First-in-human liver transplantation from a centenarian deceased donor after brain death.

Liver transplantation from elderly donors is expanding due to demand for liver grafts, aging of recipients and donors, and introduction of machine perfusion. We report on a liver transplant from a 100-year-old deceased donor after brain death. The liver was transplanted after the use of hypothermic machine perfusion to a 60-year-old recipient with advanced hepatocellular carcinoma undergoing neoadjuvant immunotherapy. Nine months after the transplant, the patient is alive with a functioning graft and no evidence of acute rejection or tumor recurrence.

Percutaneous thermal segmentectomy for liver malignancies over 3 cm: mid-term oncological performance and predictors of sustained complete response from a multicentric Italian retrospective study.

INTRODUCTION: Percutaneous thermal segmentectomy is a single-step combination of microwave ablation, performed during arterial occlusion obtained with a balloon micro catheter, followed in the same session by balloon-occluded TACE. The aim of this multicenter retrospective study is to report the mid-term oncological performance of this technique for liver malignancies > 3.0 cm and to identify risk factors for the loss of sustained complete response. METHODS: Oncological results were evaluated with CT or MRI according to m-RECIST (HCC) and RECISTv1.1 (metastasis/intra-hepatic cholangiocarcinoma, iCC) at 1-month, 3-6-month and then at regular-6-month intervals. To identify predictive variables associated with not achieving or losing complete response two mixed-effects multivariable logistic regression models were constructed. RESULTS: Sixty-three patients (40/23, male/female) with primary liver malignancies (HCC = 49; iCC = 4) and metastasis (n = 10) were treated. Median diameter of target lesion was 4.5 cm (range 3.0-7.0 cm). The median follow-up time was 9.2 months. At one-month follow-up, 79.4% of patients presented with a complete response and the remaining 20.6% were partial responders. At the 3-6-month follow-up, reached by 59 of the initial 63 patients, 83.3% showed a sustained complete response, while 10.2% had a partial response and 8.5% a local recurrence. At the last follow-up, 69.8% of the lesions showed a complete response. The initial diameter of the target lesion ≥ 5.0 cm was the only independent variable associated with the risk of failure in maintaining a complete response at 6 months (OR = 8.58, 95% CI 1.38-53.43; P = 0.02). CONCLUSION: Percutaneous thermal segmentectomy achieves promising oncological results in patients with tumors > 3.0 cm, with tumor dimension ≥ 5.0 cm being the only risk factor associated with the failure of a sustained complete response.

Personalised management of patients with hepatocellular carcinoma: a multiparametric therapeutic hierarchy concept.

Advances in the surgical and systemic therapeutic landscape of hepatocellular carcinoma have increased the complexity of patient management. A dynamic adaptation of the available staging-based algorithms is required to allow flexible therapeutic allocation. In particular, real-world hepatocellular carcinoma management increasingly relies on factors independent of oncological staging, including patients' frailty, comorbid burden, critical tumour location, multiple liver functional parameters, and specific technical contraindications impacting the delivery of treatment and resource availability. In this Policy Review we critically appraise how treatment allocation strictly based on pretreatment staging features has shifted towards a more personalised treatment approach, in which expert tumour boards assume a central role. We propose an evidence-based framework for hepatocellular carcinoma treatment based on the novel concept of multiparametric therapeutic hierarchy, in which different therapeutic options are ordered according to their survival benefit (ie, from surgery to systemic therapy). Moreover, we introduce the concept of converse therapeutic hierarchy, in which therapies are ordered according to their conversion abilities or adjuvant abilities (ie, from systemic therapy to surgery).

Cerium oxide nanoparticles administration during machine perfusion of discarded human livers: A pilot study.

