Evolution of Metastases in Space and Time under Immune Selection.

We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67+ tumor cells and CD3+ cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.

Sessile Serrated Lesion of the Appendix in a Teenage Girl.

According to the literature, serrated lesions and polyps of the appendix are extremely rare in children or teenagers. Herein, we present the pathologic and molecular features of a sessile serrated lesion (SSL) that was incidentally found in the appendix of a teenage girl. Our findings not only illustrate that appendiceal SSL may occur in young patients such as teenagers but also confirm further that BRAF V600E mutation may be found in a subset of these neoplastic lesions.

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.

BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.

Risk factors for conversion to snare resection during colorectal endoscopic submucosal dissection in an expert Western center.

BACKGROUND: There are limited data regarding the risk factors and consequences of conversion to endoscopic mucosal resection (rescue EMR) during colorectal endoscopic submucosal dissection (ESD) in Western centers. METHODS: This was a retrospective analysis of a prospectively collected database, from which 225 consecutive ESDs performed between 2013 and 2017 were selected. Of the included patients, 39 (18.6 %) required rescue EMR. Pre- and per-procedure characteristics were evaluated to determine the features associated with the need for rescue EMR. Outcomes and complications were also assessed. RESULTS: 210 patients were included, with median tumor size of 40 mm (range 20 - 110) and most tumors being in a non-rectal location (66.2 %). When compared with full ESD, rescue EMR was significantly associated with lower rates of en bloc resection (43.6 % vs. 100 %) and complete resection (R0 status; 28.2 % vs. 88.9 %), and with a higher rate of recurrence (5.1 % vs. 0 %) and more need for surgery (15.4 % vs. 3.5 %). In multivariable analysis, non-lifting (adjusted odds ratio [ORa] 3.06, 95 % confidence interval [CI] 1.23 - 7.66; P = 0.02), nongranular-type laterally spreading tumor (LST-NG; ORa 2.56, 95 %CI 1.10 - 5.99; P = 0.03), and difficult retroflexion (OR 3.22, 95 %CI 1.01 - 10.28; P = 0.049) were independent risk factors associated with conversion to rescue EMR, while tumor size and location were not. CONCLUSIONS: During ESD, the presence of poor lifting, LST-NG morphology, and a difficult retroflexed approach were factors associated with the need to convert to rescue EMR. Conversion to rescue EMR remains a valuable strategy.

[An unusual case of olmesartan induced enteropathy]. / Un cas inhabituel d'entéropathie secondaire à la prise d'olmesartan.

Olmesartan induced enteropathy was first described in 2012. It is a rare adverse effect of this antihypertensive drug. The clinical presentation commonly includes severe chronic diarrhea leading to weight loss and a variable degree of dehydration. Histological findings are most commonly observed in the duodenum and consist of partial or total villous atrophy, increased intraepithelial lymphocytes and inflammation in the lamina propria. Involvement of gastric and colic mucosa has also been described. We report on the case of a 63-year-old man, treated by olmesartan, who presented with severe chronic diarrhea. Biopsies from different levels of the gastrointestinal tract revealed a pandigestive intraepithelial lymphocytosis.

Accuracy of Pancreatic Neuroendocrine Tumour Grading by Endoscopic Ultrasound-Guided Fine Needle Aspiration: Analysis of a Large Cohort and Perspectives for Improvement.

INTRODUCTION: Since the WHO Classification of Tumours of the Digestive System has been published in 2010, resected pancreatic neuroendocrine tumours (pNETs) are graded as grade 1 (G1), grade 2 (G2) or grade 3 (G3) using the Ki67 labelling index (Ki67-LI). Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is often used for diagnosis, but few studies have assessed its value for grading. AIMS: The aims of this study were to compare the Ki67-LI obtained by cytological grading (cG) with that obtained by histological grading (hG) and to assess (1) the influence of tumour size and the number of counted cells on FNA grading as well as (2) the overall survival (OS) and progression-free survival based on cG. MATERIALS AND METHODS: EUS-FNA was performed for 102 pNETs (57 resected). cG (200 cells counted) was done on all FNAs. For 29 FNAs, >2,000 cells were counted (14 resected). A comparison was made between hG and cG for the 57 resected patients. Patients were followed up until June 2016. RESULTS: cG was consistent with hG in 39 of 57 patients with a concordance rate of 72% using a Ki67-LI cut-off of 5% for G1/G2. For Ki67-LI absolute values, the correlation was r = 0.443 and increased to r = 0.824 (p < 0.001) when only FNAs with >2,000 cells were counted. Twenty-one of 22 pNETs <2 cm had the same grading on cG and hG, whereas grading was discordant for 15 of 16 pNETs >2 cm. Thirty-eight patients died after 70.5 months of follow-up. OS for the whole cohort was 235 months and differed between cG1 (235 months), cG2 (36.3 months) and cG3 (10.9 months). CONCLUSION: cG of pNETs is more accurate when tumours measure <2 cm and more cells are counted on FNA. Discrepancies are seen between G2 tumours which are often considered G1 on FNA due to tumour heterogeneity. EUS-FNA is valuable to distinguish between patients with good (cG1) and poor (cG3) prognosis.

