A review of recent advances in optical fibre sensors for in vivo dosimetry during radiotherapy

This article presents an overview of the recent developments and requirements in radiotherapy dosimetry, with particular emphasis on the development of optical fibre dosemeters for radiotherapy applications, focusing particularly on in vivo applications. Optical fibres offer considerable advantages over conventional techniques for radiotherapy dosimetry, owing to their small size, immunity to electromagnetic interferences, and suitability for remote monitoring and multiplexing. The small dimensions of optical fibre-based dosemeters, together with being lightweight and flexible, mean that they are minimally invasive and thus particularly suited to in vivo dosimetry. This means that the sensor can be placed directly inside a patient, for example, for brachytherapy treatments, the optical fibres could be placed in the tumour itself or into nearby critical tissues requiring monitoring, via the same applicators or needles used for the treatment delivery thereby providing real-time dosimetric information. The article outlines the principal sensor design systems along with some of the main strengths and weaknesses associated with the development of these techniques. The successful demonstration of these sensors in a range of different clinical environments is also presented.Radiation dosimetry deals with methods for quantitative determination of energy deposited in a given medium directly or indirectly by ionizing radiations. A dosemeter can be defined generally as any device that is capable of providing a reading that is a measure of the average absorbed dose deposited in its (dosemeter) sensitive volume by ionizing radiation. There are commonly agreed codes of practice in the UK that define how dosimetric calibration of treatment beams should be performed,^1,2 in addition to defining the types of ionization chambers that may, or may not, be used for these measurements.Radiotherapy is in a period of rapid scientific and clinical development. The introduction of novel treatment techniques, for example, stereotactic ablative radiotherapy and volumetric modulated arc therapy (VMAT), delivered through the use of technologies such as flattening filter free (FFF) beams and dynamic multi-leaf collimation, is driving the requirement for increasing levels of accuracy and precision in dosimetry. These treatment delivery options are causing existing, well-established, dosimetric equipment to be extended to the limits of its capability. Other recent developments in treatment options include the use of protons and heavy ions, and the availability of small animal irradiation platforms provides additional scope for novel dosimetric systems. Furthermore, the increased use of image-guided radiation therapy, including the use of kilovoltage cone beam CT, MR and positron emission tomography, provides a different set of problems to existing technologies employed within traditional radiotherapy dosimetry.There are also recommendations for comprehensive quality assurance (QA) programmes^3,4 to assess the performance of all types of radiotherapy treatment equipment, including the treatment planning system (TPS), against known tolerances and for comparison with baseline measurements. The increasing complexity of modern treatment modalities has also introduced a more comprehensive patient-specific QA programme to verify, pre-treatment, an individual patient delivery. Radiotherapy also includes multiple layers of checking from the simple cross-checking of work, through independent monitor unit calculations, and on to independent audits of treatment centres'' planning and dosimetry performance.In addition to ensuring the correct calibration of treatment beams, and verification of the delivery pre-treatment, it is important to monitor dose delivery during treatment (in vivo), rather than verification of the treatment to a phantom. In an ideal scenario, the dose delivered directly within the tumour volume, and/or dose to specific organs at risk (OARs), would be measured while the patient is receiving their treatment. However, this is currently generally carried out by measuring the dose at a “surrogate” position, usually by placing a radiation detector directly on, or near to, the patient''s skin surface to provide either an entrance or exit dose value, rather than directly within the tumour itself. There is a growing interest in the need to perform such in vivo measurements in part owing to increasing awareness of the potential risks associated with incorrect delivery or planning of radiation treatments, and because of the use of increasing complex delivery techniques such as intensity-modulated radiation therapy (IMRT) and VMAT, and the move towards more hypofractionated treatments delivered with large doses per fraction.The importance of in vivo dosimetry has been further highlighted in recent years as a result of a number of major radiotherapy incidents,^5–7 and whilst the vast majority of radiotherapy sessions are performed without incident, an international review of radiotherapy incidents identified >7000 incidents over three decades (1976–2007). The incidents range from underdosing, leading to a recurrence risk, to overdosing, causing toxicity and even death.⁵ The investigations following major incidents have generally recommended that some form of in vivo dosimetry measurement would be beneficial,⁸ and professional bodies such as the American Association of Physicists in Medicine have recommended that clinics “should have access to TLD or other in vivo systems”.⁹There are a number of different options available for use as an in vivo dosemeter, with the most commonly used being thermoluminescent detectors (TLDs), diodes, metal-oxide semi-conductor field effect transistors (MOSFET), film and electronic portal imaging devices. These options each have relative strengths and weaknesses, and a number of review articles^10–12 have highlighted the merits of each. For a detailed summary of in vivo dosemeters, not restricted to optical fibre sensors, see table 1 from Mijnheer et al¹⁰ for dosemeters in external beam radiotherapy and table 3 from Tanderup et al¹² for dosemeters in brachytherapy. Methods to infer the full three-dimensional dose distribution are also being developed primarily by the use of back-projected electronic portal imaging images to reconstruct the dose within the CT volume used to plan the patient''s treatment^13–15 or through the analysis of the treatment log files to recreate the multileaf collimator (MLC) positions used during the treatment.^16,17In recent years, there has been some interest¹⁰ in investigating alternatives to the established in vivo detectors, such as plastic scintillation detectors (PSDs), optically stimulated luminescent detectors, radiophotoluminescent dosemeters and implantable MOSFETs. Some of the main reasons for the development of these alternatives to the existing options include the increasing interest in combining a MRI scanner with a radiotherapy linear accelerator (linac), the development of heavy ion and particle beams in radiotherapy and the introduction of new small animal irradiation platforms for radiobiological investigations. These new technologies present different problems from the effect of magnetic fields on dosemeters,¹⁸ the response of dosemeters in different types of treatment beams,^19,20 the miniaturization of treatment fields^21,22 and the associated complexity of radiation dosimetry at very small field sizes.^23,24Optical fibres offer a solution for in vivo radiotherapy dosimetry with many advantages over currently employed clinical dosimetry systems. An optical fibre radiation dosemeter is a photonic system based on optical fibre technology, whereby radiation introduces a modification or modulation in some of the characteristics of the optical signal. The optical fibres can be directly affected by the radiation, in which case it is called an intrinsic sensor, or it can be used for the sole purpose of transmitting the optical signal, and is known as an extrinsic sensor. There are a number of different dosimetry techniques that can incorporate optical fibres to further improve the overall system, and these techniques are discussed in turn, together with examples of such optical fibre-based systems.     

Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design

Heart failure (HF) affects >5 million patients in the United States, and its prevalence is increasing every year. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors and β-blockers reduce hospitalizations and mortality rates in patients with HF, these lifesaving therapies continue to be underused. Several studies in a variety of clinical settings have documented that a significant proportion of eligible patients with HF are not receiving treatment with these guideline-recommended, evidence-based therapies. In patients hospitalized with HF, who are at particularly high risk for re-hospitalization and death, the initiation of β-blockers is often delayed because of concern that early initiation of these agents may exacerbate HF. Recent studies suggest that β-blockers can be safely and effectively initiated in patients with HF before hospital discharge and that clinical outcomes are improved. The Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial demonstrated that pre-discharge initiation of carvedilol was associated with a higher rate of β-blocker use after hospital discharge, with no increase in hospital length of stay. In addition, there was no increase in the risk of worsening of HF. Studies of hospital-based management systems that rely on early (pre-discharge) initiation of evidence-based therapies for patients with cardiovascular disease have also found increases in post-discharge use of therapy and a reduction in the rates of mortality and hospitalization. On the basis of these pivotal studies, the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) program is designed to improve medical care and education of hospitalized patients with HF and accelerate the initiation of evidence-based HF guideline recommended therapies by administering them before hospital discharge. A registry component, planned as the most comprehensive database of the hospitalized HF population focusing on admission to discharge and 60- to 90-day follow-up, is designed to evaluate the demographic, pathophysiologic, clinical, treatment, and outcome characteristics of patients hospitalized with HF. The ultimate aim of this program is to improve the standard of HF care in the hospital and outpatient settings and increase the use of evidence-based therapeutic strategies to save lives.     

