Rare RNF213 variant in adolescent with moyamoya disease. / Variante rara de RNF213 en adolescente con enfermedad de moyamoya.

INTRODUCTION: Moyamoya disease is a progressive steno-occlusive disease of the major intracranial arteries. Affected individuals are at risk for intracranial hemorrhagic or ischemic stroke, cognitive impairment, and developmental delays. Several susceptibility genes have been identified. The p.R4810K variant in the RNF213 gene has been identified in 95% of patients with familial moyamoya disease. CASE REPORT: We present the case of a 15-year-old adolescent girl who presented with chief complaints of dysgraphia, lack of coordination in the right hand, with two months of evolution. Cerebral magnetic resonance imaging revealed several ischemic lesions with different rates of evolution and magnetic resonance angiography showed multiple subocclusive stenoses. In the study of the sequences of the coding regions and intronic flanking regions (±8 bp) of the RNF213 gene, the variant c.12185G>A, p.(Arg4062Gln) was detected in heterozygosity in the RNF213 gene. This result indicates that the patient is heterozygous for the c.12185G>A, p.(Arg4062Gln) variant in the RNF213 gene. The detected variant has already been reported in the literature as a founder variant in the Asian population, associated with moyamoya syndrome. This variant is described in ClinVar as a variant of unknown clinical significance? Furthermore, it is not described in population databases (dbSNP, ESP, gnomAD). CONCLUSION: To our knowledge, the p.(Arg406262Gln) variant has been reported in three Japanese moyamoya disease patients and one European. Therefore, our patient was the second European moyamoya disease patient with this variant identified.

TITLE: Variante rara de RNF213 en adolescente con enfermedad de moyamoya.Introducción. La enfermedad de moyamoya es una enfermedad estenooclusiva progresiva de las principales arterias intracraneales. Los individuos afectados corren el riesgo de sufrir un accidente cerebrovascular hemorrágico o isquémico intracraneal, deterioro cognitivo y retrasos en el desarrollo. Se han identificado varios genes de susceptibilidad. La variante p.R4810K en el gen RNF213 se ha identificado en el 95% de los pacientes con enfermedad de moyamoya familiar. Caso clínico. Presentamos el caso de una adolescente de 15 años que se presentó con quejas principales de disgrafía y falta de coordinación en la mano derecha con dos meses de evolución. La resonancia magnética cerebral reveló varias lesiones isquémicas con diferentes ritmos de evolución y la angiorresonancia magnética mostró múltiples estenosis suboclusivas. En el estudio de las secuencias de las regiones codificantes y de las regiones intrónicas flanqueantes (±8 pb) del gen RNF213, se detectó la variante c.12185G>A, p.(Arg4062Gln) en heterocigosidad en el gen RNF213. Este resultado indica que la paciente es heterocigota para la variante c.12185G>A, p.(Arg4062Gln) en el gen RNF213. La variante detectada ya ha sido descrita en la bibliografía como una variante fundadora en la población asiática, asociada a síndrome de moyamoya. Esta variante está descrita en ClinVar como una variante de significado clínico desconocido. Además, no está descrita en las bases de datos poblacionales (dbSNP, ESP y gnomAD). Conclusión. Hasta donde sabemos, la variante p.(Arg4062Gln) se ha notificado en tres pacientes japoneses con enfermedad de moyamoya y en uno europeo. Por lo tanto, nuestro paciente fue el segundo europeo con enfermedad de moyamoya con esta variante identificada.

Clinical guide to perioperative management for videothoracoscopy lung resection (Section of Cardiac, Vascular and Thoracic Anesthesia, SEDAR; Spanish Society of Thoracic Surgery, SECT; Spanish Society of Physiotherapy).

