection first" approach and early detection of recurrence may improve outcomes of the SLT strategy.

Early Recurrence After Hepatectomy for Colorectal Liver Metastases: What Optimal Definition and What Predictive Factors?

BACKGROUND: The purpose of this study was to determine the optimal definition and elucidate the predictive factors of early recurrence after surgery for colorectal liver metastases (CRLM). METHODS: Among 987 patients who underwent curative surgery for CRLM from 1990 to 2012, 846 with a minimum follow-up period of 24 months were eligible for this study. The minimum p value approach of survival after initial recurrence was used to determine the optimal cutoff for the definition of early recurrence. The predictive factors of early recurrence and prognostic factors of survival were analyzed. RESULTS: For 667 patients (79%) who developed recurrence, the optimal cutoff point of early recurrence was determined to be 8 months after surgery. The impact of early recurrence on survival was demonstrated mainly in patients who received preoperative chemotherapy. Among the 691 patients who received preoperative chemotherapy, recurrence was observed in 562 (81%), and survival in patients with early recurrence was significantly worse than in those with late recurrence (5-year survival 18.5% vs. 53.4%, p < .0001). Multivariate logistic analysis identified age ≤57 years (p = .0022), >1 chemotherapy line (p = .03), disease progression during last-line chemotherapy (p = .024), >3 tumors (p = .0014), and carbohydrate antigen 19-9 >60 U/mL (p = .0003) as independent predictors of early recurrence. Salvage surgery for recurrence significantly improved survival, even in patients with early recurrence. CONCLUSION: The optimal cutoff point of early recurrence was determined to be 8 months. The preoperative prediction of early recurrence is possible and crucial for designing effective perioperative chemotherapy regimens. IMPLICATIONS FOR PRACTICE: In this study, the optimal cutoff point of early recurrence was determined to be 8 months after surgery based on the minimum p value approach, and its prognostic impact was demonstrated mainly in patients who received preoperative chemotherapy. Five factors, including age, number of preoperative chemotherapy lines, response to last-line chemotherapy, number of tumors, and carbohydrate antigen 19-9 concentrations, were identified as predictors of early recurrence. Salvage surgery for recurrence significantly improved survival, even in patients with early recurrence. For better selection of patients who could truly benefit from surgery and should also receive strong postoperative chemotherapy, the accurate preoperative prediction of early recurrence is crucial.

Does pathological response after transarterial chemoembolization for hepatocellular carcinoma in cirrhotic patients with cirrhosis predict outcome after liver resection or transplantation?

BACKGROUND & AIMS: To investigate the prognostic significance of pathologic response (PR) after transarterial chemoembolization (TACE) in cirrhotic patients resected or transplanted for hepatocellular carcinoma (HCC), and to identify predictors of complete pathologic response (CPR). METHODS: Between 1990 and 2010, 373 consecutive cirrhotic patients with HCC were treated by TACE followed by either liver resection (LR:184 patients) or liver transplantation (LT:189 patients). The PR was evaluated as the mean percentage of non-viable tumor area within each tumor. CPR was defined as the absence of any viable tumor area in all the present nodules. RESULTS: A total of 59 (32%) and 37 (20%) patients had CPR after LR and LT, respectively. Five-year overall survival (OS) was higher in patients with CPR compared to those without, after LR (58% vs. 34%; p=0.0006) and tends to be higher after LT (84% vs. 65%; p=0.09). The 5-year recurrence-free survival (RFS) rates were significantly higher in both groups (24% vs. 13% after LR; p=0.008 and 94% vs. 73% after LT, p=0.007). A cut-off value of >90% necrosis emerged as an impacting factor on patient survival after LR or LT. On multivariate analysis stratified on the type of procedure (LR or LT), PR >90% remained an independent factor of better OS and RFS. Independent factors associated with CPR were: a maximal tumor size <30 mm (RR 2.17 [1.27-3.74]), a single tumor (RR 6.08 [3.29-12.07]), and an preoperative AFP<100 ng/ml (see results section) (RR 3.99 [1.63-11.98]). The probability to achieve a CPR ranged from 2% in the absence of any factors to 48% in the presence of all factors. CONCLUSION: In cirrhotic patients with HCC, a complete or nearly complete PR improves long-term survival after LR and LT independently of other pathological factors. This underlines the importance of neoadjuvant treatment to obtain a significant decrease of active tumor load.

Effects of Art on Surgical Patients: A Systematic Review and Meta-analysis.

