Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children

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High Cyclin E Staining Index in Blastemal, Stromal or Epithelial Cells Is Correlated with Tumor Aggressiveness in Patients with Nephroblastoma

PURPOSE: Identifying among nephroblastoma those with a high propensity for distant metastases using cell cycle markers: cyclin E as a regulator of progression through the cell cycle and Ki-67 as a tumor proliferation marker, since both are often deregulated in many human malignancies. METHODOLOGY/PRINCIPAL FINDINGS: A staining index (SI) was obtained by immunohistochemistry using anti-cyclin E and anti-Ki-67 antibodies in paraffin sections of 54 postchemotherapy nephroblastoma including 42 nephroblastoma without metastasis and 12 with metastases. Median cyclin E and Ki-67 SI were 46% and 33% in blastemal cells, 30% and 10% in stromal cells, 37% and 29.5% in epithelial cells. The highest values were found for anaplastic nephroblastoma. A correlation between cyclin E and Ki-67 SI was found for the blastemal component and for the epithelial component. Univariate analysis showed prognostic significance for metastases with cyclin E SI in stromal cells, epithelial cells and blastemal cells (p = 0.03, p = 0.01 and p = 0.002, respectively) as well as with Ki-67 SI in blastema (p<10(-4)). The most striking data were that both cyclin E SI and blastemal Ki-67 SI discriminated between patients with metastases and patients without metastasis among intermediate-risk nephroblastoma. CONCLUSIONS: Our findings show that a high cyclin E SI in all components of nephroblastoma is correlated with tumor aggressiveness and metastases, and that assessment of its expression may have prognostic value in the categorization of nephroblastoma

The P2Y1 receptor is involved in the maintenance of glucose homeostasis and in insulin secretion in mice

Pancreatic β cells express several P2 receptors including P2Y1 and the modulation of insulin secretion by extracellular nucleotides has suggested that these receptors may contribute to the regulation of glucose homeostasis. To determine whether the P2Y1 receptor is involved in this process, we performed studies in P2Y1 mice. In baseline conditions, P2Y1-mice exhibited a 15% increase in glycemia and a 40% increase in insulinemia, associated with a 10% increase in body weight, pointing to a role of the P2Y1 receptor in the control of glucose metabolism. Dynamic experiments further showed that P2Y1-mice exhibited a tendency to glucose intolerance. These features were associated with a decrease in the plasma levels of free fatty acid and triglycerides. When fed a lipids and sucrose enriched diet for 15 weeks, the two genotypes no longer displayed any significant differences. To determine whether the P2Y1 receptor was directly involved in the control of insulin secretion, experiments were carried out in isolated Langerhans islets. In the presence of high concentrations of glucose, insulin secretion was significantly greater in islets from P2Y1-mice. Altogether, these results show that the P2Y1 receptor plays a physiological role in the maintenance of glucose homeostasis at least in part by regulating insulin secretion

Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

SummaryHepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy

Type I interferon-mediated autoinflammation due to DNase II deficiency

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans

How to make EUS FNA a success?

L'aspiration à l'aiguille fine (FNA) sous EED est une méthode diagnostique qui s'est développée rapidement ces dernières années car elle apparaît à la fois efficace et bien adaptée pour déterminer la nature tumorale ou pseudo-tumorale de lésions pancréatiques, du foie gauche, de la voie biliaire principale, des surrénales, des parois digestives et du médiastin. L'examen cytologique bénéficiera d'une double technique associant l'étalement conventionnel sur lame et la cytologie en milieu liquide (LBC), selon Cytyc®. En effet, la technique de LBC est bien adaptée aux prélèvements pauci-cellulaires rencontrés fréquemment lorsque l'on ponctionne des tumeurs fibreuses, nécrotiques ou kystiques. De même, elle facilite les techniques complémentaires, en particulier l'immunocytochimie. L'étude réalisée sous l'égide de la Société Française de Cytologie Clinique a montré un taux significativement plus bas d'échantillons non représentatifs et une plus grande sensibilité de la technique en LBC par rapport à la cytologie conventionnelle par étalement direct. La préparation d'un bloc cellulaire est une méthode de traitement histologique complémentaire améliorant les performances diagnostiques des FNA, permettant d'enrober dans un gel des micro-fragments tissulaires dispersés dans un caillot qui sont inclus en paraffine. Les coupes sériées seront complétées à la demande par des colorations spéciales et de l'immunohistochimie. Cette procédure est simple, facile à mettre en oeuvre dans un laboratoire de pathologie. Le prélèvement comme l'interprétation des lésions nécessitent de l'expérience. Dans le domaine des ponctions d'organes profonds, il faut insister sur l'importance de la collaboration entre le clinicien et le pathologiste