The introduction of video-assisted thoracoscopic (VATS) techniques has led to a new approach in thoracic surgery. VATS is performed by inserting a thoracoscope through a small incisions in the chest wall, thus maximizing the preservation of muscle and tissue. Because of its low rate of morbidity and mortality, VATS is currently the technique of choice in most thoracic procedures. Lung resection by VATS reduces prolonged air leaks, arrhythmia, pneumonia, postoperative pain and inflammatory markers. This reduction in postoperative complications shortens hospital length of stay, and is particularly beneficial in high-risk patients with low tolerance to thoracotomy. Compared with conventional thoracotomy, the oncological results of VATS surgery are similar or even superior to those of open surgery. This aim of this multidisciplinary position statement produced by the thoracic surgery working group of the Spanish Society of Anesthesiology and Reanimation (SEDAR), the Spanish Society of Thoracic Surgery (SECT), and the Spanish Association of Physiotherapy (AEF) is to standardize and disseminate a series of perioperative anaesthesia management guidelines for patients undergoing VATS lung resection surgery. Each recommendation is based on an in-depth review of the available literature by the authors. In this document, the care of patients undergoing VATS surgery is organized in sections, starting with the surgical approach, and followed by the three pillars of anaesthesia management: preoperative, intraoperative, and postoperative anaesthesia.

Urethro-venous intravasation during retrograde urethrography in a dog.

A 9-year-old 6-kg male castrated mixed-breed dog was admitted to the hospital as a second opinion for left-sided nephrectomy. Plain radiographs, ultrasound, excretory urography and retrograde urethrography revealed left-sided hydronephrosis and calculi in the bladder and urethra. The urethral calculi were hydropropulsed into the bladder and nephrectomy and cystotomy were performed. Three days after surgery, the patient showed preputial inflammation, pain and pollakiuria. Retrograde urethrography was repeated and extra-urethral leakage of contrast medium into the penile tissue was identified, followed by filling of the draining veins, reaching the caudal vena cava, with subsequent opacification of the right renal pelvis and ureter and opacification of a lymph node. The dog improved during hospitalisation and a retrograde urography performed 6 months after the initial surgery confirmed full recovery.

Clinical guide to perioperative management for videothoracoscopy lung resection (Section of Cardiac, Vascular and Thoracic Anesthesia, SEDAR; Spanish Society of Thoracic Surgery, SECT; Spanish Society of Physiotherapy). / Guía clínica en el manejo perioperatorio para la cirugía de resección pulmonar por videotoracoscopia (Sección de Anestesia Cardiaca, Vascular y Torácica, SEDAR; Sociedad Española de Cirugía Torácica, SECT; Asociación Española de Fisioterapia, AEF).

The introduction of video-assisted thoracoscopic (VATS) techniques has led to a new approach in thoracic surgery. VATS is performed by inserting a thoracoscope through a small incisions in the chest wall, thus maximizing the preservation of muscle and tissue. Because of its low rate of morbidity and mortality, VATS is currently the technique of choice in most thoracic procedures. Lung resection by VATS reduces prolonged air leaks, arrhythmia, pneumonia, postoperative pain and inflammatory markers. This reduction in postoperative complications shortens hospital length of stay, and is particularly beneficial in high-risk patients with low tolerance to thoracotomy. Compared with conventional thoracotomy, the oncological results of VATS surgery are similar or even superior to those of open surgery. This aim of this multidisciplinary position statement produced by the thoracic surgery working group of the Spanish Society of Anesthesiology and Reanimation (SEDAR), the Spanish Society of Thoracic Surgery (SECT), and the Spanish Association of Physiotherapy (AEF) is to standardize and disseminate a series of perioperative anaesthesia management guidelines for patients undergoing VATS lung resection surgery. Each recommendation is based on an in-depth review of the available literature by the authors. In this document, the care of patients undergoing VATS surgery is organized in sections, starting with the surgical approach, and followed by the three pillars of anaesthesia management: preoperative, intraoperative, and postoperative anaesthesia.

[Genotype-phenotype association in a boy with neurofibromatosis type 1]. / Asociación genotipo-fenotipo en un niño con neurofibromatosis tipo 1.

TITLE: Asociación genotipo-fenotipo en un niño con neurofibromatosis tipo 1.

[Acute parainfectious transverse myelitis with radiculitis in a child with closed spinal dysraphism]. / Mielitis transversa parainfecciosa aguda con radiculitis en una niña con disrafismo espinal cerrado.

TITLE: Mielitis transversa parainfecciosa aguda con radiculitis en una niña con disrafismo espinal cerrado.

Human lactoferrin triggers a mitochondrial- and caspase-dependent regulated cell death in Saccharomyces cerevisiae.

