Extracellular vesicles (EVs), are naturally occurring cargo delivery tools with the potential to be used as drug vehicles of single agents or combination therapies. We previously demonstrated that ...human lung cancer cell-derived EVs could be used for the systemic delivery of oncolytic virus (OVs) and chemotherapy drugs such as paclitaxel (PTX), leading to enhanced anti-tumor effects in nude mice. In the current work, we evaluated the biodistribution of EVs by using bioluminescence and fluorescence imaging technologies, thus proving the ability of these EVs-formulations to specifically target the neoplasia, while leaving other body tissues unaffected. Moreover, in vivo imaging of NFκB activation in an immunocompetent reporter mouse model allowed to demonstrate the selective ability of EVs to induce tumor-associated inflammatory reactions, which are characterized by immunogenic cell death and CD3+/CD4+/CD8+ T-cell infiltration. While EVs have the potential to induce a systemic immune reaction by pro-inflammatory cytokines, our study provides compelling evidences of a localized inflammatory effect in the peritumoral area. Collectively, our findings strongly support the systemic administration of EVs formulations with OVs alone or in combination with chemotherapy agents as a novel strategy aimed at treating primary and metastatic cancers.
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Background
Liver resection is a potentially curative approach for hepatocellular carcinoma (HCC). Laparoscopic liver resections may reduce complication rates, especially in patients with cirrhosis. ...The aim of this study was to compare the results of laparoscopic liver resection with those of open liver resection for HCC.
Methods
Patients with cirrhosis who underwent minor liver resections for HCC from 2006 to 2013 were identified retrospectively from a prospective database according to the technique adopted (laparoscopic or open). Short‐ and long‐term outcomes were compared between the two groups before and after 1 : 1 propensity score matching.
Results
A total of 269 patients were considered: 226 who underwent open liver resection and 43 who had a laparoscopic procedure. The two groups differed at baseline in terms of median age, sex, performance status, tumour location and type of resection. After propensity score matching, two comparable groups of 43 patients each were obtained. Intraoperative bleeding, margin clearance and operative mortality were similar in the two groups, whereas complication rates were lower (49 versus 19 per cent in open versus laparoscopic groups respectively; P = 0·004) and median hospital stay was shorter (8 versus 5 days; P < 0·001) in the laparoscopic group. On multivariable logistic regression analysis, the only independent factor that reduced the risk of postoperative complications was the use of laparoscopy (odds ratio 0·12, 95 per cent c.i. 0·03 to 0·55; P = 0·006). Median overall survival was 57·8 months in the open group and 48·8 months in the laparoscopic group (P = 0·802). Median disease‐free survival was 31·7 and 25·5 months respectively (P = 0·990).
Conclusion
In comparison with the open approach, laparoscopic minor liver resections for HCC improved short‐term outcomes, with similar survival results.
Laparoscopic is better
Summary Transarterial chemoembolization (TACE) is considered the gold standard for treating intermediate-stage hepatocellular carcinoma (HCC). However, intermediate-stage HCC includes a heterogeneous ...population of patients with varying tumour burdens, liver function (Child-Pugh A or B) and disease aetiology. This suggests that not all patients with intermediate-stage HCC will derive similar benefit from TACE, and that some patients may benefit from other treatment options. Results of an extensive literature review into the treatment of unresectable HCC with TACE were combined with our own clinical experience to identify factors that may predict survival after TACE. We also report contraindications to TACE and propose a treatment algorithm for the repetition of TACE. In addition, we have constructed a number of expert opinions that may be used as a guide to help physicians make treatment decisions for their patients with intermediate-stage HCC. The data included in the literature review related almost exclusively to conventional TACE, rather than to TACE with drug-eluting beads. Therefore, the findings and conclusions of the literature review are only applicable to the treatment of HCC with conventional TACE. Treating physicians may want to consider other treatment options for patients with intermediate-stage HCC who are not suitable for or do not respond to TACE. By distinguishing those patients who represent good candidates for TACE from those where little or no benefit might be expected, it may be possible to make better use of current treatment options and improve outcomes for patients.