The human CAN protein, a putative oncogene product associated with myeloid leukemogenesis, is a nuclear pore complex protein that faces the cytoplasm.

We have carried out partial amino acid sequenceanalysis of a putative nuclear pore complex protein (nucleoporin) of rat thatreacts with wheat germ agglutinin and with the polyspecific monoclonal antibody414. Surprisingly, these partial amino acid sequence data revealed a high degreeof similarity with the human CAN protein, the complete cDNA-derived primarystructure of which was reported by Von Lindern et al. [Von Lindern, M.,Fornerod, M., van Baal, S., Jaegle, M., de Wit, T., Buijs, A. & Grosveld, G.(1992) Mol. Cell. Biol. 12, 1687-1697]. The CAN protein has been proposed to bea putative oncogene product associated with myeloid leukemogenesis. Itssubcellular localization was not established. To confirm that the putative ratnucleoporin is indeed a homolog of the human CAN protein and to determine itssubcellular localization, we expressed a 39-kDa internal segment of the213,790-Da human CAN protein in Escherichia coli and raised monospecificantibodies, which reacted with the putative rat nucleoporin. Immunofluorescencemicroscopy of HeLa cells gave a punctate nuclear surface staining patterncharacteristic of nucleoporins, and immunoelectron microscopy yielded specificdecoration of the cytoplasmic side of the nuclear pore complex. This suggeststhat the protein is part of the short fibers that emanate from the cytoplasmicaspect of the nuclear pore complex. In agreement with previously proposednomenclature for nucleoporins, we propose the alternative term nup214(nucleoporin of 214 kDa) for the CAN protein.     

Imaging diagnosis and quantification of hepatic steatosis: is it an accepted alternative to needle biopsy?

Hepatic steatosis is a frequently encountered disease in medical practice and it has a great importance due to the potential evolution towards cirrhosis. The clinical and laboratory evaluation has a quite reduced positive predictive value. On the other hand, a series of imaging techniques may be used for the diagnosis and quantification of steatosis: magnetic resonance imaging, computerized tomography, and not least, ultrasonography. The contribution of each of the afore mentioned methods in the diagnosis of the hepatic steatosis will be discussed.     

Diffuse esophageal spasm: not diffuse but distal esophageal spasm (DES)

Diffuse esophageal spasm is an uncommon motility disorder that is found in less than 5% of patients undergoing esophageal motility testing for dysphagia. It is defined manometrically by the presence of 20% or more simultaneous contractions in the distal esophageal body with normal peristalsis. This motility abnormality has been traditionally identified as occurring primarily in the smooth muscle portion of the distal esophagus yet, the term diffuse persists in the medical literature to identify DES. The aim of our study was to assess the diffuse or limited nature of this entity by evaluating the prevalence of simultaneous contractions in both proximal and distal esophagus in patients with DES. We reviewed esophageal motility tracings of 53 consecutive patients (32 F, 21 M) with DES and compared them with 53 age-matched patients with manometric normal studies. In the distal esophagus we found 195 simultaneous contractions (37% of swallows) with a median of 3 and range of 2–7 per patient. Of the 53 patients with DES a total of 13 simultaneous contractions (2% of swallows) occurred in the proximal esophagus with only 3 (5.6%) of the 53 patients having 2 or more simultaneous contractions in 10 swallows. None of the patients with normal manometry showed more than one simultaneous contraction in either proximal or distal esophagus. In conclusion, these findings suggest that the term diffuse esophageal spasm is a misnomer and the DES is more appropriately described as distal esophageal spasm.     

