Resistive intrarenal index: myth or reality?

In renal diagnosis, the B-mode ultrasound is used to provide an accurate study of the renal morphology, whereas the colour and power Doppler are of strategic importance in providing qualitative and quantitative information about the renal vasculature, which can also be obtained through the assessment of the resistive index (RI). To date, this is one of the most sensitive parameters in the study of kidney diseases and allows us to quantify the changes in renal plasma flow. If a proper Doppler ultrasound examination is carried out and a critical analysis of the values obtained is performed, the RI measurement at the interlobar artery level has been suggested in the differential diagnosis between nephropathies. The aim of this review is to highlight the pathological conditions in which the study of intrarenal RI provides useful information about the pathophysiology of renal diseases in both the native and the transplanted kidneys.Renal ultrasonography has acquired a strategic importance in the early detection of several renal diseases thanks to its non-invasivity, low cost, reliability and high sensitivity. The B-mode ultrasound is a widely used technique for the study of kidney morphology, including renal pelvis, to provide information on parenchymal echogenicity and to detect space-occupying lesions.The characteristic ultrasonographic pattern in chronic kidney disease (small kidneys, reduced parenchymal thickness and detection of cysts) allows a simple and accurate diagnosis of this pathological condition. On the other hand, the diagnostic validity of the B-mode ultrasound in the detection of acute renal disease is still under debate because of the lack of sensitivity and specificity of the commonly used parameters such as the increase of renal size and the reduction of the parenchymal echogenicity.The advantage of using Doppler ultrasound (DUS) lies in its ability in detecting not only renal morphological abnormalities but also functional ones; colour Doppler, power DUS and spectral analysis provide qualitative and quantitative haemodynamic information about the intrarenal and extrarenal vasculature highlighting changes in the renal blood flow.The measure of renal resistive index (RI) or Pourcelot index is one of the most sensitive parameters in the study of disease-derived alterations of renal plasma flow.The aim of this review is to evaluate the significance of the renal RI as a non-invasive marker of renal histological damage in several pathological conditions (

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)

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

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.     

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

Advances in MRI for the evaluation of carotid atherosclerosis

Carotid artery atherosclerosis is an important source of mortality and morbidity in the Western world with significant socioeconomic implications. The quest for the early identification of the vulnerable carotid plaque is already in its third decade and traditional measures, such as the sonographic degree of stenosis, are not selective enough to distinguish those who would really benefit from a carotid endarterectomy. MRI of the carotid plaque enables the visualization of plaque composition and specific plaque components that have been linked to a higher risk of subsequent embolic events. Blood suppressed T₁ and T₂ weighted and proton density-weighted fast spin echo, gradient echo and time-of-flight sequences are typically used to quantify plaque components such as lipid-rich necrotic core, intraplaque haemorrhage, calcification and surface defects including erosion, disruption and ulceration. The purpose of this article is to review the most important recent advances in MRI technology to enable better diagnostic carotid imaging.Internal carotid artery atherosclerosis is a significant source of mortality and morbidity in the Western world.^1,2 MRI enables the visualization of plaque composition, and specific plaque constituents have been linked to a higher risk of subsequent embolic events. Currently, either the sonographic or angiographic degree of carotid stenosis is used as a marker of severity for assessing carotid disease and risk of stroke.^3,4 However, there is mounting evidence that suggests that the degree of stenosis is not enough to accurately characterize carotid plaque burden and vulnerability.High-resolution, multicontrast carotid MRI protocols have been used to depict atherosclerotic components within carotid plaques, the validity of these protocols have been evaluated using histopathology, and the protocols have been applied in multicentre trials.^5–7 Blood suppressed T₁ and T₂ weighted and proton density (PD)-weighted fast spin echo (FSE) and gradient echo time-of-flight sequences are typically used⁸ to quantify plaque components such as lipid-rich necrotic core (LRNC),^5,9–11 intraplaque haemorrhage (IPH),^5,12–15 calcification^5,9 and surface defects including erosions, disruption and ulceration.^11,16–18 In addition, the intrareader, interreader^14,19–21 and the interscan reproducibility^20,22,23 of quantitative measures associated with both morphology and composition have been reported.Novel MR-defined plaque features of vulnerability are emerging and appear promising for the identification of the vulnerable plaque. A recent systematic review of 9 studies with 779 subjects demonstrated that the presence of IPH, LRNC and thinning/rupture of the fibrous cap (FC) is linked to an increased risk of future stroke or transient ischaemic attack (TIA).²⁴ The hazard ratios for each of them as predictors of subsequent ischaemic events were 4.59 [95% confidence interval (CI), 2.91–7.24], 3.00 (95% CI, 1.51–5.95) and 5.93 (95% CI, 2.65–13.20), respectively. In a separate meta-analysis focusing on IPH that pooled 8 clinical studies of 689 patients, the hazard ratio of MRI-depicted IPH in symptomatic patients was 11.7.²⁵ This evidence indicates that dedicated MRI-depicted plaque composition offers stroke risk information beyond measurement of luminal stenosis.Although MRI holds promise, the clinical application for plaque characterization will require further consensus regarding MRI protocols and new MRI techniques. A recent overview of 17 studies that assessed the agreement between MRI and histology indicated that MRI could characterize calcification, FC, IPH and LRNC with moderate-to-good sensitivity and specificity.²⁶ It suggests that further effort is needed to use MRI as a routine clinical imaging modality to assess carotid atherosclerosis characteristics. One pragmatic issue is the requirement of a dedicated receiver coil.The purpose of this article is to review the most important recent advances in MRI technology to enable better diagnostic carotid imaging. This article also reviews recent advances in material stress analysis and molecular imaging relevant to carotid atherosclerosis.

