In vitro and in vivo repeatability of abdominal diffusion-weighted MRI

Objective

To study the in vitro and in vivo (abdomen) variability of apparent diffusion coefficient (ADC) measurements at 1.5 T using a free-breathing multislice diffusion-weighted (DW) MRI sequence.

Methods

DW MRI images were obtained using a multislice spin-echo echo-planar imaging sequence with b-values=0, 100, 200, 500, 750 and 1000 s mm⁻². A flood-field phantom was imaged at regular intervals over 100 days, and 10 times on the same day on 2 occasions. 10 healthy volunteers were imaged on two separate occasions. Mono-exponential ADC maps were fitted excluding b=0. Paired analysis was carried out on the liver, spleen, kidney and gallbladder using multiple regions of interest (ROIs) and volumes of interest (VOIs).

Results

The in vitro coefficient of variation was 1.3% over 100 days, and 0.5% and 1.0% for both the daily experiments. In vivo, there was no statistical difference in the group mean ADC value between visits for any organ. Using ROIs, the coefficient of reproducibility was 20.0% for the kidney, 21.0% for the gallbladder, 24.7% for the liver and 28.0% for the spleen. For VOIs, values fall to 7.7%, 6.4%, 8.6% and 9.6%, respectively.

Conclusion

Good in vitro repeatability of ADC measurements provided a sound basis for in vivo measurement. In vivo variability is higher and when considering single measurements in the abdomen as a whole, only changes in ADC value greater than 23.1% would be statistically significant using a two-dimensional ROI. This value is substantially lower (7.9%) if large three-dimensional VOIs are considered.Diffusion-weighted (DW) MRI is based on the Brownian motion of water in biological tissues [1,2]. The technique has played a preponderant role in neuro-imaging over the last two decades and it is known to detect small changes before they are apparent on anatomical imaging [3,4].In recent years DW MRI has been increasingly used in other parts of the body, demonstrating great diagnostic potential in cancer imaging. To date, DW MRI has been successfully used for tissue characterisation and tumour staging. However, the apparent diffusion coefficient (ADC) is a potential biomarker that could be used to monitor treatment response or evaluate post-therapeutic changes. Details of the clinical use of DW MRI can be found in the 2009 consensus paper [5] or in general and organ-specific review articles [6-8].While DW MRI is a potentially powerful tool in diagnostic oncology, the lack of uniform protocols for imaging and data analysis hinder its clinical implementation. Large differences in ADC values are reported in the literature depending on the acquisition parameters, in particular the choice of b-values (e.g. see [9] for ADC values in the kidney or 5] highlighted the importance of quality analysis, validation and reproducibility studies. Although there are some emerging reproducibility and repeatability data in the abdomen [15,19-22], a recent review by Taouli and Koh [7] highlights the need for further work in this area. Recently, coefficients of variability of around 14% were published for both solid tumours [22] and bone marrow [23]. Other studies seem to indicate that only ADC changes of over 27% [20] or 30% [21] are significant. Substantial variations in ADC values have also been found between different scanners and vendors [24-26], further highlighting the difficulty of setting up multicentre trials.

Table 1

Apparent diffusion coefficient values measured in normal liver at 1.5 T

Ability of 18-fludeoxyglucose positron emission tomography/CT to detect incidental cancer

Objective:

To determine the prevalence and clinical features of pathologically proven incidental cancer (IC) detected by whole-body fluorine-18 fludeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/CT, as well as the incidence of false-positive and false-negative results.

Methods:

We retrospectively reviewed reports derived from ¹⁸F-FDG PET/CT images of 3079 consecutive patients with known or suspected malignancies for 3 years. Discrete focal uptake indicating IC was identified from reports as well as pathological or clinical diagnoses, and the clinical courses were investigated. The false-positive result was defined as uptake indicating IC but not pathologically confirmed as malignant during follow-up. The false-negative result was defined as pathologically proven IC detected by another modality at initial clinical work-up or diagnosed during the follow-up period.

Results:

We found ¹⁸F-FDG uptake indicating IC in 6.7% of all patients, and IC was pathologically proven in 2.2% of all patients. The most common sites were the colon, lung and stomach. The median survival duration of patients with IC was 42 months. The results were false positive in 4.5% of all patients, and the results were false negative in 2.3% of all patients.

Conclusion:

¹⁸F-FDG PET/CT is a valuable tool for detecting IC. The rates of false-positive and false-negative results are within acceptable range.

Advances in knowledge:

This is the first report to describe the survival of patients with IC, and the detailed features of false-negative results at actual clinical settings.Integrated whole-body positron emission tomography (PET)/CT using the glucose analogue fluorine-18 fludeoxyglucose (¹⁸F-FDG) is an established modality for oncologic imaging. Combined metabolic and morphological images yielded by ¹⁸F-FDG PET/CT can provide accurate information on the staging, restaging and therapeutic monitoring of many common cancers.¹ Furthermore, ¹⁸F-FDG PET and PET/CT have the potential for cancer screening. Owing to the non-specific nature of ¹⁸F-FDG uptake, a wide range of malignant tumours can be visualized as incidental foci of hypermetabolism. For instance, new malignant tumours have been detected in asymptomatic individuals,² patients with head and neck cancer,³ oesophageal cancer⁴ and malignant lymphoma.⁵ Incidental focal ¹⁸F-FDG uptake within the gastrointestinal tract frequently represents malignant and pre-malignant tumours.^6,7 The detection of incidental cancer (IC) significantly impacts clinical oncological practice. Namely, the detection of a primary cancer can lead a patient to a new treatment, and the detection of a second primary cancer can lead a patient to a more suitable treatment.IC has been detected by ¹⁸F-FDG PET or PET/CT in the past decade.^8–15 8–13 The detection rate of IC ranges from 0.9% to 4.4%,^8–15 and a few reports have described a wider range (0.1–4.4%) of false-negative findings.^13–15 However, the survival of patients with IC has not been detailed. Differences in detection rates and other findings arise owing to many factors, including country, age, symptomatic or asymptomatic individuals, ¹⁸F-FDG PET or PET/CT, judgment criteria, method and period of follow-up.

Table 1.

Previous studies evaluating detection rate of incidental cancer (IC)

Radiotherapy for non-malignant disorders: state of the art and update of the evidence-based practice guidelines

Every year in Germany about 50,000 patients are referred and treated by radiotherapy (RT) for “non-malignant disorders”. This highly successful treatment is applied only for specific indications such as preservation or recovery of the quality of life by means of pain reduction or resolution and/or an improvement of formerly impaired physical body function owing to specific disease-related symptoms. Since 1995, German radiation oncologists have treated non-malignant disorders according to national consensus guidelines; these guidelines were updated and further developed over 3 years by implementation of a systematic consensus process to achieve national upgraded and accepted S2e clinical practice guidelines. Throughout this process, international standards of evaluation were implemented. This review summarizes most of the generally accepted indications for the application of RT for non-malignant diseases and presents the special treatment concepts. The following disease groups are addressed: painful degenerative skeletal disorders, hyperproliferative disorders and symptomatic functional disorders. These state of the art guidelines may serve as a platform for daily clinical work; they provide a new starting point for quality assessment, future clinical research, including the design of prospective clinical trials, and outcome research in the underrepresented and less appreciated field of RT for non-malignant disorders.Every year about 50,000 patients in Germany are treated for “non-malignant disorders” respectively “benign disease conditions” by using ionizing radiation applied in >300 radiotherapy (RT) facilities.^1–4 The aim of these treatments are and will be the preservation or recovery of various quality of life aspects, for example, by prevention of or reduction of pain and/or improvement of formerly disabled physical body functions.Non-malignant indications for RT comprise about 10–30% of all treated patients in most academic, public and private RT facilities in Germany. Over the past decade, various so called patterns of care studies (PCSs) have focused on the general and various specific aspects of these diseases and their RT treatment conditions and concepts in Germany.^1–5 Overall, there is not a single RT institution among all 300 active RT facilities in Germany that does not offer RT for these benign or “non-malignant diseases”.^1–4Since 1995 and together with the foundation of the German Society of Radiation Therapy and Oncology (DEGRO), a scientific task force group was formed, the German Cooperative Group on Radiotherapy for Benign Diseases (GCG-BD), which undertook the task to review the large amount of clinical experience gained in several decades from 1930 to 1990 in Germany about the use of RT for non-malignant disorders; the relevant articles and clinical data were systematically discussed and evaluated by a scientific panel and a “Delphi” consensus process involving all active RT providers. The first National guideline was defined and published in the year 2000.¹ From then on, specific PCSs and prospective randomized clinical trials were developed to improve the available levels of evidence (LOEs) for various non-malignant disorders.^5–8 Meanwhile, a considerable number of clinical trials have been carried out and published.^9–14The updated National practice guideline v. 2.0 of the most common RT indications for non-malignant diseases were developed between 2010 and 2013 by a nominated group of specialists in conjunction with all members of the German Radiation Oncology Society (DEGRO) and GCG-BD; the Delphi consensus process comprised several national-held symposia, working group meetings and the circulation of all preliminary text versions within the responsible writing committee group members and the final presentation in the national scientific DEGRO meeting in the year 2013.These updated practice guidelines focus on those clearly defined RT indications that have become clinically relevant in terms of the high clinical demand (i.e. number of referrals from other medical disciplines), and the currently achieved quantity and quality of treatments, which had been determined by an evaluation of the continuously increasing number of treated patients between the first two evaluation periods within Germany (

