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International audience; Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.

Background Despite atezolizumab and bevacizumab (A + B) is currently the first‐line treatment for hepatocellular carcinoma (HCC) patients, some patients will not be adequate for this combination. In the setting of sorafenib some adverse events have been proposed as prognostic factors. Objective To characterize the early diarrhoea development as prognostic factor in 344 HCC patients. Methods The development of early diarrhoea in sorafenib treatment defined as patients who developed diarrhoea and needed dose modification within the first 60 days of treatment (e‐diarrhoea) and 3‐grouping variables were analysed: Patients with e‐diarrhoea, patients who developed diarrhoea after the first 60 days of treatment (L‐diarrhoea) and patients that never developed diarrhoea (never diarrhoea). Results The median overall survival in sorafenib treated patients was significantly different across groups (6.8 months for e‐diarrhoea, 26.7 months for L‐diarrhoea and 13.3 months for never‐diarrhoea). The emergence of e‐diarrhoea was associated with poor outcomes (hazard ratio [HR] 1.84 [95%CI 1.15–2.95]), while there was no increased/decreased risk of dismal evolution in patients with L‐diarrhoea (HR 0.66 [95%CI 0.42–1.03]). Conclusion The emergence of e‐diarrhoea in HCC patients treated with sorafenib is an early predictor of dismal evolution under this therapy. Thus, prompt identification of these non‐responders may be useful for an early switch to second‐line therapies., Key Summary Established knowledge on this subject Diarrhoea is a frequent adverse event of sorafenib and its emergence has been associated to better outcomes. What are the significant and/or new findings of this study? Early diarrhoea (e‐diarrhoea) in hepatocellular carcinoma patients treated with sorafenib is an early predictor of dismal evolution.Diarrhoea under sorafenib should not be taken as a predictive parameter of lack of benefit.E‐diarrhoea could be used as clinical biomarker for switching to second‐line therapies.

Background & aims Sorafenib and lenvatinib are the first-line treatments approved in hepatocellular carcinoma (HCC), but information is lacking about the relationships between their pharmacokinetics, patients pharmacogenetic profiles, adverse events (AE) and overall survival. We aimed to elucidate these relationships of tyrosine Kinase Inhibitors, such as sorafenib, in order to improve the design of trials testing it in combination with checkpoint inhibitors. Methods We assessed the pharmacokinetics of sorafenib and its N-oxide metabolite at day-0, day-7, day-30, day-60, day-90, day-120, day-150 and day-180 and nine single-nucleotide polymorphisms (SNP) in five genes related to sorafenib metabolism/transport to identify the best point for starting the combination between tyrosine kinases and checkpoint inhibitors. Results We prospectively included 49 patients (96% cirrhotic, 37% hepatitis-C, 82% Child-Pugh-A and 59% BCLC-C). Pharmacokinetic values peaked at day-7 and progressively declined until day-60. In the 16 patients without further dose modifications after day-60, pharmacokinetic values remained stable through day-180 (sorafenib P = .90; N-oxide P = .93). Pharmacokinetic values were higher in patients with early dermatological adverse events and lower in patients with early diarrhoea. Sorafenib and N-oxide pharmacokinetic values varied linearly with different alleles of MRP2*3972. Conclusions Sorafenib's pharmacokinetics is heterogeneous across HCC patients. This heterogeneity affects adverse events development and must be taken into account in setting the dose and timing of its combination with checkpoint inhibitors.

Purpose We aimed to determine the prevalence of mutations in the RHO gene in Spanish families with autosomal dominant Retinitis Pigmentosa (adRP), to assess genotype–phenotype correlations and to establish an accurate diagnostic algorithm after 23 years of data collection. Patients and Methods Two hundred patients were analysed through a combination of denaturing gradient gel electrophoresis, single-strand conformation polymorphism, genotyping microarray and Sanger sequencing of the RHO gene. Results Overall, 42 of 200 Spanish adRP families were mutated for RHO (21.0%). Twenty-seven different RHO mutations were detected; seven of them were novel. A genotype–phenotype correlation was established with clinical data from 107 patients. The most prevalent p.Pro347Leu mutation, responsible for 4.5% (9/200) of all mutated adRP families, was associated with a phenotype of early onset and severe course diffuse RP. Conclusions This retrospective study provides a wide spectrum of mutations in the RHO gene in Spanish patients with adRP. Also, the prevalence of mutations is similar to that reported in European population. Genotyping microarray followed by RHO sequencing is proposed as a first step in molecular diagnosis of adRP Spanish families. An increasing understanding of causal RHO alleles in adRP facilitates disease diagnosis and prognosis, especially for the prevalent p.Pro347Leu mutation.

