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

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])

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)

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]

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

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 (

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.     

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

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

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.     

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 (Clinical settingRIProposed clinical valueAll nephropathies>0.75Indicator of tubulointerstitial nephropathy1AKI>0.75Useful in discriminating between ATN and pre-renal form²Chronic renal failure>0.80Indicator of irreversible damage>0.70Independent risk factor for worsening function^3–6Renal colic>0.70Signs of complete ureteral obstruction^7,8∆RI > 0.08–0.10Kidney transplantation>0.80In SKT graft, unfavourable prognostic factor⁹>0.80Association with recipient survival¹⁰  >0.75Long-term RF for NODAT¹¹DiabetesType 1—children 7–15 years old>0.64Risk factor for diabetic nephropathy¹²Type 2>0.70Indicator of advanced glomerular lesions and/or arteriosclerotic lesions¹³ >0.73Predictor of DN and its progression¹⁴Renal artery stenosis>0.80Poor renal improvement after PTA¹⁵Cirrhosis>0.78Risk factor for HRS¹²Open in a separate windowΔRI, difference in resistive index; AKI, acute kidney injury; ATN, acute tubular necrosis; DN, diabetic nephropathy; HRS, hepatorenal syndrome; NODAT, new-onset diabetes after transplantation; PTA, percutanous transluminal angioplasty; SKT, single kidney transplantation.     

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

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)

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

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

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

Uterine sarcomas: clinical presentation and MRI features

Uterine sarcomas are a rare heterogeneous group of tumors of mesenchymal origin, accounting for approximately 8% of uterine malignancies. They comprise leiomyosarcoma, endometrial stromal sarcoma, undifferentiated endometrial sarcoma, and adenosarcoma. Compared with the more common endometrial carcinomas, uterine sarcomas behave more aggressively and are associated with a poorer prognosis. Due to their distinct clinical and biological behavior, the International Federation of Gynecology and Obstetrics introduced a new staging system for uterine sarcomas in 2009, categorizing uterine carcinosarcoma as a variant of endometrial carcinoma, rather than a pure sarcoma. Magnetic resonance imaging (MRI) has a developing role in the assessment of these malignancies. Features such as tumor localization, irregular or nodular margins, necrosis, rapid growth, intense contrast enhancement, and restriction at diffusion-weighted imaging can suggest the diagnosis and help differentiate from more common leiomyomas and endometrial carcinoma. MRI is therefore extremely useful in preoperative detection and staging and, consequently, in determination of appropriate management. This pictorial review aims to discuss the clinical features of uterine sarcomas, as well as their most common appearances and distinct characteristics in MRI.Uterine sarcomas are a rare heterogeneous group of tumors of mesenchymal origin, accounting for approximately 8% of uterine malignancies (1), although they were thought to represent only 2% to 3% of all uterine tumors in the past (2). This increased incidence may be the result of improved diagnosis, as well as a true increase in an ageing population (1).These malignancies may originate from the smooth muscle in myometrium (leiomyosarcoma), from the endometrial stroma (endometrial stromal sarcoma [ESS] and undifferentiated endometrial sarcoma [UES]) or both (adenosarcoma) (3). According to the Gynecologic Oncology Group, uterine sarcomas can be classified into two categories: nonepithelial and mixed epithelial-nonepithelial, depending on the type of cancerous cell and its presumed tissue of origin (4).The clinical presentation of uterine sarcomas is nonspecific and dependent of histologic subtype. Classically, they present as a rapidly growing pelvic mass, which may be accompanied by vaginal bleeding and abdominal or pelvic pain (1, 5).Leiomyosarcoma is the most common histological variant of uterine sarcomas and is considered an aggressive tumor associated with poor prognosis, with a five-year survival rate ranging from 18.8% to 68%. ESS is relatively indolent, associated with long-term survival, but characterized by late recurrences (14%–60% of women). In contrast, UES has a very aggressive behavior and poor prognosis, with a five-year survival rate of 25%–55%. Adenosarcomas are rare mixed tumors (glandular and mesenchymal origin) with relatively low malignant potential and slow-growth pattern, with a five-year survival rate above 80% (6).The recognition of their distinct clinical and biological behavior when compared to endometrial carcinoma, which tend to behave more aggressively and are associated with a poorer prognosis, led the International Federation of Gynecology and Obstetrics (FIGO) to develop a new staging system for uterine sarcomas in 2009 (​and2).2). One important feature of the new staging system is that carcinosarcoma (formerly referred to as “malignant mixed Müllerian tumor”) is no longer considered as part of uterine sarcomas, being classified as a dedifferentiated or metaplastic form of endometrial carcinoma (7).

Table 1.

Staging for uterine leiomyosarcoma (7)