The Role of Liver Transplantation in the Treatment of Liver Metastases from Neuroendocrine Tumors.

OPINION STATEMENT: Transplant oncology is a new field of medicine referred to the use of solid organ transplantation, particularly the liver, to improve prognosis and quality of life in cancer patients. In unresectable, liver-only metastases from neuroendocrine tumors (NETs) of the digestive tract, liver transplantation represents a competitive chance of cure. Due to the limited resource of donated organs, accurate patients' selection is crucial in order to maximize transplant benefit. Several tumor- and patient-related factors should be considered. Among them, primary tumors with a low grade of differentiation (G1-G2 or Ki67 < 10%), located in a region drained by the portal system and removed before transplantation with at least 3-6 months period of disease stability observed before transplant listing, can be considered for transplantation. In case of NET located in the pancreas, extended lymphadenectomy should complement curative pancreatic resection. A number of other features are described in this review of liver transplantation for NET metastases. Comprehensive approach including various forms of non-surgical treatment and detailed planning and timing of total hepatectomy are discussed. Open issues remain on possible expansion of current criteria while maintaining the same long-term benefit demonstrated with the Milan NET criteria with respect to other non-transplant options, with particular reference to liver resection, peptide receptor radionuclide therapy, and locoregional and systemic treatments.

Surgical Treatment of Hepatocellular Carcinoma: Multicenter Competing-risk Analysis of Tumor-related Death Following Liver Resection and Transplantation Under an Intention-to-treat Perspective.

BACKGROUND: Early-stage hepatocellular carcinoma could benefit from upfront liver resection (LR) or liver transplantation (LT), but the optimal strategy in terms of tumor-related outcomes is still debated. We compared the oncological outcomes of LR and LT for hepatocellular carcinoma, stratifying the study population into a low-, intermediate-, and high-risk class according to the risk of death at 5-y predicted by a previously developed prognostic model. The impact of tumor pathology on oncological outcomes of low- and intermediate-risk patients undergoing LR was investigated as a secondary outcome. METHODS: We performed a retrospective multicentric cohort study involving 2640 patients consecutively treated by LR or LT from 4 tertiary hepatobiliary and transplant centers between 2005 and 2015, focusing on patients amenable to both treatments upfront. Tumor-related survival and overall survival were compared under an intention-to-treat perspective. RESULTS: We identified 468 LR and 579 LT candidates: 512 LT candidates underwent LT, whereas 68 (11.7%) dropped-out for tumor progression. Ninety-nine high-risk patients were selected from each treatment cohort after propensity score matching. Three and 5-y cumulative incidence of tumor-related death were 29.7% and 39.5% versus 17.2% and 18.3% for LR and LT group ( P = 0.039), respectively. Low-risk and intermediate-risk patients treated by LR and presenting satellite nodules and microvascular invasion had a significantly higher 5-y incidence of tumor-related death (29.2% versus 12.5%; P < 0.001). CONCLUSIONS: High-risk patients showed significantly better intention-to-treat tumor-related survival after upfront LT rather than LR. Cancer-specific survival of low- and intermediate-risk LR patients was significantly impaired by unfavorable pathology, suggesting the application of ab-initio salvage LT in such scenarios.

Liver Transplantation for Hepatic Metastases from Colorectal Cancer: Current Knowledge and Open Issues.

More than 40% of patients with colorectal cancer present liver metastases (CRLM) during the course of their disease and up to 50% present with unresectable disease. Without surgical interventions, survival for patients treated with systemic therapies alone is dismal. In the past, liver transplantation (LT) for patients with unresectable CRLM failed to show any survival benefit due to poor selection, ineffective chemotherapeutic regimens, unbalanced immunosuppression and high perioperative mortality. Since then and for many years LT for CRLM was abandoned. The turning point occurred in 2013, when the results from the Secondary Cancer (SECA I) pilot study performed at Oslo University were published reporting a 60% 5-year overall survival after LT in patients with unresectable CRLM. These results effectively reignited the interest in LT as a potential therapy for CRLM, and several trials are undergoing. The aims of this article are to give a comprehensive overview of the available evidence on LT for CRLM, discuss the open issues in this rapidly evolving field, and highlight possible ways to address the future of this fascinating therapeutic alternative for selected patients with CRLM.

Safety and Efficacy of Robotic vs Open Liver Resection for Hepatocellular Carcinoma.