The combined approach of ex situ normothermic machine perfusion (NMP) and nanotechnology represents a strategy to mitigate ischemia/reperfusion injury in liver transplantation (LT). We evaluated the uptake, distribution, and efficacy of antioxidant cerium oxide nanoparticles (nanoceria) during normothermic perfusion of discarded human livers. A total of 9 discarded human liver grafts were randomized in 2 groups and underwent 4 h of NMP: 5 grafts were treated with nanoceria conjugated with albumin (Alb-NC; 50 µg/ml) and compared with 4 untreated grafts. The intracellular uptake of nanoceria was analyzed by electron microscopy (EM) and inductively coupled plasma-mass spectrometry (ICP-MS). The antioxidant activity of Alb-NC was assayed in liver biopsies by glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) assay, telomere length, and 4977-bp common mitochondrial DNA deletion (mtDNA4977 deletion). The cytokine profile was evaluated in perfusate samples. EM and ICP-MS confirmed Alb-NC internalization, rescue of mitochondrial phenotype, decrease of lipid droplet peroxidation, and lipofuscin granules in the treated grafts. Alb-NC exerted an antioxidant activity by increasing GSH levels (percentage change: +94% ± 25%; p = 0.01), SOD (+17% ± 4%; p = 0.02), and CAT activity (51% ± 23%; p = 0.03), reducing the occurrence of mtDNA4977 deletion (-67.2% ± 11%; p = 0.03), but did not affect cytokine release. Alb-NC during ex situ perfusion decreased oxidative stress, upregulating graft antioxidant defense. They could be a tool to improve quality grafts during NMP and represent an antioxidant strategy aimed at protecting the graft against reperfusion injury during LT.

Implementing a robotic liver resection program does not always require prior laparoscopic experience.

BACKGROUND: Preliminary experience in laparoscopic liver surgery is usually suggested prior to implementation of a robotic liver resection program. METHODS: This was a retrospective cohort analysis of patients undergoing robotic (RLR) versus laparoscopic liver resection (LLR) for hepatocellular carcinoma at a center with concomitant initiation of robotic and laparoscopic programs RESULTS: A total of 92 consecutive patients operated on between May 2014 and February 2019 were included: 40 RLR versus 52 LLR. Median age (69 vs. 67; p = 0.74), male sex (62.5% vs. 59.6%; p = 0.96), incidence of chronic liver disease (97.5% vs.98.1%; p = 0.85), median model for end-stage liver disease (MELD) score (8 vs. 9; p = 0.92), and median largest nodule size (22 vs. 24 mm) were similar between RLR and LLR. In the LLR group, there was a numerically higher incidence of nodules located in segment 4 (20.0% vs. 16.6%; p = 0.79); a numerically higher use of Pringle's maneuver (32.7% vs. 20%; p = 0.23), and a shorter duration of surgery (median of 165.5 vs. 217.5 min; p = 0.04). Incidence of complications (25% vs.32.7%; p = 0.49), blood transfusions (2.5% vs.9.6%; p = 0.21), and median length of stay (6 vs. 5; p = 0.54) were similar between RLR and LLR. The overall (OS) and recurrence-free (RFS) survival rates at 1 and 5 years were 100 and 79 and 95 and 26% for RLR versus 96.2 and 76.9 and 84.6 and 26.9% for LLR (log-rank p = 0.65 for OS and 0.72 for RFS). CONCLUSIONS: Based on our results, concurrent implementation of a robotic and laparoscopic liver resection program appears feasible and safe, and is associated with similar oncologic long-term outcomes.

Ex-vivo human pancreatic specimen evaluation by 7 Tesla MRI: a prospective radiological-pathological correlation study.