Post-cholecystectomy syndrome: spectrum of biliary findings at magnetic resonance cholangiopancreatography

Post-cholecystectomy syndrome (PCS) is defined as a complex of heterogeneous symptoms, consisting of upper abdominal pain and dyspepsia, which recur and/or persist after cholecystectomy. Nevertheless, this term is inaccurate, as it encompasses biliary and non-biliary disorders, possibly unrelated to cholecystectomy. Biliary manifestations of PCS may occur early in the post-operative period, usually because of incomplete surgery (retained calculi in the cystic duct remnant or in the common bile duct) or operative complications, such as bile duct injury and/or bile leakage. A later onset is commonly caused by inflammatory scarring strictures involving the sphincter of Oddi or the common bile duct, recurrent calculi or biliary dyskinesia. The traditional imaging approach for PCS has involved ultrasound and/or CT followed by direct cholangiography, whereas manometry of the sphincter of Oddi and biliary scintigraphy have been reserved for cases of biliary dyskinesia. Because of its capability to provide non-invasive high-quality visualisation of the biliary tract, magnetic resonance cholangiopancreatography (MRCP) has been advocated as a reliable imaging tool for assessing patients with suspected PCS and for guiding management decisions. This paper illustrates the rationale for using MRCP, together with the main MRCP biliary findings and diagnostic pitfalls.Post-cholecystectomy syndrome (PCS) consists of a group of abdominal symptoms that recur and/or persist after cholecystectomy [1, 2]. It is defined as early if occurring in the post-operative period and late if it manifests after months or years.Although this term is used widely, it is not completely accurate, as it includes a large number of disorders, both biliary (1, 2]. It has been reported that ∼50% of these patients suffer from organic pancreaticobiliary and/or gastrointestinal disorders, whereas the remaining patients are affected by psychosomatic or extra-intestinal diseases. Moreover, in 5% of patients who undergo laparoscopic cholecystectomy, the reason for chronic abdominal pain remains unknown [1]. Probably because of the uncertainty in nosographic definition, the reported prevalence of PCS ranges from very low [2] to 47% [1]. Symptoms include biliary or non-biliary-like abdominal pain, dyspepsia, vomiting, gastrointestinal disorders and jaundice, with or without fever and cholangitis [1, 2]. Severe symptoms are more likely to represent a complication of cholecystectomy if they occur early or to express a definite treatable cause when compared with non-specific, dyspeptic or mild symptoms. A non-biliary aetiology of PCS should be suspected if no calculi or gallbladder abnormalities are found at cholecystectomy and symptoms are similar to those suffered pre-operatively [1]. Treatment for PCS is tailored to the specific cause and includes medication, sphincterotomy, biliary stenting, percutaneous drainage of bilomas and surgical revision for severe strictures [1–4].

Table 1

Main biliary causes of post-cholecystectomy syndrome (PCS) related to cholecystectomy. (Biliary malignancies are the most frequent causes of PCS unrelated to cholecystectomy [1])

Spatial variation in T1 of healthy human articular cartilage of the knee joint

The longitudiual relaxation time T₁ of native cartilage is frequently assumed to be constant. To redress this, the spatial variation of T₁ in unenhanced healthy human knee cartilage in different compartments and cartilage layers was investigated. Knees of 25 volunteers were examined on a 1.5 T MRI system. A three-dimensional gradient-echo sequence with a variable flip angle, in combination with parallel imaging, was used for rapid T₁ mapping of the whole knee. Regions of interest (ROIs) were defined in five different cartilage segments (medial and lateral femoral cartilage, medial and lateral tibial cartilage and patellar cartilage). Pooled histograms and averaged profiles across the cartilage thickness were generated. The mean values were compared for global variance using the Kruskal–Wallis test and pairwise using the Mann–Whitney U-test. Mean T₁ decreased from 900–1100 ms in superficial cartilage to 400–500 ms in deep cartilage. The averaged T₁ value of the medial femoral cartilage was 702±68 ms, of the lateral femoral cartilage 630±75 ms, of the medial tibial cartilage 700±87 ms, of the lateral tibial cartilage 594±74 ms and of the patellar cartilage 666±78 ms. There were significant differences between the medial and lateral compartment (p<0.01). In each cartilage segment, T₁ decreased considerably from superficial to deep cartilage. Only small variations of T₁ between different cartilage segments were found but with a significant difference between the medial and lateral compartments.MRI relaxation parameters are used to evaluate cartilage degradation. T₂ has been investigated extensively and has been demonstrated to vary with water and collagen content and with collagen orientation in the different cartilage layers [1–8].The quantification of the longitudiual relaxation time T₁ of native cartilage has received less attention. In experimental studies, native T₁ has been demonstrated to correlate with mechanical properties [9] and to depend upon the macromolecular structure of cartilage [10]. However, it is frequently assumed to be constant across cartilage [11–13]. A few studies have investigated the mean values of a single compartment (10, 14–19] but have not investigated the depth-dependent variation. To our knowledge, no study has systematically compared T₁ of unenhanced human knee cartilage in different cartilage layers and in different cartilage compartments in healthy volunteers.

Table 1

T₁ of healthy human articular cartilage in the knee joint

Improving external beam radiotherapy by combination with internal irradiation

The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose that can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive, as different organs at risk are in target. However, advantages of both single treatments are combined, for example, precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of pre-clinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed.External beam radiotherapy (EBRT) alone and in combination with surgery and/or chemotherapy is one of the main modalities for cancer treatment and has a high potential to permanently cure solid tumours even in locally advanced stages by inactivation of cancer stem cells.¹ EBRT can be administered precisely to a target volume during a course of fractionated irradiation. The homogeneous energy dose has a high intensity in solid tumour lesions. For some cancers, survival rates after primary radiotherapy are high [e.g. early stage larynx cancer and early stage non-small-cell lung cancer (NSCLC)], whereas for many other entities they are not (e.g. glioblastomas, sarcomas and advanced NSCLC).²One way to improve radiotherapy is to increase the inactivation of tumour cells. However, the applicable EBRT dose is limited by the radiosensitivity of the surrounding tissue. While EBRT is directed to the local tumour disease, the use of systemic radioimmunotherapy (RIT) offers the possibility to treat both, localized and diffuse tumours and (micro)metastases.³ Radionuclides are bound to carrier molecules that target tumour cells. Thus, they are distributed according to the properties of the tracer and are continuously effective during a longer period compared with EBRT, although dose rates decrease depending on the half-life of the radionuclide. Some free therapeutic radionuclides are effective for specific indications, e.g. ¹³¹I for treatment of thyroid cancer or palliative use of ²²³Ra against bone metastases. However, these cannot be translated to treatment of other entities. Besides, radioactive-labelled cytostatic drugs and hormone derivatives,⁴ particularly monoclonal antibodies (mAb) have been radiolabelled and investigated.⁵ Given a substantial difference in the target receptor expression between the tumour cells and surrounding normal tissues, a dose fall-off between both tissues can be expected. The radiolabelled mAb Zevalin^® ibritumomab tiuxetan (Zevalin^®, Bayer Healthcare Pharmaceuticals, Berlin, Germany) directed against CD20 is approved by the Food and Drug Administration(FDA) and the European Medicines Agency (EMA) for the treatment of follicular B-cell non-Hodgkin''s lymphomas, which are generally considered as radiosensitive. However, mAb are large and are thus taken up slowly into solid tumour tissue followed by a long clearance. Additionally, accumulation in solid tumours depends on vascularization, vessel permeability, tumour size, interstitial pressure and other microenvironmental characteristics.^6,7 Furthermore, mAb are rather susceptible when labelling under rough conditions. Thus, the application of molecules such as fragment antigen-binding (Fab),^8–10 nanobodies,^11,12 affybodies,^13,14 single chain variable fragments (scFvs),^15,16 aptamers^17–19 or peptides^20,21 is considered. In addition to the effects on target cell, radionuclides with sufficient radiation path length (e.g. β-emitters) can destroy adjacent tumour cells by the crossfire effect, that is through the range of radiation in tissue, cells can be killed without having bound the radionuclide itself.²² This is regarded as a main advantage of RIT for the treatment of solid tumours as plasticity of tumour cells (e.g. loss of target antigen) and delivery barriers can be overcome by some extent. However, the dose-limiting organ in non-myelo-ablative RIT is the red bone marrow and myelosuppression the main toxicity.²² Therefore, the maximum tolerated activity that was applied in clinical RIT trials (reviewed in Navarro-Teulon et al²³) did not result in tumour doses >33 Gy in large tumours, which is not enough to achieve permanent local control of solid tumours.