Since Italian liver allocation policy was last revised (in 2012), relevant critical issues and conceptual advances have emerged, calling for significant improvements. We report the results of a ...national consensus conference process, promoted by the Italian College of Liver Transplant Surgeons (for the Italian Society for Organ Transplantation) and the Italian Association for the Study of the Liver, to review the best indicators for orienting organ allocation policies based on principles of urgency, utility, and transplant benefit in the light of current scientific evidence. MELD exceptions and hepatocellular carcinoma were analyzed to construct a transplantation priority algorithm, given the inequity of a purely MELD‐based system for governing organ allocation. Working groups of transplant surgeons and hepatologists prepared a list of statements for each topic, scoring their quality of evidence and strength of recommendation using the Centers for Disease Control grading system. A jury of Italian transplant surgeons, hepatologists, intensivists, infectious disease specialists, epidemiologists, representatives of patients’ associations and organ‐sharing organizations, transplant coordinators, and ethicists voted on and validated the proposed statements. After carefully reviewing the statements, a critical proposal for revising Italy's current liver allocation policy was prepared jointly by transplant surgeons and hepatologists.
The authors present a critical proposal for the implementation of the current liver allocation policy in Italy developed following the results of a national Consensus Conference process aimed to revise, on the basis of scientific evidence, the best indicators for guiding organ allocation policies in the urgency, utility, and benefit models. See the editorial from Berg on page 2537.
Selection criteria and benefit of liver transplantation for hepatic metastases from neuroendocrine tumors (NETs) remain uncertain. Eighty‐eight consecutive patients with metastatic NETs eligible for ...liver transplantation according to Milan‐NET criteria were offered transplant (n = 42) versus nontransplant options (n = 46) depending on list dynamics, patient disposition, and age. Tumor burden between groups did not differ. Transplant patients were younger (40.5 vs. 55.5 years; p < 0.001). Long‐term outcomes were compared after matching between groups made on multiple Cox models adjusted for propensity score built on logistic models. Survival benefit was the difference in mean survival between transplant versus nontransplant options. No patients were lost or died without recurrence. Median follow‐up was 122 months. The transplant group showed a significant advantage over nontransplant strategies at 5 and 10 years in survival (97.2% and 88.8% vs. 50.9% and 22.4%, respectively; p < 0.001) and time‐to‐progression (13.1% and 13.1% vs. 83.5% and 89%; p < 0.001). After adjustment for propensity score, survival advantage of the transplant group was significant (hazard ratio = 7.4; 95% confidence interval (CI): 2.4–23.0; p = 0.001). Adjusted transplant‐related survival benefit was 6.82 months (95% CI: 1.10–12.54; p = 0.019) and 38.43 months (95% CI: 21.41–55.45; p < 0.001) at 5 and 10 years, respectively. Liver transplantation for metastatic NETs under restrictive criteria provides excellent long‐term outcome. Transplant‐related survival benefit increases over time and maximizes after 10 years.
This comparative study from Milan establishes restrictive criteria for patient selection in cases of liver metastases from neuroendocrine tumors and demonstrates a significant 10‐year survival benefit of liver transplantation that justifies the use of donated organs for this rare indication. See Trotter's editorial on page 2775.
Abstract
Background
Laparoscopic liver resection for hepatocellular carcinoma (HCC) in Child–Pugh A cirrhosis has been demonstrated as beneficial. However, the role of laparoscopy in Child–Pugh B ...cirrhosis is undetermined. The aim of this retrospective cohort study was to compare open and laparoscopic resection for HCC with Child–Pugh B cirrhosis.
Methods
Data on liver resections were gathered from 17 centres. A 1 : 1 propensity score matching was performed according to 17 predefined variables.
Results
Of 382 available liver resections, 100 laparoscopic and 100 open resections were matched and analysed. The 90-day postoperative mortality rate was similar in open and laparoscopic groups (4.0 versus 2.0 per cent respectively; P = 0.687). Laparoscopy was associated with lower blood loss (median 110 ml versus 400 ml in the open group; P = 0.004), less morbidity (38.0 versus 51.0 per cent respectively; P = 0.041) and fewer major complications (7.0 versus 21.0 per cent; P = 0.010), and ascites was lower on postoperative days 1, 3 and 5. For laparoscopic resections, patients with portal hypertension developed more complications than those without (26 versus 12 per cent respectively; P = 0.002), and patients with a Child–Pugh B9 score had higher morbidity rates than those with B8 and B7 (7 of 8, 10 of 16 and 21 of 76 respectively; P < 0.001). Median hospital stay was 7.5 (range 2–243) days for laparoscopic liver resection and 18 (3–104) days for the open approach (P = 0.058). The 5-year overall survival rate was 47 per cent for open and 65 per cent for laparoscopic resection (P = 0.142). The 5-year disease-free survival rate was 32 and 37 per cent respectively (P = 0.742).