PURPOSE: To compare the characteristics detected by 7Tesla (7 T) MR and the histological composition of ex-vivo specimens from lesions diagnosed at preoperative CT scan as Pancreatic Ductal Adenocarcinoma (PDAC). MATERIALS AND METHODS: Ten pancreatic specimens were examined. The 7 T imaging protocol included both morphologic and quantitative sequences; the latter was acquired by conventional methods and a novel multiparametric method, the magnetic resonance fingerprinting (MRF) sequence. Two radiologists reviewed the images to: (1) evaluate the quality of the morphological and quantitative sequences by assigning an "image consistency score" on a 4-point scale; (2) identify the lesion, recording its characteristics; (3) perform the quantitative analysis on "target lesion" and "non target tissue". Finally, the specimen was analysed by two pathologists. RESULTS: Seven out of 10 lesions were PDAC, 2/10 were biliary carcinomas, whereas one lesion was an ampullary adenocarcinoma. The quality of the morphological sequences was judged "excellent". The "image consistency score" for the conventional quantitative sequences and MRF were 2.8 ± 0.42 and 2.9 ± 0.57; the "overall MR examination score" was 3.5 ± 0.53. A statistical correlation was found between the relaxation time values of conventional and MRF T1-weighted sequences (p < 0.0001), as well as between conventional and MRF fat- and water-fraction maps (p < 0.05). The "target lesion" and "non target tissue" relaxation time values were statistically different according to conventional T1-, T2-weighted, and MRF T1-weighted sequences. CONCLUSIONS: Conventional T1-, T2-weighted sequences and MRF derived relaxometries may be useful in differentiating between tumour and non-target pancreatic tissue. Moreover, the MRF sequence can be used to obtain reliable relaxation time data.

Consensus Guidelines for the Definition of Time-to-Event End Points in Image-guided Tumor Ablation: Results of the SIO and DATECAN Initiative.

There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Duration of response after DEB-TACE compared to lipiodol-TACE in HCC-naïve patients: a propensity score matching analysis.

OBJECTIVES: To retrospectively compare long-term outcomes of first-line drug-eluting particle (DEB)- transarterial chemoembolization (TACE) and lipiodol-TACE, in patients with unresectable hepatocellular (HCC). METHODS: We retrospectively reviewed our database to identify adult patients with treatment-naïve unresectable HCC, who underwent TACE from 2006 to 2013. Patients were excluded in the absence of complete medical records relative to first TACE, 1-month follow-up, and/or sufficient follow-up data. Periprocedural complications, duration of hospitalization, 1-month tumor response by mRECIST, time to tumor progression (TTP) and target tumor progression (TTTP), and overall survival (OS) were evaluated. RESULTS: Out of an initial series of 656 patients, 329 patients were excluded for unavailability of sufficient baseline and/or follow-up data. The remaining 327 patients underwent either lipiodol-TACE (n = 160) or DEB-TACE (n = 167). Patients treated with lipiodol-TACE had a significantly higher tumor burden. By propensity score, patients were matched according to baseline differences (BCLC stage, uninodular or multinodular HCC, and unilobar or bilobar HCC), resulting in 101 patients in each treatment group. Lipiodol-TACE was associated with a significantly higher incidence of adverse events (p = 0.03), and longer hospitalization (mean, 2.5 days vs 1.9 days; p = 0.03), while tumor response, TTP, and OS were comparable. In patients achieving 1-month complete response (CR) of target tumor, TTTP was significantly (p = 0.009) longer after DEB-TACE compared to lipiodol-TACE (median, 835 vs 353 days), resulting in a lower number of re-treatments during the entire follow-up (0.75 vs 1.6, p = 0.01). CONCLUSION: Compared to lipiodol-TACE, DEB-TACE offers higher tolerability, reduced hospitalization, and more durable target tumor response after CR. KEY POINTS: • Compared to lipiodol-TACE, DEB-TACE is better tolerated and has reduced side effects, which translates into shorter hospitalization. • When complete radiological response according to the mRECIST is obtained 1 month after the procedure, DEB-TACE offers a more durable local tumor control compared to lipiodol-TACE. • In these patients, the longer duration of response after DEB-TACE translates into a lower number of re-interventions.

Standardizing percutaneous Microwave Ablation in the treatment of Lung Tumors: a prospective multicenter trial (MALT study).