Diagnosis of cystic pancreatic lesions by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA): Which sampling and why? Utility of cyst wall microbiopsy and fluid analysis by monolayered processing

La découverte d'une lésion kystique du pancréas pose de difficiles problèmes de prise en charge. Le traitement est fonction de la nature bénigne ou maligne du kyste. Les données fournies par l'examen clinique et l'imagerie ne permettent pas un diagnostic préopératoire, même si l'échoendoscopie digestive a un rôle important dans le diagnostic de ces lésions kystiques dont certaines sont potentiellement malignes. L'analyse biochimique du liquide intra-kystique (marqueurs tumoraux et enzymes pancréatiques) a été proposée pour permettre de préciser la nature du kyste. L'aspiration à l'aiguille fine permet un diagnostic fiable uniquement si la ponction et le traitement de l'échantillon suivent rigoureusement un mode opératoire spécifique. Les différents points critiques concernant le prélèvement, la préparation de l'échantillon cellulaire et de la microbiopsie sont étudiés. Une étude combinée cytologique et histologique est recommandée. Dans ces conditions, il est facile de faire un diagnostic positif de lésions kystiques telles que le cystadénocarcinome mucineux, l'adénocarcinome canalaire nécrotique, le carcinome à cellules acineuses, les tumeurs endocrines et la tumeur solide pseudopapillaire. Il convient ensuite de différencier les tumeurs mucineuses de celles qui ne le sont pas. La cytologie monocouche est utile pour faire le diagnostic des tumeurs paucicellulaires comme le cystadénome séreux ; elle permet de compléter l'analyse en autorisant des études immunocytochimiques

Accuracy of cytology vs. microbiopsy for the diagnosis of well-differentiated hepatocellular carcinoma and macroregenerative nodule: Definition of standardized criteria from a study of 100 cases

To determine the accuracy of ultrasound (US)-guided fine needle aspiration (FNA) for the diagnosis of well-differentiated hepatocellular carcinoma (wd HCC) and macroregenerative nodule (MRN) and to identify the most useful cytologic and histologic criteria to distinguish between those two diagnoses. STUDY DESIGN: Cytologic and histologic specimens of 50 wd HCC and 50 MRN were reviewed blindly and the diagnosis compared to the final clinical diagnosis. Twenty-eight cytologic and 25 histologic criteria were examined and subjected to statistical analysis. RESULTS: Among 100 cases studied, the final diagnosis was available for 43. In those 43 cases, combining analysis of cytologic and histologic specimens, the sensitivity of US-guided FNA was of 75% and the specificity 100%. Cytologic analysis was better than isolated histologic analysis, with a sensitivity of 75% vs. 68%, respectively. Sensitivity of cytologic diagnosis was lower for smaller nodules and for those located in poorly accessible hepatic segments. With the use of stepwise logistic regression analysis, four cytologic features (increased nuclear/cytoplasmic ratio, cellular monomorphism, nuclear crowding, loss of bile duct cells) and four histologic features (increased nuclear/cytoplasmic ratio, decreased Kupffer cells, cellular monomorphism, increased trabeculae thickness) were identified as predictive of HCC. CONCLUSION: This study demonstrated that FNA with US guidance can provide an accurate diagnosis of wd HCC and MRN. The limiting factor of the method is sampling error, especially for small HCC and nodules located in poorly accessible hepatic segments