Objective To identify genetic markers capable of predicting the pharmacokinetics, pharmacodynamics, and adverse effects of risperidone. Methods Genotyping was performed in 70 healthy volunteers receiving a single 1mg oral dose of risperidone. Risperidone and hydroxyrisperidone plasma levels were measured using high-performance liquid chromatography combined with tandem mass spectrometry. Prolactin concentration was quantified by direct chemiluminescence. Results PoorCYP2D6metabolizersshowedhigherrisperidoneCmax,areaunderthecurve(AUC),andt1/2,aswellaslowerclearance.Theyalso showed lower Cmax and AUC and higher t1/2 for hydroxyrisperidone. Furthermore, individuals with a mutant VKORC1 genotype had a lower risperidone AUC and t1/2 and higher clearance. The hydroxyrisperidone AUC was lower in individuals with the COMT mutant genotype. Risperidone increased prolactin levels (iAUC and iCmax), which were higher in women than in men. The most frequent reactions were somnolence (47.1%), headache (21.4%), and dizziness (17.1%). Women had neurological effects and headache more frequently than men. The incidence of headache was associated with polymorphisms in the AGTR1 and NAT2; neurological effects were associated with CYP2C19. Conclusions Differences in the pharmacokinetics of risperidone are due to polymorphisms in CYP2D6, COMT ,a ndVKORC1. Differences in adverse reactions can be explained by gender and polymorphisms in CYP2C19, AGTR1 ,a ndNAT2. Copyright © 2014 John Wiley & Sons, Ltd.

Background: This study was undertaken to analyse the OA1 gene (GPR143) and its involvement in a Spanish family presenting with nystagmus, a common symptom of X-linked ocular albinism (XLOA). Methods: DNA samples from the index case and eight relatives were analysed by multiplex ligation-dependent probe amplification (MLPA). Sequence analysis and restriction assay were used to confirm the results. In addition, an analysis of a STR located in intron 1 of the OA1 gene (OA-CA) was performed. Results: The father of the proband presented with nystagmus, a feature consistent with XLOA. Mutation screening by multiplex ligation-dependent probe amplification and sequence analysis of the exon 2 of the OA1 gene led to the identification of the novel p.Glu129fsX35 (g.5815delA) mutation in two affected males and four carrier females. Three relatives were found to be non-mutated. The deletion detected resulted in a truncated protein 35 codons downstream and generated a new restriction site for the XcmI endonuclease. Additionally, microsatellite analysis showed co-segregation with the disease in the family. Conclusions: A novel deletion in the OA1 gene was identified in a Spanish family with ocular albinism. The mutation detected is likely a loss-of-function alteration. To the best of our knowledge, we describe the first Spanish family known to present with XLOA due to mutations in the OA1 gene.

Background and purpose: The presence of cell-free fetal DNA in maternal plasma could allow performing a non-invasive prenatal diagnosis of Huntington disease (HD). The great advantage of this diagnosis is the absence of risk of fetal loss that it entails. Methods: Maternal plasma from four pregnant women in their first trimester of gestation with a fetus at-risk was studied. In all the four cases, the father was affected. Results: The diagnosis was performed both by a direct study of the mutation and an indirect haplotype study. By the direct analysis, three out of the four fetuses could be correctly diagnosed whilst the indirect analysis was only conclusive in one case. Conclusions: Non-invasive prenatal diagnosis of HD is possible by the analysis of fetal DNA in maternal plasma. Direct analysis of the mutation has shown higher accuracy than the haplotype analysis except for long expansions. Haplotype analysis would need to be improved for the study of Juvenile-onset HD. This diagnostic method would be limited to those couples with an affected male however this situation represents 80–90% of the pregnancies at-risk of HD. Moreover, it could be used as a confirmation test of healthy embryos transferred on pre-implantation genetic studies of HD.

Patients with Usher syndrome type II (USH2) show moderate-to-severe hearing loss (HL), retinitis pigmentosa and normal vestibular function. The progression of HL remains controversial. To evaluate whether a phenotype-genotype correlation exists regarding the issue of progression of HL, only USH2 patients with a defined genotype were selected. Ophthalmologic, vestibular and audiometric examination along with a mutation analysis of the USH2A gene (exons 1--21) was performed in twenty-eight Spanish USH2 patients. Ten different pathogenic mutations and 17 sequence variants not associated with the disease were found. Six of the 10 mutations are novel. Disease alleles were identified in 13 of the 28 families tested. Eight of these 13 families had a mutation found in both alleles. In the other five families, only one mutation was identified. The phenotypic data provide evidence for the existence of phenotypic differences between patients with the same genotype. These differences were observed at both the interfamilial and intrafamilial levels.

