Background
Although after R0 resection of intrahepatic cholangiocarcinoma (ICC) recurrence is frequent, most guidelines do not address strategies for this. The aim of this study was to analyze the ...outcome of repeated resection and to determine criteria when repeated resection is reasonable.
Methods
Between 2008 and 2016, we consecutively collected all cases of ICC (
n
= 176) in a prospective database and further analyzed them with a focus on tumor recurrence, its surgical treatment, overall survival and recurrence-free survival.
Results
Overall, a total of 22 explorations were performed for recurrent ICC in 17 patients. Resection rate was 18 repeated resections in 13 patients. Three patients underwent repeated resection twice and one patient three times. Recurrence was solitary in 7 patients and multifocal in 11 re-resected cases. Median overall survival (OS) of patients who underwent repeated resection was 65.2 months (interquartile range 37–126.5) with a 5-year OS rate of 62%, calculated from primary resection. Patients who underwent repeated resections had a significant better OS compared to those receiving chemotherapy, transarterial chemoembolization, selective internal radiotherapy, radiofrequency ablation or best supportive care (
p
< 0.001).
Conclusion
Repeated resection of recurrent ICC is reasonable and associated with an improved survival. Re-exploration should be considered as long as resection is technically possible.
The debate about the best approach to select patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still ongoing. This study aims to identify the best variables allowing ...to discriminate between “high‐” and “low‐benefit” patients. To do so, the concept of intention‐to‐treat (ITT) survival benefit of LT has been created. Data of 2,103 adult HCC patients consecutively enlisted during the period 1987‐2015 were analyzed. Three rigorous statistical steps were used in order to create the ITT survival benefit of LT: the development of an ITT LT and a non‐LT survival model, and the individual prediction of the ITT survival benefit of LT defined as the difference between the median ITT survival with (based on the first model) and without LT (based on the second model) calculated for each enrolled patient. Four variables (Model for End‐Stage Liver Disease, alpha‐fetoprotein, Milan‐Criteria status, and radiological response) displayed a high effect in terms of delta benefit. According to these risk factors, four benefit groups were identified. Patients with three to four factors (“no‐benefit group”; n = 405 of 2,103; 19.2%) had no benefit of LT compared to alternative treatments. Conversely, patients without any risk factor (“large‐benefit group”; n = 108; 5.1%) yielded the highest benefit from LT reaching 60 months. Conclusion: The ITT transplant survival benefit presented here allows physicians to better select HCC patients waiting for LT. The obtained stratification may lead to an improved and more equitable method of organ allocation. Patients without benefit should be de‐listed, whereas patients with large benefit ratio should be prioritized for LT. (Hepatology 2017;66:1910–1919)
In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria (MC), the benefit of locoregional therapies (LRTs) in the context of liver transplantation (LT) is still debated. Initial ...biases in the selection between treated and untreated patients have yielded conflicting reported results. The study aimed to identify, using a competing risk analysis, risk factors for HCC‐dependent LT failure, defined as pretransplant tumor‐related delisting or posttransplant recurrence. The study was registered at www.clinicaltrials.gov (identification number NCT03723304). In order to offset the initial limitations of the investigated population, an inverse probability of treatment weighting (IPTW) analysis was used: 1083 MC‐in patients (no LRT = 182; LRT = 901) were balanced using 8 variables: age, sex, Model for End‐Stage Liver Disease (MELD) value, hepatitis C virus status, hepatitis B virus status, largest lesion diameter, number of nodules, and alpha‐fetoprotein (AFP). All the covariates were available at the first referral. After the IPTW, a pseudo‐population of 2019 patients listed for LT was analyzed, comparing 2 homogeneous groups of untreated (n = 1077) and LRT‐treated (n = 942) patients. Tumor progression after LRT was the most important independent risk factor for HCC‐dependent failure (subhazard ratio SHR, 5.62; P < 0.001). Other independent risk factors were major tumor diameter, AFP, MELD, patient age, male sex, and period of wait‐list registration. One single LRT was protective compared with no treatment (SHR, 0.51; P < 0.001). The positive effect was still observed when 2‐3 treatments were performed (SHR, 0.66; P = 0.02), but it was lost in the case of ≥4 LRTs (SHR, 0.80; P = 0.27). In conclusion, for MC‐in patients, up to 3 LRTs are beneficial for success in intention‐to‐treat LT patients, with a 49% to 34% reduction in failure risk compared with untreated patients. This benefit is lost if more LRTs are required. A poor response to LRT is associated with a higher risk for HCC‐dependent transplant failure.