OBJECTIVES: The aim of the study was to assess the effect of art including ambient features such as music, interior design including visual art, and architectural features on health outcomes in surgical patients. BACKGROUND: Healing environments can have a positive influence on many patients, but data focusing on art in surgical patients remain scarce. METHODS: We conducted a systematic search following the PRISMA guidelines from January 2000 to October 2014 on art in surgical patients. For music interventions, we pooled controlled studies measuring health outcomes (eg, pain, anxiety, blood pressure, and heart rate) in a meta-analysis. For other art forms (ambient and architectural features and interior design), we did a narrative review, also including nonsurgical patients, and looked for examples covering 3 countries. RESULTS: Our search identified 1101 hits with 48 studies focusing on art in surgical patients: 47 studies on musical intervention and 1 on sunlight. The meta-analysis of these studies disclosed significant effects for music on pain after surgery, anxiety, systolic blood pressure, and heart rate, when compared with control groups without music. Effects of music were larger with self-selected music, and lower in surgical interventions performed under general anesthesia. Interior design features such as nature images and more spacious rooms, and architectural features providing more sunlight had positive effects on anxiety and postoperative pain. CONCLUSIONS: Self-selected music for surgical patients is an effective and low-cost intervention to enhance well being and possibly faster recovery. Although potentially very important, the impact of environmental features and spacious architecture with wide access to sunlight remains poorly explored in surgery. Further experimental research is needed to better assess the magnitude of the impact and cost effectiveness.

Failure to Achieve a 2-Stage Hepatectomy for Colorectal Liver Metastases: How to Prevent It?

OBJECTIVES: The aim of the study was to identify predictive factors of failure of 2-stage hepatectomy (TSH) for the selection of patients with extensive bilobar colorectal liver metastases (CRLM), who are candidates for TSH. BACKGROUND: The main weakness of TSH is the risk of failure to complete both the sequential procedures. METHODS: Between 2000 and 2012, from a total cohort of 845 patients resected for CRLM, 125 patients (14.8%) with extensive CRLM were planned for TSH. All factors related to the failure of TSH were analyzed, and a predictive model was built utilizing the independent predictive factors of failure. RESULTS: Forty-four patients (35.2%) could not proceed to the second stage, and their overall survival (OS) was significantly worse than that of those who completed the TSH (5-year OS: 0% vs 44.2%; P < 0.0001). Multivariate analysis revealed that carcinoembryonic antigen >30 ng/mL [relative risk (RR) 2.73, P = 0.03], tumor size >40 mm (RR 2.89, P = 0.04), chemotherapy cycles >12 (RR 3.46, P = 0.01), and tumor progression during first-line chemotherapy (RR 6.56, P = 0.01) were independent predictive factors of failure. For patients not presenting any factors, the probability of failure was 10.5%, with a 5-year OS rate of 41.9%. The addition of each subsequent factor increased the risk to 43.5%, 72.7%, 88.5%, and 95.5%, and decreased the 5-year OS to 38.8%, 29.2%, 0%, and 0%, respectively, for 1, 2, 3, and 4 factors. CONCLUSIONS: TSH should not be recommended in patients with more than 2 risk factors. Avoidance of these factors significantly reduces the risk of failure and is crucial for long-term survival.

Risk factors associated with outcome in liver retransplantation: multicentric study.

BACKGROUND/AIMS: To externally validate the predictive mathematical model of survival designed by Linhares et al. (2006). METHODOLOGY: This retrospective study was conducted on 217 individuals submitted to liver retransplantation from January 2000 to December 2008 in four European centers. The following variables were obtained on the recipient: age, creatinine, urgency of retransplantation and time between transplantation and retransplantation. The Kaplan-Meier survival curve and ROC curve were used to validate the mathematical model. RESULTS: The present results showed a similar pattern of survival compared to the study of Linhares et al. (2006) concerning the biological variations, when survival curves were compared for each of the four variables analyzed between both samples. When compared, the areas below the ROC curve (aROC) of derivation (0.733) and validation samples (0.593) presented significant difference (p = 0.005), revealing low relationship of sensitivity and specificity between the two curves. Similarity was observed in Kaplan-Meier survival curves. CONCLUSION: This study allowed external validation by the Kaplan-Meier survival curves of the predictive mathematical model of survival in liver retransplantation proposed by Linhares et al. (2006). However, validation through the ROC curve, the aROC, evidenced weak discrimination ability.

Revisiting liver anatomy and terminology of hepatectomies.

BACKGROUND: Since the development of liver surgery, several descriptions of liver anatomical division and hepatectomies have been made, causing some confusion among surgeons. METHODS: The initial anatomical description according to Couinaud is reviewed and corrected taking into account the descriptions made in the following decades. RESULTS: It seems that by reviewing the description of the different authors, a precise anatomical division of the liver may be achieved and a simple terminology of hepatectomies may be proposed. CONCLUSIONS: It is hoped that the proposal of this anatomical description and this terminology of hepatectomies may find a consensus among the liver surgical community from America, Asia, and Europe.

Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver.