Purpose To evaluate whether MR angiography (MRA) is a useful tool for the follow-up of aortic aneurysms treated with nitinol endoluminal grafts. Materials and Methods We examined 28 patients treated with nitinol endovascular stents to repair an aortic aneurysm with CT angiography (CTA) and MRA. Eleven patients (group 1) underwent an MRA after a positive CTA for endoleak was observed. Afterwards, 17 patients (group 2) were scheduled for both follow-up examinations. The kind of endoleak that occurred and the maximum aortic diameter were compared. The sensitivity of CTA relative to MRA for detecting endoleaks in group 2 was calculated. Signal-to-noise ratios (SNRs) were measured in the aortoiliac lumen at the arterial phase in, above, and below the endoprostheses. Student's t-test was used to compare aneurysm dimensions and SNR measurements. Results Three type III leaks were correctly assessed at both examinations; however, CTA was less sensitive (50%) than MRA in depicting type II or unclassified leaks. No differences in aneurismal size were observed between the two examinations or between arterial SNRs observed in or out of the devices. Conclusion MRA can provide all relevant information necessary for the follow-up of patients treated with nitinol endoprostheses, and performs better than CTA in detecting endoleaks. J. Magn. Reson. Imaging 2004;20:803–810. © 2004 Wiley-Liss, Inc.

We report a girl with Turner syndrome phenotype, whose karyotype on amniocyte culture was 45,X, while cytogenetic analysis on peripheral blood lymphocytes showed the presence of a mosaic chromosome constitution with three different cell lines: 45,X[5]/46,XX[3]/47,XX,+18 [35]. No signs of trisomy 18 were observed and a follow up during childhood revealed normal psychomotor development. Parental origin and mechanism of formation were studied using high polymorphic microsatellites and Quantitative Fluorescent PCR. The 18-trisomic cells showed one paternal allele and two maternal homozygous alleles at different loci of chromosome 18, suggesting a maternal M-II meiotic or a postzygotic error. A biparental origin of the X-alleles in the trisomic cells were determined, being the paternal allele retained in the 45,X cells. The possible mechanism of formation implying meiotic and/or mitotic errors is discussed. © 2003 Wiley-Liss, Inc.

Purpose We compared the usefulness of Levovist-enhanced power Doppler imaging (PDI) and helical CT in the depiction of tumor vascularity before and after percutaneous ablation of small hepatocellular carcinomas (HCCs). Methods Thirty-one cirrhotic patients with solitary unresectable HCCs smaller than 5 cm (mean size, 2.7 ± 0.8 cm; range, 1.5–5.0 cm) recruited over a 15-month period were treated with percutaneous ethanol injection (n = 9) or radiofrequency ablation (n = 22). PDI, contrast-enhanced PDI (using Levovist), and multiphase contrast-enhanced helical CT were performed before and after percutaneous ablation, and vascularity findings were compared. Results Levovist significantly increased baseline intratumoral Doppler signals on PDI compared to non-contrast PDI. The most frequent tumor vascularity pattern was heterogeneous (45%). Vascularity was identified in all tumors by both contrast-enhanced PDI and helical CT before ablation. After percutaneous ablation, intratumoral vascularity was detected in 11 tumors by contrast-enhanced PDI and in 15 tumors by CT. The sensitivity, specificity, and diagnostic accuracy of contrast-enhanced PDI in demonstrating intratumoral vascularity, with CT being the gold standard, were 66%, 93%, and 81%, respectively. There was significant agreement between the 2 modalities in the depiction of tumor vascularity after ablation (κ = 0.6, p = 0.001). However, there were 5 false negatives and 1 false positive with contrast-enhanced PDI. Complete tumor necrosis was achieved in 21 patients (68%). Conclusions There was a good concordance between contrast-enhanced PDI and helical CT in the depiction of HCC vascularity before and after percutaneous ablation. However, although contrast-enhanced PDI may be useful for real-time guidance of treatment, its low sensitivity makes it inadequate to accurately assess the completeness of ablation. © 2003 Wiley Periodicals, Inc. J Clin Ultrasound 31:119–128, 2003