We have previously shown that the antifungal activity of human lactoferrin (hLf) against Candida albicans relies on its ability to induce cell death associated with apoptotic markers. To gain a deeper understanding of the mechanisms underlying hLf-induced apoptosis, we characterized this cell death process in the well-established Saccharomyces cerevisiae model. Our results indicate that hLf induces cell death in S. cerevisiae in a manner that requires energy and de novo protein synthesis. Cell death is associated with nuclear chromatin condensation, preservation of plasma membrane integrity, and is Yca1p metacaspase-dependent. Lactoferrin also caused mitochondrial dysfunction associated with ROS accumulation and release of cytochrome c. Pre-incubation with oligomycin, an oxidative phosphorylation inhibitor, increased resistance to hLf and, accordingly, mutants deficient in the F1F0-ATP synthase complex were more resistant to death induced by hLf. This indicates that mitochondrial energetic metabolism plays a key role in the killing effect of hLf, though a direct role of F1F0-ATP synthase cannot be precluded. Overexpression of the anti-apoptotic protein Bcl-xL or pre-incubation with N-acetyl cysteine reduced the intracellular level of ROS and increased resistance to hLf, confirming a ROS-mediated mitochondrial cell death process. Mitochondrial involvement was further reinforced by the higher resistance of cells lacking mitochondrial DNA, or other known yeast mitochondrial apoptosis regulators, such as, Aif1p, Cyc3p and Aac1/2/3p. This study provides new insights into a detailed understanding at the molecular level of hLf-induced apoptosis, which may allow the design of new strategies to overcome the emergence of resistance of clinically relevant fungi to conventional antifungals.

Cathepsin D protects colorectal cancer cells from acetate-induced apoptosis through autophagy-independent degradation of damaged mitochondria.

Acetate is a short-chain fatty acid secreted by Propionibacteria from the human intestine, known to induce mitochondrial apoptotic death in colorectal cancer (CRC) cells. We previously established that acetate also induces lysosome membrane permeabilization in CRC cells, associated with release of the lysosomal protease cathepsin D (CatD), which has a well-established role in the mitochondrial apoptotic cascade. Unexpectedly, we showed that CatD has an antiapoptotic role in this process, as pepstatin A (a CatD inhibitor) increased acetate-induced apoptosis. These results mimicked our previous data in the yeast system showing that acetic acid activates a mitochondria-dependent apoptosis process associated with vacuolar membrane permeabilization and release of the vacuolar protease Pep4p, ortholog of mammalian CatD. Indeed, this protease was required for cell survival in a manner dependent on its catalytic activity and for efficient mitochondrial degradation independently of autophagy. In this study, we therefore assessed the role of CatD in acetate-induced mitochondrial alterations. We found that, similar to acetic acid in yeast, acetate-induced apoptosis is not associated with autophagy induction in CRC cells. Moreover, inhibition of CatD with small interfering RNA or pepstatin A enhanced apoptosis associated with higher mitochondrial dysfunction and increased mitochondrial mass. This effect seems to be specific, as inhibition of CatB and CatL with E-64d had no effect, nor were these proteases significantly released to the cytosol during acetate-induced apoptosis. Using yeast cells, we further show that the role of Pep4p in mitochondrial degradation depends on its protease activity and is complemented by CatD, indicating that this mechanism is conserved. In summary, the clues provided by the yeast model unveiled a novel CatD function in the degradation of damaged mitochondria when autophagy is impaired, which protects CRC cells from acetate-induced apoptosis. CatD inhibitors could therefore enhance acetate-mediated cancer cell death, presenting a novel strategy for prevention or therapy of CRC.

Magnetic resonance imaging characteristics of equine head disorders: 84 cases (2000-2013).

The equine head is an anatomically complex area, therefore advanced tomographic imaging techniques, such as computed tomography or magnetic resonance imaging (MRI), are often required for diagnosis and treatment planning. The purpose of this multicenter retrospective study was to describe MRI characteristics for a large sample of horses with head disorders. Horses imaged over a period of 13 years were recruited. Eighty-four horses met the inclusion criteria, having neurological (n = 65), sinonasal (n = 14), and soft tissue (n = 5) disorders. Magnetic resonance imaging accurately depicted the anatomy and allowed identification of the primary lesion and associated changes. There were good correlations between MRI findings and intraoperative or postmortem results. Magnetic resonance imaging showed the exact localization of the lesions, their size, and relation to surrounding structures. However, in the neurological group, there were 45 horses with no MRI abnormalities, 29 of which had a history of recurrent seizures, related to cryptogenic epilepsy. Magnetic resonance imaging was otherwise a valuable diagnostic tool, and can be used for studying a broad range of head disorders using either low-field or high-field magnets.