OBJECTIVES: To evaluate the predictive value of portal vein pressure (PVP) after major liver resection for posthepatectomy liver failure (PLF) and 90-day mortality in patients without cirrhosis. BACKGROUND: As elevated PVP is associated with liver failure after living donor liver transplantation, we hypothesized that the outcome after major hepatectomy may be influenced by posthepatectomy PVP. PATIENTS AND METHODS: All patients without severe fibrosis or cirrhosis who underwent a major liver resection (≥3 segments) with an intraoperative measurement of PVP at the end of the procedure were included. Outcome was analyzed regarding 3 most widely used definitions of PLF: "50-50" criteria, peak of serum bilirubin greater than 120 µmol/L, and grade C PLF proposed by the International Study Group of Liver Surgery (ISGLS). Receiver operating characteristic curves and logistic regression model were used to determine the optimal cutoff of PVP and independent risk factors of PLF. RESULTS: The study population consisted of 277 patients. Posthepatectomy PVP was gradually correlated with the PLF risk. Probability for PLF was nil when PVP was 10 mm Hg or less, ranges from 13% to 16%, depending on PLF definitions, when PVP was 20 mm Hg, and from 24% to 33% when PVP was 30 mm Hg. The optimal value of posthepatectomy PVP to predict PLF was 22 mm Hg when considering the "50-50" criteria and grade C PLF (proposed by the International Study Group of Liver Surgery). A value of 21 mm Hg best predicted PLF defined by peak of serum bilirubin greater than 120 µmol/L and 90-day mortality. At multivariate analysis, posthepatectomy PVP remained an independent predictor of PLF as well as the extent of resection, intraoperative transfusion, and the presence of diabetes. The 90-day mortality was associated with PVP greater than 21 mm Hg, older than 70 years, and intraoperative transfusion. CONCLUSIONS: Posthepatectomy PVP is an independent predictive factor of PLF and of 90-day mortality after major liver resection in patients without cirrhosis. Intraoperative modulation of PVP would be advisable when PVP exceeds 20 mm Hg.

Liver re-transplantation: internal validation of a predictive mathematical model of survival.

BACKGROUND/AIMS: Because of the worse results from re-transplantation, a model for determining the long-term survival has been previously developed. Its effectiveness had to be tested and validated, as proposed in this study, using a different sample population than the one used to build it. METHODOLOGY: Age, recipient creatinine, urgency of re-transplantation, interval between primary liver transplant and re-transplantation (RETx) of 92 patients that received first liver RETx, from a different sample of patients, in a different time period than those used to develop the initial model. The proposed mathematical model was used to predict survival at six months after undergoing liver RETx. We compared the areas under the ROC curves (AROC) corresponding to the two independent samples (derivation and validation samples). By the log-rank technique, the survival curves were also compared and classified into tertiles according to the risk scores of the original model: high risk (>32), medium risk (24-32) and low risk (<24). RESULTS: Age, creatinine, time between primary liver transplant and re-transplantation and the urgency with which patients were enrolled, had comparable survival curves among the derivation and validation samples. When comparing the AROC of the derivation (0.733) and validation (0.741) samples, there was no statistically significant difference (p=0.915), therefore sensitivity and specificity ratios between the two are similar. CONCLUSIONS: This study made it possible to internally validate the original model for predicting survival at six months after undergoing liver RETx, although an external validation still needs to be done.

Fate of the peer review process at the ESA: long-term outcome of submitted studies over a 5-year period.

OBJECTIVE: To critically evaluate the outcome of the peer review process of the European Surgical Association (ESA) and its contribution to Annals of Surgery. BACKGROUND: The ESA was created in 1993 as an equivalent of the well-established American Surgical Association. Submitted abstracts and manuscripts were subjected to a stringent multistep peer review process to offer only the best studies for publication in the special issue of Annals of Surgery. A critical evaluation was felt necessary to identify factors that favored the acceptance of abstracts and manuscripts, respectively. The citations of the manuscripts published in Annals of Surgery and the outcome of the rejected studies were also researched. METHODS: All submissions to the ESA between 2002 and 2007 were analyzed and followed over a period of 2 years. A database was established to identify factors favoring acceptance. A comprehensive search was undertaken to identify plagiarisms and the 2-year citations of all accepted manuscripts and later publications of the rejected studies in Annals of Surgery or elsewhere. RESULTS: Altogether, 545 abstracts were submitted to the ESA during the study period. About one-third was accepted for presentation at the annual meeting, and, of those, 40% were published in Annals of Surgery. The majority of these studies originated from 4 European Countries. The only independent factors favoring presentation were randomized controlled trials and a sample size of more than 100 patients. All plagiarisms were identified before acceptance. Only 4% and 2% of the rejected abstracts and manuscripts, respectively, were published in higher impact factor journals than in Annals of Surgery. Twelve percent of the rejected manuscripts were eventually published in a later issue of Annals of Surgery, whereas more than two-thirds of the rejected studies appeared in a journal with a lower impact factor. The 2-year citations of the ESA manuscripts were in the range of all the other types of manuscripts published in Annals of Surgery. Only manuscripts originating from the American Surgical Association had slightly higher citations. CONCLUSIONS: The ESA successfully spent its early years, providing high-quality manuscripts to Annals of Surgery. Only few rejected manuscripts reached higher-ranked journals. The focus should now turn toward stimulating other European countries to submit their best studies and attract more well-designed randomized controlled trials.