A rare case report of breast sarcoma and synchronous thymoma in a 60-year-old woman.

This case report aims to describe the clinical presentation, imaging findings, histopathological features and therapeutic approach of a patient diagnosed with coexisting breast sarcoma and thymoma. A 64-year-old woman presented with a palpable lump in her left breast, and subsequent imaging studies (ultrasound, mammography, and MRI) revealed breast sarcoma, a rare and aggressive subtype of breast cancer. At the same time, the MRI revealed the presence of a thymoma. A multidisciplinary approach involving surgeon, breast specialist and oncologist is essential for optimal management and favorable outcomes in patients with this rare diagnosis.

MAX to MYCN intracellular ratio drives the aggressive phenotype and clinical outcome of high risk neuroblastoma.

Childhood neuroblastoma, a disease of the sympathetic nervous system, is the most common solid tumour of infancy, remarkably refractory to therapeutic treatments. One of the most powerful independent prognostic indicators for this disease is the amplification of the MYCN oncogene, which occurs at high levels in approximately 25% of neuroblastomas. Interestingly, amplification and not just expression of MYCN has a strong prognostic value, although this fact appears quite surprising as MYCN is a transcription factor that requires dimerising with its partner MAX, to exert its function. This observation greatly suggests that the role of MYCN in neuroblastoma should be examined in the context of MAX expression. In this report, we show that, in contrast to what is found in normal cells, MAX expression is significantly different among primary NBs, and that its level appears to correlate with the clinical outcome of the disease. Importantly, controlled modulation of MAX expression in neuroblastoma cells with different extents of MYCN amplification, demonstrates that MAX can instruct gene transcription programs that either reinforce or weaken the oncogenic process enacted by MYCN. In general, our work illustrates that it is the MAX to MYCN ratio that can account for tumour progression and clinical outcome in neuroblastoma and proposes that such a ratio should be considered as an important criterion to the design and development of anti-MYCN therapies.

Targeting the p53-MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: a new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients.

MDM2 is an important negative regulator of p53 tumor suppressor. In this study, we sought to investigate the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-acute lymphoblastic leukemia (ALL) patient samples. We demonstrated that Nutlin-3a treatment reduced viability and induced p53-mediated apoptosis in ALL cells with wild-type p53 protein, in a time and dose-dependent manner, resulting in the increased expression of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from B-ALL patients, including Ph+ ALL resistant patients carrying the T315I BCR-ABL1 mutation. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph- ALL.

Effects of a novel long noncoding RNA, lncUSMycN, on N-Myc expression and neuroblastoma progression.

BACKGROUND: Patients with neuroblastoma due to the amplification of a 130-kb genomic DNA region containing the MYCN oncogene have poor prognoses. METHODS: Bioinformatics data were used to discover a novel long noncoding RNA, lncUSMycN, at the 130-kb amplicon. RNA-protein pull-down assays were used to identify proteins bound to lncUSMycN RNA. Kaplan-Meier survival analysis, multivariable Cox regression, and two-sided log-rank test were used to examine the prognostic value of lncUSMycN and NonO expression in three cohorts of neuroblastoma patients (n = 47, 88, and 476, respectively). Neuroblastoma-bearing mice were treated with antisense oligonucleotides targeting lncUSMycN (n = 12) or mismatch sequence (n = 13), and results were analyzed by multiple comparison two-way analysis of variance. All statistical tests were two-sided. RESULTS: Bioinformatics data predicted lncUSMycN gene and RNA, and reverse-transcription polymerase chain reaction confirmed its three exons and two introns. The lncUSMycN gene was coamplified with MYCN in 88 of 341 human neuroblastoma tissues. lncUSMycN RNA bound to the RNA-binding protein NonO, leading to N-Myc RNA upregulation and neuroblastoma cell proliferation. High levels of lncUSMycN and NonO expression in human neuroblastoma tissues independently predicted poor patient prognoses (lncUSMycN: hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.06 to 3.28, P = .03; NonO: HR = 2.48, 95% CI = 1.34 to 4.57, P = .004). Treatment with antisense oligonucleotides targeting lncUSMycN in neuroblastoma-bearing mice statistically significantly hindered tumor progression (P < .001). CONCLUSIONS: Our data demonstrate the important roles of lncUSMycN and NonO in regulating N-Myc expression and neuroblastoma oncogenesis and provide the first evidence that amplification of long noncoding RNA genes can contribute to tumorigenesis.

MYCN-mediated transcriptional repression in neuroblastoma: the other side of the coin.

