The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved
efficacy of anti-miR-221 ...molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC.
A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC.
MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients.
MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance.
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Outcomes of liver transplantation for hepatocellular carcinoma (HCC) are determined by cancer-related and non-related events. Treatments for hepatitis C virus infection have reduced non-cancer events ...among patients receiving liver transplants, so reducing HCC-related death might be an actionable end point. We performed a competing-risk analysis to evaluate factors associated with survival of patients with HCC and developed a prognostic model based on features of HCC patients before liver transplantation.
We performed multivariable competing-risk regression analysis to identify factors associated with HCC-specific death of patients who underwent liver transplantation. The training set comprised 1018 patients who underwent liver transplantation for HCC from January 2000 through December 2013 at 3 tertiary centers in Italy. The validation set comprised 341 consecutive patients who underwent liver transplantation for HCC during the same period at the Liver Cancer Institute in Shanghai, China. We collected pretransplantation data on etiology of liver disease, number and size of tumors, patient level of α-fetoprotein (AFP), model for end-stage liver disease score, tumor stage, numbers and types of treatment, response to treatments, tumor grade, microvascular invasion, dates, and causes of death. Death was defined as HCC-specific when related to HCC recurrence after transplantation, disseminated extra- and/or intrahepatic tumor relapse and worsened liver function in presence of tumor spread. The cumulative incidence of death was segregated for hepatitis C virus status.
In the competing-risk regression, the sum of tumor number and size and of log10 level of AFP were significantly associated with HCC-specific death (P < .001), returning an average c-statistic of 0.780 (95% confidence interval, 0.763−0.798). Five-year cumulative incidence of non−HCC-related death was 8.6% in HCV-negative patients and 18.1% in HCV-positive patients. For patients with HCC to have a 70% chance of HCC-specific survival 5 years after transplantation, their level of AFP should be <200 ng/mL and the sum of number and size of tumors (in centimeters) should not exceed 7; if the level of AFP was 200−400 ng/mL, the sum of the number and size of tumors should be ≤5; if their level of AFP was 400−1000 ng/mL, the sum of the number and size of tumors should be ≤4. In the validation set, the model identified patients who survived 5 years after liver transplantation with 0.721 accuracy (95% confidence interval, 0.648%−0.793%). Our model, based on patients’ level of AFP and HCC number and size, outperformed the Milan; University of California, San Francisco; Shanghai-Fudan; Up-to-7 criteria (P < .001); and AFP French model (P = .044) to predict which patients will survive for 5 years after liver transplantation.
We developed a model based on level of AFP, tumor size, and tumor number, to determine risk of death from HCC-related factors after liver transplantation. This model might be used to select end points and refine selection criteria for liver transplantation for patients with HCC. To predict 5-year survival and risk of HCC-related death using an online calculator, please see www.hcc-olt-metroticket.org/. ClinicalTrials.gov ID NCT02898415.
Background & Aims Both hepatic resection and radiofrequency ablation (RFA) are considered curative treatments for hepatocellular carcinoma (HCC), but their economic impact still remains not ...determined. Aim of the present study was to analyze the cost-effectiveness (CE) of these two strategies in early stage HCC (Milan criteria). Methods As first step, a meta-analysis of the pertinent literature of the last decade was performed. Seventeen studies fulfilled the inclusion criteria: 3996 patients underwent resection and 4424 underwent RFA for early HCC. Data obtained from the meta-analysis were used to construct a Markov model. Costs were assessed from the health care provider perspective. A Monte Carlo probabilistic sensitivity analysis was used to estimate outcomes with distribution samples of 1000 patients for each treatment arm. Results In a 10-year perspective, for very early HCC (single nodule <2 cm) in Child–Pugh class A patients, RFA provided similar life-expectancy and quality-adjusted life-expectancy at a lower cost than resection and was the most cost-effective therapeutic strategy. For single HCCs of 3–5 cm, resection provided better life-expectancy and was more cost-effective than RFA, at a willingness-to-pay above € 4200 per quality-adjusted life-year. In the presence of two or three nodules ⩽3 cm, life-expectancy and quality-adjusted life-expectancy were very similar between the two treatments, but cost-effectiveness was again in favour of RFA. Conclusions For very early HCC and in the presence of two or three nodules ⩽3 cm, RFA is more cost-effective than resection; for single larger early stage HCCs, surgical resection remains the best strategy to adopt as a result of better survival rates at an acceptable increase in cost.
