Loco-regional treatment of HCC: current status.

Hepatocellular carcinoma (HCC) represents one of the few cancers for which locoregional treatments are recognised as being able to cure and/or prolong survival and are included in international guidelines. This is due to the unique nature of HCC, in most cases occurring in patients with underlying virus- or alcohol-related cirrhosis. The treatment choice in patients with HCC is therefore driven not only by tumour staging, as in the great majority of cancers, but also by careful evaluation of liver function and physical status. Another specific feature of HCC is that it is the only tumour that can be cured by organ transplantation, with the aim of treating both the cancer and underlying liver disease. These characteristics configure a complex scenario and prompt the need for close cooperation among interventional oncologists, surgeons, hepatologists, and anaesthesiologists. In patients with limited hepatic disease, preserved hepatic function and good performance status, categorised as very early and early-stage HCC according to the Barcelona Clinic Liver Cancer (BCLC) classification, image-guided tumour ablation is included among the curative treatments. More than half of patients with HCC are, however, diagnosed late, despite the widespread implementation of surveillance programmes, when curative treatments cannot be applied. For patients presenting with multinodular HCC and relatively preserved liver function, absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread transcatheter arterial chemoembolisation (TACE) is the current standard of care. Although anti-tumour activity and promising survival results has been reported in cohorts of patients with advanced HCC treated with radio-embolisation, systemic treatment with the multi-kinase inhibitor, sorafenib, is still recommended for patients at this stage. In this article, current treatment strategies for HCC according to tumour stage are discussed, underlining the latest advances in the literature and technical developments.

A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications.

INTRODUCTION: Human neutrophil elastase (HNE) is involved in a variety of serious chronic diseases, especially cardiopulmonary pathologies. For this reason, the regulation of HNE activity represents a promising therapeutic approach, which is evident by the development of a number of new and selective HNE inhibitors, both in the academic and pharmaceutical environments. AREAS COVERED: The present review analyzes and summarizes the patent literature regarding human neutrophil elastase inhibitors for the treatment of cardiopulmonary diseases over 2014-2018. EXPERT OPINION: HNE is an interesting and defined target to treat various inflammatory diseases, including a number of cardiopulmonary pathologies. The research in this field is quite active, and a number of HNE inhibitors are currently in various stages of clinical development. In addition, new opportunities for HNE inhibitor development stem from recent studies demonstrating the involvement of HNE in many other inflammatory pathologies, including rheumatoid arthritis, inflammatory bowel disease, skin diseases, and cancer. Furthermore, the development of dual HNE/proteinase 3 inhibitors is being pursued as an innovative approach for the treatment of neutrophilic inflammatory diseases. Thus, these new developments will likely stimulate new and increased interest in this important therapeutic target and for the development of novel and selective HNE inhibitors.

The ten commandments of chemoembolization: expert discussion and report from Mediterranean Interventional Oncology (MIOLive) congress 2017.

Transarterial therapies in the setting of primary and secondary liver malignancies are becoming an essential part of the oncology landscape. The mechanism of action of c-TACE is the induction of tumor necrosis due to the high concentration of the chemotherapeutic that is delivered only locally and to the embolic effect that causes ischemia and increased dwell time of the chemotherapeutic in the tumor. Recently, DEB-TACE has emerged as a variation of c-TACE with the potential for the selective delivery of large amounts of drugs to the tumor for a prolonged period, thereby decreasing plasma levels of the chemotherapeutic agent and related systemic effects. There is an increasing consensus that compared with conventional lipiodol-based regimen, DEB-TACE offers standardized methodology, is more reproducible and is associated with improved response and significantly better safety profile. Using an easy to access point by point format, this manuscript summarizes the expert discussion from the Mediterranean Interventional Oncology Live Congress (MIOLive 2017) about the role of TACE in the treatment of liver tumors.

The ten commandments of liver ablation: expert discussion and report from Mediterranean Interventional Oncology (MIOLive) congress 2017.

