Occult spinal dysraphisms in newborns with skin markers: role of ultrasonography and magnetic resonance imaging.

PURPOSE: The purpose of this paper is to investigate occult spinal dysraphisms (OSD) using lumbar ultrasonography (LUS) in newborns presenting with specific skin markers or sacrococcygeal dimple. METHOD: From 2012 to 2015, we performed LUS in newborns with cutaneous stigmata and/or sacroccygeal dimple. Magnetic resonance imaging (MRI) was performed in all patients with abnormal ultrasound or features of neurological involvement in order to detect spinal lesions. RESULTS: We prospectively evaluated 475 newborns who presented cutaneous stigmata performing LUS during their 4 weeks of life though 439 completed the study. All patients had a follow-up of almost 12 months. Of these, 39 presented abnormal ultrasonography and underwent MRI. In this group, spinal dysraphism was confirmed in 12 patients. When considering skin markers, dermal sinus correlated with higher risk of spinal cord lesions, on the other hand the presence of simple sacral dimple alone denoted a very low risk of occult spinal dysraphism. The simultaneous presence of more skin markers and/or the presence of lumbar ultrasonography abnormality regarding the level of the conus, pulsatility, and the position of the cord, thickness of the filum terminale, or the presence of an intratecal mass, lipoma, or dermal sinus tract indicated the necessity to perform MRI in order to detect spinal cord abnormalities because of higher risk of spinal lesions. CONCLUSION: LUS in newborns with specific skin markers is a valid method to select patients in which MRI can be performed to detect OSD. The presence of a simple sacral dimple alone is a negligible marker for occult neural pathology while the presence of isolated dermal sinus or more than one cutaneous marker could be considered indicative of higher risk of spinal dysraphism.

Post-natal ultrasound morpho-dynamic evaluation of mild fetal hydronephrosis: a new management.

BACKGROUND: Fetal hydronephrosis is the most common anomaly detected on antenatal ultrasound examination, affecting 1-5% pregnancies. AIM: A new management in mild antenatal renal pelvis dilatation (ARPD), using a technique based on both morphological and dynamical evaluation. MATERIALS AND METHODS: Prospective study conducted during a 36-months period in 180 consecutive newborns referred as having mild ARPD. Examinations consisted in a morphological ultra-sound (US) scan evaluating antero-posterior diameter, renal parenchyma, ureteral evidence and pelvis morphology and, subsequently, a dynamic evaluation to analyze any change of the urinary tract during bladder voiding. All children were evaluated both at 3rd day and 1 month after birth. They were divided among those with negative examinations and those with at least one positive scan, trying to discriminate within the latter, children suspected for transient pyelectasis from those suspected for organic pathology. RESULTS: 108 patients had normal US findings both at birth and at 1 month. The remaining 72 babies had at least one abnormal US examination: 54 were suspected for transient pyelectasis, while 18 suspected for organic pathology. At the end of the study, 61 babies (33.9%) had final diagnosis of transient pyelectasis and 11 cases (6.1%) of organic pathology. At one month the dynamic pattern of US findings had the highest negative predictive value, while renal parenchyma evaluation has the highest accuracy. CONCLUSIONS: a dynamic US approach allowed to better select among infants suspected for transient pyelectasis from those suspected for organic pathology, avoiding unnecessary and invasive examinations in healthy babies.

Parathyroid-gland ultrasonography in clinical and therapeutic evaluation of renal secondary hyperparathyroidism.

PURPOSE: This study evaluated the relationship between ultrasonographic (US) parameters of parathyroid glands (PTGs) in haemodialysis patients (HDP) and degree of secondary hyperparathyroidism (SHPT), therapeutic responsiveness and type of PTG hyperplasia (diffuse or nodular). MATERIALS AND METHODS: In 85 HDP, we evaluated the following US parameters of all and of the largest PTGs: number, maximum longitudinal diameter (MLD), structural (hypoechoic, heterogeneous, nodular) and vascular (nonhypovascular, intermediate, hypervascular) echo-pattern scores. Sixty-nine HDP underwent medical therapy (vitamin D, 39; vitamin D/cinacalcet, 30) and 16 underwent parathyroidectomy. The 69 HDP were classified as responders [median intact parathyroid hormone (iPTH) ≤300 pg/ml during follow-up) or nonresponders (iPTH >300 pg/ml). RESULTS: Number, MLD and structural and vascular echo patterns of PTGs were significantly correlated with iPTH and calcium concentrations. In the 41 (59%) responders, number (0-1), MLD (<10 mm) and structural and vascular scores (1-2) of the largest PTG were significantly lower than in nonresponders. Receiver operating curve (ROC) curve analysis showed high sensitivity and specificity (90% and 73%, respectively) of the MLD (<10mm) of the largest PTG in the predicting therapeutic outcome. US and histological MLD are significantly correlated and predict the type of hyperplasia. CONCLUSIONS: US parameters of PTGs are correlated to the degree of SHPT and type of hyperplasia and predict responsiveness to medical therapy.