Combination of internal and external radiotherapy

The combination of internal (incorporated) and external radiotherapy (CIERT) is a novel promising approach in radiation oncology. In this review, CIERT is defined more specifically by an integrated (without interval) application of EBRT and systemically applied RIT. Other approaches such as the combination of external radiotherapy with selective internal radiotherapy, radioembolization, brachytherapy, seed implantation, other intravenously applied radionuclide therapies or sequential application of any of these treatments will not be considered here. Furthermore, the focus will be on solid tumours.The potential benefit of such a combined irradiation is to increase the energy dose applied to the solid tumour lesion, while respecting the limitations of the surrounding normal tissues and the organs at risk (OARs) that are different for both treatment modalities (see above). Figure 1 summarizes the characteristics and OARs of EBRT and RIT and gives an overview on the advantages of the combinatorial approach. Beyond local treatment intensification, another advantage of CIERT can be the combination of local treatment, directed to the solid tumour, and systemic treatment, directed to the subclinically disseminated disease, that is, microscopic tumour lesions not detectable on imaging.Open in a separate windowFigure 1.Combination of internal and external radiotherapy (CIERT). Treatment characteristics of external beam radiotherapy (EBRT) and radioimmunotherapy (RIT) are summarized and advantages of the combination strategy (CIERT) are depicted. Local treatment of the solid tumour via precise EBRT is supplemented by a systemically applied radiotherapeutic drug. Thereby, the tumour dose is enhanced without additional toxicity and (micro)metastasis are potentially targeted. Further, usage of theragnostic radionuclide pairs has the potential to predict delivery and dose distribution of RIT before and during treatment. OAR, organ at risk.Many challenges are to be met prior to the initiation of CIERT. For example, thoughts on the treatment schedule of CIERT and dosimetry considerations are inevitable. The EBRT would usually be applied as standard treatment. Considerations on the RIT part equal usual aspects of RIT, for example, application of cold doses as well as the choice of the carrier molecule (according to the tumour target) and radionuclides. Accordingly, new developments in the field of RIT, for example, pre-targeting strategies, might be applicable for CIERT approaches in the future but have not been used in this context so far. Many of those aspects are intensively researched with regard to single treatments and reviewed elsewhere.^3,23–29 This work focuses on the presentation of pre-clinical and clinical investigations on CIERT as a promising treatment strategy.

Choice of radionuclides and theragnostic potential of combination of internal and external radiotherapy

The main factor of radiation toxicity is damage of DNA. If the amount and severity of radiation-induced damage exceeds the repair capacity of the cell, death occurs during mitosis. The linear energy transfer (LET) describes the energy released by the radiation over a certain distance and influences relative biological effectiveness (RBE).^3,30 X-rays as well as γ- and β-emitters have low LET and thus produce individual DNA lesions mainly by indirect ionization that can easily be repaired. By contrast, high and intermediate LET particle emitters cause clusters of DNA damage that are difficult to repair. Thus, α-emitters (high LET) and Auger electrons (intermediate LET) are more cytotoxic at equivalent absorbed doses. The track path length of α-emitters covers only some cell layers (50–100 µm), and Auger electrons have an even shorter range (<1 µm), which, together with the high RBE, makes them suitable for treatment of small volumes such as micrometastasis.^3,31 If larger solid tumours are targeted, microenvironmental factors such as perfusion, vessel permeability and the amount of connective tissue influence the distribution of RIT therapeutics. Thus, the application of β-particles may be most promising for CIERT because their path length of 0.5–12.0 mm enables the crossfire effect.^3,30In contrast to mitotic catastrophe caused by irradiation, apoptosis can be induced by some mAb via blockage of the respective receptor and modification of downstream signalling. Thus, the combination of irradiation and mAb may promote the manifestation of sublethal harm to severe damage, which finally lead to cell death. In case of CIERT, radiation is not only applied via EBRT but also by radionuclides bound to the mAb.A fundamental requisite for the success of radioactivity delivery into solid tumours is that the radionuclide reaches the target and accumulates for an appropriate period. Thus, the pharmacological half-life of the carrier and half-life of the radioactive decay of the chosen nuclide need to be balanced.^3,23 Most pre-clinical and clinical studies on CIERT used large mAb (approximately 150 kDa), which show a slow plasma clearance. Thus, intratumoral accumulation peaks usually several days after injection. Accordingly, most studies used β-emitters or emitters of Auger electrons with half-lives of at least several days. Pickhard et al³² recently showed the benefit of using ²¹³Bi bound to an antibody against the epidermal growth factor receptor (EGFR) in combination with EBRT. They demonstrated that different cell death pathways are triggered by this α-emitter and photon irradiation. However, the short half-life of ²¹³Bi (45 min) may limit its usage for solid tumours in vivo if the nuclide is linked to antibodies, because most doses will be applied before the tracer penetrates into tumour tissue. Thus, ²¹³Bi may only be useful to treat haematological malignancies and therefore is not feasible for CIERT. The concept of pre-targeting is intensively researched in association with RIT as a single treatment. The tumour is pre-targeted with the unlabelled complementary prepared antibody, and the radionuclide is delivered via a small molecule recognizing the antibody by the complementary system in a second step. This may lead to higher tumour uptake with lower normal tissue retention (reviewed in van de Watering et al²⁹). However, a combination with EBRT has never been investigated and substantial research on scheduling would be mandatory.The concept of theragnostic approaches is applicable for CIERT, as theragnostic radionuclide pairs can be used for the RIT part of the therapy. The goal is to combine a diagnostic tool having an imaging radionuclide (positron or γ-radiation emitter) with a derived individualized therapeutic procedure using a therapeutic radionuclide (particle emitter). The tumour and normal tissue uptake of the respective drug can be evaluated for individual patients via positron emission tomography (PET) or single photon emission CT (SPECT) and give predictive information on a potential treatment benefit. The selection of appropriate radionuclides for imaging with regard to their replacement by a radionuclide for therapeutic purposes that exhibit similar chemical and physical properties is a crucial matter. Thus, it is important to consider different characteristics of radiation according to the requirements, such as decay characteristics, dose range and physical half-life of the radionuclides.³⁰ Imaging with radionuclide-labelled conjugates provides pre-therapeutic information such as biodistribution, hints of a limiting or critical organ or tissue, and maximum tolerated dose. Dosimetry is most challenging, as pre-therapeutic imaging may not be congruent to actual delivered doses.³³ However, this field is extensively investigated for peptide receptor radionuclide therapy (PRRT), and results are directly transferable to CIERT approaches. After applying therapeutic nuclide-labelled conjugates, the results of such treatment may again be monitored via imaging. A selection of theragnostic combinations of radionuclides are shown in 51 but its production is difficult and expensive.⁵² The positron emitters ⁸⁶Y and ¹²⁴I have been described controversially as PET nuclides since besides high β⁺-radiation energy they emit multiple high-energy γ photons that cause so-called multiple coincidences disturbing PET imaging quality. However, different correction methods allow improved quantitative imaging.⁵⁰ Moreover, for the application of ⁹⁰Y-labelled radiopharmaceuticals, it is suggested to estimate the uptake and dosimetry with the nuclide counterpart ⁸⁶Y.³⁶ Nevertheless, ⁸⁶Y-PET is far from clinical routine, at least in the near future. Furthermore, ¹³¹I also emits γ-radiation that has been used for imaging, and ¹¹¹In and ¹²³I have a potential for treatment owing to their released Auger electrons.

Table 1.

Potential theragnostic radionuclides^a

Ultrasonography-guided ethanol ablation of predominantly solid thyroid nodules: a preliminary study for factors that predict the outcome

Objectives

The aim of this study was to evaluate the success rate in ultrasonography-guided ethanol ablation (EA) of benign, predominantly solid thyroid nodules and to assess the value of colour Doppler ultrasonography in prediction of its success.

Methods

From January 2008 to June 2009, 30 predominantly solid thyroid nodules in 27 patients were enrolled. Differences in the success rate of EA were assessed according to nodule vascularity, nodule size, ratio of cystic component, amount of injected ethanol, degree of intranodular echo-staining just after ethanol injection and the number of EA sessions.

Results

On follow-up ultrasonography after EA for treatment of thyroid nodules, 16 nodules showed an excellent response (90% or greater decrease in volume) and 2 nodules showed a good response (50–90% decrease in volume) on follow-up ultrasonography. However, 5 nodules showed an incomplete response (10–50% decrease in volume) and 7 nodules showed a poor response (10% or less decrease in volume). Statistical analysis revealed a significant association of nodule vascularity (p = 0.002) and degree of intranodular echo-staining just after ethanol injection (p = 0.003) with a successful outcome; however, no such association was observed with regard to nodule size, ratio of cystic component, amount of infused ethanol and the number of EA sessions. No serious complications were observed during or after EA.

Conclusion

The success rate of EA was 60%, and nodule vascularity and intranodular echo-staining on colour Doppler ultrasonography were useful in predicting the success rate of EA for benign, predominantly solid thyroid nodules.Livraghi et al [1] used ultrasonography-guided ethanol ablation (EA) for the treatment of hyperfunctioning thyroid nodules; EA has since been established as the first-line treatment for benign cystic thyroid nodules, and may be considered an appropriate alternative to clinical follow-up, radioiodine therapy or thyroid surgery for treatment of autonomous functioning thyroid nodules (AFTNs) or toxic nodules. Advantages of EA include low risk, low cost, practicability in the outpatient clinic and ease of performance [2-14]. However, radioiodine therapy and surgery remain the treatments of choice for large toxic thyroid nodules [5,8,9,15].Following the initial use of EA in the treatment of benign cystic thyroid nodules [16], many published studies have reported appreciable efficacy of EA in the treatment of benign cystic thyroid nodules and recurrent cystic nodules [17-26]. However, published data regarding the EA of solid thyroid nodules have shown varying results, depending on nodule size, the volume of ethanol instilled and the presence of nodule toxicity (2-14]. Thus, the use of EA in the treatment of solid thyroid nodules has been limited owning to controversy over its efficacy and clinical indications. Several studies have attempted to determine factors that might be predictive of the effectiveness of EA in AFTNs or toxic nodules. These studies found that an initial nodule volume [5,8-10] and the presence of a cystic component making up more than 30% of the total volume are important factors in predicting a positive response to EA [14]. Despite these results, EA is rarely selected for the treatment of a solid thyroid nodule compared with the options of clinical follow-up, radioiodine therapy or surgery. Identification of factors that might aid in the accurate prediction of the success of EA in the treatment of solid thyroid nodules could result in more frequent clinical use of EA. To the best of our knowledge, no study of the feasibility of colour Doppler ultrasonography for predicting the success in EA of predominantly solid thyroid nodules has been conducted to date.

