Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects

Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are two different subtypes of primary tumors arising from liver parenchymal cells. These tumors differ by many histoclinical characteristics, and comparative analysis of genetic alterations in HB and HCC might provide some clues on the molecular oncogenic pathways leading to hepatocyte transformation. Recent outcomes have been provided by the assessment of global genetic changes in tumor cells, using conventional cytogenetic approaches, PCR-based microsatellite analysis and Comparative genomic Hybridization (CGH). Cytogenetic studies of HB, microsatellite analysis of HCC and recent CHG data have outlined common and distinctive characters between the two tumor types. HBs are characterized by a low number of chromosomal changes, consisting mainly of gains at chromosomes 1q, 2, 8q, 17q, and 20. By contrast, HCCs harbor multiple chromosomal abnormalities, predominantly losses, with increased chromosomal instability in tumors associated with hepatitis B virus infection. Common alterations in HB and HCC include gain of chromosomes 1q, 8q, and 17q, and loss of 4q. Another important common feature shared by the two tumor types is the frequent activation of Wnt/beta-catenin signaling by stabilizing mutations of beta-catenin. Immunohistochemical analysis of beta-catenin has demonstrated nuclear/cytoplasmic accumulation of the protein in most HBs and in more than one third of HCCs. Strikingly, beta-catenin mutations are associated with chromosomal stability in both tumor types. Together, these studies define different pathways in liver cell transformation, reflecting various developmental stages and multiple risk factors. A detailed understanding of the molecular hits underlying liver tumorigenesis, combined with clinicopathological parameters, will permit an accurate evaluation of major targets for prognostic and therapeutic intervention.     

Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal,...and get ready to face autoimmunity

Cellular immune responses can destroy cancer cells, achieving the cure of experimental malignancies. An expanding wealth of knowledge on the molecular basis of how to prime and amplify a T cell response has fueled a number of strategies successful at treating established tumors (rather than merely preventing tumor grafting). The most efficacious approaches operate at different stages, including: 1) priming the immune response using tumor antigen-expressing dendritic cells or tumor cells transfected with genes that render them immunogenic, 2) sustaining and amplifying immunity using agonistic monoclonal antibodies against costimulatory molecules or immune-potentiating cytokines, and 3) eliminating mechanisms that self-regulate the strength of the immune response, such as inhibitory receptors or regulatory T cells. A rational combination of such approaches holds great hope for cumulative and synergistic effects, but there is also evidence that they can open the flood-gates for unwanted inflammatory reactions. The next decade can be envisioned as the time when the first reproducibly efficacious combination regimes for cancer immunotherapy will become available and widely used in the clinic, as clinicians learn the best strategies and try to harness their potentially damaging effects.     

Transcatheter versus Surgical Closure of Secundum Atrial Septal Defect in Adults: Impact of Age at Intervention. A Concurrent Matched Comparative Study

Objectives. To compare the short‐ and mid‐term outcomes of surgical (SUR) vs. transcatheter closure of secundum atrial septal defect (ASD) using Amplatzer septal occluder (ASO) in adults with a very similar spectrum of the disease; and to identify predictors for the primary end point. Design. Single‐center, concurrent comparative study. Surgically treated patients were randomly matched (2:1) by age, sex, date of procedure, ASD size, and hemodynamic profile. Setting. Tertiary referral center. Patients. One hundred sixty‐two concurrent patients with ASD submitted to ASO (n = 54) or SUR closure (n = 108) according with their preferences. Main Outcome Measures. Primary end point was a composite index of major events including failure of the procedure, important bleeding, critical arrhythmias, serious infections, embolism, or any major cardiovascular intervention‐related complication. Predictors of these major events were investigated. Results. Atrial septal defects were successfully closed in all patients, and there was no mortality. The primary event rate was 13.2% in ASO vs. 25.0% in SUR (P = .001). Multivariate analysis showed that higher rate of events was significantly associated with age >40 years; systemic/pulmonary output ratio <2.1; and systolic pulmonary arterial pressure >50 mm Hg; while in the ASO group the event rate was only associated with the ASD size (>15 cm²/m²; relative risk = 1.75, 95% confidence interval 1.01–8.8). There were no differences in the event‐free survival curves in adults with ages <40 years. Conclusions. The efficacy for closure ASD was similar in both groups. The higher morbidity observed in SUR group was observed only in the patients submitted to the procedure with age >40 years. The length of hospital stay was shorter in the ASO group. Surgical closure is a safe and effective treatment, especially in young adults. There is certainly nothing wrong with continuing to do surgery in countries where the resources are limited.     