Objectives— Several attempts have been made to determine the gestational period in which the maximum number of fetal cells can be found in maternal blood and consequently which is the best week in which to perform a reliable non-invasive prenatal diagnosis. Most studies conclude that the number of nucleated red blood cells (NRBC) increases in line with gestation, but the number of cells that are fetal in origin (FNRBC) decreases in the third trimester. The aim of the present study was to make a practical comparative evaluation of the first and second trimesters to ascertain the period in which a greater number of FNRBC can be found of the total number of NRBC identified. Methods— Double density gradient and a posterior positive selection (CD71) by magnetic activated cell sorting (MACS) were employed. In the final fraction, erythroblasts were identified using Kleihauer staining and were studied using the fluorescence in situ hybridization (FISH) interphasic technique. Results— There was a significant difference (p

We report noggin mutations in three Spanish families with fibrodysplasia ossificans progressiva (FOP). The three propositi have typical FOP findings; in the first and third families the parents are unaffected, while in the second family the father is partially affected. DNA of the three propositi and their parents was screened by sequencing for mutations in the noggin gene (NOG). Sequencing indicated a G to C mutation at nucleotide 274 of the NOG gene in the first propositus, encoding for the G92R substitution at the peptide level; this first mutation is de novo, the corresponding change not being observed in parents. In the second propositus, a G to T mutation at nucleotide 271 encodes for the G91C substitution, transmitted in the corresponding family by the partially affected father. In the third propositus, sequencing indicated a G to A mutation at nucleotide 275, encoding for the G92E substitution; this third mutation is de novo. All three mutations, as well as the Delta42 deletion already reported, resulted in the alteration of the portion of the NOG gene at positions 265-282, encoding for the potential N-myristoylation site at residues 89-GGGGGA-94.

The potential use of fetal cells circulating in maternal blood for a non-invasive prenatal diagnosis has been widely described. Several authors have developed different methods for the enrichment of fetal cells from maternal peripheral blood. The aim of this study was to make a practical valuation of this new prenatal diagnosis technique, using those methods described as efficient and easy to carry out in a prenatal diagnosis unit. These methods consist of the double-density gradient and the positive selection by magnetic activated cell sorting (MACS) of the fetal erythroblasts, and the posterior study of the cells applying the FISH interphasic technique. Once the technique was ready, we obtained results from the study of 66 venous blood samples from women coming for prenatal diagnosis. Using a specific staining for fetal haemoglobin, fetal cells were identified in 63 cases. Fetal sex was well determined in 56 cases, 23 females and 33 males; in 7 cases the sex determination failed. All the aneuploidies found in a previous prenatal diagnosis were confirmed.

Retinitis pigmentosa is a term commonly given to a group of inherited and progressive disorders which affect the photoreceptors of the retina. As part of an ongoing research programme throughout Spain, clinical, epidemiological, and genetic studies have been carried out on these diseases. Here, we report the relative frequencies of the different genetic types in 503 non-syndromic and 89 syndromic RP families of Spanish origin. The most frequent syndromic RP forms were Usher syndrome type 1 (20/89 families = 30%) and Usher syndrome type 2 (44 families = 49%). Among non-syndromic RP forms, 12% were autosomal dominant, 39% autosomal recessive and 4% X-linked. Forty-one percent were isolated or simplex cases and in 4% the genetic type could not be established.

The discovery of fetal DNA in maternal plasma from early pregnancies has led to new opportunities for clinical application. In the last few years there have been numerous reported applications, mainly fetal gender and RhD genotyping. The prenatal diagnosis of some inherited genetic diseases such as Huntington disease is also very frequently required in the prenatal diagnosis routine. We have successfully diagnosed, with a non-invasive procedure, an unaffected HD fetus at the 13th week of gestation using fetal DNA from maternal plasma and the quantitative fluorescent PCR method, which is one of the most sensitive ways to detect fetal DNA in maternal plasma at such an early time of gestation.

Objectives Maternal plasma and serum are being used to detect fetal DNA by PCR in order to determine certain conditions such as fetal gender and RhD without invasive procedures. Because of the presence of maternal DNA in plasma, these approaches are limited to paternally inherited disorders or those de novo present in the fetus. We have assessed the possibility of performing the detection of a single-gene disorder such as a fetal paternally inherited Cystic Fibrosis mutation (Q890X) in maternal plasma. Methods The analysis was performed at 13 weeks of gestation using DNA extracted from maternal plasma. We used a PCR amplification of the Q890X mutation and a posterior restriction analysis of the PCR product. Results We were able to detect the presence of the mutation and thus the fetal condition of being a carrier of the paternal mutation. Conclusions We have made evident the possibility of detecting an inherited paternal mutation in a non-invasive way at the 13thr weeks of pregnancy. This methodology could be very useful in cases of paternally inherited dominant disorders. The technical improvements in fetal DNA detection and analysis might lead to the development of new applications in the non-invasive prenatal diagnosis field. Copyright © 2002 John Wiley & Sons, Ltd.