Retrospective analysis of outcome and prognostic factors of subcutaneous mast cell tumours in dogs undergoing surgery with or without adjuvant treatment.

Subcutaneous mast cell tumours (SC MCTs) can display a different biological behaviour in dogs when compared to their cutaneous counterpart. There is a paucity of information with regards to the outcome of dogs with SC MCTs treated with surgery and/or receiving adjuvant chemotherapy. The aim of this study was to retrospectively review the outcome of dogs with surgically excised SC MCTs undergoing adjuvant treatment or not. A secondary aim was to assess prognostic factors in the same group. Fifty-two cases were included. Recurrence rate was 15% and 63% of evaluated lymph nodes were consistent with early or overt metastasis. Median survival time (range 83-1357 days) and median time to progression (range 14-1357 days) were not reached. Factors predictive of shorter overall survival time included increasing age (HR 1.29, 95% CI 1.06-1.55, p = .0092), presence of clinical signs at presentation (HR 10.44, 95% CI 2.69-40.52, p = .0007), mitotic count >4 (HR 8.69, 95% CI 2.55-29.55, p = 0.0005), presence of multinucleation (HR 4.21, 95% CI 1.35-13.18, p = .0135), use of neoadjuvant and adjuvant chemotherapy (HR 7.16, 95% CI 1.26-40.73, p = .0266). The same factors, together with increasing tumour dimensions, were predictive for shorter progression-free survival (PFS), including increasing age (p = .0012), presence of clinical signs at presentation (p = .0045), increasing tumour dimensions (p = .0004), MC > 4 (p = .0004), presence of multinucleation (p = .0282), use of neoadjuvant and adjuvant chemotherapy (p = .0485). No variables remained significant for overall survival using multivariate analysis. There was a longer survival in cases where chemotherapy was not required (HR 0.14, 95% CI 0.03-0.68, p = .0148), and this variable remained significant for PFS on multivariate analysis (HR 0.13, 95% CI 0.02-0.76, p = .02). In conclusion, our study suggests that dogs with SC MCTs, in the absence of negative prognostic factors, may have a prolonged survival when treated with surgery alone. Further studies are needed to clarify the role of adjuvant treatment for biologically aggressive SC MCTs in dogs.

Augmentative and alternative communication improves quality of life in the early stages of amyotrophic lateral sclerosis.

This study aimed to evaluate the efficacy of low-tech augmentative and alternative communication (AAC) aids in improving quality of life (QoL) and mood disorders, as well as the psychosocial impact of assistive devices, in 10 patients affected by amyotrophic lateral sclerosis (ALS) in the early stage of the disease, when speech difficulties appear. The AACtraining (AAC-T) study lasted around six months and comprised two phases of three months each: AAC-intervention (AAC-I) followed by AAC-familiarization (AAC-F). All the patients were assessed at the beginning (T0) and at the end (T1) of AAC-I, as well as at the end of AAC-F (T2). During the AAC-I phase, we applied a three-phase AAC intervention model to evaluate intelligibility of language, participation patterns, communication needs and adaptation to the AAC tools. All the patients showed a gradual and significant improvement, especially in acceptance of the AAC aids, mood and QoL. Moreover, a reduction of caregiver burden was noted. Our study has demonstrated the utility of the AAC aids also in the early stages of the disease in patients with ALS presenting with dysarthria. In our opinion, AAC-T may act as a bridge between the initial and later phases of the disease, when patients need to use high-tech aids, including an eye-tracking communication device. In conclusion, in this study we highlighted how early AAC-T in patients with ALS may be a valuable tool to demonstrate how specific strategies and low-technology aids can improve QoL of these patients and their caregivers, also decreasing stress and depression.

Migraine as possible red flag of PFO presence in suspected demyelinating disease.