MR sequences for carotid plaque composition analysis

The de facto standard for blood suppressed carotid imaging is double inversion recovery (DIR) preparation. Intraluminal blood signal is suppressed by applying a 180° non-selective pulse to invert the magnetization within the transmit volume, which is immediately followed by a 180° slice selective pulse to revert the magnetization within the imaging plane. The magnetization in the blood outside the imaging plane reaches a null point after a period of time defined as the inversion time. Also after a period of time, for any given flow rate, inflowing blood from outside the imaging plane will replace in the intraluminal space within the defined imaging plane.DIR is typically implemented as a gated single slice technique as black blood (BB) imaging is originally developed for cardiac application where gating is a fundamental prerequisite. However, gated acquisitions lead to variations in T₁ relaxation and the signal slice implementation results in scan times, which preclude clinical adoption. In response, Yarnykh and Yuan²⁷ implemented an ungated multislice DIR protocol; this in effect accelerates the acquisition as a function of the number of slices that are simultaneously acquired. However, DIR is known to be sensitive at producing plaque-mimicking artefacts. This is understood to frequently occur at the carotid bifurcation, as complex flow patterns exist where blood signal within the imaging plane is not fully displaced from the imaging plane.More advanced methods for blood suppression have subsequently been proposed, which are even more time efficient and can null residual blood signal. Wang et al²⁸ presented a technique known as improved motion-sensitized driven-equilibrium (iMSDE), in which blood suppression can be directly controlled by the size of the motion-sensitizing gradients. This method effectively suppresses blood signal, however, the technique induces additional T₂ decay. In 2012, Li et al²⁹ presented Delays Alternating with Nutations for Tailored Excitation (DANTE). This study demonstrated how blood signal could be suppressed by both a function of the DANTE preparation echo-train length and flip angle. To date, there are no studies that have systematically compared all three methods; however, results of our initial validation studies are presented in Figure 1.Open in a separate windowFigure 1.Normal volunteer: comparison of advanced blood suppression techniques. The double inversion recovery preparation commonly exhibits plaque-mimicking artefacts (arrow). Both improved motion-sensitized driven-equilibrium (iMSDE) and Delays Alternating with Nutations for Tailored Excitation (DANTE) are more time efficient and can mitigate these artefacts. DIR, double inversion recovery.Currently, the majority of MRI is performed on 1.5-T systems. The continuous advances in MR technology have allowed carotid imaging at higher magnetic strengths, and multiphase coils increase the potential for parallel imaging. Preliminary experience with eight-channel coils at 3.0 T indicates an increase in signal-to-noise ratio (SNR) to contrast-to-noise ratio (CNR) compared with 1.5 T. In a study by Young et al,³⁰ 18 subjects with carotid atherosclerosis were imaged on both 1.5- and 3.0-T systems using the same receiver coil. T₁, T₂ and PD images were obtained, and multiple slices were prescribed to encompass both the carotid bifurcation and the plaque. In this study, the mean improvements in SNR were 1.9, 2.1 and 2.1, respectively, which were statistical significant.Yuan et al,³¹ recently reported on 19 patients at 3.0 T and noted significant associations between the presence of thin/ruptured FC (100% vs 36%; p = 0.006) and LRNC (100% vs 39%; p = 0.022), with a borderline association with haemorrhage (86% vs 33%; p = 0.055).