Neuroblastoma is the most common extra cranial solid tumor in childhood and the most frequently diagnosed neoplasm during the infancy. MYCN amplification and overexpression occur in about 25% of total neuroblastoma cases and this percentage increases at 30% in advanced stage neuroblastoma. So far, MYCN expression profile is still one of the most robust and significant prognostic markers for neuroblastoma outcome. MYCN is a transcription factor that belongs to the family of MYC oncoproteins, comprising c-MYC and MYCL genes. Deregulation of MYC oncoprotein expression is a crucial event involved in the occurrence of different types of malignant tumors. MYCN, as well as c-MYC, can heterodimerize with its partner MAX and activate the transcription of several target genes containing E-Box sites in their promoter regions. However, recent several lines of evidence have revealed that MYCN can repress at least as many genes as it activates, thus proposing a novel function of this protein in neuroblastoma biology. Whereas the mechanism by which MYCN can act as a transcriptional activator is relatively well known, very few studies has been done in the attempt to explain how MYCN can exert its transcription repression function. Here, we will review current knowledge about the mechanism of MYCN-mediated transcriptional repression and will emphasize its role as a repressor in the recruitment of a precise set of proteins to form complexes capable of down-regulating specific subsets of genes whose function is actively involved in apoptosis, cell differentiation, chemosensitivity, and cell motility. The finding that MYCN can also act as a repressor has widen our view on its role in oncogenesis and has posed the bases to search for novel therapeutic drugs that can specifically target its transcriptional repression function.

CDKL5, a novel MYCN-repressed gene, blocks cell cycle and promotes differentiation of neuronal cells.

Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene are associated with a severe epileptic encephalopathy (early infantile epileptic encephalopathy type 2, EIEE2) characterized by early-onset intractable seizures, infantile spasms, severe developmental delay, intellectual disability, and Rett syndrome (RTT)-like features. Despite the clear involvement of CDKL5 mutations in intellectual disability, the function of this protein during brain development and the molecular mechanisms involved in its regulation are still unknown. Using human neuroblastoma cells as a model system we found that an increase in CDKL5 expression caused an arrest of the cell cycle in the G(0)/G(1) phases and induced cellular differentiation. Interestingly, CDKL5 expression was inhibited by MYCN, a transcription factor that promotes cell proliferation during brain development and plays a relevant role in neuroblastoma biology. Through a combination of different and complementary molecular and cellular approaches we could show that MYCN acts as a direct repressor of the CDKL5 promoter. Overall our findings unveil a functional axis between MYCN and CDKL5 governing both neuron proliferation rate and differentiation. The fact that CDKL5 is involved in the control of both neuron proliferation and differentiation may help understand the early appearance of neurological symptoms in patients with mutations in CDKL5.

Cardiac MRI: comparison between single-shot fast spin echo and conventional spin echo sequences in the morphological evaluation of the ventricles.

PURPOSE: Black blood single shot FSE sequences (Nffse) employ 180 degrees RF refocalisation pulses preceded by an inversion RF double pulse associated to presaturation pulses. The latter produce signal void of the external volume, and possible reduction of the field of view without wrap-around artifacts along the phase coding direction. The aim of our study was to compare the diagnostic possibilities of the Nffse sequences with those of conventional SE study of cardiac morphology. MATERIAL AND METHODS: Twenty-five patients (19 males and 9 females with age ranging from 20 to 54 years) presented findings suggesting right ventricular arrhythmogenic dysplasia. MR examinations were performed with a 1,5 T unit (GE Signa Horizon Echospeed 8.3, Milwaukee, USA) and Torso Phased Array coil positioned at thoracic level. The morphologic study was performed with SE multiphase-multislice ECG-gated sequences (TR: R-R, TE: 30 ms, FOV 320X250, matrix 160X256, slice thickness 10 mm, acquisition time about 5 minutes) and Single-Shot FSE Half Fourier sequences (TR: R-R, TE: 30 ms, flip angle 120 degrees, ETL 30-40, FOV 360X180, Phase FOV 0,5, VBW 64 MHz, slice tickness 10 mm, acquisition time about 10-12 seconds), by imaging along the long and short axis. The study was completed with Fast Gradient Echo sequences (TR: 9ms, TE: 8,2ms, flip angle 25 degrees, VBW 15,63 MHz, FOV 320X250, 10 mm slice thickness, matrix 128X256), subsequently assessed by cine-MR. In order to compare both sequences, two experienced radiologists performed an analysis of quantitative parameters (signal intensity ratio between fat and muscular interventricular septum) and qualitative parameters (double blind evaluation for the presence of cardiac and respiratory artifacts). RESULTS: The signal intensity ratio for the Nffse sequence images was 4.63 +/- 1.56 on the long axis and 7.69 +/- 2.46 on the short axis, whereas it was 3.17 +/- 0.64 on the long axis and 3,50 +/- 0,75 on the axis one for SE images, with a statistically significant difference (p<0,001 and p<0.002 for the long and short axis, respectively). The two radiologists evaluation of the magnitude of artifacts on the SE and Nffse images was similar only as regards the images with significant artefacts alone. Nffse images consistently afforded a detailed evaluation of the right ventricular wall, although blurring artifacts were more common than with good quality SE images. Presence of fatty infiltration of the right ventricle wall was observed in 5 out of 25 patients. In the remaining 20 patients no fatty substitution of the muscular wall of the right ventricle was observed. DISCUSSION AND CONCLUSIONS: The Nffse sequences provide a number of gated multiphase-multislice images, similar to that obtained by conventional SE sequences, in one breath-hold time interval. Due to high intrinsic contrast and reduction of motion artifacts, the Nffse sequences allow a good evaluation of the ventricular morphology and subepicardial and paracardiac adipose tissue. Image quality can be suboptimal due to blurring artifacts. Therefore Nffse sequences can be advantageously employed to image patients with suspected right ventricular arrhythmogenic dysplasia, whenever conventional SE images exhibit substandard quality.