Yeast as a tool to explore cathepsin D function.

Cathepsin D has garnered increased attention in recent years, mainly since it has been associated with several human pathologies. In particular, cathepsin D is often overexpressed and hypersecreted in cancer cells, implying it may constitute a therapeutic target. However, cathepsin D can have both anti- and pro-survival functions depending on its proteolytic activity, cellular context and stress stimulus. Therefore, a more detailed understanding of cathepsin D regulation and how to modulate its apoptotic functions is clearly needed. In this review, we provide an overview of the role of cathepsin D in physiological and pathological scenarios. We then focus on the opposing functions of cathepsin D in apoptosis, particularly relevant in cancer research. Emphasis is given to the role of the yeast protease Pep4p, the vacuolar counterpart of cathepsin D, in life and death. Finally, we discuss how insights from yeast cathepsin D and its role in regulated cell death can unveil novel functions of mammalian cathepsin D in apoptosis and cancer.

Perioperative management of pulmonary hypertension during lung transplantation (a lesson for other anaesthesia settings).

Patients with pulmonary hypertension are some of the most challenging for an anaesthesiologist to manage. Pulmonary hypertension in patients undergoing surgical procedures is associated with high morbidity and mortality due to right ventricular failure, arrhythmias and ischaemia leading to haemodynamic instability. Lung transplantation is the only therapeutic option for end-stage lung disease. Patients undergoing lung transplantation present a variety of challenges for anaesthesia team, but pulmonary hypertension remains the most important. The purpose of this article is to review the anaesthetic management of pulmonary hypertension during lung transplantation, with particular emphasis on the choice of anaesthesia, pulmonary vasodilator therapy, inotropic and vasopressor therapy, and the most recent intraoperative monitoring recommendations to optimize patient care.

Simultaneous determination of the UV-filters benzyl salicylate, phenyl salicylate, octyl salicylate, homosalate, 3-(4-methylbenzylidene) camphor and 3-benzylidene camphor in human placental tissue by LC-MS/MS. Assessment of their in vitro endocrine activity.

UV-filters are widely used in many personal care products and cosmetics. Recent studies indicate that some organic UV-filters can accumulate in biota and act as endocrine disruptors, but there are few studies on the occurrence and fate of these compounds in humans. In the present work, a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to assess the presence of six UV-filters in current use (benzyl salicylate, phenyl salicylate, octyl salicylate, homosalate, 3-(4-methylbenzylidene) camphor, and 3-benzylidene camphor) in human placental tissue is proposed. The method involves the extraction of the analytes from the samples using ethyl acetate, followed by a clean-up step using centrifugation prior to their quantification by LC-MS/MS using an atmospheric pressure chemical ionization (APCI) interface. Bisphenol A-d16 was used as surrogate for the determination of benzyl salicylate, phenyl salicylate, octyl salicylate and homosalate in negative mode and benzophenone-d10, was used as surrogate for the determination of 3-(4-methylbenzylidene) camphor and 3-benzylidene camphor in positive mode. The found limits of detection ranged from 0.4 to 0.6ngg(-1) and the limits of quantification ranged from 1.3 to 2.0ngg(-1), while variability was under 13.7%. Recovery rates for spiked samples ranged from 97% to 104%. Moreover, the interactions of these compounds with the human estrogen receptor alpha (hERα) and androgen receptor (hAR), using two in vitro bioassays based on reporter gene expression and cell proliferation assessment, were also investigated. All tested compounds, except benzyl salicylate and octyl salicylate, showed estrogenic activity in the E-Screen bioassay whereas only homosalate and 3-(4-methylbenzylidene) camphor were potent hAR antagonists. Although free salicylate derivatives and free camphor derivatives were not detected in the human placenta samples analyzed, the observed estrogenic and anti-androgenic activities of some of these compounds support the analysis of their occurrence and their role as endocrine disrupters in humans.

Acetate-induced apoptosis in colorectal carcinoma cells involves lysosomal membrane permeabilization and cathepsin D release.