Assessment of carotid plaque morphology using three-dimensional MR sequences

In a three-dimensional (3D) sequence, a radiofrequency (RF) pulse is applied to excite an imaging volume. Phase encoding is performed in both the convention phase encoding axis and in the slice select direction. 3D sequences typically result in higher SNR efficiency. In a study by Balu et al,³² a total of 18 subjects with significant carotid stenosis were imaged with two-dimensional (2D) (2-mm slice thickness) and 3D [1-mm/0.5-mm (acquired/interpolated) slice thickness] T₁ weighted FSE BB imaging sequences with DIR blood suppression. Morphological measurements, SNR in the wall and lumen, and wall-lumen CNR were compared between the 2D and 3D images. The lumen SNR, wall SNR and CNR were comparable between the two methods. There was also no difference in average volumetric measurements between 2D/3D. By contrast, the distributions of small plaque components such as calcification were better characterized by the 3D acquisition while there was a higher sensitivity to motion artefacts with 3D imaging, resulting in a small number of examinations with low image quality. The conclusion from this study was that 2D and 3D protocols can provide comparable morphometric and volumetric measurements of the carotid artery with the 3D imaging offering an advantage in terms of small plaque component visualization but with the price of lower reliability for image quality.In another study by Takano et al,³³ 22 patients scheduled for carotid endarterectomy underwent carotid plaque MRI with both a conventional FSE 2D sequence and 3D FSE sequence with variable refocusing flip angles. This 3D sequence enables the acquisition of longer echo-train lengths whilst reducing the T₂ blurring effect that would typically accrue by attempting to maintain magnetization across the train of refocusing pulse. Image quality and SNR were evaluated; observations were compared for each plaque component according to the histological category of the plaque between 2D and 3D sequences (Figure 2). No significant differences were observed among the overall imaging quality scores of the two modalities, although 3D sequences allowed visualization in random orientations, as well as better depiction of small plaque components such as ulcerations and calcifications. The SNR of the plaque to the submandibular gland on T₁ weighted 3D sequence was significantly higher than that on the 2D sequence. In addition, it was shown that the SNR of the plaque to the submandibular gland of histology-defined soft-plaque components were significantly higher on T₁ weighted 3D sequence than on 2D sequence. From this study, it was concluded that 3D variable-flip-angle turbo spin echo (TSE) is a promising tool for diagnostic imaging.Open in a separate windowFigure 2.T₁ weighted MRI of (a) two-dimensional (2D) fast spin echo (FSE) with 3-mm thickness, and (b) three-dimensional (3D) variable flip angle FSE with 0.6-mm thickness. The lipid core is clearly seen in 3D FSE (arrow, b), while the partial volume effect limits the resolution of 2D FSE (arrow, a).In 2011, Balu et al³⁴ proposed a BB 3D gradient echo sequence (3D-MERGE), the sequence was evaluated on nine patients with carotid atheroma. The proposed sequence incorporated BB preparation using iMSDE preparation prior to 3D spoiled gradient echo readout. The proposed gradient sequence enabled isotropic resolution (0.7 mm³) and was more time efficient than the 3D FSE alternatives (imaging time, approximately 2 min).In addition, the advances in MR technology allow the use of non-gated sequences instead of gated sequences for atherosclerotic vessel wall imaging without compromising image quality. This may shorten examination time and improve patient comfort.³⁵ Other examples of technological advances include the 3D diffusion-prepared segmented steady–steady free precession cardiovascular MR sequence for BB,³⁶ which allows for 3D acquisition of thin and contiguous slices with BB image contrast. Finally, TSE-based motion-sensitized driven-equilibrium sequence has been developed as an alternative to BB carotid MRI providing a more accurate depiction of the lumen boundaries by eliminating plaque-mimicking artefacts in carotid plaque imaging.³⁷