Importance: Long-term oncologic outcomes of robotic surgery remain a hotly debated topic in surgical oncology, but sparse data have been published thus far. Objective: To analyze short- and long-term outcomes of robotic liver resection (RLR) for hepatocellular carcinoma (HCC) from Western high-volume centers to assess the safety, reproducibility, and oncologic efficacy of this technique. Design, Setting, and Participants: This cohort study evaluated the outcomes of patients receiving RLR vs open liver resection (OLR) for HCC between 2010 and 2020 in 5 high-volume centers. After 1:1 propensity score matching, a group of patients who underwent RLR was compared with a validation cohort of OLR patients from a high-volume center that did not perform RLR. Main Outcomes and Measures: A retrospective analysis was performed of prospectively maintained databases at 2 European and 2 US institutions of patients who underwent RLR for HCC between January 1, 2010, and September 30, 2020. The main outcomes were safety and feasibility of RLR for HCC and its oncologic outcomes compared with a European OLR validation cohort. A 2-sided P < .05 was considered significant. Results: The study included 398 patients (RLR group: 125 men, 33 women, median [IQR] age, 66 [58-71] years; OLR group: 315 men, 83 women; median [IQR] age, 70 [64-74] years), and 106 RLR patients were compared with 106 OLR patients after propensity score matching. The RLR patients had a significantly longer operative time (median [IQR], 295 [190-370] minutes vs 200 [165-255] minutes, including docking; P < .001) but a significantly shorter hospital length of stay (median [IQR], 4 [3-6] days vs 10 [7-13] days; P < .001) and a lower number of admissions to the intensive care unit (7 [6.6%] vs 21 [19.8%]; P = .002). Incidence of posthepatectomy liver failure was significantly lower in the RLR group (8 [7.5%] vs 30 [28.3%]; P = .001), with no cases of grade C failure. The 90-day overall survival rate was comparable between the 2 groups (RLR, 99.1% [95% CI, 93.5%-99.9%]; OLR, 97.1% [95% CI, 91.3%-99.1%]), as was the cumulative incidence of death related to tumor recurrence (RLR, 8.8% [95% CI, 3.1%-18.3%]; OLR, 10.2% [95% CI, 4.9%-17.7%]). Conclusions and Relevance: This study represents the largest Western experience to date of full RLR for HCC. Compared with OLR, RLR performed in tertiary centers represents a safe treatment strategy for patients with HCC and those with compromised liver function while achieving oncologic efficacy.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

Therapeutic strategies for post-transplant recurrence of hepatocellular carcinoma.

Despite stringent selection criteria, hepatocellular carcinoma recurrence after liver transplantation (LT) still occurs in up to 20% of cases, mostly within the first 2-3 years. No adjuvant treatments to prevent such an occurrence have been developed so far. However, a balanced use of immunosuppression with minimal dose of calcineurin inhibitors and possible addition of mammalian target of rapamycin inhibitors is strongly advisable. Moreover, several pre- and post-transplant predictors of recurrence have been identified and may help determine the frequency and duration of post-transplant follow-up. When recurrence occurs, the outcomes are poor with a median survival of 12 mo according to most retrospective studies. The factor that most impacts survival after recurrence is timing (within 1-2 years from LT according to different authors). Several therapeutic options may be chosen in case of recurrence, according to timing and disease presentation. Surgical treatment seems to provide a survival benefit, especially in case of late recurrence, while the benefit of locoregional treatments has been suggested only in small retrospective studies. When systemic treatment is indicated, sorafenib has been proved safe and effective, while only few data are available for lenvatinib and regorafenib in second line. The use of immune checkpoint inhibitors is controversial in this setting, given the safety warnings for the risk of acute rejection.

Long-term outcomes of resection versus transplantation for neuroendocrine liver metastases meeting the Milan criteria.

Liver resection (LR) is considered the treatment of choice for resectable neuroendocrine liver metastases (NELM), while liver transplantation (LT) is currently reserved for highly selected unresectable patients. We retrospectively analyzed data from consecutive patients undergoing either curative resection or transplantation for liver-only NELM meeting Milan criteria at a single center between 1984 and 2019. Patients who fit Milan criteria were 48 in the transplantation group and 56 in the resection group. After a median follow-up of 158 months for the transplantation group and 126 for the resection group, the 10-year survival rate was 93% for transplantation and 75% for resection (p = .007). The 10-year disease-free survival rate was 52% for transplantation and 18% for resection (p < .001). Transplantation was associated with improved survival at univariate analysis. The median disease-free interval between surgery and recurrence was 78 months for transplantation vs. 24 months for resection (p < .001). The transplantation group had more multisite recurrences (12/25, 48% vs. 5/42, 12% in the resection group, p = .001), while most recurrences in the resection group were intra-hepatic (37/42, 88%, versus 2/25, 8% in the transplantation group). In conclusion, LT was associated with improved survival outcomes in NELM meeting the Milan criteria compared with LR.