Percutaneous liver ablation has become a cornerstone of the recently developed subspecialty of radiology - that is, interventional oncology. Thermal ablation technology has evolved rapidly during the past decades, with substantial technical and procedural improvements that can help obtain better clinical outcomes and safety profiles. Due to the widespread use of percutaneous ablation, a comprehensive review of the methodologic and technical considerations seems to be mandatory. This article summarizes the expert discussion and report from Mediterranean Interventional Oncology Live Congress (MIOLive 2017) that was held in Rome, Italy, integrating evidence-reported literature and experience-based perceptions, to assist not only residents and fellows who are training in interventional radiology but also practicing colleagues who are approaching to this locoregional treatment.

The ten commandments of hepatic radioembolization: expert discussion and report from Mediterranean Interventional Oncology (MIOLive) congress 2017.

Microsphere and particle technology represent the next-generation agents that have formed the basis of interventional oncology, an evolving subspecialty of interventional radiology. One of these platforms, yttrium-90 microspheres, is increasingly being used as a treatment modality for primary and secondary liver tumors. Due to the widespread use of radioembolization, a comprehensive review of the methodologic and technical considerations seems to be mandatory. This article summarizes the expert discussion and report from Mediterranean Interventional Oncology Live Congress (MIOLive 2017) that was held in Rome, Italy, integrating evidence-reported literature and experience-based perceptions, to assist not only residents and fellows who are training in interventional radiologists but also practicing colleagues who are approaching to this intra-arterial treatment.

Assessment of therapeutic effect of liver tumor ablation procedures.

Interventional procedures for percutaneous tumor ablation have gained an increasingly important role in the treatment of liver malignancies. After interventional therapies, diagnostic imaging has the key role in determining if the treated lesion is completely ablated or contains areas of residual viable neoplastic tissue. This is particularly important since in case of incomplete necrosis of the lesion, treatment can be repeated, and tumor ablation can be further pursued. The evaluation of the therapeutic effect of the procedure leads to different problems according to the histotype of the malignancy. In the case of hepatocellular carcinoma, detection of residual viable tumor is facilitated by the typical hypervascular pattern of this neoplasm. Contrast-enhanced color Doppler ultrasonography can be used to monitor tumor response, and, in case of partial necrosis, to target the areas of residual viable tumor. With spiral computed tomography or dynamic magnetic resonance imaging, residual viable hepatocellular carcinoma tissue is reliably depicted as it stands out in the arterial phase images against the unenhanced areas of coagulation necrosis. In the case of hypovascular metastases, a confident diagnosis of successful ablation can be made when an area of thermal necrosis exceeding that of the original lesion is depicted. Peripheral inflammatory reaction following ablation procedures should not be misinterpreted as tumor progression.

Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. METHODS: This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. RESULTS: Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). CONCLUSIONS: Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

How to differentiate liver lesions in cirrhosis.

The diagnosis of hepatocellular carcinoma is based on imaging examinations in combination with clinical and laboratory findings. Despite technological advances, imaging cirrhotic patients remains a challenging issue, since preneoplastic hepatocellular lesions, such as dysplastic nodules, mimic a small hepatocellular carcinoma. One of the key pathologic factors for differential diagnosis that is reflected in imaging appearances is the vascular supply to the lesion. It is accepted that imaging techniques may establish the diagnosis of hepatocellular carcinoma in nodules larger than 1 cm showing arterial hypervascularization and venous wash-out. In lesions that do not show a typical pattern, biopsy is still recommended. Contrast-enhanced ultrasound, spiral computed tomography or dynamic magnetic resonance imaging are required for characterization of lesions in cirrhotic liver. However, during the development of hepatocellular carcinoma, significant histological changes are present with or without an evident arterial supply of the nodule. Due to the ability of magnetic resonance to investigate differences in soft tissues and to exploit the properties of tissue-specific contrast agents, this imaging modality is particularly useful in the demonstration of the pathologic changes that take place at the histological level and at the level of the biliary and reticuloendothelial systems during carcinogenetic process in liver cirrhosis.

Radiofrequency thermal ablation of hepatocellular carcinoma: using contrast-enhanced harmonic power doppler sonography to assess treatment outcome.