OBJECTIVES: To investigate a possible association between isolated white matter lesions suggestive of demyelinating disease in magnetic resonance imaging (MRI) and patent foramen ovale (PFO) evidence in migraine patients, with or without aura. MATERIALS: 31 migraine patients, 28 females and 3 males, with MRI evidence of white matter lesions suggestive of demyelinating disease according to the Barkhof Criteria. All patients underwent further diagnostics including lumbar puncture, autoimmunity panel and cardiological evaluation to detect the presence of PFO. The mean duration of follow-up was 3.46 years and MIPAV software was used to analyze MRI imaging. RESULTS: 14 of the 31 patients (45%) had PFO. A significant association was found between PFO and migraine with visual aura (p < 0.001). No difference in lesion number, volume or area between patients with and without PFO was found, but the distribution was mainly occipital (p < 0.001) in patients with PFO. The follow-up showed a stationary lesion load in all PFO patients; no infratentorial or spinal cord lesion and no enhancement or corpus callosum lesion was ever detected. At the end of follow-up four patients developed multiple sclerosis: younger age at first MRI and oligoclonal bands were associated risk factors. CONCLUSIONS: Migraine is often one of the main symptoms leading to MRI, and in many cases white matter lesions of unspecific significance are discovered, thus placing demyelinating diseases in the differential diagnosis. Our study underlines the potential pathogenetic role of PFO in generating white matter lesions in migraine patients (45%), particularly those with visual aura and occipital lesions. For this reason, we affirm that PFO represents a cardinal point in the differential diagnosis of suspected demyelinating disease.

DNA methylation and Cancer: Identifying and targeting epigenetic modifications may be the future of cancer therapy?

DNA methylation has been recognized as one of the most important epigenetic mechanisms regulating the expression and inhibition of genes giving rise to an organism's phenotype. It is hence of no surprise that when DNA methylation mechanisms are disrupted by intrinsic or extrinsic causes, the likelihood of tumourigenesis increases. Both hypermethylation and hypomethylation may predispose to cancer formation through aberrant inhibition or expression of particular genes and this is seen in different types of cancers, such as laryngeal squamous cell carcinoma and acute myeloid leukaemia. By increasing our knowledge and understanding of these epigenetic mechanisms, we will be able to develop diagnostic techniques such as methylation profiling, to screen for and detect aberrant methylation patterns which may predispose to cancer formation in our patients. This would enable early diagnosis and treatment which may also involve the use of drugs developed to provide directed epigenetic therapy, shifting away from the current trend which involves the use of radical anti-cancer therapy. These diagnostic and treatment options may be the future of cancer management.

New prospects for ultrasound contrast agents.

Considering the several suggestions regarding the future developments of echocontrast agents, there is a striking difference between the few compounds actually available on the market and used in clinical practice and those undergoing experimental clinical trials. It is therefore difficult to predict what will be the actual impact of these agents in the next future. Future developments will probably go beyond color enhancement which was the end-point till a very short time ago. They can be schematically summarized as follows: (1) development of new substances which enhance both color and gray scales; (2) use of new-generation substances, such as BR1 (Bracco, Milan, Italy) and EchoGen (Sonus, Bothell, WA), which use a gas other than air, such as perfluorate compounds which are more stable and guarantee longer and stronger effects; (3) use of more complex compounds acting at different levels. For example, SHU 536A (Sonovist) produces resonance phenomena with the second and third harmonics, and also stimulated acoustic emission which permits the morphological study of liver parenchyma. Other promising compounds are liposomes and aerosomes. Among the new possibilities in recording and observing phenomena, we can distinguish two main application fields: one is based on the physics of ultrasound and related to the presence of microbubbles in an acoustic field. These phenomena are generally obtained increasing the emission acoustic pressure, which eventually results in microbubble destruction and they are called nonlinear because there is no direct relationship between emission and return frequencies. These phenomena, which are detectable only with dedicated equipment, include: the resonance phenomenon with harmonic emission; intermittent harmonic emission and stimulated acoustic emission. The other application field is not strictly related to ultrasound physics and includes all the systems which can detect the presence of microbubles qualitatively or quantitatively. Other possible applications are related to the possibility of acquiring not only morphological but also functional data, especially in cardiology and neurology. Finally, targeted agents are potentially capable of demonstrating receptor sites or specific molecules, which may open very interesting therapeutic routes.

