Update on the Cytogenetics and Molecular Genetics of Chordoma

Chordoma is a rare mesenchymal tumour of complex biology for which only histologic and immunohistochemical criteria have been defined, but no biomarkers predicting the clinical outcome and response to treatment have yet been recognised. We herein review the interdisciplinary information achieved by epidemiologists, neurosurgeons and basic scientists on chordoma, usually a sporadic tumour, which also includes a small fraction of familial cases. Main focus is on the current knowledge of the genetic alterations which might pinpoint candidate genes and molecular mechanisms shared by sporadic and familiar chordomas. Due to the scarcity of the investigated tumour specimens and the multiple chromosome abnormalities found in tumours with aberrant karyotypes, conventional cytogenetics and Fluorescence In Situ Hybridization failed to detect recurrent chordoma-specific chromosomal rearrangements. Genome-wide approaches such as Comparative Genomic Hybridization (CGH) are yet at an initial stage of application and should be implemented using BAC arrays either genome-wide or targeting selected genomic regions, disclosed by Loss of Heterozygosity (LOH) studies. An LOH region was shown by a systematic study on a consistent number of chordomas to encompass 1p36, a genomic interval where a candidate gene was suggested to reside. Despite the rarity of multiplex families with chordoma impaired linkage studies, a chordoma locus could be mapped to chromosome 7q33 by positive lod score in three independent families. The role in chordomagenesis of the Tuberous Sclerosis Complex (TSC) genes has been proved, but the extent of involvement of TSC1 and TSC2 oncosuppressors in chordoma remains to be assessed. In spite of the scarce knowledge on the genetics and molecular biology of chordoma, recent initiation of clinical trials using molecular-targeted therapy, should validate new molecular targets and predict the efficacy of a given therapy. Comparative genetic and biomolecular studies should enhance the molecular taxonomy of chordoma which might have a prognostic significance and better orient the therapeutic options

A novel electromagnetic tracking system for surgery navigation

Objective: This paper proposes the development of a novel electromagnetic tracking system for navigation surgery. Main objective is to provide a system able to operate in a wide tracking volume to make easier and efficient the surgical procedures by assuring high measurement accuracy. Methods: A new field generator consisting in five transmitting coils excited with Frequency Division Multiplexing technique has been developed. Attention is devoted to designing and arrangement of the coils to assure high sensitivity, system scalability and a homogeneous magnetic field inside working volume. A suitable technique based on Look-Up-Table is applied for sensor position calculation and an anthropomorphic robot is used for table calibration. Results: Experimental tests highlight a good repeatability of the measurement data and a negligible noise influence for the proposed system. The obtained tracking volume is wider with respect to the commercial tracking device used in surgical applications and seem promising. Conclusion: The main characteristic of the developed system consists of: scalable and modular configuration of Field Generator, high measured sensitivity due to the increased number of transmitting coils with respect to the classical configuration and large tracking volume. The development of the proposed magnetic tracking systems with high accuracy and wide working volume allows to promote broader utilization of advantaged techniques in surgery procedures for both improving the effectiveness and decreasing the invasiveness of medical interventions

Management of Celiac Patients with Growth Failure

Celiac disease (CD) may be considered as a systemic immune-mediated disorder that is triggered by dietary gluten in genetically susceptible subjects. CD children and adolescents show typical intestinal symptoms such as diarrhea, loss of weight and abdominal distension, or extraintestinal signs, the so-called nonclassical CD, such as short stature and delayed puberty. An endocrinological investigation including an evaluation of growth hormone (GH) secretion should be performed in CD subjects who show no catch-up growth after at least 1 year on a strict gluten-free diet (GFD) in the presence of a seronegativity of anti-transglutaminase and/or antiendomysial antibodies. When the diagnosis of GH deficiency is formulated, a substitutive therapy with GH must be promptly started to obtain a complete catch-up growth. The long-term effects of GH therapy in CD children who follow a strict GFD are comparable to those found in children with idiopathic GHD. A widely documented association has been observed between CD and type I diabetes mellitus and/or Hashimoto thyroiditis and/or Addison’s disease. During follow-up, pediatricians should check antibody serology, thyroid and adrenal function and glucose-metabolic profile in order to verify the compliance with both diet and GH treatment. Adherence to a strict gluten-free diet promotes regular linear growth and may prevent CD complications as well as the onset of other autoimmune diseases