OBJECTIVE: We evaluated the accuracy of contrast-enhanced harmonic power Doppler sonography in assessing the outcome of radiofrequency thermal ablation of hepatocellular carcinoma. SUBJECTS AND METHODS: Fifty patients with 65 hepatocellular carcinoma nodules (1-5 cm in diameter; mean diameter, 2.5 cm) were studied using unenhanced and contrast-enhanced harmonic power Doppler sonography before and after IV administration of a microbubble contrast agent. The examinations were repeated after treatment of the tumors with radiofrequency ablation. Findings of the Doppler studies were compared with those of dual-phase helical CT, which were used as points of reference for assessing treatment outcome. RESULTS: Before radiofrequency treatment, intratumoral blood flow was revealed by unenhanced power Doppler sonography in 48 (74%) of 65 hepatocellular carcinoma nodules. After injection of the contrast agent, intratumoral enhancement was observed in 61 (94%) of 65 hepatocellular carcinomas (p < 0.01). After radiofrequency treatment, all 51 (84%) of the 61 hepatocellular carcinomas found to be necrotic on helical CT scans failed to show enhancement on power Doppler sonograms. In nine of the 10 lesions that showed a residual viable tumor on helical CT scans, persistent intratumoral enhancement-matching the enhancing areas on helical CT images-was revealed by power Doppler sonography. These nine hepatocellular carcinomas were subjected to repeated radiofrequency thermal ablation with the guidance of contrast-enhanced power Doppler sonography. Complete necrosis was seen after the second treatment session in six of the nine lesions. CONCLUSION: Contrast-enhanced harmonic power Doppler sonography is an accurate technique for assessing the outcome of radiofrequency thermal ablation of hepatocellular carcinoma and may be useful in guiding additional treatment in patients with incomplete response to initial efforts.

MnDPDP-enhanced MRI vs dual-phase spiral CT in the detection of hepatocellular carcinoma in cirrhosis.

The objectives of this study were twofold: (a) to assess safety and tolerability of the hepatobiliary MR contrast agent MnDPDP; and (b) to investigate the sensitivity of MnDPDP-enhanced MRI, in comparison with dual-phase spiral CT, in the detection of hepatocellular carcinoma (HCC) in cirrhosis. Fifty patients with liver cirrhosis and histologically proven HCC were enrolled in a prospective phase-IIIB clinical trial. All patients underwent evaluation with dual-phase spiral CT and pre-contrast and post-contrast MRI at 1.5 T. The MR examination protocol included spin-echo (SE) and gradient-recalled-echo (GRE) T1-weighted images acquired before and 60-120 min after administration of 0.5 micromol/kg (0.5 ml/kg) MnDPDP (Teslascan, Nycomed Amersham, Oslo, Norway); and fast T2-weighted SE images obtained solely before contrast injection. Gold standard was provided by findings at Lipiodol CT in combination with follow-up spiral CT studies, which were repeated at 4-month intervals over a 10- to 27-month (mean +/- SD 20.1 +/- 5.1 months) follow-up period. No serious adverse event occurred. Eighty tumors ranging 0.8-9.1 cm in diameter (mean +/- SD 3.2 +/- 2.4 cm) were detected by Lipiodol CT or confirmed as cancerous foci by follow-up CT studies. Pre-contrast MRI detected 38 of 80 lesions (48%); MnDPDP-enhanced MRI, 65 of 80 lesions (81%); pre-contrast plus post-contrast MRI, 69 of 80 lesions (86%); and dual-phase spiral CT, 64 of 80 lesions (80%). The difference between unenhanced and MnDPDP-enhanced MRI was statistically significant (p < 0.001). The difference between MRI (pre-contrast plus post-contrast) and dual-phase spiral CT was not statistically significant (p = 0.33). The confidence in the final diagnosis, however, was significantly higher for MRI as compared with spiral CT (p<0.001). MnDPDP is a safe and well-tolerated hepatobiliary MR contrast agent. Magnetic resonance imaging with use of MnDPDP is significantly more sensitive than unenhanced MRI and as good as dual-phase spiral CT for detection of HCC in cirrhosis.