Table 1

The published data of ethanol ablation for solid thyroid nodules

Pulmonary embolism: investigation of the clinically assessed intermediate risk subgroup

Objectives

The simplified Wells pre-test probability scoring algorithm for pre-investigation evaluation of pulmonary emboli (PE) is a commonly utilised and validated assessment tool. We sought to identify whether use of a dichotomised scoring system altered the overall negative predictive value (NPV) in patients referred for CT pulmonary angiography (CTPA) assessment of suspected PE.

Methods

Prospective data collection of all patients referred for CTPA evaluation of suspected acute PE during a 3 year period was carried out. Pre-test risk stratification was performed according to simplified Wells criteria in conjunction with plasma d-Dimer (Bio-Pool and IL test) estimation. Retrospective dichotomisation was also performed.

Results

2531 patients were investigated for suspected acute PE; acute thromboemboli were confirmed in 22.7%. The overall NPV for negative d-Dimer and intermediate pre-test probability (PTP) was 98.9% [95% confidence interval (CI) 96.3–99.7%]; with retrospective dichotomisation, the NPV for the PE unlikely group was 99.0% (95% CI 94.8–99.8%). Implementation of dichotomised scoring, excluding PE unlikely with negative d-Dimer cases from further imaging, would have yielded a 4% reduction in CTPA referral pathway imaging at our institution.

Conclusion

We demonstrate no significant difference between exclusion in the intermediate subgroup and the retrospectively dichotomised PE unlikely group and demonstrate the high negative predictive power of the Bio-Pool and IL tests in conjunction with the Wells PTP tool. Prior to implementation of new guidelines for exclusion of patients with suspected PE from further imaging, hospitals should audit their own practice and validate the d-Dimer assay utilised at their institution.The overall annual incidence of pulmonary emboli (PE) is quoted at 60–70 cases per 100 000 [1-3]. Associated with significant morbidity and mortality, prompt diagnosis and expeditious therapeutic intervention is of paramount importance for optimal patient management. Indiscriminate and often inappropriate d-Dimer assay evaluation coupled with frequently inexperienced clinical assessment of the presenting patient results in inappropriate referrals and reduced diagnostic yield. The challenge is to identify the patients referred for radiological assessment of suspected PE who actually have a thromboembolic event [4].The British Thoracic Society (BTS) guidelines advise that the patient is fully evaluated by an experienced middle-grade doctor so that alternative diagnoses can be considered and a clinical probability documented; such practice should yield a 25% incidence of PE in investigated cases [1]. Numerous validated guidelines for initial assessment of PE identify the need for a clinical probability score using a validated scoring system and sensitive, appropriately taken, d-Dimer evaluation [1,4-6].With the improved diagnostic capability of modern helical CT, referring clinicians have lower thresholds for patient referral for CT pulmonary angiography (CTPA) as it is deemed to offer an increasingly definitive detection of PE. However, increased CTPA examinations are associated with cost implications and increasing ionising radiation burden [7]. Patients referred for diagnostic work-up must be carefully selected to avoid unnecessary radiation and expenditure and to yield the desired prevalence of 25% or greater. Pivotally, patients not requiring further diagnostic evaluation, as proposed by major guidelines [1,4,5], should be identified (if inappropriately referred) and safely excluded prior to any imaging [8].A commonly utilised validated pre-test clinical probability (PTP) assessment tool is the Wells score [9]. The simplified Wells score incorporates seven variables from the patient''s history and initial clinical assessment from which a clinical probability of PE is determined as either low, moderate (intermediate) or high (9,10]. Used in conjunction with a sensitive d-Dimer assay PE can be safely excluded in patients with a negative d-Dimer estimation and low PTP [1,4,5,8,11-13]. The intermediate subgroup present a more challenging diagnostic enigma with variable recommendations pertaining to those with negative d-Dimer assays; in part, this is secondary to variable assay sensitivities. The BTS guidelines indicate that PE can safely be excluded with intermediate PTP in conjunction with a highly sensitive d-Dimer assay [Vidas (bioMerieux, Marcy L''Etoile, France) or MDA (bioMerieux, Durham, NC)]; individual units should however validate the sensitivity and specificity of their particular d-Dimer assay and, as such, all patients with suspected PE, except those with low PTP and negative d-Dimer, are accepted for imaging at our institution. Dichotomisation of the Wells score into PE unlikely vs PE likely has been proposed to further increase the scoring system''s utility and permit safe exclusion from imaging in a larger subset of patients [4].

Table 1

The simplified Wells score. Cumulative points total <2 implies low clinical pre-test probability of pulmonary emboli (PE), a total of 2–6 points represents moderate (intermediate) pre-test probability and >6 a high pre-test probability of PE [9]. Using a dichotomised scoring system PE “unlikely” represents a simplified Wells score of 4 or less vs PE “likely” score of greater than 4 points

Can a revised paediatric radiation dose reduction CT protocol be applied and still maintain anatomical delineation,diagnostic confidence and overall imaging quality?

Objective:

To compare multidetector CT (MDCT) radiation doses between default settings and a revised dose reduction protocol and to determine whether the diagnostic confidence can be maintained with imaging quality made under the revised protocol in paediatric head, chest and abdominal CT studies.

Methods:

The study retrospectively reviewed head, chest, abdominal and thoracoabdominal MDCT studies, comparing 231 CT studies taken before (Phase 1) and 195 CT studies taken after (Phase 2) the implemented revised protocol. Image quality was assessed using a five-point grading scale based on anatomical criteria, diagnostic confidence and overall quality. Image noise and dose–length product (DLP) were collected and compared.

Results:

The relative dose reductions between Phase 1 and Phase 2 were statistically significant in 35%, 51% and 54% (p < 0.001) of head, chest and abdominal CT studies, respectively. There were no statistically significant differences in overall image quality score comparisons in the head (p = 0.3), chest (p = 0.7), abdominal (p = 0.7) and contiguous thoracic (p = 0.1) and abdominal (p = 0.2) CT studies, with the exception of anatomical quality in definition of bronchial walls and delineation of intrahepatic portal branches in thoracoabdominal CTs, and diagnostic confidence in mass lesion in head CTs, liver lesion (>1 cm), splanchnic venous thrombosis, pancreatitis in abdominal CTs, and emphysema and aortic dissection in thoracoabdominal CTs.

Conclusion:

Paediatric CT radiation doses can be significantly reduced from manufacturer''s default protocol while still maintaining anatomical delineation, diagnostic confidence and overall imaging quality.

Advances in knowledge:

Revised paediatric CT protocol can provide a half DLP reduction while preserving overall imaging quality.The use of CT has been rapidly increasing all over the world during the past two decades, driven by advanced technology and the invention of the multidetector CT (MDCT). Use of MDCT has risen 12-fold in the UK and 20-fold in the USA during this time, and the mean effective dose from all medical X-rays in the USA has increased 7-fold during this period.^1–3 6–11% of all CT examinations in developed countries are performed on children aged from 0 to 15 years.^2,4–6 The organ-absorbed doses reported in adult and paediatric patients undergoing single CT examination are considerably lower than the threshold for initiation of a deterministic effect and the estimated effective doses are still within the annual exposure dose from natural background radiation.⁷ The UK Radiation Protection Division of the Health Protection Agency, the US National Council on Radiological Protection and Measurement and the US National Academy of Sciences Biological Effects of Ionizing Radiation committees have proposed that, for doses <100 mSv, which is roughly equal to the dose range for multiple CT examinations, the radiation-induced cancers decrease linearly with decreasing dose with no threshold or a so called “linear no-threshold” model.^3,8,9 There was a linearly increasing risk for all solid cancers with increasing radiation dose and a higher radio sensitivity in children resulting in a larger attributable lifetime cancer risk in this patient group.^1,3Although the association of diagnostic medical radiation exposures in maternal pre-natal, children''s post natal and parental pre-conception periods with paediatric cancer risks are summarized in various studies, a CT scan-related cancer risk in children and adolescents has not been definitively proven.⁶ A retrospective cohort study by Pearce et al¹⁰ did, however, find a significant association between estimated cumulative radiation doses delivered by CT scan to the bone marrow and brain and subsequent increased risk of leukaemia and brain tumours in childhood.Diagnostic reference level (DRL) values are required for CT optimization, and these values are recommended by the International Commission on Radiological Protection; also each region or country is responsible for and authorized to enact details and implementation of their own DRLs.¹¹ Several age-based and weight-based DRLs for paediatric CT have been published.^12–17 General strategies for CT dose reduction in paediatric healthcare include such things as avoiding a CT scan if adequate clinical information can be obtained from ultrasound or MRI, avoiding multiphase examinations and designing CT protocols to minimize exposure time.¹⁸ Nowadays, many professional societies, regulators and manufacturers have been trying innovative new technologies for reducing radiation dose while maintaining optimal image quality.Two of the most commonly used image quality parameters in diagnostic imaging are high-contrast (spatial) resolution and low-contrast resolution. Spatial resolution is the ability to distinguish small objects close to one another on an image and is influenced by various factors such as focal spot size, detector width and ray, pixel size and properties of the reconstruction filter. Low-contrast resolution refers to the visibility of an object against the background. In the absence of artefacts, the low-contrast resolution scan is affected mostly by noise.^19,20 Although noise derivative is a quality index that is more relevant to assess image quality than image noise, it is difficult to translate in clinical practice.²¹ Image noise is measured by standard deviation (SD) of CT number, and it depends on milliamperes (mA), scan time, kilovoltage peak (kVp), patient size, pitch or table speed, slice thickness and reconstruction algorithm. If the milliampere–seconds value is reduced by 50%, the radiation dose will be reduced by the same amount, with an attendant noise increase of 41%, calculated by the equation (1/√2 = 1.41, a 41% increase). Tube voltage or beam energy has a direct influence on patient radiation dose. Reducing the peak kilovoltage results in a significant decrease in radiation dose owing to the square law relationship of these two values.^{19,20,22–25} Thus, the image noise and tissue contrast will be affected by adjusting kilovoltage; however, reduced peak tube potential is useful for chest, airway and skeletal studies owing to a high contrast-to-noise ratio requirement in imaging evaluation.¹⁸In our hospital (Songklanagarind Hospital, Hat Yai, Thailand), we began a revised CT dose reduction protocol in August 2010 that involved lowering kVp and mA, and using dose–length product (DLP) and DRLs based on the Nievelstein et al²³ protocol and national dose surveys from the UK and Canada^12,15 (CT scanned body partPhase 1

