Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma.

Melanoma tumors usually retain wild-type p53; however, its tumor-suppressor activity is functionally disabled, most commonly through an inactivating interaction with mouse double-minute 2 homolog (Mdm2), indicating p53 release from this complex as a potential therapeutic approach. P53 and the tumor-promoter insulin-like growth factor type 1 receptor (IGF-1R) compete as substrates for the E3 ubiquitin ligase Mdm2, making their relative abundance intricately linked. Hence we investigated the effects of pharmacological Mdm2 release from the Mdm2/p53 complex on the expression and function of the IGF-1R. Nutlin-3 treatment increased IGF-1R/Mdm2 association with enhanced IGF-1R ubiquitination and a dual functional outcome: receptor downregulation and selective downstream signaling activation confined to the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. This Nutlin-3 functional selectivity translated into IGF-1-mediated bioactivities with biphasic effects on the proliferative and metastatic phenotype: an early increase and late decrease in the number of proliferative and migratory cells, while the invasiveness was completely inhibited following Nutlin-3 treatment through an impaired IGF-1-mediated matrix metalloproteinases type 2 activation mechanism. Taken together, these experiments reveal the biased agonistic properties of Nutlin-3 for the mitogen-activated protein kinase pathway, mediated by Mdm2 through IGF-1R ubiquitination and provide fundamental insights into destabilizing p53/Mdm2/IGF-1R circuitry that could be developed for therapeutic gain.

Contrast-enhanced ultrasound (CEUS) for the evaluation of focal liver lesions - a prospective multicenter study of its usefulness in clinical practice.

PURPOSE: To assess the value of contrast-enhanced ultrasound (CEUS) for differentiating malignant from benign focal liver lesions (FLLs) and for diagnosing different FLL types. MATERIAL AND METHODS: CEUS performed in 14 Romanian centers was prospectively collected between February 2011 and June 2012. The inclusion criteria were: age > 18 years; patients diagnosed with 1 - 3 de novo FLLs on B-mode ultrasound; reference method (computed tomography (CT), magnetic resonance imaging (MRI) or biopsy) available; patient's informed consent. FLL lesions were characterized during CEUS according to the European Federation of Societies for Ultrasound in Medicine and Biology guidelines. For statistical analysis, indeterminate FLLs at CEUS were rated as false classifications. RESULTS: A total number of 536 cases were included in the final analysis, 344 malignant lesions (64.2 %) and 192 benign lesions (35.8 %). The reference method was: CT/MRI - 379 cases (70.7 %), pathological exam - 150 cases (27.9 %) and aspiration of liver abscesses - 7 cases (1.4 %). CEUS was conclusive in 89.3 % and inconclusive in 10.7 % of cases. To differentiate between malignant and benign FLLs, CEUS had 85.7 % sensitivity, 85.9 % specificity, 91.6 % positive predictive value, 77.1 % negative predictive value and 85.8 % accuracy. The CEUS accuracy for differentiation between malignant and benign liver lesions was similar in tumors with diameter ≤ 2 cm and those with diameter > 2 cm. CONCLUSION: CEUS represents a useful method in clinical practice for differentiating between malignant and benign FLLs detected on standard ultrasonography, and the results of this study are in concordance with previous multicenter studies: DEGUM (Germany) and STIC (France).

[Primary obstructive megaureter- diagnosis and treatment]. / Modalitati de diagnostic si tratament în megaureterul primar obstructiv.

The authors have treated 13 cases of primary obstructive megaureter (POM) in children, presenting without vesicoureteric reflux. The diagnostic possibilities and the surgical approach options are discussed. Both Cohen and Leadbetter--Politano uretero-vesical reimplantation techniques proved to be successful in this series. Ureteric folding was done in 2 cases. Reported final results are good in 10 cases.

[Achalasia in children: Diagnostic opportunities and therapeutical options]. / Acalazia cardiei la copil--posibilitati diagnostice si optiuni terapeutice.

Achalasia is a functional disorder of the distal esophagus, which fails to relax during swallowing. Although being rare, this disorder is the source of a significant morbidity, including developmental disorders in children. Several therapeutical options are available: myorelaxants administration, esophageal dilations and surgery--distal esophageal myomectomy followed by an antireflux procedure. The paper introduces our experience in treating a number of 5 children between 1991 and 1998.

[The results of the Ravitch-Sutherland technic for surgical correction in pectus excavatum]. / Rezultate dupa tehnica Ravitch-Sutherland pentru corectia chirurgicala în pectus excavatum.

The aim of our study was to assess the functional and cosmetic results after performing a modified Ravitch-Sutherland procedure in children presenting with excavatum. A series of 31 children with ages ranging between 5 and 16 years, presenting with pectus excavatum, were operated between 1986-1996 in our service. In 5 cases surgical treatment was required by the presence of respiratory and/or cardiac functional impairment due to the malformation. In the other 23 cases operation was performed mainly for cosmetic reasons. In all cases a modified Ravitch-Sutherland procedure was performed. Modification consisted in renouncing at the plicature of the perichondra and in associating a diaphragmatic elongation and Bedouelle laparoplasty in all cases. Longitudinal sternotomy was performed in 2 cases with severely impaired ventilatory capacity. Functional and cosmetic results were good in all cases. In 2 cases, in which recurrence of the condition was observed, a second identical procedure was performed, with a good result. The interval between the operation and the moment of long-term evaluation ranged between 3 months and 11 years. We conclude that the modified Ravitch-Sutherland procedure represents an effective method for the treatment of pectus excavatum cases, offering good functional and cosmetic long-term results.

[The results of the Ravitch-Sutherland technic for surgical correction in pectus excavatum]. / Rezultate dupa tehnica Ravitch-Sutherland pentru corectia chirurgicala în pectus excavatum.

The aim of our study was to asses the functional and cosmetic results after performing a modified Ravitch-Sutherland procedure in children presenting with pectus excavatum. A series of 31 children with ages ranging between 5 and 16 years, presenting with pectus excavatum, were operated between 1986-1996 in our service. In 5 cases surgical treatment was required by the presence of respiratory and/or cardiac functional impairment due to the malformation. In the other 23 cases operation was performed mainly for cosmetic reasons. In all cases a modified Ravitch-Sutherland procedure was performed. Modifications consisted in renouncing at the plication of the perichondrium and in associating a diaphragmatic elongation and Bedouelle laparoplasty in all cases. Longitudinal sternotomy was performed in 2 cases with severely impaired ventilatory capacity. Functional and cosmetic results were good in all cases. In 2 cases, in which recurrence of the condition was observed, a second identical procedure was performed, with a good result. The interval between the operation and the moment of long-term evaluation ranged between 3 months and 11 years. We conclude that the modified Ravitch-Sutherland procedure represents an effective method for the treatment of pectus excavatum cases, offering good functional and cosmetic long-term results.