OBJECTIVES: To prospectively assess reproducibility, safety, and efficacy of microwave ablation (MWA) in the treatment of unresectable primary and secondary pulmonary tumors. METHODS: Patients with unresectable primary and metastatic lung tumors up to 4 cm were enrolled in a multicenter prospective clinical trial and underwent CT-guided MWA. Treatments were delivered using pre-defined MW power and duration settings, based on target tumor size and histology classifications. Patients were followed for up to 24 months. Treatment safety, efficacy, and reproducibility were assessed. Ablation volumes were measured at CT scan and compared with ablation volumes obtained on ex vivo bovine liver using equal treatment settings. RESULTS: From September 2015 to September 2017, 69 MWAs were performed in 54 patients, achieving technical success in all cases and treatment completion without deviations from the standardized protocol in 61 procedures (88.4%). Immediate post-MWA CT scans showed ablation dimensions smaller by about 25% than in the ex vivo model; however, a remarkable volumetric increase (40%) of the treated area was observed at 1 month post-ablation. No treatment-related deaths nor complications were recorded. Treatments of equal power and duration yielded fairly reproducible ablation dimensions at 48-h post-MWA scans. In comparison with the ex vivo liver model, in vivo ablation sizes were systematically smaller, by about 25%. Overall LPR was 24.7%, with an average TLP of 8.1 months. OS rates at 12 and 24 months were 98.0% and 71.3%, respectively. CONCLUSIONS: Percutaneous CT-guided MWA is a reproducible, safe, and effective treatment for malignant lung tumors up to 4 cm in size. KEY POINTS: • Percutaneous MWA treatment of primary and secondary lung tumors is a repeatable, safe, and effective therapeutic option. • It provides a fairly reproducible performance on both the long and short axis of the ablation zone. • When using pre-defined treatment duration and power settings according to tumor histology and size, LPR does not increase with increasing tumor size (up to 4 cm) for both primary and metastatic tumors.

Predicting the coagulation volume induced by microwave ablation of hepatocellular carcinoma: the role of deposited energy, ex-vivo bovine liver charts and central hyperdense area on post-treatment CT.

PURPOSE: To study the correlation between the overall coagulation zone (A) attained in percutaneous microwave ablation (MWA) of hepatocellular carcinomas (HCC) and: (1) the hyperdense zone (C) visible in the central part of zone A on post-treatment unenhanced CT scans; (2) the deposited energy; (3) the coagulation zones observed on ex-vivo bovine liver. MATERIALS AND METHODS: The post-procedural computed tomography (CT) scans of HCCs treated with a single energy deployment through the same 2450 MHz MWA system were retrospectively analyzed, retrieving the dimensions of A and C zones and the deposited energy (E). Ex-vivo bovine liver MWA with the same system were performed and analyzed to determine the same quantities by gross-pathologic examination and CT imaging. RESULTS: A total of 101 HCC treatments were analyzed. The average coagulation volumes increased linearly with deposited energy (1.11 cc/kJ, R2 = 0.90, 4.2 kJ ≤ E ≤ 48 kJ), similarly to ex-vivo findings (1.38 cc/kJ, R2 =0.97, 7.2 kJ ≤ E ≤ 144 kJ). The long axis (L) and short axis (D) of zones A and C held a fairly constant ratio both in-vivo (LC/LA=0.43 ± 0.13; DC/DA=0.42 ± 0.10) and ex-vivo (LC/LA = 0.49 ± 0.07; DC/DA = 0.28 ± 0.06). CONCLUSIONS: The average dimensions of the ablation zone induced by the considered system on HCC increase linearly with the deposited energy and are fairly well predicted by the corresponding ex-vivo dimensions. The ratio between each linear dimension of A and C zones was found to be roughly constant over a large deposited energy span, both ex-vivo and in-vivo.

Yttrium-90 Radioembolization for Hepatocellular Carcinoma with Portal Vein Invasion: Validation of the Milan Prognostic Score.