Changes in body composition are associated with poor outcomes in cancer patients including hepatocellular carcinoma (HCC). Sarcopenia, defined as the loss of skeletal muscle mass, quality and ...function, has been associated with a higher rate of complications and recurrences in patients with cirrhosis and HCC. The assessment of patient general status before HCC treatment, including the presence of sarcopenia, is a key-point for achieving therapy tolerability and to avoid short- and long-term complications leading to poor patients’ survival. Thus, we aimed to review the current literature evaluating the role of sarcopenia assessment related to HCC treatments and to critically provide the clinicians with the most recent and valuable evidence. As a result, sarcopenia can be predictive of poor outcomes in patients undergoing liver resection, transplantation and systemic therapies, offering the chance to clinicians to improve the muscular status of these patients, especially those with high-grade sarcopenia at high risk of mortality. Further studies are needed to clarify the predictive value of sarcopenia in other HCC treatment settings and to evaluate its role as an additional staging tool for identifying the most appropriate treatment. Besides, interventional studies aiming at increasing the skeletal muscle mass for reducing complications and increasing the survival in patients with HCC are needed.
The aim of this study was to estimate probabilities of achieving the statistical cure from hepatocellular carcinoma (HCC) with hepatic resection (HR) and liver transplantation (LT).
Statistical cure ...occurs when the mortality of a specific population returns to values of that of general population. Resection and transplantation are considered potentially curative therapies for HCC, but their effect on the residual entire life-expectancy has never been investigated.
Data from 3286 HCC patients treated with LT (n = 1218) or HR (n = 2068) were used to estimate statistical cure. Disease-free survival (DFS) was the primary survival measure to estimate cure fractions through a nonmixture model. Overall survival (OS) was a secondary measure. In both, patients were matched with general population by age, sex, year, and race/ethnicity. Cure variations after LT were also adjusted for different waiting-list drop-outs.
Considering DFS, the cure fraction after LT was 74.1% and after HR was 24.1% (effect size >0.8). LT outperformed HR within all transplant criteria considered (effect size >0.8), especially for multiple tumors (>0.9) and even in presence of a drop-out up to 20% (>0.5). Considering OS, the cure fraction after LT marginally increased to 75.8%, and after that HR increased to 40.5%. The effect size of LT over HR in terms of cure decreased for oligonodular tumors (<0.5), became small for drop-out up to ∼20% (<0.2), and negligible for single tumors <5 cm (∼0.1).
As other malignancies, statistical cure can occur for HCC, primarily with LT and secondarily with HR, depending on waiting-list capabilities and efficacy of tumor recurrence therapies after resection.
The recurrence of hepatocellular carcinoma,the sixth most common neoplasm and the third leading cause of cancer-related mortality worldwide,represents an important clinical problem,since it may occur ...after both surgical and medical treatment.The recurrence rate involves 2 phases:an early phase and a late phase.The early phase usually occurs within 2 years after resection;it is mainly related to local invasion and intrahepatic metastases and,therefore,to the intrinsic biology of the tumor.On the other hand,the late phase occurs more than 2 years after surgery and is mainly related to de novo tumor formation as a consequence of the carcinogenic cirrhotic environment.Since recent studies have reported that early and late recurrences may have different risk factors,it is clinically important to recognize these factors in the individual patient as soon as possible.The aim of this review was,therefore,to identify predicting factors for the recurrence of hepatocellularcarcinoma,by means of invasive and non-invasive methods,according to the different therapeutic strategies available.In particular the role of emerging techniques(e.g.,transient elastography)and biological features of hepatocellular carcinoma in predicting recurrence have been discussed.In particular,invasive methods were differentiated from non-invasive ones for research purposes,taking into consideration the emerging role of the genetic signature of hepatocellular carcinoma in order to better allocate treatment strategies and surveillance follow-up in patients with this type of tumor.