Identification of intraplaque haemorrhage

The characterization of IPH using a 3D gradient echo sequence with a selective water excitation pulse was first presented by Moody et al¹³ in 2003. The sequence was coined MR direct thrombus imaging. Their study demonstrates using histopathology validation, the sequence utility in detecting thrombus. A subsequent variant of this technique was proposed by Zhu et al³⁸ in 2010. This sequence referred to as 3D SHINE (3D spoiled gradient-recalled echo pulse sequence for haemorrhage assessment using inversion recovery and multiple echos) enables the simultaneous detection and ageing of thrombus based on its respective T₁ and T₂* relaxation properties. The differentiation between IPH and thrombus can be challenging, and a general guide can be seen at ​and22.

Table 1.

MRI characteristics of various carotid plaque components

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 (Non-malignant diseases (treatment groups)19992004Increase (%)Inflammatory45650310.9Degenerative12,60023,75488.5Hyperproliferative972125228.8Functional/other609910,63774.4Overall20,08237,41086.3Open in a separate windowThe largest group of patients with non-malignant disorders and indications for the use of RT are those suffering from painful degenerative joint disorders.^1–3,5There are several general rules established in the field of RT for non-malignant disorders: (1) RT of non-malignant conditions is usually carried out with much shorter time schedules and with much lower single and total RT doses than those applied for malignant tumours; however, the responsibilities of the involved radiation oncologists and therapists with regard to quality and delivery of RT treatment are the same as those for malignant disorders; (2) careful preparation, diligent performance and complete documentation of all RT treatments for non-malignant disorders are mandatory; (3) long-term follow-up evaluation of the whole treatment process has to be performed with utmost care and attention, as it is the case with any patient suffering from a malignant disorder.With regard to the specific national medical and jurisdictional background and the different justifications in Germany and in other European countries, there is a special need for updated and established national treatment guidelines for RT of non-malignant diseases similar to those already developed for most malignant disorders.^5,6,15,16 Additionally, the European Society of Therapeutic Radiation and Oncology has performed two symposia in the past (Brussels, 1999, and Nice, 2005) on this issue, which resulted in general recommendations for the different practitioners in European countries.¹⁷     