The aim of the present study was to retrospectively analyze clinical outcomes of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT) treated with yttrium-90 radioembolization stratified by Milan PVTT score according to PVTT extension, tumor burden, and bilirubin levels. Seventy patients were included and classified into good (n = 15; 21.4%), intermediate (n = 33; 47.1%), and dismal (n = 22; 31.4%) prognostic groups. Median overall survival durations were 24.6 mo, 13 mo (hazard ratio = 3.2; 95% confidence interval [CI], 1.2-9.7; P = .016), and 5.9 mo (hazard ratio = 4.1; 95% CI, 1.4-13.4; P = .0096), respectively. The Milan score represents an easy tool to select patients with HCC with PVTT who may benefit from radioembolization.

Inferior vena cava filters: Concept review and summary of current guidelines.

Anticoagulation is the first-line approach in the prevention and treatment of pulmonary embolism. In some instances, however, anticoagulation fails, or cannot be administered due to a high risk of bleeding. Inferior vena cava filters are metal alloy devices that mechanically trap emboli from the deep leg veins halting their transit to the pulmonary circulation, thus providing a mechanical alternative to anticoagulation in such conditions. The Greenfield filter was developed in 1973 and was later perfected to a model that could be inserted percutaneously. Since then, this model has been the reference standard. The current class I indication for this device includes absolute contraindication to anticoagulants in the presence of acute thromboembolism and recurrent thromboembolism despite adequate therapy. Additional indications have been more recently proposed, due to the development of removable filters and of progressively less invasive techniques. Although the use of inferior vena cava filters has solid theoretical advantages, clinical efficacy and adverse event profile are still unclear. This review analyzes the most important studies related to such devices, open issues, and current guideline recommendations.

The Paradox of Modern Technology in Standardizing Thermal Liver Ablation: Fostering Uniformity or Diversity?

PURPOSE: Currently, significant medical practice variation exists in thermal ablation (TA) of malignant liver tumors with associated differences in outcomes. The IMaging and Advanced Guidance for workflow optimization in Interventional Oncology (IMAGIO) consortium aims to integrate interventional oncology into the standard clinical pathway for cancer treatment in Europe by 2030, by development of a standardized low-complex-high-precision workflow for TA of malignant liver tumors. This study was conducted at the start of the IMAGIO project with the aim to explore the current state and future role of modern technology in TA of malignant liver tumors. MATERIALS AND METHODS: A cross-sectional questionnaire was conducted followed by an expert focus group discussion with core members and collaborating partners of the consortium. RESULTS: Of the 13 participants, 10 respondents filled in the questionnaire. During the focus group discussion, there was consensus on the need for international standardization in TA and several aspects of the procedure, such as planning based on cross-sectional images, the adoption of different techniques for needle placement and the importance of needle position- and post-ablative margin confirmation scans. Yet, also considerable heterogeneity was reported in the adoption of modern technology, particularly in navigational systems and computer-assisted margin assessment. CONCLUSION: This study mirrored the current diversity in workflow of thermal liver ablation. To obtain comparable outcomes worldwide, standardization is needed. While advancements in tools and software hold the potential to homogenize outcome measurement and minimize operator-dependent variability, the rapid increase in availability also contributes to enhanced workflow variation.

Image-guided ablation for hepatocellular carcinoma.

Image-guided ablation is accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when surgical options-including resection and transplantation-are precluded. The term image-guided tumor ablation is defined as the direct application of chemical substances or sources of energy to a focal tumor in an attempt to achieve eradication or substantial tumor destruction. Over the past 25 years, several methods for local tumor destruction have been developed and clinically tested. Radiofrequency ablation (RFA) has shown superior anticancer effect and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials, and is currently established as the standard ablative modality. Nevertheless, novel thermal and nonthermal techniques for tumor ablation-including microwave ablation and irreversible electroporation-seem to have potential to improve the efficacy of RFA and are currently undergoing clinical investigation.

Thermal ablation of hepatocellular carcinoma.