Clinical outcome in patients treated with endoscopic submucosal dissection for superficial Barrett's neoplasia.

BACKGROUND AND STUDY AIMS: The role of endoscopic submucosal dissection (ESD) in Barrett's neoplasia is ill-defined, although it might provide a higher curative resection rate and better histologic assessment than endoscopic mucosal resection (EMR). We aimed to assess efficacy, safety, and long-term results of ESD. PATIENTS AND METHODS: A retrospective analysis was done of 75 consecutive patients with Barrett's esophagus who underwent ESD between January 2007 and February 2014. ESD was performed for visible lesions that were multiple, larger than 15 mm, or poorly lifting, or suspected of submucosal infiltration. The primary end point was the rate of curative resection of carcinoma. RESULTS: Median patient age was 68 years (interquartile range [IQR] 61 - 76), median follow-up was 20 months (IQR 8.5 - 37.5), and median maximum specimen diameter was 52.5 mm (IQR 43 - 71). En bloc resection rate was 90 % (66 /73), and rates of curative resection of carcinoma and high grade dysplasia/carcinoma were 85 % (47 /55) and 64 % (42 /66), respectively. G3 differentiation and invasion to greater than pT1m2 were observed in 25 % (14 /55) and 67 % (37 /55) of patients with adenocarcinoma, respectively. There were 5 early ( < 48 hours) adverse events (2 delayed hemorrhages and 3 perforations), all treated endoscopically. No ESD-specific death occurred. Esophageal strictures developed in 60 % of patients, all treated endoscopically. Additional treatment (median sessions 2 [IQR 2 - 3]) for residual Barrett's esophagus were recommended to 62 % (42 /68). At latest follow-up, complete remission of neoplasia and intestinal metaplasia was found in 92 % (54 /59) and 73 % (43 /59) of patients, respectively. CONCLUSION: ESD appears to be safe and effective, with a high rate of curative resection of carcinoma. ESD should be considered for patients with Barrett's neoplasia at risk of incomplete resection or poor pathologic assessment with conventional EMR.

Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants.

BACKGROUND/AIMS: Idiopathic pancreatitis is considered to be a multigenic and multifactorial disease. Genetically determined pancreatitis is associated with mutations in the PRSS1,SPINK1 and CFTR genes. This study aimed at examining the clinical and morphological characteristics of patients diagnosed with genetically determined sporadic pancreatitis. METHODS: Inclusion criteria were the presence of PRSS1,CFTR or SPINK1 gene mutations in patients with idiopathic recurrent or chronic pancreatitis. Patients with hereditary pancreatitis were excluded. Age- and sex-matched patients with idiopathic pancreatitis and negative genetic testing served as controls (n = 68). RESULTS: Genetic testing was performed in 351 probands referred to our centre since 1999. Sixty-one patients (17.4%) carried at least 1 detected mutation in 1 of the 3 tested genes (34 CFTR, 10 PRSS1 and 13 SPINK1 mutations), and 4 patients showed a combination of mutations. Follow-up has been currently extended to a median of 5 years (range 1-40). Similar clinical features were noted in the case and matched groups except for an earlier age of onset of pancreatic symptoms and a higher incidence of pancreatic cancer in the case group and in patients with CFTR mutations compared to the control group (p < 0.05). The standardized incidence ratio, the ratio of observed to expected pancreatic cancers, averaged 26.5 (95% confidence interval 8.6-61.9). All pancreatic cancer patients were smokers. CONCLUSION: Clinical parameters of patients with sporadic idiopathic pancreatitis and gene mutations are similar to those of age- and sex-matched patients without gene mutations, except for the age of pancreatic disease onset. A significantly higher occurrence of pancreas cancer was observed in the case group, particularly in those patients carrying CFTR mutations. We therefore suggest to include patients with CFTR variants presenting with risk factors in a screening and surveillance programme and to strongly advise them to stop smoking.

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer.

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4−82.6), 88.1% (95%-CI, 85.7−90.4), 93.4% (95%-CI, 91.1−95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18−0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17−0.50); p < 0.0001) of the patient's gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01−0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial).

Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204−0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104−1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.

Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study.

BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I−III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I−III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10−4.55) p = 0.0269) of the patient's gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.

Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore.