Colorectal carcinoma (CRC) is one of the most common causes of cancer-related mortality. Short-chain fatty acids secreted by dietary propionibacteria from the intestine, such as acetate, induce apoptosis in CRC cells and may therefore be relevant in CRC prevention and therapy. We previously reported that acetic acid-induced apoptosis in Saccharomyces cerevisiae cells involves partial vacuole permeabilization and release of Pep4p, the yeast cathepsin D (CatD), which has a protective role in this process. In cancer cells, lysosomes have emerged as key players in apoptosis through selective lysosomal membrane permeabilization (LMP) and release of cathepsins. However, the role of CatD in CRC survival is controversial and has not been assessed in response to acetate. We aimed to ascertain whether LMP and CatD are involved in acetate-induced apoptosis in CRC cells. We showed that acetate per se inhibits proliferation and induces apoptosis. More importantly, we uncovered that acetate triggers LMP and CatD release to the cytosol. Pepstatin A (a CatD inhibitor) but not E64d (a cathepsin B and L inhibitor) increased acetate-induced apoptosis of CRC cells, suggesting that CatD has a protective role in this process. Our data indicate that acetate induces LMP and subsequent release of CatD in CRC cells undergoing apoptosis, and suggest exploiting novel strategies using acetate as a prevention/therapeutic agent in CRC, through simultaneous treatment with CatD inhibitors.

Time-of-flight magnetic resonance angiography (TOF-MRA) of the normal equine head.

REASONS FOR PERFORMING STUDY: Noncontrast magnetic resonance angiography (MRA) is widely used in human and small animal medicine. However, this technique has not yet been described in the horse, and compared to other angiographic techniques MRA could be more cost efficient and potentially safer. OBJECTIVES: The aim of this study was to provide a comprehensive anatomical reference of the normal equine head vasculature using a noncontrast MRA technique, on both low- and high-field MRI. METHODS: Five healthy adult horses were examined, 4 with a low-field magnet (0.23T) and the remaining one with a high-field magnet (1.5T). The magnetic resonance angiography sequence used was TOF (time-of-flight) 2D-MRA and CT images of a vascular corrosion cast were subsequently used as anatomical references. RESULTS: The MRA imaging protocol provided good visualisation of all major intra- and extracranial vessels down to a size of approximately 2 mm in diameter on both low- and high-field systems. This resulted in identification of vessels to the order of 3rd-4th branches of ramification. The visibility of the arteries was higher than of the veins, which showed lower signal intensity. Overall, MRA obtained with the high-field protocol provided better visualisation of the arteries, showing all the small arterial branches with a superior resolution. CONCLUSIONS: The use of a specific vascular sequence such as TOF 2D-MRA allows good visualisation of the equine head vasculature and eliminates the need for contrast media for MRA. POTENTIAL RELEVANCE: Magnetic resonance angiography allows for visualisation of the vasculature of the equine head. Vessel morphology, symmetry and size can be evaluated and this may possibly play a role in preoperative planning or characterisation of diseases of the head, such as neoplasia or guttural pouch mycosis.

[Percutaneous and intra-arterial treatment of hepatocellular carcinoma]. / Tratamiento percutáneo e intraarterial del carcinoma hepatocelular.

Most patients with hepatocellular carcinoma (CHC) are not candidates for surgical resection or liver transplantation because of their stage at the time of diagnosis. There are a series of locoregional treatments that achieve a high objective response rate in this group of patients. Percutaneous ablation is considered the best treatment option for CHC (BCLC stage 0/A) not amenable to surgical treatment. In multifocal hepatocellular carcinoma without vascular invasion or extrahepatic extension (BCLC stage B), the only treatment option that has been shown to improve survival in randomized controlled trials is chemoembolization. The evaluation of the effectiveness of these treatments is based on the reduction of viable tumor observed at CT, MRI, or contrast-enhanced US. In this article, we review the indications, technique, and therapeutic efficacy of the different locoregional treatments for CHC.

Selective activation of protein kinase C-delta and -epsilon by 6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U).