Interstitial Outburst of Angiogenic Factors During Skeletal Muscle Regeneration After Acute Mechanical Trauma

Angiogenesis is a key event during tissue regeneration, but the intimate mechanisms controlling this process are still largely unclear. Therefore, the cellular and molecular interplay along normal tissue regeneration should be carefully unveiled. To this matter, we investigated by xMAP assay the dynamics of some angiogenic factors known to be involved in tissue repair, such as follistatin (FST), Placental Growth Factor‐2 (PLGF‐2), epidermal growth factor (EGF), betacellulin (BTC), and amphiregulin (AREG) using an animal model that mimics acute muscle contusion injuries. In situ immunofluorescence was used for the evaluation and tissue distribution of their cellular sources. Tissue levels of explored factors increased significantly during degeneration and inflammatory stage of regeneration, peaking first week postinjury. However, except for PLGF‐2 and EGF, their levels remained significantly elevated after the inflammatory process started to fade. Serum levels were significantly increased only after 24 h for AREG and EGF. Though, for all factors except FST, the levels in injured samples did not correlate with serum or contralateral tissue levels, excluding the systemic influence. We found significant correlations between the levels of EGF and AREG, BTC, FST and FST and AREG in injured samples. Interstitial cells expressing these factors were highlighted by in situ immunolabeling and their number correlated with measured levels dynamics. Our study provides evidence of a dynamic level variation along the regeneration process and a potential interplay between selected angiogenic factors. They are synthesized, at least partially, by cell populations residing in skeletal muscle interstitium during regeneration after acute muscle trauma. Anat Rec, 298:1864–1879, 2015. © 2015 Wiley Periodicals, Inc.     

The Heart Failure Association Atlas: rationale,objectives, and methods

Heart failure (HF) constitutes the growing cardiovascular burden and the major public health issue, but comprehensive statistics on HF epidemiology and related management in Europe are missing. The Heart Failure Association (HFA) Atlas has been initiated in 2016 in order to close this gap, representing the continuity directly rooted in the European Society of Cardiology (ESC) Atlas of Cardiology. The major aim of the HFA Atlas is to establish a contemporary dataset on HF epidemiology, resources and reimbursement policies for HF management, organization of the National Heart Failure Societies (NHFS) and their major activities, including education and HF awareness. These data are gathered in collaboration with the network of NHFS of the ESC member and ESC affiliated countries. The dataset will be continuously improved and advanced based on the experience and enhanced understanding of data collection in the forthcoming years. This will enable revealing trends, disparities and gaps in knowledge on epidemiology and management of HF. Such data are highly needed by the clinicians of different specialties (aside from cardiologists and cardiac surgeons), researchers, healthcare policy makers, as well as HF patients and their caregivers. It will also allow to map the snapshot of realities in HF care, as well as to provide insights for evidence‐based health care policy in contemporary management of HF. Such data will support the ESC/HFA efforts to improve HF management ant outcomes through stronger recommendations and calls for action. This will likely influence the allocation of funds for the prevention, treatment, education and research in HF.     

Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompromised mice

Little is known regarding the role of NK cells during primary and secondary disseminated Candida albicans infection. We assessed the role of NK cells for host defense against candidiasis in immunocompetent, as well as immunodeficient, hosts. Surprisingly, depletion of NK cells in immunocompetent WT mice did not increase susceptibility to systemic candidiasis, suggesting that NK cells are redundant for antifungal defense in otherwise immunocompetent hosts. NK‐cell‐depleted mice were found to be protected as a consequence of attenuation of systemic inflammation. In contrast, the absence of NK cells in T/B/NK‐cell‐deficient NSG (NOD SCID gamma) mice led to an increased susceptibility to both primary and secondary systemic C. albicans infections compared with T/B‐cell‐deficient SCID mice. In conclusion, this study demonstrates that NK cells are an essential and nonredundant component of anti‐C. albicans host defense in immunosuppressed hosts with defective T/B‐lymphocyte immunity, while contributing to hyperinflammation in immunocompetent hosts. The discovery of the importance of NK cells in hosts with severe defects of adaptive immunity might have important consequences for the design of adjunctive immunotherapeutic approaches in systemic C. albicans infections targeting NK‐cell function.