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Phase 2

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Age/body massCTDIkVpmAs with automatic tube current modulation^bAge/body massCTDIkVpmAHead<18 months20120150<6 months14.01209018 months to <6 years251202006 months to <3 years22.01201356–10 years321202503 to <6 years28.0120175    6 to <12 years32.0120200    >12 years50.0120315Chest<10 kg3.2120504 to <10 kg1.6809510 to <30 kg5.21208010 to <20 kg2.08012030–50 kg6.512010020 to <30 kg2.480140    30 to <40 kg2.812070    40 to <50 kg3.512090    50–64 kg4.3120110Abdomen<10 kg5.2120804 to <10 kg2.18013010 to <30 kg7.112011010 to <20 kg3.08018030–50 kg7.812012020 to <30 kg3.812090    30 to <40 kg4.1120105    40 to <50 kg4.9120125    50–64 kg5.9120150Open in a separate windowCTDI, CT dose index; kVp, kilovoltage peak; mA, milliamperes.^aReproduced from Nievelstein et al²³ with permission from Springer-Verlag.^bAutomatic tube current modulation in chest and abdominal CT.     

Pulmonary arterial hypertension: an imaging review comparing MR pulmonary angiography and perfusion with multidetector CT angiography

Pulmonary hypertension (PH) is a progressive disease that leads to substantial morbidity and eventual death. Pulmonary multidetector CT angiography (MDCTA), pulmonary MR angiography (MRA) and MR-derived pulmonary perfusion (MRPP) imaging are non-invasive imaging techniques for the differential diagnosis of PH. MDCTA is considered the gold standard for the diagnosis of pulmonary embolism, one of the most common causes of PH. MRA and MRPP are promising techniques that do not require the use of ionising radiation or iodinated contrast material, and can be useful for patients for whom such material cannot be used. This review compares the imaging aspects of pulmonary MRA and 64-row MDCTA in patients with chronic thromboembolic or idiopathic PH.Pulmonary hypertension (PH) is an insidious and progressive disease that leads to substantial morbidity and eventual death. PH results from a number of diseases with different physiopathologies, treatments and prognoses [1]. One of the most frequent causes of PH is chronic thromboembolic pulmonary hypertension (CTEPH).The current classification of PH (2], resulted from a review of the previous classification developed at the 2003 3rd World Symposium in Venice, Italy. During the 4th World Symposium on PH, an international group of experts agreed to maintain the general philosophy and organisation of the Evian–Venice classifications. However, in response to a questionnaire regarding the previous classification, a majority (63%) of experts felt that modification of the Venice classification was required to accurately reflect information published in the past 5 years and to provide clarification in some areas [2].

Table 1

Classification of pulmonary hypertension according to the 4th World Symposium, Dana Point, CA, 2008 [2]

The value of image-guided intensity-modulated radiotherapy in challenging clinical settings

Objective

To illustrate the wider potential scope of image-guided intensity-modulated radiotherapy (IG-IMRT), outside of the “standard” indications for IMRT.

Methods

Nine challenging clinical cases were selected. All were treated with radical intent, although it was accepted that in several of the cases the probability of cure was low. IMRT alone was not adequate owing to the close proximity of the target to organs at risk, the risk of geographical miss, or the need to tighten planning margins, making image-guided radiotherapy an essential integral part of the treatment. Discrepancies between the initial planning scan and the daily on-treatment megavoltage CT were recorded for each case. The three-dimensional displacement was compared with the margin used to create the planning target volume (PTV).

Results

All but one patient achieved local control. Three patients developed metastatic disease but benefited from good local palliation; two have since died. A further patient died of an unrelated condition. Four patients are alive and well. Toxicity was low in all cases. Without daily image guidance, the PTV margin would have been insufficient to ensure complete coverage in 49% of fractions. It was inadequate by >3 mm in 19% of fractions, and by >5 mm in 9%.

Conclusion

IG-IMRT ensures accurate dose delivery to treat the target and avoid critical structures, acting as daily quality assurance for the delivery of complex IMRT plans. These patients could not have been adequately treated without image guidance.

Advances in knowledge

IG-IMRT can offer improved outcomes in less common clinical situations, where conventional techniques would provide suboptimal treatment.The recent advances in radiation delivery can improve tumour control probability and reduce treatment-related toxicity. The use of intensity-modulated radiotherapy (IMRT) allows for an improved radiation dose distribution compared with conventional techniques, ensuring safe dose escalation in selected cases. However, IMRT treatments are less forgiving of set-up inaccuracies owing to steep dose gradients. The integration of image-guided radiotherapy (IGRT) to the IMRT workflow (IG-IMRT) not only enables correction for set-up errors in real time but also permits tighter planning margins.Currently, there is limited evidence on the clinical benefits of IGRT. In addition, patients need to be clinically prioritised for IMRT, owing to limited capacity in the UK. This report illustrates the wider potential of IG-IMRT, where the integration of an IG-IMRT approach allows for radiation treatment which would be considered as non-feasible with conventional techniques.The success of radiotherapy in ablating a tumour depends principally on the total radiation dose, but this dose is limited by the tolerance of the surrounding normal tissues. Techniques such as three-dimensional conformal radiotherapy (3D-CRT) and, more recently, IMRT have allowed for a reduction in normal tissue dose, and therefore toxicity, for a given level of tumour dose. In turn, this may allow for dose escalation, with the expectation of a higher probability of tumour control. In some circumstances, IMRT enables treatment which might previously have been entirely impossible because of toxicity.There is now excellent evidence of the clinical value of IMRT in reducing toxicity by sparing the dose to the surrounding healthy tissue in various tumour sites [1-6]. These results are consistent with the fundamental proof of principle that better dose distributions lead to improved outcomes.One of the capabilities of IMRT is the ability to deliver very steep dose gradients where the target lies close to a critical normal structure. The dose may drop rapidly over just a few millimetres (e.g. 12 Gy over 3 mm), which may have important clinical value. However, it also makes IMRT less forgiving of set-up inaccuracies. In this situation, some form of image guidance to verify that the gradient is correctly located before treatment is desirable, for the dual goals of achieving an adequate target dose (avoiding geographical miss) and minimising the dose to normal tissues (avoiding excess toxicity). IGRT therefore acts as a quality assurance measure for the delivery of high-quality IMRT [7].The existence of discrepancies (positional errors) in patient set-up, resulting from a combination of systematic and random errors, is well understood [8,9]. For a mobile structure, such as the prostate, this also includes an important contribution from random day-to-day variation in the position of the prostate within the patient [10]. Image guidance has been revolutionised by the integration of online imaging capability on linear accelerators, with full software integration for image matching and positional correction. It allows for correction of positional discrepancies in real time, before treatment, so that each daily treatment can be accurately targeted, potentially allowing for tighter planning margins or greater security of target coverage. It also provides an opportunity for treatment adaptation based on changes in tumour volume or patient anatomy [11,12]. IGRT also has a role in quantifying positional discrepancies. It is likely that IGRT will at least contribute to more reliable target volume coverage, as well as a reduction in dose to the surrounding normal tissue [11,13]. In this way, IGRT is complementary to IMRT. However, caution is required, given that IGRT does not necessarily allow for planning target volume (PTV) margin reduction [14].Initial estimates for the expansion of the national IMRT programme suggested that 33% of radical fractions should be delivered with IMRT to maximise the clinical benefit from radiotherapy [15]. This figure of one-third was composed of 24% inverse-planned IMRT cases and 9% forward-planned IMRT cases. These figures have been helpful in developing the national service, but may need to be revised upwards. Significant progress is being made in the roll out of IMRT in the UK [16]. In general, the experience of centres treating with IMRT is that it has wider applicability, particularly when combined with IGRT [17-19]. Nevertheless, limitations in capacity are common, so it is necessary to prioritise those cases for which IG-IMRT is considered likely to give the greatest benefit. For tumours in the head and neck, the close proximity of the target to other structures makes IMRT an attractive option, and the evidence for reduction in long-term side effects with IMRT is most notable in this site. Image guidance is attractive for mobile internal targets such as the prostate [10,18]. Many other sites may also benefit from the combined techniques.The process of clinical prioritisation is a key component of IMRT service implementation [18,20-24]. This is simple for tumour sites where evidence of benefit exists. However, it may not be possible to generate such evidence for all tumour sites, nor should this be expected. In addition, there are situations in which it is impossible to achieve a worthwhile tumour dose without the use of IMRT. In our initial IG-IMRT series this amounted to 5% of cases [18].We report on a group of challenging clinical cases (CaseDiagnosisAge (years)Summary and reasoning for use of IG-IMRTF/U (months)Local recurrenceMetastatic diseaseOutcome1Pelvic Ewing''s sarcoma18Radical treatment, sparing normal tissue structures24NoNoAlive2Chest wall chondrosarcoma18Radical treatment for patient with normal anatomy, where radical treatment was not possible with CRT owing to OAR constraints24NoYesAlive3Prostate adenocarcinoma53Radical treatment for patient with challenging (abnormal) anatomy21NoNoAlive4Carcinoma of the larynx (post op)54Radical treatment for patient with challenging (abnormal) anatomy1NoNoDied5Prostate and rectal adenocarcinomas76Radical treatment of synchronous tumours simultaneously23NoYesDied6Carcinoma of the cervical oesophagus68Radical treatment following previous radiotherapy (occurrence of a different tumour)13NoNoAlive7Nasopharyngeal carcinoma60Radical retreatment (recurrence of the same tumour)15YesNoAlive8Carcinoma of the cervix38Radical retreatment (recurrence of the same tumour)15NoYesDied9Vertebral chordoma39Substitute for proton therapy in patients with metal reconstruction30NoNoAliveOpen in a separate windowCRT, conformal radiotherapy; F/U, follow-up; OAR, organ at risk; post op, post operation.There are different technical solutions for IG-IMRT and we used the TomoTherapy HiArt™ system (TomoTherapy Inc., Madison, WI) for IG-IMRT delivery. The concepts described here also apply to other platforms using rotational therapy.     