Multi-centre clinical study evaluating the efficacy of SonoVue (BR1), a new ultrasound contrast agent in Doppler investigation of focal hepatic lesions.

OBJECTIVES: SonoVue is a new ultrasound contrast agent, which consists of stabilised microbubbles of a sulphur hexafluoride gas. The aim of the study was to assess its efficacy in the Doppler investigation of focal hepatic lesions. MATERIALS AND METHODS: Seventy patients with focal liver tumours were studied. Four doses (0.3, 0.6, 1.2 and 2.4 ml) of SonoVue were administered intravenously with at least 10 min delay between each injection. A complete colour/power and spectral Doppler imaging investigation of the lesions was performed at baseline pre-dosing and after each SonoVue injection. All examinations were recorded on SVHS videotapes. Baseline and post contrast videotapes were reviewed by the on-site (un-blinded) investigators and by two off-site blinded readers (a) to grade the global quality of the Doppler scans of the focal lesions vascularity and the normal parenchymal vessels (b) to measure the duration of clinically useful Doppler signal enhancement and (c) to determine the diagnostic accuracy and performance of the enhanced versus unenhanced scans using histopathology, tumour markers, CT and/or MR as the reference standard. RESULTS: A statistically significant improvement was observed at all four SonoVue doses in the off site assessment of global quality of the Doppler examination of tumoral and normal parenchymal vessels in comparison with the baseline (P < 0.05). The median duration of clinically useful enhancement was significantly increased with increasing doses (P < 0.001), ranging between 1.4-2.2 min for the lowest dose and 3.2-3.8 min for the highest dose for the off-site readers. On-site assessment of diagnostic accuracy showed a significant increase in the specificity of the Doppler diagnoses (P < 0.0016) with an increase in the positive and negative predictive values and in the likelihood ratio in differentiating between benign and malignant lesions. Off-site evaluation showed a significant increase in the accuracy of enhanced Doppler diagnosis in comparison with the baseline performance. CONCLUSION: The results suggest that SonoVue is effective in improving the display of tumoral vascularisation and may be useful in the characterisation of focal liver lesions.

Diagnostic imaging of differentiated thyroid carcinoma.

The role of diagnostic imaging in differentiated thyroid carcinoma is analyzed. 99mTc-pertechnetate 123I and 131I scintigraphy allows the evaluation of nodules with their differentiation in cold (hypofunctioning) and hot (functionally autonomous) nodules; thyroid carcinomas are cold nodules even if most of them are benign. On sonography thyroid nodules are well visualized with the definition of their site, number, size (not very useful parameters for the diagnosis of malignancy), echoic structure, and vascularization on color Doppler. The sonographic findings suggestive of differentiated thyroid carcinoma are: solid and hypoechoic structure, irregular ill-defined margins, absent or discontinuous peripheral ring, microcalcification, intranodular vascularization, local lymphadenopathies. These findings are characteristic but not pathognomonic, mostly for papillary carcinoma, while in the frequently isoechoic follicular carcinoma microcalcification and lymph node metastases are rare. Only the finding, although rather infrequent, of the dissemination to adjacent structures (muscles and vessels) is a definite indication for malignancy of a thyroid nodule. Color Doppler sonography plays a major role in the postoperative staging and follow-up, in combination with thyroglobulin determination and 131I whole body scintigraphy and it allows the detection of local and/or laterocervical lymph node recurrence. The most typical sonographic findings of metastatic lymphadenopathy are the roundish shape (length/anteroposterior diameter ratio-L/A < 1.5), not visible or displaced nodal hilum, thickened cortical layer with echoic structure similar to that of thyroid parenchyma, at times with microcalcification, cortical vascularization and dismantled angioarchitecture. CT and MRI are occasionally more useful to evaluate the substernal or retrosternal extension of voluminous thyroid masses and to identify local or distant metastases.

[Role of Doppler color ultrasonography in the diagnosis of thyroid carcinoma]. / Ruolo dell'eco-color-doppler nella diagnosi dei carcinomi tiroidei.