Small supernumerary marker chromosomes are seldom found in prenatal diagnosis and the majority of them are difficult to identify. The only possibility to give a more precise prognosis is by establishing its origin. FISH is the best technique to identify the chromosomal origin, but in the majority of cases large amounts of chromosomal material are needed and this is time consuming. We have used a modification of the FISH technique that allows the hybridization of several probes on one slide. Using this method, we have identified the first de novo mosaic dicentric supernumerary marker derived from chromosome 16 (smaller than chromosome 21) in amniotic fluid. The gestation and the follow-up of the baby were normal.

We report on a girl with minor anomalies and developmental delay carrying an apparently balanced paracentric inversion of chromosome 6q (q22qter). Fluorescent in situ hybridization analysis demonstrated a deletion of the subtelomeric region of 6q. This illustrates the use of specific subtelomeric fluorescent in situ hybridization probes to detect cryptic deletions as an important cause of mental retardation in seemingly balanced chromosome rearrangements.

It has been postulated that the deletion of band 13q22 may be associated with digital malformations, especially thumb and big toe anomalies. We report a family where the mother is carrying a balanced translocation between chromosomes 5p15 and 13q22. The offspring have a specific and well-defined phenotype depending on which is the unbalanced chromosome in the karyotype. When a partial trisomy of 13q22-->qter is present, the fetuses have polydactyly in the four limbs, and when the fetus is carrying a partial monosomy of this portion, an oligodactyly in all members can be observed.

Purpose: Recently a new gene encoding for a ceramide kinase like protein (CERKL) has been identified in a Spanish population and described to be associated with RP26. CERKL is assumed to be involved in sphingolipid-mediated apoptosis in the retina. Here we present a phenotypic study of patients carrying CERKL mutations. Methods: 210 unrelated Spanish families with autosomal recessive RP were screened using the ASPER arRP chip. Seven of these families presented a change in the CERKL sequence. Affected individuals of that families were investigated clinically including fundus examination, visual field testing and electroretinograhy. Results: The mutation p.Arg257ter was identified in homozygous state in all seven families. The 9 affected individuals presented a common phenotype with characteristic macular and peripheral lesions, the later resembling those found with Gyrate Atrophy. In fact, one of the affected individuals has initially been diagnosed as Gyrate Atrophy. Conclusions: This study presents the first genotype/phenotype correlation for persons carrying CERKL mutations From this initial study it seems likely that the p.Arg257ter mutation has a characteristic phenotype distinct from other arRP phenotypes.

Purpose: Supported by EVI-Genoret (EU LSHG-CT-512036) To build a patient registry that provides comprehensive, well standardized and high quality information on the phenotype and genotype of patients with hereditary and age related retinal diseases. To foster international collaboration by providing easy access to this resource of uniformly phenotyped patients for researchers worldwide. Methods: Within the EU funded project EVI-Genoret standards for comprehensive phenotyping of patients with ARMD and hereditary retinal dystrophies (HRD) have been developed. These standards are implemented as electronic Case Report Form (CRF) in the patient registry. SOPs for clinical procedures assure high level of data quality. A 3 level system of datasets ensures comprehensive data acquisition and protection of sensible data. Data accessibility tags are used in order to establish and share data between collaborators. The database is SQL based and uses Java-script as a platform independent user interface. Legal and ethical questions that arise in different countries are addressed by a professional project management. Results: The registry can be easily accessed by Internet after a registration process. The user interface enables simple access irrespective of the operating system, no special software must be installed. The electronic CRF guides through the examination. An intelligent system checks in real-time for plausibility of entered data, supports consequent entries and automatically hides non-relevant fields, thus facilitating time effective work. All entries are stored based on a 3 level system. Level1 as basic catalogue of entries is accessible to all users, only after one to one cooperation agreement mandatory level2 can be accessed. So far 4 European centres (Coimbra, London, Paris, Madrid, Tubingen) and one in the US contribute to the registry with more than 2000 entries for AMD and HRD in the first year since its implementation. Conclusions: We preset the first international patient registry for patients with HRD and ARMD based on widely accepted CRFs and clinical SOPs. This registry will serve as a valuable resource for clinical trials in both ARMD and HRD and for basic research in this field and is open for collaborators to join.

Several investigators have reported in vitro instability of ring chromosomes. We have evaluated the clinical and cytogenetic course over 8 years in a patient with ring chromosome 6 and found stability in this ring chromosome. The different cell lines remained constant, and the phenotype showed little variation. This syndrome seems to be related to the deletion in the ring rather than to its instability.

The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. Conclusion: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib. (Hepatology 2018;67:612-622).