Extragonadal teratomas of the adult abdomen and pelvis: a pictorial review

Teratomas comprise a spectrum of tumours that have striking imaging appearances and are commonly considered when evaluating a mass in the female pelvis. A subgroup of these tumours located in an extragonadal abdominopelvic location, in contrast, are extremely rare and can affect both sexes. Extragonadal teratomas can occur at all ages, are particularly unusual in adults and can cause confusion in the differential diagnosis, especially in children. Familiarity with the imaging features of the spectrum of teratomas within the abdominal cavity is therefore of great importance, as radiological diagnosis can guide treatment, prevent delays in diagnosis and avoid sequelae. This article summarizes the radiological appearances of these rare extragonadal tumours in adults in relation to their pathology, malignant potential, location and behaviour. Although uncommon, teratomas should be considered in the differential diagnosis of extragonadal abdominal masses, particularly in young adults.Teratomas are neoplasms with tissue components resembling normal derivatives of the three germ layers. They comprise a spectrum of tumours with striking imaging appearances and are commonly considered when evaluating pelvic masses in females. Extragonadal abdominopelvic teratomas are, in contrast, very rare and are seen in both sexes. They represent only 1–5% of germ cell tumours (GCTs)¹ and therefore may not be readily considered by clinicians. Their radiological appearances are, however, characteristic, and familiarity with these features will lead to more accurate radiological diagnoses that not only guide treatment but also prevent avoidable complications from diagnostic delay.Teratomas can present at any age. They contain tissue elements foreign to the organ or anatomic site of origin.² Arising from totipotent germ cells, they contain derivatives of one to all three germ cell layers (the ectoderm, endoderm and mesoderm)^2–4 and occur most frequently in the ovary or testis. Gonadal teratomas are well described; however, the extragonadal variants are under-represented in the literature. These encompass mature cystic teratomas (MCTs), which are most frequently tridermal lineage, and epidermoid cysts, which are frequently classified pathologically as monodermal teratomas (MTs) (LineageTumourBi-/tridermalMature cystic/benign teratomaBi-/tridermalImmature teratoma (containing immature neural/neuroectodermal tissue)Bi-/tridermalMalignant (teratoma plus malignant foci)MonodermalEpidermoid cystMonodermalStruma ovariiOpen in a separate windowHistologically, both MCT (Figure 1a) and MT (Figure 1b) are lined by squamous epithelium but MTs lack skin appendageal structures. Postulated theories for the extragonadal location of teratomas include origin from displaced germ cells during embryologic migration,¹ ectopic ovarian tissue and ovarian dermoids reimplanting in an extragonadal site.³Open in a separate windowFigure 1.(a) Photomicrograph of mature cystic teratoma with a fibrous wall lined by keratinizing stratified squamous epithelium (bottom right of field). The wall contains skin appendageal structures, including sebaceous follicles (arrow), a hair follicle (thin arrow) and arrector pili muscle bundles (thick arrow). (b) Photomicrograph of monodermal teratoma with a fibrous tissue wall of the cyst (thin arrow), lined by mature, keratinizing stratified squamous epithelium (arrow). Keratin flakes and keratinous debris are present within the lumen (thick arrow).     

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

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])

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

Mepilex Lite dressings for the management of radiation-induced erythema: a systematic inpatient controlled clinical trial

Erythema occurs in 80–90% of women treated for breast cancer with radiation therapy. There is currently no standard treatment for radiation-induced skin reactions. This study investigates the clinical efficacy of Mepilex Lite dressings in reducing radiation-induced erythema in women with breast cancer. A total of 28 patients were recruited; of these, 24 participants presented with 34 erythematous areas of skin for analysis. When erythema was visible, each affected skin area was randomly divided into two similar halves: one half was treated using Mepilex Lite dressings, the other half with standard aqueous cream. Skin reactions were assessed by the Radiation-Induced Skin Reaction Assessment Scale. We also evaluated any potential dose build-up by the dressings using a white water phantom, the dose distribution over the breast via thermoluminescent dosimeters (TLDs) and the surface skin temperature with an infrared thermographic scanner. Mepilex Lite dressings significantly reduced the severity of radiation-induced erythema compared with standard aqueous cream (p <0.001), did not affect surface skin temperature and caused only a small (0.5 mm) dose build-up. TLD measurements showed that the inframammary fold was exposed to significantly higher doses of radiation than any other breast region (p <0.0001). Mepilex dressings reduce radiation-induced erythema.Breast cancer is the most common malignancy for women in New Zealand. Most of these women will receive radiation therapy treatment, and skin reactions will occur in 80–90% of patients by treatment completion [1]. To date, there is no standard treatment for radiation-induced skin reactions and practice tends to be based on historical and anecdotal evidence [1–3]. A promising new range of Swedish silicon-foam skin dressings, Mepilex Lite (MV Bamford and Company Ltd, Lower Hutt, New Zealand and Mölnlycke Health Care Gothenburg, Sweden) is currently used in New Zealand for the treatment of burns and slow-healing wounds. This absorbent, self-adhesive dressing consists of a thin, flexible sheet of absorbent hydrophilic polyurethane foam bonded to a water vapour-permeable polyurethane film backing layer. The contact surface of the dressing is coated with a soft silicone adhesive layer without any added chemicals. It adheres to healthy skin, thus retaining the dressing in position but without causing trauma on removal, and provides a moist wound-healing environment. The material does not add or react to chemicals in or on the skin, does not stick to wounds and can be left on the skin for several days [1, 4].Preliminary case studies conducted in our department showed that Mepilex Lite dressings reduced the extent of all radiation-induced skin reactions. These results are consistent with previous case studies carried out in Scotland and Stockholm [1, 5]. The current study is the first clinical study that compares the clinical efficacy of Mepilex Lite dressings on the severity of radiation-induced erythema with a standard aqueous cream using the Radiation-Induced Skin Reaction Assessment Scale (RISRAS) (5, 6]. Because anecdotal evidence suggests that the dressings may have a cooling effect, we also determined their effect on surface skin temperature as well as the extent of dose build-up caused by the dressings if they were left on the patient during treatment.