The aim of this study is to assess the efficacy and accuracy of color flow-Doppler sonography (CFDS) in predicting the malignancy of thyroid nodules. Seventy eight consecutive patients (52 females and 26 males), with 78 thyroid nodules (29 single nodules and 49 in a nodular goiter) have been examined by CFDS, before surgery, evaluating the hypoechogenicity of the nodule, the presence of microcalcifications and the halo sign absent and the vascular pattern, which has been classified as follows: absence of blood flow (type I), perinodular blood flow (type II), intranodular, with or without perinodular blood flow (type III), which is considered the most typical pattern of malignancy. On histology 22 nodules as carcinoma (CA) and 56 as benign nodules (BN) have been diagnosed. The most predictive for malignancy, sonographic pattern, "microcalcifications", has been found in 13/22 CA and in 4/56 BN (P < 0.0001, specificity 93%, sensitivity 59%); "hypoechogenicity" in 16/22 CA and in 8/56 BN (P < 0.0001, specificity 86%, sensitivity 73%), "absent halo sign" in 18/22 CA and in 16/56 BN (P < 0.0001, specificity 71%, sensitivity 82%.) have been found. On CFD type III pattern has been detected in 17/22 CA and in 24/56 BN (P < 0.15, specificity 57%, sensitivity 77%); type IIIa pattern (intranodular without perinodular blood flow) has been the most predictive for malignancy (P < 0.0001, specificity 100%, sensitivity 36%). The combination of type III pattern with "hypoechogenicity" in 13/22 CA and in 2/56 BN (p < 0.0001, specificity 93%, sensitivity 59%) has been found, with "absent halo sign" in 15/22 CA and in 3/56 BN (P < 0.0001, specificity 94.6%, sensitivity 68%), has been found, with "microcalcification" in 10/22 CA and in 0/56 BN (P < 0.0001, specificity 100%, sensitivity 45%) has been found. The combination of "microcalcifications" and absent halo sign" with type III pattern has been the most specific for malignancy, being detected in 11/22 Ca and 2/56 BN (P < 0.0001, specificity 96%, sensitivity 50%). In conclusion our results suggest that CFDS has an useful role in the assessment of thyroid nodules and it may provide information highly predictive for malignancy, above all when multiple, sonographic and vascular patterns are contemporaneously present in a thyroid nodule.

[Echography in the study of renal pathology in childhood]. / L'ecografia nello studio della patologia renale in età pediatrica.

Results of US study in 30 children with various renal lesions are reported, and compared with clinical and surgical features. Different ultrasonographic aspects are discussed with special interest on cogenital abnormalities. US is proposed as first choice investigation in newborns with antenatal ultrasonographic demonstration of renal lesions and in all patients where a mass of renal origin is suspected. Renal function, nevertheless, must be investigated with radiologic and/or radioisotopic techniques. US have still a large indication in short term follow-up of renal lesions where surgical treatment is not indicated.

MYCN gene expression is required for the onset of the differentiation programme in neuroblastoma cells.

Neuroblastoma is an embryonic tumour of the sympathetic nervous system and is one of the most common cancers in childhood. A high differentiation stage has been associated with a favourable outcome; however, the mechanisms governing neuroblastoma cell differentiation are not completely understood. The MYCN gene is considered the hallmark of neuroblastoma. Even though it has been reported that MYCN has a role during embryonic development, it is needed its decrease so that differentiation can be completed. We aimed to better define the role of MYCN in the differentiation processes, particularly during the early stages. Considering the ability of MYCN to regulate non-coding RNAs, our hypothesis was that N-Myc protein might be necessary to activate differentiation (mimicking embryonic development events) by regulating miRNAs critical for this process. We show that MYCN expression increased in embryonic cortical neural precursor cells at an early stage after differentiation induction. To investigate our hypothesis, we used human neuroblastoma cell lines. In LAN-5 neuroblastoma cells, MYCN was upregulated after 2 days of differentiation induction before its expected downregulation. Positive modulation of various differentiation markers was associated with the increased MYCN expression. Similarly, MYCN silencing inhibited such differentiation, leading to negative modulation of various differentiation markers. Furthermore, MYCN gene overexpression in the poorly differentiating neuroblastoma cell line SK-N-AS restored the ability of such cells to differentiate. We identified three key miRNAs, which could regulate the onset of differentiation programme in the neuroblastoma cells in which we modulated MYCN. Interestingly, these effects were accompanied by changes in the apoptotic compartment evaluated both as expression of apoptosis-related genes and as fraction of apoptotic cells. Therefore, our idea is that MYCN is necessary during the activation of neuroblastoma differentiation to induce apoptosis in cells that are not committed to differentiate.