Proton radiography and tomography with application to proton therapy

Proton radiography and tomography have long promised benefit for proton therapy. Their first suggestion was in the early 1960s and the first published proton radiographs and CT images appeared in the late 1960s and 1970s, respectively. More than just providing anatomical images, proton transmission imaging provides the potential for the more accurate estimation of stopping-power ratio inside a patient and hence improved treatment planning and verification. With the recent explosion in growth of clinical proton therapy facilities, the time is perhaps ripe for the imaging modality to come to the fore. Yet many technical challenges remain to be solved before proton CT scanners become commonplace in the clinic. Research and development in this field is currently more active than at any time with several prototype designs emerging. This review introduces the principles of proton radiography and tomography, their historical developments, the raft of modern prototype systems and the primary design issues.Despite a history going back over 50 years,¹ proton radiography (pRG) and tomography have been slow to reach the clinic.² Few manufacturers currently offer a clinical imaging system suitable for pRG and none for proton tomography. In fact, it turns out that the use of protons instead of X-rays for transmission imaging has some disadvantages. These include the need for large expensive equipment to produce proton beams (e.g. a cyclotron or synchrotron) and the limitations on image quality arising from the multiple scattering of protons.Proton sources of sufficient energy do, however, exist for several purposes, one application being for proton therapy. The multiple scattering effects remain a fundamental difficulty: protons do not move through a medium in straight lines. So why should we even attempt proton transmission imaging? The prime motivation is with application to proton therapy planning. It was Cormack¹ who was the first to realize the possibilities of proton CT (pCT). In a seminal article of the 1960s on tomographic reconstruction, the Nobel Laureate wrote:

The next application of the solution [for CT] … concerns the recent use of the peak in the Bragg curve for the ionization caused by protons, to produce small regions of high ionization in tissue. The radiotherapist is confronted with the problem of determining the energy of the incident protons necessary to produce the high ionization at just the right place, and this requires knowing the variable-specific ionization of the tissue through which the protons must pass.

This is still a fair assessment of the problem facing any proton therapy team today. Cormack went on to propose that the energy loss of protons passing through a patient can tell us about proton stopping power inside the patient—something that X-rays can never give us directly.Typically, in both photon and proton external beam therapy, prior to treatment, an X-ray CT scan is acquired for treatment planning purposes. This is used for outlining structures, but also provides a map of electron density that is used to calculate dose deposition. In proton therapy, the translation of electron density to proton stopping power provides an extra and appreciable source of error. The most advanced X-ray CT calibration method in common usage is probably the stoichiometric method.³ The resulting overall uncertainty (1σ) in stopping-power ratio (SPR) for protons in different tissue types has been estimated as 1.6% (soft tissue), 2.4% (bone) and 5.0% (lung).⁴ As an illustration, note that the estimate of 1.6% for soft tissue includes contributions for (added in quadrature): stoichiometric parameterization (0.8%), human tissue composition variation (1.2%) and mean excitation energy (0.2%) and other sources (0.6%). None of the first three sources of errors contribute in a calibration in pCT and the ambition with this type of imaging should be to reduce the uncertainty in SPR substantially (to <1%). Reduced uncertainties offer the possibility of smaller planning margins and additional beam directions, potentially leading to superior patient outcomes. The surge in the number of operational and planned proton therapy centres in recent years therefore makes the exploitation of this modality timely.⁵Before proceeding further, some clarification of topic coverage should be made. pRG and pCT, in the context of this review, mean the imaging of an object using the transmission of protons through it. The energy loss of the transmitted protons is the primary mechanism for image contrast. The greatest emphasis will be given to proton-tracking systems: as will be seen, these are best able to cope with the difficulties imposed by proton multiple scattering. Some requirements for a practical pCT scanner for proton therapy are summarized in 10 For comparison, note that a typical head scan using a diagnostic X-ray CT scanner or X-ray cone beam CT (CBCT) might deliver 40 mGy.¹¹

Table 1.

Requirements for a practical (proton-tracking) CT scanner for proton therapy

Advancing pharmacovigilance through academic–legal collaboration: the case of gadolinium-based contrast agents and nephrogenic systemic fibrosis—a research on adverse drug events and reports (RADAR) report

Objective:

To compare and contrast three databases, that is, The International Centre for Nephrogenic Systemic Fibrosis Registry (ICNSFR), the Food and Drug Administration Adverse Event Reporting System (FAERS) and a legal data set, through pharmacovigilance and to evaluate international nephrogenic systemic fibrosis (NSF) safety efforts.

Methods:

The Research on Adverse Drug events And Reports methodology was used for assessment—the FAERS (through June 2009), ICNSFR and the legal data set (January 2002 to December 2010). Safety information was obtained from the European Medicines Agency, the Danish Medicine Agency and the Food and Drug Administration.

Results:

The FAERS encompassed the largest number (n = 1395) of NSF reports. The ICNSFR contained the most complete (n = 335, 100%) histopathological data. A total of 382 individual biopsy-proven, product-specific NSF cases were analysed from the legal data set. 76.2% (291/382) identified exposure to gadodiamide, of which 67.7% (197/291) were unconfounded. Additionally, 40.1% (153/382) of cases involved gadopentetate dimeglumine, of which 48.4% (74/153) were unconfounded, while gadoversetamide was identified in 7.3% (28/382) of which 28.6% (8/28) were unconfounded. Some cases involved gadobenate dimeglumine or gadoteridol, 5.8% (22/382), all of which were confounded. The mean number of exposures to gadolinium-based contrast agents (GBCAs) was gadodiamide (3), gadopentetate dimeglumine (5) and gadoversetamide (2). Of the 279 unconfounded cases, all involved a linear-structured GBCA. 205 (73.5%) were a non-ionic GBCA while 74 (26.5%) were an ionic GBCA.

Conclusion:

Clinical and legal databases exhibit unique characteristics that prove complementary in safety evaluations. Use of the legal data set allowed the identification of the most commonly implicated GBCA.