Surgical resection of colorectal liver metastases combined with systemic treatment aims to maximize patient survival. However, recurrence rates are very high postsurgery. In order to assess patient prognosis after metastasis resection, we evaluated the main patho-molecular and immune parameters of all surgical specimens. Two hundred twenty-one patients who underwent, after different preoperative treatment, curative resection of 582 metastases were analyzed. Clinicopathological parameters, RAS tumor mutation, and the consensus Immunoscore (I) were assessed for all patients. Overall survival (OS) and time to relapse (TTR) were estimated using the Kaplan-Meier method and compared by log-rank tests. Cox proportional hazard models were used for uni- and multivariate analysis. Immunoscore and clinicopathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariate analysis. Overall, pathological score (PS) that combines relevant clinicopathological factors for relapse, and I, were prognostic for TTR (2-year TTR rate PS 0-1: 49.8.% (95% CI: 42.2-58.8) versus PS 2-4: 20.9% (95% CI: 13.4-32.8), hazard ratio (HR) = 2.54 (95% CI: 1.82-3.53), p < 0.0000; and 2-year TTR rate I 0: 25.7% (95% CI: 16.3-40.5) versus I 3-4: 60% (95% CI: 47.2-76.3), HR = 2.87 (95% CI: 1.73-4.75), p = 0.0000). Immunoscore was also prognostic for OS (HR [I 3-4 versus I 0] = 4.25, 95% CI: 1.95-9.23; p = 0.0001). Immunoscore (HR [I 3-4 versus I 0] = 0.27, 95% CI: 0.12-0.58; p = 0.0009) and RAS mutation (HR [mutated versus WT] = 1.66, 95% CI: 1.06-2.58; p = 0.0265) were significant for OS. In conclusion, PS including relevant clinicopathological parameters and Immunoscore permit stratification of stage IV colorectal cancer patient prognosis in terms of TTR and identify patients with higher risk of recurrence. Immunoscore remains the major prognostic factor for OS.

Factors predicting the quality of total mesorectal excision for rectal cancer.

OBJECTIVE: To determine preoperative tumor-, patient-, and treatment-related factors that are independently associated with incomplete mesorectal excision. SUMMARY OF BACKGROUND DATA: Incomplete total mesorectal excision (TME) for rectal cancer is associated with increased local and overall recurrences. Factors predicting incomplete mesorectal excision have scarcely been studied. METHODS: In the context of PROCARE, a Belgian multidisciplinary project on rectal cancer, the quality of 266 consecutive and anonymized TME specimens submitted by 33 candidate-TME-trainers was graded by a blinded pathology review board in a standardized manner. Uni- and multivariable analysis were performed to identify factors that can independently predict incomplete mesorectal excision. RESULTS: Mesorectal resection was complete in 21%, nearly complete in 47%, and incomplete in 32%. Of 57% of TME specimens the grade of resection had not been reported by the local pathologist. Incomplete TME doubled the incidence of a positive circumferential resection margin (P = 0.004). Factors found to be significantly related to incomplete TME in univariate analysis were as follows: surgeon, female gender, pathologic body mass index, low rectal cancer, negative clinical nodal status, the absence of downstaging after long-course chemoradiation, laparoscopic and converted laparoscopic resection, and abdominoperineal resection. Multivariable analysis identified pathologic body mass index (P = 0.017), the absence of downstaging after long-course chemoradiation (P = 0.0005), and laparoscopic or converted laparoscopic resection (P = 0.014) as factors that are independently associated with incomplete mesorectal excision. CONCLUSION: Good TME quality cannot be guaranteed. This peer-reviewed TME assessment revealed a number of factors that are independently related to incomplete TME. Both specimen and pathology report need to be audited.

Endoscopic mucosal or submucosal resection of early neoplasia in Barrett's esophagus after antireflux surgery.

BACKGROUND: Endoscopic resection and radiofrequency ablation are now established therapies for high-grade intraepithelial neoplasia and mucosal cancer complicating Barrett's esophagus. These techniques may be more challenging in patients with previous antireflux surgery, because of poor visibility and accessibility. OBJECTIVE: To assess the results of endoscopic resection for early neoplasia complicating Barrett's esophagus after antireflux surgery. DESIGN: Case series, retrospective review. SETTING: Single tertiary-care referral center. PATIENTS: This study involved 7 patients treated for Barrett's neoplasia by endoscopic resection between 2001 and 2009. INTERVENTIONS: Endoscopic resection was performed by using the EMR cap technique or by endoscopic submucosal dissection. MAIN OUTCOME MEASUREMENTS: The curative resection rate, complications, follow-up, and complete remission status were determined. RESULTS: Seven patients underwent endoscopic resection (mean number of sessions, 3.1; range, 1-6): endoscopic submucosal dissection in 3 patients and EMR in 4 patients. Two patients needed additional argon plasma coagulation. Pathology examination disclosed invasive adenocarcinoma in 3 patients and high-grade intraepithelial neoplasia in 4 patients. At the last follow-up examination, all patients were in complete remission. Major procedure-related complications were not encountered. LIMITATIONS: Small number of patients, single center, retrospective study. CONCLUSIONS: We demonstrated that full endoscopic resection by using EMR or endoscopic submucosal dissection in patients with previous antireflux surgery can be achieved successfully and safely. These patients can be treated endoscopically, similarly to patients without previous surgery.

Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.

Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984-2007, nine (1.1%) of 824 adult LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4x), and/or a diffuse tumor localization (3x) and/or a refractory hormonal syndrome (5x). Median post-LT patient survival is 60.9 months (range 4.8-119). One-, 3- and 5-year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5 years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease-free at 78, 84 and 96 months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo- and adjuvant surgical as well as medical treatment. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.