Table 1

Radiation-Induced Skin Reaction Assessment Scale (RISRAS)

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

Multimodality imaging of primary extrahepatic portal vein obstruction (EHPVO): what every radiologist should know

Portal vein thrombosis (PVT) is a frequent complication of liver cirrhosis, but it can also occur as a primary vascular disorder amid absent liver disease. Extrahepatic portal vein obstruction (EHPVO) refers to the obstruction of the extrahepatic portal vein with or without involvement of the intrahepatic portal vein branches, splenic and/or superior mesenteric vein. It is a distinct disorder that excludes PVT occurring in concurrence with liver cirrhosis or hepatocellular carcinoma. The term “EHPVO” implies chronicity and is principally reserved for a long-standing condition characterized by cavernous transformation of the portal vein. The most characteristic imaging manifestation is the formation of portoportal collaterals (via the venous plexi of Petren and Saint) that allow hepatopetal flow. However, this collateral circulation is insufficient resulting in clinically significant pre-hepatic portal hypertension, wherein the liver function and structure remain preserved until late. Although the long-term (more than 10 years) survival with controlled variceal bleeding is up to 100%, affected individuals have an impaired quality of life owing to portal cavernoma cholangiopathy, hypersplenism, neurocognitive dysfunction and growth retardation. Imaging diagnosis is not always straightforward as the collaterals can also present as a tumour-like solid mass that can be inadvertently biopsied. Moreover, EHPVO has its implications for the biliary tree, arterial circulation, liver/splenic volumes and stiffness, which merit proper understanding but have not been so well described in literature. In this review, we present the complete spectrum of the vascular, biliary and visceral changes with a particular emphasis on what our medical/surgical hepatology colleagues need to know from us in the pre-operative and post-operative settings.Extrahepatic portal vein obstruction (EHPVO) refers to the obstruction of the extrahepatic portal vein with or without involvement of the intrahepatic branches, splenic vein (SV) and/or superior mesenteric vein (SMV). The term EHPVO implies chronicity and is principally reserved for a long-standing condition characterized by cavernous transformation of the portal vein. It is a distinct (primary) vascular disorder that excludes acute or chronic portal vein thrombosis (PVT) occurring in concurrence with liver cirrhosis or hepatocellular carcinoma.^1,2 Along with obliterative portal venopathy (OPV), EHPVO constitutes an important cause of non-cirrhotic (pre-hepatic) portal hypertension (NCPH), wherein the liver function and structure remain preserved until late. It has been proposed that an infection or a prothrombotic event occurring early in life (in a genetically predisposed individual) precipitates thrombosis of the main portal vein leading to EHPVO. By contrast, repetitive microthrombotic events occurring late in life, which involve smaller intrahepatic portal venous branches, are responsible for OPV.¹EHPVO is primarily a disorder of children and young adults and is the most common cause of paediatric portal hypertension (PHT) in developing countries. Also, it is the most common cause of gastrointestinal bleed in children and adolescents (68–84%). Whereas non-cirrhotic non-tumoral PVT in the Western world constitutes the second most frequent cause of PHT in adults, it is responsible for only 11% of cases of paediatric PHT.¹ The aetiology of EHPVO differs in paediatric and adult populations (1,2

Table 1.