Advances in knowledge:

This article is the first to demonstrate explicitly the utility of a legal data set to pharmacovigilance research.Nephrogenic systemic fibrosis (NSF) induces cutaneous and subcutaneous “scleroderma-like” changes with acute-onset thickening and hardening of the skin.¹ This condition was first reported in 2000 as a debilitating disorder in persons with chronic kidney disease (CKD) who were on dialysis.^1–11 Although initially named “nephrogenic fibrosing dermopathy”, since the condition seemed to be limited to the skin, it is now well documented that lesions extend beyond the dermis and can involve the joints, skeletal muscles, testes, kidney, myocardium and dura.^12–14 Currently, the diagnosis is made by clinicopathological correlation.¹⁵ Major clinical diagnostic criteria include patterned plaques of bound-down skin, sometimes leading to a “peau d''orange” appearance, overlying hard subcutaneous tissue on the extremities, at times extending to the lower trunk and leading to joint contractures.^15,16 Histologically, dermal changes include increased cellularity with numerous spindle-shaped fibroblasts, CD34⁺ tram tracks, thick collagen bundles with surrounding clefts, mucin deposition and retention of elastic fibres extending into widened subcutaneous septae. Electron microscopy has identified increased elastic fibres apposed to dendritic cell processes.¹⁷ Although information regarding gadolinium exposure is not necessary for the diagnosis of NSF, it is highly recommend that this information be sought to better clarify the role of prior gadolinium exposure in the pathogenesis of NSF.¹⁵ Cardiac, vascular and nervous system complications have been reported as NSF can have systemic fibrotic effects.^18–21Gadolinium-based contrast agents (GBCAs) are gadolinium chelates and may be divided into four classes: linear vs macrocyclic and ionic vs non-ionic. Linear, non-ionic GBCAs have predominantly been implicated in the development of NSF (16 In 2007, the European Medicines Agency (EMA) mandated that only protein-binding linear agents (intermediate risk group) and macrocyclic formulations be used in patients with Stage 4 or 5 CKD. In 2007, the Food and Drug Administration (FDA) required that a “boxed warning” be placed on each of the five FDA-approved GBCAs.²² No differentiation was made between the various agents as to the strength of their associations with NSF. In one reported series of 36 patients, more than half of the patients with NSF died from NSF or underlying comorbidities within 18 months of diagnosis.²³

Table 1.

Identification of the different gadolinium-based contrast agents

An investigation of the radiation doses to the lower legs and feet of staff undertaking interventional procedures

Objective:

Occupational radiation doses from fluoroscopic procedures are some of the highest doses of exposure amongst medical staff using radiography. Protective equipment and dose monitoring are used to minimize and control the risk from these occupational doses. Other studies have considered the effectiveness of this protection, but this study further considers whether protection is adequate for the lower leg and foot and the extent to which these doses can be reduced.

Methods:

Scatter air kerma profiles at toe level were measured with an ionization chamber. Thermoluminescent dosemeters and lower extremity phantoms were used to estimate the dose variation with the height of patient couch. A 7-week period of in situ toe dose monitoring of four radiologists was also undertaken.

Results:

The use of protective curtains effectively reduced the exposure to most of the lower extremities. Toe doses were found to be high and increased with increase in couch height. In situ monitoring indicated annual toe doses of 110 mSv for two of the four radiologists monitored.

Conclusion:

Protective curtains should be used, but they might have limitations with respect to toe doses. Annual toe doses approaching the classification threshold of 150 mSv were measured for two radiologists. Caution should be exercised when there is a gap below curtains and, when possible, staff should step back from the couch. Lower legs and toes should be included in local radiation protection programmes.

Advances in knowledge:

Toe doses in interventional radiology may be higher than expected and may have to be included in radiation protection programmes.The occupational radiation doses from interventional procedures with fluoroscopic image guidance are the highest dose exposures amongst medical staff using radiography.¹ Fluoroscopic screening times per procedure vary owing to many factors, including procedure complexity, the experience of the interventionist and the equipment used. Interventional procedures generally necessitate more imaging than diagnostic procedures.² Lengthy screening times may result in significant overall doses to the staff, most notably the interventionist, who remains in close proximity to the patient throughout a procedure and is therefore at risk from exposure to both primary and scattered radiation. The risk from primary radiation is minimized in staff avoiding the main beam; scattered radiation is therefore the main source of radiation exposure in staff. The monitoring of radiation exposure is a legal requirement in some jurisdictions,³ but the implementation of radiation safety procedures and the exact methods of monitoring vary between centres. Methods include personnel and dosimetry monitoring programmes, along with the use of personal protective equipment (PPE) in the form of aprons, eye shields, mobile and fixed shields and protective curtains. Some areas of the body, such as the hands, are difficult to protect; hand doses to staff are often monitored using finger dosemeters to ensure that dose limits are not exceeded. However, lower extremities are neither routinely protected nor monitored.Protection at this level is almost solely reliant on a protective lead curtain hanging from the patient couch. In the UK, these curtains are typically manufacturer-standard supplied protection made from 0.5-mm lead-equivalent rubber with multiple- or single-piece blades. The dimensions of the blades are typical, but the attachment and drop may vary depending on the manufacturer. Protective lead curtains are, however, detachable and optional.From anecdotal feedback, the operator''s toes have been observed to protrude under the curtain, particularly if a high couch height is used, as required for certain procedures, and for taller interventionists. This suggests a limitation to the effectiveness of using curtains in reducing the radiation exposure to an operator''s lower extremities.The International Commission on Radiological Protection⁴ recommends annual hand and feet dose limits of 500 mSv against deterministic risks of erythema at 2 Gy and temporary epilation at 3 Gy; these limits have been adopted by the UK Ionising Radiations Regulations 1999 (IRR99).³ The IRR99 also requires employers to classify employees who are exposed to doses exceeding three-tenths of this limit, which for hands and feet is 150 mSv. The IRR99 instructs employers to take all necessary steps to restrict the extent to which its employees are exposed to ionizing radiation to as low as reasonably practicable (ALARP).For fluoroscopy-guided interventional procedures, the recommended positioning for a vertical X-ray beam is to orientate the C-arm, such that the radiographic tube is under the couch and the detector is over the couch.⁵ This orientation is recommended to protect the hands and eyes of the medical staff because the scattered radiation reaching these areas would have been attenuated by the patient. Radiation is scattered from the patient in all directions. This implies that a component that is largely unattenuated by the patient, and therefore more intense, is scattered downwards back through the couch.⁶ In interventional fluoroscopy, there are two further types of radiation to consider in addition to the scattered radiation; these are primary radiation and leakage radiation. The primary radiation is not incident upon an operator''s lower extremities in procedures where this set-up is used. A portion of the leakage radiation from the radiographic tube is incident on the lower extremities of the radiologists; however, under clinical conditions, the amount of leakage radiation will be considerably less than that of the scattered radiation.⁷ Scattered radiation is therefore the main source of concern regarding safety against radiation exposure in lower extremities.Radiation shielding can provide some protection from the radiation backscattered underneath the couch to the lower extremities; this includes protective curtains attached to the side of a patient couch, portable radiographic screens and shin guards. Further radiation shielding available includes patient drapes and protective aprons, which provide protection from the radiation scattered on the exit side of the patient but do not protect the lower extremities [assuming a posteroanterior (PA) projection]. Portable shields are available, fixed to the patient couch, for protecting the lower extremities in regions where an interventionist''s toes can protrude under the curtain; however, these are not widely in use. The use of shielding varies between interventional radiology departments, and only the protective curtains are in widespread use to shield against lower extremity doses. The use of protective equipment available depends on local factors, including staff diligence and awareness, the degree of involvement of the radiation protection adviser and the commitment of the radiation protection supervisor.⁸Compared with research on radiation doses to upper extremities and eyes, research on lower extremity doses in interventional radiology is limited. Whitby and Martin⁹ carried out air kerma measurements and monitored the hand and foot doses to radiologists for a range of procedures. Thermoluminescent dosemeters (TLDs) were fixed 80 mm below the patella and on the upper aspect of each foot during monitoring, although it was not stated where on the upper aspect of the foot. The group found that, without protection, the lower limb dose was frequently greater than the hand dose, with a mean leg dose between 0.19 and 2.61 mSv per procedure without any protection and between 0.02 and 0.5 mSv per procedure with a protective curtain. The group also identified that, during biliary stent procedures, a greater couch height was required than during other clinical procedures, which resulted in a larger lower extremity dose, even if a protective curtain was used.Shortt et al¹⁰ monitored nine interventional radiologists with TLDs positioned just above the ankle for 1 month before and 1 month after the installation of a protective curtain to the patient couch. Extrapolation of the results by monitoring for a month before installation of a lead curtain showed that a radiologist would have exceeded the annual dose threshold for both lower extremities for a non-classified worker of 150 mSv. The mean monthly left foot dose of the nine radiologists was 6.50 mSv before and 2.31 mSv after curtain installation. The group reported “alarmingly” high lower extremity doses, which were reduced by 64% after the introduction of a protective curtain. The group did not specifically address toe doses or the presence of a gap between the curtain and the floor.A study focused on the radiation exposure to various anatomical locations by Hausler et al¹¹ identified that exposure of the extremities needs more attention. Furthermore, they stated that the lower extremity dose should not restrict the annual number of procedures; however, this is based on a 500-mSv dose limit. They did not state whether they were suggesting that the 150-mSv non-classified extremity dose threshold could be exceeded. They concluded that the hanging of shielding blades from the couch “may give sufficient shielding”. Ubeda et al¹² focused on paediatric interventional cardiology and measured scatter dose rates at the radiologist''s eye and lower extremity levels without shielding. Scatter dose rates at the lower extremities were around double those at eye level, and a lower extremity dose of 0.1 mSv per paediatric cardiology single-plane procedure and 1 mSv per biplane procedure was estimated.Tsapaki et al¹³ reported mean cardiologist foot doses of 0.036 mSv per coronary angiography (CA) procedure and 0.046 mSv per percutaneous transluminal coronary angioplasty (PTCA) procedure when a protective curtain was used. Without the use of a curtain, the group reported foot doses of 0.245 mSv for each CA and 0.479 mSv for each PTCA procedure. They did not state where on the foot the TLDs were positioned.Schueler et al⁷ conducted a study to investigate how operator exposure in interventional radiology is affected by various common fluoroscopic imaging conditions. Stray radiation around a C-arm was measured in clinically representative conditions, and the isodose curves were plotted. The measurements were taken in a vertical plane at a number of distances above the floor level; notably, the lowest height measured was 30 cm. The study did not therefore address radiation dose levels at the floor level.A study by Domienik et al¹⁴ estimated maximum annual doses of 55 mSv to the knees and 328 mSv to the ankles of physicians working across three hospitals. The group emphasized the need for the proper use of PPE. Efstathopoulos et al¹⁵ monitored the radiation doses to personnel working in interventional radiology and cardiology over 25 procedures. They included monitoring of both legs using TLDs positioned below a person''s lead apron, and, in all procedures, a protective curtain was fixed to the patient table. The group''s findings of interventionists'' leg doses were 0.124 mSv (average) and 1.459 mSv (maximum) per procedure. Koukorava et al¹⁶ monitored 2 operators for 50 procedures and reported the maximum leg dose for a single procedure of 0.6 mSv, which was measured using TLDs positioned around 5 cm below the bottom of the operator''s lead apron.A pilot study in our institution was implemented prior to embarking on the main body of work described in this publication. Upper foot dose monitoring of 4 radiologists for a total of 12 interventional fluoroscopic procedures was implemented. Local clinical practice involves the use of a protective curtain hanging from the side of the patient couch on the side that the radiologist is working. Local clinical practice does not require further shielding of lower extremities. An aluminium oxide TLD of a minimum reportable dose of 0.01 mSv and a radiographic photon energy response range of 5 keV–6 MeV (Landauer Inc., Glenwood, IL) was positioned on the upper surface of each foot, around midway, distally between the toe and ankle of a radiologist. The ranges of right and left foot results of 0–0.12 and 0–0.26 mSv per procedure were similar to the results published by Whitby and Martin⁹ and Tsapaki et al¹³ and demonstrated a need for further investigation.The body of literature indicates that the use of protective curtains hanging from the couch does effectively reduce the radiation dose to the lower leg, as summarized in StudyPosition of dosemetersMean procedure dose (mSv)Maximum procedure dose (mSv)Efstathopoulos et al15Lower leg0.1431.959Koukorava et al¹⁶Lower leg0.1000.600Tsapaki et al¹³ (PTCA)Foot0.0460.100 (mean + 1 standard deviation)Whitby and Martin⁹Lower leg0.0200.500Ubeda et al¹²Ankle0.100 (single plane)1.000 (bi-plane)Domienik et al¹⁴Ankle0.1001.459Open in a separate windowPTCA, percutaneous transluminal coronary angioplasty.Only results where protective curtains were used are included.The aim of this study was to monitor radiation doses to the lower extremities, particularly the toes, as these are the most distal part of the foot and are prone to protruding under the protective curtain. The results will provide information to determine whether classification levels of radiation were being exceeded at our centre and whether we and the other centres should be doing more to achieve the IRR99 requirement of keeping staff doses ALARP.³     