The role of lymphadenectomy in the surgical treatment of intrahepatic cholangiocarcinoma: A review.

Cholangiocarcinoma is the second most common primary tumor of the liver. The incidence and mortality of its intrahepatic form has been increasing over the past 2 decades. Currently, the only available curative treatment for intrahepatic cholangiocarcinoma is surgical resection. There is still no prospective evidence to support neoadjuvant systemic treatments in resectable disease, while adjuvant chemotherapy with Capecitabine is currently the only recommended systemic treatment after liver resection based on the results of randomised trial. Despite the implementation of perioperative treatments and improvements in resective surgery, intrahepatic cholangiocarcinoma remains a disease characterized by high incidence of recurrence and poor long-term survival. Lymph node metastases can be found in 45-65% of patients and are one of the most impacting prognostic factors after surgical resection. Preoperative imaging is not always sufficient in assessing lymph node status, thus hepatic pedicle lymphadenectomy can be important to ensure precise staging in surgical patients. An increasing trend in performing lymph node dissection during liver resection for intrahepatic cholangiocarcinoma has been observed in the last 20 years, although its actual efficacy compared to the potential complications remains debated. The current evidence on the prognostic role of the lymph node status, its preoperative predictability, the basis for a correct hepatic pedicle lymphadenectomy and its prognostic role in the surgical treatment of intrahepatic cholangiocarcinoma are presented.

Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies.

Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to gastroesophageal reflux disease, recurrent peptic ulcers, and chronic diarrhea. As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders, the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years. The critical step for the diagnosis of ZES is represented by the initial clinical suspicion. Hypergastrinemia is the hallmark of ZES; however, hypergastrinemia might recognize several causes, which should be ruled out in order to make a final diagnosis. Gastrin levels > 1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma; some specific tests, including esophageal pH-recording and secretin test, might be useful in selected cases, although they are not widely available. Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES, particularly in the setting of multiple endocrine neoplasia type 1. Some controversies about the management of these tumors also exist. For the localized stage, the combination of proton pump inhibitory therapy, which usually resolves symptoms, and surgery, whenever feasible, with curative intent represents the hallmark of gastrinoma treatment. The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure. Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms, and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series. The multidisciplinary approach remains the cornerstone for the proper management of this composite disease. Herein, we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis, providing potential diagnostic and therapeutic algorithms.

Improved management of grade B biliary leaks after complex liver resections using gadoxetic acid disodium-enhanced magnetic resonance cholangiography.

BACKGROUND: Bile leaks occurring after complex liver resection and lasting >1 week (grade B) usually are managed by means of invasive cholangiography either endoscopic or percutaneous, with a substantial risk of procedure-related complications. The aim of this study was to investigate the ability of gadoxetic acid disodium-enhanced magnetic resonance cholangiography to detect postoperative biliary leaks and avoid invasive cholangiography in case of peripheral location of the fistula. METHODS: Patients with grade B biliary leak after complex liver resection from January 2018 to March 2020 underwent magnetic resonance cholangiography to guide the management of the leak (study group). The primary endpoint was the ability of magnetic resonance cholangiography to reduce the need for invasive cholangiography with respect to similar posthepatectomy leaks collected in the previous 2 years and approached with upfront invasive cholangiography (controls). A series of in-hospital outcomes also were compared. RESULTS: Out of 533 liver resections, 11 study patients versus 11 control patients with grade B leaks were compared. Magnetic resonance cholangiography achieved 100% accuracy in detection and location of the leak. Five out of 6 peripheral leaks healed without invasive cholangiography. Overall, 50% reduction in the use of invasive cholangiography was observed in the study versus control patients. Median healing time and hospital stay were 38 and 40 days in patients undergoing invasive cholangiography versus 10 and 11 days in patients treated conservatively (P = .007 and 0.012, respectively). Infection rate and other complications rate were 82% vs 20% (P = .01) and 35% vs 40% (P = .5), respectively. CONCLUSION: Magnetic resonance cholangiography is a safe, precise, noninvasive tool to detect posthepatectomy bile leaks that can help clinicians in decision-making on conservative versus invasive treatment of fistulas.

No benefit after neoadjuvant chemoradiation in stage IV rectal cancer: A propensity score-matched analysis on a real-world population.