Aetiology of extrahepatic portal vein obstruction

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

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]

Current practice of periprocedural haematological management for patients undergoing image-guided procedures

Objective:

To evaluate current UK practice of periprocedural haematological management for image-guided procedures in relation to Cardiovascular and Interventional Radiological Society guidelines, which provide recommendations according to bleeding risk of procedures from Category 1 (lowest) to 3 (highest).

Methods:

Survey of practice in UK radiology departments conducted over a 1-year period

Results:

48 radiology departments responded. The percentage of departments that stop antithrombotics pre-procedurally are as follows (for Category 1, 2 and 3, respectively): aspirin (31.3%, 43.8%, 54.2%); clopidogrel (54.2%, 68.8%, 72.9%); therapeutic low-molecular-weight heparin (56.3%, 77.1%, 75.0%). The percentage of departments that perform pre-procedural laboratory testing are as follows (for Category 1, 2 and 3, respectively): international normalized ratio (INR; 81.3%, 95.8%, 93.8%); activated partial thrombin time ratio (APTTR; 60.4%, 75.0%, 93.8%); platelet (77.1%, 91.7%, 95.7%); haemoglobin (70.8%, 85.4%, 87.5%). Mean threshold (standard deviation) of laboratory results for conducting procedures (Level 1, 2 and 3, respectively) are as follows: INR [1.53 (0.197), 1.47 (0.186), 1.47 (0.188)]; APTTR [1.50 (0.392), 1.50 (0.339), 1.48 (0.344)]; platelet count (x10³ cells per microlitre) [74.4 (28.7), 79.9 (29.1), 80.5 (29.3)]; haemoglobin (grams per decilitre) [9.05 (1.40), 9.00 (1.33), 8.92 (1.21)]. No department practices conformed to current recommendations for (1) pre-procedural cessation of antithrombotics and (2) pre-procedural laboratory testing. Two (4.2%) department practices conformed to recommendations for thresholds of haematological parameters.

Conclusion:

Current peri-procedural haematological management is variable and often does not conform to existing recommendations. Further research into the impact of this variation in practice on patient outcome is required

Advances in Knowledge:

This study demonstrates wide variation in practice in haematological management for image-guided procedures.Periprocedural haematological management, such as correction of coagulopathy, cessation of antithrombotics and pre-procedural laboratory testing (e.g. for haemoglobin levels and platelet count), is an important consideration for patients undergoing image-guided procedures.¹ The challenges of periprocedural haematological management are multifactorial in aetiology. In addition to the increasing range of complex image-guided procedures being performed, the patient population undergoing such procedures may also be complicated.² Many of these patients have comorbidities requiring antithrombotic therapy, or may have liver and marrow dysfunction, which can affect bleeding risk. Decisions on the optimal periprocedural haematological management are also confounded by the lack of high-level evidence, and existing guidelines within the literature can be variable even for equivalent procedures. For example, in two separate internationally accepted guidelines, the recommended international normalized ratio (INR) for chest drain insertion is <1.5 and <2.0.^3,4 There is also limited scope to transfer existing evidence on haematological management from other domains such as open surgery to image-guided interventions. Unlike conventional open surgical procedures where bleeding may be visualized immediately and controlled by direct pressure or vessel ligation, bleeding from image-guided procedures may be difficult to control owing to issues with access and identification.⁵The lack of high-level evidence is unsurprising, given the potential ethical issues in conducting the necessary studies; it would be difficult to justify the randomization of patients to receiving or not receiving coagulopathy correction prior to undergoing various image-guided procedures for the purpose of research.⁶ As a result, current evidence is often based on retrospective studies. To address this complex issue, the Society of Interventional Radiology in conjunction with the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) has previously produced guidelines based on existing evidence and expert consensus on periprocedural haematological management for image-guided procedures which are stratified into three categories according to the bleeding risk (4 However, despite the existence of such guidelines, from our experience, significant variation in practice exists between clinicians, even within our own institution.

Table 1.

Society of Interventional Radiology/Cardiovascular and Interventional Radiological Society of Europe consensus guidelines on periprocedural haematological management for image-guided procedures according to category of bleeding risk