A national dosimetry audit of intraoperative radiotherapy

Objective:

National dosimetry audits are a fundamental part of quality assurance in radiotherapy, especially for new techniques. Intraoperative radiotherapy with a compact mobile kilovoltage X-ray source is a novel approach for the treatment of breast and other cancers. All seven current clinical sites in the UK were audited by a single visiting group and set of measurement equipment.

Methods:

Measurements of output, isotropy and depth doses were performed using an ion chamber in solid water, thermoluminescent dosemeters and radiochromic film, respectively.

Results:

The mean difference between measured and planned dose across all centres was −3.2±2.7%. Measured isotropy was within ±3% around the lateral plane of the X-ray source and +11±4% in the forward direction compared with the lateral plane. Measured depth doses were agreed within 5±2% of manufacturer-provided calibration values or a mean gamma index of 97% at a tolerance of 7%/0.5 mm.

Conclusion:

Agreement within measurement uncertainties was found for all three parameters except forward anisotropy, which is unlikely to be clinically significant. Steep dose gradients increase the sensitivity to small variations in positioning, but these tests are practical for use in interdepartmental audits and local baseline comparison.

Advances in knowledge:

The first UK interdepartmental audit of intraoperative radiotherapy builds confidence in the delivery of this treatment.Dosimetry audits have been a fundamental part of quality assurance (QA) in UK radiotherapy departments for over 20 years [1–6]. More recently, ongoing verification of established systems has been delegated to regional audit groups; however, new techniques such as intensity-modulated radiotherapy [7,8] or volumetric modulated arc therapy [9] have been assessed on a national level. This gives confidence in the accurate, safe and consistent delivery of complex treatments, regardless of location or prior experience.Intraoperative radiotherapy (IORT) has also been practised in the UK for nearly 20 years, using a compact mobile 50 kV X-ray device called PRS400 (Photoelectron Corporation, Lexington, MA) and, more recently, INTRABEAM® (PRS500; Carl Zeiss Surgical, Oberkochen, Germany). Initially, the system was used for intracranial stereotaxy [10] but found wider application in the delivery of a single fraction of radiation soon after surgical excision of breast tumours [11]. Most patients have been treated as part of the targeted intraoperative radiotherapy (TARGIT) international randomised controlled trial [12], although some other cases have also been successfully treated where external beam therapy was contraindicated [13]. Full calibration of the system is provided by the manufacturer, but recently, methods for independent dosimetry and quality assurance have been described [14,15]. The aim of this study was to audit all UK clinical centres in 2012 (Ninewells, Dundee, UKGuy''s and St Thomas'', London, UKNorth Middlesex, London, UKPrincess Grace, London, UKRoyal Free, London, UK (visiting centre)St John and St Elizabeth, London, UKRoyal Hampshire County, Winchester, UKOpen in a separate window     

Non-cutaneous melanoma: is there a role for 18F-FDG PET-CT?

Non-cutaneous melanomas (NCM) are diverse and relatively uncommon. They often differ from cutaneous melanomas in their epidemiology, genetic profile and biological behaviour. Despite the growing body of evidence regarding the utility of positron emission tomography (PET)/CT in cutaneous melanoma, the data on its use in NCM are scarce. In this review, we will summarize the existing literature and present cases from our experience with NCM to illustrate current knowledge on the potential role and limitations of fluorine-18 fludeoxyglucose PET/CT in NCM.Non-cutaneous melanomas (NCM) are classified according to origin: ocular, mucosal or unknown primary. Ocular melanomas may arise from the uvea or conjunctiva. Mucosal melanomas may originate from mucosal surfaces in the head and neck (oral cavity, nasal and paranasal sinuses) and gastrointestinal and genitourinary tracts. NCM are relatively rare, with ocular and mucosal melanomas accounting for only 5.5% and 1.3% of all melanomas in North America, respectively. The incidence of mucosal melanoma may vary according to the population studied (range, 0.2–10.0%) and is higher in Asian populations. By contrast, uveal melanomas are more common in Caucasians. 1,2 Staging and management of NCM varies by location and differs from cutaneous melanoma. In NCM, primary therapy consists of local resection, often with adjuvant radiotherapy. There may be a role for chemotherapy and immunotherapy; however, this approach has largely been extrapolated from experience with cutaneous tumours.

Table 1.

Comparison of cutaneous and non-cutaneous melanoma^1,2

Use of cardiac CT and calcium scoring for detecting coronary plaque: implications on prognosis and patient management

Clinicians often use risk factor-based calculators to estimate an individual''s risk of developing cardiovascular disease. Non-invasive cardiovascular imaging, particularly coronary artery calcium (CAC) scoring and coronary CT angiography (CTA), allows for direct visualization of coronary atherosclerosis. Among patients without prior coronary artery disease, studies examining CAC and coronary CTA have consistently shown that the presence, extent and severity of coronary atherosclerosis provide additional prognostic information for patients beyond risk factor-based scores alone. This review will highlight the basics of CAC scoring and coronary CTA and discuss their role in impacting patient prognosis and management.Coronary artery disease (CAD) is the leading cause of morbidity and mortality in most industrialized nations throughout the world.¹ Given the burden of coronary heart disease (CHD) to patients and society as a whole, much work has been carried out to determine patients'' risk of adverse cardiovascular events. Such risk estimations are important as they often inform the need for preventive therapies such as lipid-lowering medications and aspirin. For instance, the Framingham risk score (FRS) uses age, gender, total cholesterol, high-density lipoprotein cholesterol, smoking status, systolic blood pressure and blood pressure treatment status to estimate 10-year risk of a myocardial infarction in patients without heart disease or diabetes.² More recently, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on treatment of blood cholesterol identified four groups of individuals who may potentially benefit from statin therapy: patients with known atherosclerotic cardiovascular disease (ASCVD), low-density lipoprotein cholesterol ≥190 mg dl⁻¹, diabetes and a ≥7.5% estimated 10-year risk of developing ASCVD determined by a risk calculator.³ However, these guidelines also suggest that in selected individuals not in the aforementioned groups, and for whom a decision to initiate statin therapy is otherwise unclear, additional risk factors such as a coronary artery calcium (CAC) score of ≥300 Agatsiton units or ≥75th percentile for age, sex and ethnicity can be considered.³ The European Society of Cardiology also included CAC in its 2012 European Guidelines on cardiovascular disease (CVD) prevention by stating that CAC should be considered for cardiovascular risk assessment in asymptomatic adults at moderate risk (3–6

Table 1.

Recommendations for coronary artery calcium testing according to recent guidelines