Going Mobile with a Multiaccess Service for the Management of Diabetic Patients

Diabetes mellitus is one of the chronic diseases exploiting the largest number of telemedicine systems. Our research group has been involved since 1996 in two projects funded by the European Union proposing innovative architectures and services according to the best current medical practices and advances in the information technology area. We propose an enhanced architecture for telemedicine giving rise to a multitier application. The lower tier is represented by a mobile phone hosting the patient unit able to acquire data and provide first-level advice to the patient. The patient unit also facilitates interaction with the health care center, representing the higher tier, by automatically uploading data and receiving back any therapeutic plan supplied by the physician. On the patient’s side the mobile phone exploits Bluetooth technology and therefore acts as a hub for a wireless network, possibly including several devices in addition to the glucometer. A new system architecture based on mobile technology is being used to implement several prototypes for assessing its functionality. A subsequent effort will be undertaken to exploit the new system within a pilot study for the follow-up of patients cared at a major hospital located in northern Italy. We expect that the new architecture will enhance the interaction between patient and caring physician, simplifying and improving metabolic control. In addition to sending glycemic data to the caring center, we also plan to automatically download the therapeutic protocols provided by the physician to the insulin pump and collect data from multiple sensors

Continuous Glucose and Heart Rate Monitoring in Young People with Type 1 Diabetes: An Exploratory Study about Perspectives in Nocturnal Hypoglycemia Detection

A combination of information from blood glucose (BG) and heart rate (HR) measurements has been proposed to investigate the HR changes related to nocturnal hypoglycemia (NH) episodes in pediatric subjects with type 1 diabetes (T1D), examining whether they could improve hypoglycemia prediction. We enrolled seventeen children and adolescents with T1D, monitored on average for 194 days. BG was detected by flash glucose monitoring devices, and HR was measured by wrist-worn fitness trackers. For each subject, we compared HR values recorded in the hour before NH episodes (before-hypoglycemia) with HR values recorded during sleep intervals without hypoglycemia (no-hypoglycemia). Furthermore, we investigated the behavior after the end of NH. Nine participants (53%) experienced at least three NH. Among these nine subjects, six (67%) showed a statistically significant difference between the before-hypoglycemia HR distribution and the no-hypoglycemia HR distribution. In all these six cases, the before-hypoglycemia HR median value was higher than the no-hypoglycemia HR median value. In almost all cases, HR values after the end of hypoglycemia remained higher compared to no-hypoglycemia sleep intervals. This exploratory study support that HR modifications occur during NH in T1D subjects. The identification of specific HR patterns can be helpful to improve NH detection and prevent fatal events

Patient-Generated Health Data Integration and Advanced Analytics for Diabetes Management: The AID-GM Platform

Diabetes is a high-prevalence disease that leads to an alteration in the patient’s blood glucose (BG) values. Several factors influence the subject’s BG profile over the day, including meals, physical activity, and sleep. Wearable devices are available for monitoring the patient’s BG value around the clock, while activity trackers can be used to record his/her sleep and physical activity. However, few tools are available to jointly analyze the collected data, and only a minority of them provide functionalities for performing advanced and personalized analyses. In this paper, we present AID-GM, a web application that enables the patient to share with his/her diabetologist both the raw BG data collected by a flash glucose monitoring device, and the information collected by activity trackers, including physical activity, heart rate, and sleep. AID-GM provides several data views for summarizing the subject’s metabolic control over time, and for complementing the BG profile with the information given by the activity tracker. AID-GM also allows the identification of complex temporal patterns in the collected heterogeneous data. In this paper, we also present the results of a real-world pilot study aimed to assess the usability of the proposed system. The study involved 30 pediatric patients receiving care at the Fondazione IRCCS Policlinico San Matteo Hospital in Pavia, Italy

Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes

Objectives: Despite the widespread diffusion of continuous glucose monitoring (CGM) systems, which includes both real-time CGM (rtCGM) and intermittently scanned CGM (isCGM), an effective application of CGM technology in clinical practice is still limited. The study aimed to investigate the relationship between isCGM-derived glycemic metrics and glycated hemoglobin (HbA1c), identifying overall CGM targets and exploring the inter-subject variability.Methods: A group of 27 children and adolescents with type 1 diabetes under multiple daily injection insulin-therapy was enrolled. All participants used the isCGM Abbott's FreeStyle Libre system on average for eight months, and clinical data were collected from the Advanced Intelligent Distant-Glucose Monitoring platform. Starting from each HbA1c examdate, windows of past 30, 60, and 90 days were considered to compute several CGM metrics. The relationships between HbA1c and each metric were explored through linear mixed models, adopting an HbA1c target of 7%.Results: Time in Range and Time in Target Range show a negative relationship with HbA1c (R-2>0.88) whereas Time Above Range and Time Severely Above Range show a positive relationship (R-2>0.75). Focusing on Time in Range in 30-day windows, random effect represented by the patient's specific intercept reveals a high variability compared to the overall population intercept.Conclusions: This study confirms the relationship between several CGM metrics and HbA1c; it also highlights the importance of an individualized interpretation of the CGM data