Frequent amplification of c-myc in ground squirrel liver tumors associated with past or ongoing infection with a hepadnavirus.

Persistent infection with hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC) in humans. HCC has also been observed in animals chronically infected with two other hepadnaviruses: ground squirrel hepatitis virus (GSHV) and woodchuck hepatitis virus (WHV). A distinctive feature of WHV is the early onset of woodchuck tumors, which may be correlated with a direct role of the virus as an insertional mutagen of myc genes: c-myc, N-myc, and predominantly the woodchuck N-myc2 retroposon. In the present study, we searched for integrated GSHV DNA and genetic alterations of myc genes in ground squirrel HCCs. Viral integration into host DNA was detected in only 3/14 squirrel tumors and did not result in insertional activation of myc genes, despite the presence of a squirrel locus homologous to the woodchuck N-myc2 gene. This suggests that GSHV may differ from WHV in its reduced ability to induce mutagenic integration events. However, the high frequency of c-myc amplification (6/14) observed in ground squirrel HCCs indicates that myc genes might be preferential effectors in the tumorigenic processes associated with rodent hepadnaviruses, a feature not reported so far in HBV-induced carcinogenesis. Together with previous observations, our results suggest that hepadnaviruses, despite close genetic and biological properties, may use different pathways in the genesis of liver cancer.     

The clinical features and diagnosis of a discordant atrioventricular connexion

Seventy-three patients were studied with a discordant atrioventricular connexion (ages 3 months to 46 years). In 58 the diagnosis was proved by angiography and in the other 15 at necropsy. Forty-eight had usual atrial arrangement and 25 mirror-image atria. Fifty-two patients had ventriculo-arterial discordance, 13 double outlet right ventricle, 4 ventriculoarterial concordance, 3 single outlet of the heart and 1 double outlet left ventricle. Nine with ventriculoarterial discordance had no other associated defects. The spatial relationship of the ventricles was variable, but in usual atrial arrangement the morphologically left ventricle tended to be on the right, and in mirror-image arrangement to the left of the morphologically right ventricle. The spatial relationship between the arterial valves was also variable, but in ventriculoarterial discordance and double outlet right ventricle the aortic valve was anterior and either to the right or left of the pulmonary valve in all but 3 cases. There is no typical clinical picture for these malformations. Symptoms depend upon the associated anomalies or the presence of atrioventricular dissociation. The diagnosis of a discordant atrioventricular connexion is best achieved by the echocardiographic and haemodynamic studies, but the electrocardiogram, chest radiograph and nuclear medicine studies may suggest its presence. Most patients are asymptomatic and progress normally to adult life. Only the symptomatic patients require surgical correction. Postoperative follow-up in the survivors is excellent, only 2 of 14 patients dying after surgery.     

Increased 5-Methylcytosine and Decreased 5-Hydroxymethylcytosine Levels are Associated with Reduced Striatal A2AR Levels in Huntington’s Disease

Adenosine A_2A receptor (A_2AR) is a G-protein-coupled receptor highly expressed in basal ganglia. Its expression levels are severely reduced in Huntington’s disease (HD), and several pharmacological therapies have shown its implication in this neurodegenerative disorder. The main goal of this study was to gain insight into the molecular mechanisms that regulate A_2AR gene (ADORA2A) expression in HD. Based on previous data reported by our group, we measured the methylcytosine (5mC) and hydroxymethylcytosine (5hmC) content in the 5′UTR region of ADORA2A in the putamen of HD patients and in the striatum of R6/1 and R6/2 mice at late stages of the disease. In this genomic region, 5mC and 5hmC remained unchanged in both mice strains, although low striatal A_2AR levels were associated with reduced 5mC levels in 30-week-old R6/1 mice and reduced 5hmC levels in 12-week-old R6/2 mice in exon m2. In order to analyze when this mechanism appears during the progression of the disease, a time course for A_2AR protein levels was carried out in R6/1 mice striatum (8, 12, and 20 weeks of age). A_2AR levels were reduced from 12 weeks of age onwards, and this downregulation was concomitant with reduced 5hmC levels in the 5′UTR region of ADORA2A. Interestingly, increased 5mC levels and reduced 5hmC were found in the 5′UTR region of ADORA2A in the putamen of HD patients with respect to age-matched controls. Therefore, an altered DNA methylation pattern in ADORA2A seems to play a role in the pathologically decreased A_2AR expression levels found in HD.