BACKGROUND: Stage IV rectal cancer occurs in 25% of patients and locoregional control of primary tumor is usually poorly considered, since priority is the treatment of metastatic disease. AIMS: This study evaluates impact of neoadjuvant chemoradiation followed by surgery (nCHRTS) vs. upfront surgery on locoregional control and overall survival in stage IV rectal cancer. METHODS: All patients diagnosed with stage IV rectal carcinoma between 2009 and 2019, undergone elective surgery at the National Cancer Institute of Milan (Italy), were included. Propensity score-based matching was performed between the two study groups. Loco-regional recurrence-free survival (LRRFS) and overall survival (OS) were analysed using Kaplan-Meyer method. RESULTS: A total of 139 patients were analyzed. After propensity score matching, 88 patients were included in the final analysis. The 3-yr LRRFS rates were 80.3% for nCHRTS vs. 90.4% for upfront surgery patients (p = 0.35). The 3-yr OS rates were respectively 81.8% vs. 58% (p = 0.36). KRAS mutation (HR 2.506, p = 0.038) and extra-liver metastases (HR 4.308, p = 0.003) were both predictive of worse OS in univariate analysis. CONCLUSION: The present study failed to demonstrate a significant impact of nCHRTS on LRRFS or OS in stage IV rectal cancer.

Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial.

BACKGROUND: Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. METHODS: We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18-65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503. FINDINGS: Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4-11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60-85). 5-year tumour event-free survival was 76·8% (95% CI 60·8-96·9) in the transplantation group versus 18·3% (7·1-47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07-0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9-97·1) in the transplantation group versus 31·2% (16·6-58·5) in the control group (HR 0·32, 95% CI 0·11-0·92; p=0·035). The most common registered grade 3-4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). INTERPRETATION: Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. FUNDING: Italian Ministry of Health.

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study.

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017-2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.

pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma.

Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies.

The role of wireless capsule endoscopy (WCE) in the detection of occult primary neuroendocrine tumors.

BACKGROUND AND AIMS: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with unclear etiology that may show functioning or non-functioning features. Primary tumor localization often requires integrated imaging. The European Neuroendocrine Tumors Society (ENETS) guidelines proposed wireless-capsule endoscopy (WCE) as a possible diagnostic tool for NETs, if intestinal origin is suspected. However, its impact on therapeutic management is debated. We aimed to evaluate the yield of WCE in detecting intestinal primary tumors in patients showing liver NET metastases when first-line investigations are inconclusive. METHOD: Twenty-four patients with a histological diagnosis of metastatic NET from liver biopsy and no evidence of primary lesions at first-line investigations were prospectively studied in an ENETS-certified tertiary care center. Wireless-capsule endoscopy was requested before explorative laparotomy and intra-operative ultrasound. The diagnostic yield of WCE was compared to the surgical exploration. RESULTS: Sixteen subjects underwent surgery; 11/16 had positive WCE identifying 16 bulging lesions. Mini-laparotomy found 13 NETs in 11/16 patients (9 small bowel, 3 pancreas, 1 bile ducts). Agreement between WCE and laparotomy was recorded in 9 patients (Sensitivity=75%; Specificity=37.5%; PPV=55%; NPV=60%). Correspondence assessed per-lesions produced similar results (Sensitivity=70%; Specificity=25%; PPV=44%; NPV=50%). No capsule retentions were recorded. CONCLUSIONS: Wireless-capsule endoscopy is not indicated as second-line investigation for patients with gastro-entero-pancreatic NETs. In the setting of a referral center, it might provide additional information when conventional investigations are inconclusive about the primary site.

Competing risk analysis on outcome after hepatic resection of hepatocellular carcinoma in cirrhotic patients.

AIM: To investigate death for liver failure and for tumor recurrence as competing events after hepatectomy of hepatocellular carcinoma. METHODS: Data from 864 cirrhotic Child-Pugh class A consecutive patients, submitted to curative hepatectomy (1997-2013) at two tertiary referral hospitals, were used for competing-risk analysis through the Fine and Gray method, aimed at assessing in which circumstances the oncological benefit from tumour removal is greater than the risk of dying from hepatic decompensation. To accomplish this task, the average risk of these two competing events, over 5 years of follow-up, was calculated through the integral of each cumulative incidence function, and represented the main comparison parameter. RESULTS: Within a median follow-up of 5.6 years, death was attributable to tumor recurrence in 63.5%, and to liver failure in 21.2% of cases. In the first 16 mo, the risk of dying due to liver failure exceeded that of dying due to tumor relapse. Tumor stage only affects death from recurrence; whereas hepatitis C infection, Model for End-stage Liver Disease score, extent of hepatectomy and portal hypertension influence death from liver failure (P < 0.05 in all cases). The combination of these clinical and tumoral features identifies those patients in whom the risk of dying from liver failure did not exceed the tumour-related mortality, representing optimal surgical candidates. It also identifies those clinical circumstances where the oncological benefit would be borderline or even where the surgery would be harmful. CONCLUSION: Having knowledge of these competing events can be used to weigh the risks and benefits of hepatic resection in each clinical circumstance, separating optimal from non-optimal surgical candidates.