Percutaneous treatment of hepatocellular carcinoma (HCC) by means of thermal ablation (TA) has been introduced in clinical guidelines as a potentially curative treatment for the early stages of the disease since the early 2000s. Due to its safety profile and cost-effectiveness, TA can be offered as a first-line treatment for patients with HCC smaller than 3 cm. Thermal ablative techniques are in fact widely available at many centres worldwide and include radiofrequency (RF) and microwave (MW) ablation, with the latter increasingly applied in clinical practice in the last decade. Pre-clinical studies highlighted, as potential advantages of MW-based ablation, the ability to achieve higher temperatures (>100°C) and larger ablation zones in shorter times, with less susceptibility to blood flow-induced heat sink effects. Despite these advantages, there is no evidence of superior overall survival in patients treated with MW as compared to those treated with RF ablation. Local control has been proven to be superior to MW ablation with a similar complication rate. It is expected that further improvement of TA results in the treatment of HCC will result from the refinement of guidance and monitoring tools and the careful assessment of ablation margins. Thermal ablative treatments may also be performed on nodules larger than 3 cm by applying multiple devices or combining percutaneous and intra-arterial approaches. The role of novel immunotherapy regimens in combination with ablation is also currently under evaluation in clinical trials, with several potential benefits. In this review, indications, technical principles, results, and future prospects of TA for the treatment of HCC will be examined.

Vessel-Guided Mesohepatectomy for Liver Partition and Staged Major Parenchyma-Sparing Hepatectomies with Super-Selective Portal Vein Embolization or Enhanced ALPPS to Achieve R0 Resection for Colorectal Liver Metastases at the Hepatocaval Confluence.

Background. R0 minor parenchyma-sparing hepatectomy (PSH) is feasible for colorectal liver metastases (CRLM) in contact with hepatic veins (HV) at hepatocaval confluence since HV can be reconstructed, but in the case of contact with the first-order glissonean pedicle (GP), major hepatectomy is mandatory. To pursue an R0 parenchyma-sparing policy, we proposed vessel-guided mesohepatectomy for liver partition (MLP) and eventually combination with liver augmentation techniques for staged major PSH. Methods. We analyzed 15 consecutive vessel-guided MLPs for CRLM at the hepatocaval confluence. Patients had a median of 11 (range: 0-67) lesions with a median diameter of 3.5 cm (range: 0.0-8.0), bilateral in 73% of cases. Results. Grade IIIb or more complications occurred in 13%, median hospital stay was 14 (range: 6-62) days, 90-day mortality was 0%. After a median follow-up of 17.5 months, 1-year OS and RFS were 92% and 62%. In nine (64%) patients, MLP was combined with portal vein embolization (PVE) or ALPPS to perform staged R0 major PSH. Future liver remnant (FLR) volume increased from a median of 15% (range: 7-20%) up to 41% (range: 37-69%). Super-selective PVE was performed in three (33%) patients and enhanced ALPPS (e-ALPPS) in six (66%). In two e-ALPPS an intermediate stage of deportalized liver PSH was necessary to achieve adequate FLR volume. Conclusions. Vessel-guided MLP may transform the liver in a paired organ. In selected cases of multiple bilobar CRLM, to guarantee oncological radicality (R0), major PSH is feasible combining advanced surgical parenchyma sparing with liver augmentation techniques when FLR volume is insufficient.

Local-regional treatment of hepatocellular carcinoma.

Local-regional treatments play a key role in the management of hepatocellular carcinoma (HCC). Image-guided tumor ablation is recommended in patients with early-stage HCC when surgical options are precluded and can replace resection in selected patients. Radiofrequency (RF) ablation has shown superior anticancer effects and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials and is currently established as the standard method for local tumor treatment. Novel thermal and nonthermal techniques for tumor ablation, including microwave ablation and irreversible electroporation, seem to have potential to overcome the limitations of RF ablation and warrant further clinical investigation. Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with asymptomatic noninvasive multinodular tumors in intermediate-stage disease. Embolic microspheres that have the ability to release a drug in a controlled and sustained fashion have been shown to substantially increase the safety and efficacy of TACE in comparison to conventional ethiodized oil-based regimens. The available data for radioembolization with yttrium 90 suggest that this is a potential new option for patients with HCC, and future studies should be devoted to assessments of the role of radioembolization in the treatment algorithm for HCC.