Summary
Liver transplantation (LT) is the first‐line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these ...patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP‐ (11 Val30Met, 13 nonVal30Met) and 23 DR‐patients. DR symptoms referred to post‐DLT only, while those of FAP patients were both pre‐ and post‐transplantation. Symptoms of TTR‐amyloidosis in Val30Met and Non‐Val30Met patients pre‐ and post‐LT were similarly distributed. Biopsy‐proven de novo amyloidosis occurred in 4/23 DR after a mean observation of 10 years. Analysis for manifestations of amyloidosis only included patients with available 5‐year follow‐up data (n = 13 FAP, n = 12 DR). Compared to Val30Met FAP patients pre‐LT, Val30Met DR patients had better NCV (P = 0.04) and HRV (P = 0.015). In the Non‐Val30Met group no differences were found between DR and FAP patients pre‐LT. TTR‐amyloidosis symptoms showed no differences in FAP patients pre‐ and 5 years post‐LT, irrespective of Val30Met status. In DR patients, de novo amyloidosis occurred earlier than expected. Therefore, recipients for DLT need to be carefully selected and followed.
Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved ...outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out 25.2%) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre‐LT levels of alpha‐fetoprotein, Model for End‐Stage Liver Disease Sodium score, and tumor burden score was recalibrated among a randomly selected cohort (n = 1,021) and validated in the remainder (n = 3,068). This study demonstrated significant heterogeneity by site and year, reflecting practice trends over the last decade. On explant pathology, both vascular invasion (VI) and poorly differentiated component (PDC) increased with increasing HALTHCC score. The lowest‐risk patients (HALTHCC 0‐5) had lower rates of VI and PDC than the highest‐risk patients (HALTHCC > 35) (VI, 7.7% 1.2‐14.2 vs. 70.6% 48.3‐92.9 and PDC:4.6% 0.1%‐9.8% vs. 47.1% 22.6‐71.5; P < 0.0001 for both). This trend was robust to MC status. This international study was used to adjust the coefficients in the HALTHCC score. Before recalibration, HALTHCC had the greatest discriminatory ability for overall survival (OS; C‐index = 0.61) compared to all previously reported scores. Following recalibration, the prognostic utility increased for both recurrence (C‐index = 0.71) and OS (C‐index = 0.63). Conclusion: This large international trial validated and refined the role for the continuous risk metric, HALTHCC, in establishing pre‐LT risk among candidates with HCC worldwide. Prospective trials introducing HALTHCC into clinical practice are warranted.
Abbreviations AFP alpha-fetoprotein AI artificial intelligence CI confidence interval HCC hepatocellular cancer LT liver transplantation MC Milan Criteria MELD model for end-stage liver disease ...TRAIN-AI Time_Radiological-response_Alpha-fetoproteIN_Artificial-Intelligence Dear Editor, In recent years, criteria based on the combination of morphology and biology have been proposed for improving the selection of hepatocellular cancer (HCC) patients waiting for liver transplantation (LT) 1, 2. Since all the proposed models showed suboptimal results in predicting the risk of post-LT recurrence, a prediction model constructed using artificial intelligence (AI) could be an attractive way to surpass this limit 3, 4. ...the Time_Radiological-response_Alpha-fetoproteIN_Artificial-Intelligence (TRAIN-AI) model was developed, combining morphology and biology tumor variables. TRAIN-AI MODEL VARIABLES Eight variables were significantly associated with the risk of recurrence and used for constructing the TRAIN-AI model: target lesion diameter, nodules number, alpha-fetoprotein, waiting time length, radiological response, model for end-stage liver disease (MELD), living donor liver transplantation, and center volume (Supplementary Table S3). ...the study is retrospective.