The place of liver transplantation in the treatment of hepatic metastases from neuroendocrine tumors: Pros and cons.

Liver metastases occur in nearly half of NET patients (MNETs) and heavily affect prognosis, with 5-yr. OS around 19-38%. Although it is difficult to show outcome differences for available treatments, due to the long course of disease, surgery for MNETs remains the most effective option in terms of survival and symptom control. Since MNETs frequently present as an oligo-metastatic, liver-limited disease, unresectable in 80% of cases, liver transplantation (LT) has emerged as a potential curative treatment. Nevertheless, experience with LT for MNETs is limited and burdened by highly heterogeneous outcomes and significant recurrence rate, mostly explained by the variability of selection criteria. Several prognostic factors have been identified: extended surgery on primary tumor associated to LT, elderly patients, pancreatic primary (pNET), extensive liver involvement, poorly differentiated tumors, high Ki67 levels and short wait time to LT. A proper patients' selection based on these data (Milan NET criteria) allows a significant survival advantage over non-transplant strategies, with excellent outcomes in recent series (69-97.2% 5-yr. OS) as opposed to patients undergoing non-surgical treatments (34-50.9%). Evidence indicates LT as the best option for selected patients with MNETs. The use of organs for MNETs is therefore justified.

Hierarchic Interaction of Factors Associated With Liver Decompensation After Resection for Hepatocellular Carcinoma.

IMPORTANCE: Liver resection is the treatment of choice for hepatocellular carcinoma (HCC) in well-compensated liver cirrhosis. Postoperative liver decompensation (LD) is the most representative and least predictable cause of morbidity and mortality. OBJECTIVES: To determine the hierarchy and interaction of factors associated with the risk for LD and to define applicable risk classes among surgical candidates. DESIGN, SETTING, AND PARTICIPANTS: This retrospective review collected data from 543 patients with chronic liver disease who underwent hepatic resection for HCC from January 1, 2000, through December 31, 2013, in a tertiary comprehensive cancer center. Final follow-up was completed on January 31, 2015, and data were assessed from February 1 to 28, 2015. MAJOR OUTCOMES AND MEASURES: Preoperative prognostic factors and risk stratification for postoperative LD. Multivariate logistic regression was performed, and the independent risk factors for LD were included in a recursive partitioning analysis model. Results were validated by means of 10-fold cross-validation. RESULTS: The analysis included 543 patients, of whom 411 (75.7%) were male, 132 (24.3%) were female, and the median age was 68 (interquartile range, 62-73) years. An independent association with LD was found for major hepatectomy (odds ratio [OR], 2.41; 95% CI, 1.17-4.30; P = .01), portal hypertension (OR, 2.20; 95% CI, 1.13-4.30; P = .01), and Model for End-Stage Liver Disease (MELD) score greater than 9 (OR, 2.26; 95% CI, 1.10-4.58; P = .02). Recursive partitioning analysis confirmed portal hypertension as the most important factor (OR, 2.99; 95% CI, 1.93-4.62; P < .001), followed by extension of hepatectomy with (OR, 2.76; 95% CI, 1.85-4.77; P = .03) and without (OR, 2.98; 95% CI, 1.97-4.52; P < .001) portal hypertension, and MELD score (OR, 1.79; 95% CI, 1.23-2.13; P < .001). Low-risk patients (LD rate, 4.9% [11 of 226]) without portal hypertension underwent minor resection with a MELD score of 9 or less; intermediate-risk patients (LD rate, 28.6% [85 of 297]) had no portal hypertension and underwent major resections or, in case of minor resections, had portal hypertension or a MELD score greater than 9; and high-risk patients (LD rate, 60.0% [12 of 20]) underwent major resection with portal hypertension. Risk-class progression paralleled median length of stay (7, 8, and 11 days, respectively; P < .001) and liver-related mortality (4.4% [10 of 226], 9.0% [27 of 297], and 25.0% [5 of 20], respectively; P = .001). A 10-fold cross-validation of the model resulted in a C index of 0.78 (95% CI, 0.74-0.82) and an overall error rate of 0.06. CONCLUSIONS AND RELEVANCE: The risk for postoperative LD after resection for HCC in chronic liver disease is associated with preoperative hierarchic interaction of portal hypertension, planned extension of hepatectomy, and the MELD score.