6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U) is a diterpene compound isolated from Plectranthus grandidentatus with an antiproliferative effect on several human cancer cell lines. Herein, we studied the modulatory activity of coleon U on individual isoforms of the three protein kinase C (PKC) subfamilies, classical (cPKC-alpha and -betaI), novel (nPKC-delta and -epsilon) and atypical (aPKC-zeta), using a yeast PKC assay. The results showed that, whereas the PKC activator phorbol-12-myristate-13-acetate (PMA) activated every PKC tested except aPKC, coleon U had no effect on aPKC and cPKCs. Besides, the effect of coleon U on nPKCs was higher than that of PMA. This revealed that coleon U was a potent and selective activator of nPKCs. The isoform-selectivity of coleon U for nPKC-delta and -epsilon was confirmed using an in vitro PKC assay. Most importantly, while PMA activated nPKCs inducing an isoform translocation from the cytosol to the plasma membrane and a G2/M cell cycle arrest, coleon U induced nPKCs translocation to the nucleus and a metacaspase- and mitochondrial-dependent apoptosis. This work therefore reconstitutes in yeast distinct subcellular translocations of a PKC isoform and the subsequent distinct cellular responses reported for mammalian cells. Together, our study identifies a new isoform-selective PKC activator with promising pharmacological applications. Indeed, since coleon U has no effect on cPKCs and aPKC, recognised as anti-apoptotic proteins, and selectively induces an apoptotic pathway dependent on nPKC-delta and -epsilon activation, it represents a promising compound for evaluation as an anti-cancer drug.

Transarterial chemoembolization for patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has gained interest among the scientific community due to its increasing incidence in developed countries and the improvement of its diagnostic algorithm and therapeutic approach. Despite the universal implementation of screening programs in cirrhotics through biannual abdominal ultrasound, only 30% of HCC are diagnosed at an early stage, when radical treatments, surgical resection, liver transplantation and percutaneous ablation, are possible. Several therapies have been proposed for patients who cannot benefit from a radical approach, but only transarterial chemoembolization has demonstrated survival benefits. However, it can only be performed in patients withpreserved liver function, absence of extrahepatic spread/vascular invasion, and no significant cancer-related symptoms. Therefore, no more than 20% of the patients affected by HCC can be benefited by this therapeutic modality. The objective responses after procedure vary between 20% and 50%, with a significant rate of adverse-effects, particularly post-embolization syndrome. Further randomized controlled trials are needed to assess the best chemotherapeutic agent and the ideal re-treatment schedule.

Anesthetic management of a combined heart and liver transplantation in an amyloidotic patient: a case report.

Few cases of combined heart and liver transplantation (CHLT) have been reported for familial amyloidosis. Our first CHLT was performed on a female patient with familial amyloidosis due to a genetic defect in transthyretin, characterized by deposition of amyloid in various organs and tissues. This disease produced autonomic heart dysfunction that preceded the development of clinical manifestations and may be an important factor in determining the optimal timing for liver transplantation. CHLT can be performed successfully, even in patients with advanced disease. However, the most compromised patients are more exposed to intraoperative risks, postoperative complications, and worsening of extracardiac and extrahepatic symptoms. Our patient presented severe cardiac dysfunction requiring CHLT. The operative technique is far from being consolidated, despite this, both organs were transplanted in the same day with 2 hours in the intensive care unit (ICU) between surgeries. The outcome of both organs has been favorable. The amyloidotic liver was transplanted to another patient, a sequential (domino) transplantation.

Treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third cause of cancer-related death. Despite therapeutic advances, the overall survival of patients with HCC has not significantly improved in the last two decades. In the majority of the cases there is underlying cirrhosis, so the prognosis of HCC depends on not only tumor stage but also liver function. There is not a widely accepted HCC staging system. In our group we have developed a new staging classification that stratifies HCC patients into four major categories and simultaneously links staging with treatment. Patients at an early stage are those who present with an asymptomatic single HCC with a maximum diameter of 5cm or up to three nodules each less than 3cm. They will benefit from curative therapies, including resection, liver transplantation (LT), and percutaneous ablation. Patients exceeding these limits, but who are free of cancer-related symptoms and vascular invasion or extrahepatic spread fit into the intermediate stage and may benefit from palliation with chemoembolization. The patients with mild cancer-related symptoms and/or vascular invasion or extrahepatic spread are included in the advanced stage. In this stage there is not effective therapy, and these patients may profit from new therapies in the setting of randomized controlled trials (RCTs). Finally, the patients with severe cancer-related symptoms or great tumor burden belong to the terminal stage and only benefit from symptomatic treatment.