With the aim to explore innovative tools for organ preservation, especially in marginal organs, we hereby describe a clinical trial of ex-vivo hypothermic oxygenated perfusion (HOPE) in the field of ...liver (LT) and kidney transplantation (KT) from Extended Criteria Donors (ECD) after brain death. A matched-case analysis of donor and recipient variables was developed: 10 HOPE-ECD livers and kidneys (HOPE-L and HOPE-K) were matched 1:3 with livers and kidneys preserved with static cold storage (SCS-L and SCS-K). HOPE and SCS groups resulted with similar basal characteristics, both for recipients and donors. Cumulative liver and kidney graft dysfunction were 10% (HOPE L-K) vs. 31.7%, in SCS group (p = 0.05). Primary non-function was 3.3% for SCS-L vs. 0% for HOPE-L. No primary non-function was reported in HOPE-K and SCS-K. Median peak aspartate aminotransferase within 7-days post-LT was significantly higher in SCS-L when compared to HOPE-L (637 vs.344 U/L, p = 0.007). Graft survival at 1-year post-transplant was 93.3% for SCS-L vs. 100% of HOPE-L and 90% for SCS-K vs. 100% of HOPE-K. Clinical outcomes support our hypothesis of machine perfusion being a safe and effective system to reduce ischemic preservation injuries in KT and in LT.
Very few data are available in literature about the role of radiofrequency ablation (RFA) in intrahepatic cholangiocarcinoma (ICC) and previous studies are mainly case reports and case series on a ...very small number of patients and nodules. In this study, we aimed to evaluate effectiveness and safety of RFA for the treatment of unresectable ICC.
This is a retrospective observational cohort study comprising all consecutive patients treated with RFA for unresectable ICC at Policlinico Sant'Orsola Malpighi Hospital, Bologna, Italy. Primary endpoint was Local Tumor Progression-Free Survival (LTPFS) while Overall Survival (OS) was also assessed as secondary endpoint.
From January 2014 to June 2019, 29 patients with 117 nodules underwent RFA. Technique effectiveness 1 month after RFA was 92.3%; median LTPFS was 9.27 months. Univariate analysis and multivariate analysis showed that LTPFS was significantly related to tumor size ≥20 mm. At a median follow up of 39.9 months, median OS from the date of RFA was 27.5 months, with an OS of 89%, 45% and 11% at 1, 2 and 4 years, respectively. Number of overall lesions and the sum of their diameter at the moment of the first RFA significantly affected OS in multivariate analysis. Minor and major complication rates were 14% and 7%, respectively.
Tumor size ≥20 mm was associated with lower LTPFS, representing a potential useful threshold value. A careful evaluation of tumor burden appears as a crucial element in choosing the best therapeutic strategy in unresectable ICC.
Background
The aim of the study was to evaluate perioperative outcomes and to evaluate factors influencing rative morbidity and adoption of minimally invasive technique in 1-team (1-T) versus two ...teams (2-T) management of synchronous colorectal liver metastases.
Methods
Within four referral centers, a group of 234 patients treated in 1-T centers was identified and compared with a group of 253 patients treated in 2-T. A nonparametric bootstrap process was applied to the original cohorts of 1-T group and 2-T group as a resampling method to obtain bootstrapped cohorts (155 patients per group).
Results
33.5% of patients in 1-T boot group and 38.1% in the 2-T boot group were operated by laparoscopic approach. Multivariate analysis revealed that approach to primary tumor (laparoscopic or open) and intraoperative blood loss were independent prognostic factors for morbidity. Team approach did not show any significant correlation with incidence of postoperative complications nor with choice for laparoscopic approach.
Conclusion
The optimization of team strategy for patients with SCRLM is not solely based on the adoption of a 1-T or 2-T approach, but should instead be based on the implementation of a standard protocol for management of these patients.
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