Whither Magnetic Hyperthermia? A Tentative Roadmap.

The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia.

Correction to: SentimagIC: A Non-inferiority Trial Comparing Superparamagnetic Iron Oxide Versus Technetium-99m and Blue Dye in the Detection of Axillary Sentinel Nodes in Patients with Early-Stage Breast Cancer.

In the original article the authors' disclosures were incomplete.

SentimagIC: A Non-inferiority Trial Comparing Superparamagnetic Iron Oxide Versus Technetium-99m and Blue Dye in the Detection of Axillary Sentinel Nodes in Patients with Early-Stage Breast Cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a highly accurate method for staging the axilla in early breast cancer. Superparamagnetic iron oxide mapping agents have been explored to overcome the disadvantages of the standard SLNB technique, which uses a radioisotope tracer with or without blue dye. One such agent, Sienna+, was shown to be non-inferior to the standard technique for SLNB in a number of studies. The SentimagIC trial was designed to establish the non-inferiority of a new formulation of this magnetic tracer, Magtrace (formerly SiennaXP). METHODS: Patients with clinically node-negative early-stage breast cancer were recruited from six centers in the US. Patients received radioisotope and isosulfan blue dye injections, followed by an intraoperative injection of magnetic tracer, prior to SLNB. The sentinel node identification rate was compared between the magnetic and standard techniques to evaluate non-inferiority and concordance. RESULTS: Data were collected for 146 procedures in 146 patients. The per patient detection rate was 99.3% (145/146) when using the magnetic tracer and 98.6% (144/146) when using the standard technique, while the nodal detection rate was 94.3% (348/369 nodes) when using the magnetic tracer and 93.5% (345/369) when using the standard technique (difference 0.8%, 95% binomial confidence interval lower bound - 2.1%). Of the 22 patients with positive sentinel lymph nodes (SLNs), 21 (95.4%) were detected by both the magnetic tracer and the standard technique. All malignant nodes detected by standard technique were also identified by the magnetic technique. CONCLUSION: The magnetic technique is non-inferior to the standard technique of radioisotope and blue dye for axillary SLN detection in early-stage breast cancer. The magnetic technique is therefore a viable alternative.

Impact of Locally Administered Carboxydextran-Coated Super-Paramagnetic Iron Nanoparticles on Cellular Immune Function.

Interstitially administered iron oxide particles are currently used for interoperative localization of sentinel lymph nodes (LNs) in cancer staging. Several studies have described concerns regarding the cellular accumulation of iron oxide nanoparticles relating them to phenotype and function deregulation of macrophages, impairing their ability to mount an appropriate immune response once an insult is present. This study aims to address what phenotypic and functional changes occur during lymphatic transit and accumulation of these particles. Data show that 60 nm carboxydextran-coated iron nanoparticles use a noncellular mechanism to reach the draining LNs and that their accumulation in macrophages induces transient phenotypic and functional changes. Nevertheless, macrophages recover their baseline levels of response within 7 days, and are still able to mount an appropriate response to bacterially induced inflammation.

Recommendations for clinical translation of nanoparticle-enhanced radiotherapy.

A multi-disciplinary cooperative for nanoparticle-enhanced radiotherapy (NERT) has been formed to review the current status of the field and identify key stages towards translation. Supported by the Colorectal Cancer Healthcare Technologies Cooperative, the cooperative comprises a diverse cohort of key contributors along the translation pathway including academics of physics, cancer and radio-biology, chemistry, nanotechnology and clinical trials, clinicians, manufacturers, industry, standards laboratories, policy makers and patients. Our aim was to leverage our combined expertise to devise solutions towards a roadmap for translation and commercialisation of NERT, in order to focus research in the direction of clinical implementation, and streamline the critical pathway from basic science to the clinic. A recent meeting of the group identified barriers to and strategies for accelerated clinical translation. This commentary reports the cooperative's recommendations. Particular emphasis was given to more standardised and cohesive research methods, models and outputs, and reprioritised research drivers including patient quality of life following treatment. Nanoparticle design criteria were outlined to incorporate scalability of manufacture, understanding and optimisation of biological mechanisms of enhancement and in vivo fate of nanoparticles, as well as existing design criteria for physical and chemical enhancement. In addition, the group aims to establish a long-term and widespread international community to disseminate key findings and create a much-needed cohesive body of evidence necessary for commercial and clinical translation.

Identifying the features of an easy-to-use and intuitive dry powder inhaler for asthma and chronic obstructive pulmonary disease therapy: results from a 28-day device handling study, and an airflow resistance study.

BACKGROUND: Many patients with asthma and chronic obstructive pulmonary disease (COPD) symptoms remain insufficiently controlled despite inhalation treatment, with poor inhaler technique recognized as a significant contributor. Dry powder inhalers (DPIs) need less coordination of actuation and inspiration than pressured metered dose inhalers. OBJECTIVES: To assess whether consideration of 'ideal inhaler' features during design and development of a new DPI device (Forspiro® Sandoz AG, Switzerland) led to an easy-to-use and reliable inhaler. METHODS: Two studies are reported here: i) 24 adult Accuhaler® users received either limited written instructions (n = 12) or fully illustrated instructions (n = 12) for the Forspiro device; and ii) peak inspiratory flow rates through the Forspiro device were assessed in 30 adult and 10 pediatric patients with asthma and 10 adult patients with COPD. RESULTS: All subjects understood the correct sequence of actions for the Forspiro device and rated all aspects of handling the device as 'very easy' or 'fairly easy' (except one uninstructed subject who rated 'ease of determining number of doses left' as 'fairly difficult'). All patients achieved ≥ 35 l/min, thus demonstrating that the Forspiro device provides low-medium airflow resistance. CONCLUSIONS: Inhaler design providing good drug delivery with maximum ease of use may lead to more reliable therapy and improved control of airway diseases.

Active and intelligent inhaler device development.

The dry powder inhaler, which has traditionally relied on the patient's inspiratory force to deaggregate and deliver the active agent to the target region of the lung, has been a successful delivery device for the provision of locally active agents for the treatment of conditions such as asthma and chronic obstructive pulmonary disease (COPD). However, such devices can suffer from poor delivery characteristics and/or poor reproducibility. More recently, drugs for systemic delivery and more high value compounds have been put into DPI devices. Regulatory, dosing, manufacturing and economic concerns have demanded that a more efficient and reproducible performance is achieved by these devices. Recently strategies have been put in place to produce a more efficient DPI device/formulation combination. Using one novel device as an example the paper will examine which features are important in such a device and some of the strategies required to implement these features. All of these technological advances are invisible, and may be irrelevant, to the patient. However, their inability to use an inhaler device properly has significant implications for their therapy. Use of active device mechanisms, which reduce the dependence on patient inspiratory flow, and sensible industrial design, which give the patient the right clues to use, are important determinants of performance here.