Hepatocellular carcinoma (HCC) is one of the most common human malignancies, the incidence of which is growing worldwide. The prognosis of HCC is very poor and it is often accompanied by a high rate ...of recurrence. Conventional chemotherapeutic approaches are largely inefficient. In order to develop novel effective methods for the early detection and prognosis of HCC, novel markers and therapeutic targets are urgently required. The present study focused on the effects of the expression of the tumor suppressor gene insulin‑like growth factor‑2 receptor (IGF2R) on patient survival and tumor recurrence in patients with HCC; this study paid specific attention to the influence of transarterial chemoembolization (TACE) prior to surgery. The mRNA expression levels of IGF2R were measured in primary human HCC and corresponding non‑neoplastic tumor‑surrounding tissue (TST) by reverse transcription‑polymerase chain reaction (RT‑PCR) (n=92). Subsequently, the associations between IGF2R expression and clinicopathological parameters, outcomes of HCC and TACE pretreatment prior to surgery were determined. Furthermore, the effects of the IGF2R gene polymorphisms rs629849 and rs642588 on susceptibility and on clinicopathological features of HCC were investigated. RT‑PCR demonstrated that the mRNA expression levels of IGF2R were downregulated in HCC compared with in TST samples (P=0.004), which was associated with a worse recurrence‑free survival of patients with HCC (P=0.002) and a lower occurrence of cirrhosis (P=0.05). TACE‑pretreated patients with HCC (n=26) exhibited significantly higher IGF2R mRNA expression in tumor tissues (P=0.019). In addition, significantly more patients with HCC in the TACE‑pretreated group exhibited upregulated IGF2R mRNA expression compared with in the non‑treated patients (P=0.032). The IGF2R SNPs rs629849 and rs642588 were not significantly associated with HCC risk, whereas a homozygous IGF2R rs629849 GG genotype was associated with a significantly elevated risk of non‑viral liver cirrhosis (P=0.05). In conclusion, these data suggested an important role for IGF2R expression in HCC, particularly with regards to TACE treatment prior to surgery.
Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. ...The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).
OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs.
Real time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p ≤ 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression.In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC.
The downregulation of OCT1 is associated with tumor progression and a worse patient survival.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Barcelona Clinic Liver Cancer (BCLC) system has been endorsed by international guidelines as a staging algorithm of hepatocellular carcinoma. This analysis was performed to assess the outcome of ...liver transplantation in patients treated against the BCLC recommendations.
The data of 198 patients who underwent liver transplantation for hepatocellular carcinoma were extracted from a prospectively maintained database to classify the patients according to the BCLC system.
BCLC staging was as follows: 0, n = 5; A, n = 77; B, n = 41; C, n = 53; and D, n = 22. Accordingly, liver transplantation was performed in the majority of patients against BCLC recommendations. Surgery (n = 16), radiofrequency ablation (n = 15) and transarterial chemoembolization (n = 151) preceded liver transplantation in 182 patients. Sixteen patients were transplanted without pretreatment. The1-, 5- and 10-year survival rates were 83.8%, 62.4% and 45.9%, and 1-, 5-, and 10-year recurrence rates were 7.7%, 22.7% and 26.7%. The BCLC classification did neither impact survival (P = 0.796) nor recurrence (P = 0.693). In the Cox analysis, RECIST tumor progression and initial alpha fetoprotein were independent predictors of outcome.
Neither the oncological nor the functional stratification imposed by the BCLC system was of importance for outcome. Lack of flexibility and disregard of biological parameters hamper its clinical applicability in liver transplantation.
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