Conclusion
Patients without preoperative portal hypertension and Child–Pugh B7 cirrhosis may benefit most from laparoscopic liver surgery.
Outcomes of laparoscopic liver resection for hepatocellular carcinoma with Child–Pugh B cirrhosis are undetermined. This propensity score matching study demonstrated that laparoscopic resection was associated with reduced blood loss and morbidity, and lower risk of postoperative liver decompensation, leading to shorter hospital stay and with oncological outcomes similar to those of open resection.
Benefit when no portal hypertension
Background
The benefit of surgical intervention for cancer should be estimated in relation to the life expectancy of the general population. The aim of this study was to provide a measure of relative ...survival after hepatectomy for hepatocellular carcinoma (HCC).
Methods
Consecutive patients with liver cirrhosis and HCC who underwent hepatectomy were divided into age quartiles for analysis. Short‐ and mid‐term survival rates were used to estimate survival until death for all patients, in relation to age and other co‐variables. Years of life lost (YLL) were estimated using a reference cohort, derived from the general population matched for sex, age and year of diagnosis.
Results
Some 919 patients were included in the study. The following age quartiles were identified: less than 60 years (229 patients), 60–66 years (230), 67–70 years (231) and over 70 years (229). Postoperative mortality rates were similar between age quartiles, as were survival rates up to 3 years (P = 0·404). A statistically significant reduction in 5–10‐year survival rates was observed with ageing (P = 0·001). Relative survival calculation showed that the youngest age quartile (less than 60 years) experienced the longest entire postoperative lifespan (15·6 years) but also the greatest number of YLL (11·0 years). Patients aged over 70 years had the shortest entire postoperative lifespan (6·4 years) but also the smallest number of YLL (3·7 years).
Conclusion
Although survival after liver resection for HCC is shortest in elderly patients, relative survival estimates suggest that hepatectomy can be of benefit in these patients, with a small loss of the entire individual lifespan.
Hepatectomy for HCC of benefit in elderly
The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very ...early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 2.5‐4.4 versus 1.6 1.5‐1.8). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178‐1188)
Background
This study aimed to assess the best achievable outcomes in laparoscopic liver resection (LLR) after risk adjustment based on surgical technical difficulty using a national registry.
...Methods
LLRs registered in the Italian Group of Minimally Invasive Liver Surgery registry from November 2014 to March 2018 were considered. Benchmarks were calculated according to the Achievable Benchmark of Care (ABC™). LLRs at each centre were divided into three clusters (groups I, II and III) based on the Kawaguchi classification. ABCs for overall and major morbidity were calculated in each cluster. Multivariable analysis was used to identify independent risk factors for overall and major morbidity. Significant variables were used in further risk adjustment.
Results
A total of 1752 of 2263 patients fulfilled the inclusion criteria: 1096 (62·6 per cent) in group I, 435 (24·8 per cent) in group II and 221 (12·6 per cent) in group III. The ABCs for overall morbidity (7·8, 14·2 and 26·4 per cent for grades I, II and II respectively) and major morbidity (1·4, 2·2 and 5·7 per cent) increased with the difficulty of LLR. Multivariable analysis showed an increased risk of overall morbidity associated with multiple LLRs (odds ratio (OR) 1·35), simultaneous intestinal resection (OR 3·76) and cirrhosis (OR 1·83), and an increased risk of major morbidity with intestinal resection (OR 4·61). ABCs for overall and major morbidity were 14·4 and 3·2 per cent respectively for multiple LLRs, 30 and 11·1 per cent for intestinal resection, and 14·9 and 4·8 per cent for cirrhosis.
Conclusion
Overall morbidity benchmarks for LLR ranged from 7·8 to 26·4 per cent, and those for major morbidity from 1·4 to 5·7 per cent, depending on complexity. Benchmark values should be adjusted according to multiple LLRs or simultaneous intestinal resection and cirrhosis.
