Development and Testing of a System for Controlled Ultrasound Hyperthermia Treatment With a Phantom Device

Hyperthermia is the process of raising tissue temperatures in the range 40 degrees C-45 degrees C for a prolonged time (up to hours). Unlike in ablation therapy, raising the temperature to such levels does not cause necrosis of the tissue but has been postulated to sensitize the tissue for radiotherapy. The ability to maintain a certain temperature in a target region is key to a hyperthermia delivery system. The aim of this work was to design and characterize a heat delivery system for ultrasound hyperthermia able to generate a uniform power deposition pattern in the target region with a closed-loop control, which would maintain the defined temperature over a defined period. The hyperthermia delivery system presented herein is a flexible design with the ability to strictly control the induced temperature rise with a feedback loop. The system can be reproduced elsewhere with relative ease and is adaptable for various tumor sizes/locations and for other temperature elevation applications, such as ablation therapy. The system was fully characterized and tested on a newly designed custom-built phantom with controlled acoustic and thermal properties and containing embedded thermocouples. Additionally, a layer of thermochromic material was fixed above the thermocouples, and the recorded temperature increase was compared to the red, green, and blue (RGB) color change in the material. The transducer characterization allowed for input voltage to output power curves to be generated, thus allowing for the comparison of power deposition to temperature increase in the phantom. Additionally, the transducer characterization generated a field map of the symmetric field. The system was capable of increasing the temperature of the target area by 6 degrees C above body temperature and maintains the temperature to within +/- 0.5 degrees C over a defined period. The increase in temperature correlated with the RGB image analysis of the thermochromic material. The results of this work have the potential to contribute toward increasing confidence in the delivery of hyperthermia treatment to superficial tumors. The developed system could potentially be used for phantom or small animal proof-of-principle studies. The developed phantom test device may be used for testing other hyperthermia systems

Ultrasound boosts doxorubicin efficacy against sensitive and resistant ovarian cancer cells

Ovarian cancer (OC) is characterised by the highest mortality of all gynaecological malignancies, frequent re-lapses, and the development of resistance to drug therapy. Sonodynamic therapy (SDT) is an innovative anti-cancer approach that combines a chemical/drug (sonosensitizer) with low-intensity ultrasound (US), which are both harmless per se ', with the sonosensitizer being acoustically activated, thus yielding localized cytotoxicity often via reactive oxygen species (ROS) generation. Doxorubicin (Doxo) is a potent chemotherapeutic drug that has also been recommended as a first-line treatment against OC. This research work aims to investigate whether Doxo can be used at very low concentrations, in order to avoid its significant side effects, as a sonosensitiser under US exposure to promote cancer cell death in Doxo non-resistant (A2780/WT) and Doxo resistant (A2780/ ADR) human OC cell lines. Moreover, since recurrence is an important issue in OC, we have also investigated whether the proposed SDT with Doxo induces immunogenic cell death (ICD) and thus hinders OC recurrence. Our results show that the sonodynamic anticancer approach with Doxo is effective in both A2780/WT and A2780/ADR cell lines, and that it proceeds via a ROS-dependent mechanism of action and immune sensitization that is based on the activation of the ICD pathway

Ultrasounds induce blood-brain barrier opening across a sonolucent polyolefin plate in an in vitro isolated brain preparation

The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system. The combined use of low-intensity pulsed ultrasound waves and intravascular microbubbles (MB) represents a promising solution to this issue, allowing reversible disruption of the barrier. In this study, we evaluate the feasibility of BBB opening through a biocompatible, polyolefin-based plate in an in vitro whole brain model. Twelve in vitro guinea pig brains were employed; brains were insonated using a planar transducer with or without interposing the polyolefin plate during arterial infusion of MB. Circulating MBs were visualized with an ultrasonographic device with a linear probe. BBB permeabilization was assessed by quantifying at confocal microscopy the extravasation of FITC-albumin perfused after each treatment. US-treated brains displayed BBB permeabilization exclusively in the volume under the US beam; no significant differences were observed between brains insonated with or without the polyolefin plate. Control brains not perfused with MB did not show signs of FITC-albumin extravasation. Our preclinical study suggests that polyolefin cranial plate could be implanted as a skull replacement to maintain craniotomic windows and perform post-surgical repeated BBB opening with ultrasound guidance to deliver therapeutic agents to the central nervous system

Safety and Immunogenicity of Conventional Subunit and MF59-adjuvanted Influenza Vaccines in Human Immunodeficiency Virus-1-seropositive Patients

In this study of influenza vaccination, 37 human immunodeficiency virus (HIV)-1-seropositive patients were randomized to receive either a vaccine with a conventional subunit or one adjuvanted with MF59. Blood samples were collected at the time of vaccination, and then 30 and 180 days later, to evaluate immunogenicity, CD4+ T-lymphocyte count and HIV-1 RNA levels. Seroconversion rates against the three viral strains included in the vaccine ranged between 44% and 72% and 53% and 68% for the adjuvanted vaccine and the subunit vaccine, respectively. Other criteria of the European Medicines Evaluation Agency were also met. Vaccination was not associated with serious adverse events. Local and systemic effects were mild and of short duration. CD4+ T-lymphocyte counts and viraemia levels were not negatively affected by vaccination. These results confirmed the safety and immunogenicity of these currently available vaccines in HIV-1-seropositive patients, thus supporting the recommendation for influenza immunization in this high-risk category

Molecular epidemiology and case-control approaches for management of an outbreak of hepatitis A in Liguria, Italy

Introduction and methods. Hepatitis A remains an important public health problem in low endemicity areas, because of the social and economic high burden of cyclical outbreaks. In this study we described an outbreak of HAV infection occurred in the city of Genoa and in its proximity and the viral circulation in the post-epidemic period. In order to identify risk factors associated to the illness and to determine the source of infection and the dynamics of virus evolution, we conducted an epidemiological and molecular investigation by a case-control study and by sequence analysis of high variable regions of the genome. Results. From May to October 2005, 58 HAV hepatitis cases were notified. The case-control study showed that beach establishment attending is strongly associated with HAV hepatitis (OR = 24.5, p-value inf. 0.01), at multivariate analysis. The profile of epidemic curve, the clinical onset of primary cases who occurred in few weeks and the geographic distribution of cases clearly indicated a common exposure to a point source: the outbreak can be probably associated with a contaminated food product dispensed in the affected area. The outbreak has been mainly caused by a single variant, confirming the common exposure to a point source; this variant previously circulated within homosexual man (MSM) network in Northern Europe. During the outbreak and in the following months, different variants originating from Southeast Asia, Southern America and Northern Africa, have co-circulated: all these cases were related to international travel and none of these had determined secondary cases. Discussion. The epidemiological picture of hepatitis A in Liguria is characterized by a wide heterogeneity of circulating HAV strains. This pattern could be associated with the increase of imported cases and transmission within network of persons with similar risk factors. Molecular approach coupled to descriptive and analytical epidemiological studies appeared un-replaceable tools for management and control of HAV outbreaks, because of their capacity to recognize infection origin, transmission patterns and dynamics of virus evolution