Antecedentes
Este estudio tuvo como objetivo evaluar los mejores resultados que se pueden conseguir en la resección hepática laparoscópica (laparoscopic liver resection, LLR) después del ajuste por riesgos basado en la dificultad de la técnica quirúrgica utilizando un registro nacional.
Métodos
Se consideraron las LLRs incluidas en el Registro del Grupo Italiano de Cirugía Hepática Mínimamente Invasiva desde 11/2014 a 03/2018. Los resultados de referencia (benchmarks) se calcularon de acuerdo con el Achievable Benchmark of Care (ABC™). Las LLRs de cada uno de los centros se dividieron en 3 grupos (Grupo I, II y III) en base a la clasificación de Kawaguchi. Se calculó el ABC de la morbilidad global y de la morbilidad mayor para cada grupo. Se realizó un análisis multivariable para identificar los factores independientes de riesgos para la morbilidad global y morbilidad mayor. Se utilizaron variables significativas para realizar ajustes de riesgo adicionales.
Resultados
Un total de 1.752 pacientes de los 2.263 cumplían los criterios de inclusión, de los cuales 1.096 (62,6%) se incluyeron en el Grupo I, 435 (24,8%) en el Grupo II y 221 (12,6%) en el Grupo III. El ABC de la morbilidad global (7,8%, 14,2%, 26,4%) y de la morbilidad mayor (1,4%, 2,2%, 5,7%) aumentó del Grupo I al Grupo III. El análisis multivariable mostró un incremento del riesgo para la morbilidad global asociada con múltiples LLRs (razón de oportunidades, odds ratio, OR 1,349), resección intestinal simultánea (OR 3,760) y cirrosis (OR 1,825), y para la morbilidad mayor con la resección intestinal (OR 4,606). Los ABC de la morbilidad global y morbilidad mayor fueron 14,4% y 3,2% para las LLR múltiples, 30% y 11% para la resección intestinal, y 14,9% y 4,8% para la cirrosis, respectivamente.
Conclusión
Los resultados de referencia (benchmark) para la morbilidad global y morbilidad mayor en la LLR variaron entre un 8% y un 26% y entre un 1,4% y un 5,7%, dependiendo de la complejidad. Los valores de referencia deberían ajustarse de acuerdo con la práctica de LLRs múltiples o resección intestinal simultánea y cirrosis.
Data from the I Go MILS registry were used to calculate the benchmarks for outcomes in laparoscopic liver resection (LLR). Depending on the technical complexity of LLR, the benchmarks ranged between 7·8 and 26·4 per cent for overall morbidity, and 1·4 and 5·7 per cent for major morbidity. Multiple LLRs, simultaneous intestinal resection and cirrhosis worsened benchmark values.
Benchmarks may be useful
Background
When comparing the efficacy of surgical and non‐surgical therapies for hepatocellular carcinoma (HCC), a major limitation is the causal inference problem. This concerns the impossibility ...of seeing both outcomes of two different treatments for the same individual at the same time because one is inevitably missing. This aspect can be addressed methodologically by estimating the so‐called average treatment effect (ATE).
Methods
To estimate the ATE of hepatic resection over locoregional therapies for HCC, data from patients treated in two tertiary care settings between August 2000 and December 2014 were used to obtain counterfactual outcomes using an inverse probability weight survival adjustment.
Results
A total of 1585 patients were enrolled: 815 underwent hepatic resection, 337 radiofrequency ablation (RFA) and 433 transarterial chemoembolization (TACE). The option of operating on all patients who had tumour ablation returned an ATE of +9·8 months for resection (effect size 0·111; adjusted P = 0·064). The option of operating on all patients who had TACE returned an ATE of +27·9 months (effect size 0·383; adjusted P < 0·001). The ATE of surgery was negligible in patients undergoing ablation for very early HCCs (effect size 0·027; adjusted P = 0·627), independently of albumin–bilirubin (ALBI) grade; or in patients with ALBI liver function grade 2 (effect size 0·083; adjusted P = 0·213), independently of tumour stage. In all other instances, the ATE of surgery was notably greater. Operating on patients who had TACE with multinodular HCC beyond the Milan criteria resulted in a mild ATE (effect size 0·140; adjusted P = 0·037).
Conclusion
ATE estimation suggests that hepatic resection is a better treatment option than ablation and TACE in patients with HCC.
Resection is better
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